Sabiston Textbook of Surgery 19th Edition

SABISTON TEXTBOOK OF SURGERY 19TH EDITION

SABISTON TEXTBOOK OF SURGERY:

THE BIOLOGICAL BASIS OF MODERN SURGICAL PRACTICE 19TH EDITION COURTNEY M. TOWNSEND, JR., MD

Professor and John Woods Harris Distinguished Chairman Robertson-Poth Distinguished Chair in General Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas

R. DANIEL BEAUCHAMP, MD

J.C. Foshee Distinguished Professor and Chairman, Section of Surgical Sciences Professor of Surgery and Cell and Developmental Biology and Cancer Biology Vanderbilt University School of Medicine Surgeon-in-Chief, Vanderbilt University Hospital Nashville, Tennessee

B. MARK EVERS, MD

Professor and Vice-Chair for Research, Department of Surgery Director, Lucille P. Markey Cancer Center Markey Cancer Foundation Endowed Chair Physician-in-Chief, Oncology Service Line UK Healthcare The University of Kentucky Lexington, Kentucky

KENNETH L. MATTOX, MD

Professor and Vice Chairman Michael E. DeBakey Department of Surgery Baylor College of Medicine Chief of Staff and Chief of Surgery Ben Taub General Hospital Houston, Texas with 1645 illustrations

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

SABISTON TEXTBOOK OF SURGERY

ISBN: 978-1-4377-1560-6 International Edition ISBN: 978-1-4557-1146-8

Copyright © 2012, 2008, 2004, 2001, 1997, 1991, 1986, 1981, 1977, 1972, 1968, 1964, 1960, 1956 by Saunders, an imprint of Elsevier Inc. Copyright 1949, 1945, 1942, 1939, 1936 by Elsevier Inc. Copyright renewed 1992 by Richard A. Davis, Nancy Davis Regan, Susan Okum, Joanne R. Artz, and Mrs. Mary E. Artz. Copyright renewed 1988 by Richard A. Davis and Nancy Davis Regan. Copyright renewed 1977 by Mrs. Frederick Christopher. Copyright renewed 1973, 1970, 1967, 1964 by W.B. Saunders Company. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data or Control Number Sabiston textbook of surgery : the biological basis of modern surgical practice.—19th ed. / [edited by] Courtney M. Townsend Jr. … [et al.]. p. ; cm. Textbook of surgery Includes bibliographical references and index. ISBN 978-1-4377-1560-6 (hardcover : alk. paper) I. Sabiston, David C., 1924-2009. II. Townsend, Courtney M. III. Title: Textbook of surgery. [DNLM: 1. Surgical Procedures, Operative. 2. General Surgery. 3. Perioperative Care. WO 500] 617—dc23 2011040621 Global Content Development Director: Judith Fletcher Content Developmental Manager: Maureen Iannuzzi Publishing Services Manager: Catherine Jackson Senior Project Manager: Rachel E. McMullen Design Direction: Louis Forgione Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

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DEDICATION

who grant us the privilege of practicing our craft; to our students, residents, and colleagues, from whom we learn; and to our wives—Mary, Shannon, Karen, and June—without whose support this would not have been possible.

O OUR PATIENTS,

CONTRIBUTORS ANDREW B. ADAMS, MD, PHD Associate, Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia Transplantation Immunobiology and Immunosuppression

B. TIMOTHY BAXTER, MD Professor of Vascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska The Lymphatics

CHARLES A. ADAMS, JR., MD Chief of Trauma and Surgical Critical Care, Rhode Island Hospital; Assistant Professor of Surgery, Alpert Medical School of Brown University, Providence, Rhode Island Surgical Critical Care

R. DANIEL BEAUCHAMP, MD J.C. Foshee Distinguished Professor and Chairman, Section of Surgical Sciences, Professor of Surgery and Cell and Developmental Biology and Cancer Biology, Vanderbilt University School of Medicine; Surgeon-in-Chief, Vanderbilt University Hospital, Nashville, Tennessee Perioperative Patient Safety

AHMED AL-MOUSAWI, MD Clinical Fellow, Burns & Critical Care, Shriners Burns Hospital for Children, Department of Surgery, University of Texas Medical Branch, Galveston, Texas Metabolism in Surgical Patients WADDAH B. AL-REFAIE, MD, FACS Co-Director, Minnesota Surgical Outcomes Workgroup, Associate Professor of Surgery and Staff Surgeon, Division of Surgical Oncology, Department of Surgery, University of Minnesota and Minneapolis VAMC, Minneapolis, Minnesota Exocrine Pancreas NANCY L. ASCHER, MD, PHD Professor and Chair, Department of Surgery, University of California at San Francisco, San Francisco, California Liver Transplantation STANLEY W. ASHLEY, MD Chief Medical Officer, Vice President for Medical Affairs, Brigham and Women’s Hospital; Frank Sawyer Professor of Surgery, Harvard Medical School, Boston, Massachusetts Acute Gastrointestinal Hemorrhage

YOLANDA BECKER, MD, FACS Professor of Surgery, Director, Kidney and Pancreas Program, Division of Transplant Surgery, University of Chicago, Chicago, Illinois Kidney and Pancreas Transplantation PAUL R. BEERY, MD Clinical Assistant Professor, Department of Surgery, Ohio State University Grant Medical Center, Columbus, Ohio Surgery in the Pregnant Patient DAVID H. BERGER, MD Professor of Surgery and Vice-Chair, Michael E. DeBakey Department of Surgery, Baylor College of Medicine; Operative Care Line Executive, Michael E. DeBakey VA Medical Center, Houston, Texas Surgery in the Geriatric Patient JOSHUA I.S. BLEIER, MD, FACS, FASCRS Assistant Professor, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Colon and Rectum

PAUL S. AUERBACH, MD, MS, FACEP Redlich Family Professor of Surgery, Department of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California Bites and Stings

DANIEL BORJA-CACHO, MD HPB Fellow, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Exocrine Pancreas

BRIAN BADGWELL, MD Assistant Professor, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas Abdominal Wall, Umbilicus, Peritoneum, Mesenteries, Omentum, and Retroperitoneum

HOWARD BRODY, MD, PHD Director, Institute for the Medical Humanities; John P. McGovern Centennial Chair in Family Medicine, Family Medicine, University of Texas Medical Branch, Galveston, Texas Ethics and Professionalism in Surgery

FAISAL G. BAKAEEN, MD, FACS Chief of Cardiothoracic Surgery, The Michael E. DeBakey VA Medical Center; Associate Professor, Cardiothoracic Surgery, Baylor College of Medicine, Houston, Texas Acquired Heart Disease: Coronary Insufficiency

BRUCE D. BROWNER, MD, MS, FACS Gray-Gossling Chair, Professor and Chairman Emeritus, Department of Orthopedic Surgery, New England Musculoskeletal Institute, University of Connecticut Health Center; Director of Orthopaedics, Hartford Hospital, Farmington, Connecticut Emergency Care of Musculoskeletal Injuries

PHILIP S. BARIE, MD, MBA, FIDSA, FCCM, FACS Professor of Surgery and Public Health, Weill Cornell Medical College; Chief, Preston A. (Pep) Wade Acute Care Surgery Service, New York–Presbyterian Hospital–Weill Cornell Medical Center, New York, New York Surgical Infections and Antibiotic Use

THOMAS A. BUCHHOLZ, MD, FACR Head, Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas Diseases of the Breast

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BRIAN B. BURKEY, MD, FACS Vice-Chairman and Section Head, Head and Neck Surgery and Oncology, Head and Neck Institute, Cleveland Clinic Foundation; Adjunct Professor, Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, Tennessee Head and Neck KATHLEEN E. CARBERRY, BSN, RN, MPH Research Specialist—Clinical Outcomes, Center for Clinical Outcomes, Congenital Heart Surgery Service, Texas Children’s Hospital, Houston, Texas Congenital Heart Disease CHARLIE C. CHENG, MD Assistant Professor, Division of Vascular Surgery and Endovascular Therapy, University of Texas Medical Branch, Galveston, Texas Peripheral Arterial Occlusive Disease KENNETH J. CHERRY, JR., MD Professor, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia Aorta LORI CHOI, MD Assistant Professor, Division of Vascular Surgery and Endovascular Therapy, University of Texas Medical Branch, Galveston, Texas Peripheral Arterial Occlusive Disease DANNY CHU, MD Associate Chief of Cardiothoracic Surgery, Operative Care Line, Michael E. DeBakey VA Medical Center; Assistant Professor of Surgery, Michael E. DeBakey Department of Surgery, Texas Heart Institute/Baylor College of Medicine, Houston, Texas Acquired Heart Disease: Coronary Insufficiency DAI H. CHUNG, MD Professor and Chairman, Janie Robinson and John Moore Lee Endowed Chair, Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, Tennessee Pediatric Surgery WILLIAM G. CIOFFI, MD Surgeon-in-Chief, Department of Surgery, Rhode Island Hospital; Professor and Chairman of Surgery, Alpert Medical School of Brown University, Providence, Rhode Island Surgical Critical Care MICHAEL COBURN, MD Professor and Chair, Scott Department of Urology, Baylor College of Medicine; Carlton-Scott Chair in Urologic Education; Chief of Urology, Ben Taub General Hospital, Houston, Texas Urologic Surgery MARION E. COUCH, MD, PHD Associate Professor, Department of Otolaryngology/Head and Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina Head and Neck

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MICHAEL D’ANGELICA, MD Associate Member, Department of Surgery, Memorial SloanKettering Cancer Center; Associate Attending Surgeon, Department of Surgery, Memorial Hospital for Cancer and Allied Diseases; Associate Professor, Department of Surgery, Cornell University, Weill Medical College, New York, New York The Liver ALAN DARDIK, MD, PHD Associate Professor of Surgery, Yale University School of Medicine; Chief, Peripheral Vascular Surgery, VA Connecticut Healthcare System, West Haven, Connecticut Surgery in the Geriatric Patient MERRIL T. DAYTON, MD Professor and Chairman, Department of Surgery, State University of New York–Buffalo; Chief of Surgery, Kaleida Health System, Buffalo General Hospital, Buffalo, New York Surgical Complications JOSE J. DIAZ, MD, CNS, FACS, FCCM Professor of Surgery, Chief Acute Care Surgery, R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, Maryland Bedside Surgical Procedures; The Difficult Abdominal Wall QUAN-YANG DUH, MD Professor of Surgery, University of California San Francisco; Surgical Service, San Francisco VA Medical Center, San Francisco, California The Adrenal Glands WILLIAM D. DUTTON, MD, CDR, MC, USN Instructor of Surgery, Acute Care Surgery Fellow, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee The Difficult Abdominal Wall TIMOTHY J. EBERLEIN, MD Bixby Professor and Chairman of the Department of Surgery, Spencer T. and Ann W. Olin Distinguished Professor and Director, The Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine; Surgeon-in-Chief, Barnes-Jewish Hospital, St. Louis, Missouri Tumor Biology and Tumor Markers JAMES S. ECONOMOU, MD, PHD Beaumont Professor of Surgery, Chief of Division of Surgical Oncology, Professor of Microbiology, Immunology and Molecular Genetics, Professor of Molecular and Medical Pharmacology, UCLA School of Medicine; Vice Chancellor for Research, University of California, Los Angeles, California Tumor Immunology and Immunotherapy E. CHRISTOPHER ELLISON, MD Robert M. Zollinger Professor and Chair, Department of Surgery, Ohio State University Medical Center, Columbus, Ohio Surgery in the Pregnant Patient

STEVEN R.T. EVANS, MD Professor of Surgery, Chief Medical Officer and Vice President for Medical Affairs, Georgetown University Hospital, Washington, DC Biliary System B. MARK EVERS, MD Professor and Vice-Chair for Research, Department of Surgery, Director, Lucille P. Markey Cancer Center, Markey Cancer Foundation Endowed Chair, Physician-in-Chief, Oncology Service Line UK Healthcare, The University of Kentucky, Lexington, Kentucky Small Intestine FARHOOD FARJAH, MD, MPH Department of Surgery, University of Washington, Seattle, Washington Evidence-Based Surgery: Critically Assessing Surgical Literature MITCHELL P. FINK, MD Professor, Departments of Surgery and Anesthesiology, ViceChair of Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, California The Inflammatory Response NICHOLAS A. FIORE, II, MD, FACS Cy-Fair Hand and Wrist, Houston, Texas Hand Surgery DAVID R. FLUM, MD, MPH Professor of Surgery and Adjunct Professor of Health Services and Pharmacy, Director of the Surgical Outcomes Research Center, University of Washington, Seattle, Washington Evidence-Based Surgery: Critically Assessing Surgical Literature YUMAN FONG, MD Murray F. Brennan Chair in Surgery, Department of Surgery, Division of Hepatopancreatobiliary Surgery, Memorial SloanKettering Cancer Center; Professor of Surgery, Weill Cornell Medical Center, New York, New York The Liver CHARLES D. FRASER, JR., MD Chief and The Donovan Chair in Congenital Health Surgery, Surgeon-in-Chief, Texas Children’s Hospital; Professor of Surgery and Pediatrics, Susan V. Clayton Chair in Surgery, Baylor College of Medicine, Houston, Texas Congenital Heart Disease JULIE A. FREISCHLAG, MD The William Steward Halsted Professor and Chair, Department of Surgery, Johns Hopkins University, Baltimore, Maryland Venous Disease GERALD M. FRIED, MD, CM, FRCS(C), FACS, FCAHS Adair Family Professor and Chairman, Department of Surgery, McGill University; Surgeon-in-Chief, McGill University Health Centre, Montreal, Quebec, Canada Emerging Technology in Surgery: Informatics, Robotics, and Electronics

ROBERT D. FRY, MD Emilie and Roland deHellebranth Professor of Surgery, Chief of the Division of Colon and Rectal Surgery, University of Pennsylvania Health System; Chairman, Department of Surgery, Pennsylvania Hospital, Philadelphia, Pennsylvania Colon and Rectum DAVID A. FULLERTON, MD Head, Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Aurora, Colorado Acquired Heart Disease: Valvular JAIME GASCO, MD Assistant Professor, Division of Neurological Surgery, University of Texas Medical Branch, Galveston, Texas Neurosurgery GERD G. GAUGLITZ, MMS, MD Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany Burns JASON P. GLOTZBACH, MD Postdoctoral Research Fellow, Stanford University Department of Surgery, Stanford, California; General Surgery Resident, University of North Carolina Department of Surgery, Chapel Hill, North Carolina Regenerative Medicine S. PETER GOEDEGEBUURE, PHD Research Associate Professor, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri Tumor Biology and Tumor Markers RAJA R. GOPALDAS, MD Assistant Professor of Cardiothoracic Surgery, Hugh E. Stephenson Department of Surgery, University of MissouriColumbia School of Medicine, Columbia, Missouri Acquired Heart Disease: Coronary Insufficiency MARJORIE C. GREEN, MD Associate Professor of Medicine and Internist, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas Diseases of the Breast OLIVER L. GUNTER, MD Assistant Professor, Division of Trauma and Surgical Critical Care, Vanderbilt University School of Medicine, Nashville, Tennessee Bedside Surgical Procedures GEOFFREY C. GURTNER, MD, FACS Professor and Associate Chair of Surgery, Stanford University Department of Surgery, Stanford, California Regenerative Medicine FADI HANBALI, MD, FACS Assistant Professor of Neurosurgery, Texas Tech University Health Science Center, El Paso, Texas Neurosurgery

JOHN B. HANKS, MD C. Bruce Morton Professor and Chief, Division of General Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia Thyroid ALDEN H. HARKEN, MD Chairman, Department of Surgery, University of California at San Francisco (East Bay), San Francisco, California Acquired Heart Disease: Valvular JENNIFER A. HELLER, MD Assistant Professor of Surgery, Director of Johns Hopkins Vein Center, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Venous Disease DAVID N. HERNDON, MD, FACS Chief of Staff, Shriners Burns Hospital for Children; Professor of Surgery and Jesse H. Jones Distinguished Chair in Burn Surgery, The University of Texas Medical Branch, Galveston, Texas Burns; Metabolism in Surgical Patients MICHAEL S. HIGGINS, MD, MPH Professor, Department of Anesthesiology, Surgery and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee Perioperative Patient Safety ASHER HIRSHBERG, MD, FACS Professor of Surgery, State University of New York Downstate College of Medicine; Director of Emergency Vascular Surgery, Kings County Hospital Center, Brooklyn, New York The Surgeon’s Role in Mass Casualty Incidents

ERIC H. JENSEN, MD Assistant Professor of Surgery, University of Minnesota, Minneapolis, Minnesota Exocrine Pancreas MARC JESCHKE, MD, PHD, FACS, FRCSC Director, Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre; Associate Professor, Department of Surgery, Division of Plastic Surgery, University of Toronto; Senior Scientist, Sunnybrook Research Institute, Toronto, Ontario, Canada Burns HOWARD W. JONES, III, MD Professor and Chairman, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee Gynecologic Surgery ALLAN D. KIRK, MD, PHD Professor, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia Transplantation Immunobiology and Immunosuppression KIMBERLY S. KIRKWOOD, MD, FACS Professor of Surgery, Department of Surgery, University of California at San Francisco, San Francisco, California The Appendix SAE HEE KO, MD Postdoctoral Research Fellow, Stanford University Department of Surgery, Stanford, California; General Surgery Resident, University of Pittsburgh Department of Surgery, Pittsburgh, Pennsylvania Regenerative Medicine

GINGER E. HOLT, MD Associate Professor, Department of Orthopaedic Surgery, Vanderbilt Orthopaedic Institute, Vanderbilt University Medical Center, Nashville, Tennessee Bone Tumors

TIEN C. KO, MD Jack H. Mayfield, M.D. Distinguished Professor in Surgery; Vice Chairman for Harris County Hospital District, The University of Texas Health Science Center; Chief of Surgery, Lyndon B. Johnson General Hospital, Houston, Texas Molecular and Cell Biology

MICHAEL D. HOLZMAN, MD, MPH Associate Professor of Surgery and Lester and Sara Jayne Williams Chair in Academic Surgery, General Surgery Division, Vanderbilt University Medical Center, Nashville, Tennessee The Spleen

SETH B. KRANTZ, MD Research Fellow, Robert H. Lurie Comprehensive Cancer Center and the Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois Stomach

KELLY K. HUNT, MD Hamill Foundation Distinguished Professor of Surgery, Chief of Surgical Breast Oncology, M.D. Anderson Cancer Center, Houston, Texas Diseases of the Breast

MAHMOUD N. KULAYLAT, MD Associate Professor of Surgery, Department of Surgery, State University of New York–Buffalo, Buffalo General Hospital, Buffalo, New York Surgical Complications

PATRICK G. JACKSON, MD Chief of Gastrointestinal Surgery, Department of Surgery, Georgetown University Hospital, Washington, DC Biliary System

TERRY C. LAIRMORE, MD Professor of Surgery and Director, Division of Surgical Oncology, Scott and White Memorial Hospital and Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas The Multiple Endocrine Neoplasia Syndromes

CHRISTIAN P. LARSEN, MD, DPHIL Joseph B. Whitehead Professor and Chairman of Surgery; Associate Vice-President and Executive Director, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia Transplantation Immunobiology and Immunosuppression MIMI LEONG, MD, MS Assistant Professor, Plastic Surgery Division, Baylor College of Medicine; Staff Physician, Section of Plastic Surgery, Operative Care Line, Michael E. DeBakey Department of Surgery, Houston, Texas Wound Healing MICHAEL T. LONGAKER, MD, MBA, FACS Deane P. and Louise Mitchell Professor and Vice-Chair in Department of Surgery, Co-Director of Stanford Institute for Stem Cell Biology and Regenerative Medicine, Director of Program in Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California Regenerative Medicine ROBERT R. LORENZ, MD, MBA Medical Director Payment Reform, Risk & Contracting; Head and Neck Surgery, Laryngotracheal Reconstruction and Oncology, Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio Head and Neck JOHN MAA, MD Assistant Professor, Department of Surgery, University of California at San Francisco, San Francisco, California The Appendix NAJJIA N. MAHMOUD, MD Associate Professor of Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Colon and Rectum DAVID M. MAHVI, MD James R Hines Professor, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois Stomach MARY S. MAISH, MD, MPH Associate Professor of Surgery, Director of the UCLA Center for Esophageal Disorders, UCLA David Geffen School of Medicine, Los Angeles, California Esophagus MARK A. MALANGONI, MD Associate Executive Director; American Board of Surgery, Philadelphia, Pennsylvania Hernias DAVID J. MARON, MD, MBA Associate Director of Colorectal Surgery Residency Program, Staff Surgeon, Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida Colon and Rectum

SILAS T. MARSHALL, MD Resident, Department of Orthopaedic Surgery, University of Connecticut, Farmington, Connecticut Emergency Care of Musculoskeletal Injuries ABIGAIL E. MARTIN, MD Assistant Professor of Surgery, Divisions of Pediatric General Surgery and Abdominal Transplant Surgery, Duke University Medical Center, Durham, North Carolina Small Bowel Transplantation R. SHAYN MARTIN, MD Assistant Professor of Surgery, Department of Surgery, Wake Forest School of Medicine; Director, Surgical Critical Care, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina Management of Acute Trauma NADER MASSARWEH, MD, MPH Surgical Resident, Department of Surgery, University of Washington, Seattle, Washington Evidence-Based Surgery: Critically Assessing Surgical Literature ADDISON K. MAY, MD Professor of Surgery and Anesthesiology, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee Bedside Surgical Procedures MARY H. MCGRATH, MD, MPH, FACS Professor, Division of Plastic Surgery, Department of Surgery, University of California San Francisco, San Francisco, California Plastic Surgery SHAUN MCKENZIE, MD Assistant Professor, University of Kentucky Department of Surgery, Markey Cancer Center, Lexington, Kentucky Small Intestine KELLY M. MCMASTERS, MD, PHD Ben A. Reid, Sr. M.D. Professor and Chairman, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky Melanoma and Cutaneous Malignancies J. WAYNE MEREDITH, MD, FACS Richard T. Meyers Professor and Chair, Department of Surgery, Wake Forest University School of Medicine; Chief of Surgery, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina Management of Acute Trauma DEAN J. MIKAMI, MD Assistant Professor of Surgery, Department of Surgery, Ohio State University Medical Center, Columbus, Ohio Surgery in the Pregnant Patient

RICHARD S. MILLER, MD, FACS Professor of Surgery, Chief of the Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee The Difficult Abdominal Wall AARON MOHANTY, MD Assistant Professor, Pediatric Neurosurgery, University of Texas Medical Branch, Galveston, Texas Neurosurgery JEFFREY F. MOLEY, MD Professor of Surgery, Department of Surgery, Chief, Section of Endocrine and Oncologic Surgery, Washington University School of Medicine; Associate Director, Alvin Siteman Cancer Center; Attending Surgeon, Surgical Service, St. Louis VA Medical Center, St. Louis, Missouri The Multiple Endocrine Neoplasia Syndromes KEVIN MURPHY, MD, MCH, FRCS(PLAST.) Hand Surgery Fellow, Division of Plastic Surgery, Baylor College of Medicine, Houston, Texas Hand Surgery ELAINE E. NELSON, MD, FACEP Chairman, Department of Emergency Medicine, Regional Medical Center of San Jose, San Jose, California Bites and Stings HEIDI NELSON, MD Fred C. Andersen Professor, Department of Surgery, Chair Division of Surgery Research, Mayo Clinic, Rochester, Minnesota Anus DAVID NETSCHER, MD Clinical Professor, Division of Plastic Surgery; Professor, Department of Orthopedic Surgery, Baylor College of Medicine; Adjunct Professor of Clinical Surgery (Plastic Surgery), Weill Medical College, Cornell University; Chief of Hand Surgery, St. Luke’s Episcopal Hospital; Chief of Plastic Surgery, VA Medical Center, Houston, Texas Hand Surgery LEIGH NEUMAYER, MD Professor of Surgery, Department of Surgery, University of Utah; Jon and Karen Huntsman Presidential Professor in Cancer Research, Huntsman Cancer Institute; Co-Director, Multidisciplinary Breast Program, Huntsman Cancer Hospital, Salt Lake City, Utah Principles of Preoperative and Operative Surgery ROBERT L. NORRIS, MD Professor, Department of Surgery and Chief, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California Bites and Stings

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BRANT K. OELSCHLAGER, MD, FACS Byers Endowed Professor of Esophageal Research, Chief, Gastrointestinal and General Surgery and Center for Videoendoscopic Surgery, University of Washington, Seattle, Washington Hiatal Hernia and Gastroesophageal Reflux Disease JOEL T. PATTERSON, MD Associate Professor of Neurosurgery and Otolaryngology, Samuel R. Snodgrass, MD Professorship in Neurosurgery, Chief and Program Director, Division of Neurosurgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas Neurosurgery CARLOS A. PELLEGRINI, MD, FACS, FRCSI(HON) The Henry N. Harkins Professor and Chairman, Department of Surgery, University of Washington Medical Center, Seattle, Washington Hiatal Hernia and Gastroesophageal Reflux Disease REBECCA P. PETERSEN, MD, MSC Senior Fellow and Acting Instructor, Department of Surgery, University of Washington, Seattle, Washington Hiatal Hernia and Gastroesophageal Reflux Disease LINDA G. PHILLIPS, MD Truman G. Blocker, Jr., MD, Distinguished Professor and Chief, Division of Plastic Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas Wound Healing; Breast Reconstruction IRAKLIS I. PIPINOS, MD Professor, Vascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska The Lymphatics JASON POMERANTZ, MD Assistant Professor, Department of Surgery, University of California San Francisco, San Francisco, California Plastic Surgery RUSSELL G. POSTIER, MD John A. Schilling Professor and Chairman, Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Acute Abdomen DONALD S. PROUGH, MD Professor and Chair, Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas Anesthesiology Principles, Pain Management, and Conscious Sedation JOE B. PUTNAM, JR., MD Ingram Professor of Surgery, Chairman of Department of Thoracic Surgery, Professor of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee Lung, Chest Wall, Pleura, and Mediastinum

PETER RHEE, MD, MPH, DMCC Professor of Surgery and Molecular Cellular Biology, Chief of Trauma, Critical Care and Emergency Surgery, University of Arizona, Tucson, Arizona Shock, Electrolytes, and Fluid TAYLOR S. RIALL, MD, PHD Associate Professor, John Sealy Distinguished Chair in Clinical Research, Department of Surgery, University of Texas Medical Branch, Galveston, Texas Endocrine Pancreas WILLIAM O. RICHARDS, MD Professor and Chair, Department of Surgery, University of South Alabama College of Medicine, Mobile, Alabama Morbid Obesity NOE A. RODRIGUEZ, MD Post-Doctoral Fellow Burn Research, Department of Surgery, University of Texas Medical Branch, Galveston, Texas Metabolism in Surgical Patients KENDALL R. ROEHL, MD Assistant Professor, Division of Plastic and Reconstructive Surgery, Texas A&M Health Sciences Center, Scott and White Hospital Clinics, Temple, Texas Breast Reconstruction MICHAEL J. ROSEN, MD Chief of Gastrointestinal Surgery, Director Case Comprehensive Hernia Center Department of Surgery, University Hospitals Case Medical Center, Cleveland, Ohio Hernias RONNIE A. ROSENTHAL, MD Professor of Surgery, Yale University School of Medicine, New Haven and Chief, Surgical Service, VA Connecticut Healthcare System, West Haven, Connecticut Surgery in the Geriatric Patient IRA RUTKOW, MD, MPH, DRPH Clinical Professor of Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey History of Surgery LESLIE J. SALOMONE, MD Clinical Endocrinologist, Jacksonville, Florida Thyroid HERBERT S. SCHWARTZ, MD Professor and Chairman, Department of Orthopaedic Surgery, Vanderbilt Orthopaedic Institute, Vanderbilt University Medical Center, Nashville, Tennessee Bone Tumors STEVEN R. SHACKFORD, MD, FACS Professor Emeritus, Department of Surgery, College of Medicine, University of Vermont, Burlington, Vermont Vascular Trauma

JULIA SHELTON, MD Resident, Department of General Surgery, Vanderbilt University Medical Center, Nashville, Tennessee The Spleen EDWARD R. SHERWOOD, MD, PHD Professor, James F. Arens Endowed Chair, Vice Chair for Research, Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas Anesthesiology Principles, Pain Management, and Conscious Sedation JASON K. SICKLICK, MD Department of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California at San Diego, La Jolla, California The Liver MICHAEL B. SILVA, JR., MD Fred J. and Dorothy E. Wolma Professor in Vascular Surgery, Professor of Radiology, Chief, Division of Vascular Surgery and Endovascular Therapy, Director, Texas Vascular Center, University of Texas Medical Branch, Galveston, Texas Peripheral Arterial Occlusive Disease SAMUEL SINGER, MD Chief, Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York Soft Tissue Sarcomas MICHAEL J. SISE, MD Clinical Professor of Surgery, University of California, San Diego School of Medicine; Medical Director, Division of Trauma, Scripps Mercy Hospital, San Diego, California Vascular Trauma PHILIP W. SMITH, MD Assistant Professor of Surgery, Endocrine and General Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia Thyroid JULIE ANN SOSA, MD, MA, FACS Associate Professor of Surgery and Medicine (Medical Oncology), Divisions of Endocrine Surgery and Surgical Oncology, Yale University School of Medicine, New Haven, Connecticut The Parathyroid Glands RONALD A. SQUIRES, MD Professor, Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Acute Abdomen MICHAEL STEIN, MD Director of Trauma, Rabin Medical Center, Petach Tivka, Israel The Surgeon’s Role in Mass Casualty Incidents

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ANDREW STEPHEN, MD Staff, Division of Trauma and Surgical Critical Care, Rhode Island Hospital; Alpert Medical School of Brown University, Providence, Rhode Island Surgical Critical Care

MARSHALL M. URIST, MD Champ Lyons Professor and Vice-Chairman, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama Melanoma and Cutaneous Malignancies

RONALD M. STEWART, MD Professor and Chair, Jocelyn and Joe Straus Endowed Chair, Department of Surgery, University of Texas Health Science Center San Antonio, San Antonio, Texas Bites and Stings

CHERYL E. VAIANI, PHD Assistant Professor, Clinical Ethicist, Institute for the Medical Humanities, University of Texas Medical Branch, Galveston, Texas Ethics and Professionalism in Surgery

DEBRA L. SUDAN, MD Professor of Surgery and Pediatrics, Division Chief Abdominal Transplant Surgery, Vice-Chair for Clinical Operations, Duke University School of Medicine, Durham, North Carolina Small Bowel Transplantation

DANIEL VARGO, MD, FACS Associate Professor, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah Principles of Preoperative and Operative Surgery

MARCUS C.B. TAN, MBBS(HONS) Resident in General Surgery, Department of Surgery, BarnesJewish Hospital, Washington University in St. Louis, St. Louis, Missouri Tumor Biology and Tumor Markers ALI TAVAKKOLIZADEH, MD Associate Surgeon, Brigham and Women’s Hospital; Assistant Professor of Surgery, Harvard Medical School, Boston, Massachusetts Acute Gastrointestinal Hemorrhage JAMES S. TOMLINSON, MD, PHD Assistant Professor of Surgery, Division of Surgical Oncology, University of California, Los Angeles, Los Angeles, California Tumor Immunology and Immunotherapy COURTNEY M. TOWNSEND, JR., MD Professor and John Woods Harris Distinguished Chairman, Robertson-Poth Distinguished Chair in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas Endocrine Pancreas MARGARET C. TRACCI, MD, JD Assistant Professor, Division of Vascular and Endovascular Surgery, University of Virginia, Charlottesville, Virginia Aorta RICHARD H. TURNAGE, MD Academic Affiliation; Professor and Chairman; University of Arkansas for Medical Sciences (UAMS); Little Rock, Arkansas Abdominal Wall, Umbilicus, Peritoneum, Mesenteries, Omentum, and Retroperitoneum ROBERT UDELSMAN, MD, MBA William H. Carmalt Professor of Surgery and Oncology and Chairman, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut The Parathyroid Glands

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SELWYN M. VICKERS, MD, FACS Jay Phillips Professor and Chairman, Department Chair, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Exocrine Pancreas BRADON J. WILHELMI, MD Leonard Weiner Endowed Professor, Chief of Plastic Surgery, Residency Program Director, Division of Plastic and Reconstructive Surgery, University of Louisville, Louisville, Kentucky Breast Reconstruction COURTNEY G. WILLIAMS, MD Associate Professor, Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas Anesthesiology Principles, Pain Management, and Conscious Sedation FELICIA N. WILLIAMS, MD Chief Resident, Department of Surgery, East Carolina University, Pitt County Memorial Hospital, Greenville, North Carolina Burns JAMES C. YANG, MD Senior Investigator, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Tumor Immunology and Immunotherapy MICHAEL W. YEH, MD, FACS Associate Professor of Surgery and Medicine (Endocrinology), Chief, Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, California The Adrenal Glands

FOREWORD “How many a man has dated a new era in his life from the reading of a book.” Henry David Thoreau (1817-1862)

This 19th edition of Sabiston Textbook of Surgery, the fourth edited by Dr. Townsend and his co-editors Drs. Maddox, Beauchamp, and Evers, extends the tradition of textbook excellence and leadership initiated 18 editions ago. The emphasis on clinical relevance and outcomes characteristic of earlier editions has been enhanced by the addition of three new chapters on organ transplantation, two new chapters in the vascular section: “The Aorta” and “Peripheral Arterial Occlusive Disease,” and new chapters on the cutting edge topics of tumor immunology and immunotherapy and the “difficult abdominal wall.” Other chapters have been embellished by inclusion of the latest information on biomaterials, organ procurement issues, specific gene therapy, biliary tumors, urinary system tumors, and simulation in surgery. Still other content has been revised to increase the focus on evidence-based practice by coverage of comparative effectiveness and patient-specific therapeutics. The recruitment of more than 50 new authors and coauthors has guaranteed timeliness of the text, ensured full display of state of the art technology, and refreshed the trove of

illustrations which by tradition have amplified and corroborated the text. The authors have also provided over 400 self-assessment questions which will assist the reader in preparing for and successfully achieving recertification. As was true with the previous edition, ownership of the print text of this edition gives free access to the online product “Expert Consult,” which includes full text and art, updates (journal articles selected by the editors and authors and keyed to chapter topics), board review questions, and videos on topics ranging from pleural effusion to hand transplantation and total aortic replacement. Expert Consult makes access to the text and all related material as convenient as the nearest computer. This 19th edition of Sabiston successfully integrates print and electronic media to provide complete coverage of surgical practice. Full use of all features of this text will increase the reader’s practice of evidence-based surgery, facilitate the reader’s recertification activities, and promote the reader’s acquisition and maintenance of the professional competencies. In short this is truly a text that as foretold by Thoreau will launch each reader on a new era in his or her surgical life. BASIL A. PRUITT, JR., MD, FACS, FCCM

PREFACE

URGERY CONTINUES TO EVOLVE as new technology, techniques, and knowledge are incorporated into the care of surgical patients. The 19th edition of the Sabiston Textbook of Surgery reflects these exciting changes and new information. We have incorporated eight new chapters and more than 77 new authors to ensure that the most current information is presented. For example, safety is paramount in the care of our surgical patients; our chapter on safety describes the surgeon’s roles and responsibilities to ensure safety. We have included a new chapter on management of the difficult abdominal wall, which can be a vexing problem for even the most experienced surgeon. Distant surgery, using robotic and telementoring technology, has become a reality, and minimally invasive techniques are being used in almost all invasive procedures. This new edition has revised and enhanced the current chapters to reflect these changes. Finally, we have extensively updated chapters dealing with basic science

aspects that are important to surgeons and, in many cases, represent scientific advances in which surgeons are leading the charge. This is most evident in the chapters on tumor biology and tumor immunology, transplantation immunology, and the rapidly emerging field of regenerative medicine. The primary goal of this new edition is to remain the most thorough, useful, readable, and understandable textbook presenting the principles and techniques of surgery. It is designed to be equally useful to students, trainees, and experts in the field. We are committed to maintaining this tradition of excellence, begun in 1936. Surgery, after all, remains a discipline in which the knowledge and skill of a surgeon combine for the welfare of all patients. COURTNEY M. TOWNSEND, JR., MD

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ACKNOWLEDGMENTS

recognize the invaluable contributions of Karen Martin, Steve Schuenke, Eileen Figueroa, and administrator Barbara Petit. Their dedicated professionalism, tenacious efforts, and cheerful cooperation are without parallel. They accomplished whatever was necessary, often on short or immediate deadlines, and were vital for the successful completion of the endeavor. Our authors, respected authorities in their fields, all busy physicians and surgeons, did an outstanding job in sharing their wealth of knowledge. E WOULD LIKE TO

We would also like to acknowledge the professionalism of our colleagues at Elsevier: Maureen R. Iannuzzi, Content Developmental Manager; Louis Forgione, Senior Book Designer; Rachel E. McMullen, Senior Project Manager; Catherine Jackson, Publications Services Manager; and Judith Fletcher, Global Content Development Director.

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VIDEO CONTENTS SECTION 1 SURGICAL BASIC PRINCIPLES CHAPTER 6 Metabolism in Surgical Patients VIDEO 6-1 Indirect Calorimetry Noe A. Rodriguez VIDEO 6-2 Dexa Noe A. Rodriguez VIDEO 6-3 Treadmill Noe A. Rodriguez

SECTION 2 PERIOPERATIVE MANAGEMENT CHAPTER 15 Morbid Obesity VIDEO 15-1 Laparoscopic Roux-en-Y Gastric Bypass William O. Richards VIDEO 15-2 Laparoscopic Adjustable Gastric Band William O. Richards VIDEO 15-3 Laparoscopic Sleeve Gastrectomy William O. Richards

CHAPTER 17 Emerging Technology in Surgery: Informatics, Robotics, and Electronics VIDEO 17-1 Robot-Assisted Resection Guillermo Gomez

SECTION 3 TRAUMA AND CRITICAL CARE CHAPTER 19 The Difficult Abdominal Wall VIDEO 19-1 Fistula in Open Abdomen Oliver Gunter

SECTION 4 TRANSPLANTATION AND IMMUNOLOGY CHAPTER 26 Transplantation Immunobiology and Immunosuppression VIDEO 26-1 Results of World’s First Successful Hand Transplant Darla K. Granger and Suzanne T. Ildstad

SECTION 8 ENDOCRINE CHAPTER 39 The Parathyroid Glands VIDEO 39-1 Minimally Invasive Parathyroidism Robert Udelsman

CHAPTER 42 The Multiple Endocrine Neoplasia Syndromes VIDEO 42-1 Parathyroid Autotransplantation Jeffrey F. Moley VIDEO 42-2 Extensive Thyroid Cancer with MEN 2B and MTC Jeffrey F. Moley

SECTION 10 ABDOMEN CHAPTER 51 The Appendix VIDEO 51-1 Laparoscopic 3-Port Appendectomy Jonathan Carter

VIDEO 51-2 Laparoscopic Appendectomy in Pregnancy Lawrence W. Way VIDEO 51-3 SILS Appendectomy Kazunori Sato, Beemen N. Khalil, Ranna Tabrizi, and Jonathan Carter

CHAPTER 56 Exocrine Pancreas VIDEO 56-1 Laparoscopic Distal Pancreatectomy Eric H. Jensen

SECTION 11 CHEST CHAPTER 58 Lung, Chest Wall, Pleura, and Mediastinum VIDEO 58-1 Pleural Effusion Christopher J. Dente and Grace S. Rozycki VIDEO 58-2 Pleural Sliding Christopher J. Dente and Grace S. Rozycki VIDEO 58-3 Pneumothorax Christopher J. Dente and Grace S. Rozycki

SECTION 12 VASCULAR CHAPTER 62 Aorta VIDEO 62-1 Total Aortic Replacement Hazim J. Safi, Anthony L. Estrera, Eyal E. Porat, Ali Azizzadeh, and Riad Meada

CHAPTER 63 Peripheral Arterial Occlusive Disease VIDEO 63-1 Aortoiliac Stenting Michael B. Silva, Jr. and Lori Choi VIDEO 63-2 Carotid Stenting Michael B. Silva, Jr. and Lori Choi VIDEO 63-3 Occlusive Diseases Michael B. Silva, Jr. and Lori Choi VIDEO 63-4 Renal Artery Stenting Michael B. Silva, Jr. and Lori Choi VIDEO 63-5 Splenic Aneurysm Coil Embolization Michael B. Silva, Jr. and Lori Choi VIDEO 63-6 Internal Jugular Vein Christopher J. Dente and Grace S. Rozycki

CHAPTER 65 Venous Disease VIDEO 65-1 TRIVEX Jennifer Heller VIDEO 65-2 Endovenous Ablation Jennifer Heller

SECTION 13 SPECIALTIES IN GENERAL SURGERY CHAPTER 71 Gynecologic Surgery VIDEO 71-1 Total Laparoscopic Hysterectomy Howard Jones and Amanda Yunker VIDEO 71-2 Unilateral salpingo-oophorectomy Howard Jones and Amanda Yunker

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CHAPTER 1

HISTORY OF SURGERY Ira Rutkow

importance of understanding surgical history early 20th century modern era 20th century surgical highlights future trends

IMPORTANCE OF UNDERSTANDING SURGICAL HISTORY It 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 philosophic tastes. Clearly, the study of medicine is a lifelong learning process that should be an enjoyable and rewarding experience. For a surgeon, the study of surgical history can contribute toward making this educational effort more pleasurable and can provide constant invigoration. Tracing the evolution of what one does on a daily basis and understanding it from a historical perspective become enviable goals. In reality, there is no way to separate present-day surgery and one’s own clinical practice from the experience of all surgeons and all the years that have gone before. For budding surgeons, it is a magnificent adventure to appreciate what they are currently learning within the context of past and present cultural, economic, political, and social institutions. Active physicians will find that the study of the profession—dealing, as it rightly must, with all aspects of the human condition—affords an excellent oppor tunity to approach current clinical concepts in ways not previously appreciated. In studying our profession’s past, it is certainly easier to relate to the history of so-called modern surgery over the past 100 or so years than to the seemingly primitive practices of previous periods because the closer to the present, the more likely it is that surgical practices will resemble current practices. Nonetheless, writing the history of modern surgery is in many respects more difficult than describing the development of surgery before the late 19th century. One significant reason for this difficulty is the ever-increasing pace of scientific devel opment in conjunction with unrelenting fragmentation (i.e., specialization and subspecialization) within the profession. The craft of surgery is in constant flux and, the more rapid the change, the more difficult it is to obtain a satisfactory historical 2

perspective. Only the lengthy passage of time permits a truly valid historical analysis. Historical Relationship Between Surgery and Medicine Despite outward appearances, it was actually not until the latter decades of the 19th century that the surgeon truly emerged as a specialist within the whole arena of medicine to become a recognized and respected clinical physician. Similarly, it was not until the first decades of the 20th century that surgery could be considered to have achieved the status of a bona fide profession. Before this time, the scope of surgery remained limited. Surgeons, or at least those medical men who used the sobriquet surgeon, whether university-educated or trained in private apprenticeships, at best treated only simple fractures, dislocations, and abscesses and occasionally performed amputations with dexterity, but also with high mortality rates. They managed to ligate major arteries for common and accessible aneurysms and made heroic attempts to excise external tumors. Some individuals focused on the treatment of anal fistulas, hernias, cataracts, and bladder stones. Inept attempts at reduction of incarcerated and strangulated hernias were made and, hesitatingly, rather rudimentary colostomies or ileostomies were created by simply incising the skin over an expanding intra-abdominal mass, which represented the end stage of a long-standing intestinal obstruction. Compound fractures of the limbs, with attendant sepsis, remained mostly unmanageable, with staggering morbidity being a likely surgical outcome. Although a few bold surgeons endeavored to incise the abdomen in the hope of dividing obstructing bands and adhesions, abdominal and other types of intrabody surgery were almost unknown. Despite it all, including an ignorance of anesthesia and antisepsis tempered with the not uncommon result of the patient suffering from or succumbing to the effects of a surgical operation (or both), surgery was long considered an important and medically valid therapy. This seeming paradox, in view of the terrifying nature of surgical intervention, its limited technical scope, and its damning consequences before the development of modern conditions, is explained by the simple fact that surgical procedures were usually performed only for external difficulties that required an objective anatomic diagnosis. Surgeons or followers of the surgical cause saw what needed to be fixed (e.g., abscesses, broken bones, bulging tumors, cataracts, hernias) and would treat the problem in as rational a manner as the times permitted. Conversely, the physician was forced to render

History of Surgery Chapter 1 3

(1514-1564; Fig. 1-1). As professor of anatomy and surgery in Padua, Italy, Vesalius taught that human anatomy could be learned only through the study of structures revealed by human dissection. In particular, his great anatomic treatise, De Humani Corporis Fabrica Libri Septem (1543), provided fuller and more detailed descriptions of human anatomy than any of his illustrious predecessors. Most importantly, Vesalius corrected errors in traditional anatomic teachings propagated 13 centuries earlier by Greek and Roman authorities, whose findings were based on animal rather than human dissection. Even more radical was Vesalius’ blunt assertion that anatomic dissection must be completed by physician-surgeons themselves—a direct renunciation of the long-standing doctrine that dissection was a grisly and loathsome task to be performed by a diener-like individual while the perched physician-surgeon lectured by reading from an orthodox anatomic text from on high. This principle of hands-on education would remain Vesalius’ most important and longlasting contribution to the teaching of anatomy. Vesalius’ Latin literae scriptae ensured its accessibility to the most well-known physicians and scientists of the day. Latin was the language of the intelligentsia and the Fabrica became instantly popular, so it was only natural that over the next 2 centuries, the work would go through numerous adaptations, editions, and revisions, although always remaining an authoritative anatomic text.

Knowledge of Human Anatomy Few individuals have had an influence on the history of surgery as overwhelmingly as that of the Brussels-born Andreas Vesalius

Method of Controlling Hemorrhage The position of Ambroise Paré (1510-1590) in the evolution of surgery remains of supreme importance (Fig. 1-2). He played

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subjective care for disease processes that were neither visible nor understood. After all, it is a difficult task to treat the symptoms of illnesses such as arthritis, asthma, heart failure, and diabetes, to name but a few, if there is no scientific understanding or internal knowledge of what constitutes their basic pathologic and physiologic underpinnings. With the breathtaking advances made in pathologic anatomy and experimental physiology during the 18th and first part of the 19th centuries, physicians would soon adopt a therapeutic viewpoint that had long been prevalent among surgeons. It was no longer a question of just treating symptoms; the actual pathologic problem could ultimately be understood. Internal disease processes that manifested themselves through difficult to treat external signs and symptoms were finally described via physiology-based experimentation or viewed pathologically through the lens of a microscope. Because this reorientation of internal medicine occurred within a relatively short time and brought about such dramatic results in the classification, diagnosis, and treatment of disease, the rapid ascent of mid-19th century internal medicine might seem more impressive than the agonizingly slow, but steady, advance of surgery. In a seeming contradiction of mid-19th century scientific and social reality, medicine appeared as the more progressive branch, with surgery lagging behind. The art and craft of surgery, for all its practical possibilities, would be severely restricted until the discovery of anesthesia in 1846 and an understanding and acceptance of the need for surgical antisepsis and asepsis during the 1870s and 1880s. Still, surgeons never needed a diagnostic and pathologic revolution in the manner of the physician. Despite the imperfection of their scientific knowledge, the pre–modern era surgeon did cure with some technical confidence. That the gradual evolution of surgery was superseded in the 1880s and 1890s by the rapid introduction of startling new technical advances was based on a simple culminating axiom— the four fundamental clinical prerequisites that were required before a surgical operation could ever be considered a truly viable therapeutic procedure had finally been identified and understood: 1. Knowledge of human anatomy 2. Method of controlling hemorrhage and maintaining intraoperative hemostasis 3. Anesthesia to permit the performance of pain-free procedures 4. Explanation of the nature of infection, along with the elaboration of methods necessary to achieve an antiseptic and aseptic operating room environment The first two prerequisites were essentially solved in the 16th century, but the latter two would not be fully resolved until the ending decades of the 19th century. In turn, the ascent of 20th century scientific surgery would unify the profession and allow what had always been an art and craft to become a learned vocation. Standardized postgraduate surgical education and training programs could be established to help produce a cadre of scientifically knowledgeable physicians. Moreover, in a final snub to an unscientific past, newly established basic surgical research laboratories offered the means of proving or disproving the latest theories while providing a testing ground for bold and exciting clinical breakthroughs.

FIGURE 1-1 Andreas Vesalius (1514-1564).

4 SECTION I SURGICAL BASIC PRINCIPLES

FIGURE 1-3 John Hunter (1728-1793). FIGURE 1-2 Ambroise Paré (1510-1590).

the major role in reinvigorating and updating Renaissance surgery and represents severing of the final link between surgical thought and techniques of the ancients and the push toward more modern eras. From 1536 until just before his death, Paré was engaged as an army surgeon, during which time he accompanied different French armies on their military expeditions, or was performing surgery in civilian practice in Paris. Although other surgeons made similar observations about the difficulties and nonsensical aspects of using boiling oil as a means of cauterizing fresh gunshot wounds, Paré’s use of a less irritating emollient of egg yolk, rose oil, and turpentine brought him lasting fame and glory. His ability to articulate such a finding in a number of textbooks, all written in the vernacular, allowed his writings to reach more than just the educated elite. Among Paré’s important corollary observations was that when performing an amputation, it was more efficacious to ligate individual blood vessels than to attempt to control hemorrhage by means of mass ligation of tissue or with hot oleum. Described in his Dix Livres de la Chirurgie avec le Magasin des Instruments Necessaires à Icelle (1564), the free or cut end of a blood vessel was doubly ligated and the ligature was allowed to remain undisturbed in situ until, as a result of local suppuration, it was cast off. Paré humbly attributed his success with patients to God, as noted in his famous motto, “Je le pansay. Dieu le guérit,”—that is, “I treated him. God cured him.” Pathophysiologic Basis of Surgical Diseases Although it would be another 3 centuries before the third desideratum, that of anesthesia, was discovered, much of the scientific understanding concerning efforts to relieve discomfort secondary to surgical operations was based on the 18th century work of England’s premier surgical scientist, John Hunter (1728-1793; Fig. 1-3). Considered one of the most influential surgeons of all time, his endeavors stand out because of the prolificacy of his written word and the quality of his research, especially in using

experimental animal surgery as a way to understand the pathophysiologic basis of surgical diseases. Most impressively, Hunter relied little on the theories of past authorities but rather on personal observations, with his fundamental pathologic studies first described in the renowned textbook A Treatise on the Blood, Inflammation, and Gun-Shot Wounds (1794). Ultimately, his 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. It represented a unique warehousing of separate organ systems, with comparisons of these systems—from the simplest animal or plant to humans—demonstrating the interaction of structure and function. For decades, Hunter’s collection, housed in England’s Royal College of Surgeons, remained the outstanding museum of comparative anatomy and pathology in the world, until a World War II Nazi bombing attack of London created a conflagration that destroyed most of Hunter’s assemblage. Anesthesia Since time immemorial, the inability of surgeons to complete pain-free operations had been among the most terrifying of medical problems. In the preanesthetic era, surgeons were forced to be more concerned about the speed with which an operation was completed than with the clinical efficacy of their dissection. In a similar vein, patients refused or delayed surgical procedures for as long as possible to avoid the personal horror of experiencing the surgeon’s knife. Analgesic, narcotic, and soporific agents such as hashish, mandrake, and opium had been used for thousands of years. However, the systematic operative invasion of body cavities and the inevitable progression of surgical history could not occur until an effective means of rendering a patient insensitive to pain was developed. As anatomic knowledge and surgical techniques improved, the search for safe methods to prevent pain became more pressing. By the early 1830s, chloroform, ether, and nitrous oxide had been discovered and so-called laughing gas parties and ether frolics were in vogue, especially in America. Young people were

History of Surgery Chapter 1 5

Antisepsis, Asepsis, and Understanding the Nature of Infection In many respects, the recognition of antisepsis and asepsis was a more important event in the evolution of surgical history than the advent of inhalational 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 procedure could still be performed, albeit with much difficulty. Such was not the case with listerism. Without antisepsis and asepsis, major surgical operations 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 to be of greater singular impact. In the long evolution of world surgery, the contributions of several individuals stand out as being preeminent. Lister, an English surgeon, can be placed on such a select list because of his monumental efforts to introduce systematic, scientifically

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amusing themselves with the pleasant side effects of these compounds as itinerant so-called professors of chemistry traveled to hamlets, towns, and cities to lecture on and demonstrate the exhilarating effects of these new gases. It soon became evident to various physicians and dentists that the pain-relieving qualities of ether and nitrous oxide could be applicable to surgical operations and tooth extraction. On October 16, 1846, William T.G. Morton (1819-1868), a Boston dentist, persuaded John Collins Warren (1778-1856), professor of surgery at the Massachusetts General Hospital, to let him administer sulfuric ether to a surgical patient from whom Warren went on to remove a small, congenital vascular tumor of the neck painlessly. After the operation, Warren, greatly impressed with the new discovery, uttered his famous words, “Gentlemen, this is no humbug.” Few medical discoveries have been so readily accepted as inhalational anesthesia. News of the momentous event spread rapidly throughout the United States and Europe, and a new era in the history of surgery had begun. Within a few months after the first public demonstration in Boston, ether was used in hospitals throughout the world. Yet, no matter how much it contributed to the relief of pain during surgical operations and decreased the surgeon’s angst, the discovery did not immediately further the scope of elective surgery. Such technical triumphs awaited the recognition and acceptance of antisepsis and asepsis. Anesthesia helped make the illusion of surgical cures more seductive, but it could not bring forth the final prerequisite— all-important hygienic reforms. Still, by the mid-19th century, both physicians and patients were coming to hold surgery in relatively high regard for its pragmatic appeal, technologic virtuosity, and unambiguously measurable results. After all, surgery appeared a mystical craft to some. To be allowed to consensually cut into another human’s body, to gaze at the depth of that person’s suffering, and to excise the demon of disease seemed an awesome responsibility. It was this very mysticism, however, long associated with religious overtones, that so fascinated the public and their own feared but inevitable date with a surgeon’s knife. Surgeons had finally begun to view themselves as combining art and nature, essentially assisting nature in its continual process of destruction and rebuilding. This regard for the natural would spring from the eventual, although preternaturally slow, understanding and use of Joseph Lister’s (1827-1912) techniques (Fig. 1-4).

FIGURE 1-4 Joseph Lister (1827-1912).

based antisepsis in the treatment of wounds and the performance of surgical operations. He pragmatically applied others’ research into fermentation and microorganisms to the world of surgery by devising a means of preventing surgical infection and securing its adoption by a skeptical profession. It was evident to Lister that a method of destroying bacteria by excessive heat could not be applied to a surgical patient. He turned, instead, to chemical antisepsis and, after experimenting with zinc chloride and the sulfites, decided on carbolic acid. By 1865, Lister was instilling pure carbolic acid into wounds and onto dressings. He would eventually make numerous modifications in the technique of dressings, manner of applying and retaining them, and choice of antiseptic solutions of varying concentrations. Although the carbolic acid spray remains the best remembered of his many contributions, it was eventually abandoned in favor of other germicidal substances. Lister not only used carbolic acid in the wound and on dressings but also went so far as to spray it into the atmosphere around the operative field and table. He did not emphasize hand scrubbing but merely dipped his fingers into a solution of phenol and corrosive sublimate. Lister was incorrectly convinced that scrubbing created crevices in the palms of the hands where bacteria would proliferate. A second important advance by Lister was the development of sterile absorbable sutures. He believed that much of the deep suppuration found in wounds was created by previously contaminated silk ligatures. Lister evolved a carbolized catgut suture that was better than any previously produced. He was able to cut the ends of the ligature short, thereby closing the wound tightly and eliminating the necessity of bringing the ends of the suture out through the incision, a surgical practice that had persisted since the days of Paré. The acceptance of listerism was an uneven and distinctly slow process, for many reasons. First, the various procedural

6 SECTION I SURGICAL BASIC PRINCIPLES changes that Lister made during the evolution of his methodology created confusion. Second, listerism, as a technical exercise, was complicated by the use of carbolic acid, an unpleasant and time-consuming nuisance. Third, various early attempts to use antisepsis in surgery had proved abject failures, with many leading surgeons unable to replicate Lister’s generally good results. Finally, and most importantly, acceptance of listerism depended entirely on an understanding and ultimate recognition of the veracity of the germ theory, a hypothesis that many practical-minded surgeons were loath to accept. As a professional group, German-speaking surgeons would be the first to grasp the importance of bacteriology and the germ theory. Consequently, they were among the earliest to expand on Lister’s message of antisepsis, with his spray being discarded in favor of boiling and use of the autoclave. The availability of heat sterilization led to the development of sterile aprons, drapes, instruments, and sutures. Similarly, the use of face masks, gloves, hats, and operating gowns also naturally evolved. By the mid1890s, less clumsy aseptic techniques had found their way into most European surgical amphitheaters and were approaching total acceptance by American surgeons. Any lingering doubts about the validity and significance of the momentous concepts that Lister had put forth were eliminated on the battlefields of World War I. There, the importance of just plain antisepsis became an invaluable lesson for scalpel bearers, whereas the exigencies of the battlefield helped bring about the final maturation and equitable standing of surgery and surgeons within the worldwide medical community. X-Rays Especially prominent among other late 19th century discoveries that had an enormous impact on the evolution of surgery was research conducted by Wilhelm Roentgen (1845-1923), which led to his 1895 elucidation of x-rays. Having grown interested in the phosphorescence from metallic salts that were exposed to light, Roentgen made a chance observation when he passed a current through a vacuum tube and noticed a greenish glow coming from a screen on a shelf 9 feet away. This strange effect continued after the current was turned off. He found that the screen had been painted with a phosphorescent substance. Proceeding with full experimental vigor, Roentgen soon realized that there were invisible rays capable of passing through solid objects made of wood, metal, and other materials. Most significantly, these rays also penetrated the soft parts of the body in such a manner that the more dense bones of his hand were able to be revealed on a specially treated photographic plate. In a short time, numerous applications were developed as surgeons rapidly applied the new discovery to the diagnosis and location of fractures and dislocations and the removal of foreign bodies. EARLY 20TH CENTURY By the late 1890s, the interactions of political, scientific, socioeconomic, and technical factors set the stage for what would become a spectacular showcasing of surgery’s newfound prestige and accomplishments. Surgeons were finally wearing antisepticlooking white coats. Patients and tables were draped in white, and basins for bathing instruments in bichloride solution abounded. Suddenly, all was clean and tidy, with conduct of the surgical operation no longer a haphazard affair. This reformation would be successful not because surgeons had fundamentally changed but because medicine and its relationship to scientific

FIGURE 1-5 Theodor Billroth (1829-1894).

inquiry had been irrevocably altered. Sectarianism and quackery, the consequences of earlier medical dogmatism, would no longer be tenable within the confines of scientific truth. With all four fundamental clinical prerequisites in place by the turn of the century, highlighted by the emerging clinical triumphs of various English surgeons, including Robert Tait (1845-1899), William Macewen (1848-1924), and Frederick Treves (1853-1923); German-speaking surgeons, including Theodor Billroth (1829-1894; Fig. 1-5), Theodor Kocher (1841-1917; Fig. 1-6), Friedrich Trendelenburg (1844-1924), and Johann von Mikulicz-Radecki (1850-1905); French surgeons, including Jules Peán (1830-1898), Just Lucas-Championière (1843-1913), and Marin-Theodore Tuffiér (1857-1929); Italian surgeons, most notably Eduardo Bassini (1844-1924) and Antonio Ceci (1852-1920); and several American surgeons, exemplified by William Williams Keen (1837-1932), Nicholas Senn (1844-1908), and John Benjamin Murphy (1857-1916), scalpel wielders had essentially explored all cavities of the human body. Nonetheless, surgeons retained a lingering sense of professional and social discomfort and continued to be pejoratively described by nouveau scientific physicians as nonthinkers who worked in little more than an inferior and crude manual craft. It was becoming increasingly evident that research models, theoretical concepts, and valid clinical applications would be necessary to demonstrate the scientific basis of surgery to a wary public. The effort to devise new operative methods called for an even greater reliance on experimental surgery and its absolute encouragement by all concerned parties. Most importantly, a scientific basis for therapeutic surgical recommendations— consisting of empirical data, collected and analyzed according to nationally and internationally accepted rules and set apart from individual authoritative assumptions—would have to be

History of Surgery Chapter 1 7

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FIGURE 1-6 Theodor Kocher (1841-1917). FIGURE 1-7 William Halsted (1852-1922).

developed. In contrast to previously unexplainable doctrines, scientific research would triumph as the final arbiter between valid and invalid surgical therapies. In turn, surgeons had no choice but to allay society’s fear of the surgical unknown by presenting surgery as an accepted part of a newly established medical armamentarium. This would not be an easy task. The immediate consequences of surgical operations, such as discomfort and associated complications, were often of more concern to patients than the positive knowledge that an operation could eliminate potentially devastating disease processes. Accordingly, the most consequential achievement by surgeons during the early 20th century was ensuring the social acceptability of surgery as a legitimate scientific endeavor and the surgical operation as a therapeutic necessity. Ascent of Scientific Surgery William Stewart Halsted (1852-1922), more than any other surgeon, set the scientific tone for this most important period in surgical history (Fig. 1-7). He moved surgery from the melodramatics of the 19th-century operating theater to the starkness and sterility of the modern operating room, commingled with the privacy and soberness of the research laboratory. As professor of surgery at the newly opened Johns Hopkins Hospital and School of Medicine, Halsted proved to be a complex personality, but the impact of this aloof and reticent man would become widespread. He introduced a new surgery and showed that research based on anatomic, pathologic, and physiologic principles and the use of animal experimentation made it possible to develop sophisticated operative procedures and perform them clinically with outstanding results. Halsted proved, to an often leery profession and public, that an unambiguous sequence could be constructed from the laboratory of basic surgical research to the clinical operating room. Most importantly, for surgery’s own self-respect, he demonstrated during this turn of

the century renaissance in medical education that departments of surgery could command a faculty whose stature was equal in importance and prestige to that of other more academic or research-oriented fields, such as anatomy, bacteriology, biochemistry, internal medicine, pathology, and physiology. As a single individual, Halsted developed and disseminated a different system of surgery so characteristic that it was termed a school of surgery. More to the point, Halsted’s methods revolutionized the world of surgery and earned his work the epithet “halstedian principles,” which remains a widely acknowledged and accepted scientific imprimatur. Halsted subordinated technical brilliance and speed of dissection to a meticulous and safe, albeit sometimes slow performance. As a direct result, Halsted’s effort did much to bring about surgery’s self-sustaining transformation from therapeutic subservience to clinical necessity. Despite his demeanor as a professional recluse, Halsted’s clinical and research achievements were overwhelming in number and scope. His residency system of training surgeons was not merely the first such program of its type—it was unique in its primary purpose. Above all other concerns, Halsted desired to establish a school of surgery that would eventually disseminate throughout the surgical world the principles and attributes that he considered sound and proper. His aim was to train able surgical teachers, not merely competent operating surgeons. There is little doubt that Halsted achieved his stated goal of producing “not only surgeons but surgeons of the highest type, men who will stimulate the first youth of our country to study surgery and to devote their energies and their lives to raising the standards of surgical science.” So fundamental were his contributions that without them, surgery might never have fully developed and could have remained mired in a quasiprofessional state. The heroic and dangerous nature of surgery seemed appealing in less scientifically sophisticated times, but now surgeons

8 SECTION I SURGICAL BASIC PRINCIPLES were courted for personal attributes beyond their unmitigated technical boldness. A trend toward hospital-based surgery was increasingly evident, in equal parts resulting from new, technically demanding operations and modern hospital physical structures within which surgeons could work more effectively. The increasing complexity and effectiveness of aseptic surgery, diagnostic necessity of the x-ray and clinical laboratory, convenience of 24-hour nursing, and availability of capable surgical residents living within a hospital were making the hospital operating room the most plausible and convenient place for a surgical operation to be performed. It was obvious to both hospital superintendents and the whole of medicine that acute care institutions were becoming a necessity, more for the surgeon than for the physician. As a consequence, increasing numbers of hospitals went to great lengths to supply their surgical staffs with the finest facilities in which to complete operations. For centuries, surgical operations had been performed under the illumination of sunlight, candles, or both. Now, however, electric lights installed in operating rooms offered a far more reliable and unwavering source of illumination. Surgery became a more proficient craft because surgical operations could be completed on stormy summer mornings, as well as on wet winter afternoons. Internationalization, Surgical Societies, and Journals As the sophistication of surgery grew, internationalization became one of its underlying themes, with surgeons crossing the great oceans to visit and learn from one another. Halsted and Hermann Küttner (1870-1932), director of the surgical clinic in Breslau, Germany (now known as Wroclaw and located in southwestern Poland), instituted the first known official exchange of surgical residents in 1914. This experiment in surgical education was meant to underscore the true international spirit that had engulfed surgery. Halsted firmly believed that young surgeons achieved greater clinical maturity by observing the practice of surgery in other countries, as well as in their own. An inevitable formation of national and international surgical societies and the emergence and development of periodicals devoted to surgical subjects proved to be important adjuncts to the professionalization process of surgery. For the most part, professional societies began as a means of providing mutual improvement via personal interaction with surgical peers and the publication of presented papers. Unlike surgeons of earlier centuries, who were known to guard so-called trade secrets closely, members of these new organizations were emphatic about publishing transactions of their meetings. In this way, not only would their surgical peers read of their clinical accomplishments, but a written record was also established for circulation throughout the world of medicine. The first of these surgical societies was the Académie Royale de Chirurgie in Paris, with its Mémoires appearing sporadically from 1743 through 1838. Of 19th century associations, the most prominent published proceedings were the Mémoires and Bulletins of the Société de Chirurgie of Paris (1847), the Verhandlungen of the Deutsche Gesellschaft für Chirurgie (1872), and the Transactions of the American Surgical Association (1883). No surgical association that published professional reports existed in 19th century Great Britain, and the Royal Colleges of Surgeons of England, Ireland, and Scotland never undertook such projects. Although textbooks, monographs, and treatises

had always been the mainstay of medical writing, the introduction of monthly journals, including August Richter’s (1742-1812) Chirurgische Bibliothek (1771), Joseph Malgaigne’s (1806-1865) Journal de Chirurgie (1843), Bernard Langenbeck’s (1810-1887) Archiv für Klinische Chirurgie (1860), and Lewis Pilcher’s (1844-1917) Annals of Surgery (1885), had a tremendous impact on updating and continuing the education of surgeons. World War I Austria-Hungary and Germany continued as the dominant forces in world surgery until World War I. However, results of the conflict proved disastrous to the central powers (AustriaHungary, Bulgaria, Germany, and the Ottoman Empire), especially to German-speaking surgeons. Europe took on a new social and political look, with the demise of Germany’s status as the world leader in surgery a sad but foregone conclusion. As with most armed conflicts, because of the massive human toll, especially battlefield injuries, tremendous strides were made in multiple areas of surgery. Undoubtedly, the greatest surgical achievement was in the treatment of wound infection. Trench warfare in soil contaminated by decades of cultivation and animal manure made every wounded soldier a potential carrier of any number of pathogenic bacilli. On the battlefront, sepsis was inevitable. Most attempts to maintain aseptic technique proved inadequate, but the treatment of infected wounds by antisepsis was becoming a pragmatic reality. Surgeons experimented with numerous antiseptic solutions and various types of surgical dressing. A principle of wound treatment entailing débridement and irrigation eventually evolved. Henry Dakin (1880-1952), an English chemist, and Alexis Carrel (1873-1944; Fig. 1-8), the Nobel prize–winning French American surgeon, were the principal protagonists in the development of this extensive system of wound management. In addition to successes in wound sterility, surgical advances were made in the use of x-rays in the diagnosis of battlefield injuries, and remarkable operative ingenuity was evident in

FIGURE 1-8 Alexis Carrel (1873-1944).

History of Surgery Chapter 1 9

American College of Surgeons 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 and influential of these societies was the American College of Surgeons, founded in 1913 by Franklin Martin (1857-1935), a Chicago-based gynecologist. 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 graduate in medicine who practiced in surgery and conferred the designation Fellow of the American College of Surgeons (FACS) on its members. From the outset, its primary aim was the continuing education of surgical physicians. Accordingly, the requirements for fellowship were always related to the educational opportunities of the period. In 1914, an applicant had to be a licensed graduate of medicine, receive the backing of three fellows, and be endorsed by the local credentials committee. In view of the stipulated peer recommendations, many physicians, realistically or not, viewed the American College of Surgeons as an elitist organization. With an obvious so-called blackball system built into the membership requirements, there was a difficult to deny belief that many surgeons who were immigrants, females, or members of particular religious and racial minorities were granted fellowships sparingly. Such inherent bias, in addition to questionable accusations of fee splitting along with unbridled contempt of certain surgeons’ business practices, resulted in some very prominent American surgeons never being permitted the privilege of membership. The 1920s and beyond proved to be a prosperous time for American society and its surgeons. After all, the history of world surgery in the 20th century is more a tale of American triumphs than it ever was in the 18th or 19th centuries. Physicians’ incomes dramatically increased and surgeons’ prestige, aided by the ever-mounting successes of medical science, became securely established in American culture. Still, a noticeable lack of standards and regulations in surgical specialty practice became a serious concern to leaders in the profession. The difficulties of World War I had greatly accentuated this realistic need for specialty standards, when many of the physicians who were selfproclaimed surgical specialists were found to be unqualified by military examining boards. In ophthalmology, for example, more than 50% of tested individuals were deemed unfit to treat diseases of the eye. It was an unmistakable reality that there were no established criteria with which to distinguish a well-qualified ophthalmologist from an upstart optometrist or to clarify the differences in clinical expertise between a well-trained, full-time ophthalmologic specialist and an inadequately trained, part-time general physician–ophthalmologist. In recognition of the gravity of the situation, the self-patrolling concept of a professional examining board, sponsored by leading voluntary ophthalmologic organizations, was proposed as a mechanism for certifying competency. In 1916, uniform standards and regulations were set forth in the form of minimal educational requirements and written and oral examinations, and the American Board for Ophthalmic Examinations, the country’s first, was formally incorporated. By 1940, six additional surgical specialty boards were established—orthopedic (1934), colon and rectal (1934),

urologic (1935), plastic (1937), surgical (1937), and neurologic (1940). As order was introduced into surgical specialty training and the process of certification matured, it was apparent that the continued growth of residency programs carried important implications for the future structure of medical practice and the social relationship of medicine to overall society. Professional power had been consolidated, and specialization, which had been evolving since the time of the Civil War, was now recognized as an essential, if not integral, part of modern medicine. Although the creation of surgical specialty boards was justified under the broad imprimatur of raising the educational status and evaluating the clinical competency of specialists, board certification undeniably began to restrict entry into the specialties. As the specialties evolved, the political influence and cultural authority enjoyed by the profession of surgery were growing. This socioeconomic strength was most prominently expressed in reform efforts directed toward the modernization and standardization of America’s hospital system. Any vestiges of so-called kitchen surgery had essentially disappeared, and other than numerous small private hospitals predominantly constructed by surgeons for their personal use, the only facilities in which major surgery could be adequately conducted and postoperative patients appropriately cared for were the well-equipped and physically impressive modern hospitals. Thus, the American College of Surgeons and its expanding list of fellows had a strong motive to ensure that America’s hospital system was as up to date and efficient as possible. On an international level, surgeons were confronted with the lack of any formal organizational body. Not until the International College of Surgeons was founded in 1935 in Geneva would such a society exist. At its inception, this organization was intended to serve as a liaison to the existing colleges and surgical societies in the various countries. However, its goals of elevating the art and science of surgery, creating greater understanding among the surgeons of the world, and affording a means of international postgraduate study never came to full fruition, in part because the American College of Surgeons adamantly opposed the establishment—and continues to do so—of a viable American chapter of the International College of Surgeons. Women Surgeons One of the many overlooked areas of surgical history concerns the involvement of women. Until recent times, women’s options for obtaining advanced surgical training were severely restricted. The major reason was that through the mid-20th century, only a handful of women had performed enough surgery to become skilled mentors. Without role models and with limited access to hospital positions, the ability of the few practicing female physicians to specialize in surgery seemed an impossibility. Consequently, women surgeons were forced to use different career strategies than men and to have more divergent goals of personal success to achieve professional satisfaction. Despite these difficulties, and through the determination and aid of several enlightened male surgeons, most notably William Byford (1817-1890) of Chicago and William Keen of Philadelphia, a small cadre of female surgeons did exist in late 19th century America. Mary Dixon Jones (1828-1908), Emmeline Horton Cleveland (1829-1878), Mary Harris Thompson (1829-1895), Anna Elizabeth Broomall (1847-1931), and Marie Mergler

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reconstructive facial surgery and the treatment of fractures resulting from gunshot wounds.

10 SECTION I SURGICAL BASIC PRINCIPLES

FIGURE 1-9 Olga Jonasson (1934-2006). (Courtesy University of Illinois, Chicago.)

(1851-1901) would act as a nidus toward greater gender equality in 20th century surgery. Olga Jonasson (1934-2006; Fig. 1-9), a pioneer in the field of clinical transplantation, played a leading role in encouraging women to enter the modern, maledominated world of surgery. In 1987, when she was named chair of the department of surgery at Ohio State University College of Medicine, Jonasson became the first woman in the United States to head an academic surgery department at a coeducational medical school. African American Surgeons There is little disputing the fact that both gender and racial bias have influenced the evolution of surgery. Every aspect of society is affected by such discrimination, and African Americans, like women, were innocent victims of injustices that forced them into never-ending struggles to attain competency in surgery. As early as 1868, a department of surgery was established at Howard University. However, the first three chairmen were all white Anglo-Saxon Protestants. Not until Austin Curtis was appointed professor of surgery in 1928 did the department have its first African American head. Like all black physicians of his era, he was forced to train at so-called Negro hospitals, in Curtis’ case Provident Hospital in Chicago, where he came under the tutelage of Daniel Hale Williams (1858-1931), the most influential and highly regarded of early African American surgeons. In 1897, Williams received considerable notoriety when he reported successful suturing of the pericardium for a stab wound of the heart. With little likelihood of obtaining membership in the American Medical Association or its related societies, African American physicians joined together in 1895 to form the National Medical Association. Black surgeons identified an even more specific need when the Surgical Section of the

FIGURE 1-10 Charles Drew (1904-1950).

National Medical Association was opened in 1906. These National Medical Association surgical clinics, which preceded the Clinical Congress of Surgeons of North America, the forerunner to the annual congress of the American College of Surgeons by almost half a decade, represented the earliest examples of organized, so-called “show me” surgical education in the United States. Admittance to surgical societies and attainment of specialty certification were important social and psychological accomplishments for early African American surgeons. When Daniel Williams was named a Fellow of the American College of Surgeons in 1913, the news spread rapidly throughout the African American surgical community. Still, African American surgeons’ fellowship applications were often acted on rather slowly, which suggests that denials based on race were clandestinely conducted throughout much of the country. As late as the mid-1940s, Charles Drew (1904-1950; Fig. 1-10), chairman of the department of surgery at Howard University School of Medicine, acknowledged that he refused to accept membership in the American College of Surgeons because this so-called nationally representative surgical society had, in his opinion, not yet begun to accept capable and well-qualified African American surgeons freely. Claude H. Organ, Jr. (1926-2005; Fig. 1-11), was a distinguished editor, educator, and historian. Among his books, the two-volume A Century of Black Surgeons: The U.S.A. Experience and the authoritative Noteworthy Publications by AfricanAmerican Surgeons underscored the numerous contributions made by African American surgeons to the nation’s health care system. In addition, as the long-standing editor-in-chief of Archives of Surgery, as well as serving as president of the American College of Surgeons and chairman of the American Board of Surgery, Organ wielded enormous influence over the direction of American surgery.

History of Surgery Chapter 1 11

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FIGURE 1-11 Claude H. Organ, Jr. (1926-2005). (Courtesy the American College of Surgeons, Chicago, and Dr. James C. Thompson.)

FIGURE 1-12 Alfred Blalock (1899-1964).

MODERN ERA Despite the global economic depression in the aftermath of World War I, the 1920s and 1930s signaled the ascent of American surgery to its current position of international leadership. Highlighted by educational reforms in its medical schools, Halsted’s redefinition of surgical residency programs, and the growth of surgical specialties, the stage was set for the blossoming of scientific surgery. Basic surgical research became an established reality as George Crile (1864-1943), Alfred Blalock (1899-1964; Fig. 1-12), Dallas Phemister (1882-1951), and Charles Huggins (1901-1997) became world-renowned surgeon-scientists. Much as the ascendancy of the surgeon-scientist brought about changes in the way in which the public and profession viewed surgical research, the introduction of increasingly sophisticated technologies had an enormous impact on the practice of surgery. Throughout the evolution of surgery, the practice of surgery—the art, the craft and, finally, the science of working with one’s hands—had largely been defined by its tools. From the crude flint instruments of ancient peoples, through the simple tonsillotomes and lithotrites of the 19th century, up to the increasingly complex surgical instruments developed in the 20th century, new and improved instruments usually led to a better surgical result. Progress in surgical instrumentation and surgical techniques went hand in hand. Surgical techniques would, of course, become more sophisticated with the passage of time but, by the conclusion of World War II, essentially all organs and areas of the body had been fully explored. In fact, within a short half-century, the domain of surgery had become so well established that the profession’s

foundation of basic operative procedures was already completed. As a consequence, there were few technical surgical mysteries left. What surgery now needed to sustain its continued growth was the ability to diagnose surgical diseases at an earlier stage, locate malignant growths while they remained small, and have more effective postoperative treatment so that patients could survive ever more technically complex operations. Such thinking was exemplified by the introduction of cholecystography in 1924 by Evarts Graham (1883-1957) and Warren Cole (1898-1990). In this case, an emerging scientific technology introduced new possibilities into surgical practice that were not necessarily related solely to improvements in technique. To the surgeon, the discovery and application of cholecystography proved most important, not only because it brought about more accurate diagnoses of cholecystitis but also because it created an influx of surgical patients where few had previously existed. If surgery was to grow, large numbers of individuals with surgical diseases were needed. It was an exciting era for surgeons, with important clinical advances being made in the operating room and basic science laboratory. Among the most notable highlights were the introduction in 1935 of pancreaticoduodenectomy for cancer of the pancreas by Allen Oldfather Whipple (1881-1963) and a report in 1943 on vagotomy for the operative treatment of peptic ulcer disease by Lester Dragstedt (1893-1976). Other significant advances included the following:

12 SECTION I SURGICAL BASIC PRINCIPLES • Frank Lahey (1880-1953) stressed the importance of identifying the recurrent laryngeal nerve during the course of thyroid surgery. • Owen Wangensteen (1898-1981) successfully decompressed mechanical bowel obstructions by using a newly devised suction apparatus in 1932. • George Vaughan (1859-1948) successfully ligated the abdominal aorta for aneurysmal disease in 1921. • Max Peet (1885-1949) presented splanchnic resection for hypertension in 1935. • Walter Dandy (1886-1946) performed intracranial section of various cranial nerves in the 1920s. • Walter Freeman (1895-1972) described prefrontal lobotomy as a means of treating various mental illnesses in 1936. • Harvey Cushing (1869-1939) introduced electrocoagulation in neurosurgery in 1928. • Marius Smith-Petersen (1886-1953) described a flanged nail for pinning a fracture of the neck of the femur in 1931 and introduced Vitallium cup arthroplasty in 1939. • Vilray Blair (1871-1955) and James Brown (18991971) popularized the use of split-skin grafts to cover large areas of granulating wounds. • Earl Padgett (1893-1946) devised an operative dermatome that allowed calibration of the thickness of skin grafts in 1939. • Elliott Cutler (1888-1947) performed a successful section of the mitral valve for relief of mitral stenosis in 1923. • Evarts Graham completed the first successful removal of an entire lung for cancer in 1933. • Claude Beck (1894-1971) implanted pectoral muscle into the pericardium and attached a pedicled omental graft to the surface of the heart, thus providing collateral circulation to that organ, in 1935. • Robert Gross (1905-1988) reported the first successful ligation of a patent arterial duct in 1939 and resection for coarctation of the aorta with direct anastomosis of the remaining ends in 1945. • John Alexander (1891-1954) resected a saccular aneurysm of the thoracic aorta in 1944. With such a wide variety of technically complex surgical operations now possible, it had clearly become impossible for any single surgeon to master all the manual skills and pathophysiologic knowledge necessary to perform such cases. Therefore, by the middle of the century, a consolidation of professional power inherent in the movement toward specialization, with numerous individuals restricting their surgical practice to one highly structured field, had become among the most significant and dominating events in 20th century surgery. Ironically, the United States, which had been much slower than European countries to recognize surgeons as a distinct group of clinicians separate from physicians, would now spearhead this move toward surgical specialization with great alacrity. Clearly, the course of surgical fragmentation into specialties and subspecialties was gathering tremendous speed as the dark clouds of World War II settled over the world. The socioeconomic and political ramifications of this war would bring about a fundamental change in the way that surgeons viewed themselves and their interactions with the society in which they lived and worked.

Last Half of the 20th Century The decades of economic expansion after World War II had a dramatic impact on surgery’s scale, particularly in the United States. It was as though being victorious in battle permitted medicine to become big business overnight, with the singleminded pursuit of health care rapidly transformed into society’s largest growth industry. Spacious hospital complexes were built that not only represented the scientific advancement of the healing arts, but also vividly demonstrated the strength of American’s postwar socioeconomic boom. Society was willing to give surgical science unprecedented recognition as a prized national asset. The overwhelming impact of World War II on surgery was the sudden expansion of the profession and the beginnings of an extensive distribution of surgeons throughout the country. Many of these individuals, newly baptized to the rigors of technically complex trauma operations, became leaders in the construction and improvement of hospitals, multispecialty clinics, and surgical facilities in their home towns. Large urban and community hospitals established surgical education and training programs and found it relatively easy to attract interns and residents. For the first time, residency programs in general surgery were rivaled in growth and educational sophistication by those in all the special fields of surgery. These changes served as fodder for further increases in the number of students entering surgery. Not only would surgeons command the highest salaries, but society was also enamored of the drama of the operating room. Television series, movies, novels, and the more than occasional live performance of a heart operation broadcast on a network beckoned the lay individual. Despite lay approval, success and acceptability in the biomedical sciences are sometimes difficult to determine, but one measure of both in recent times has been awarding of the Nobel Prize in medicine and physiology. Society’s continued approbation of surgery’s accomplishments can be seen in the naming of nine surgeons as Nobel laureates (Table 1-1). Cardiac Surgery and Organ Transplantation Two clinical developments truly epitomized the magnificence of post–World War II surgery and concurrently fascinated the public—the maturation of cardiac surgery as a new surgical specialty and the emergence of organ transplantation. Together, they would stand as signposts along the new surgical highway. Fascination with the heart goes far beyond that of clinical medicine. From the historical perspective of art, customs, literature, philosophy, religion, and science, the heart has represented the seat of the soul and the wellspring of life itself. Such reverence also meant that this noble organ was long considered a surgical untouchable. The late 19th and 20th centuries witnessed a steady march of surgical triumphs in opening successive cavities of the body, but the final achievement awaited the perfection of methods for surgical operations in the thoracic space. Such a scientific and technologic accomplishment can be traced back to the repair of cardiac stab wounds by direct suture and the earliest attempts at fixing faulty heart valves. As triumphant as Luther Hill’s (1862-1946) first known successful suture of a wound that penetrated a cardiac chamber was in 1902, it would not be until the 1940s that the development of safe intrapleural surgery could be counted on as something other than an occasional event. During World War II, Dwight Harken (1910-1993) gained extensive battlefield experience in removing

History of Surgery Chapter 1 13

SURGEON

COUNTRY

FIELD (YEAR OF AWARD)

Theodor Kocher (1841-1917)

Switzerland

Thyroid disease (1909)

Allvar Gullstrand (1862-1930)

Sweden

Ocular dioptrics (1911)

Alexis Carrel (1873-1944)

France and United States

Vascular surgery (1912)

Robert Bárány (1876-1936)

Austria

Vestibular disease (1914)

Frederick Banting (1891-1941)

Canada

Insulin (1922)

Walter Hess (1881-1973)

Switzerland

Midbrain physiology (1949)

Werner Forssmann (1904-1979)

Germany

Cardiac catheterization (1956)

Charles Huggins (1901-1997)

United States

Oncology (1966)

Joseph Murray (1919-)

United States

Organ transplantation (1990)

bullets and shrapnel in or in relation to the heart and great vessels without a single fatality. Building on his wartime experience, Harken and other pioneering surgeons, including Charles Bailey (1910-1993) of Philadelphia and Russell Brock (1903-1980) of London, proceeded to expand intracardiac surgery by developing operations for the relief of mitral valve stenosis. The procedure was progressively refined and evolved into the open commissurotomy repair used today. Despite mounting clinical successes, surgeons who operated on the heart had to contend not only with the quagmire of blood flowing through an area in which difficult dissection was taking place, but also with the unrelenting to and fro movement of a beating heart. Technically complex cardiac repair procedures could not be developed further until these problems were solved. John Gibbon (1903-1973; Fig. 1-13) addressed this enigma by devising a machine that would take on the work of the heart and lungs while the patient was under anesthesia, in essence pumping oxygen-rich blood through the circulatory system while bypassing the heart so that the organ could be operated on at leisure. The first successful open heart operation in 1953, conducted with the use of a heart-lung machine, was a momentous surgical contribution. Through single-mindedness of purpose, Gibbon’s research paved the way for all future cardiac surgery, including procedures for correction of congenital heart defects, repair of heart valves, revascularization operations, and heart transplantation. David Sabiston (1924-2009; Fig. 1-14) was an inspirational surgical leader who served 30 years as chairman of the department of surgery at Duke University. Trained under Alfred Blalock at Johns Hopkins, Sabiston performed early and innovative coronary artery bypass operations that paved the way for more effective cardiac surgery procedures. Sabiston assumed numerous leadership roles throughout his career, including President of the American College of Surgeons, the American Surgical Association, and the American Association for Thoracic Surgery. As an eminent editor-in-chief, he guided the Annals of Surgery for 25 years and oversaw six previous editions of this text, the legendary Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. Michael DeBakey (1908-2008; Fig. 1-15) was a renowned cardiac and vascular surgeon, clinical researcher, medical educator, and international medical statesman, who was the long-time Chancellor of Baylor College of Medicine and senior attending surgeon of the Methodist Hospital in Houston. He pioneered the use of Dacron grafts to replace or repair blood vessels, invented the

FIGURE 1-13 John Gibbon (1903-1973).

roller pump, developed ventricular assist devices, was among the first to perform a coronary artery bypass and carotid endarterectomy, demonstrated the link between cigarette smoking and lung cancer, and created an early version of what became the mobile army surgical hospital or MASH unit. DeBakey was an influential advisor to the federal government about health care policy and served as chairman of the President’s Commission on Heart Disease, Cancer, and Stroke during the Johnson administration. Among DeBakey’s numerous honors were the Presidential Medal of Freedom, Congressional Gold Medal, and Lasker Clinical Medical Research Award.

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Table 1-1 Nobel Laureate Surgeons in Medicine and Physiology

14 SECTION I SURGICAL BASIC PRINCIPLES

FIGURE 1-14 David Sabiston (1924-2009). (From Anderson R: David C. Sabiston, Jr, MD. J Thorac Cardiovasc Surg 137:1307–1308, 2009.)

FIGURE 1-15 Michael DeBakey (1908-2008). (Courtesy Baylor College of Medicine, Houston.)

Since time immemorial, the focus of surgery was mostly on excision and repair. However, beginning in the 20th century, the opposite end of the surgical spectrum—reconstruction and transplantation—became realities. Experience in the 19th century had shown that skin and bone tissues could be autotransplanted from one site to another in the same patient. It would take the horrendous and mutilating injuries of World War I to advance skin transplantation decisively and legitimize the concept of surgery as a method of reconstruction. With Harold Gillies (1882-1960) of England and Vilray Blair of the United States establishing military-based plastic surgery units to deal with complex maxillofacial injuries, a turning point in the way in which society viewed surgery’s raison d’être occurred. Now,

not only would surgeons enhance nature’s healing powers, but they could also dramatically alter what had previously been little more than one’s physical foregone conclusion. For example, Hippolyte Morestin (1869-1919) described a method of mammaplasty in 1902. John Staige Davis (1872-1946) of Baltimore popularized a manner of splinting skin grafts and later wrote the first comprehensive textbook on this new specialty, Plastic Surgery: Its Principles and Practice (1919). Immediately after the war, Blair would go on to establish the first separate plastic surgery service in a civilian institution at Barnes Hospital in St. Louis. Vladimir Filatov (1875-1956) of Odessa, Russia, used a tubed pedicle flap in 1916 and, in the following year, Gillies introduced a similar technique. What about the replacement of damaged or diseased organs? After all, even in the mid-20th century, the very thought of successfully transplanting worn-out or unhealthy body parts verged on scientific fantasy. At the beginning of the 20th century, Alexis Carrel had developed revolutionary new suturing techniques to anastomose the smallest of blood vessels. Using his surgical élan on experimental animals, Carrel began to transplant kidneys, hearts, and spleens. Technically, his research was a success, but some unknown biologic process always led to rejection of the transplanted organ and death of the animal. By the middle of the century, medical researchers had begun to clarify the presence of underlying defensive immune reactions and the necessity of creating immunosuppression as a method to allow the host to accept the foreign transplant. Using highpowered immunosuppressant drugs and other modern modalities, kidney transplantation soon blazed the way, and it was not long before many organs and even hands and faces were being replaced. Political and Socioeconomic Influences Despite the 1950s and 1960s witnessing some of the most magnificent advances in the history of surgery, political and socioeconomic influences were starting to overshadow many of the clinical triumphs by the 1970s. It was the beginning of a schizophrenic existence for surgeons in that complex and dramatic lifesaving operations were completed to innumerable accolades whereas concurrently public criticism of the economics of medicine, in particular, high-priced surgical practice, portrayed the scalpel holder as a greedy, financially driven, selfish individual. This was in stark contrast to the relatively selfless and sanctified image of the surgeon before the growth of specialty work and the introduction of government involvement in health care delivery. Although they are philosophically inconsistent, the dramatic and theatrical features of surgery that make surgeons heroes from one perspective and symbols of corruption, mendacity, and greed from the opposite point of view are the very reasons why society demands so much of its them. There is the precise and definitive nature of surgical intervention, expectation of success that surrounds an operation, short time frame in which outcomes are realized, high income levels of most surgeons, and almost insatiable inquisitiveness of lay individuals about all aspects of the act of consensually cutting into another human’s flesh. These phenomena, ever more sensitized in this age of mass media and instantaneous telecommunication, make surgeons seem more accountable than their medical colleagues and, simultaneously, symbolic of the best and worst in medicine. In ways that were previously unimaginable, this vast social

History of Surgery Chapter 1 15

20TH CENTURY SURGICAL HIGHLIGHTS Among the difficulties in studying 20th century surgery is the abundance of famous names and important written contributions—so much so that it becomes a difficult and invidious task to attempt any rational selection of representative personalities along with their significant writings. Although many justly famous names might be missing, the following description of surgical advances is intended to highlight some of the stunning clinical achievements of the past century chronologically. In 1900, the German surgeon Hermann Pfannenstiel (1862-1909) described his technique for a suprapubic surgical incision. That same year, William Mayo (1861-1939) presented his results on partial gastrectomy before the American Surgical Association. The treatment of breast cancer was radically altered when George Beatson (1848-1933), professor of surgery in Glasgow, proposed oophorectomy and the administration of thyroid extract as a possible cure (1901). John Finney (1863-1942) of the Johns Hopkins Hospital authored a paper on a new method of gastroduodenostomy, or widened pyloroplasty (1903). In Germany, Fedor Krause (1856-1937) was writing about total cystectomy and bilateral ureterosigmoidostomy. In 1905, Hugh Hampton Young (1870-1945) of Baltimore was presenting early studies of his radical prostatectomy for carcinoma. William Handley (1872-1962) was surgeon of the Middlesex Hospital in London when he authored Cancer of the Breast and Its Treatment (1906). In that work, he advanced the theory that in breast cancer, metastasis is caused by extension along lymphatic vessels and not by dissemination via the bloodstream. That same year, José Goyanes (1876-1964) of Madrid used vein grafts to restore arterial flow. William Miles (1869-1947) of England first wrote about his technique of abdominoperineal resection in 1908, the same year that Friedrich Trendelenburg (1844-1924) attempted pulmonary embolectomy. Martin Kirschner (1879-1942) of Germany described a wire for skeletal traction and for stabilization of bone fragments or joint immobilization 3 years later. Donald Balfour (1882-1963) of the Mayo Clinic provided the initial account of his important operation for resection of the sigmoid colon, as did William Mayo for his radical operation for carcinoma of the rectum in 1910. In 1911, Fred Albee (1876-1945) of New York began to use living bone grafts as internal splints. Wilhelm Ramstedt (1867-1963), a German surgeon, described a pyloromyotomy (1912) at the same time that Pierre Fredet (1870-1946) was reporting a similar operation. In 1913, Henry Janeway (1873-1921) of New York developed a technique for gastrostomy in which he wrapped the anterior wall of the stomach around a catheter and sutured it in place, thereby establishing a permanent fistula. Hans Finsterer (1877-1955), professor of surgery in Vienna, improved on Franz von Hofmeister’s (1867-1926) description of a partial gastrectomy with closure of a portion of the lesser curvature and retrocolic anastomosis of the remainder of the stomach to the jejunum (1918). Thomas Dunhill (1876-1957) of London was a pioneer in thyroid surgery, especially in his operation for exophthalmic goiter

(1919). William Gallie (1882-1959) of Canada used sutures fashioned from the fascia lata in herniorrhaphy (1923). Barney Brooks (1884-1952), professor of surgery at Vanderbilt University in Nashville, Tennessee, initially introduced clinical angiography and femoral arteriography in 1924. Reynaldo dos Santos (1880-1970), a Portuguese urologist, reported the first translumbar aortogram 5 years later. Cecil Joll (1885-1945), professor of surgery in London, described the treatment of thyrotoxicosis by means of subtotal thyroidectomy in the 1930s. In 1931, George Cheatle (1865-1951), professor of surgery in London, and Max Cutler (1899-1984), a surgeon from New York, published their important treatise, Tumours of the Breast. In that same year, Cutler detailed his systemic use of ovarian hormone for the treatment of chronic mastitis. Around the same time, Ernst Sauerbruch (1875-1951) of Germany completed the first successful surgical intervention for cardiac aneurysm and his countryman, Rudolph Nissen (1896-1981), removed an entire bronchiectatic lung. Geoffrey Keynes (1887-1982) of St. Bartholomew’s Hospital in England articulated the basis for the opposition to radical mastectomy and his favoring of radium treatment for breast cancer (1932). The Irish surgeon Arnold Henry (1886-1962) devised an operative approach for femoral hernia in 1936. Earl Shouldice (1891-1965) of Toronto first began to experiment with a groin hernia repair based on overlapping layers brought together by a continuous wire suture during the 1930s. René Leriche (1879-1955) proposed an arteriectomy for arterial thrombosis in 1937 and, later, periarterial sympathectomy to improve arterial flow. Leriche also described a syndrome of aortoiliac occlusive disease in 1940. In 1939, Edward Churchill (1895-1972) of the Massachusetts General Hospital performed a segmental pneumonectomy for bronchiectasis. Charles Huggins (1901-1997; Fig. 1-16), a pioneer in endocrine therapy for cancer, found that antiandrogenic treatment consisting of orchiectomy or the administration of estrogens could produce long-term regression in patients with advanced prostatic cancer. These observations formed the basis for the current treatment of prostate and breast cancer by hormonal manipulation; Dr. Huggins was awarded the Nobel Prize in 1966 for these

FIGURE 1-16 Charles Huggins (1901-1997). (Used with permission from the University of Chicago Hospitals, Chicago.)

SECTION I SURGICAL BASIC PRINCIPLES

transformation of surgery controls the fate of the individual physician in the present era to a much greater extent than surgeons as a collective force can control it by their attempts to direct their own profession.

16 SECTION I SURGICAL BASIC PRINCIPLES

FIGURE 1-17 Francis D. Moore (1913-2001).

monumental discoveries. Clarence Crafoord (1899-1984) pioneered his surgical treatment of coarctation of the aorta in 1945. The following year, Willis Potts (1895-1968) completed an anastomosis of the aorta to a pulmonary vein for certain types of congenital heart disease. Chester McVay (1911-1987) popularized a repair of groin hernias based on the pectineal ligament in 1948. Working at Georgetown University Medical Center in Washington, DC, Charles Hufnagel (1916-1989) designed and inserted the first workable prosthetic heart valve in a man (1951). That same year, Charles Dubost (1914-1991) of Paris performed the first successful resection of an abdominal aortic aneurysm and insertion of a hom*ologous graft. Robert Zollinger (1903-1994) and Edwin Ellison (1918-1970) first described their eponymic polyendocrine adenomatosis in 1955. The following year, Donald Murray (1894-1976) completed the first successful aortic valve hom*ograft. At the same time, John Merrill (1917-1986) was performing the world’s first successful hom*otransplantation of the human kidney between identical twin brothers. Francis D. Moore (1913-2001; Fig. 1-17) defined objectives of metabolism in surgical patients and in 1959 published his widely quoted book, Metabolic Care of the Surgical Patient. Moore was also a driving force in the field of transplantation and pioneered the technique of using radioactive isotopes to locate abscesses and tumors. In the 1960s, Jonathan E. Rhoads (1907-2002; Fig. 1-18), in collaboration with colleagues Harry Vars and Stan Dudrick, described the technique of total parenteral nutrition, which has become an important and lifesaving treatment for the management of a critically ill patient who cannot tolerate standard enteral feedings. James D. Hardy (1918-2003), at the University of Mississippi, performed the first lung (1963) and heart (1964) transplants in a human. Judah

FIGURE 1-18 Jonathan Rhoads (1907-2002). (Courtesy Dr. James C. Thompson.)

FIGURE 1-19 Judah Folkman (1933-2008). (Courtesy Children’s Hospital, Boston.)

History of Surgery Chapter 1 17 Billings JS: The history and literature of surgery. In Dennis FS, editor: System of Surgery, vol 1, Philadelphia, 1895, Lea Brothers, pp 17– 144.

FUTURE TRENDS Throughout most of its evolution, the practice of surgery has been largely defined by its tools and the manual aspects of the craft. The last decades of the 20th century saw unprecedented progress in the development of new instrumentation and imaging techniques. These refinements have not come without noticeable social and economic cost. Advancement will assuredly continue because if the study of surgical history offers any lesson, it is that progress can always be expected, at least relative to technology. There will be more sophisticated surgical operations with better results. Eventually, automation may even robotize the surgeon’s hand for certain procedures. Still, the surgical sciences will always retain their historical roots as fundamentally a manually based art and craft. In many respects, the surgeon’s most difficult future challenges are not in the clinical realm but instead in better understanding the socioeconomic forces that affect the practice of surgery and in learning how to manage them effectively. Many splendid schools of surgery now exist in almost every major industrialized city, but none can lay claim to dominance in all the disciplines that comprise surgery. Similarly, the presence of authoritative individual personalities who help guide surgery is more unusual today than in previous times. National aims and socioeconomic status have become overwhelming factors in securing and shepherding the future growth of surgery worldwide. In light of an understanding of the intricacies of surgical history, it seems an unenviable and obviously impossible task to predict what will happen in the future. In 1874, John Erichsen (1818-1896) of London wrote that “the abdomen, chest, and brain will forever be closed to operations by a wise and humane surgeon.” A few years later, Theodor Billroth remarked that “A surgeon who tries to suture a heart wound deserves to lose the esteem of his colleagues.” Obviously, the surgical crystal ball is a cloudy one at best. To study the fascinating history of our profession, with its many magnificent personalities and outstanding scientific and social achievements, may not necessarily help us predict the future of surgery. However, it does shed much light on current clinical practices. To a certain extent, if surgeons in the future wish to be regarded as more than mere technicians, the profession needs to appreciate the value of its past experiences better. Surgery has a distinguished heritage that is in danger of being forgotten. Although the future of the art, craft, and science of surgery remains unknown, it assuredly rests on a glorious past.

Bishop WJ: The Early History of Surgery, London, 1960, Robert Hale.

SELECTED REFERENCES Allbutt TC: The Historical Relations of Medicine and Surgery to the End of the Sixteenth Century, London, 1905, Macmillan. An incisive and provocative address by the Regius Professor of Physics in the University of Cambridge concerning the sometimes strained relationships between early medical and surgical physicians.

Surgeon, hospital architect, originator of Index Medicus, and director of the New York Public Library, Billings has written a comprehensive review of surgery, albeit based on a hagiographic theme.

This book by Bishop, a distinguished medical bibliophile, is best for its description of surgery in the Middle Ages, the Renaissance, and 17th and 18th centuries.

Bliss M: Harvey Cushing, A Life in Surgery, New York, 2005, Oxford. Prized as a fascinating biography of one of America’s most influential surgeons. Bliss is a wonderful writer who provides an incisive and colorful description of surgery during the late 19th and early 20th centuries.

Cartwright FF: The Development of Modern Surgery from 1830, London, 1967, Arthur Barker. An anesthetist at King’s College Hospital in London, Cartwright has produced a work rich in detail and interpretation.

Cope Z: A History of the Acute Abdomen, London, 1965, Oxford University Press. Cope Z: Pioneers in Acute Abdominal Surgery, London, 1939, Oxford University Press. These two works by the highly regarded English surgeon provide overall reviews of the evolution of surgical intervention for intra-abdominal pathology.

Earle AS: Surgery in America: From the Colonial Era to the Twentieth Century, New York, 1983, Praeger. A fascinating compilation of journal articles by well-known surgeons that traces the development of the art and science of surgery in America.

Edmondson JM: American Surgical Instruments, San Francisco, 1997, Norman Publishing. Although a wealth of information is available about the practice of surgery and the men who performed it in colonial and 19th-century America, this book details the lost story of the instrument makers and dealers who supplied the all-important tools for these physicians.

Gurlt EJ: Geschichte der Chirurgie und ihrer Ausübung, 3 vols 1–3, Berlin, 1898, A. Hirschwald. A monumentally detailed history of surgery from the beginnings of recorded history to the end of the 16th century. Gurlt, a German surgeon, includes innumerable translations from ancient manuscripts. Unfortunately, this work has not been translated into English.

Hurwitz A, Degenshein GA: Milestones in Modern Surgery, New York, 1958, Hoeber-Harper.

SECTION I SURGICAL BASIC PRINCIPLES

Folkman (1933-2008; Fig. 1-19) was surgeon-in-chief at Children’s Hospital in Boston, where he devoted much of his time to basic science research. He was best known for his studies on angiogenesis, the process whereby a tumor forms blood vessels to nourish itself and grow. Folkman’s work led to antiangiogenesis therapy—the concept that cancers can be contained by using chemotherapeutic agents to inhibit their blood supply.

18 SECTION I SURGICAL BASIC PRINCIPLES

The numerous chapters by these surgical attending physicians at Maimonides Hospital in Brooklyn contain prefatory information, including a short biography of various surgeons (with portrait) and a reprinted or translated excerpt of each one’s most important surgical contribution.

Kirkup J: The Evolution of Surgical Instruments: An Illustrated History from Ancient Times to the Twentieth Century, Novato, Calif, 2006, Norman Publishing. Surgeons are often defined by their surgical armamentarium, and this treatise provides detailed discussions on the evolution of all manner of surgical instruments and the materials from which they are constructed.

Leonardo RA: History of Surgery, New York, 1943, Froben. Leonardo RA: Lives of Master Surgeons, New York, 1948, Froben. Leonardo RA: Lives of Master Surgeons, Supplement 1, New York, 1949, Froben. These texts by the eminent Rochester, New York, surgeon and historian together provide an in-depth description of the whole of surgery, from ancient times to the mid-20th century. Especially valuable are the countless biographies of famous and near-famous scalpel bearers.

Malgaigne JF: Histoire de la chirurgie en occident depuis de VIe jusqu’au XVIe siècle, et histoire de la vie et des travaux d’Ambroise Paré. In Malgaigne JF, editor: Ambroise Paré, oeuvres complètes, vol 1, introduction, Paris, 1840–1841, JB Baillière. This history by Malgaigne, considered among the most brilliant French surgeons of the 19th century, is particularly noteworthy for its study of 15th and 16th century European surgery. This entire work was admirably translated into English by Wallace Hamby, an American neurosurgeon, in Surgery and Ambrose Paré by JF Malgaigne (Norman, Oklahoma, 1965, University of Oklahoma Press).

Meade RH: An Introduction to the History of General Surgery, Philadelphia, 1968, WB Saunders. Meade RH: A History of Thoracic Surgery, Springfield, Ill, 1961, Charles C. Thomas. Meade, an indefatigable researcher of historical topics, practiced surgery in Grand Rapids, Michigan. With extensive bibliographies, his two books are among the most ambitious of such systematic works.

Porter R: The Greatest Benefit to Mankind, a Medical History of Humanity, New York, 1997, WW Norton. A wonderful literary tour de force by one of the most erudite and entertaining of modern medical historians. Although more a history of the whole of medicine than of surgery specifically, this text has become an instantaneous classic and should be required reading for all physicians and surgeons.

Ravitch MM: A Century of Surgery: 1880–1980, The History of the American Surgical Association, vols 1 and 2, Philadelphia, 1981, JB Lippincott. Ravitch, among the first American surgeons to introduce mechanical stapling devices for use in the United States, was highly regarded as a medical historian. This text provides a year by year account of the

meetings of the American Surgical Association, the most influential of America’s numerous surgical organizations.

Richardson, R: The Story of Surgery: An Historical Commentary, Shrewsbury, England, 2004, Quiller Press. An absorbing account of surgical triumphs written by a physician turned medical historian.

Rutkow IM: American Surgery, An Illustrated History, Philadelphia, 1998, Lippincott-Raven. Rutkow IM: Bleeding Blue and Gray: Civil War Surgery and the Evolution of American Medicine, New York, 2005, Random House. Rutkow IM: James A. Garfield, New York, 2006, Times Books/Henry Holt and Company. Rutkow IM: Seeking the Cure: A History of Medicine in America, New York, 2010, Scribner. Rutkow IM: Surgery, An Illustrated History, St. Louis, 1993, Mosby– Year Book. Rutkow IM: The History of Surgery in the United States, 1775–1900, vols 1 and 2, San Francisco, 1988 and 1992, Norman Publishing. Using biographic compilations, colored illustrations, and detailed narratives, these books explore the evolution of medicine and surgery, internationally and in the United States.

Schwartz S: Gifted Hands: America’s Most Significant Contributions to Surgery, Amherst, NY, 2009, Prometheus Books. A remarkably researched book that details the wide-ranging tale of American surgery’s rise to world eminence.

Thorwald J: The Century of the Surgeon, New York, 1956, Pantheon. Thorwald J: The Triumph of Surgery, New York, 1960, Pantheon. In a most dramatic literary fashion, Thorwald uses a fictional eyewitness narrator to create continuity in the story of the development of surgery during its most important decades of growth, the late 19th and early 20th centuries. Imbued with a myriad of true historical facts, these books are among the most enjoyable to be found within the genre of surgical history.

Wangensteen OH, Wangensteen SD: The Rise of Surgery, from Empiric Craft to Scientific Discipline, Minneapolis, 1978, University of Minnesota Press. Not a systematic history but an assessment of various operative techniques (e.g., gastric surgery, tracheostomy, ovariotomy, vascular surgery) and technical factors (e.g., débridement, phlebotomy, surgical amphitheater, preparations for surgery) that contributed to or retarded the evolution of surgery. Wangensteen was a noted teacher of experimental and clinical surgery at the University of Minnesota and his wife was an accomplished medical historian.

Zimmerman LM, Veith I: Great Ideas in the History of Surgery, Baltimore, 1961, Williams & Wilkins. Zimmerman, late professor of surgery at the Chicago Medical School, and Veith, a masterful medical historian, provide well-written biographic narratives to accompany numerous readings and translations from the works of almost 50 renowned surgeons of varying eras.

CHAPTER 2

ETHICS AND PROFESSIONALISM IN SURGERY Cheryl E. Vaiani and Howard Brody

the importance of ethics in surgery end-of-life care cultural sensitivity shared decision making professionalism conclusion

THE IMPORTANCE OF ETHICS IN SURGERY Although the ethical precepts of respect for persons, beneficence, nonmaleficence, and justice have been fundamental to the practice of medicine since ancient times, ethics has assumed an increasingly visible and codified position in health care over the past 50 years. The Joint Commission, the courts, presidential commissions, medical school and residency curriculum planners, professional organizations, the media, and the public have all grappled with determining the right course of action in health care matters. The explosion of medical technology and knowledge, changes in the organizational arrangement and financing of the health care system, and challenges to traditional precepts posed by the corporatization of medicine have all created new ethical questions. The practice of medicine or surgery is, at its center, a moral enterprise. Although clinical proficiency and surgical skill are crucial, so are the moral dimensions of a surgeon’s practice. According to sociologist Charles Bosk, the surgeon’s actions and patient outcome are more closely linked in surgery than in medicine, and that linkage dramatically changes the relationship between surgeon and patient.1 Surgeon and humanist Miles Little has suggested that there is a distinct moral domain within the surgeon-patient relationship. According to Little, “testing and negotiating the reality of the category of rescue, negotiating the inherent proximity of the relationship, revealing the nature of the ordeal, offering and providing support through its course, and being there for the other in the aftermath of the surgical encounter, are ideals on which to build a distinctively surgical ethics.”2 Because surgery is an extreme experience for the patient, surgeons have a unique opportunity to understand their patients’ stories and provide support for them. The virtue and duty of engaged presence as described by Little extends beyond a warm, friendly personality and can be taught by both precept and example. Although Little does not specifically identify trust as a component of presence, it seems inherent to the moral

depth of the surgeon-patient relationship. During surgery the patient is in a totally vulnerable position and a high level of trust is demanded for the patient to place his or her life directly in the surgeon’s hands. Such trust, in turn, requires that the surgeon strive to act always in a trustworthy manner. From the Hippocratic Oath to the 1847 American Medical Association statement of medical principles through the present, the traditional ethical precepts of the medical profession have included the primacy of patient welfare. The American College of Surgeons was founded in 1913 on the principles of highquality care for the surgical patient and the ethical and competent practice of surgery. The preamble to its Statement on Principles states the following3: The American College of Surgeons has had a deep and effective concern for the improvement of patient care and for the ethical practice of medicine. The ethical practice of medicine establishes and ensures an environment in which all individuals are treated with respect and tolerance; discrimination or harassment on the basis of age, sexual preference, gender, race, disease, disability, or religion, are proscribed as being inconsistent with the ideals and principles of the American College of Surgeons.

The Code of Professional Conduct continues4: As Fellows of the American College of Surgeons, we treasure the trust that our patients have placed in us, because trust is integral to the practice of surgery. During the continuum of pre-, intra-, and post operative care, we accept responsibilities to: • Serve as effective advocates of our patients’ needs. • Disclose therapeutic options, including their risks and benefits. • Disclose and resolve any conflict of interest that might influence decisions regarding care. • Be sensitive and respectful of patients, understanding their vulnerability during the perioperative period. • Fully disclose adverse events and medical errors. • Acknowledge patients’ psychological, social, cultural, and spiritual needs. • Encompass within our surgical care the special needs of terminally ill patients. • Acknowledge and support the needs of patients’ families. • Respect the knowledge, dignity, and perspective of other health care professionals.

20 SECTION I SURGICAL BASIC PRINCIPLES These same expectations are echoed in the Accreditation Council for Graduate Medical Education core competencies that medical-surgical training programs are expected to achieve: compassion, integrity, respect, and responsiveness that supersedes self-interest, accountability, and responsiveness to a diverse patient population.5 Historically, the surgeon’s decisions were often unilateral ones. Surgeons made decisions about medical benefit with little if any acknowledgment that patient benefit might be a different matter. Current surgical practice recognizes the patient’s increasing involvement in health care decision making and grants that the right to choose is shared between surgeon and patient. A focus on informed consent, confidentiality, and advance directives acknowledges this changed relationship of the surgeon and patient. However, the moral dimensions of a surgeon’s practice extend beyond those issues to ask how the conscientious, competent, ethical surgeon should reveal damaging mistakes to a family when they have occurred, balance the role of patient advocate with that of being a gatekeeper, handle a colleague who is too old or too impaired to operate safely, or think about surgical innovation. Jones and colleagues,6 in a helpful casebook of surgical ethics, have noted that even a matter as mundane as the order of patients in a surgical schedule may conceal important ethical decisions. END-OF-LIFE CARE Care of patients at the end of life has garnered increasing attention in recent years. The decade of the 1990s was characterized by the expansion of efforts to educate physicians and inculcate palliative care practices into medical institutions. Surgeons who often are best known for their ability to be decisive—to do something—began to recognize their role in appropriate end-oflife care and to develop standards for palliative surgical care. In February 1998, The American College of Surgeons approved “The Statement of Principles of Care at the End of Life,” which includes a responsibility to provide appropriate palliative and hospice care and respect a patient’s right to refuse treatment and the physician’s responsibility to forgo futile interventions.7 A Surgeons Palliative Care Workgroup met in 2000 to foster awareness, education, and research in palliative care. In the first of a series of articles concerning palliative care by the surgeon in the Journal of the American College of Surgeons, Dunn and Milch8 have explained that palliative care provides the surgeon with a “new opportunity to rebalance decisiveness with introspection, detachment with empathy.” They also suggested that although surgeons might appreciate cognitively the need for palliative care, it also presents surgeons with difficult emotional challenges and ambiguities. In recognition of his leadership in the areas of hospice and palliative care, Robert A. Milch received the inaugural Hastings Center Cunniff-Dixon Physician Award in 2010 for leadership in care near the end of life. Dr. Milch said, in accepting the award, that “to the extent that we are able to play a part in that wonder, helping to heal even when we cannot cure, tending the wounds of body and spirit, we are ourselves elevated and transformed.”9 Resuscitation in the Operating Room One of the most difficult issues in end-of-life care for the surgical patient concerns resuscitation. Informed decisions about cardiopulmonary resuscitation (CPR) require that patients have an accurate understanding of their diagnosis, prognosis,

likelihood of CPR’s success in their situation, and risks involved. Surgeons sometimes are reluctant to honor a patient’s request not to be resuscitated when the patient is considering an operative procedure. Patients with terminal illness may desire surgery for palliation, pain relief, or vascular access yet not desire resuscitation if they experience cardiac arrest. Both the American College of Surgeons and American Society of Anesthesiologists have rejected the unilateral suspension of orders not to resuscitate in surgery without a discussion with the patient, but some physicians believe that patients cannot have surgery without being resuscitated and view a DNR order as “as an unreasonable demand to lower the standard of care.”10 Providers may worry that an order to forgo CPR may be extended inappropriately to withholding other critical interventions, such as measures required to control bleeding and maintain blood pressure. They may also fear being prevented from resuscitating patients for whom the arrest is the result of a medical error. Discussions with the patient or surrogate about his or her goal for care and desires in various scenarios can help guide decision making. Such conversations allow a mutual decision that respects the patient’s autonomy and physician’s professional obligations. A patient who refuses resuscitation because the current health status is burdensome can clearly be harmed by intervening to resuscitate while in the operating room (OR). On the other hand, a patient who refuses because of the (presumed) low likelihood of success may change this decision once she or he understands the more favorable outcomes of intraoperative resuscitation.11 A physician can certainly choose to transfer the care of the patient to another physician if he or she is uncomfortable with the patient’s decision about interventions but should not impose this decision on the patient. CPR is not appropriate for every patient who has a cardiac or pulmonary arrest, even if that patient is in the operating room. Physicians need to develop skills in communicating accurate information about the risks and benefits of resuscitation with patients and families in light of the patient’s condition and prognosis, make this discussion a routine part of the plan of care, and develop an appropriate team relationship between the surgeon and anesthesiologist to implement the decision. CULTURAL SENSITIVITY Much has been said about the culture of surgery and the personality type of surgeons. The slogan “when in doubt, cut it out” is representative of the surgeon’s imperative to act. Harsh generalizations of surgeons as egotistical, having a “God complex,” and acting as playground bullies are frequent. As an oftenstereotyped specialty, surgeons should have an astute appreciation for the impact of culture in the clinical encounter. The interaction between the surgeon who recommends operative treatment, and the patient who believes that the pain is from a spiritual source and cannot be treated by surgery, is unlikely to go well unless the surgeon has the tools to understand and respect the patient’s cultural beliefs, values, and ways of doing things. Training for cultural competence in health care is an essential clinical skill in the increasingly diverse U.S. population and has been recognized and integrated into the current education of medical professionals. Strong evidence of racial and ethnic disparities in health care supports the critical need for such training. Patient-centered care must recognize culture as a major force in shaping an individual’s expectations of a

Ethics and Professionalism in Surgery Chapter 2 21

Beliefs about health: What caused your illness/problem? Explanation: Why did it happen at this time? Learn: Help me to understand your belief/opinion. Impact: How is this illness/problem impacting your life? Empathy: This must be very difficult for you. Feelings: How are you feeling about it? These models demand the skills of good listening, astute observation, and skillful communication used within the framework of respect and flexibility on the part of the physician. Bridging the cultural divide uses the same skills and traits that engender patient trust and satisfaction and improve quality of care. As Kleinman and associates16 have explained in a classic paper, BELIEF types of questions are excellent to ask during every patient encounter, and not only those with patients from markedly different cultures. They stress the usefulness of regarding every patient interaction as a type of cross-cultural experience. SHARED DECISION MAKING Ethically and legally, informed consent is at the heart of the relationship between the surgeon and patient. The term informed consent originated in the legal sphere and still conveys a sense of legalism and bureaucracy to many physicians. The term shared decision making has become more popular recently. It is, for all purposes, essentially synonymous with the idea of informed

consent, but suggests a clinical and educational context that most physicians find more congenial. Shared decision making is the process of educating the patient and assessing that he or she has understood and given permission for diagnostic or therapeutic interventions. The underlying ethical principle is respect for persons, or autonomy. Informed consent reflects the legal and ethical rights people have to make choices about what happens to their body in accordance with their values and goals and the ethical duty of the physician to enhance the patient’s well-being. There is no absolute formula for obtaining informed consent for a procedure, treatment plan, or therapy. A common error is to confuse the signing of a consent form with the process of informed consent. At best, the form is documentation that the process of shared decision making has occurred, not a substitute for that process. The process should include explanations from the physician in language the patient can understand and provide the opportunity for the patient to ask questions and consult with others, if necessary. Clarification of the patient’s understanding is an important part of the decision making process. Asking patients to explain in their own words what they expect to happen and possible outcomes is much more indicative of their understanding than the ability merely to repeat what the physician has stated (What do you understand about the surgery that has been recommended to you?). Ideally, the process allows the physician and patient to work together to choose a course of treatment using the physician’s expertise and the patient’s values and goals. Determining a patient’s capacity to participate in decision making is an important role of the physician and inherent in the process of informed consent. Although capacity is generally assumed in adult patients, there are numerous occasions when the capacity for decision making is questionable or absent. Illness, medication, and altered mental status may result in an inability to participate independently in medical decision making. Capacity for decision making occurs along a continuum, and the more serious the consequences of the decision, the higher the level of capacity that it is prudent to require. Decisional capacity may also change over time; an individual may be capable of medical decisions one day or even at a particular time of day, but not at another. Probably the most common reason for questioning a patient’s capacity is patient refusal of a treatment, procedure, or plan that the physician thinks is indicated. A patient’s refusal certainly raises a red flag and may be an appropriate indicator for an evaluation of capacity, but it should not be the only one. Determination of capacity should be an essential part of the informed consent process for any decision. How does a physician best evaluate a patient’s capacity? There is no one definitive assessment tool for capacity. Although there are many guides and standards for evaluating capacity, it is most generally a common sense judgment that arises from a clinician’s interaction with the patient. Mental status tests that assess orientation to person, place, and time are less useful than direct assessment of patient’s ability to make a particular medical decision. Simple questions such as these assess the evaluation of capacity in the clinical setting more directly23,24: • What do you understand about what is going on with your health right now? • What treatment, diagnostic test, and/or procedure has been proposed to you?

SECTION I SURGICAL BASIC PRINCIPLES

physician, perceptions of good and bad health, understanding of a disease’s cause, methods of preventive care, interpretation of symptoms, and recognition of appropriate treatment. Being a culturally competent surgeon is more than having knowledge about specific cultures; in fact, cultural knowledge must be carefully handled to avoid stereotyping or oversimplification. Instead, cultural competence involves the “exploration, empathy, and responsiveness to patients’ needs, values, and preferences.”12 Self-assessment is often the first step to developing the attitude and skill of cultural competence. Honest and insightful inquiry into one’s own feelings, beliefs, and values, including assumptions, biases, and stereotypes, is essential to awareness of the impact of culture on care. The Association of American Medical Colleges’ statement on education for cultural competence lists the following clinical skills as essential for medical students to acquire13: 1. Knowledge, respect, and validation of differing values, cultures, and beliefs, including sexual orientation, gender, age, race, ethnicity, and class 2. Dealing with hostility and discomfort as a result of cultural discord 3. Eliciting a culturally valid social and medical history 4. Communication, interaction, and interviewing skills 5. Understanding language barriers and working with interpreters 6. Negotiating and problem-solving skills 7. Diagnosis, management, and patient-adherent skills leading to patient compliance Various models for effective cross-cultural communication and negotiation exist14-21 to assist the physician in discovering and understanding the patient’s cultural frame of reference. The BELIEF instrument by Dobbie and colleagues22 is one such model:

22 SECTION I SURGICAL BASIC PRINCIPLES • What are the benefits and risks? • Why have you decided …? PROFESSIONALISM Within medical ethics, the topic of professionalism has received increasing attention in the last decade or so. Although the more usual approaches to ethics focus on what decisions one ought to make in a particular situation, professionalism instead addresses questions of enduring moral character—what sort of physician one is, rather than only what one does or does not do. A common way to address professionalism is to list a series of desirable character traits.25 Almost all discussions of professionalism, however, ultimately rely heavily on two simple points. First, physicians are presumed, by virtue of entering into practice, to have made a moral commitment to place the interests of their patients above their own self-interests, at least to a considerable degree. Second, approaching medicine as a profession is commonly contrasted with viewing medical practice as merely a business. Common challenges to surgeons’ professionalism arise during interactions with the pharmaceutical and medical device industries, in which one may earn a substantial monetary reward for activities that promote the marketing interests of companies, even if those activities fail to promote better health for patients. If care is to remain affordable for most patients, the need to control U.S. health care costs represents another major challenge to professionalism. Will physicians and their professional societies act like special interest lobbies, mainly interested in maintaining generous reimbursem*nts for their favored procedures, regardless of evidence about the procedures’ efficacy? Or, will physicians rise to the challenge of supporting evidence-based medicine and take leadership in identifying low-efficacy procedures whose restricted use could conserve scarce health care resources?26 CONCLUSION The challenges of contemporary surgical practice necessitate attention not only to the lessons of the past but also contemplation of the future. Traditional codes and oaths provide guidance but reflection, self-assessment, and deliberation about what it means to be a good surgeon and how a good surgeon ought to act are essential. Educational efforts must inculcate the professional attitudes, values, and behaviors that recognize and support a culture of integrity and ethical accountability. SELECTED REFERENCES Brody H: Hooked: Ethics, the Medical Profession, and the Pharmaceutical Industry, Lanham, Md, 2007, Rowman & Littlefield. Examines the relationships between physicians and the pharmaceutical industry and how the integrity of the professional of medicine is threatened by those relationships.

Cassell EJ: The Nature of Suffering and the Goals of Medicine, New York, 1991, Oxford University Press. Experienced internist’s reflections on suffering and the relationship between patient and physician.

Chen PW: Final Exam: A Surgeon’s Reflections on Mortality, New York, 2007, Alfred A. Knopf. A transplant surgeon’s narrative about her own fears and doubts about confronting death and how she helps her patients face the same issues.

Gawande A: Complications: A Surgeon’s Notes on an Imperfect Science, New York, 2002, Metropolitan Books. A young surgeon’s thoughts on fallibility, mystery, and uncertainty in surgical practice.

Jonsen AR, Siegler M, Winslade WJ: Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine, ed 7, New York, 2010, McGraw-Hill. The standard physician’s pocket guide to clinical and ethical decision making.

May WF: The Physician’s Covenant: Images of the Healer in Medical Ethics, Philadelphia, 1983, Westminster John Knox Press. Reflections on the physician as parent, fighter, technician, and teacher.

McCullough LB, Jones JW, Brody BA: Surgical Ethics, New York, 1998, Oxford University Press. Nineteen chapters on surgical ethics, varying from principles and practice through research and innovation to finances and institutional relationships.

Nuland SB: How We Die: Reflections on Life’s Final Chapter, New York, 1994, Vintage Books. A national bestseller by a senior surgeon, writer, and historian of medicine.

Selzer R: Letters to a Young Doctor, New York, 1982, Simon & Schuster. Sage advice for young surgeons from a seasoned surgeon-writer.

REFERENCES 1. Bosk CL: Forgive and remember: managing medical failure, ed 2, Chicago, 2003, University of Chicago Press. 2. Little M: Invited commentary: Is there a distinctively surgical ethics? Surgery 129:668–671, 2001. 3. American College of Surgeons: Statements on principles, 2004 (http://www.facs.org/fellows_info/statements/stonprin.html). 4. American College of Surgeons: Code of professional conduct, 2003 (http://www.facs.org/memberservices/codeofconduct.html). 5. Accreditation Council for Graduate Medical Education (ACGME): Common program requirements: General competencies, 2007 (http://www.acgme.org/outcome/comp/GeneralCompetencies Standards21307.pdf ). 6. Jones JW, McCullough LB, Richman BW: The Ethics of Surgical Practice: Cases, Dilemmas, and Resolutions, New York, 2008, Oxford University Press. 7. American College of Surgeons’ Committee on Ethics: Statement on principles guiding care at the end of life. Bull Am Coll Surg 83:46, 1998.

Ethics and Professionalism in Surgery Chapter 2 23 18. Flores G: Culture and the patient-physician relationship: Achieving cultural competency in health care. J Pediatr 136:14– 23, 2000. 19. Carrillo JE, Green AR, Betancourt JR: Cross-cultural primary care: A patient-based approach. Ann Intern Med 130:829–834, 1999. 20. Betancourt JR, Carrillo JE, Green AR: Hypertension in multicultural and minority populations: Linking communication to compliance. Curr Hypertens Rep 1:482–488, 1999. 21. Berlin EA, Fowkes WC, Jr: A teaching framework for crosscultural health care. Application in family practice. West J Med 139:934–938, 1983. 22. Dobbie AE, Medrano M, Tysinger J, et al: The BELIEF Instrument: A preclinical teaching tool to elicit patients’ health beliefs. Fam Med 35:316–319, 2003. 23. Boyle RJ: The process of informed consent. In Fletcher JC, Lombardo PA, Marshall MF, et al, editors: Introduction to Clinical Ethics, ed 2, Hagerstown, Md, 1997, University Publishing Group, pp 89–105. 24. Lo B: Resolving Ethical Dilemmas: A Guide for Clinicians, ed 3, New York, 2005, Lippincott Williams & Wilkins. 25. Medical Professionalism Project: Medical professionalism in the new millennium: A physician’s charter. Lancet 359:520–522, 2002. 26. Brody H: Medicine’s ethical responsibility for health care reform— the Top Five list. N Engl J Med 362:283–285, 2010.

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8. Dunn GP, Milch RA: Introduction and historical background of palliative care: Where does the surgeon fit in? J Am Coll Surg 193:325–328, 2001. 9. Hastings Center: Surgeon and hospice founder accepts Hastings Center Cunniff-Dixon Physician Award, 2011 (http://www. thehastingscenter.org/News/Detail.aspx?id=4422). 10. Youngner SJ, Cascorbi HF, Shuck JM: DNR in the operating room. Not really a paradox. JAMA 266:2433–2434, 1991. 11. Girardi LN, Barie PS: Improved survival after intraoperative cardiac arrest in noncardiac surgical patients. Arch Surg 130:15– 18, 1995. 12. Betancourt JR: Cultural competence—marginal or mainstream movement? N Engl J Med 351:953–955, 2004. 13. Association of American Medical Colleges: Cultural competence education, 2005 (https://www.aamc.org/download/54338/data/ culturalcomped.pdf ). 14. Stuart MR, Lieberman JA, III: The Fifteen-Minute Hour: Applied Psychotherapy for the Primary Care Physician, New York, 1993, Praeger. 15. Levin SJ, Like RC, Gottlieb JE: ETHNIC: A framework for culturally competent ethical practice. Patient Care 34:188–189, 2000. 16. Kleinman A, Eisenberg L, Good B: Culture, illness, and care: clinical lessons from anthropologic and cross-cultural research. Ann Intern Med 88:251–258, 1978. 17. Green AR, Betancourt JR, Carrillo JE: Integrating social factors into cross-cultural medical education. Acad Med 77:193–197, 2002.

CHAPTER 3

MOLECULAR AND CELL BIOLOGY Tien C. Ko

human genome recombinant dna technology cell signaling cell division cycle cell death human genome project novel treatment strategies ethical, psychological, and legal implications

Since the 1980s, there has been an explosion in knowledge regarding molecular and cellular biology. These advances will transform the practice of surgery to one that is based on molecular techniques for the prevention, diagnosis, and treatment of many surgical diseases. This has been made possible by the achievements of the Human Genome Project, which is intended to reveal the complete genetic instruction of humans. The core knowledge of molecular and cellular biology has been presented in detail in several textbooks.1,2 An overview of the field is presented here, with emphasis on basic concepts and techniques. HUMAN GENOME Mendel first defined genes as information-containing elements that are distributed from parents to offspring. Genes contain the design that is essential for the development of each human. The field of molecular biology began in 1944, when Avery demonstrated that DNA was the hereditary material that made up genes. Translation of this genetic information into RNA and then protein leads to the expression of specific biologic characteristics or phenotypes. Major advances made in the field of molecular biology are listed in Table 3-1. In this section, the structures of genes and DNA are reviewed, as are the processes whereby genetic information is translated into biologic characteristics. Structure of Genes and DNA DNA is composed of two antiparallel strands of unbranched polymer wrapped around each other to form a right-handed double helix (Fig. 3-1).3 Each strand is composed of four types of deoxyribonucleotides containing the bases adenine (A), cytosine (C), guanine (G), and thymine (T). The nucleotides are joined together by phosphodiester bonds that join the 5′carbon of one deoxyribose group to the 3′ carbon of the next. Whereas the sugar-phosphate backbone remains constant, the attached 24

bases can vary to encode different genetic information. The nucleotide sequences of the opposing strands of DNA are complementary to each other, thus allowing the formation of hydrogen bonds that stabilize the double-helix structure. Complementary base pairs require that A always pairs with T and C always pairs with G. The entire human genetic information, or human genome, contains 3 × 109 nucleotide pairs. However, less than 10% of the DNA sequences are copied into messenger RNA (mRNA) molecules, which encode proteins, or structural RNA, such as transfer RNA (tRNA) or ribosomal RNA (rRNA) molecules. Each nucleotide sequence in a DNA molecule that directs the synthesis of a functional RNA molecule is called a gene (Fig. 3-2). DNA sequences that do not encode genetic information may have structural or other unknown functions. Human genes commonly contain more than 100,000 nucleotide pairs, yet most mRNA molecule–encoding proteins consist of only 1000 nucleotide pairs. Most of the extra nucleotides consist of long stretches of noncoding sequences, called introns, that interrupt the relatively short segments of coding sequences called exons. For example, the thyroglobulin gene has 300,000 nucleotide bases and 36 introns, whereas its mRNA has only 8700 nucleotide bases. The processes whereby genetic information encoded in DNA is transferred to RNA and protein molecules are discussed later. The human genome contains 24 different DNA molecules; each DNA has 108 bases and is packaged in a separate chromosome. Thus, the human genome is organized into 22 different autosomes and two different sex chromosomes. Because humans are diploid organisms, each somatic cell contains two copies of each different autosome and two sex chromosomes, for a total of 46 chromosomes. One copy of chromosomes is inherited from the mother and one is inherited from the father. Germ cells contain only 22 autosomes and one sex chromosome. Each chromosome contains three types of specialized DNA sequences that are important in the replication or segregation of chromosomes during cell division (Fig. 3-3). To replicate, each chromosome contains many short, specific DNA sequences that act as replication origins. A second sequence element, called a centromere, attaches DNA to the mitotic spindle during cell division. The third sequence element is a telomere, which contains G-rich repeats located at each end of the chromosome. During DNA replication, one strand of DNA becomes a few bases shorter at its 3′ end because of limitation in the replication machinery. If this is not remedied, DNA molecules will become progressively

Molecular and Cell Biology Chapter 3 25

DNA Replication and Repair Before cell division, DNA must be duplicated precisely so that a complete set of chromosomes can be passed to each progeny. DNA replication must occur rapidly, yet with extremely high Table 3-1 Major Events in Molecular Biology YEAR

EVENT

1941

Genes are found to encode proteins.

1944

DNA is determined to carry the genetic information.

1953

DNA structure is determined.

1962

Restriction endonucleases are discovered.

1966

Genetic code is deciphered.

1973

DNA cloning technique is established.

1976

First oncogene is discovered.

1977

Human growth hormone is produced in bacteria.

1978

Human insulin gene is cloned.

1981

First transgenic animal is produced.

1985

Polymerase chain reaction is invented. First tumor suppressor gene is discovered.

1990

Human Genome Project is created.

1998

First mammal is cloned.

accuracy. In humans, DNA is replicated at the rate of approximately 50 nucleotides/second, with an error rate of one in every 109 base pair replications. This efficient replication of genetic material requires an elaborate replication machinery consisting of several enzymes. Because each strand of DNA double helix encodes nucleotide sequences complementary to its partner strand, both strands contain identical genetic information and serve as templates for the formation of an entirely new strand. Eventually, two complete DNA double helices are formed that contain identical genetic information. The fidelity of DNA replication is of critical importance because any mistake, called a mutation, will result in wrong DNA sequences being copied to daughter cells. Mistake in a single base pair is called a point mutation, which results in a missense mutation or nonsense mutation (Fig. 3-4). In a missense mutation, a single amino acid is changed, which can cause changes in the structure of the protein, leading to altered biologic activity. In a nonsense mutation, point mutation results in the replacement of an amino acid codon with a stop codon, leading to premature termination of translation and truncation of the encoded protein. If there is an addition or deletion of a few base pairs, it is called a frameshift mutation, which leads to the introduction of unrelated amino acids or a stop codon. Some mutations are silent and will not affect the function of the organism. Several proofreading mechanisms are used to eliminate mistakes during DNA replication. RNA and Protein Synthesis In the early 1940s, geneticists demonstrated that genes specify the structure of individual proteins. The transfer of information from DNA to protein proceeds through the synthesis of an intermediate molecule known as RNA. RNA, like DNA, is made up of a linear sequence of nucleotides composed of four complementary bases. RNA differs from DNA in two respects: 1. Its sugar-phosphate backbone contains ribose instead of deoxyribose sugar 2. Thymine (T) is replaced by uracil (U), a closely related base that pairs with adenine (A) RNA molecules are synthesized from DNA by a process known as DNA transcription, which uses one strand of DNA as a template. DNA transcription differs from DNA replication in that RNA is synthesized as a single-stranded molecule and is

DNA STRUCTURE Sugar–phosphate backbone Phosphate 5´

Pentose Adenine base

Thymine base 3´

FIGURE 3-1 DNA double-helix structure. The sequence of four bases (guanine, adenine, thymine, and cytosine) determines the specificity of genetic information. The bases face inward from the sugar-phosphate backbone and form pairs (dashed lines) with complementary bases on the opposing strand. (Adapted from Rosenthal N: DNA and the genetic code. N Engl J Med 331:39–41, 1994.)

SECTION I SURGICAL BASIC PRINCIPLES

shorter in their telomere segments with each cell division. This problem is solved by an enzyme called telomerase, which periodically extends the telomerase sequence by several bases. Each chromosome, when stretched out, would span the cell nucleus thousands of times. To facilitate DNA replication and segregation, each chromosome is packaged into a compact structure with the aid of special proteins, including histones. DNA and histones form a repeated array of particles called nucleosomes; each consists of an octomeric core of histone proteins around which the DNA is wrapped twice. The condensed complex of DNA and proteins is known as chromatin. Not only does chromosome packaging facilitate DNA replication and segregation, but it also influences the activity of genes (see later).

26 SECTION I SURGICAL BASIC PRINCIPLES relatively short in comparison to DNA. Several classes of RNA transcripts are made, including mRNA, tRNA, and rRNA. Even though all these RNA molecules are involved in the translation of information from RNA to protein, only mRNA serves as the template. RNA synthesis is a highly selective process, with only approximately 1% of the entire human DNA nucleotide sequence transcribed into functional RNA sequences. Although each cell contains the same genetic material, only specific genes are transcribed. RNA transcription is controlled by regulatory proteins that bind to specific sites on DNA, close to the coding sequence of a gene. The complex regulation of gene transcription occurs during development and tissue differentiation and allows differential patterns of gene expression. After transcription, mRNA is processed for transport out of the nucleus (Fig. 3-5). One important step is RNA splicing, which removes noncoding sequences or introns. Once in the cytoplasm, RNA directs the synthesis of a particular protein through a process called RNA translation. The sequence of nucleotides in mRNA is translated into the amino acid sequence of a protein. Each triplet of nucleotides forms a codon that specifies one amino acid. Because RNA is composed of four types of nucleotides, there are 64 possible codon triplets (4 × 4 × 4). However, only 20 amino acids are commonly found in proteins, so most amino acids are specified by several codons.

The rule whereby different codons are translated into amino acids is called the genetic code (Table 3-2). Protein translation requires a ribosome, which is composed of more than 50 different proteins and several rRNA molecules. Ribosomes bind an mRNA molecule at the initiation codon (AUG) and begin translation in the 5′ to 3′ direction. Protein synthesis ceases once one of the three termination codons is encountered. The rate of protein synthesis is controlled by initiation factors that respond to the external environment, such as growth factor and nutrients. These regulatory factors help coordinate cell growth and proliferation. Control of Gene Expression The human body is made up of millions of specialized cells, each performing predetermined functions. This is characteristic of all multicellular organisms. In general, different human cell types contain the same genetic material (i.e., DNA), yet they synthesize and accumulate different sets of RNA and protein molecules. This difference in gene expression determines whether a cell is a hepatocyte or a cholangiocyte. Gene expression can be controlled at six major steps in the synthetic pathway from DNA to RNA to protein.4 The first control is at the level of gene transcription, which determines when and how often a given gene is transcribed into RNA molecules. The next step is RNA

FIGURE 3-2 Gene structure. The DNA sequences that are transcribed as RNA are collectively called the gene and include exons (expressed sequences) and introns (intervening sequences). Introns invariably begin with the nucleotide sequence GT and end with AG. An AT-rich sequence in the last exon forms a signal for processing the end of the RNA transcript. Regulatory sequences that make up the promoter and include the TATA box occur close to the site where transcription starts. Additional regulatory elements are located at variable distances from the gene. (Adapted from Rosenthal N: Regulation of gene expression. N Engl J Med 331:931–933, 1994.)

Telomere sequence

Replication origin sequence + Centromere sequence

Replication bubble

Kinetochore

Daughter chromosomes in separate cells

FIGURE 3-3 Chromosome structure. Each chromosome has three types of specific sequences that facilitate its replication during the cell cycle. Origins of replication are located throughout each chromosome to facilitate DNA synthesis. The centromere holds the duplicated chromosome together and is attached to the mitotic spindle through a protein complex called a kinetochore. Telomere sequences are located at each end of the chromosome and are replicated in a special way to preserve chromosome integrity.

Molecular and Cell Biology Chapter 3 27

Amino acid N-Phe Arg mRNA 5'–UUU CGA 3'–AAA GCT DNA 5'–TTT CGA Missense

Nonsense

Trp Ile Ala Asn-C UGG AUA GCC AAU–3' ACC TAT CGG TTA–5' TGG ATA GCC AAT–3'

3'–AAT GCT ACC TAT CGG TTA–5' 5'–TTA CGA TGG ATA GCC AAT–3' N-Leu Arg Trp Ile Ala Asn-C 3'–AAA GCT ATC TAT CGG TTA–5' 5'–TTT CGA TAG ATA GCC AAT–3' N-Phe Arg Stop

Frameshift by addition 3'–AAA GCT ACC ATA TCG GTT A–5' 5'–TTT CGA TGG TAT AGC CAA T–3' N-Phe Arg Trp Tyr Ser Gln Frameshift by deletion GCTA CGAT 3'–AAA CCT ATC GGT TA–5' 5'–TTT GGA TAG CCA AT–3' N-Phe Gly Stop FIGURE 3-4 Different types of mutations. Point mutations involve alteration in a single base pair. Small additions or deletions of several base pairs directly affect the sequence of only one gene. A wild-type peptide sequence and the mRNA and DNA encoding it are shown at the top. Altered nucleotides and amino acid residues are enclosed in a box. Missense mutations lead to a change in a single amino acid in the encoding protein. In a nonsense mutation, a nucleotide base change leads to the formation of a stop codon that results in premature termination of translation, thereby generating a truncated protein. Frameshift mutations involve the addition or deletion of any number of nucleotides that is not a multiple of three, thus causing a change in the reading frame. (From Lodish HF, Baltimore D, Berk A, et al [eds]: Molecular cell biology, ed 3, New York, 1998, Scientific American, p 267.)

processing control, which regulates how many mature mRNA molecules are produced in the nucleus. The third step is RNA transport control, which determines which mature mRNA molecules are exported into the cytoplasm where protein synthesis occurs. The fourth step involves mRNA stability control, which determines the rate of mRNA degradation. The fifth step involves translational control, which determines how often mRNA is translated by ribosomes into proteins. The final step is post-translational control, which regulates the function and fate of protein molecules. Control of gene transcription is the best studied step of regulation for most genes. RNA synthesis begins with assembly and binding of the general transcription machinery to the promoter region of a gene (see Fig. 3-5). The promoter is located upstream of the transcription initiation site at the 5′ end of the gene and consists of a stretch of DNA sequence primarily composed of T and A nucleotides (i.e., the TATA box). The general transcription machinery is composed of several proteins, including RNA polymerase II and general transcription proteins. These general transcription factors are abundantly expressed in all cells and are required for the transcription of most mammalian genes. The rate of assembly of the general transcription machinery to

the promoter determines the rate of transcription, which is regulated by gene regulatory proteins. In contrast to the small number of general transcription proteins, there are thousands of different gene regulatory proteins. Most bind to specific DNA sequences, called regulatory elements, to activate or repress transcription. Gene regulatory proteins are expressed in small amounts in a cell, and different selections of proteins are expressed in different cell types. Similarly, different combinations of regulatory elements are present in each gene to allow differential control of gene transcription. Many human genes have more than 20 regulatory elements; some bind transcriptional activators, whereas others bind transcriptional repressors. Ultimately, the balance between transcriptional activators and repressors determines the rate of transcription, which can vary by a factor of more than 106 between genes that are expressed and those that are repressed. Most regulatory elements are located at a distance (i.e., thousands of nucleotide bases) away from the promoter. These distant regulatory elements are brought into the proximity of the promoter through DNA bending, thus enabling control of promoter activity. In summary, the combination of regulatory elements and the types of gene regulatory proteins expressed determines where and when a gene is transcribed. Post-translational control is another important step in the regulation of gene expression because most proteins are modified in one form or another.5 Modifications such as proteolytic cleavage, disulfide formation, glycosylation, lipidation, and biotinylation allow the protein to achieve the proper structural conformation essential for its biologic activity. The complexity of regulation is greatly increased by additional amino acid modifications that can occur at multiple sites of a protein. Examples of amino acid modification include phosphorylation, acetylation, methylation, ubiquitination, and sumoylation. RECOMBINANT DNA TECHNOLOGY Advances in recombinant DNA technology, beginning in the 1970s, have greatly facilitated study of the human genome. It is now routine practice in molecular laboratories to excise a specific region of DNA, produce unlimited copies of it, and determine its nucleotide sequences. Furthermore, isolated genes can be altered (engineered) and transferred back into cells in culture or into the germline of an animal or plant so that the altered gene is inherited as part of the organism’s genome. The most important recombinant DNA technology includes the ability to cut DNA at specific sites by restriction nucleases, rapidly amplify DNA sequences, quickly determine the nucleotide sequences, clone a DNA fragment, and create a DNA sequence.6 Restriction Nucleases Restriction nucleases are bacterial enzymes that cut the DNA double helix at specific sequences of four to eight nucleotides. More than 400 restriction nucleases have been isolated from different species of bacteria and they recognize over 100 different specific sequences. Commonly used restriction enzymes often recognize a six–base pair palindromic sequence, such as GAATTC. Each restriction nuclease will cut a DNA molecule into a series of specific fragments, which can be joined to other DNA fragments with compatible ends (Fig. 3-6A). By using a combination of different restriction enzymes, a restriction map of each DNA can be created, thus facilitating the isolation of individual genes.

SECTION I SURGICAL BASIC PRINCIPLES

Wild-type sequences

28 SECTION I SURGICAL BASIC PRINCIPLES

GENE EXPRESSION

Transcription factors

RNA polymerase Exon 1 Exon 2

Exon 3 DNA

Transcription-inflation complex

Transcription 5′

Transcript processing

premRNA

RNA-clipping enzyme

Nucleus

Cytopiasm

FIGURE 3-5 Process of gene transcription. Gene expression begins with the binding of multiple protein factors to enhancer AAUAAA sequences and promoter sequences. These factors help form the 5′ cap transcription-initiation complex, which includes the enzyme RNA polymerase and multiple polymerase-associated proteins. The polyA tail primary transcript (pre-mRNA) includes exon and intron sequences. AAAA.... Post-transcriptional processing begins with changes at both ends Adenosine-adding of the RNA transcript. At the 5′ end, enzymes add a special Intron lariat enzyme (terminal transferase) nucleotide cap; at the 3′ end, an enzyme clips the pre-mRNA Splicing approximately 30 base pairs after the AAUAAA sequence in the AAAA.... last exon. Another enzyme adds a polyadenylate (polyA) tail, Spliceosome which consists of as many as 200 adenine nucleotides. Next, Processed spliceosomes remove the introns by cutting the RNA at the boundmRNA transcript AAAA.... aries between exons and introns. The process of excision forms lariats of the intron sequences. The spliced mRNA is then mature and can leave the nucleus for protein translation in the cytoplasm. (Adapted from Rosenthal N: Regulation of gene expression. N Engl Translation into protein J Med 331:931–933, 1994.)

Table 3-2 The Genetic Code Second Position FIRST POSITION (5′ END)

THIRD POSITION (3′ END)

U (uracil)

Phe

Ser

Tyr

Cys

Phe

Ser

Tyr

Cys

Leu

Ser

Stop

Leu

Ser

Stop

Trp

Leu

Pro

His

Arg

Leu

Pro

His

Arg

Leu

Pro

Gln

Arg

Leu

Pro

Gln

Arg

Ile

Thr

Asn

Ser

Ile

Thr

Asn

Ser

Ile

Thr

Lys

Arg

Met

Thr

Lys

Arg

Val

Ala

Asp

Gly

Val

Ala

Asp

Gly

Val

Ala

Glu

Gly

Val

Ala

Glu

Gly

C (cytosine)

A (adenine)

G (guanine)

Polymerase Chain Reaction An ingenious technique to amplify a segment of a DNA sequence in vitro rapidly was developed in 1985 by Saiki and coworkers.7 This method, called the polymerase chain reaction (PCR), can enzymatically amplify a segment of DNA a billion-fold. The principle of the PCR technique is illustrated in Figure 3-6B. To amplify a segment of DNA, two single-stranded oligonucleotides, or primers, must be synthesized, each designed to complement one strand of the DNA double helix and lying on opposite sides of the region to be amplified. The PCR reaction mixture consists of the double-stranded DNA sequence (the template), two DNA oligonucleotide primers (heat stable), DNA polymerase, and four types of deoxynucleotide triphosphate. Each round of amplification involves separation of the DNA template into two single strands, hybridization of the two DNA primers to complementary sequences on each strand of the DNA template, and DNA synthesis downstream of each primer. Each round of PCR requires only approximately 5 minutes and results in a doubling of the double-stranded DNA molecules, which serve as templates for subsequent reactions. After only 32 cycles, more than 1 billion copies of the desired DNA segment are produced. Not only is the PCR technique extremely powerful, but it is also the most sensitive technique to detect a single copy of a DNA or RNA molecule in a sample. To detect RNA molecules, they must first be transcribed into complementary DNA sequences with the enzyme reverse transcriptase. The number of research and clinical applications for PCR continues to grow. In molecular laboratories, PCR has been used for cloning of DNA, engineering of DNA, analysis of allelic sequence variations, and sequencing of DNA. PCR techniques have many clinical applications, including the

Molecular and Cell Biology Chapter 3 29

Ligation

Genomic DNA

Plasmid vector Recombinant DNA molecule

Incorporation of DNA fragment into plasmid vector

Amplification of recombinant DNA molecules in bacteria

Primers

Heat

Separation of strands

Primers

Cycle 3

Separation of strands

Sequence to be amplified

Separation of strands

AMPLIFICATION OF DNA BY PCR Cycle 1 Cycle 2

Heat

diagnosis of genetic diseases, assay of infectious agents, and genetic fingerprinting for forensic samples. DNA Sequencing DNA encodes information for proteins and, ultimately, the phenotype of a human being. Each gene may contain over 3000 nucleotide bases. Identification of the nucleotide sequences of a fragment of DNA has been made possible through the development of rapid techniques that take advantage of the ability to separate DNA molecules of different lengths, even those differing by only a single nucleotide. Currently, the standard method for sequencing DNA is based on an enzymatic method requiring in vitro DNA synthesis. This method is rapid and can be automated to allow sequencing of large segments of DNA. With these techniques, it is possible to determine the boundaries of a gene and the amino acid sequence of the protein that it codes. Sequencing techniques have enabled the identification and in vitro synthesis of important proteins such as insulin, interferon, hemoglobin, and growth hormones. DNA Cloning DNA cloning techniques allow identification of a gene of interest from the human genome. First, the entire DNA content of a cell is cut with a restriction nuclease to generate DNA fragments, which are joined to a self-replicating genetic element (a virus or plasmid). Viruses or plasmids are small circular DNA molecules that occur naturally and can replicate rapidly when introduced into bacterial cells. They are extremely useful tools for amplifying a segment of unknown DNA. With this method,

FIGURE 3-6 Amplification of recombinant DNA and amplification by PCR. A, The DNA segment to be amplified is separated from surrounding genomic DNA by cleavage with a restriction enzyme. The enzymatic cuts often produce staggered, or sticky, ends. In the example shown, the restriction enzyme EcoRI recognizes the sequence GAATTC and cuts each strand between G and A; the two strands of genomic DNA are shown as black. The same restriction enzyme cuts the circular plasmid DNA (gray) at a single site, thereby generating sticky ends that are complementary to the sticky ends of the genomic DNA fragment. The cut genomic DNA and the remainder of the plasmid, when mixed together in the presence of a ligase enzyme, form smooth joints on each side of the plasmid–genomic DNA junction. This new molecule, recombinant DNA, is carried into bacteria, which replicate the plasmid as they grow in culture. B, The DNA sequence to be amplified is selected by primers, which are short synthetic oligonucleotides that correspond to sequences flanking the DNA to be amplified. After an excess of primers is added to the DNA, together with a heat-stable DNA polymerase, the strands of both the genomic DNA and primers are separated by heating and allowed to cool. A heat-stable polymerase elongates the primers on either strand, thus generating two new, identical, doublestranded DNA molecules and doubling the number of DNA fragments. Each cycle takes just a few minutes and doubles the number of copies of the original DNA fragment. (From Rosenthal N: Tools of the trade—recombinant DNA. N Engl J Med 331:315– 317, 1994.)

a collection of bacteria plasmids containing the entire human genome can be created. This human DNA library can then be used to identify genes of interest. DNA Engineering One of the most important outcomes of recombinant DNA technologies is the ability to generate new DNA molecules of any sequence through DNA engineering. New DNA molecules can be synthesized by the PCR method or by using automated oligonucleotide synthesizers. The PCR method can be used to amplify any known segment of the human genome and to redesign its two ends. Automated oligonucleotide synthesizers enable the rapid production of DNA molecules, up to approximately 100 nucleotides in length. The sequence of such synthetic DNA molecules is entirely determined by the experimenter. Larger DNA molecules are formed by combining two or more DNA molecules that have complementary cohesive ends created by restriction enzyme digestion. One powerful application of DNA engineering is the synthesis of large quantities of cellular proteins for medical applications. Most cellular proteins are produced in small amounts in human cells, making it difficult to purify and study these proteins. However, with DNA engineering, it is possible to place a human gene into an expression vector that is introduced into bacterial, yeast, insect, or mammalian cells to produce a large quantity of protein. The protein can easily be purified and used for scientific studies or clinical applications. Medically useful proteins, such as human insulin, growth hormone, interferon, and viral antigens for vaccines, have been produced by engineering expression vectors containing these genes of interest.

SECTION I SURGICAL BASIC PRINCIPLES

Cleavage AMPLIFICATION OF RECOMBINANT DNA BY BACTERIAL CLONING by restriction enzymes Sticky ends

30 SECTION I SURGICAL BASIC PRINCIPLES DNA engineering techniques are also important for solving problems in cell biology. One of the fundamental challenges of cell biology is to identify the biologic functions of the protein product of a gene. With the use of DNA engineering techniques, it is now possible to alter the coding sequence of a gene to alter the functional properties of its protein product or the regulatory region of a gene and thus produce an altered pattern of its expression in the cell. The coding sequence of a gene can be changed in such subtle ways that the protein encoded by the gene has only one or a few alterations in its amino acid sequence. The modified gene is then inserted into an expression vector and transfected into the appropriate cell type to examine the function of the redesigned protein. With this strategy, one can analyze which parts of the protein are important for fundamental processes, such as protein folding, enzyme activity, and protein-ligand interactions. Transgenic Animals The ultimate test of the function of a gene is to overexpress the gene in an organism and observe its effect or delete it from the genome and evaluate the consequences. It is much easier to overexpress a gene of interest than to delete it from the genome of an organism. To overexpress a gene, the DNA fragment encoding the gene of interest, the transgene, must be constructed with recombinant DNA techniques.7,8 The DNA fragment must contain all the components necessary for efficient expression of the gene, including a promoter and regulatory region that drives transcription. The type of promoter used can determine whether the transgene is expressed in many tissues of the transgenic animal or in a specific tissue. For example, selective expression in the acinar pancreas can be achieved by linking the amylase promoter to the coding sequence of the transgene. The transgene DNA fragments are introduced into the male pronucleus of a fertilized egg via microinjection techniques. Animals are then screened for the presence of the transgene. Analysis of these animals has provided important insight into the functions of many human genes, as well as animal models of human diseases. For example, transgenic animals engineered to overexpress a mutant form of the gene for the β-amyloid protein precursor (the APP gene) have neuropathologic changes similar to those in patients with Alzheimer’s disease. This transgenic model not only supports the role of the APP gene in the development of Alzheimer’s disease, but is also a model for testing methods of prevention or treatment of Alzheimer’s disease. A major disadvantage of using transgenic animals is that they will reveal only dominant effects of the transgene because these animals still retain two normal copies of the gene in their genome. Therefore, it is extremely useful to produce animals that do not express both copies of the gene of interest.9 These knockout animals are much more difficult to develop than transgenic animals and require gene-targeting techniques. To knock out a gene, it is important to modify the gene of interest by DNA engineering to create a nonfunctioning gene. This altered gene is inserted into a vector and then inserted into germ cell lines. Although most mutated genes are inserted randomly into one of the chromosomes, a mutated gene will, rarely, replace one of the two copies of the normal gene by hom*ologous recombination. Germ cells with one copy of the normal gene and one copy of the mutated gene will give rise to heterozygous animals. Heterozygous males and females are generated and can then be

bred to produce animals that are hom*ozygous for the mutated gene. These knockout animals can be studied to determine which cellular functions are altered in comparison to normal animals, thereby identifying the biologic function of the gene of interest. The ability to produce knockout animals that lack a known normal gene has greatly facilitated studies of the functions of specific mammalian genes. RNA Interference Because most of the approximately 21,000 human genes encoding potential proteins have unknown function, uncovering their biologic activities has been an area of intense investigation. The most effective way to assess the function of a gene is by using reverse genetics (i.e., target deletion of the expression of a specific gene) and examining the biologic consequences. Until rather recently, only a few reverse genetic approaches have been available, such as hom*ologous recombination and antisense oligonucleotide strategies. Each of these technologies has significant limitations that make reverse genetic studies slow and costly. However, a newer, more powerful tool was developed in 1998 by Andrew Fire and Craig Mello that is based on the silencing of specific genes by double-stranded RNA (dsRNA).10 This technology, termed RNA interference (RNAi), requires the synthesis of a dsRNA that is hom*ologous to the target gene.11 Once taken up by the cells, the dsRNA is cleaved into 21- to 23-nucleotide-long RNA molecules termed short interfering RNAs (also called small interfering RNAs, siRNAs) by an enzyme complex (Dicer-RDE-1; Fig. 3-7). The antisense strand of the siRNA binds to the target mRNA, which leads to its degradation by an RNAi silencing complex. Advancements have allowed the direct design and synthesis of siRNAs, as well as placement of

FIGURE 3-7 RNA interference. Long double-stranded RNA (dsRNA) is processed by the Dicer-RDE-1 complex to form siRNA. The antisense strand of siRNA is used by an RNA interference (RNAi) silencing complex to guide specific mRNA cleavage, thus promoting mRNA degradation. RDE-1, RNAi deficient-1.

Molecular and Cell Biology Chapter 3 31

CELL SIGNALING The human body is composed of billions of cells that must be coordinated to form specific tissues. Both neighboring and distant cells influence the behavior of cells through intercellular signaling mechanisms. Whereas normal cell signaling ensures the health of the human, abnormal cell signaling can lead to diseases such as cancer. Through powerful molecular techniques, the sophisticated signaling mechanisms used by mammalian cells have become better understood. This section reviews the general principles of intercellular signaling and examines the signaling mechanisms of the two main families of cell surface receptor proteins.12 Ligands and Receptors Cells communicate with one another by means of multiple signaling molecules, including proteins, small peptides, amino acids, nucleotides, steroids, fatty acid derivatives, and even dissolved gases, such as nitric oxide and carbon monoxide. Once these signaling molecules are synthesized and released by a cell, they may act on the signaling cell (autocrine signaling), affect adjacent cells (paracrine signaling), or enter the systemic circulation to act on distant target cells (endocrine signaling). These signaling molecules, also called ligands, bind to specific proteins, called receptors, expressed in the plasma membrane or the cytoplasm of the target cells. On ligand binding, the receptor becomes activated and generates a cascade of intracellular signals that alter the behavior of the cell. Each human cell is exposed to hundreds of different signals from its environment, but it is genetically programmed to respond only to specific sets of signals. Cells may respond to one set of signals by proliferating, to another set by differentiating, and to another by achieving cell death. Furthermore, different cells may respond to the same set of signals with different biologic activities. Most extracellular signals are mediated by hydrophilic molecules that bind to receptors on the cell surface of the target cells. These cell surface receptors are divided into three classes based on the transduction mechanism used to propagate signals intracellularly. Ion channel–coupled receptors are involved in rapid synaptic signaling between electrically excitable cells. These receptors form gated ion channels that open or close rapidly in response to neurotransmitters. G protein–coupled receptors regulate the activity of other membrane proteins through a guanosine triphosphate–binding regulatory protein, called G protein.13 Enzyme-coupled receptors act directly as enzymes or are associated with enzymes.14 Most of these receptors are protein kinases or are associated with protein kinases that phosphorylate specific proteins in the cell. Some extracellular signals are small hydrophobic molecules, such as steroid hormones, thyroid hormones, retinoids, and vitamin D. They communicate with target cells by diffusing across the plasma membrane and binding to intracellular receptor proteins. These cytoplasmic receptors are structurally related and constitute the intracellular receptor superfamily. On ligand activation, the intracellular receptors enter the nucleus, bind specific DNA sequences, and regulate transcription of the adjacent gene.

Some dissolved gases, such as nitric oxide and carbon monoxide, act as local signals by diffusing across the plasma membrane and activating intracellular enzymes in the target cells. In the case of nitric oxide, it binds and activates the enzyme guanylyl cyclase, which leads to the production of the intra cellular mediator cyclic guanosine monophosphate (cGMP). G Protein–Coupled Receptors G protein–coupled receptors are the largest family of cell surface receptors and mediate cellular responses to a broad range of signaling molecules, including hormones, neurotransmitters, and local mediators.15 These receptors include β-adrenergic receptors, α2-adrenergic receptors, and glucagon receptors. They share a similar structure with an extracellular domain that binds ligand and an intracellular domain that binds to a specific trimeric G protein. There are at least six distinct trimeric G proteins based on their intracellular signaling mechanisms; each is composed of three different polypeptide chains, called α, β, and γ.13 On ligand binding, the G protein–coupled receptor activates its trimeric G protein (Fig. 3-8). Activated trimeric G protein alters the concentration of one or more small intracellular signaling molecules, referred to as second messengers. Two major second messengers regulated by G protein– coupled receptors are cyclic adenosine monophosphate G protein– coupled receptors

α βγ

cAMP

Cytoplasm

PLC

PKC

[Ca2+]

PKA FIGURE 3-8 G protein–coupled receptor signaling pathway. G protein–coupled receptors are seven–transmembrane domain proteins activated by the binding of ligands. Activated receptors initiate a cascade of events leading to amplification of the original signal. First, the receptor activates a trimer G protein consisting of α, β, and γ subunits. G proteins can activate adenylyl cyclase (AC) to generate cAMP or phospholipase C (PLC) to release intracellular calcium. cAMP can activate protein kinase A (PKA), whereas PLC or intracellular calcium can activate PKC.

SECTION I SURGICAL BASIC PRINCIPLES

these siRNAs into viral vectors. Not only will this technology transform future studies in the analysis of gene function, but siRNAs might also be used as gene therapy to silence the function of specific genes.

32 SECTION I SURGICAL BASIC PRINCIPLES (cAMP) and calcium. cAMP is synthesized by the enzyme adenylyl cyclase and can be rapidly degraded by cAMP phosphodiesterase.16 Intracellular calcium is stored in the endoplasmic reticulum and released into the cytoplasm on proper signaling. Some trimeric G proteins can activate adenylyl cyclase, whereas others inhibit its activity. Trimeric G protein can also activate the enzyme phospholipase C, which produces the necessary signal molecules to activate release of calcium from the endoplasmic reticulum. Activation of phospholipase C can also lead to the activation of protein kinase C (PKC), which initiates a cascade of kinases. Changes in cAMP or calcium concentrations in the cell directly affect the activities of specific kinases that phosphorylate target proteins. The end result is altered biologic activity of these target proteins, which leads to a specific biologic response to the initial signal molecule. Despite the differences in signaling details, all G protein–coupled receptors use a complex cascade of intracellular mediators to amplify the biologic response to the initial extracellular signals greatly. Enzyme-Coupled Receptors Enzyme-coupled receptors are a diverse family of transmembrane proteins with similar structures. Each receptor has an extracellular ligand-binding domain and a cytosolic domain that has intrinsic enzyme activity or is associated directly with an enzyme. Enzyme-coupled receptors are classified according to the type of enzymatic activity used for their intracellular signal transduction. Some receptors have guanylyl cyclase activity and generate cGMP as an intracellular mediator. Others have tyrosine kinase activity or are associated with tyrosine kinase proteins that phosphorylate specific tyrosine residues on intracellular proteins to propagate intracellular signals. Finally, some enzymecoupled receptors have serine-threonine kinase activity and can phosphorylate specific serine or threonine residues to transduce intracellular signals. The receptors for most known growth factors belong to the tyrosine kinase receptor family.14 These include receptors for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin, insulin-like growth factor I (IGF-I), vascular endothelial growth factor (VEGF), and macrophage colony-stimulating factor (M-CSF). These growth factor receptors play crucial roles during normal development and tissue homeostasis. Furthermore, many of the genes that encode proteins in the intracellular signaling cascades that are activated by receptor tyrosine kinases were first identified as oncogenes in cancer cells. Inappropriate activation of these proteins causes a cell to proliferative excessively. Similar to G protein–coupled receptors, tyrosine kinase receptors use a complex cascade of intracellular mediators to propagate and amplify the initial signals (Fig. 3-9). On ligand binding, the tyrosine kinase receptor dimerizes, which activates the kinase. Activated receptor kinase initiates an intracellular relay system, first by cross-phosphorylation of tyrosine residues of the cytoplasmic domain of the receptor. Next, small intracellular signaling proteins bind to phosphotyrosine residues on the receptor and form a multiprotein signaling complex from which the signal propagates to the nucleus. The Ras proteins serve as crucial links in the signaling cascade.17 On activation, Ras proteins initiate a cascade of serine-threonine phosphorylation that converges on mitogen-activated protein (MAP) kinases.

Tyrosine kinase receptors

Src

Shc

SOS

GRB2

Ras

Cytoplasm

Raf

MEKK

MEK

SEK

ERK

JNK

FIGURE 3-9 Tyrosine kinase receptor signaling pathway. Tyrosine kinase receptors are single transmembrane proteins that form a dimer on ligand binding. The activated receptors bind to several proteins (Src, Shc, SOS, GRB2) to form a multiprotein signal complex. This protein complex can activate Ras, which can initiate several kinase cascades. One kinase cascade includes the Raf, MEK, and ERK members, whereas another includes the MEKK, SEK, and JNK proteins.

Activated MAP kinases relay signals downstream by phosphorylating transcription factors, thereby leading to the regulation of gene expression. As noted, human cells integrate many different extracellular signals and respond with biologic behaviors such as proliferation, differentiation, and cell death. In the following sections, we review the mechanisms governing these important biologic processes. CELL DIVISION CYCLE The cell division cycle is the fundamental means whereby organisms propagate and normal tissue homeostasis is maintained. The cell division cycle is an organized sequence of complex biologic processes that is traditionally divided into four distinct phases (Fig. 3-10). Replication of DNA occurs in the S phase (S = synthesis), whereas nuclear division and cell fission occur in the mitotic (M) phase. The intervals between these two phases are called the G1 and G2 phases (G = gap). After division, cells enter the G1 phase, where they can receive extracellular signals and a determination is made whether to proceed with DNA replication or to exit the cell cycle. In this section, we review the proteins that regulate progression through each phase of the cell cycle and how they control key checkpoints of the cell cycle, followed by a discussion of how many cell cycle proteins are mutated or deleted in human cancers.

Molecular and Cell Biology Chapter 3 33

Cyclin A,B + Cdk1

M G1

Cyclin D’s + Cdk4, 6

pRb Phosphorylation

Cyclin A + Cdk2 Cyclin E + Cdk2

FIGURE 3-10 Mechanisms regulating mammalian cell cycle progression. The cell cycle consists of four phases: Gl (first gap) phase, S (DNA synthetic) phase, G2 (second gap) phase, and M (mitotic) phase. Progression through the cell cycle is regulated by a highly conserved family of serine-threonine protein kinases composed of a regulatory subunit (the cyclins) and a catalytic subunit (the Cdks). Cell cycle progression can be inhibited by a class of regulators called the cyclin kinase inhibitors and by phosphorylation of the retinoblastoma (pRb) protein.

Regulation of the Cell Division Cycle by Cyclin, Cyclin-Dependent Kinase, and Cdk Inhibitory Proteins Progression of the mammalian cell cycle through these specific phases is governed by the sequential activation and inactivation of a highly conserved family of regulatory proteins, cyclindependent kinases (Cdks).18 Cdk activation requires the binding of a regulatory protein (cyclin) and is controlled by positive and negative phosphorylation. Cdk activities are inhibited by Cdk inhibitory proteins (CKIs). The active cyclin-Cdk complex is involved in the phosphorylation of other cell cycle regulatory proteins. Cyclin proteins are classified according to their structural similarities. Each cyclin exhibits a cell cycle–phase-specific pattern of expression. In contrast, Cdk proteins are expressed throughout the cell cycle. The cyclins, Cdks, and CKIs form the fundamental regulatory units of the cell cycle machinery. Cell Cycle Checkpoints In proliferating cells, cell cycle progression is regulated at two key checkpoints, the G1-S and the G2-M transitions. Progression through early to mid-G1 is dependent on Cdk4 and Cdk6, which are activated by association with one of the D-type cyclins, D1, D2, or D3.18 Progression through the late G1 phase and into the S phase requires the activation of Cdk2, which is sequentially regulated by cyclins E and A, respectively. The subsequent activation of Cdk1 (cdc2) by cyclin B is essential for the transition from the G2 phase into the M phase. There are two families of CKIs, the CIP-KIP family and the INK family. The four known INK proteins (p15INK4B, p16INK4A, p18INK4C, and p19INK4D) selectively bind and inhibit Cdk4 and Cdk6 and are expressed in a tissue-specific pattern. The three members of the CIP-KIP family (p21CIP1, p27KIP1, and p57KIP2)

share a conserved amino-terminal domain that is sufficient for binding to cyclin-Cdk complexes and inhibition of Cdkassociated kinase activity. Each CIP-KIP protein can inhibit all known Cdks. One of the key targets of the G1 Cdks is the retinoblastoma tumor suppressor protein (pRb), which belongs to the Rb family of pocket proteins (pRb, p107, p130).19 In their hypophosphorylated form, pocket proteins can sequester cell cycle regulatory transcription factors, including heterodimers of the E2F and DP families of proteins.20 Phosphorylation of pRb, first by cyclin D–dependent kinases and then by cyclin E-Cdk2 during late G1, leads to the release of E2F-DP and subsequent activation of genes that participate in the entry into the S phase. Oncogenes and Tumor Suppressor Genes The genes encoding cell cycle regulatory proteins are often targets of mutation during neoplastic transformation. If the mutated gene is cancer-causing, it is referred to as an oncogene and its normal counterpart is called a proto-oncogene. Many proto-oncogenes have been identified and are typically involved in the relay of stimulatory signals from growth factor receptors to the nucleus. They include the intracellular signaling protein Ras and the cell cycle regulatory protein cyclin D1. Mutation of a single copy of a proto-oncogene is sufficient to bring about increased cellular proliferation, one of the hallmarks of cancer. Several antiproliferative gene–encoding proteins such as pRb, p15, and p16 also negatively control the cell division cycle. These genes are often referred to as tumor suppressor genes because they prevent excess and uncontrolled cellular proliferation. These genes are inactivated in some forms of cancer to bring about the loss of control of proliferation. However, unlike proto-oncogenes, both copies of a tumor suppressor gene must be deleted or inactivated during malignant transformation. CELL DEATH Cell proliferation must be balanced by an appropriate process of cell death to maintain tissue homeostasis. There are three type of cell death based on the morphologic appearance of the dying cell.21 Type 1 cell death, or apoptosis, has been best studied and is characterized by chromatin condensation, nuclear fragmentation, shrunken cytoplasm with intact cytoplasmic organelles, and eventual formation of plasma membrane–bound vesicles termed apoptotic bodies, which are then eliminated by neighboring phagocytic cells. Type 2 cell death, or autophagic cell death, is characterized by massive vacuolization of the cytoplasm without chromatin condensation. Type 3 cell death, or necrosis, is characterized by increased cell volume, swelling of cytoplasmic organelles, and rupture of plasma membrane. Cell death has important physiologic functions, including the remodeling of tissues during development, removal of senescent cells and cells with genetic damage beyond repair, and maintenance of tissue homeostasis. In this section, we review the molecular machinery that controls apoptosis and autophagic cell death. Apoptosis Two main pathways of apoptosis have been characterized, the extrinsic or death receptor pathway and intrinsic or stress pathway.22 In the extrinsic pathway, cell surface death receptors bind to proapoptotic ligands, such as tumor necrosis factor (TNF), leading to the recruitment of a multiprotein complex called the death-inducing signaling complex (DISC) and an

SECTION I SURGICAL BASIC PRINCIPLES

pRb Dephosphorylation

Regulators

Stimuli

34 SECTION I SURGICAL BASIC PRINCIPLES Free radical formation

Activation death receptor

Growth factor withdrawal

Ionizing radiation

p53 activation

Proapoptotic Bax Bad Bak Bcl-XS Amplification Caspase activation ? loop Antiapoptotic Bcl-2 Bcl-XL

Execution

Caspase cascade

Morphologic characteristics

Chemotherapy antimetabolites

Nuclear targets PARP Lamins Rb DNA-PKCs MDM2

Activation of transglutaminases Plasma membrane alterations

Cytoplasmic targets Activation of DFF PKCs Phospholipase A2 Fodrin Actin

Cytoplasmic shrinking Chromatin condensation DNA fragmentation Nuclear collapse Apoptotic body formation Cell death by apoptosis

adapter protein called Fas-associated death domain (FADD). By contrast, the intrinsic pathway is activated when intracellular sensors detect proapoptotic stimuli, such as genotoxic damage or growth factor and nutrient deprivation, leading to the activation of Bax and Bak, which are proapoptotic members of the Bcl-2 family of proteins (see Fig. 3-11).23 Bax and Bak are inserted in and destabilize the mitochondrial membrane, resulting in cytochrome c leakage. Prosurvival members of the Bcl-2 family such as Bcl-2, Bcl-xL and Bcl-w associate with the mitochondrial membrane to maintain its integrity. An example of intracellular sensors is the p53 tumor suppressor gene, which recognizes DNA damage. Activation of p53 results in G1 phase cell cycle arrest to allow DNA repair; however, irreparable damage commits the cell to death by apoptosis.24 Regardless of the many different signals and signal sensors involved in the activation of apoptosis, both the extrinsic and intrinsic pathways activate downstream caspases, the executioner of apoptosis. Caspases, or cysteine aspartate proteases, are highly conserved proteins first recognized as the ced-3 gene product from the nematode Caenorhabditis elegans25 and are intimately involved in the conserved biochemical pathway that mediates apoptosis. These proteolytic enzymes are synthesized as inactive proenzymes that require cleavage for activation. The protein substrates cleaved by activated caspases play a functional role in the morphologic and biochemical features seen in apoptotic cells. As indicated in Figure 3-11, activated caspases result in the destruction of cytoskeletal and structural proteins (α-fodrin and actin), nuclear structural components (NuMA and lamins), and

FIGURE 3-11 The apoptotic pathways of cell death. The molecular mechanisms involved in apoptosis are divided into three parts. First, stimuli of the apoptotic pathway include DNA damage by ionizing radiation or chemotherapeutic agents (p53 activation), activation of death receptors, free radical formation, and loss of growth factor signaling. Second, progression of these stimuli to the central execution pathway is positively or negatively regulated by expression of the Bcl-2 family of proteins. Third, the execution phase of apoptosis involves the activation of a family of evolutionarily conserved proteases called caspases. Caspase activation targets various nuclear and cytoplasmic proteins for activation or destruction, thereby leading to the morphologic and biochemical characteristics of apoptosis. (From Papaconstantinou HT, Ko TC: Cell cycle and apoptosis regulation in GI cancers. In Evers BM [ed]: Molecular mechanisms in gastrointestinal cancer, Austin, Tex, 1999, RG Landes, p 59.)

cell adhesion factors (FAK). They induce cell cycle arrest through Rb cleavage, cytoplasmic release of p53 by cleavage of the regulatory double minute 2 (MDM2) protein, and subsequent nuclear translocation and activation of PKC-δ. DNA repair enzymes, such as poly(adenosine diphosphate [ADP]-ribose) polymerase and the 140-kDa component of DNA replication complex C, are inactivated by caspase proteolysis. Finally, DNA fragmentation is induced by the activation and nuclear translocation of a 45-kDa cytoplasmic protein called DNA fragmentation factor (DFF). Overall, the net effect of caspase activation is to halt cell cycle progression, disable homeostatic and repair mechanisms, initiate detachment of the cell from its surrounding tissue structures, disassemble structural components, and mark the dying cell for engulfment by surrounding phagocytic cells. The complex molecular machinery of apoptosis, involving signaling, regulation of activation, promotion (or inhibition), and then execution, is a carefully choreographed process. Perturbations in this process at any of these three phases can result in loss of the apoptotic cell elimination pathway. Because apoptosis is a key regulator of cell number and therefore tissue homeostasis, it is easy to see how dysregulation of apoptosis can result in diseases such as cancer or autoimmunity. Autophagy Although apoptosis is a well-characterized process, less is known about the autophagic cell death process. Autophagic cell death is a degradative process characterized by the sequestering of

Molecular and Cell Biology Chapter 3 35

Autophagosome

Lysosome

Autolysosome

FIGURE 3-12 The autophagy pathway. Autophagy proceeds through a series of regulated steps, including the formation of phagophores, leading to autophagosome. Autophagosomes fuse with lysosomes to form autolysosomes, in which cellular materials and organelles are degraded and building blocks are recycled.

organelles and portions of the cytoplasm in double-membrane vesicles known as autophagosomes.22 Autophagosomes fuse with cytoplasmic lysosomes to form autolysosomes, enabling the lysosomal hydrolases to degrade engulfed cytoplasmic material and organelles (Fig. 3-12). This degradative process is genetically regulated and evolutionarily conserved, and is called autophagy. Autophagy plays an important role in protecting against infection, neurodegeneration, and tumor development. Autophagy is associated with cell death, but it is also associated with cell survival by sequestering and recycling damaged proteins and organelle during stress, or by regenerating building blocks for macromolecular synthesis during starvation. Autophagy is controlled by a group of genes (ATG genes) with at least 11 mammalian members. ATG genes control each step of autophagy, including the induction and formation of autophagic vesicles, fusion with lysosomes, and degradation of engulfed material. It is increasingly clear that dysregulation of autophagy con tributes to the development of cancer, liver disease, aging, and inflammation.26 HUMAN GENOME PROJECT One of the most significant scientific undertakings of all times involved the identification and sequencing of the entire human genome, which was completed in the spring of 2003. The Human Genome Project has had a significant impact on the field of medicine by providing clinicians with an unprecedented arsenal of genetic information that will, it is hoped, lead to a better understanding and treatment of a variety of genetic diseases. For example, the Human Genome Project has been providing new information on the genetic variations in the human population by identifying DNA variants such as single nucleotide polymorphisms (SNPs), which occur approximately once every 300 to 500 bases along the 3 billion–base human genome.27 SNPs are thought to serve as genetic markers for identifying disease genes by linkage studies in families or by the discovery of genes involved in human diseases. These findings may lead to better screening and help implement preventive medical therapy in the hope of reducing the development of certain diseases in patients found to have predisposing conditions. It is anticipated that knowing the sequence of human DNA will allow scientists to understand a host of diseases better. With new information and techniques to unravel the mysteries of human biology, this information will dramatically accelerate the development of new strategies for the diagnosis, prevention, and treatment of disease, not just for single-gene disorders, but for more common complex

diseases, such as diabetes, heart disease, and cancer, for which genetic differences may contribute to the risk of contracting the disease and response to particular therapies. The transition from genetics to genomics marks the evolution from an understanding of single genes and their individual functions to a more global understanding of the actions of multiple genes and their control of biologic systems. Technology emanating from the Human Genome Project is available to assess an array of genes that may change (increase or decrease) over time or with treatment. Such technology, using so-called DNA chips, provides one of the most promising approaches to large-scale studies of genetic variations, detection of heterogeneous gene mutations, and gene expression. DNA chips, which are also called microarrays, generally consist of a thin slice of glass or silicone approximately the size of a postage stamp on which threads of synthetic nucleic acids are arrayed.28 Literally thousands of genes can be assessed on a single DNA chip. A clinical example of the use of microarrays includes the detection of human immunodeficiency virus (HIV) sequence variations, p53 gene mutations in breast tissue, and expression of cytochrome P-450 genes. In addition, microarray technology has been applied to genomic comparisons across species, genetic recombination, and large-scale analyses of gene copy number and expression, as well as protein expression in cancers. As genome technology moves from the laboratory to the clinical setting, new methods will make it possible to read the instructions contained in an individual person’s DNA. Such knowledge may predict future disease and alert patients and their health care providers to initiate preventive strategies. Individual DNA profiles, as well as the DNA profiles of tumors, may provide better stratification of patients for cancer therapies. The Human Genome Project is certain to have an important impact on all areas of clinical medicine. All surgical disciplines will be directly affected by this information. We focus on some specific examples here for which we foresee major developments that will greatly influence our clinical management. Transplantation Despite the remarkable advances made in transplantation, organ procurement, and immunosuppression, a significant impediment remains the availability of suitable organs. The level of organ and tissue demand cannot be met by organ donation alone. Xenotransplantation has been proposed as a possible solution to the problem of organ availability and suitability for transplantation. A number of investigators have examined the

SECTION I SURGICAL BASIC PRINCIPLES

Phagophore

36 SECTION I SURGICAL BASIC PRINCIPLES possibility of using xenotransplanted organs. However, although short-term successes have been reported, there have been no long-term survivors with the use of these techniques. Data obtained from the Human Genome Project may enable transplant investigators to engineer animals genetically to potentially have more specific combinations of human antigens. It is anticipated that in the future, animals can be developed whose immune systems have been engineered to more closely resemble those of humans, thus eliminating dependence on organ donors. Another possibility to address the organ donation problem is the potential for organ cloning. With the cloning of sheep and cattle, this topic has received a considerable amount of attention. Although the issue of whole-animal cloning is fascinating, the area that offers the greatest hope for transplant patients is the growing field of stem cell biology. By identifying stem cells of interest, the information gathered from the Human Genome Project could enable scientists to develop organ-cloning techniques that will revolutionize the field of transplantation. These pluripotent stem cells have the ability to divide without limit and give rise to many types of differentiated and specialized tissues with a specific purpose. It is anticipated that the identification of stem cells and the potential modification of these cells by gene therapy may allow investigators to engineer tissues of interest genetically. Oncology The results of the Human Genome Project will have farreaching effects on diagnostic studies, treatment, and counseling of cancer patients and family members.28 Genetic testing is currently available for many disorders, including Tay-Sachs disease and cystic fibrosis. New tests have been developed to detect predispositions to Alzheimer’s disease, colon cancer, breast cancer, and other conditions. Identification of the entire human genome will provide an unprecedented and powerful modality to increase our ability to screen high-risk groups and the general population. With the identification of certain high-risk groups for the development of cancer, surgeons are playing an ever-increasing role in genetic assessment and ultimate therapy. Prophylactic surgery may soon become more prevalent as a first-line treatment in the fight against cancer. For example, discovery of the association between mutations of the ret proto-oncogene and hereditary medullary thyroid carcinoma has allowed surgeons to identify patients in whom medullary thyroid cancer will eventually develop. Genetic screening for mutations of the ret protooncogene in patients with multiple endocrine neoplasia type II allows prophylactic thyroidectomy to be performed at an earlier stage of the disease process than traditional biochemical screening. Other areas of active interest include testing of patients with familial adenomatous polyposis, in which the timing and extent of therapy may be based on the exact location of adenomatous polyposis coli (APC) mutations. Furthermore, additional testing will allow investigators to determine other genes that may contribute to this syndrome. Another area of controversy concerns the treatment of patients with mutations of the breast cancer susceptibility genes BRCA1 and BRCA2. As more information becomes known regarding mutations of these genes and the clinical implications of these mutations, cancer treatment protocols will be altered accordingly.

Pediatric and Fetal Surgery Identification of the human genome will further aid in prenatal diagnostic testing and screening. With the identification of fetuses at risk for a number of identifiable genetic diseases, the Human Genome Project will increase research and activity in the field of fetal surgery by expanding the current knowledge of genetic diseases and rate of fetal surgical interventions involving current techniques and the combination or use of somatic gene therapy. In utero manipulation of identifiable genetic defects may, in the future, become a common intervention. Proteomics An important offshoot of the Human Genome Project has been the realization for the need to examine the expression and function of the end product of the gene (i.e., the protein). This has led to the development of the field of proteomics, which is the study of the proteome. The term proteome was first coined by Marc Wilkins in 1995 to describe the entire collection of proteins of an organism.29 The importance of proteomics is underscored by the fact that almost all cellular phenotypes and activities are directed by proteins. Protein expression and modifications are regulated under normal physiologic conditions (e.g., differentiation, apoptosis, aging and are altered during pathophysiologic stresses, leading to the development and progression of disease). However, the human proteome is complex and dynamic, and its examination requires the development of new tools and technologies. The basic steps in proteomic studies consist of sample preparation, protein separation, protein imaging, and protein identification. Protein separation usually involves two-dimensional gel electrophoresis and protein identification by mass spectrometry (Fig. 3-13).30 With the use of proteomic technologies, investigators have begun to elucidate patterns of protein changes between health and disease states by profiling complex biologic samples such as serum, urine, and tissues.31,32 The field of proteomics has been advancing rapidly with the development of new and more powerful technologies to examine complex protein interactions and protein modifications. These advancements will lead to better detection and risk assessment, therapeutic targeting, and patient-tailored therapy for human diseases. NOVEL TREATMENT STRATEGIES Gene Therapy The ability to alter specific genes of interest represents an exciting and powerful tool in the potential treatment of a wide array of diseases.33-35 Instead of giving a patient a drug to treat or control the symptoms of a genetic disorder, physicians may be capable of treating the basic problem by altering the genetic makeup of the patient’s cells. Several methods are available to introduce new genetic material into mammalian cells. Typically, two strategies have been considered, germline and somatic cell gene therapy. In the germline strategy, foreign DNA is introduced into the zygote or early embryo with the expectation that the newly introduced material will contribute to the germline of the recipient and therefore be passed to the next generation. In contrast, somatic cell gene therapy models represent the introduction of genetic material into somatic cells, which is then not transmitted to the germ cells. A wide array of somatic cell gene therapy protocols designed to treat single-gene diseases, a variety of cancers, or HIV are

Molecular and Cell Biology Chapter 3 37

Prefractionation and extraction Protein mixture

Protein identification Database search MS data

Separation by 2-DE Protein spots

MS analysis

Spot excision and in-gel digestion (e.g., tryspin digestion) Peptides

under development, with some gene therapy protocols in clinical trials. The goals of human somatic gene therapy are generally one of the following: repair or compensate for a defective gene, enhance the immune response directed at a tumor or pathogen, protect vulnerable cell populations against treatments such as chemotherapy, or kill tumor cells directly.36,37 Several single-gene disorders are candidates for gene therapy and a number of protocols have been developed. In addition, current thinking has expanded from the treatment of single-gene disorders to include the treatment of acquired immunodeficiency syndrome (AIDS) and atherosclerosis with gene therapy techniques. Moreover, many protocols for the treatment of cancer are under evaluation, particularly for otherwise untreatable conditions. Strategies include the alteration of cancer cells or other host cells to produce cytokines or other molecules to alter the host response to the malignancy, expression of antigens on cancer cells to induce a host immune response, insertion of tumor suppressor genes or their sequences to slow cell growth, and introduction of drug-resistant genes into normal cells to facilitate more aggressive chemotherapy. Although a number of in vitro experiments have shown great promise, in vivo trials have failed to match the in vitro results, partly as a result of the vehicles used for transfecting the DNA into cells. A repertoire of viral-based vectors have been analyzed, with each generation showing more promise than the previous modification.38 Initially, retroviruses were used as vectors and are still used in certain cases. However, other potential vectors include adenovirus, herpesvirus, vaccinia, and other viruses. Nonviral systems, such as liposomes, DNA-protein conjugates, and DNA–protein-defective virus conjugates, also appear promising.39 Safety issues, improvement of in vivo gene delivery, efficiency, and gene regulation after cellular transduction are the difficult issues that must be resolved in vector design. However, exciting and appealing the prospects of gene therapy may appear, this technique is still in the experimental stages. Short Interfering RNA The discovery of siRNA as a method of gene silencing has provided another novel treatment strategy by targeting diseasecausing genes. This powerful tool has already been tested in experimental conditions of viral infectious diseases and cancers. In infectious diseases, siRNAs against hepatitis B virus, HIV-1,

FIGURE 3-13 Basic approach of proteomics-based research. 2-DE, Two-dimensional gel electrophoresis; MS, mass spectrometry. (From Lam L, Lind J, Semsarian C: Application of proteomics in cardiovascular medicine. Int J Cardiol 108:12– 19, 2006.)

and respiratory syncytial virus have been shown to inhibit viral replication.40 Silencing of oncogenes such as K-ras and HER2/neu has been shown to inhibit cancer cell growth. Although siRNA-based therapy holds great promise because of its potential for high selectivity and less toxicity, its clinical applications require overcoming the problem of the short half-life of siRNA and effective delivery to target tissues. Scientists are developing modifications of siRNA that will extend its half-life and improve cellular uptake. Drug Design Based on information from the fields of genomics and structural biology, rational drug design can be devised to treat a host of diseases.41 This technique has been used to generate potent drugs, many of which are currently in use or under study. For example, a rational design based on crystallographic data has led to the development of new classes of anti-HIV agents targeted against HIV protease. Once the critical proteins accounting for a disease are identified and their abnormal function understood, drugs can be designed to stimulate, inhibit, or substitute function. Identification of human genetic variations will eventually allow clinicians to subclassify diseases and adapt therapies that are appropriate to the individual patient.42 There may be differences in the effectiveness of medicines from one patient to the next. Furthermore, toxic reactions can occur that may be a consequence of genetically encoded host factors. These observations have spawned the field of pharmacogenomics, which attempts to use information on genetic variations in patients to predict responses to drug therapies. In addition to genetic tests that will predict responsiveness to therapies currently available, these genetic approaches to disease prevention and treatment should provide an expanding array of gene products that will be used in developing future drug therapies. Genetic Engineering of Antibodies Monoclonal antibodies directed against specific antigens have been generated by using hybridoma techniques and are widely used in a number of fields of medicine, including oncology and transplantation. However, a major drawback is the fact that repeated treatment with murine antibodies results in an immune response directed against the antibody. Genetic engineering

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Sample (e.g., cells/serum/tissues)

38 SECTION I SURGICAL BASIC PRINCIPLES techniques have allowed the modification of mouse monoclonal antibodies to reduce the immune response directed against them by human recipients and to provide nonhuman resources for human antibodies.43 This modification involves cloning the variable or hypervariable regions of the antibody from the mRNA of a hybridoma and fusing them with a human constant region, thus resulting in clones that can be expressed in human cell lines to produce large amounts of modified antibody. It is anticipated that such techniques will become more common in the future and provide a ready source of antibodies directed against a wide array of antigens.

Fadeel B, Orrenius S: Apoptosis: A basic biological phenomenon with wide-ranging implications in human disease. J Intern Med 258:479–517, 2005.

ETHICAL, PSYCHOLOGICAL, AND LEGAL IMPLICATIONS The possibilities of genetic-based medicine are endless, and one can predict that in the next decade our lives will be greatly altered because of these rapid advances.44 A number of ethical, psychological, and legal implications can be envisioned and will need to be addressed.45,46 Such issues include ownership of the genetic information and who should have access to this information.47 Another issue is how to counsel the patient and other family members correctly based on information obtained from genetic testing. The surgeon of the future will need to participate actively and be knowledgeable in these emerging technologies because our management of specific problems will be greatly altered by the new knowledge gained from analysis of the human genome.44,48,49 Most assuredly, these rapid advances will continue to alter current treatment strategies and challenge existing dogmas. Surgeons have the opportunity to be active participants and leaders in the research and complex decision making process that will affect the treatment of patients who require surgery. Surgeons, and all physicians, must rise to the occasion or otherwise be relegated to bystander status, with the possibility of these complex clinical and ethical decisions being made by nonclinicians.

Papaconstantinou HT, Ko TC: Cell cycle and apoptosis regulation in GI cancers. In Evers BM, editor: Molecular mechanisms of gastrointestinal cancers, Austin, Tex, 1999, Landes Bioscience, pp 49–78.

SELECTED REFERENCES Alberts B, Johnson A, Lewis J, et al, editors: Molecular biology of the cell, ed 5, New York, 2008, Garland. This textbook provides an excellent primer for the reader to understand the fundamental concepts of molecular biology.

Calvo KR, Liotta LA, Petricoin EF: Clinical proteomics: From biomarker discovery and cell signaling profiles to individualized personal therapy. Biosci Rep 25:107–125, 2005. This is an extensive review of proteomics and its potential applications in clinical practice.

Collins FS: Shattuck Lecture—medical and societal consequences of the Human Genome Project. N Engl J Med 341:28–37, 1999. This paper by the leader of the Human Genome Project provides an assessment of the progress toward completing this project, as well as future implications regarding human disease prevention and treatment.

This is a review of the mechanism of apoptosis and its implications for medicine.

Malumbres M, Barbacid M: Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641, 2005. This is an excellent review of the proteins that regulate cell cycle progression.

This chapter provides an excellent review for the reader to understand regulation of the cell cycle and apoptosis.

Rychahou PG, Jackson LN, Farrow BJ, et al: RNA interference: Mechanisms of action and therapeutic consideration. Surgery 140: 719–725, 2006. This is a review of progress in RNA interference technology and its potential clinical applications.

Sambrook J, Russell D, editors: Molecular cloning: A laboratory manual, ed 3, Plainview, NY, 2001, Cold Spring Harbor Laboratory Press. This manual is a collection of laboratory protocols, including detailed discussion of DNA recombinant technology.

The Chipping Forecast. Nat Genet 21(Suppl):1–60, 1999. This entire supplement provides an excellent primer for the reader to understand and appreciate the vast scientific potential and usefulness of microarray (i.e., gene chip) technology. A basic description of these techniques and possible limitations is presented.

REFERENCES 1. Alberts B, Johnson A, Lewis J, et al: Molecular biology of the cell, ed 5, New York, 2008, Garland. 2. Lodish H, Berk A, Kaiser CA, et al: Molecular cell biology, ed 6, New York, 2008, WH Freeman. 3. Rosenthal N: DNA and the genetic code. N Engl J Med 331:39–41, 1994. 4. Mata J, Marguerat S, Bahler J: Post-transcriptional control of gene expression: A genome-wide perspective. Trends Biochem Sci 30: 506–514, 2005. 5. Yang XJ: Multisite protein modification and intramolecular signaling. Oncogene 24:1653–1662, 2005. 6. Rosenthal N: Tools of the trade—recombinant DNA. N Engl J Med 331:315–317, 1994. 7. Templeton NS: The polymerase chain reaction. History, methods, and applications. Diagn Mol Pathol 1:58–72, 1992. 8. Hofker MH, Breuer M: Generation of transgenic mice. Methods Mol Biol 110:63–78, 1998.

Molecular and Cell Biology Chapter 3 39 29. Wilkins MR, Sanchez JC, Gooley AA, et al: Progress with proteome projects: Why all proteins expressed by a genome should be identified and how to do it. Biotechnol Genet Eng Rev 13: 19–50, 1996. 30. Lam L, Lind J, Semsarian C: Application of proteomics in cardiovascular medicine. Int J Cardiol 108:12–19, 2006. 31. Colantonio DA, Chan DW: The clinical application of proteomics. Clin Chim Acta 357:151–158, 2005. 32. Plebani M: Proteomics: The next revolution in laboratory medicine? Clin Chim Acta 357:113–122, 2005. 33. Prieto J, Herraiz M, Sangro B, et al: The promise of gene therapy in gastrointestinal and liver diseases. Gut 52(Suppl 2):49–54, 2003. 34. Meyerson SL, Schwartz LB: Gene therapy as a therapeutic intervention for vascular disease. J Cardiovasc Nurs 13:91–109, 1999. 35. Petrie NC, Yao F, Eriksson E: Gene therapy in wound healing. Surg Clin North Am 83:597–616, vii, 2003. 36. Lee JH, Klein HG: Cellular gene therapy. Hematol Oncol Clin North Am 9:91–113, 1995. 37. Crystal RG: In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene transfer vectors. Cancer Chemother Pharmacol 43(Suppl):S90–S99, 1999. 38. Mah C, Byrne BJ, Flotte TR: Virus-based gene delivery systems. Clin Pharmaco*kinet 41:901–911, 2002. 39. Niidome T, Huang L: Gene therapy progress and prospects: Nonviral vectors. Gene Ther 9:1647–1652, 2002. 40. Rychahou PG, Jackson LN, Farrow BJ, et al: RNA interference: mechanisms of action and therapeutic consideration. Surgery 140:719–725, 2006. 41. Bailey DS, Bondar A, Furness LM: Pharmacogenomics—it’s not just pharmacogenetics. Curr Opin Biotechnol 9:595–601, 1998. 42. Evans WE, McLeod HL: Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348:538–549, 2003. 43. Brekke OH, Sandlie I: Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov 2:52–62, 2003. 44. Hernandez A, Evers BM: Functional genomics: clinical effect and the evolving role of the surgeon. Arch Surg 134:1209–1215, 1999. 45. Vineis P: Ethical issues in genetic screening for cancer. Ann Oncol 8:945–949, 1997. 46. Grady C: Ethics and genetic testing. Adv Intern Med 44:389–411, 1999. 47. Nowlan W: Human genetics. A rational view of insurance and genetic discrimination. Science 297:195–196, 2002. 48. Vogelstein B: Genetic testings for cancer: The surgeon’s critical role. Familial colon cancer. J Am Coll Surg 188:74–79, 1999. 49. Moulton G: Surgeons have critical role in genetic testing decisions, medical, legal experts say. J Natl Cancer Inst 90:804–805, 1998.

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9. Majzoub JA, Muglia LJ: Knockout mice. N Engl J Med 334: 904–907, 1996. 10. Fire A, Xu S, Montgomery MK, et al: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811, 1998. 11. McManus MT, Sharp PA: Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 3:737–747, 2002. 12. Signal transduction: Crosstalk. Trends Biochem Sci 17:367–443, 1992. 13. Wettschureck N, Offermanns S: Mammalian G proteins and their cell type specific functions. Physiol Rev 85:1159–1204, 2005. 14. Perona R: Cell signalling: Growth factors and tyrosine kinase receptors. Clin Transl Oncol 8:77–82, 2006. 15. Marinissen MJ, Gutkind JS: G-protein–coupled receptors and signaling networks: Emerging paradigms. Trends Pharmacol Sci 22:368–376, 2001. 16. Hurley JH: Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem 274:7599–7602, 1999. 17. Campbell SL, Khosravi-Far R, Rossman KL, et al: Increasing complexity of Ras signaling. Oncogene 17:1395–1413, 1998. 18. Malumbres M, Barbacid M: Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641, 2005. 19. Tonini T, Hillson C, Claudio PP: Interview with the retinoblastoma family members: Do they help each other? J Cell Physiol 192:138–150, 2002. 20. DeGregori J: The genetics of the E2F family of transcription factors: Shared functions and unique roles. Biochim Biophys Acta 1602:131–150, 2002. 21. Galluzzi L, Maiuri MC, Vitale I, et al: Cell death modalities: Classification and pathophysiological implications. Cell Death Differ 14:1237–1243, 2007. 22. Thorburn A: Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis 13:1–9, 2008. 23. Cory S, Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656, 2002. 24. Vousden KH, Lu X: Live or let die: The cell’s response to p53. Nat Rev Cancer 2:594–604, 2002. 25. Lavrik IN, Golks A, Krammer PH: Caspases: Pharmacological manipulation of cell death. J Clin Invest 115:2665–2672, 2005. 26. Kroemer G, White E: Autophagy for the avoidance of degenerative, inflammatory, infectious, and neoplastic disease. Curr Opin Cell Biol 22:121–123, 2010. 27. Wang DG, Fan JB, Siao CJ, et al: Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280:1077–1082, 1998. 28. Khan J, Bittner ML, Chen Y, et al: DNA microarray technology: The anticipated impact on the study of human disease. Biochim Biophys Acta 1423:M17–M28, 1999.

CHAPTER 4

THE INFLAMMATORY RESPONSE Mitchell P. Fink

the danger hypothesis: danger-associated molecular patterns, pathogen-associated molecular patterns, and alarmins cytokines and chemokines neuroendocrine control of the inflammatory response

Celsus is credited with describing the cardinal clinical signs of inflammation—calor (warmth), dolor (pain), tumor (swelling), and rubor (redness). Classically, the term inflammation was used to denote the pathologic reaction whereby fluid and circulating leukocytes accumulate in extravascular tissue in response to injury or infection. Today, inflammation connotes not only localized effects, such as edema, hyperemia, and leukocytic infiltration, but also systemic phenomena—for example, fever and increased synthesis of certain acute-phase proteins and mediators of inflammation. The inflammatory response is closely inter related with the processes of healing and repair. In fact, wound healing is impossible in the absence of inflammation. Accordingly, inflammation is involved in almost every aspect of surgery because proper healing of traumatic wounds, surgical incisions, and various types of anastomoses is entirely dependent on the expression of a tightly orchestrated and well-controlled inflammatory process. Inflammation is fundamentally a protective response that has evolved to permit higher forms of life to rid themselves of injurious agents, remove necrotic cells and cellular debris, and repair damage to tissues and organs. However, the mechanisms used to kill invading microorganisms or to ingest and destroy devitalized cells as part of the inflammatory response can also be injurious to normal tissue. Thus, inflammation is a major pathogenic mechanism underlying numerous diseases and syndromes. Many of these pathologic conditions, such as inflammatory bowel disease (IBD), sepsis, and adult respiratory distress syndrome (ARDS), are of importance in the practice of surgery. Initiation, maintenance, and termination of the inflammatory response are extremely complex processes involving numerous different cell types, as well as hundreds of different humoral mediators. A truly comprehensive account of the inflammatory response is beyond the scope of a single chapter in a text covering many other topics. Necessarily, therefore, this chapter will focus on the main initiators of inflammation and the most important cellular and humoral mediators of the inflammatory response. 40

For the purpose of describing the inflammatory process, this overview will make frequent mention of a common, but complicated, clinical entity—severe sepsis—as a paradigm of the inflammatory response. Severe sepsis is a syndrome caused by a systemic inflammatory response run amok. Sepsis is the most common cause of mortality in patients requiring care in an intensive care unit. Severe sepsis, which occurs in approximately 750,000 people in the United States every year, carries a mortality rate close to 30%. It is generally believed that the incidence of sepsis and septic shock is increasing, probably as a result of advances in many fields of medicine that have extended the use of complex invasive procedures and potent immunosuppressive agents. Given the importance of sepsis as a public health problem, efforts have been made to translate improvements in our understanding of inflammation and inflammatory mediators into the development of useful therapeutic agents. Some of these therapeutic agents are noted in the context of the overall discussion of inflammation. THE DANGER HYPOTHESIS: DANGER-ASSOCIATED MOLECULAR PATTERNS, PATHOGEN-ASSOCIATED MOLECULAR PATTERNS, AND ALARMINS The immune system protects the host against disease caused by a wide range of exogenous pathogenic agents, such as viruses, bacteria, fungi, protozoa, and parasitic worms. The immune system, however, also plays a role in detecting and dealing with other threats to health, such as trauma, tissue necrosis, and malignant transformation, which typically are not caused by exogenous pathogens. To accomplish these goals, the immune system uses a layered strategy. The first layer consists of the innate responses, which occur early and are not antigen-specific. The innate responses depend largely on the proper functioning of natural killer (NK) cells and phagocytic cells, such as monocytes, macrophages, and neutrophils. The second layer is composed of adaptive responses, which develop later after the processing of antigen(s) by dendritic cells and the clonal expansion of T and B cell subsets. Adaptive responses are antigenspecific. From an evolutionary standpoint, the innate immune system is truly ancient, whereas the adaptive immune system is a more recent biologic innovation. Aspects of the innate immune system can be found in primitive multicellular organisms, plants, insects, and other invertebrates. In contrast, an adaptive immune system is present only in vertebrate species. Key components of the innate immune system include the following: cells, such as

The Inflammatory Response Chapter 4 41 Inducing cytokines

CD4+ T cell subset “Signature” cytokines Th1

IFN-γ, IL-2

Th2

IL-4, IL-10, IL-13

Th17

IL-17A, TNF, IL-1

Treg

TGF-β, IL-10

IL-12 + IL-18 IL-4 Th0

TGF-β + IL-6 or IL-23 TGF-β

FIGURE 4-1 Simplified representation of the differentiation of naïve helper T cells (Th0) into the four known CD4+ helper T cell subtypes, which are called Th1, Th2, Th17, and Treg. A specific cytokine, secreted by the various helper T cell subtypes, constitutes a signature for that particular class of cells. Differentiation of Th0 cells into the various subtypes is driven by specific cytokines or, in some cases, a specific combination of two cytokines. For example, differentiation of Th0 cells along the Th1 pathway is driven by IL-12 in combination with IL-18, whereas differentiation of Th0 cells along the Th2 pathway is driven by IL-4.

come in the form of trauma or malignant transformation. The molecules that signal the presence of something dangerous share a number of recognizable biochemical features, and collectively are referred to as danger (or damage)-associated molecular patterns (DAMPs). Some DAMPs are host-derived; compounds in this class are called alarmins.3 Other DAMPs are derived from pathogenic microorganisms and are called pathogen-associated molecular patterns (PAMPs). Cells of the innate immune system recognize PAMPs and alarmins via a limited number of germline-encoded pattern recognition receptors (PRRs). The interaction between a DAMP and a PRR initiates intracellular signaling cascades that ultimately culminate in the expression of a broad range of molecules, including cytokines and chemokines, cell surface adhesion molecules, and enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which underlie the development of the inflammatory response. Lipopolysaccharide Much of our understanding of the innate immune system and the pathophysiology of inflammation has come from experimental studies with a compound called lipopolysaccharide (LPS) or endotoxin, which is a proinflammatory component of the cell wall of gram-negative bacteria. When experimental animals are injected with purified LPS, they manifest clinical and biochemical findings reminiscent of those observed in patients with severe sepsis or septic shock. Depending on myriad factors (e.g., the animal species being studied, the dose of LPS, its route of administration), the features of acute endotoxemia can include fever (or hypothermia), systemic arterial hypotension, leukocytosis or leukopenia, renal dysfunction, pulmonary dysfunction, hepatocellular damage, and metabolic acidosis.

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macrophages, neutrophils, mast cells, and dendritic cells; the complement system; various secreted proteins, called cytokines and chemokines; and myriad small molecule mediators, such as prostaglandins, bradykinin, reactive oxygen species (ROS), and nitric oxide (NO·). The adaptive immune response is characterized by antigen specificity and memory (i.e., the ability to mount a more vigorous response to an antigen that has been encountered previously). T and B lymphocytes are the main cellular mediators of adaptive immune responses. B cells and their progeny, plasma cells, are responsible for the production of antibodies, which are the humoral mediators of the adaptive immune system. T cells, which can be classified into various subtypes, play important roles in innate and adaptive immune responses. For example, natural killer T cells bridge the gap between the innate and adaptive immune systems because they are activated by glycolipid antigens presented by the glycoprotein, CD1d, on antigen-presenting cells. T helper cells (Th), which express the surface protein, CD4, also play key roles in the orchestration of innate and adaptive immune responses. Naïve CD4+ T cells (Th0 cells) can differentiate into at least four different Th subsets, called Th1, Th2, Th17, and T regulatory cells (Treg cells; Fig. 4-1). Th1 cells are responsible for directing the cell-mediated immune responses necessary for the eradication of intracellular pathogens, and favor macrophage activation. Th2 cells have been implicated in the pathogenesis of atopy and allergic inflammation and favor B cell growth and differentiation. Th1 cells produce the potent proinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β; also called lymphotoxin). Th2 cells produce the cytokines interleukin-4 (IL-4), IL-5, IL-6, IL-10, and IL-13. The actions of IL-4, IL-10, and IL-13 are largely anti-inflammatory in nature. The actions of IL-6 can be both pro- and anti-inflammatory. Th17 cells produce several cytokines, notably IL-17A and IL-17F. Both IL-17A and IL-17F tend to be proinflammatory. The signature cytokines produced by Treg cells—namely transforming growth factor-β (TGF-β) and IL-10—are both anti-inflammatory. Thus, Th1 and Th17 lymphocytes are often viewed as being proinflammatory, whereas Th2 lymphocytes and Tregs are thought of as being antiinflammatory. The cytokine, IL-12, drives Th1 differentiation, IL-4 induces Th2 differentiation, and TGF-β in combination with IL-6 promotes Th17 differentiation, but TGF-β in the absence of IL-6 promotes precursor cells to differentiate into Treg cells.1 Historically, activation of the immune system was thought to be triggered by the presence of antigens, which were recognized as being non-self in nature. However, the self-nonself model of immune surveillance and discrimination was burdened by the inability to account for numerous observations satisfactorily, such as the necessity for the presence of a tissue-damaging adjuvant to obtain a vigorous immune response to the nonself proteins present in vaccines. To address these concerns, the innovative immunologist, Polly Matzinger, formulated the danger model to explain immune system activation and discrimination.2 According to this hypothesis, which is now widely accepted, activation of the innate immune system is triggered by a diverse set of molecules that indicate the presence of danger to the host (i.e., something that could threaten health and wellbeing). Danger might come in the form of an invasion of host tissues by a pathogenic microorganism, but danger also might

42 SECTION I SURGICAL BASIC PRINCIPLES LPS is a complex glycolipid composed of a polysaccharide tail attached to a lipophilic domain called lipid A. The polysaccharide portion of the molecule tends to be structurally different in different species and strains of gram-negative bacteria, whereas the structure of lipid A (as well as a few neighboring sugar residues) is highly conserved across different species and strains of gram-negative microorganisms. A complex of LPS and a serum protein, LPS-binding protein (LBP), initiates the activation of monocytes and macrophages by binding to a surface protein, CD14. Because it is a glycophosphatidylinositol-anchored membrane protein, CD14 lacks a cytosolic domain and is unable to initiate intracellular signaling directly. Accordingly, investigators sought to identify another protein that presumably participates with CD14 to initiate the cellular response to LPS. The putative LPS coreceptor was ultimately identified as a Toll-like receptor (TLR).4 Toll-Like Receptors TLR4, as well as other members of the TLR family of PRRs, is a hom*ologue of a protein, Toll, which plays roles in embryogenesis as well as antifungal immunity in fruit flies. TLR4 was originally identified by studying an inbred strain of mice, C3H/ HeJ, that is congenitally hyporesponsive to endotoxin. Subsequently, TLR4 knockout mice were generated and shown to be as hyporesponsive to LPS as C3H/HeJ mice, thus confirming the concept that expression of functional TLR4 is necessary for the activation of macrophages and monocytes by endotoxin. TLR4 mutations are also associated with endotoxin hypo responsiveness in humans. MD-2, another protein associated with the extracellular domain of TLR4, is required for LPS responsiveness. In addition to LPS, other PAMPs and alarmins are recognized by various TLRs (Table 4-1). For example, TLR2 recognizes various bacterial lipoproteins, as well as peptidoglycan derived from gram-positive bacteria. TLR5 recognizes flagellin, a 55-kDa protein found in the flagella of certain bacteria. TLR9 recognizes certain oligonucleotides containing unmethylated CpG motifs that are more common in bacterial DNA than in mammalian DNA. Among the TLRs, TLR4 seems to be particularly important, because this receptor recognizes not only the PAMP, LPS, but several endogenous danger signals as well. These endogenous ligands for TLR4 include the following: heat shock protein (HSP) 70, an inducible cytosolic protein, which is important for the proper folding of nascent proteins; high-mobility group box-1(HMGB1), an abundant DNA-binding protein, which is important for transcription and repair of DNA; extra domain A of fibronectin, an abundant protein in the extracellular matrix; and fragments of hyaluronan, a glycosaminoglycan, which is one of the chief components of the extracellular matrix. Some of these alarmins, such as HMGB1, are actively secreted by immunostimulated macrophages or enterocytes, whereas others, such as hyaluronan fragments, are probably generated as a consequence of trauma to tissues. Accumulating evidence obtained by the Billiar group at the University of Pittsburgh has suggested that many of the deleterious host responses to severe trauma and/or hemorrhagic shock are mediated by the interaction of endogenous alarmins with TLR4.4 TLRs are glycoproteins. Their structure includes a ligandbinding domain, containing leucine-rich repeat (LRR) motifs, and a signaling domain, which is hom*ologous to the signaling

domain for the receptor for the cytokine IL-1 (see later). To date, 10 TLRs have been identified in humans, and these receptors can be divided into subfamilies based on the ligands they recognize. The receptors TLR3, TLR7, TLR8, and TLR9, are located intracellularly on membrane-bound endosomes, whereas the remaining members of the TLR family of receptors are situated so that they span the cytosolic membrane on the surface of cells. Other Families of Pattern Recognition Receptors In addition to members of the TLR family, there are two other families of PRRs that are important for recognizing DAMPs and initiating innate immune responses. These two families are the retinoid acid-inducible gene I (RIG-I)–like receptors (RLRs) and the nucleotide-binding oligomerization domain (NOD)– like receptors (NLRs).5 The two RIG-I–like receptors, RIG-I and melanoma differentiation-associated gene (MDA) 5, play a pivotal role in sensing the presence of viral double-stranded (ds) RNA in the cytoplasm. The interaction of ds-RNA with the C-terminal domains of RLRs initiates a signaling cascade, leading ultimately to the expression of cytokines important in antiviral immunity. The two most extensively studied members of the NLR family of receptors are NOD1 and NOD2.5 These PRRs sense PAMPs derived from the synthesis and degradation of bacterial peptidoglycan. NOD1 is activated by diaminopimelic acid produced by gram-negative bacteria, whereas NOD2 is activated by muramyl dipeptide (MDP), produced by gram-negative and gram-positive bacteria. As will be discussed in greater detail, NLRs are not only important for sensing certain intracellular pathogens, but these receptors also play a key role in the processing for secretion of two important proinflammatory cytokines, IL-1β and IL-18. The receptor for advanced glycation end products (RAGE) is a receptor that has multiple potential ligands, including HMGB1, amyloid-β peptide, and certain members of the S100calgranulin family of proteins.6 Because RAGE-dependent signaling may be important for transducing some of the proinflammatory effects the alarmin, HMGB1, RAGE can be considered a PRR involved in innate immunity. High-Mobility Group Box 1 When mice are injected with a lethal bolus dose of LPS, circulating levels of TNF peak approximately 60 to 90 minutes later and are almost undetectable within 4 hours. Although mice show clinical signs of endotoxemia (e.g., decreased activity and ruffled fur) within a few hours after the injection of LPS, mortality typically does not occur until more than 24 hours later, long after circulating levels of the so-called alarm phase cytokines, TNF and IL-1β, have returned to normal. These observations suggested the possibility to Wang and colleagues that LPS-induced lethality might be mediated by a previously unidentified factor that is released much later than TNF or IL-1β.6a Prompted by this idea, these investigators carried out a prolonged search for the putative late-acting mediator. This research program ultimately resulted in the identification of HMGB1 (formerly called HMG-1) as a novel mediator of LPS-induced lethality. HMGB1 was originally identified in 1973 as a nonhistone nuclear protein with high electrophoretic mobility. A characteristic feature of the protein is the presence of two folded DNAbinding motifs termed the A domain and the B domain. Both these domains contain a characteristic grouping of aromatic and

The Inflammatory Response Chapter 4 43

PRR1

PAMP2 OR ALARMIN

COMPOUND

ORIGIN

TLR1/TLR2

PAMP

Triacyl lipopeptides

Bacteria

TLR2/TLR6

PAMP

Diacyl lipopeptides

Bacteria

TLR2/TLR6

PAMP

Lipoteichoic acid

Gram-positive bacteria

TLR2

PAMP

Lipoproteins

Bacteria

TLR2

PAMP

Peptidoglycan

Bacteria

TLR2

PAMP

Lipoarabinomannan

Mycobacteria

TLR2

PAMP

Porins

Neisseria spp.

TLR2

PAMP

Envelope glycoproteins

Viruses

TLR2

PAMP

Glycoinositol-phospholipids

Trypanosoma cruzi

TLR2

PAMP

Glycolipids

Treponema maltophilum

TLR2

PAMP

Phospholipoprotein

Candida spp.

TLR2

PAMP

Zymosan

Fungi

TLR2

PAMP

β-Glycan

Fungi

TLR2

Alarmin

HMGB1

Host cells

TLR2

Alarmin

EDN

Host hepatocytes, PMNs, macrophages

TLR3

PAMP

ds-DNA4

Viruses

TLR4

PAMP

LPS5

Gram-negative bacteria

TLR4

PAMP

Envelope glycoproteins

Viruses

TLR4

PAMP

Mannan

Candida spp.

TLR4

Alarmin

HSP706

Host cells

TLR4

Alarmin

HMGB1

Host cells

TLR4

Alarmin

β-Defensin 2

Host PMNs and epithelial cells

TLR4

Alarmin

Hyaluronan oligomers

Host extracellular matrix

TLR4

Alarmin

Heparan sulfate fragments

Host extracellular matrix

TLR4

Alarmin

Extradomain A fragment of fibronectin

Host extracellular matrix

TLR5

PAMP

Flagellin

Gram-negative bacteria with flagella

TLR7/8

PAMP

ss-RNA7

RNA viruses

TLR9

PAMP

CpG DNA8

Viruses, bacteria, protozoa

TLR10

Unknown

TLR11

PAMP

Profilin-like protein

Toxoplasma gondii

NOD110

PAMP

Diaminopimelic acid

Gram-negative bacteria

NOD2

PAMP

Muramyl dipeptide

Bacteria

NALP1

PAMP

Muramyl dipeptide

Bacteria

NALP3

Alarmin

ATP

Host cells

NALP3

Alarmin

Uric acid crystals

Host cells

RIG-I13

PAMP

ds-RNA, short

Viruses

MDA514

PAMP

ds-RNA, long

Viruses

RAGE15

Alarmin

HMGB1

Host cells

RAGE

Alarmin

S100A12

Host phagocytic cells

PAMP

ds-RNA

Viruses

TLR

NLR9

RLR12

Miscellaneous

PKR

EDN, Eosinophil-derived neurotoxin; PMN, polymorphonuclear cell.

SECTION I SURGICAL BASIC PRINCIPLES

Table 4-1 Recognition of Pathogen-Associated Molecular Patterns and Alarmins by Pattern Recognition Receptors

44 SECTION I SURGICAL BASIC PRINCIPLES basic amino acids within a block of 75 residues termed the HMG box. HMGB1 has several functions within the nucleus, including facilitation of DNA repair and support of the transcriptional regulation of genes. When released by cells into the extracellular milieu, HMGB1 can interact with several different receptors, including TLR2, TLR4, and RAGE, on macrophages, endothelial cells, and enterocytes.7 Activation of these receptors leads to the release of other proinflammatory mediators, such as TNF and NO·. Although HMGB1 is normally not secreted by cells and levels of this protein are usually undetectable in plasma or serum, high circulating concentrations of HMGB1 can be detected in mice 16 to 32 hours after the onset of endotoxemia. Immunostimulated macrophages and enterocytes actively secrete HMGB1. Moreover, necrotic but not apoptotic cells release nuclear HMGB1. In this way, unexpected cell death, such as that secondary to trauma or infection, can act as a danger signal and lead to the induction of an inflammatory response. Delayed passive immunization of mice with antibodies against HMGB1 confers significant protection against LPSinduced mortality. Furthermore, the administration of highly purified recombinant HMGB1 to mice is lethal. Thus, HMGB1 fulfills a modified version of Koch’s criteria for being a mediator of LPS-induced lethality in mice. Direct application of HMGB1 into the airways of mice initiates an acute inflammatory response and lung injury that is reminiscent of ARDS in humans. In addition, HMGB1 (or a truncated form of the protein, including only the B box domain) increases the permeability of human enterocyte-like monolayers in culture and promotes intestinal barrier dysfunction when injected into mice.8 Thus, it seems plausible that HMGB1 contributes to the development of organ dysfunction in human sepsis, a notion that is supported by the observation that circulating HMGB1 concentrations are significantly higher in patients with ultimately fatal sepsis than in patients with a less severe form of the syndrome.9 Circulating levels of HMGB1 are also increased in victims of trauma10 or burn injury.11 Administration of a neutralizing anti-HMGB1 antibody improves survival in mice subjected to lethal hemorrhagic shock.12 Ethyl pyruvate, a compound that blocks the release of HMGB1 from LPS-stimulated murine macrophagelike cells and inhibits release of the mediator in vivo, improves survival in mice with bacterial peritonitis, even when treatment with the compound is delayed for 24 hours after the onset of infection.13 Heat Shock Proteins The heat shock proteins were first identified as a family of molecules that are induced when cells or experimental animals are subjected to sublethal thermal stress. These proteins are also induced by many other stimuli, such as inflammation, oxidative stress, and infection. The primary role of HSPs is to serve as molecular chaperones to facilitate the proper folding of nascent proteins. Like HMGB1, heat shock proteins are normally found inside cells but, under certain conditions, these proteins can be detected in the extracellular milieu. For example, elevated circulating levels of HSP70 have been found in trauma patients and patients in the immediate period after coronary artery bypass graft surgery. In addition, immunostimulated monocytes appear to be capable of actively secreting HSP70. Extracellular HSP70 (and the related protein, HSP60) can activate innate immune

cells via a TLR4-dependent mechanism. Thus, like HMGB1, these proteins may serve as endogenous danger signals and trigger activation of the inflammatory response after damage to tissues. CYTOKINES AND CHEMOKINES Cytokines are small proteins or glycoproteins secreted for the purpose of altering the function of target cells in an endocrine (uncommon), paracrine, or autocrine fashion. In contrast to classic hormones, such as insulin or thyroxine, cytokines are not secreted by specialized glands but, instead, are produced by cells individually (e.g., lymphocytes or macrophages) or as components of a tissue (e.g., the intestinal epithelium). Many cytokines are pleiotropic; these cytokines are capable of inducing many different biologic effects, depending on the target cell types involved and the presence or absence of other modulating factors. Redundancy is another characteristic feature of cytokines—that is, several different cytokines can exert very similar biologic effects. Chemokines are a special family of cytokines that are small proteins with molecular weights in the range of 8 to 11 kDa. The chemokines have as their primary biologic activity the ability to act as chemoattractants for leukocytes or fibroblasts. Another cytokine subclass is a group of proteins that act primarily to stimulate the growth or differentiation (or both) of hematopoietic progenitor cells; these mediators are collectively referred to as colony-stimulating factors. Other growth and differentiation factors, including the various platelet-derived growth factors, epidermal growth factor, and keratinocyte growth factor, also fit into the broad category of cytokines. Overall, hundreds of soluble proteins involved in cell to cell signaling, variously called cytokines, chemokines, interleukins, colony-stimulating factors, and growth factors, have been identified and characterized. Some pertinent facts about some of the most important cytokines are provided in Table 4-2 and some of these mediators are discussed in greater detail in the sections that follow. Interferon-γ and Granulocyte-Macrophage Colony-Stimulating Factor The interferons, named for their ability to interfere with viral infection, were initially discovered in the 1950s as soluble factors secreted by leukocytes. The type 1 interferons, IFN-α and IFNβ, are primarily involved as mediators of innate (and acquired) immune responses to viral infection. IFN-γ, although also important in the immune response to viral infection, has much broader activity as a proinflammatory mediator. For the most part, IFN-γ is produced by three types of cells—CD4+ Th1 cells, CD8+ Th1 cells, and natural killer (NK) cells. IFN-γ, along with IL-12, plays a critical role in promoting the differentiation of CD4+ T cells into the Th1 phenotype. Because Th1 cells also produce IFN-γ, the potential exists for a positive feedback loop. IL-12, produced by monocytes and macrophages, stimulates the production of IFN-γ by Th1 and NK cells. In turn, IFN-γ further activates monocytes and macrophages, thereby creating another positive feedback loop. In addition to promoting the differentiation of uncommitted CD4+ T cells into Th1 cells, IFN-γ inhibits the differentiation of lymphocytes into cells with the Th2 phenotype. Because Th2 cells secrete the counterregulatory cytokines IL-4 and IL-10, the effect of IFN-γ to downregulate the production of these

The Inflammatory Response Chapter 4 45

CYTOKINE

ABBREVIATION

MAIN SOURCES

IMPORTANT BIOLOGIC EFFECTS

Tumor necrosis factor

TNF

Mφ, others

See Table 4-3

Lymphotoxin-α

LT-α

Th1, NK

Same as TNF

Interferon-α

IFN-α

Leukocytes

Increases expression of cell surface class I MHC molecules; inhibits viral replication

Interferon-β

IFN-β

Fibroblasts

Same as IFN-α

Interferon-γ

IFN-γ

Th1

Activates Mφ; promotes differentiation of CD4+ T cells + cells into cells into Th1 cells; inhibits differentiation of CD4+ T cells into Th2 cells

Interleukin-1α

IL-1α

Keratinocytes, others

See Table 4-3

Interleukin-1β

IL-1β

Mφ, NK, DC

See Table 4-3

Interleukin-2

IL-2

Th1

In combination with other stimuli, promotes proliferation of T cells; promotes proliferation of activated B cells; stimulates secretion of cytokines by T cells; increases cytotoxicity of NK cells

Interleukin-3

IL-3

T cells, NK

Stimulates pluripotent bone marrow stem cells to increase production of leukocytes, erythrocytes, and platelets

Interleukin-4

IL-4

Th2

Promotes growth and differentiation of B cells; promotes differentiation of CD4+ T cells into Th2 cells; inhibits secretion of proinflammatory cytokines by Mφ

Interleukin-5

IL-5

T cells, mast cells, Mφ

Induces production of eosinophils from myeloid precursor cells

Interleukin-6

IL-6

Mφ, Th2, EC, enterocytes

Induces fever; promotes B cell maturation and differentiation; stimulates hypothalamic- pituitary-adrenal axis; induces hepatic synthesis of acutephase proteins

Interleukin-8

IL-8

Mφ, EC, enterocytes

Stimulates chemotaxis by PMN; stimulates oxidative burst by PMN

Interleukin-9

IL-9

Th2

Promotes proliferation of activated T cells; promotes immunoglobulin secretion by B cells

Interleukin-10

IL-10

Th2, Mφ

Inhibits secretion of proinflammatory cytokines by Mφ

Interleukin-11

IL-11

DC, bone marrow

Increases production of platelets; inhibits proliferation of fibroblasts

Interleukin-12

IL-12

Mφ, DC

Promotes differentiation of CD4+ T cells into Th1 cells; enhances IFN-γ secretion by TH1 cells

Interleukin-13

IL-13

Th2, others

Inhibits secretion of proinflammatory cytokines by Mφ

Interleukin-17A

IL-17A

Th17

Stimulates production of proinflammatory cytokines by Mφ and many other cell types

Interleukin-18

IL-18

Mφ, others

Costimulation with IL-12 of IFN-γ secretion by Th1 cells and NK cells

Interleukin-21

IL-21

Th2, Th17

Modulation of B cell survival; inhibition of IgE synthesis; inhibition of proinflammatory cytokine production by Mφ

Interleukin-23

IL-23

Mφ, DC

In conjunction with TGF-β, promotes differentiation of naïve T cells into Th17 cells

Interleukin-27

IL-27

Mφ, DC

Suppresses effector functions of lymphocytes and Mφ

Monocyte chemotactic protein-1

MCP-1

EC, others

Stimulates chemotaxis by monocytes; stimulates oxidative burst by Mφ

Granulocytemacrophage colony-stimulating factor

GM-CSF

T cells, Mφ, EC, others

Enhances production of granulocytes and monocytes by bone marrow; primes Mφ to produce proinflammatory mediators after activation by another stimulus

Granulocyte colonystimulating factor

G-CSF

Mφ, fibroblasts

Enhances production of granulocytes by bone marrow

Erythropoietin

EPO

Kidney cells

Enhances production of erythrocytes by bone marrow

Transforming growth factor-β

TGF-β

T cells, Mφ, platelets, others

Stimulates chemotaxis by monocytes and induces synthesis of extracellular proteins by fibroblasts; promotes differentiation of naïve T cells into Treg cells; with IL-6 or IL-23, promotes differentiation of naïve T cells into TH17 cells; inhibits immunoglobulin secretion by B cells; downregulates activation of NK cells

DC, Dendritic cells; EC, endothelial cells; Mφ, cells of the monocyte-macrophage lineage; MHC, major histocompatibility complex; NK, natural killer cells; PMN, polymorphonuclear neutrophils; Th1, Th2, Th17, subsets of differentiated CD4+ T helper cells.

SECTION I SURGICAL BASIC PRINCIPLES

Table 4-2 Cellular Sources and Important Biologic Effects of Selected Cytokines

46 SECTION I SURGICAL BASIC PRINCIPLES cytokines by Th2 cells further promotes the development of an inflammatory response to an invading pathogen. In target cells, such as macrophages or enterocytes, IFN-γ induces the expression or activation of a number of key proteins involved in the innate immune response to microbes. Among these proteins are other cytokines, such as TNF and IL-1, and enzymes, such as iNOS and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Thus, IFN-γ stimulates the release of a number of other proinflammatory mediators, including cytokines, such as TNF, and small molecules, such as superoxide radical anion (O2−·), an oxidant produced by NADPH oxidase, and NO·, produced by iNOS. Secretion of these inflammatory mediators by activated macrophages and other cell types is inhibited by IL-4 and IL-10. Accordingly, IFN-γ–mediated downregulation of the Th2 phenotype—and thereby production of IL-4 and IL-10—further promotes the development of an inflammatory response. The crucial role of IFN-γ in the host’s innate immune response to microbial invasion, particularly by intracellular pathogens, has been emphasized by experiments using transgenic mice with targeted disruption of the genes coding for IFN-γ or the ligand-binding subunit of the IFN-γ receptor (IFN-γR). These knockout mice manifest increased susceptibility to infections caused by Listeria monocytogenes, Mycobacterium tuberculosis, or bacille Calmette-Guérin. When responsive target cells are exposed to IFN-γ, a number of genes are activated within minutes and without the synthesis of new copies of intermediate signaling proteins. IFNγ–induced signal transduction occurs through the activation of a protein tyrosine phosphorylation cascade known as the JAKSTAT pathway (Fig. 4-2). JAK initially stood for “just another kinase” because the biologic role of these proteins was not established when they were initially discovered. Because these receptor-associated kinases look both outside and inside the cell, JAK has now come to stand for Janus kinases, after the two-faced Roman god. The moniker STAT, an acronym for signal transducers and activators of transcription, was appropriately chosen because, in medical parlance, an action to be carried out immediately is a stat order and signaling involving these proteins similarly occurs without delay. In addition to IFN-γ, a large number of other cytokines, including IL-6 and IL-11 (see later), also use versions of the JAK-STAT signaling mechanism. In mammals, there are seven mammalian STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6) and four JAK proteins (JAK1, JAK2, JAK3, and TYK2). IFN-γR is a heterodimer that consists of a 90-kDa glycoprotein, the α chain, which is required for binding of the ligand, and a transmembrane protein, the β chain, which is required for signaling. Associated with the receptor are two members of the JAK family of kinases, JAK1 and JAK2. Interaction of IFN-γ with its receptor results in the dimerization of IFN-γR, which brings JAK1 and JAK2 into close association and leads to mutual phosphorylation and activation (see Fig. 4-2). The activated JAK kinases then catalyze the phosphorylation of tyrosine residues on the α chains of IFN-γR, which results in docking to the receptor complex by the transcription factor STAT1. After tyrosine phosphorylation, two copies of STAT1 form a hom*odimer (IFN-γ activation factor [GAF]) that subsequently dissociates from the receptor complex and translocates to the nucleus, where binding to the regulatory regions of target genes

IFN-γ Receptor

Plasma membrane Cytosol

A IFN-γ

JAK1

= PO4

JAK2

B IFN-γ = STAT1α

JAK1

JAK2

Translocation to nucleus; induction of IFN-γ-responsive genes

FIGURE 4-2 Simplified representation of intracellular signaling mediated by binding of IFN-γ to its receptor (IFN-γR). A, IFN-γR is a dimer that consists of a ligand-binding α chain and a transmembrane signaling β chain. B, Binding of IFN-γ leads to dimerization of IFN-γR and brings two signaling proteins, JAK1 and JAK2, into association with the receptor complex. C, The association of JAK1 and JAK2 with the receptor leads to mutual tyrosine phosphorylation of these proteins, as well as phosphorylation of tyrosine residues on the ligand-binding chains of IFN-γR and docking of two copies of the preformed transcription factor STAT1α to the receptor complex. After tyrosine phosphorylation, STAT1α forms a hom*odimer. The hom*odimer dissociates from the receptor complex and translocates to the nucleus, where binding to the promoter regions of various IFN-γ–responsive genes leads to transcriptional activation.

The Inflammatory Response Chapter 4 47 in vivo studies, treatment with GM-CSF primes monocytes to produce more proinflammatory cytokines, such as TNF, in response to LPS. A randomized trial of adjuvant treatment with recombinant GM-CSF in neonates with sepsis and neutropenia has shown that survival is significantly improved in the group treated with the cytokine–growth factor.15 Similarly, in a single-center randomized controlled trial (RCT), adjuvant treatment with recombinant GM-CSF significantly shortened hospital stay and decreased the number of infectious complications in patients with intra-abdominal sepsis.16 A more recent multicentric RCT has suggested that adjuvant treatment with GM-CSF can improve outcome for selected patients with sepsis.17 This study randomized 38 patients with severe sepsis and evidence of sepsisinduced immunosuppression to treatment with GM-CSF or placebo for 8 days. Although survival was similar in both groups, the GM-CSF–treated patients required mechanical ventilation and care in an ICU for a significantly shorter period of time Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal (GI) tract. Treatment with corticosteroids often ameliorates symptoms of the disease, but chronic administration of corticosteroids is associated with many adverse side effects. Accordingly, clinicians and scientists are actively seeking better approaches to treat Crohn’s disease. Because there is considerable evidence that Crohn’s disease may result, at least in part, from impaired innate immunity (e.g., caused by a mutation in the NOD2 gene),18 recombinant GM-CSF might be a therapeutic option for this condition. This hypothesis has been supported by the results from two RCTs, which showed that therapy with GM-CSF can induce remission in the absence of treatment with corticosteroids.19,20 Interleukin-1 and Tumor Necrosis Factor IL-1 and TNF are structurally dissimilar pluripotent cytokines. Although these compounds bind to different cellular receptors, their multiple biologic activities overlap considerably. For example, in vitro, both cytokines are capable of activating endothelial cells, leading to increased expression of cell surface adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which play important roles in the process whereby neutrophils extravasate from circulation into tissues at the site of infection and/or inflammation. Similarly, incubating cultured monocytes, neutrophils, endothelial cells, hepatocytes, mesangial cells, articular chondrocytes, or synovial fibroblasts with IL-1 or TNF leads to secretion of a chemokine, IL-8 (see later), which is important for recruiting neutrophils into inflammatory foci. Recombinant forms of IL-1β and TNF have been available for many years. Table 4-3 summarizes some of the biologic effects, which are observed when human subjects are injected with recombinant IL-1β or TNF. The information in this table should convince the reader that many of the features associated with the systemic inflammatory response syndrome (SIRS), such as increased circulating leukocyte count and fever, can be reproduced by injecting subjects with the alarm phase cytokines, IL-1β or TNF. Through their ability to potentiate the activation of helper T cells, IL-1 and TNF can promote almost all types of humoral and cellular immune responses. Furthermore, both these cytokines are capable of activating neutrophils and macrophages and inducing the expression of many other cytokines and inflammatory mediators. Many of the biologic effects of

SECTION I SURGICAL BASIC PRINCIPLES

containing the IFN-γ activation site (GAS) nucleotide sequence leads to transcriptional activation. JAK-STAT–dependent signaling is regulated in cells by a variety of mechanisms. Because STATs are activated by tyrosine phosphorylation, phosphotyrosine phosphatases are implicated in the negative regulation of JAK-STAT signaling pathways. In this regard, the first to be described were Src hom*ology 2 domain (SH2)–containing tyrosine phosphatases such as SHP1 and SHP2. The presence of a characteristic amino acid sequence, the SH2 domain, in these cytoplasmic enzymes promotes the association of these phosphatases with phosphotyrosines present on activated receptors or on signaling molecules, as well as on activated JAKs.14 The transmembrane tyrosine phosphatase CD45, which is expressed on T and B cells, also downregulates JAKSTAT signaling. Two other important classes of proteins that regulate JAK-STAT signaling are the protein inhibitors of activated STAT (PIAS) and the inducible suppressors of cytokine signaling (SOCS). The pivotal role played by IFN-γ in the regulation and expression of innate immunity to microbial pathogens led investigators to use this cytokine as a therapeutic agent to increase host resistance to infection, particularly for patients with congenital or acquired immunosuppression. For example, prophylactic treatment with recombinant IFN-γ has been shown to reduce the frequency of infections markedly in patients with chronic granulomatous disease, a life-threatening condition caused by an inherited defect in NADPH oxidase, the enzyme complex responsible for generating ROS in phagocytes. IFN-γ has been approved for this indication by the U.S. Food and Drug Administration (FDA). Severe trauma and burns are associated with defects in host antibacterial and antifungal defense and, in animal models of these conditions, treatment with IFN-γ has been found to increase resistance to infection. Three major clinical trials of prophylactic IFN-γ treatment were conducted in patients with multiple trauma or major thermal injury. Unfortunately, in all three studies, the incidence of infection and mortality was similar in cytokine- and placebo-treated patients. It is unclear why treatment with IFN-γ failed to improve outcomes in these trials. However, treatment with IFN-γ was not individualized according to immunologic phenotype, and thus some of the deleterious effects of inflammation might have been fostered in certain subjects by administration of this potent proinflammatory cytokine. This concept is supported by results from an uncontrolled trial in which patients with sepsis and laboratory findings indicative of excessive immunosuppression (downregulation of human leukocyte antigen [HLA]-DR expression on circulating monocytes) were treated with IFN-γ. In this small study, administration of IFN-γ resulted in the resolution of sepsis in eight of nine patients. A small pilot study evaluated the use of prophylactic perioperative IFN-γ therapy to decrease the risk for infection in anergic high-risk patients undergoing major operations. Results from this study were inconclusive. Another approach may be to substitute granulocytemacrophage colony-stimulating factor (GM-CSF) for IFN-γ. GM-CSF is a hematopoietic growth factor and proinflammatory cytokine produced by multiple cell types, including bronchial epithelial cells, monocytes, and endothelial cells. As a growth factor, GM-CSF promotes an increase in the number of circulating polymorphonuclear nuclear cells (PMNs). However, in addition, GM-CSF has a number of IFN-γ–like features, including the use of JAK-STAT signaling pathways. In both in vitro and

48 SECTION I SURGICAL BASIC PRINCIPLES

Table 4-3 Partial List of Physiologic Effects Induced by Infusing Interleukin-1 or Tumor Necrosis Factor Into Human Subjects EFFECT

IL-1

TNF

Fever

Headache

Anorexia

Increased plasma adrenocorticotropic hormone level

Hypercortisolemia

Increased plasma nitrite-nitrate levels

Systemic arterial hypotension

Neutrophilia

Transient neutropenia

Increased plasma acute-phase protein levels

Hypoferremia

+ +

Hypozincemia Increased plasma level of IL-1RA

Increased plasma level of TNF-R1and TNF-R2

Increased plasma level of IL-6

Increased plasma level of IL-8

Activation of coagulation cascades

−

Increased platelet count

−

Pulmonary edema

−

Hepatocellular injury

−

IL-1 or TNF are greatly potentiated by the presence of the other cytokine. Interleukin-1 and the Interleukin-1 Receptor IL-1 was first described as a lymphocyte-activating factor produced by stimulated macrophages. IL-1 is not a single compound, but rather a family of three distinct proteins, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA), which are products of different genes located close to one another on the long arm of human chromosome 2. The genes for the two receptors for IL-1, IL-1RI and IL-1RII, are also located on chromosome 2. IL-1α and IL-1β are peptides composed of 159 and 153 amino acids, respectively. Although IL-1α and IL-1β are structurally distinct—only 26% of their amino acid sequences are hom*ologous—the two compounds are almost identical from a functional standpoint. IL-1RA, the third member of the IL-1 family of proteins, is biologically inactive but competes with IL-1α and IL-1β for binding to IL-1 receptors on cells and thereby functions as a competitive inhibitor to limit IL-1– mediated effects. IL-1 is synthesized by a wide variety of cell types, including monocytes, macrophages, B lymphocytes, T lymphocytes, NK cells, keratinocytes, dendritic cells, fibroblasts, neutrophils, endothelial cells, and enterocytes. Compounds that can trigger the production of IL-1 by monocytes, macrophages, or other cell types include PAMPs such as LPS (from gram-negative bacteria), lipoteichoic acid (from gram-positive bacteria), and zymosan (from yeast). Production of IL-1 can also be stimulated by other cytokines, including TNF, GM-CSF, and IL-1 itself.

Although many cell types express genes for both IL-1α and IL-1β, most cells produce predominantly one form of the cytokine. For example, human monocytes produce mostly IL-1β, whereas keratinocytes produce predominantly IL-1α. The two forms of IL-1 are both initially synthesized as 31-kDa precursors (pro–IL-1α and pro–IL-1β), which are then modified posttranslationally to create the carboxyl terminal 17-kDa peptide forms of the mature cytokines. IL-1α is stored in the cytoplasm as pro–IL-1α or, after being phosphorylated or myristoylated, in a membrane-bound form. Whereas both pro–IL-1α and membrane-bound IL-1α are biologically active, pro–IL-1β is devoid of biologic activity. Pro–IL-1α is converted to the mature peptide by calpain and other nonspecific extracellular proteases. Pro–IL-1β is cleaved to its mature active form by a specific intracellular cysteine protease called IL-1β converting enzyme (ICE) or caspase-1. Like IL-1β, ICE–caspase-1 is stored in cells in an inactive form and must be proteolytically cleaved to become enzymatically active. Transgenic mice deficient in ICE–caspase-1 are resistant to endotoxic shock and manifest an impaired ability to mount a local inflammatory response to intraperitoneal zymosan, a known inducer of sterile peritonitis. In contrast, ICE–caspase-1 knockout mice manifest increased susceptibility to infections caused by various pathogens, including E. coli, Shigella flexneri, Salmonella typhimurium, Listeria monocytogenes, and Candida albicans. Taken together, these data suggest that ICE-dependent processes, including secretion of the mature forms of IL-1β and the related cytokine, IL-18 (see later), are important for host defense against microbial infection but also are crucial for the pathologic manifestations of poorly controlled inflammation.21 Various ICE-like enzymes, the caspases, have been identified as being important mediators of the process of programmed cell death, or apoptosis. A special form of apoptosis, called pyroptosis, can occur within minutes after macrophages are infected with certain intracellular pathogens. Pyroptosis is an ICEdependent process. The activation of ICE–caspase-1 can be triggered in cells by the formation of a molecular complex called the inflammasome.21 Inflammasomes are oligomeric complexes, which are composed of ICE–caspase-1 as well as various members of the NLR family of PRRs called NALPs (NACHT domain leucinerich repeat and PYD-containing protein) and an adapter protein called ASC (apoptosis-associated specklike protein containing a CARD). Assembly of the inflammasome, which in many cases is triggered when an NLR family member senses the presence of PAMP molecules and ultimately leads to ICE–caspase-1 activation and secretion of IL-1β (and IL-18). Inflammasomes that contain a particular NALP (NALP3), can activate ICE–caspase-1 in response to a wide variety of unrelated compounds, including certain toxins, high concentrations of adenosine triphosphate (ATP), and crystals of monosodium urate (the mineral-like structures that are associated with gout). Alum, the adjuvant used in most vaccines to enhance immune responses to antigens, also has been shown to induce activation of the NALP3 inflammasome. All these compounds can lead to ICE–caspase-1 activation and secretion of IL-1β and the related cytokines, IL-18 and IL-33. The mature 17-kDa form of IL-1β lacks a secretory signal peptide and is not secreted via the classic exocytic pathway used for the secretion of most proteins (including most other cytokines) from cells. ICE-dependent processing of pro–IL-1β and

The Inflammatory Response Chapter 4 49 IL-1

CYTOSOL

IL-1RI

IL-1RAcP

PLASMA MEMBRANE

P IRAK-1

Myd88 IRAK-2

TRAF6 Kinase cascades

FIGURE 4-3 Simplified representation of the intracellular signal transduction steps, which are initiated by the binding of IL-1 to its receptor. There are two IL-1 receptors, IL-1RI and IL-1RII. Only IL-1RI participates in signal transduction, and signaling via this receptor requires the participation of another transcytoplasmic protein, IL-1RAcP. The interaction of IL-1 with IL-1RI and IL-1RAcP leads to the formation of a trimolecular complex, which in turn results in the docking of yet another protein, IRAK-1. As a result of its interaction with MyD88, IRAK-1 is phosphorylated and activates another signaling protein, TRAF6. The IRAK-TRAF6 complex activates various downstream kinase cascades, ultimately leading to the activation of key transcription factors, such as NF-κB, and transcriptional activation of various IL-1–responsive genes.

pathway, an adapter protein, myeloid differentiation primary response factor 88 (MyD88), links the receptor to another protein called IL-1 receptor–associated kinase 1 (IRAK-1). On binding of the ligand to the TLR (or IL-1RI), IRAK-1 is phosphorylated and dissociates from the receptor complex, thereby allowing it to interact with another signaling protein, TNF receptor–activated factor 6 (TRAF6). This process results in the activation of nuclear factor κB (NF-κB), a pivotal proinflammatory transcription factor, as well as the phosphorylation signaling cascades involving mitogen-activated protein kinases (MAPKs). In the case of activation of this signaling pathway by the binding of IL-1β to IL-1RI, the ligand-receptor interaction does not initiate signal transduction without the association of another transcytoplasmic protein called IL-1 receptor accessory protein (IL-1RAcP). Interestingly, the interaction of IL-18 (structurally related to IL-1) with IL-18R (another member of the IL-1R–TLR superfamily) does not trigger downstream signal transduction without the cooperation of a similar accessory protein called IL-18RAcP (or AcPL). LPS can still activate MAPKs and NF-κB in macrophages derived from MyD88 knockout mice, although this activation occurs in a temporally delayed fashion.22 This finding indicates that the interaction of LPS with TLR4 must be able to initiate MyD88-dependent and MyD88-independent signaling pathways. LPS-TLR4–induced signaling via the MyD88-independent pathway requires the adaptor proteins, TIR domain-containing adapter-inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM), and leads to the activation of the transcription factor, interferon regulatory factor 3 (IRF3). Translocation

SECTION I SURGICAL BASIC PRINCIPLES

the secretory step appear to occur at the same time. Secretion of the leaderless mature peptide apparently occurs through the action of a specific transporter called ABC1, which can be inhibited by the oral hypoglycemic agent glyburide. Similar to the other members of the IL-1 family, IL-1RA can be produced by a variety of cell types. However, unlike IL-1α and IL-1β, IL-1RA is synthesized with a leader peptide that allows normal secretion of the protein. A specialized form of IL-1RA, intracellular IL-1RA, is synthesized without a leader peptide sequence and therefore accumulates intracellularly in certain cell types. In some tissues, such as intestinal epithelium, the formation of intracellular IL-1RA may serve a counterregulatory function to limit inflammation and thereby confer mucosal protection. Moreover, an imbalance between the production of IL-1 and IL-1RA may promote the development of chronic inflammation in certain pathologic conditions, such as Crohn’s disease. Cellular production of IL-1 and IL-1RA is differentially regulated. Certain cytokines, notably IL-4, IL-10, and IL-13, serve as anti-inflammatory mediators, in part by promoting the synthesis of IL-1RA. IL-6, although not usually considered an anti-inflammatory cytokine, is also capable of triggering the production of IL-1RA. The importance of IL-1β as a proinflammatory cytokine and IL-1RA as an anti-inflammatory cytokine is emphasized by experiments using transgenic mouse strains deficient in IL-1RA, IL-1α, IL-1β, or both IL-1α and IL-1β (double knockout mice). In these studies, IL-1α knockout mice were able to mount a normal inflammatory response, whereas the IL-1β knockout animals manifested an impaired ability to mount a normal inflammatory response. In contrast, mice functionally deficient in IL-1RA manifested an exaggerated response to a systemic proinflammatory stimulus (intraperitoneal injection of turpentine). There are two distinct IL-1 receptors, IL-1RI and IL-1RII. IL-1RI is an 80-kDa transmembrane protein with a long cytoplasmic tail. In contrast, IL-1RII, a 60-kDa protein, has only a very short cytoplasmic tail and is incapable of initiating intracellular signaling. As a consequence, IL-1RII is actually a decoy receptor that serves a counterregulatory role by competing with IL-1RI, the fully functional IL-1 receptor, for IL-1 in the extracellular space. IL-1RI is present on a wide variety of cell types, including T cells, endothelial cells, hepatocytes, and fibroblasts. IL-1RII is the predominant IL-1 receptor found on B cells, monocytes, and neutrophils. The extracellular domains of IL-1RI and IL-1RII are shed by activated neutrophils and monocytes. The shed receptors can act as a sink for secreted IL-1 and, thus, along with IL-1RA, represent an important counterregulatory component of the inflammatory response. IL-1RI is a member of the IL-1R–TLR superfamily of receptors. The cytoplasmic portions of all the members of this superfamily of transmembrane proteins are hom*ologous and are called Toll IL-1 receptor (TIR) domains. In contrast, the extracellular domains fall into two main subdivisions. In one subdivision, the extracellular portion of the molecule contains three immunoglobulin-like regions and is hom*ologous to the structure of IL-1RI. In the other subdivision, which includes the TLRs, the extracellular domain contains leucine-rich repeats. Because the cytoplasmic TIR domains of the TLRs are hom*ologous to the cytoplasmic region of IL-1RI, it is not surprising that some shared mechanisms are responsible for downstream signaling (Figs. 4-3 and 4-4). In the MyD88-dependent

50 SECTION I SURGICAL BASIC PRINCIPLES = PO4

LBP PLASMA MEMBRANE

MD2

LPS

CD14

CYTOSOL

Upstream-proinflammatory signals

TLR4

CYTOSOL MyD88-independent pathway

TIRAP TRAM TRIF

IKKα

NEMO

IKKβ

NEMO

p65 Proteosomal degradation

IRF3 activation TRAF6

p50

TBK1

IRAK-4

MyD88

IRAK-1

TLR4

MyD88-dependent pathway

IkB

PLASMA MEMBRANE

Kinase cascades

FIGURE 4-4 Simplified representation of the intracellular signal transduction steps, which are initiated by the binding of the microbial product, LPS, to TLR4. The interaction of LPS with TLR4 requires several extracellular accessory proteins—LBP, CD14 (a glycophosphoinositol-anchored cell surface receptor), and MD2. After assembly of the extracellular LPS-LBP-CD14-TLR4-MD2 complex, signaling can follow two different pathways. In the more immediate MyD88-dependent signaling pathway, an adapter protein, MyD88, links the intracellular portion of TLR4 to other adaptor proteins called IRAK-1 and IRAK-4. Phosphorylation of IRAK-1 allows it to dissociate from the receptor complex, thereby permitting it to interact with another signaling protein, TRAF6. This process results in the activation of NF-κB, a pivotal proinflammatory transcription factor, as well as signaling cascades involving MAPKs.6 In the more delayed MyD88independent pathway, the adapter proteins, TRIF and TRAM, lead to the activation of the serine-threonine kinase, TANK-binding kinase (TBK) 1, which leads to the activation of the transcription factor, IRF3. After phosphorylation, IRF3 forms a complex with cyclic adenosine monophosphate (cAMP) response element-binding (CREB) proteinbinding protein (CREBBP), and this complex translocates to the nucleus, leading to the transcription of the genes for IFN-α and IFNβ, as well as other interferon-induced genes. The association of TRIF with the TIR domain of TLR4 also leads to the activation of NF-κB via pathways, which involve TRAF6 as well as another adapter protein called RIP1 (not shown).

of activated IRF3 to the nucleus leads to transcription of the genes for IFN-α and IFN-β. The association of TRIF with the TIR domain of TLR4 also leads to the activation of NF-κB via pathways that involve TRAF6 and another adapter protein called RIP1. The transcription factor, NF-κB, plays a central role in the orchestration of the inflammatory response. The Nobel Laureate, David Baltimore, originally identified NF-κB as a nuclear transcription factor involved in the activation of transcription of κ light chain immunoglobulin genes in B lymphocytes. Subsequently, NF-κB has been shown to regulate the transcription of more than 150 genes, particularly those related to inflammation, such as TNF, IL-6, IL-8, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and LBP. The transcriptionally active form of NF-κB is a hom*o- or heterodimer comprised of various proteins belonging to the NF-κB family. In mammals, these proteins include RelA–p65, c-Rel,

DNA

p50

p65

NUCLEUS FIGURE 4-5 Simplified representation of the canonical pathway, leading to activation of the transcription factor NF-κB. In resting cells, the heterodimers, consisting of the NF-κB subunits p50 and p65, exist in the cytoplasm in an inactive form because of binding by a third inhibitory protein, IκB. On stimulation of the cell by a proinflammatory trigger (e.g., TNF, IL-1, or LPS), upstream signaling events lead to the phosphorylation of IκB on two key serine residues. Phosphorylation of IκB targets the molecule for ubiquitination and subsequent proteosomal degradation. Phosphorylation of IκB is mediated by an enzyme complex called IκB kinase (IKK), which contains two catalytic subunits, IKKα and IKKβ, as well as two copies of a regulatory scaffold protein called NF-κB essential modulator (NEMO). Phosphorylation and subsequent degradation of IκB permit translocation of transcriptionally active p50-p65 heterodimers into the nucleus. Binding of the transcription factor to cis-acting elements in the promoter regions of various NF-κB–responsive genes leads to transcription and ultimately translation of various proinflammatory proteins.

NF-κB1 (p50-p105), NF-κB2 (p52-p100), and RelB. The most abundant form of NF-κB in many cell types is a heterodimer consisting of p65 and p50, and NF-κB is often loosely used to mean this particular entity. In resting cells, the hom*o- or heterodimeric forms of NF-κB exist in the cytoplasm in an inactive form caused by binding by a third inhibitory protein, called IκB. In mammalian species, five IκB-like proteins have been identified—IκBα, IκBβ, IκBγ, IκBε, and Bcl-3. Several pathways exist for the activation of NF-κB–dependent signaling. Only the so-called canonical pathway will be described here (Fig. 4-5). On stimulation of the cell by a proinflammatory trigger (e.g., TNF, IL-1, or LPS), IκB is phosphorylated on two key serine residues (Ser32 and Ser36), which targets the molecule for ubiquitination and subsequent proteosomal degradation. Phosphorylation of IκB is mediated by an enzyme complex called IκB kinase (IKK) that contains two catalytic subunits, IKKα and IKKβ, as well as two copies of a regulatory scaffold protein called NF-κB essential modulator (NEMO) or, alternatively, IKKγ. Phosphorylation and subsequent degradation of IκB permit translocation of the transcriptionally active form of NF-κB into the nucleus and subsequent binding of the transcription factor to cis-acting elements in the promoter regions of various NF-κB-responsive genes.

The Inflammatory Response Chapter 4 51

Tumor Necrosis Factor TNF was initially obtained from LPS-challenged animals and identified as a serum factor that was capable of killing tumor cells in vitro and causing necrosis of transplantable tumors in mice. The gene coding for the protein was sequenced and cloned shortly thereafter. At about the same time, another protein, cachectin, was identified in supernatants from LPS-stimulated macrophages on the basis of its ability to suppress the expression of lipoprotein lipase and other anabolic hormones in adipocytes. TNF and cachectin were later demonstrated to be the same protein. Administration of a large dose of TNF-cachectin to mice was shown to induce a lethal shocklike state remarkably similar to that induced by the injection of LPS, and passive immunization with antibodies to TNF-cachectin was shown to protect mice from endotoxin-induced mortality. Thus, a modern version of Koch’s postulates was satisfied, and TNF-cachectin was identified as a pivotal mediator of endotoxic shock in animals. Gradually, the name cachectin was abandoned; the name TNF has survived. TNF is sometimes called TNF-α because it is structurally related to another cytokine that was originally called TNF-β but is now generally referred to as lymphotoxin α (LT-α). TNF and LT-α are both members of a large family of ligands that activate a corresponding family of structurally similar receptors. Other members of the TNF family include Fas ligand (FasL), receptor activator of NF-κB ligand (RANKL), CD40 ligand (CD40L) and TNF-related apoptosisinducing ligand (TRAIL). Although cells of the monocytemacrophage lineage are the major sources of TNF, other cell types, including mast cells, keratinocytes, T cells, and B cells, are also capable of releasing the cytokine. A wide variety of

endogenous and exogenous stimuli (e.g., alarmins and PAMPs) can trigger induction of TNF expression. LT-α is produced by lymphocytes and NK cells. TNF is initially synthesized as a 26-kDa cell surface– associated molecule anchored by an N-terminal hydrophobic domain. This membrane-bound form of TNF possesses biologic activity. The membrane-bound form of TNF is cleaved to form a soluble 17-kDa form by a specific TNF converting enzyme that is a member of the matrix metalloproteinase family of proteins. Like most of the other members of the TNF family of ligands, the soluble form of TNF exists as a hom*otrimer, a feature that is important for the cross linking and activation of TNF receptors. TNF and LT-α are both capable of binding to two different receptors, TNFR1 (p55) and TNFR2 (p75). Both these receptors, like other receptors in the TNF receptor family, are transmembrane proteins that consist of two identical subunits. The extracellular domains of TNFR1 and TNFR2 are relatively hom*ologous and manifest similar affinity for TNF, but the cytoplasmic regions of the two receptors are distinct. Accordingly, TNFR1 and TNFR2 signal through different pathways. Both receptors are present on most cell types except erythrocytes, but TNFR1 tends to be quantitatively dominant on cells of non hematopoietic lineage. The precise functions of the two TNF receptors remain to be elucidated. Nevertheless, considerable information about the roles of TNFR1 and TNFR2 has already been gleaned from experiments using genetically engineered strains of mice lacking one or the other or both of the TNF receptors. TNFR1 knockout mice are relatively resistant to LPS-induced lethality but manifest increased susceptibility to mortality caused by infection with the intracellular pathogens L. monocytogenes and S. typhimurium. TNFR2 knockout mice are relatively resistant to lethality induced by large doses of recombinant TNF but have an exaggerated circulating TNF response and manifest exacerbated pulmonary inflammation after intravenous (IV) challenge with LPS. Double knockout mice deficient in both TNFR1 and TNFR2 are phenotypically similar to mice lacking only TNFR1. Most of the members of the TNF family of ligands are involved primarily in the regulation of cellular proliferation or the converse process, programmed cell death (apoptosis). For example, interaction of FasL with the Fas receptor is essential for the normal process of apoptosis in T lymphocytes. TNF itself is somewhat different from other members of the TNF family of ligands in that it is both an initiator of apoptosis and a potent proinflammatory mediator. Activation of inflammation by TNF depends, at least in part, on activation of the transcription factor NF-κB. Because activation of NF-κB tends to suppress apoptosis, it is generally necessary to suppress the synthesis of new proteins to observe TNF-mediated induction of apoptosis. TNF-mediated signaling is initiated by trimerization of receptor subunits. The subsequent downstream events involved in TNF-mediated signaling are different for the two TNF receptors because the cytoplasmic domains for TNFR1 and TNFR2 are distinct. After ligand-induced trimerization of TNFR1, the first protein recruited to the receptor complex is TNFR1associated death domain protein (TRADD). Subsequently, three more proteins are recruited to the receptor complex: receptor-interacting protein 1 (RIP1), Fas-associated death domain protein (FADD), and TNF receptor–associated factor 2 (TRAF2). When TNFR2 is trimerized after association of the

SECTION I SURGICAL BASIC PRINCIPLES

IL-1 is an extremely potent mediator. Injecting healthy humans with as little as 1 ng/kg of recombinant IL-1β induces symptoms. Many IL-1–induced physiologic effects occur as a result of enhanced biosynthesis of other inflammatory mediators, including prostaglandin E2 (PGE2) and NO·. Thus, IL-1 increases the expression of the enzyme COX-2 in many cell types, thereby leading to increased production of PGE2. IL-1– induced hyperthermia is mediated by enhanced biosynthesis of PGE2 within the central nervous system (CNS) and can be blocked by the administration of COX inhibitors. IL-1 induces the enzyme iNOS in vascular smooth muscle cells and in other cell types. Induction of iNOS, which leads to increased production of the potent vasodilator NO· in the vascular wall, probably plays a key role in mediating hypotension triggered by the production of IL-1 and other cytokines released in response to LPS or other bacterial products. Elevated circulating concentrations of IL-1β have been detected in normal human volunteers injected with tiny doses of LPS and in patients with septic shock. However, in subjects with acute endotoxemia or septic shock, circulating concentrations of IL-1β are relatively low in comparison to levels of other cytokines such as IL-6, IL-8, and TNF. In contrast, in normal subjects injected with LPS and in patients with sepsis or septic shock, circulating levels of IL-1RA increase substantially and, in some studies, have been shown to correlate with the severity of disease. Plasma levels of IL-1RII also increase dramatically in patients with serious infections. Although circulating concentrations of IL-1β tend to be relatively low in patients with sepsis, local concentrations of the cytokine can be elevated in patients with sepsis or related conditions, such as ARDS.

52 SECTION I SURGICAL BASIC PRINCIPLES

TNF

ligand with the receptor, TRAF2 is recruited directly. TRAF1 then associates with TRAF2. The cytoplasmic domains of Fas, TNFRI, FADD, and TRADD all share a highly conserved sequence of appoximately 80 amino acids called the death domain, which seems to serve as a mediator of critical protein-protein interactions involved in Fas- and TNFR1-mediated signaling. The downstream events leading to the activation of caspases (i.e., apoptosis) or gene transcription (i.e., inflammation) after recruitment of TRADD, TRAF2, or both are exceedingly complex. A deliberately oversimplified model is depicted in Figure 4-6. In the proapoptotic pathway, TRADD interacts with FADD, which in turn interacts with a protein called caspase-8 (also known as Fas-associated death domain–like IL-1β converting enzyme [FLICE]), the proximal element in the caspase cascade leading to programmed cell death. In the proinflammatory pathway induced by activation of TNFR1 or TNFR2, TRAF2 plays a central role in the early events that lead to activation of NF-κB and two important MAPK pathways—namely, those involving the proteins p38 MAPK and c-Jun N-terminal

PLASMA MEMBRANE CYTOSOL

TNFR1

Apoptosis pathway

Kinase cascades

ASK1

FADD

TRAF2

TRADD

RIP

Procaspase 8

Inflammation pathway

Caspase cascade

FIGURE 4-6 Simplified view of intracellular signal transduction events initiated by TNF binding to its cellular receptors. There are two TNF receptors, TNFR1 and TNFR2. Both receptors are hom*odimeric transmembrane proteins. Although TNFR1 and TNFR2 are capable of initiating signal transduction, different pathways are involved. After TNF binds to TNFR1, a number of proteins, including RIP, FADD, and TRADD, associate with the receptor. The intracytoplasmic tail of TNFR1 and portions of these other signaling molecules share a highly conserved sequence of approximately 80 amino acids, called the death domain. hom*otypic interactions among the death domains of these various proteins are essential for the formation of the functional signaling complex. After docking to the receptor complex, TRADD recruits other proteins (e.g., TRAF2 and MADD), which in turn initiate protein kinase pathways leading to the activation of the nuclear transcription factor NF-κB and the protein kinase JNK. TRAF2 can also interact with TNFR2. Association of FADD with the TNFR1 receptor complex leads to the activation of the proteolytic enzyme caspase-8, which is the proximal element in a signaling cascade leading to apoptosis (programmed cell death).

kinase (JNK). Overexpression of TRAF2 in engineered cells is sufficient to activate signaling pathways leading to the activation of NF-κB, as well as another proinflammatory transcription factor, activator protein-1 (AP-1). By triggering the association of FADD with the receptor complex, the interaction of FasL with Fas leads directly to the induction of apoptosis, whereas recruitment of FADD to the TNF-TNFR1 receptor complex requires an adaptor protein, TRADD, and thus initiates apoptotic processes less directly. Furthermore, the FasL-Fas interaction does not lead to activation of NF-κB, whereas signaling through NF-κB can apparently be initiated by TNF through more than one pathway (TRAF2 and RIP1). The extracellular domains of TNFR1 and TNFR2 are constitutively released by monocytes, and release of these soluble receptors is markedly increased when the cells are activated by LPS or phorbol ester. Both soluble TNFR1 (sTNFR1) and sTNFR2 are present at low concentrations in the circulation of normal subjects. In patients with sepsis or septic shock, circulating levels of sTNF-R1 and sTNF-R2 increase significantly. Higher concentrations portend a worse prognosis. When present in great molar excess, sTNF receptors can inhibit the biologic effects of TNF. However, when present at lower concentrations, sTNF receptors can stabilize the cytokine and potentially augment some of its actions. The amount of TNF produced in response to a proinflammatory stimulus, such as exposure of cells to LPS, is determined, in part, by inherited differences (polymorphisms) in noncoding regions of the TNF gene. For example, if the base at position −308 in the TNF promoter is adenine (A), in vitro spontaneous and stimulated TNF production by monocytes is greater than if the base at this position is guanine (G). The more common allelic form of the TNF gene (TNF1) has guanine at position −308, whereas the less common allele (TNF2) has adenine at this position. Some studies have suggested that presence of the TNF2 allele markedly increases the risk for mortality in patients with septic shock, although other data dispute this notion. Interestingly, a G to A substitution at position +250 in the LT-α gene is similarly associated with increased production of TNF by stimulated mononuclear cells, and patients carrying this allele are also at higher risk for mortality from septic shock. In patients with community-acquired pneumonia (a relatively hom*ogeneous population of patients with infection), the risk for development of septic shock is greatest for those who are hom*ozygous for the so-called high TNF secretor genotype (i.e., AA) at position +250 in the LT-α gene.23 Data such as these suggest that genotyping of patients may prove to be valuable in the coming years for tailoring anticytokine and other forms of adjuvant therapy for critically ill patients. Interleukin-1 and Tumor Necrosis Factor as Targets for Anti-Inflammatory Therapeutic Agents In view of the central importance of IL-1 and TNF as mediators of the inflammatory response, investigators have regarded blocking the production or the actions of these cytokines as a reasonable strategy for treating a variety of conditions associated with excessive or poorly controlled inflammation. Although clearly different in many respects from sepsis in humans, the shocklike syndrome induced in rodents by injecting LPS IV or intraperitoneally has served as a useful paradigm for evaluating various anti-inflammatory strategies. In this model system, survival is

The Inflammatory Response Chapter 4 53 organisms to a limited area. TNF, IL-1, and IL-6 (as well as some other proinflammatory cytokines) can activate the extrinsic pathway of coagulation, in part by promoting expression of tissue factor (TF), a transmembrane 45-kDa protein, on endothelial cells and monocytes. In addition, these cytokines also downregulate the expression of an important endogenous inhibitor of coagulation, thrombomodulin, on the surface of endothelial cells. Thus, TNF, IL-1, and IL-6 promote activation of the coagulation cascade. Numerous studies have documented that the extrinsic coagulation pathway is activated in patients with sepsis, even in the absence of frank, clinically evident disseminated intravascular coagulation (DIC). Key components of the coagulation cascade are a group of proteins that function as endogenous anticoagulants and thus help provide counterregulatory balance to the system. It is therefore noteworthy that the inflammatory response leads not only to TF-mediated activation of coagulation but also to downregulation of these natural anticoagulant pathways. The result is a hypercoagulable state that in its most severe form is characterized by DIC. Three major anticoagulant pathways exist and all can be inhibited by the inflammatory cascade—antithrombin, the protein C system, and tissue factor pathway inhibitor (TFPI). Antithrombin is a serine protease inhibitor that antagonizes thrombin and factor Xa. During severe inflammatory responses, antithrombin levels are markedly decreased as the result of consumption, impaired synthesis (negative acute phase response), and degradation by elastase from activated neutrophils. Protein C is activated by thrombin bound to thrombomodulin. During systemic inflammation, protein C levels are reduced because of impaired synthesis and degradation by neutrophil elastase. Furthermore, the protein C system is inhibited by TNF- and IL-1β–mediated decreases in the expression of thrombomodulin. In addition to its role in regulating coagulation, the protein C system also modulates the inflammatory response. Activated protein C binds to the endothelial protein C receptor. Activation of this signaling pathway inhibits LPS-induced NF-κB nuclear translocation and thereby inhibits secretion of TNF, IL-1β, IL-6, and IL-8 by endothelial cells. Circulating levels of protein C decrease in patients with severe sepsis or septic shock, and a marked deficiency of protein C in these patients is a prognostic indicator for an unfavorable outcome. Various strategies to inhibit excessive activation of the coagulation system have been extensively evaluated in animal models of endotoxemia and sepsis and in clinical trials. One of these approaches, the administration of recombinant human activated protein C, also called drotrecogin alfa (activated), was shown in a large multicentric randomized clinical trial to improve survival significantly in patients with severe sepsis25; it was FDA-approved for this indication. Because it is a protein, which inhibits coagulation, administration of drotrecogin alfa (activated) can be associated with bleeding complications.26 Furthermore, its administration was not found to be beneficial for septic patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score less than 25, postoperative patients with single-organ system dysfunction,27 or pediatric patients with severe sepsis.28 Prompted by concerns about the safety and efficacy of the recombinant protein, the European Medicines Agency (EMEA [European equivalent of the FDA]) threatened to withdraw its

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improved when animals are treated with any one of a variety of different pharmacologic, immunologic, or genetic strategies that block the release of TNF or prevent this cytokine from interacting with its receptors after it is released. To a lesser extent, the same statement also applies to IL-1. Glucocorticoids are a broad-spectrum and nonselective way to block IL-1– or TNF-mediated proinflammatory effects. As our understanding of the role of cytokines as mediators of inflammation has progressed, newer and more specific pharmacologic anti-inflammatory strategies have been developed and evaluated as adjunctive therapy for the treatment of sepsis in placebo-controlled prospective clinical trials. Unfortunately, results in these trials were disappointing. Positive results were obtained in only a single study, an open-label trial of recombinant IL-1RA that enrolled a relatively small number of patients. With the exception of this study, none of the agents tested significantly improved survival. In one trial, treatment of septic patients with a so-called fusion protein incorporating the extracellular domain of TNFR2 resulted in increased mortality, particularly in patients with gram-positive infection. Despite the negative results obtained in sepsis trials, several agents designed to neutralize the effects of secreted TNF or IL-1β have significant clinical efficacy in other important inflammatory conditions such as Crohn’s disease and rheumatoid arthritis. Infliximab, a monoclonal anti-TNF antibody, has been FDA-approved for administration to patients to provide long-term remission level control of the debilitating symptoms of Crohn’s disease. Infliximab was approved for use, in combination with methotrexate, to reduce the signs and symptoms, inhibit the progression of structural damage, and improve physical function in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. Adalimumab, another monoclonal anti-TNF antibody, was FDA-approved for administration with or without methotrexate to patients with rheumatoid arthritis to ameliorate symptoms and disability. Etanercept, the TNFR2 fusion protein evaluated unsuccessfully for the treatment of sepsis, has been FDA-approved for the management of psoriatic arthritis. It can reduce the signs and symptoms and inhibit the progression of structural damage in patients with moderately to severely active rheumatoid arthritis, as well as reduce the signs and symptoms in patients 4 years of age and older with moderately to severely active polyarticular-course juvenile rheumatoid arthritis. Anakinra (recombinant human IL-1RA) was FDAapproved for administration alone or with other drugs (except TNF-modifying agents) to reduce the symptoms and modify the progression of structural damage in patients with moderate or severe rheumatoid arthritis who have failed one or more other disease-modifying antirheumatic drugs. TNF expression is upregulated in patients with severe asthma, and etanercept has been shown to decrease bronchial hyperreactivity in this condition.24 Thus, cytokine-specific approaches to managing inflammatory conditions have moved from the research bench to the clinic and occupy an important role in the clinical management of common clinical conditions, even though this approach has not yet proven its efficacy for the treatment of sepsis and septic shock. The network of cytokines associated with the inflammatory response interacts at multiple points with another component of the host’s defense against injury and infection, the coagulation system. Thrombosis and coagulation help contain the invading

54 SECTION I SURGICAL BASIC PRINCIPLES approval of drotrecogin alfa (activated) unless a second (postmarketing) pivotal trial yielded positive findings. This trial is currently in progress. Interleukin-6 and Interleukin-11 IL-6 and IL-11 warrant consideration together because along with several other proteins (e.g., oncostatin M), these cytokines use a specific transmembrane protein, gp130, for receptor function. IL-6 consists of 184 amino acids plus a 28–amino acid hydrophobic signal sequence. The protein is variably phosphorylated and glycosylated before secretion. IL-11 is translated as a precursor protein containing 199 amino acids, including a 21– amino acid leader sequence. Like IL-1 and TNF, IL-6 is a pluripotent cytokine, which is intimately associated with the inflammatory response to injury or infection. IL-6 can be produced not only by immunocytes (e.g., monocytes, macrophages, lymphocytes) but also by many other cell types, including endothelial cells and intestinal epithelial cells. Factors known to induce the expression of IL-6 include IL-1, TNF, platelet-activating factor, LPS, and reactive oxygen metabolites. The promoter region of the IL-6 gene contains functional elements capable of binding NF-κB, as well as another important transcription factor, CCAAT (cytidinecytidine-adenosine-adenosine-thymidine)/enhancer binding protein (C/EBP), previously called NF–IL-6. The cellular and physiologic effects of IL-6 are diverse and include induction of fever, promotion of B cell maturation and differentiation, stimulation of T cell proliferation and differentiation, promotion of differentiation of nerve cells, stimulation of the hypothalamicpituitary-adrenal axis, and induction of the synthesis of acute-phase proteins (e.g., C-reactive protein) by hepatocytes. Plasmacytosis and hypergammaglobulinemia develop in transgenic mice that overexpress IL-6. Conversely, IL-6 knockout mice have an impaired acute-phase response to inflammatory stimuli, abnormal B cell maturation, deficient mucosal immunoglobulin A (IgA) production, and impaired host resistance to the intracellular pathogen L. monocytogenes. In other murine models of inflammation, the effects of genetic IL-6 deficiency have proven to be highly variable. For example, in a murine model of acute pancreatitis induced by repetitive injections of cerulein, inflammation was exacerbated in IL-6 knockout mice as compared with wild-type controls, a finding that emphasizes the anti-inflammatory effects of IL-6.29 In contrast, in a murine model of hemorrhagic shock and resuscitation, IL-6 knockout mice exhibited less pulmonary inflammation and lung and gut mucosal injury than wild-type controls, findings that emphasize the proinflammatory effects of IL-6.30 Although IL-6 knockout mice were not protected from the lethal effects of sepsis, treatment of septic wild-type mice with a carefully calibrated dose of an anti–IL-6 antibody improved survival. IL-11 is expressed in a variety of cell types, including neurons, fibroblasts, and epithelial cells. Although constitutive expression of IL-11 can be detected in a range of normal adult tissues, expression of IL-11 can also be upregulated by IL-1, TGF-β, and other cytokines or growth factors. Regulation of IL-11 expression is under transcriptional and translational control. From a functional standpoint, IL-11 is a hematopoietic growth factor with particular activity as a stimulator of megakaryocytopoiesis and thrombopoiesis. IL-11 can also interact with epithelial cells in the gastrointestinal tract and inhibit the proliferation of enterocytic cell lines in vitro.

The mechanisms whereby IL-6– or IL-11–induced signals are transduced in target cells have been studied extensively. Activation of target cells via the IL-6 or IL-11 receptor complexes requires the cooperation of two distinct proteins. In the case of IL-6, the ligand-binding subunit is called IL-6R, whereas in the case of IL-11, the ligand-binding subunit is called IL-11R. For both receptors, a distinct protein called gp130 is required for signal transduction. Intracellular signal transduction involves association of the IL-6–IL-6R complex or the IL-11–IL-11R complex with gp130. Dimerization of gp130 leads to downstream signaling via members of the JAK family of protein tyrosine kinases. JAK kinase activation in turn leads to phosphorylation and activation of STAT3, a member of the STAT family of signaling proteins. Phosphorylation of STAT proteins leads to dimerization, translocation to the nucleus, binding to DNA, and transcriptional activation. Circulating concentrations of IL-6 increase dramatically after tissue injury—for example, as a consequence of elective surgical procedures, accidental trauma, or burns. Elevated plasma levels of IL-6 are consistently observed in patients with sepsis or septic shock. The degree to which circulating IL-6 levels are elevated after tissue trauma or during sepsis has been shown to correlate with the risk for postinjury complications or death. Although it remains to be established whether high circulating IL-6 levels are directly or indirectly injurious to patients with sepsis or are simply a marker of the severity of illness, the observation that immunoneutralization of IL-6 improves outcome in experimental bacterial peritonitis suggests that elevated concentrations of this cytokine are deleterious. Circulating levels of IL-11 increase in patients with DIC and sepsis. IV or oral administration of recombinant IL-11 improves survival in neutropenic rodents with sepsis, possibly by preserving the integrity of the intestinal mucosal barrier.31 In a small phase 2 clinical study, treatment with recombinant IL-11 increased expression of von Willebrand factor in patients with mild von Willebrand disease. Interleukin-8 and Other Chemokines Chemotaxis is the term used to denote the directed migration of cells toward increasing concentrations of an activating substance (chemotaxin). The ability to recruit leukocytes to an inflammatory focus by promoting chemotaxis is the primary biologic activity of a special group of cytokines called chemokines. More than 40 of these small proteins have been identified. Each contains approximately 70 to 80 amino acids, including three or four conserved cysteine residues. Four chemokine subgroups have been described. The subgroups are defined by the degree of separation of the first two NH2-terminal cysteine residues. In the CXC or α-chemokines, the first two cysteine moieties are separated by a single nonconserved amino acid residue, whereas in the CC or β-chemokines, the NH2-terminal cysteines are directly adjacent to each other. The C chemokine subgroup is characterized by the presence of only a single NH2-terminal cysteine moiety. The CX3C subgroup has only one member (fractalkine); in this chemokine, the NH2-terminal cysteine residues are separated by three intervening amino acids. A subclass of the CXC chemokines, exemplified by IL-8, contains a characteristic amino acid sequence (glutamate-leucine-arginine) near the NH2-terminal end of the protein; these chemokines act primarily on PMNs. Other chemokines, including the CC chemokines and members of the CXC subgroup not containing the

The Inflammatory Response Chapter 4 55

Interleukin-12 IL-12, a cytokine produced primarily by antigen-presenting cells, is a heterodimeric protein composed of two disulfidelinked peptides (p35 and p40) encoded by distinct genes. Both subunits are required for biologic activity. The IL-12 receptor is expressed on T cells and NK cells. The most important biologic activity associated with IL-12 is to promote Th1 responses by helper T cells. In this regard, IL-12 promotes the differentiation of naive T cells into Th1 cells capable of producing IFN-γ after activation and serves to augment IFN-γ secretion by Th1 cells responding to an antigenic stimulus. Stimulation of IFN-γ production by IL-12 can be synergistically enhanced by the presence of other proinflammatory cytokines, notably TNF, IL-1, or IL-2. Conversely, counterregulatory cytokines, such as IL-4 and IL-10, are capable of inhibiting IL-12–induced IFN-γ secretion. The immunologic responses governed by Th1 cells are central to the development of cell-mediated immunity necessary

for appropriate host resistance to intracellular pathogens. It is not surprising, therefore, that transgenic mice deficient in IL-12 manifest increased susceptibility to infections caused by a number of intracellular pathogens, including Mycobacterium avium and Cryptococcus neoformans. IL-12 may be a key factor in some of the deleterious inflammatory responses to LPS and gram-negative bacteria. Elevated circulating levels of IL-12 were measured in endotoxemic mice and baboons infused with viable E. coli. Elevated plasma levels of IL-12 were also detected in children with meningococcal septic shock and were correlated with outcome. However, in patients with postoperative sepsis, circulating IL-12 levels were lower than those in control subjects without sepsis and did not correlate with outcome.32 Defective production of IL-12 by peripheral blood mononuclear cells after stimulation with IFN-γ and LPS is associated with an increased risk for the development of postoperative sepsis in preoperative patients.33 IL-12 has also been implicated in the pathogenesis of IBD. T cells eluted from the lamina propria of intestinal resection specimens from patients with Crohn’s disease secrete cytokines consistent with a Th1-like profile. In addition, IL-12–secreting macrophages are present in large numbers in tissue specimens from patients with Crohn’s disease but are rare in histologic sections from appropriate control subjects. Treatment with anti– IL-12 antibodies ameliorates the severity of disease in certain murine models of IBD. Treatment of patients with refractory IBD with thalidomide, a potent anti-inflammatory agent, decreases the production of TNF and IL-12 by mononuclear cells isolated from the lamina propria of gut mucosal biopsy samples and decreases disease activity. Although excessive production of IL-12 has been implicated in the pathogenesis of acute inflammatory conditions such as septic shock and chronic inflammatory states, such as Crohn’s disease, adequate production of IL-12 appears to be essential for orchestration of the normal host response to infection. When antibodies to IL-12 are administered to mice with fecal peritonitis induced by cecal ligation and perforation, mortality is increased and clearance of the bacterial load is impaired. Conversely, pretreatment or even post-treatment with recombinant IL-12 has been shown to improve survival in a murine model of bacterial peritonitis. IL-12 is not the only member of the IL-12 family of cytokines. Two other cytokines, IL-23 and IL-27, are structurally related to IL-12. All three IL-12 family members are heterodimeric proteins, containing the IL-12p40 subunit or a hom*ologue of IL-12p40 called Ebstein-Barr virus (EBV)-induced molecule 3 (EBI3). As noted, IL-12 is an IL-12p40–IL-12p35 heterodimer, IL-23 is an IL-12p40–IL-23p19 heterodimer, and IL-27 is a heterodimeric protein, consisting of EBI3 and IL-27p28. As will be discussed, IL-23 is clearly a proinflammatory cytokine, whereas IL-27 seems to be capable of exerting both proinflammatory and anti-inflammatory (or immunosuppressive) effects, depending on the experimental conditions being studied.34 Interleukin-17 and Related Cytokines IL-17, now sometimes called IL-17A, was discovered in 1995 by Yao and coworkers and shown to induce IL-6 and IL-8 production from human fibroblasts.34a Although it was not recognized at the time, IL-17 and other related cytokines were

SECTION I SURGICAL BASIC PRINCIPLES

glutamate-leucine-arginine sequence, act, for the most part, on monocytes, macrophages, lymphocytes, or eosinophils. Many different cell types are capable of secreting chemokines; cells of the monocyte-macrophage lineage and endothelial cells are particularly important in this regard. Numerous proinflammatory stimuli, including cytokines, such as TNF and IL-1, and PAMPs, such as LPS, can stimulate the production of chemokines. IL-8, the prototypical CXC chemokine, was first identified as a chemotactic protein by Yoshimura and associates in 1987.31a IL-8 is translated as a 99–amino acid precursor and is secreted after cleavage of a 20–amino acid leader sequence. In addition to attracting neutrophils along a chemotactic gradient, IL-8 also activates these cells by triggering degranulation, increased expression of surface adhesion molecules, and production of reactive oxygen metabolites. There are at least two distinct IL-8 receptors, CXCR1 (IL-8R1) and CXCR2 (IL-8R2). CXCR1 is predominantly expressed on neutrophils. Like other chemokine receptors, CXCR1 and CXCR2 are coupled to G proteins, and binding of ligand to these receptors leads to intracellular signal transduction via the generation of inositol triphosphate, activation of protein kinase C, and perturbations in intracellular ionized calcium concentrations. Increased circulating concentrations of IL-8 were detected in experimental animal models of infection or endotoxemia and in patients with sepsis. Treatment of experimental animals with antibodies against IL-8 improves survival or prevents pulmonary injury in models of sepsis or ischemia-reperfusion injury. These observations support the concept that IL-8–mediated activation of neutrophils plays an important role in the pathogenesis of organ system damage in these syndromes. Monocyte chemotactic protein-1 (MCP-1), the prototypical CC chemokine, was identified in the same year by two groups of investigators. MCP-1 is a chemotaxin for monocytes (but not neutrophils) and also activates monocytes by triggering the production of reactive oxygen metabolites and the expression of β2 integrins (cell surface adhesion molecules). Elevated circulating concentrations of MCP-1 have been detected in endotoxemic mice and patients with sepsis. Pretreatment of mice with a polyclonal anti–MCP-1 antiserum ameliorates LPS-induced lung injury, thus suggesting an important role for this chemokine in the pathogenesis of sepsis-induced ARDS.

56 SECTION I SURGICAL BASIC PRINCIPLES subsequently shown to play important and distinctive roles in host immunity and the development of various pathologic conditions. In 1987, Mossman and Coffman proposed a model for adaptive immunity based on the concept that naïve precursor helper T cells can differentiate into one or the other of different classes of helper T cells (i.e., Th1 or Th2) characterized by different functions and different patterns of secreted cytokines.34b The Th1-Th2 paradigm proved to be robust and was accepted with little or no modification until approximately 2005, when a series of discoveries led to the recognition that a third, completely distinct subset of helper T cells, now called Th17, was important in the pathogenesis of inflammation associated with autoimmune conditions. The discovery that IL-17 and related cytokines define a subset of helper T cells originally stemmed from studies of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis in humans.35 According to the Th1-Th2 paradigm, autoimmunity was thought to be mediated by Th1 cells with specificity of self antigens. Unexpectedly, however, it was observed that IFN-γ and IFN-γR knockout mice, as well as mice deficient for other molecules (e.g., IL-12p35 or IL-18) involved in Th1 differentiation, were not protected from EAE but, on the contrary, developed a more severe form of the disease. These observations raised the possibility that a subset of T helper cells other than Th1 might be responsible for the induction of EAE or other organ-specific autoimmune conditions. Meanwhile, in 2000, a novel cytokine chain, p19, was discovered in the process of screening for IL-6 hom*ologues.35 Whereas IL-12 is heterodimer, consisting of p35 and p40 chains, a newly discovered cytokine, IL-23, was shown to be a heterodimer made up of p40 and p19 chains. IL-23p19 knockout mice were shown to be protected from the development of EAE. Moreover, it was shown that IL-23 expands a population of T cells that produce IL-17 and, when adoptively transferred into naïve wild-type mice, induces EAE. These and other studies have established IL-17 as a key mediator of EAE and have also suggested that IL-23 is essential for the differentiation of the cells that produce IL-17. However, results from other studies called into question whether IL-23 is responsible for the differentiation of Th17 cells, and it is now established that a combination of TGF-β plus another cytokine (usually IL-6 but, under some conditions, also IL-23 or IL-21) is required to induce IL-17 production in a population of naïve T cells. It is noteworthy, therefore, that IL-6 knockout mice are resistant to the development of EAE, except under certain conditions. Differentiation of naïve helper T cells into Th17 cells under the influence of TGF-β and IL-6 (or TGF-β plus IL-21) requires intracellular signaling mediated by a steroid receptor type of transcription factor, called RAR-related orphan receptor (ROR) γt. Cooperation with other transcription factors, such as interferon regulatory factor (IRF) 4, is probably also required. There are six members of the IL-17 gene family named, in order of their discovery, IL-17A through IL-17F.36 These molecules have a similar molecular weight (20 to 30 kDa), share sequence hom*ology, and demonstrate overlapping, but not completely identical, biologic activities. The receptor for IL-17 is called IL-17R, and its structure is unlike that for any other cytokine receptor. In susceptible cells types, IL-17 activates signaling via multiple routes, including the MAPK pathways, various JAK-STAT pathways, and NF-κB. IL-17 or IL-17R

knockout mice manifest increased susceptibility to selected pathogens, most notably Klebsiella pneumoniae and C. albicans, but are also partially protected from the development of EAE. Interestingly, in a murine model of IBD, IL-17A ameliorates the disease, whereas IL-17F exacerbates the disease.35 Treatment with neutralizing anti–IL-17A antibodies improves survival in mice with sepsis induced by cecal ligation and puncture, even when therapy is instituted 12 hours after the onset of infection.37 Interleukin-18 IL-18 is constitutively expressed by human peripheral blood mononuclear cells and murine intestinal epithelial cells, but IL-18 production can also be stimulated by a variety of proinflammatory microbial products. The main biologic activity of IL-18 is to induce production of IFN-γ by T cells and NK cells. In this regard, IL-18 acts most potently as a costimulant in combination with IL-12. IL-12–induced IFN-γ expression appears to depend on the presence of IL-18 inasmuch as transgenic mice (or cells from mice) deficient in IL-18 or ICE produce little IFN-γ in response to appropriate stimulation, even in the presence of ample IL-12. In addition to stimulating IFN-γ production, IL-18 induces the production of CC and CXC chemokines from human mononuclear cells and activates neutrophils, an effect that may contribute to organ injury and dysfunction in conditions such as sepsis and ARDS. Circulating concentrations of IL-18 are higher in patients with sepsis than in those only with injuries, and high levels of this cytokine are associated with a fatal outcome in patients with postoperative sepsis. Interleukin-4, Interleukin-10, and Interleukin-13 IL-4, IL-10, and IL-13 can be regarded as inhibitory, antiinflammatory, or counterregulatory cytokines. All three of these cytokines are produced by Th2 cells and, among other roles, serve to modulate the production and effects of proinflammatory cytokines such as TNF and IL-1. IL-4, originally described as a B cell growth factor, is a 15- to 20-kDa glycoprotein synthesized by Th2 cells, mast cells, basophils, and eosinophils. IL-4 has many biologic actions that promote the expression of the Th2 phenotype, characterized by downregulation of proinflammatory and cell-mediated immune responses and upregulation of humoral (B cell–mediated) immune responses. IL-4 induces differentiation of CD4+ T cells into Th2 cells and, conversely, downregulates differentiation of CD4+ T cells into Th1 cells. IL-4 inhibits the production of TNF, IL-1, IL-8, and PGE2 by stimulated monocytes or macrophages and downregulates endothelial cell activation induced by TNF. IL-4 acts as a comitogen for B cells and promotes expression of the class II major histocompatibility complex (MHC) on B cells. IL-10, originally called cytokine synthesis inhibitory factor, was first isolated from supernatants of cultures of activated T cells. This cytokine is an 18-kDa protein produced primarily by Th2 cells but is also released by activated monocytes and other cell types. IL-10 acts to downregulate the inflammatory response through numerous mechanisms. For example, IL-10 inhibits the production of numerous proinflammatory cytokines, including IL-1, TNF, IL-6, IL-8, IL-12, and GM-CSF, by monocytes and macrophages; on the other hand, it increases synthesis of the counterregulatory cytokine IL-1RA by activated monocytes. In addition, IL-10 downregulates the proliferation and secretion of IFN-γ and IL-2 by activated Th1 cells, primarily by inhibiting

The Inflammatory Response Chapter 4 57 IL-13, and another that binds IL-13 with high affinity. Binding of IL-4 or IL-13 to their respective receptors induces signaling by activating the same JAK kinases, JAK1 and Tyk2. IL-4, but not IL-13, also activates JAK3. The biologic activities of IL-13 are very similar to those of IL-4 with respect to B cell function although, unlike IL-4, IL-13 does not have any direct affects on T cells. IL-13 downregulates the production of proinflammatory cytokines (e.g., IL-1, TNF, IL-6, IL-8, IL-12, G-CSF, GM-CSF, MIP-1α) and PGE2 by activated monocytes and macrophages and, by the same token, increases the production of antiinflammatory proteins, including IL-1RA and IL-1RII, from these cells. Additional anti-inflammatory properties of IL-13 include inhibition of induction of the enzyme COX-2, required for the production of prostaglandins, and induction of an enzyme, 15-lipoxygenase, that catalyzes the formation of a lipid mediator (lipoxin A4) with anti-inflammatory properties. Treatment of mice with recombinant IL-13 has been shown to prevent LPS-induced lethality and to decrease circulating levels of TNF and other proinflammatory cytokines. Conversely, treatment of septic mice with an anti–IL-13 antibody has been shown to increase mortality. Transforming Growth Factor-β The TGF-β family of mediators exerts a number of effects on most cell types, including modulation of cell growth, inflammation, matrix synthesis, and apoptosis. Although more than 45 peptides in the TGF-β family have been isolated, TGF-β1 was the first identified and is the isoform most associated with modulation of immune function. The bioactive forms of the TGF-β proteins are produced from 50-kDa monomers that dimerize to form the 100-kDa TGF-β precursor. The TGF-β precursor undergoes intracellular cleavage by furin proteases to yield the active 25-kDa TGF-β hom*odimer. This active form of TGF-β remains associated with the remaining portion of its pro form, latency-associated peptide (LAP). This complex has been called latent TGF-β and is secreted in this inactive form into the extracellular matrix. This unusual mode of secretion allows the latent TGF-β complex to be considered to be an extracellular sensor. Latent TGF-β can be activated by the dissociation and degradation of LAP via proteolysis (catalyzed by plasmin or matrix metallopeptidases) or the nonenzymatic activity of integrins, thrombospondin-1, oxygen and nitrogen free radicals, or low pH. These activating factors are often perturbations of the extracellular matrix that are associated with phenomena such as angiogenesis, wound repair, inflammation, or cell growth. Thus, post-translational extracellular activation of TGF-β is the most important regulatory mechanism for this cytokine, a mode of activation that is unique among the cytokines. Once activated, TGF-β–mediated signaling involves a cell surface heteromeric complex of transmembrane serine–threonine kinase receptors. Each receptor complex contains a pair of both TGF-β type I (TβRI) and type II (TβRII) receptors, which are activated by TGF-β binding and regulated by a number of intracellular proteins that interact directly with the receptor complex in a constitutive or ligand-induced manner. The intracellular signal transduction pathway responsible for gene induction or repression involves a family of structurally related proteins known as Smads. TGF-β receptor–activated Smads are phosphorylated by TβRI, form a heterotrimeric complex with the common partner Smad4, and translocate to the nucleus, where they can repress or activate transcription.

SECTION I SURGICAL BASIC PRINCIPLES

the production of IL-12 by macrophages or other accessory cells. Conversely, IFN-γ downregulates IL-10 production by monocytes. At least some of the inhibitory effects of IL-10 are mediated by blocking IFN-γ–induced tyrosine phosphorylation of STAT1α, a key protein in the signal transduction pathway for IFN-γ. The importance of IL-10 as a regulatory cytokine has been illustrated in experiments using transgenic mice deficient in IL-10. Such animals manifest increased resistance to the intracellular bacterial pathogen L. monocytogenes, thus suggesting that IL-10–mediated suppression of the Th1-type phenotype can impair the host’s ability to eradicate certain types of infection. In contrast to these results, IL-10 knockout mice succumbed to the lethal effects of excessive inflammation when infected with another intracellular pathogen, the protozoan parasite Toxoplasma gondii. Results have been variable in mice with severe sepsis, but a genetic deficiency of IL-10 production alters the kinetics of the inflammatory process without affecting long-term survival. IL-10–deficient mice spontaneously develop a form of enterocolitis that is reminiscent of IBD in humans. Because the IBD-like syndrome in these animals can be suppressed by treating the animals with exogenous IL-10 or a neutralizing anti– IFN-γ antibody, the enterocolitis associated with IL-10 deficiency is thought to be caused by excessive expression of the Th1-type phenotype. Production of IL-10 by peripheral blood mononuclear cells and CD4+ T cells is increased in trauma patients, and elevated circulating concentrations of this cytokine have been measured in patients with trauma or sepsis. Moreover, in trauma and burn patients, increased production of IL-10 has been associated with a greater risk for serious infection and, in patients with sepsis, a greater risk for mortality or shock. These findings support the view that although excessive production of proinflammatory mediators may be deleterious in trauma and sepsis, development of the Th2 phenotype, characterized by increased production of IL-10 and IL-4 and decreased expression of the MHC type II antigen HLA-DR on monocytes, may lead to excessive immunosuppression and deleteriously affect the outcome on this basis. Evidence has been presented supporting the view that HLA-DR expression on monocytes is post-translationally downregulated by IL-10 in patients with sepsis. Administering exogenous IL-10 in an effort to blunt excessive inflammation has led to mixed results in experimental models of sepsis or septic shock. In models in which experimental animals are challenged with IV LPS, treatment with recombinant IL-10 ameliorates fever and improves survival. In models such as cecal ligation and perforation, wherein the sepsis syndrome is induced by infection with viable bacteria, administration of exogenous IL-10 is beneficial or without effect. However, in mice with pneumonia caused by Pseudomonas aeruginosa, survival is improved when the animals are treated with an anti– IL-10 antibody to neutralize endogenous IL-10. Thus, although the use of recombinant IL-10 as an adjuvant treatment of sepsis is appealing, caution will need to be exercised in the design and conduct of clinical trials because excessive immunosuppression could adversely affect antibacterial defense mechanisms. IL-13 is a 12-kDa protein closely related to IL-4. The two proteins have approximately 25% hom*ology and share many structural characteristics. IL-13 is produced by Th2 cells and also undifferentiated CD4+ T cells and CD8+ T cells. The IL-13 receptor consists of two chains, one of which binds IL-4 but not

58 SECTION I SURGICAL BASIC PRINCIPLES From a number of studies using transgenic and knockout mice, TGF-β1 was found to play an important role in leukocyte development and function, wound healing, inflammation, suppression of tumorigenesis, and organogenesis and homeo stasis in tissues such as liver, kidney, pancreas, and lung. Furthermore, TGF-β1 administration reduces LPS-induced hypotension and mortality in a murine model of sepsis and, in trauma patients, lower circulating TGF-β1 levels are associated with the development of liver and kidney dysfunction, whereas higher TGF-β1 circulating levels 6 hours after admission to the intensive care unit are associated with an increased risk for sepsis. TGF-β plays a dual role in the differentiation of naïve T helper cells. When present by itself, TGF-β promotes expression of the transcription factor, Foxp3, a differentiation of naïve helper T cells into Treg cells. However, when presented with IL-6 or IL-21, TGF-β abrogates Treg cell development and, instead, promotes differentiation of naïve helper T cells into Th17cells.35 In the inactivated state, production of TGF-β fosters production of Treg cells, which tends to dampen immunologic or inflammatory responses. However, when IL-6 is produced in massive amounts as part of the acute-phase response to injury or infection, the balance is shifted to TGF-β–mediated induction of proinflammatory Th17 cells.35 Macrophage Migration Inhibitory Factor Macrophage migration inhibitory factor (MIF) was the first functional cytokine described. MIF is produced by monocytes and macrophages and acts in an autocrine and paracrine fashion to activate various cell types during inflammation. Immunostimulated macrophages secrete MIF. MIF appears to function proximally in the inflammatory cascade because MIF knockout mice exhibit a global reduction in the production of other inflammatory mediators such as TNF, IL-1β, and PGE2. MIF is encoded by a unique gene that displays very high sequence conservation across species. MIF is constitutively expressed and, after translation, preformed MIF remains in cytoplasmic pools and is readily released from macrophages after inflammatory stimulation. The rapid release of preformed MIF is unlike most other cytokines, which are typically released after transcriptional activation and translation of new protein. The receptor for MIF, CD74, is also distinct from the other cytokine receptor superfamilies. Apoptosis is an important mechanism for the resolution of the inflammatory response via the removal of activated monocytes and macrophages, and the proinflammatory action of MIF is caused, in part, by suppression of apoptosis. MIF also upregulates the expression of TLR4 on macrophages, thereby amplifying the response of the innate immune system to LPS (and possibly other proinflammatory substances such as HMGB1). Circulating MIF levels are increased in patients with sepsis and septic shock, but not in noninfected trauma patients. In mice with peritonitis, treatment with a neutralizing anti-MIF antibody improves survival. Complement Complement was first identified as a heat-labile component in serum that complemented the function of humoral immunity in the killing of microorganisms. Rather than a single factor, complement is a complex system of more than 30 plasma and membrane-bound proteins. The nomenclature used to describe

the multiple elements in the complement cascade follows their order of discovery rather than their sequential activation. Complement functions in consort with proteins of the coagulation, fibrinolysis, and kinin systems to augment the response to pathogenic stimuli via a series of catalytic reactions. The complement system is evolutionarily well preserved, thus suggesting that it represents a common ancestral host defense system. Although the complement system plays a key role in the host’s defense against pathogenic microbes, dysregulated activation of the complement cascade can be deleterious and excessive complement activation has been implicated in the pathogenesis of a wide variety of immune and inflammatory conditions, ranging from ARDS and sepsis to asthma.38 Activation of complement occurs via three distinct pathways: the classical pathway is activated by antigen-antibody (IgG or IgM) complexes, the alternative pathway is initiated by recognition of certain bacterial cell surface markers, such as LPS, and the lectin-binding pathway is activated by detection of bacterial surface sugars, such as mannose (Fig. 4-7). Most of the complement proteins circulate in inactive form until they are cleaved by an upstream protease, which in turn activates their proteolytic activity. Thus, sequential activation of catalytically active proteins produces an escalating cascade of activity (similar to the coagulation system). Regardless of the activation pathway, the most important active products are the anaphylatoxins C3a and C5a and the membrane attack complex C5b-C9, which causes lysis of gram-negative bacteria. C3a induces the release of histamine from mast cells and causes smooth muscle cell contraction. C5a binds to its receptor (C5aR) on neutrophils and macrophages and triggers intracellular signaling, chemotaxis, enzyme release, and the generation of ROS, which participate in the killing of microorganisms. Activation of the classical pathway is triggered by the interaction of antigen-antibody complexes with C1, which is a 790-kDa complex composed of a recognition protein C1q and a Ca2q-dependent tetramer consisting of two copies each of two proteases, C1r and C1s. Binding of C1 to a cellular or molecular target is mediated by C1q and results in the self-activation of C1r, which subsequently activates C1s. C1s then cleaves C4 and C2, thereby resulting in their activation. At this point, all pathways converge at C3 and lead to the activation of C3a and C5a and the terminal membrane attack complex C5b-C9, which creates pores in prokaryotic cell membranes that lead to bacterial cell lysis. Genetic defects in the classical pathway result in increased susceptibility to bacterial infections caused by organisms such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae. The alternative pathway, triggered by bacterial products such as LPS, results in the sequential activation of C3a, C5a, and the membrane attack complex. The lectin-binding pathway, triggered by binding of bacterial sugars such as mannose to mannose-binding lectin protein, activates C4a and C5a and then joins the common pathway for activation of the membrane attack complex. Activated complement products exert a number of biologic functions. C3b opsonizes pathogenic bacteria, which results in their enhanced phagocytosis by macrophages and neutrophils. Immune complexes bind to C3a and are then removed by binding with complement receptor 1 (CR1, discussed later). Clearance of necrotic and apoptotic cells may be facilitated by interaction with C1q. Complement factor deficiencies, which

The Inflammatory Response Chapter 4 59

Lectin

Alternative

C1q binding to antigenantibody complexes

MBL binding to mannose

SECTION I SURGICAL BASIC PRINCIPLES

Classical

LPS C1inactive

C1s

C1inh

Factor H

MBLactive

MBLinactive

Membrane C3b

C4b + C4a Factor I

C4 binding protein

C3b + C3a

Factor B

C3bB

C4b2

Factor D

C3bB + Ba

C4b2a

Properdin (P)

C3 convertases C3

C3bBbP

C3a + C3b C5 convertases

(C4b2a3b and C3b2Bb)

C5b + C5a

C6, C7, C8

Factor S C5b-C8

CD59 C5b-C9

result in inadequate clearance of immune complexes and dead cells, may give rise to the development of autoimmunity. Many of the effects of complement activation are mediated by the binding of activated complement products to specific receptors. Some receptors bind several different complement factors with varying affinity, thereby resulting in a variety of effects on different cells. Binding of C3b, C4b, and C1q by CR1, also known as CD35, results in the cleavage of C3 and C5 convertases, clearance of C3b-bound immune complexes, and activation of T lymphocytes. CR2, also known as CD21, is present on B and T lymphocytes and some endothelial cells. CR2 binds iC3b and C3d (C3b cleavage products) and causes stimulation of B lymphocytes and antibody production. EBV also binds to CR2. CR3 and CR4 are members of the integrin family and are expressed on myeloid cells. CR3 and CR4 bind iC3b, C3b, fibrinogen, ICAM-1, and other ligands. Binding of ligands to these receptors enhances antibody-mediated phagocytosis by neutrophils and macrophages. Although a number of different ligands bind to complement receptors 1 through 4, C3a and C5a bind to specific receptors (C3aR and C5aR, respectively). Both these receptors are present on a wide variety of cell types. Binding of C3a or C5a to their respective receptors activates intracellular signaling cascades involving MAPK pathways.

FIGURE 4-7 Activation of the complement cascade via the classical, lectin, or alternative pathways leads to formation of the membrane attack complex (C5bC9). Various complement inhibitors antagonize several steps in the cascade: C1 inhibitor (C1inh), factor I, factor H, C4-binding protein, factor S, and CD59, among others not shown here. MBL, Mannosebinding lectin.

Detrimental actions of the complement system on the host are mediated by the overproduction of C3a and C5a during complement activation and the excessive formation of membrane attack complexes. In rodent models of sepsis, treatment with a neutralizing anti-C5a antibody improves survival and also decreases circulating levels of TNF and IL-6, thus suggesting that the activation of C5 receptors is associated with the release of these other mediators.38 Several inhibitors are present in plasma or are membranebound to prevent uncontrolled activation of the complement system. C1 inhibitor is present in plasma and prevents the activation of C1s and C1r, thereby antagonizing the classical pathway. In addition, C1 inhibitor also inhibits the lectin pathway. Heterozygous deficiency of C1 inhibitor results in lifethreatening angioedema. Factor H and C4 binding protein are plasma proteins that inhibit C3 and C4 activation, thereby inhibiting all complement activation pathways. Factor I is a serine protease that inactivates C3b and C4b and therefore C3 and C5 convertases. C3a and C5a are also antagonized by carboxypeptidase N. S protein, fibronectin, and clusterin are plasma proteins that prevent insertion of C5b-C9 into cellular membranes. The membrane-bound complement inhibitors act at several points in the complement pathways. CD59 is a glycoprotein that prevents polymerization of C9 and blocks

60 SECTION I SURGICAL BASIC PRINCIPLES insertion of C9 into the membrane-bound C5b-C9 complex. Membrane cofactor protein and decay-accelerating factor act directly and with factor I to inhibit C3 and C5 convertases and cleave C3b and C4b, thereby inhibiting all complement pathways. Eicosanoids: Thromboxane, Prostaglandins, and Leukotrienes The prostaglandins, including PGE2 and PGI2 (prostacyclin), and thromboxane A2 (TXA2) are lipid mediators derived from the unstable intermediate compound PGG2. Formation of PGG2 depends on the activity of two families of enzymes. First, isoforms of the enzyme phospholipase A2 liberate the polyunsaturated fatty acid arachidonate from membrane phospholipids. Second, the two cyclooxygenase isoforms COX-1 and COX-2 catalyze the stereospecific oxidation of arachidonate to form the cyclic endoperoxide PGG2. Both these reactions are major regulatory steps in the formation of prostaglandins and TXA2. COX-1 is expressed constitutively in a variety of tissues and mediators produced by this isoform are thought to be important in various homeostatic processes, such as regulating renal perfusion and salt and water handling, maintaining hemostasis by modulating platelet aggregation, and preserving gastrointestinal mucosal integrity. COX-2, however, is an inducible enzyme. Expression of COX-2 is induced by a number of stimuli, including various growth factors and proinflammatory cytokines. In cells subjected to inflammatory stimuli, activation of COX-2 is thought to be mediated by the powerful oxidant ONOO−, thereby providing a tight functional linkage between the NO· and prostaglandin mediator systems. Once expressed and activated, COX-2 promotes the formation of PGG2 and PGH2 and, ultimately, various prostaglandins and TXA2. These mediators, in turn, interact with cell surface receptors belonging to the G protein–coupled receptor superfamily. Interaction of these receptors with cytosolic signaling pathways leads to rapid alterations in cell physiology manifested as physiologic or pathophysiologic phenomena such as vasodilation and increased microvascular permeability. Pharmacologic inhibition of cyclooxygenase activity is the basis for the anti-inflammatory actions of the class of compounds called nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas the anti-inflammatory effects of NSAIDs are thought to be mediated by blocking the enzymatic activity of COX-2, some adverse side effects of these agents (e.g., gastric mucosal ulceration) are thought to be mediated by inhibition of COX-1. Accordingly, identification of COX-2 as the so-called inflammatory isoform of cyclooxygenase led to intense efforts to develop drugs selective for the inducible enzyme. Selective COX-2 inhibitors were initially widely prescribed by clinicians. However, data from large multicenter trials of rofecoxib, one of the compounds in this class, showed that treatment with this agent was associated with an increased risk for death from cardiovascular complications.39,40 As a result of these findings, rofecoxib was withdrawn from the market. The increased risk for cardiovascular complications associated with rofecoxib, however, does not seem to be peculiar only to this specific agent but rather is thought to be a class effect associated with therapy with all isoform-selective COX-2 inhibitors, possibly as a result of greater inhibition of the synthesis of PGI2 (a vasodilator and inhibitor of platelet aggregation) relative to inhibition of the

synthesis of TXA2 (a potent vasoconstrictor and promoter of platelet aggregation). Nitric Oxide Many of the downstream actions of the proinflammatory cytokines occur as a result of increased expression of two key enzymes, iNOS (NOS-2) and COX-2. These enzymes share some common features and are both centrally involved in many aspects of the inflammatory response. iNOS is one of three isoforms of an enzyme, nitric oxide synthase (NOS), that catalyzes conversion of the amino acid L-arginine to the free radical gas NO·. One of the simplest stable molecules in nature, NO· is produced by many different types of cells and serves as a signaling and an effector molecule in mammalian biology. Whereas NOS-1 (also called neuronal NOS or nNOS) and NOS-3 (also called endothelial or eNOS) tend to be expressed constitutively in various cell types, iNOS is expressed for the most part only after stimulation of cells by proinflammatory cytokines (particularly IFN-γ, TNF, and IL-1) or LPS. NOS-1 and NOS-2 produce small puffs of NO· in response to transient changes in the intracellular ionized calcium concentration. In contrast, iNOS, once induced, produces large quantities of NO· for a prolonged period. All three NOS isoforms require L-arginine as a substrate and, in a complex five-electron redox reaction, convert one of the guanidino nitrogens of the amino acid into NO·. In addition to L-arginine, the redox reaction catalyzed by the various NOS isoforms requires the presence of molecular oxygen and a number of cofactors, including flavin mononucleotide, flavin adenine dinucleotide, iron-protoporphyrin IX, and tetrahydrobiopterin (BH4). The rate-limiting step in the biosynthesis of BH4 is the reaction catalyzed by guanosine triphosphate (GTP) cyclohydrolase I, an enzyme that like iNOS, is induced in certain cell types by cytokines, LPS, or both. Many of the biologic actions of NO·, including vasodilation, induction of vascular hyperpermeability, and inhibition of platelet aggregation, are mediated through the activation of the enzyme soluble guanylyl cyclase (sGC). Binding of NO· to the heme moiety of sGC activates the enzyme, thereby enabling it to catalyze the conversion of GTP to cyclic guanosine monophosphate (cGMP). NO· is not the only ligand that is capable of activating sGC; carbon monoxide (CO), another small gaseous molecule produced by mammalian cells, has also been shown to activate this enzyme. Signal transduction via the NO·sGC (or the CO-sGC) pathway entails the activation of various cGMP-dependent protein kinase (PKG) isoforms. In vascular smooth muscle cells, NO·-induced vasodilation occurs as a result of PKG-mediated opening of high-conductance calcium and voltage-activated potassium channels. Excessive production of NO· as a result of iNOS induction in vascular smooth muscle cells is thought to be a major factor contributing to the loss of vasomotor tone and loss of responsiveness to vasopressor agents (vasoplegia) in patients with septic shock. Treatment with a drug that blocks production of NO·, such as NG-monomethyl-Larginine (L-NMMA), ameliorates hypotension in patients with septic shock. Unfortunately, treatment of septic patients with L-NMMA actually worsens survival, possibly because the drug does not selectively inhibit iNOS but also inhibits NOS-3 as well and therefore interferes with the normal regulation of microcirculatory perfusion. Some studies have suggested that iNOS knockout mice are partially resistant to the lethal effects of acute endotoxemia. In contrast, one study has shown that

The Inflammatory Response Chapter 4 61

Carbon Monoxide Although CO was identified as a poison in the mid-19th century, its role as an endogenous signaling molecule has been recognized only in the past few years. The toxicity of CO relates to its ability to impair the oxygen-carrying capacity of hemoglobin. Two mechanisms are involved. First, CO binds to hemoglobin with 250-fold greater affinity than O2, thereby inhibiting O2 binding and transport. Second, CO causes a conformational change in the hemoglobin molecule that impairs its ability to release bound O2, thus shifting the oxyhemoglobin dissociation curve to the left. In addition, CO binds to and inactivates cytochrome a3, thereby impairing mitochondrial respiration. The concentrations of endogenously generated CO are far below the toxic level. Endogenously generated CO is a product of heme catabolism. The CO-generating reaction is catalyzed by a family of enzymes called heme oxygenases. There are three isoforms of heme oxygenase called HO-1, HO-2, and HO-3, although only HO-1 and HO-2 have been widely studied. HO-2 is constitutively expressed, whereas HO-1 is an inducible enzyme. HO-1 expression is induced by a wide variety of agents, including heme itself, heat shock stress, ROS, LPS, heavy metals, and ultraviolet radiation. HO-1 plays an important role in the defense of cells against oxidative stress, and both products of the degradation of heme by HO-1, bilirubin and CO, are important in this regard. CO exerts a variety of physiologic effects. It causes relaxation of smooth muscle cells, which results in vasodilation and bronchodilation. CO inhibits the activation and aggregation of

platelets. Like NO·, CO functions as a neurotransmitter. Finally, CO exerts a number of cytoprotective effects. Pretreatment of rodents with 250 ppm of inhaled CO ameliorates the development of acute lung injury after subsequent exposure to LPS or hyperoxia. CO also has antiproliferative effects on tumor cells and vascular endothelial and smooth muscle cells. Finally, CO has an anti-inflammatory role mediated via the MAPK pathway that results in suppression of TNF release and upregulation of IL-10 secretion. Similar to NO·, CO mediates its effects by binding to the ferrous heme moieties of hemoproteins. Although the affinity of heme for NO· is higher than that for CO, the off rate for dissociation of CO from heme is much slower, so CO displaces NO· from heme over time. Thus, CO can modulate the effects of NO· in this manner. Binding of CO to the heme moiety of sGC results in the activation of sGC and is the primary mechanism responsible for many of the biologic effects of CO. Hydrogen Sulfide In the past few years, it has become increasingly apparent that NO· and CO are not the only gaseous molecules used by mammalian species as signaling molecules. A third gas, hydrogen sulfide (H2S), also seems to be important.43 Long recognized as an environment pollutant, H2S, a colorless gas with a characteristic odor of rotten eggs, is produced in mammalian cells from the amino acid, L-cysteine, via either of two enzymes, cystathionine γ-lyase or cystathione β-lyase. H2S is a potent vasodilator and produces this effect through a mechanism that is not dependent on the activation of sGC. In rodents with LPSinduced shock or septic shock, H2S levels are inversely correlated with arterial blood pressure, suggesting that it has a pathogenic role in the development of hypotension. Treatment of septic rats with propylargylglycine, a compound that blocks enzymatic H2S production, improves survival and decreases biochemical evidence of inflammation. These findings support the view that H2S is a proinflammatory mediator, although other findings have suggested that some of the effects of H2S are antiinflammatory. Reactive Oxygen Species ROS are reactive, partially reduced derivatives of molecular oxygen (O2). Important ROS in biologic systems include superoxide radical anion (O2−·), hydrogen peroxide (H2O2), and hydroxyl radical (OH·). Closely related species include the hypohalous acids, particularly hypochlorous acid (HOCl), chloramine (NH2Cl) and substituted chloramines (RNHCl or R′R′′NCl), and singlet oxygen (1O2). Free radicals are atomic or molecular species with unpaired electrons. As a consequence of these unpaired electrons, free radicals are usually highly reactive and capable of modifying a wide range of cellular constituents, including lipids, proteins, and nucleic acids. ROS that are also free radicals include O2−·, OH·, peroxyl radical (RO2·), and hydroxyperoxyl radical (HO2·). A variety of enzymatic and nonenzymatic processes can generate ROS in mammalian cells. Nevertheless, a few key reactions or processes constitute the main sources of these reactive species: • NADPH oxidase catalyzes a one-electron reduction of O2 to form O2−· according to the following equation: 2O2 +  NADPH → 2O2−· + NADP + 2H+. NADPH oxidase is an

SECTION I SURGICAL BASIC PRINCIPLES

iNOS knockout mice are more susceptible than wild-type controls to lethality induced by bacterial peritonitis, possibly because enhanced NO· production is important for the host’s defense against infection. In contrast, iNOS knockout mice are protected from sepsis-induced acute lung injury.41 Signaling via the sGC-PKG pathway is not the only way that NO· functions as an inflammatory mediator. In addition, NO· reacts rapidly with another free radical, superoxide anion (O2−·), to form peroxynitrite anion (ONOO−), the conjugate base of the weak acid peroxynitrous acid (ONOOH). Being a potent oxidizing and nitrosating agent, ONOO−-ONOOH is thought to be responsible for many of the toxic effects of NO·. For example, ONOO−-ONOOH is capable of oxidizing sulfhydryl groups on various proteins at a rapid rate, peroxidizing membrane lipids, and inactivating mitochondrial aconitase. ONOO−-ONOOH is also capable of damaging nuclear DNA, thus setting up a chain of events that ultimately leads to the activation of the enzyme poly(adenosine ribose diphosphate[ADP]) polymerase-1 (PARP-1). On activation, PARP-1 catalyzes the poly(ADP) ribosylation of proteins, a reaction that consumes oxidized nicotine adenine dinucleotide (NAD+) and leads to energetic failure in cells.42 Treatment with pharmacologic agents that do the following has been shown to improve organ system function, survival, or both in certain experimental models of inflammation, such as acute endotoxemia, mesenteric ischemia and reperfusion, hemorrhagic shock and resuscitation, and stroke: 1. Scavenge ONOO−-ONOOH. 2. Selectively block iNOS (without blocking NOS-1 or NOS-3). 3. Block the activity of PARP-1.

62 SECTION I SURGICAL BASIC PRINCIPLES enzyme complex that is assembled and activated after the activation of phagocytes by microbes or microbial products (e.g., LPS) or various proinflammatory mediators such as leukotriene B4, platelet activating factor, TNF, or IL-8. In resting cells, the components of NADPH oxidase are present in the cytosol and membranes of various intracellular organelles. When the cell is activated, the components are assembled on a membrane-bound vesicle, which then fuses with the plasma membrane, and O2−· is released outward into the extracellular milieu and inward into the phagocytic vesicle. The reaction catalyzed by NADPH oxidase is critical for the formation of ROS in phagocytic cells, such as macrophages and PMNs. NADPH oxidase, however, is also present in other cell types, including vascular smooth muscle cells and endothelial cells. • Superoxide dismutase (SOD) catalyzes the conversion (dismutation) of two moles of O2− to form one mole each of O2 and H2O2. Two forms of SOD are present in cells. Copper-zinc SOD (CuZn-SOD) is a constitutive enzyme localized to the cytoplasm, whereas manganese SOD (Mn-SOD) is an inducible enzyme present in mitochondria. Increased expression of Mn-SOD is induced by oxidant stress or various proinflammatory cytokines. • In the presence of free ionized iron or copper in a low oxidation state (i.e., Fe2+ or Cu+, respectively), H2O2 reacts nonenzymatically to form OH· and hydroxyl anion according to the following equation: H2O2 + Fe2+ → OH· + OH− + Fe3+. The lower oxidation state of the transition metal cation can then be regenerated by the action of any number of reducing agents within the cellular milieu (e.g., ascorbic acid) and the cycle then repeated. This cycle constitutes the so-called Fenton reaction. • Myeloperoxidase (MPO) is an enzyme present in phagocytes that catalyzes oxidation of the halide ions chloride (Cl−), bromide (Br−), and iodide (I−) by H2O2 to form the corresponding hypohalous acids (HOCl, HOBr, and HOI, respectively). MPO, a colored heme-containing enzyme, is responsible for the greenish tint that is sometimes noticeable in purulent exudates. • Xanthine oxidase (XO) catalyzes the oxidation of xanthine (or hypoxanthine) by molecular oxygen to form uric acid and O2−· according to the following equation: xanthine + H2O + 2O2 → uric acid + 2O2− + 2H+. An enzyme related to XO, xanthine dehydrogenase (XDH), uses reduced nicotinamide adenine dinucleotide (NADH) as a cofactor and converts xanthine (or hypoxanthine) to uric acid without forming partially reduced forms of molecular oxygen. During episodes of tissue ischemia, XDH is proteolytically converted to XO, and adenosine triphosphate is degraded to xanthine and hypoxanthine. During reperfusion, O2 is available and XO acts on the accumulated substrates (xanthine and hypoxanthine), which leads to a burst in the production of ROS. • Although the various NOS isoforms ordinarily catalyze the formation of NO· and L-citrulline from L-arginine, these enzymes can generate O2−· if L-arginine availability is limiting. • ROS are also produced as a byproduct of the normal metabolism of oxygen in mitochondria and have important roles in cell signaling. Leakage of electrons from the mitochondrial electron transport chain with resultant formation of O2−· is quantitatively the most important mechanism, leading to ROS production within cells. Somewhat paradoxically, tissue

hypoxia, such as that occurring during hemorrhagic shock, can enhance mitochondrial ROS production. It is note worthy, therefore, that administration of a synthetic ROS scavenger, which has been designed to be concentrated in mitochondria, can prolong survival of rats with lethal hemorrhagic shock.44 To counter the activity of ROS, cells are equipped with a number of antioxidant systems, including SOD, catalase, glutathione, glutathione peroxidase, ascorbic acid (vitamin C), α-tocopherol (vitamin E), and thioredoxin. Under normal circ*mstances, the reducing milieu in cells prevents ROS-induced cellular damage. However, during times of stress, ROS production can increase dramatically and overwhelm normal antioxidant defenses, thereby leading to so-called oxidative stress and damage to cells and tissues on this basis. Sepsis is associated with oxidative stress. Low plasma ascorbate levels are predictive of the development of multiorgan dysfunction in septic patients, and some data have shown a reduction in the incidence of organ failure when antioxidants are administered to critically ill surgical patients. NEUROENDOCRINE CONTROL OF THE INFLAMMATORY RESPONSE The neuroendocrine system plays an important role in regulating immune and inflammatory responses. From a teleologic standpoint, regulation of innate immune responses by the CNS makes good sense. Innate immune responses to danger signals, whether caused by infection or trauma, need to occur quickly, and the CNS is capable of responding to external stimuli within milliseconds to minutes. Additionally, the CNS recognizes and responds to painful stimuli, which are often associated with trauma of various sorts. The three main components of regulatory influence of the CNS are mediated by hormones secreted by the adrenal cortex, hormones secreted by the adrenal medulla, and a neurotransmitter, acetylcholine, released by terminals of the vagus nerve. Corticosteroids The adrenal cortex synthesizes the mineralocorticoid, aldosterone, various weak androgens (e.g., dehydroepiandrosterone), and the glucocorticoid, cortisol (hydrocortisone). Because it is lipophilic, cortisol diffuses across the cytosolic membrane of cells and binds to a cytosolic receptor. The cortisol-receptor complex translocates into the nucleus, where it interacts with glucocorticoid responsive elements in the regulatory regions of hundreds of genes. The production of cortisol is regulated by the CNS via the hypothalamic-pituitary axis. In response to physiologic or psychological stress, secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland increases, which leads to increased secretion of cortisol from the adrenal cortex. Clinicians and scientists have long recognized that the natural and synthetic glucocorticoids, such as hydrocortisone and dexamethasone, are potent anti-inflammatory agents. Glucocorticoids modulate the secretion of cytokines and chemokines by lymphocytes, macrophages, and other cell types. The effects of glucocorticoids on the pattern of cytokine and chemokine secretion are myriad, but some of the most important, as summarized by Prigent and colleagues,45 are as follows:

The Inflammatory Response Chapter 4 63

Catecholamines The catecholamines, norepinephrine and epinephrine, are the principal neuroendocrine mediators of the sympathoadrenal axis. Norepinephrine is a neurotransmitter released by the terminals of postganglionic sympathetic neurons, whereas epinephrine is a hormone secreted by chromaffin cells in the

adrenal medulla in response to stimulation via preganglionic sympathetic nerve fibers. To a lesser extent, the adrenal medulla also releases two other catecholamines, norepinephrine and dopamine. Epinephrine and norepinephrine released from nerve terminals or the adrenal gland can bind to and activate β2-adrenergic receptors on macrophages and monocytes, upregulating secretion of IL-10 and downregulating secretion of TNF. Although α2-adrenergic stimulation can have the opposite effect and increase TNF secretion, activation of the sympathoadrenal axis has anti-inflammatory effects almost exclusively.49 Cholinergic Anti-Inflammatory Pathway In addition to the fight-or-flight responses of the sympathoadrenal axis, there is another neural pathway that clearly plays a role in modulating innate immune responses. This pathway, which has both afferent and efferent arms and uses the vagus nerve as a conduit, was identified in a series of ground-breaking studies carried out by the neurosurgeon and immunologist, Kevin Tracey.50 It is now clear that macrophages express a receptor for the neurotransmitter, acetylcholine. This receptor, called the α7 acetylcholine receptor, belongs to the nicotinic subclass of cholinergic receptors. Occupation of this receptor by acetylcholine or a pharmacological nicotinic cholinergic agonist suppresses the secretion of proinflammatory cytokines by immunostimulated macrophages. In experimental animals, stimulating the vagus nerve with an electrode suppresses innate immune responses, whereas sectioning the vagus nerve leads to exacerbation of pathologic inflammatory responses. In extensive preclinical studies, using animal models of human diseases, activation of the cholinergic anti-inflammatory pathway via various means has been shown to ameliorate the manifestations of acute pancreatitis, visceral ischemia-reperfusion injury, hemorrhagic shock, arthritis, and severe sepsis. At present, it is not known whether manipulation of vagal tone or the cholinergic anti-inflammatory pathway can ameliorate human diseases associated with dysregulated inflammation, but is likely that studies to address this topic will be carried out within the next few years. SELECTED REFERENCES Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310, 2001. A large observational cohort study that estimates that the incidence of severe sepsis is over 750,000 cases/year in the United States, with an expected growth rate of 1.5%/annum. It is also estimated that 215,000 patients with severe sepsis die annually, a number roughly equal to that associated with acute myocardial infarction.

Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709, 2001. Large, multicentric randomized trial demonstrating that treatment with recombinant human activated protein C (rhAPC) reduces mortality in patients with severe sepsis. The incidence of serious bleeding events was higher in the group that received rhAPC, but this did not reach statistical significance.

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inhibition of IL-2 and IFN-γ secretion by T cells; inhibition of IL-1β, TNF, IL-6, IL-8 and IL-12 secretion by monocytes and macrophages; increased secretion of anti-inflammatory cytokines (IL-10, IL-1RA and TGF-β) secretion by various cell types; downregulation of COX-2 and iNOS expression; and inhibition of adhesion molecule expression on various cell types. These anti-inflammatory actions of hydrocortisone and related compounds are mediated by more than one mechanism. One important action of glucocorticoids is to downregulate signaling mediated by a key transcription factor, NF-κB, known to activate many genes associated with the inflammatory response. Glucocorticoid-induced downregulation of NF-κB activation is a result of augmented expression of a protein, IκB, that is an inhibitory component of the NF-κB complex. An additional anti-inflammatory action of glucocorticoids is to inhibit the activation of another signaling pathway, the JNKSAPK cascade, which leads to decreased translation of TNF mRNA and thus decreased production of TNF. Still another mechanism whereby glucocorticoids inhibit inflammation is through decreased expression of the enzyme ICE, required for post-translational processing of pro–IL-1β and thus decreased secretion of mature IL-1β. In some experimental models of sepsis, early treatment with high doses of a potent synthetic glucocorticoid, such as methylprednisolone or dexamethasone, improves survival. Unfortunately, several large clinical trials have failed to confirm the benefit of high-dose glucocorticoid therapy for the adjuvant treatment of patients with septic shock or the related condition, ARDS. As a result, the notion of using glucocorticoids for these indications seemed to be a dead issue. However, the concept of using glucocorticoids as anti-inflammatory agents in the management of ARDS or septic shock has been resurrected, at least transiently. Several small studies have shown that prolonged therapy with relatively low doses of hydrocortisone or methylprednisolone improve systemic hemodynamics, pulmonary function, or both in patients with ARDS or septic shock. These findings were confirmed by the results obtained in a 300-patient, multicenter RCT carried out in one country (France).46 Although somewhat controversial, the results of this study supported the view that administration of a relatively low dose of hydrocortisone could improve survival in patients with volume-unresponsive pressor-dependent septic shock and an inadequate circulating cortisol response to an injection of ACTH. Prompted by the results from this study, 499 patients with volume-unresponsive pressor-dependent septic shock were enrolled in a multicenter trial of IV hydrocortisone.47 At 28 days, there was no difference in mortality between patients in the two study groups, although the corticosteroid-treated patients had more episodes of superinfection. Similarly disappointing results were obtained in a study of the administration of corticosteroids during the late (so-called fibroproliferative) phase of ARDS.48 Although some experts still advocate treating selected patients with sepsis or septic shock with corticosteroids, the results of these most recent studies suggest that this practice should be abandoned.

64 SECTION I SURGICAL BASIC PRINCIPLES Bettelli E, Carrier Y, Gao W, et al: Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441: 235–238, 2006. A landmark paper that identified the key role of IL-6 in the determination of whether naïve T cell exposed to TGF-β will differentiate into Th17 or Treg cells.

Matzinger P: The danger model: A renewed sense of self. Science 296:301–305, 2002. The classic view of the immune system proposed that an immunologic distinction is made between self and nonself. This article proposes a paradigm shift in this concept. In fact, the immune system may be more concerned with entities that do damage than with those that are foreign, and the release of so-called danger signals from dead or dying cells may alert the immune system to such substances.

Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008; 358:111–124. Important contribution to the evidence-based critical care literature demonstrating that treatment with low doses of glucocorticosteroids significantly fails to reduce mortality in patients with septic shock.

REFERENCES 1. Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145, 2007. 2. Matzinger P: The danger model: A renewed sense of self. Science 296:301–305, 2002. 3. Bianchi ME: DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 81:1–5, 2007. 4. Mollen KP, Anand RJ, Tsung A, et al: Emerging paradigm: Tolllike receptor 4-sentinel for the detection of tissue damage. Shock 26:430–437, 2006. 5. Mogensen TH: Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273, 2009. 6. Yan SF, Ramasamy R, Schmidt AM: Receptor for AGE (RAGE) and its ligands—cast into leading roles in diabetes and the inflammatory response. J Mol Med 87:235–247, 2009. 6a. Wang H, Bloom O, Zhang M, et al: HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251, 1999. 7. Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342, 2005. 8. Sappington PL, Yang R, Yang H, et al: HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123:790– 802, 2002. 9. Fink MP: Bench-to-bedside review: High-mobility group box 1 and critical illness. Crit Care 11:229, 2007. 10. Peltz ED, Moore EE, Eckels PC, et al: HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans. Shock 32:17–22, 2009. 11. Lantos J, Foldi V, Roth E, et al: Burn trauma induces early HMGB1 release in patients: Its correlation with cytokines. Shock 33:562–567, 2010.

12. Yang R, Harada T, Mollen KP, et al: Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol Med 12:105–114, 2006. 13. Ulloa L, Ochani M, Yang H, et al: Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 99:12351–12356, 2002. 14. Valentino L, Pierre J: JAK-STAT signal transduction: Regulators and implication in hematological malignancies. Biochem Pharmacol 71:713–721, 2006. 15. Bilgin K, Yaramis A, Haspolat K, et al: A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics 107:36–41, 2001. 16. Orozco H, Arch J, Medina-Franco H, et al: Molgramostim (GMCSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: A randomized, double-blind, placebo-controlled clinical trial. Arch Surg 141:150–153, 2006. 17. Meisel C, Schefold JC, Pschowski R, et al: Granulocytemacrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: A double-blind, randomized, placebocontrolled multicenter trial. Am J Respir Crit Care Med 180:640– 648, 2009. 18. Ogura Y, Bonen DK, Inohara N, et al: A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606, 2001. 19. Valentine JF, Fedorak RN, Feagan B, et al: Steroid-sparing properties of sargramostim in patients with corticosteroid-dependent Crohn’s disease: A randomised, double-blind, placebo-controlled, phase 2 study. Gut 58:1354–1362, 2009. 20. Korzenik JR, Dieckgraefe BK, Valentine JF, et al: Sargramostim for active Crohn’s disease. N Engl J Med 352:2193–2201, 2005. 21. McIntire CR, Yeretssian G, Saleh M: Inflammasomes in infection and inflammation. Apoptosis 14:522–535, 2009. 22. Kawai T, Akira S: TLR signaling. Semin Immunol 19:24–32, 2007. 23. Waterer GW, Quasney MW, Cantor RM, et al: Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med 163:1599–1604, 2001. 24. Berry MA, Hargadon B, Shelley M, et al: Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 354:697–708, 2006. 25. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709, 2001. 26. Castelli EE, Culley CM, Fink MP: Challenge and rechallenge: Drotrecogin alfa (activated)-induced prolongation of activated partial thromboplastin time in a patient with severe sepsis. Pharmacotherapy 25:1147–1150, 2005. 27. Abraham E, Laterre PF, Garg R, et al: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1332–1341, 2005. 28. Goldstein B, Nadel S, Peters M, et al: ENHANCE: Results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis. Pediatr Crit Care Med 7:200–211, 2006. 29. Cuzzocrea S, Mazzon E, Dugo L, et al: Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice. Cytokine 18:274–285, 2002. 30. Yang R, Han X, Uchiyama T, et al: IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and

The Inflammatory Response Chapter 4 65 39. Bresalier RS, Sandler RS, Quan H, et al: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102, 2005. 40. Curfman GD, Morrissey S, Drazen JM: Expression of concern: Bombardier et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” N Engl J Med 2000;343:1520–1528. N Engl J Med 353:2813– 2814, 2005. 41. Razavi HM, Werhun R, Scott JA, et al: Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury. Crit Care Med 30:868–873, 2002. 42. Fink MP: Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin 17:219–237, 2001. 43. Lowicka E, Beltowski J: Hydrogen sulfide (H2S)—the third gas of interest for pharmacologists. Pharmacol Rep 59:4–24, 2007. 44. Macias CA, Chiao JW, Xiao J, et al: Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock. Ann Surg 245:305–314, 2007. 45. Prigent H, Maxime V, Annane D: Clinical review: Corticotherapy in sepsis. Crit Care 8:122–129, 2004. 46. Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871, 2002. 47. Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124, 2008. 48. Steinberg KP, Hudson LD, Goodman RB, et al: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671–1684, 2006. 49. Pavlov VA, Tracey KJ: Neural regulators of innate immune responses and inflammation. Cell Mol Life Sci 61:2322–2331, 2004. 50. Tracey KJ: Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117:289–296, 2007.

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resuscitation in mice. Am J Physiol Gastrointest Liver Physiol 285:G621–629, 2003. 31. Opal SM, Keith JC Jr, Jhung J, et al: Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis. J Infect Dis 187:70–76, 2003. 31a. Yoshimura T, Matsushima K, Tanaka S, et al: Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci U S A 84:9233–9237, 1987. 32. Emmanuilidis K, Weighardt H, Matevossian E, et al: Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis: high serum IL-18 as an early predictive indicator of lethal outcome. Shock 18:301–305, 2002. 33. Weighardt H, Heidecke CD, Westerholt A, et al: Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis. Ann Surg 235:560–567, 2002. 34. Hunter CA: New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5:521–531, 2005. 34a. Yao Z, Painter SL, Fanslow WC, et al: Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483–5486, 1995. 34b. Mossmann TR, Coffman RL: Two types of mouse helper T-cell clone. Immunol Today 8:223–227, 1987. 35. Korn T, Bettelli E, Oukka M, et al: IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517, 2009. 36. Kawaguchi M, Adachi M, Oda N, et al: IL-17 cytokine family. J Allergy Clin Immunol 114:1265–1273; quiz 1274, 2004. 37. Flierl MA, Rittirsch D, Gao H, et al: Adverse functions of IL-17A in experimental sepsis. FASEB J 22:2198–2205, 2008. 38. Guo RF, Ward PA: Role of C5a in inflammatory responses. Annu Rev Immunol 23:821–852, 2005.

CHAPTER 5

SHOCK, ELECTROLYTES, AND FLUID Peter Rhee

history physiology of shock resuscitation perioperative fluid management electrolytes

Surgeons are the masters of fluids because they need to be. They care for patients who cannot eat or drink for various reasons— for example, they have hemorrhaged, undergone surgery, or lost fluids from tubes, drains, or wounds. Surgeons are obligated to know how to care for these patients, as they have put their lives in our hands. This topic might appear simple only for those who do not understand the complexities of the human body and its ability to regulate and compensate fluids. In reality, the task of managing patients’ blood volume is one of the most challenging burdens surgeons face, often requiring complete control of the intake and output of fluids and electrolytes, often in the presence of blood loss. Surgeons do not yet completely understand the physiology of shock and resuscitation, and our knowledge is superficial. Given the nature of our profession, we have studied fluids and electrolytes as we dealt with patients who have bled and even exsanguinate. Historically, wartime experience has always helped us move ahead in our knowledge of the management of fluids and resuscitation are no exceptions as we have learned much from them as well. The current wars in Iraq and Afghanistan. Constant attention to, and titration of, fluid loss therapy is required, because the human body is dynamic. The key to treatment is to realize the patient’s initial condition and understand that the fluid status is constantly changing. Bleeding, sepsis, neuroendocrine disturbances, and dysfunctional regulatory systems can all affect patients who are undergoing the dynamic changes of illness and healing. The correct management of blood volume is highly time-dependent. If managed well, surgeons are afforded the chance to deal with other aspects of surgery, such as nutrition, administration of antibiotics, drainage of abscesses, relief of obstruction and incarceration, treatment of ischemia, and resection of tumors. Knowing the difference among dehydration, anemia, hemorrhage, and overresuscitation is vital. The human body is predominantly water, which resides in the intravascular, intracellular, and interstitial (or third) spaces. Water moves among these spaces and depends on many 66

variables. Because surgeons can only control the intravascular space, this chapter will concentrate on the correct management of the intravascular space, because this is the only means to control the other two fluid compartments. This chapter will also examine historical aspects of shock, fluids, and electrolytes—not just to note interesting facts or pay tribute to deserving physicians, but also to try to understand how this knowledge was gained. Doing so is vital to understanding past changes in management and to accept future changes. Surgeons are often awed at the discoveries made, yet also astounded by how often they were wrong, and why. Future surgeons will look back at the current body of knowledge and be amazed at how little was known. Recent changes in the management of shock, fluids, and electrolytes have been major ones. Knowledge of the history helps explain why these changes were required. As a consequence of not studying the past, we have often repeated history in many ways. After the historical highlights, this chapter will discuss fluids that are now used, along with fluids under development. Finally, caring for perioperative patients will be explored from a daily needs perspective. HISTORY History may be disliked by those who are in a hurry to learn only the basics. Learning from the past, however, is essential, to know treatments that have and have not worked. Dogma must always be challenged and questioned. Were the treatments based on science? To understand what to do, surgeons must know how the practice evolved to the current management methods. Studying the history of shock is important for at least three reasons: 1. Physicians and physiologists have been fascinated with blood loss out of necessity. 2. Experiments that have been carried out need to be reassessed. 3. It is necessary to know more, because the current understanding of shock is elementary. Resuscitation One of the earliest authenticated resuscitations in the medical literature is the miraculous deliverance of Anne Green, who was executed by hanging on December 14, 1650. Green was executed in the customary way by being forced off a ladder to hang by the neck. She hung for 30 minutes, during which time some of her friends pulled “with all their weight upon her legs, sometimes lifting her up, and then pulling her down again with a sudden jerk, thereby the sooner to dispatch her out of her pain”1

Shock, Electrolytes, and Fluid Chapter 5 67

(Fig. 5-1). When everyone thought she was dead, the body was taken down, put in a coffin, and carried to the private house of Dr. William Petty—who, by the king’s orders, was allowed to perform autopsies on the bodies of everyone who had been executed. When the coffin was opened, Green was observed to take a breath and a rattle was heard in her throat. Petty and his colleague, Thomas Willis, abandoned all thoughts of a dissection and proceeded to revive their patient. They held her up in the coffin and then, by wrenching her teeth apart, poured hot cordial into her mouth, which caused her to cough. They rubbed and chafed her fingers, hands, arms, and feet; after 15 minutes of these efforts, they put more cordial into her mouth. Then, after tickling her throat with a feather, she opened her eyes momentarily. At that stage, they opened a vein and bled 5 ounces of blood. They continued administering the cordial and rubbing her arms and legs. Next, they applied compression bandages to her arms and legs. Heating plasters were put to her chest, and another plaster was inserted as an enema “to give heat and warmth to her bowels.” They then put her in a warm bed, with another woman to lie with her to keep her warm. After 12 hours, Green began to speak; 24 hours after her revival, she was answering questions freely. After 2 days, her memory was normal, apart from her recollection of her execution and the resuscitation. Shock Hemorrhagic shock has been extensively studied and written about for many years. Injuries, whether intentional or not, have occurred so frequently that much of the understanding of shock has been learned by surgeons taking care of the injured. What is shock? The current widely accepted definition is inadequate perfusion of tissue. However, many subtleties lie behind this statement. Nutrients for cells are required, but which nutrients are not well defined at this point. The most critical nutrient is oxygen, but concentrating on oxygenation alone probably represents elemental thinking. Blood is highly complex and carries countless nutrients, buffers, cells, antibodies, hormones, chemicals, electrolytes, and antitoxins. Even if we think

SECTION I SURGICAL BASIC PRINCIPLES

FIGURE 5-1 Miraculous deliverance of Anne Green, who was executed in 1650. (From Hughes JT: Miraculous deliverance of Anne Green: an Oxford case of resuscitation in the seventeenth century. Br Med J [Clin Res Ed] 285:1792–1793, 1982; by kind permission of the Bodleian Library, Oxford.)

in an elemental fashion and try to optimize the perfusion of tissue, the delivery side of the equation is affected by blood volume, anemia, and cardiac output. Moreover, the use of nutrients is affected by infection and drugs. The vascular tone plays a role as well; for example, in neurogenic shock, the sympathetic tone is lost and, in sepsis, systemic vascular resistance decreases, because of a broken homeostatic process or possibly because of evolutionary factors. Many advances in medicine have been achieved by battlefield observations. Unfortunately, in military and civilian trauma, hemorrhagic shock is the leading cause of preventable death. Repeatedly, wounded patients have survived their initial injuries, with adequate control of the hemorrhage, only to undergo malaise and deterioration, resulting in death. Such cases led to many explanations; most observers theorized a circulating toxic agent, thought to be secondary to the initial insult. The first record available that shows an understanding of the need for fluid in injured patients was apparently from Ambroise Paré (1510-1590), who urged the use of clysters (enemas to administer fluid into the rectum) to prevent “noxious vapors from mounting to the brain.” Yet, he also wrote that phlebotomy is “required in great wounds when there is fear of deflexion, pain, delirium, raving, and unquietness”; he and others practiced bloodletting during that era, because shock accompanying injury was thought to be from toxins. The term shock appears to have been first used in 1743 in a translation of the French treatise of Henri Francois Le Dran regarding battlefield wounds. He used the term to designate the act of impact or collision, rather than the resulting functional and physiologic damage. However, the term can be found in the book Gunshot Wounds of the Extremities, published in 1815 by Guthrie, who used it to describe the physiologic instability. Humoral theories persisted until the late 19th century but, in 1830, Herman provided one of the first clear descriptions of intravenous (IV) fluid therapy. In response to a cholera epidemic, he attempted to rehydrate patients by injecting 6 ounces of water into the vein. In 1831, O’Shaughnessy also treated cholera patients by administering large volumes of salt solutions intravenously and published his results in Lancet.2 Those were the first documented attempts to replace and maintain the extracellular internal environment or the intravascular volume. Note, however, that the treatment of cholera and dehydration is not the ideal treatment of hemorrhagic shock. In 1872, Gross defined shock as “a manifestation of the rude unhinging of the machinery of life.” His definition, given its accuracy and descriptiveness, has been repeatedly quoted in the literature. Theories on the cause of shock persisted through the late 19th century; although it was unexplainable, it was often observed. George Washington Crile investigated it and concluded, at the beginning of his career, that the lowering of the central venous pressure in the shock state in animal experiments was caused by a failure of the autonomic nervous system.3 Surgeons witnessed a marked change in ideas about shock between 1888 and 1918. In the late 1880s, there were no all-encompassing theories, but most surgeons accepted the generalization that shock resulted from a malfunctioning of some part of the nervous system. Such a malfunctioning has now been shown not to be the main reason—but surgeons are still perplexed by the mechanisms of hemorrhagic shock, especially regarding the complete breakdown of the circulatory system that occurs in the later stages of shock.

68 SECTION I SURGICAL BASIC PRINCIPLES In 1899, using contemporary advances with sphygmomanometers, Crile proposed that a profound decline in blood pressure (BP) could account for all symptoms of shock. He also helped alter how physicians diagnosed shock and followed its course. Before Crile, most surgeons relied on respiration, pulse, or declining mental status when evaluating the condition of patients. After Crile’s first books were published, many surgeons began measuring BP. In addition to changing how surgeons thought about shock, Crile was part of the therapeutic revolution. His theories remained generally accepted for almost 2 decades, predominantly in surgical circles. Crile’s work persuaded Harvey Cushing to measure BP during all operations, which in part led to the general acceptance of BP measurement in clinical medicine. Crile also concluded that shock was not a process of dying, but rather a marshaling of the body’s defenses in patients struggling to live. He later deduced that the reduced volume of circulating blood, rather than the diminished BP, was the most critical factor in shock. Crile was instrumental in forming numerous theories of shock but was also known for the “anoci-association” theory of shock, which accounted for pain and its physiologic response during surgery. He realized that the constant administration of nitrous oxide during surgery was required, which necessitated having an additional professional at the operating table—the skilled nurse anesthetist. In 1908, he trained Agatha Hodgins, one of his nurses at Western Reserve, who later founded the American Association of Nurse Anesthetists. Crile’s theories evolved as he continued his experimentations; in 1913, he proposed the kinetic system theory. He was interested in thyroid hormone and its response to wounds, but realized that adrenalin was a key component of the response to shock. He relied on experiments by Walter B. Cannon, who found that adrenalin was released in response to pain or emotion, shifting blood from the intestines to the brain and extremities. Adrenalin release also stimulated the liver to convert glycogen to sugar for release into the circulation. Cannon argued that all the actions of adrenalin aided the animal in its effort to defend itself.4 Crile incorporated Cannon’s study into his theory. He proposed that impulses from the brain after injury stimulated glands to secrete their hormones, which in turn resulted in sweeping changes throughout the body. Crile’s kinetic system included a complex interrelationship among the brain, heart, lungs, blood vessels, muscles, thyroid gland, and liver. He also noted that if the body underwent too much stress, the adrenal glands would run out of adrenalin, the liver of glycogen, the thyroid of its hormone, and the brain itself of energy, accounting for autonomic changes. Once the kinetic system ran out of energy, BP would fall, and the animal would go into shock. At the end of the 19th century, surgeons for the most part used a wide variety of tonics, stimulants, and drugs. Through careful testing, Crile demonstrated that most of those agents were ineffective, stressing that only saline solutions, adrenalin, blood transfusions, and safer forms of anesthesia were beneficial for treating shock. In addition, he vigorously campaigned against the customary approach of polypharmacy, instead promoting only drugs of proven value. He stated that stimulants, long a mainstay of treatment in shock, did not raise BP and should be discarded: “a surgeon should not stimulate an exhausted vasomotor center with strychnine. That would be as futile as flogging a dead horse.”

BOX 5-1 Causes of Shock (According to Blalock) • Hematogenic (oligemia) • Neurogenic (caused primarily by nervous influences) • Vasogenic (initially decreased vascular resistance and increased vascular capacity, as in sepsis) • Cardiogenic (failure of the heart as a pump, as in cardiac tamponade or myocardial infarction) • Large volume loss (extracellular fluid, as in patients with diarrhea, vomiting, and fistula drainage) Data from Blalock A: Principles of surgical care: Shock and other problems, St Louis, 1940, CV Mosby.

Henderson recognized the importance of decreased venous return and its effect on cardiac output and arterial pressure. His work was aided by advances in techniques that allowed careful recording of the volume curves of the ventricles. Fat embolism also led to a shocklike state, but its possible contribution was questioned because study results were difficult to reproduce. The vasomotor center and its contributions in shock were heavily studied in the early 1900s. In 1914, Mann noted that unilaterally innervated vessels of the tongues of dogs, ears of rabbits, and paws of kittens appeared constricted during shock, as compared with contralaterally denervated vessels. Battlefield experiences continued to intensify research on shock. During the World War I era, Cannon used clinical data from the war and data from animal experiments to examine the shock state carefully. He theorized that toxins and acidosis contributed to the previously described lowering of vascular tone. He and others then focused on acidosis and the role of alkali in preventing and prolonging shock. The adrenal gland and effect of cortical extracts on adrenalectomized animals were studied with fascination during this period. Then, in the 1930s, a unique set of experiments by Blalock5 determined that almost all acute injuries were associated with changes in fluid and electrolyte metabolism. Such changes were primarily the result of reductions in the effective circulating blood volume. Blalock showed that those reductions after injury could be the result of several mechanisms (Box 5-1). He clearly showed that fluid loss in injured tissues involved the loss of extracellular fluid (ECF) that was unavailable to the intravascular space for maintaining circulation. The original concept of a “third space,” in which fluid is sequestered and therefore unavailable to the intravascular space, evolved from Blalock’s studies. Carl John Wiggers first described the concept of irreversible shock.6 His 1950 textbook, Physiology of Shock, represented the attitudes toward shock at that time. In an exceptionally brilliant summation, Wiggers assembled the various signs and symptoms of shock from various authors in that textbook (Fig. 5-2), along with his own findings. His experiments used what is now known as the Wiggers prep. In his usual experiments, he used previously splenectomized dogs and cannulated their arterial systems. He took advantage of an evolving technology that allowed him to measure the pressure in the arterial system, and he studied the effects of lowering BP through blood withdrawal. After removing the dogs’ blood to an arbitrary set point (typically, 40 mm Hg), he noted that their BP soon spontaneously rose as fluid was spontaneously recruited into the intravascular space.

Shock, Electrolytes, and Fluid Chapter 5 69

General appearance and reactions Mental state Apathy Delayed responses Depressed cerebration Weak voice Listless or restlessness Countenance Drawn–anxious Lusterless eyes Sunken eyeballs Ptosis of upper lids (slight) Upward rotation of eyeballs (slight) Neuromuscular state Hypotonia Muscular weakness Tremors and twitchings Involuntary muscular movements Difficulty in swallowing Neuromuscular tests Depressed tendon reflexes Depressed sensibilities Depressed visual and auditory reflexes General but variable symptoms Thirst Vomiting Diarrhea Oliguria Visible or occult blood in vomitus, and stools

Skin and mucous membranes

Circulation and blood

Skin Pale, livid, ashen gray Slightly cyanotic Moist, clammy Mottling of dependent parts Loose, dry, inelastic, cold

Superficial veins Collapsed and invisible Failure to fill on compression or massage Inconspicuous jugular pulsations

Mucous membranes Pale, livid, slightly cyanotic

Heart Apex sounds feeble Rate, usually rapid

Conjunctiva Glazed, lusterless

Radial pulse Usually rapid Small volume “feeble,” “thready”

Tongue Dry, pale, parched, shriveled Respiration and metabolism Respiration Variable but not dyspneic Usually increased rate Variable depth Occasional deep sighs Sometimes irregular or phasic Temperature Subnormal, normal, supernormal Basal metabolic rate reduced (?)

SECTION I SURGICAL BASIC PRINCIPLES

SYMPTOM COMPLEX OF SHOCK

Brachial blood pressures Lowered Pulse pressure small Retinal vessels Narrowed Blood volume Reduced Blood chemistry Hemoconcentration or hemodilution Venous O2 decreased A-V O 2 difference increased Arterial CO 2 reduced Alkali reserve reduced

To keep the dogs’ BP at 40 mm Hg, Wiggers had to continually withdraw additional blood during this compensated stage of shock. During compensated shock, the dogs could use their reserves to survive. Water was recruited from the intracellular compartment as well as the extracellular space. The body tried to maintain the vascular flow necessary to survive. However, after a certain period, he found that to keep the dogs’ BP at the arbitrary set point of 40 mm Hg, he had to reinfuse shed blood; he termed this phase uncompensated or irreversible shock. Eventually, after a period of irreversible shock, the dogs died. If the dogs had not yet gone into the uncompensated phase, any type of fluid used for resuscitation would have made survival likely. In fact, most dogs at that stage, even without resuscitation, would self-resuscitate by going to a water source. Once they entered the uncompensated phase of shock, however, their reserves were exhausted; even if blood were given back, survival rates were better if additional fluid of some sort was

FIGURE 5-2 Wiggers’ description of symptom complex of shock. (From Wiggers CJ: Present status of shock problem. Physiol Rev 22:74, 1942.)

administered. Uncompensated shock is surely what Gross meant by “unhinging of the machinery of life.” Currently, hemorrhagic shock models are classified as involving controlled or uncontrolled hemorrhage. The Wiggers prep is controlled hemorrhage and is referred to as pressure-controlled hemorrhage. Another animal model that uses controlled hemorrhage is the volume-controlled model. Arguments against this model include the inconsistency of the blood volume from one animal to another and the variability in response. Calculating blood volume is usually based on a percentage of body weight (typically, 7% of body weight), but such percentages are not exact and result in variability from one animal to another. However, proponents of the volume model and critics of the pressure model argue that a certain pressure during hypotension elicits a different response from one animal to another. Even in the pressure-controlled hemorrhage model, animals vary highly in regard to when they go from compensated to uncompensated

70 SECTION I SURGICAL BASIC PRINCIPLES shock. The pressure typically used in the pressure-controlled model is 40 mm Hg; the volume used in the volume-controlled model is 40%. The variance in the volume-controlled model can be minimized by specifying a narrow weight range for the animals (e.g., rats within 10 g, large animals within 5 pounds). It is also important to have the same experimenters doing the exact same procedure at the same time of the day in animals that were prepared and hydrated in exactly the same way. The ideal model is uncontrolled hemorrhage, but its main problem is that the volume of hemorrhage is uncontrolled by the nature of the experiment. Variability is the highest in this model, even though it is the most realistic. Computer-assisted pressure models can be used that mimic the pressures during uncontrolled shock to reduce the artificiality of the pressurecontrolled model. Fluids How did the commonly used IV fluids, such as normal saline, enter medical practice? It is often taken for granted, given the vast body of knowledge in medicine, that they were adopted through a rigorous scientific process but that was not actually the case. Normal saline has been used for many years and is extremely beneficial, but we now know that it also can be harmful. Hartog Jakob Hamburger, in his in vitro studies of red cell lysis in 1882, incorrectly suggested that 0.9% saline was the concentration of salt in human blood. This fluid is often referred to as physiologic or normal saline, but it is neither physiologic nor normal. Supposedly, 0.9% normal saline originated during the cholera pandemic that afflicted Europe in 1831, but an examination of the composition of the fluids used by physicians of that era found no resemblance to normal saline. The origin of the concept of normal saline remains unclear.7 In 1831, O’Shaughnessy described his experience in the treatment of cholera8: Universal stagnation of the venous system, and rapid cessation of the arterialization of the blood, are the earliest, as well as the most characteristic effects. Hence the skin becomes blue—hence animal heat is no longer generated—hence the secretions are suspended; the arteries contain black blood, no carbonic acid is evolved from the lungs, and the returned air of expiration is cold as when it enters these organs.

O’Shaughnessy wrote those words at the age of 22, having just graduated from Edinburgh Medical School. He tested his new method of infusing intravenous saline on a dog and observed no ill effects. Eventually, he reported that the aim of his method was to restore blood to its natural specific gravity and to restore its deficient saline matters. His experience with human cholera patients taught him that the practice of bloodletting, then highly common, was good for “diminishing the venous congestion” and that nitrous oxide (laughing gas) was not useful for oxygenation. In 1832, Robert Lewins reported that he witnessed Thomas Latta injecting extraordinary quantities of saline into veins, with the immediate effects of “restoring the natural current in the veins and arteries, of improving the color of the blood, and [of ] recovering the functions of the lungs.” Lewins described Latta’s saline solution as consisting of “two drachms of muriate, and two scruples of carbonate, of soda, to sixty ounces of water.” Later, however, Latta’s solution was found to equate to having

FIGURE 5-3 Sydney Ringer, credited for the development of lactated Ringer’s solution. (From Baskett TF: Sydney Ringer and lactated Ringers’s solution. Resuscitation 58:5–7, 2003.)

134 mmol/liter of Na+, 118 mmol/liter of Cl−, and 16 mmol/ liter of HCO3−. Over the next 50 years, many reports cited various recipes to treat cholera, but none resembled 0.9% saline. In 1883, Sydney Ringer reported on the influence exerted by the constituents of the blood on the contractions of the ventricle (Fig. 5-3). Studying hearts cut out of frogs, he used 0.75% saline and a blood mixture made from dried bullocks’ blood.9 In his attempts to identify which aspect of blood caused better results, he found that a “small quantity of white of egg completely obviates the changes occurring with saline solution.” He concluded that the benefit of white of egg was because of the albumin or potassium chloride. To show what worked and what did not, he described endless experiments, with alterations of multiple variables. However, Ringer later published another article stating that his previously reported findings could not be repeated; through careful study, he realized that the water used in his first article was actually not distilled water, as reported, but rather tap water from the New River Water Company. It turned out that his laboratory technician, who was paid to distill the water, took shortcuts and used tap water instead. Ringer analyzed the water and found that it contained many trace minerals (Fig. 5-4). Through careful and diligent experimentation, he found that calcium bicarbonate or calcium chloride—in doses even smaller than those in blood—restored good contractions of the frog ventricles. The third component that he found essential to good contractions was sodium bicarbonate. He knew the importance of the trace elements. He also stated that fish could live for weeks unfed in tap water, but would die in distilled water in a few hours; minnows, for example, died in an average of 4.5 hours.

Shock, Electrolytes, and Fluid Chapter 5 71

Calcium Magnesium Sodium Potassium

38.3

per million.

4.5

”

23.3

”

7.1

”

Combined carbonic acid

78.2

”

Sulphuric acid

55.8

”

7.1

”

54.2

”

Chlorine Silicates Free carbonic acid

FIGURE 5-4 Sidney Ringer’s report of contents in water from the New River Water company. (From Baskett TF: Sydney Ringer and lactated Ringers’s solution. Resuscitation 58:5–7, 2003.)

Thus, the three ingredients that he found essential were potassium, calcium, and bicarbonate. Ringer’s solution soon became ubiquitous in physiologic laboratory experiments. In the early 20th century, fluid therapy by injection under the skin (hypodermoclysis) and infusion into the rectum (proctoclysis) became routine. Hartwell and Hoguet reported its use in intestinal obstruction in dogs, laying the foundation for saline therapy in human patients with intestinal obstruction. As IV crystalloid solutions were developed, Ringer’s solution was modified, most notably by pediatrician Alexis Hartmann. In 1932, attempting to develop an alkalinizing solution to administer to his acidotic patients, Hartmann modified Ringer’s solution by adding sodium lactate. The result was lactated Ringer’s (LR), or Hartmann’s solution. He used sodium lactate (instead of sodium bicarbonate)—the conversion of lactate into sodium bicarbonate was slow enough to lessen the danger posed by sodium bicarbonate, which could rapidly shift patients from compensated acidosis to uncompensated alkalosis. In 1924, Rudolph Matas, regarded as the originator of modern fluid treatment, introduced the concept of the continued IV drip but also warned of the potential dangers of saline infusions. He stated that “Normal saline has continued to gain popularity but the problems with metabolic derangements have been repeatedly shown but seem to have fallen on deaf ears.” In healthy volunteers, normal saline has been shown to cause abdominal discomfort and pain, nausea, drowsiness, and decreased mental capacity to perform complex tasks. The point is that normal saline and LR solutions have been formulated for conditions other than the replacement of blood, and the reasons for the formulation are archaic. Such solutions have been useful for dehydration; when used in relatively small volumes (1 to 3 liters/day), they are well tolerated and relatively harmless, they provide water, and the human body can tolerate the amounts of electrolytes they contain. Over the years, LR has attained widespread use for the treatment of hemorrhagic shock. However, normal saline and LR are mostly permeable through the vascular membrane, but are poorly retained in the vascular space. After a few hours, only about 175 to 200 mL of a 1-liter infusion remains in the intravascular space. In countries other than the United States, LR is often referred to as Hartmann’s solution, and normal saline is referred to as physiologic (sometimes even spelled “fisiologic”) solution. With the advances in

science in the last 50 years, it is hard to understand why more advances in resuscitation fluids have not been made. Blood Transfusions Concerned about the blood that injured patients lost, Crile began to experiment with blood transfusions. As he stated, “After many accidents, profuse hemorrhage often led to shock before the patient reached the hospital. Saline solutions, adrenalin, and precise surgical technique could substitute only up to a point for the lost blood.” At the turn of the 19th century, transfusions were seldom used. Their use waxed and waned in popularity because of transfusion reactions and difficulties in preventing clotting in donated blood. Through his experiments in dogs, Crile showed that blood was interchangeable: he transfused blood without blood group matching. Alexis Carrel was able to sew blood vessels together with his triangulation technique, using it to connect blood vessels from one person to another for the purpose of transfusions. However, Crile found Carrel’s technique too slow and cumbersome in humans, so he developed a short cannula to facilitate transfusions. By World War II, shock was recognized as the single most common cause of treatable morbidity and mortality. At the time of the Japanese attack on Pearl Harbor on December 7, 1941, no blood banks or effectual blood transfusion facilities were available. Most military locations had no stocks of dried pooled plasma. Although the wounded of that era were evacuated quickly to a hospital, the mortality rate was still high. IV fluids of any type were essentially unavailable, except for a few liters of saline manufactured by means of a still in the operating room. IV fluid was usually administered using an old Salvesen flask and reused rubber tubing. Often, a severe febrile reaction resulted from the use of that tubing. The first written documentation of resuscitation in World War II patients was 1 year after Pearl Harbor, in December 1942, in notes from the 77th Evacuation Hospital in North Africa. Churchill stated that “The wounded in action had for the most part either succumbed or recovered from any existing shock before we saw them. However, later cases came to us in shock, and some of the early cases were found to be in need of whole blood transfusion. There was plenty of reconstituted blood plasma available. However, some cases were in dire need of whole blood. We had no transfusion sets, although such are available in the United States: no sodium citrate; no sterile distilled water; and no blood donors.” The initial decision to rely on plasma rather than blood appears to have been based in part on the view held by the Office of the Surgeon General of the Army, and in part on the opinion of the civilian investigators of the National Research Council. Those civilian investigators thought that in shock, the blood was thick and the hematocrit level high. On April 8, 1943, the Surgeon General stated that no blood would be sent to the combat zone. Seven months later, he again refused to send blood overseas because of the following: (1) his observations of overseas theaters had convinced him that plasma was adequate for the resuscitation of wounded men; (2) from a logistics standpoint, it was impractical to make locally collected blood more available than that from general hospitals in the combat zone; and (3) shipping space was too small. Vasoconstricting drugs such as adrenalin were condemned because they were thought to decrease blood flow and tissue perfusion as they dammed the blood in the arterial portion of the circulatory system.

SECTION I SURGICAL BASIC PRINCIPLES

They consist of:

72 SECTION I SURGICAL BASIC PRINCIPLES

Table 5-1 Four Classes of Hemorrhagic Shock* PARAMETER

Class I

III

Blood loss (%)

0-15

15-30

30-40

>40

Central nervous system

Slightly anxious

Mildly anxious

Anxious or confused

Confused or lethargic

Pulse (beats/min)

100

>120

>140

Blood pressure

Normal

Decreased

Pulse pressure

Normal

Decreased

Respiratory rate

14-20/min

20-30/min

30-40/min

>35/min

Urine (mL/hr)

>30

20-30

5-15

Negligible

Fluid

Crystalloid

Crystalloid + blood

*According to the ATLS course.

During World War II, out of necessity, efforts to make blood transfusions available heightened and led to the institution of blood banking for transfusions. Better understanding of hypovolemia and inadequate circulation favored the use of plasma as a resuscitative solution, in addition to whole blood replacement. Thus, the treatment of traumatic shock greatly improved. The administration of whole blood was thought to be extremely effective, so it was widely used. Mixed with sodium citrate in a 6 : 1 ratio to bind the calcium in the blood, which prevented clotting, worked well. However, no matter which solution was used—blood, colloids, or crystalloids—the blood volume seemed to increase by only a fraction of what was lost. In the Korean War era, it was recognized that more blood had to be infused to regain the blood volume that was lost adequately. The reason for the need for more blood was unclear, but was thought to be because of hemolysis, pooling of blood in certain capillary beds, and loss of fluid into tissues. Considerable attention was given to elevating the feet of patients in shock. PHYSIOLOGY OF SHOCK Bleeding Research and experience have both taught us much about the physiologic responses to bleeding. The Advanced Trauma Life Support (ATLS) course defines four classes of shock (Table 5-1). In general, that categorization has helped point out the physiologic responses to hemorrhagic shock, emphasizing the identification of blood loss and guiding treatment. Shock can be thought of anatomically at three levels (Fig. 5-5). It can be cardiogenic, with extrinsic abnormalities (e.g., tamponade) or intrinsic abnormalities (e.g., pump failure caused by infarct, overall cardiac failure, or contusion). Large vessels can cause shock if they are injured and bleeding results. If the anatomic problem is at the small vessel level, neurogenic dysfunction or sepsis can be the culprit. The four classes of shock as taught in the ATLS course are problematic because they were not rigorously tested and proven. The developers of the ATLS course have agreed that these classes were fairly arbitrary and not necessarily based on rigorous scientific data. Patients in shock do not always follow the

physiology as taught in the ATLS course, and a high degree of variance exists among patients, particularly in children and older patients. Children, in general, seem to be able to compensate, even after large volumes of blood loss, because of the higher water composition of their bodies. However, when they decompensate, the process can be rapid. Older patients do not compensate well; when they start to collapse physiologically, the process can be devastating because their ability to recruit fluid is not as good and their cardiac reserves are less. The problem with the signs and symptoms classically shown in the ATLS classes is that in reality, the manifestations of shock can be confusing and difficult to assess. For example, consider whether an individual patient’s change in mental status is caused by factors such as blood loss, traumatic brain injury (TBI), pain, or illicit drugs. The same dilemma applies for respiratory rate and skin changes. Are alterations in a patient’s respiratory rate or skin caused by factors such as pneumothorax, rib fractures, or inhalation injury? To date, despite the many potential methods of monitoring shock, none has been found clinically reliable for replacing BP. Clinicians all know that there is a wide range of normal BPs. The question often is this: What is the baseline BP of the patient being treated? When a seemingly normal BP is treated, is that hypotension or hypertension compared with the patient’s normal BP? How do we know how much blood has been lost? Even if blood volume is measured directly (rapid methods are now available), what was the patient’s baseline blood volume? To what blood volume should the patient be resuscitated? The end point of resuscitation has been elusive. The variance in all the variables makes assessment and treatment a challenge. One important factor to recognize is that clinical symptoms are relatively few in patients who are in class I shock. The only change in class I shock is anxiety, which is practically impossible to assess—is it the result of factors such as blood loss, pain, trauma, or drugs? A heart rate higher than 100 beats/min has been used as a physical sign of bleeding, but evidence of its significance is minimal. Brasel and colleagues10 have shown that heart rate is neither sensitive nor specific in determining the need for emergent intervention, need for packed red blood cell (PRBC) transfusions in the first 2 hours after an injury, or severity of an injury. Heart rate was not altered by the presence of hypotension (systolic BP 90 beats/min).11 The physiologic response to bleeding also differs subtly according to whether the source of bleeding is arterial or venous. Arterial bleeding is obviously problematic, but often stops temporarily on its own; the human body has evolved to trap the blood loss in adventitial tissues, and the transected artery will spasm and thrombose. A lacerated artery can actually bleed more than a transected artery because the spasm of the lacerated artery can actually enlarge the hole in the vessel. Thrombosis of the artery sometimes does not occur in transected or lacerated vessels. Arterial bleeding, when constantly monitored, results in rapid hypotension: there is a leak in the arterial system and, because the arterial system is valveless, the recorded BP drops early, even before large-volume loss occurs. In these patients, hypotension ensues quickly but because ischemia has not yet had a chance to occur, measurements of lactate or base deficit often yield normal results. Venous bleeding, however, is slower; the human body compensates, and sometimes large volumes of blood are lost before hypotension ensues. In venous bleeding, there is time for lactate and base deficit results to be abnormal. Blood loss is often slower, but can still be massive before it is reflected in hypotension. The slower nature of venous bleeding also allows for compensatory mechanisms to interact because water is recruited intravascularly from cells and the interstitial spaces. It is generally taught that the hematocrit or hemoglobin level is not reliable for predicting blood loss. This is true for patients with a high hematocrit or hemoglobin level but in patients resuscitated with fluids, a rapid drop in the hematocrit and hemoglobin levels can occur immediately. Bruns and associates12 have shown that the hemoglobin level can be low within the first 30 minutes after the patient arrives at a trauma center. Therefore, although patients with a high or normal hemoglobin level may have significant bleeding, a low hemoglobin level, because it occurs rapidly, usually reflects the actual hemoglobin level and extent of blood loss. Infusion of acellular fluids often will dilute the blood and decrease the hemoglobin levels even further. The lack of good indicators to distinguish which patients are bleeding has led many investigators to examine heart rate variability or complexity as a potential new vital sign. Many clinical studies have shown that heart rate variability or complexity is associated with poor outcome, but this has yet to catch on, perhaps because of the difficulty of calculating it. Heart rate variability or complexity would have to be calculated using software, with a resulting index on which clinicians would have to rely; this information would not be available merely by

examining patients. Another issue with heart rate variability or complexity is that the exact physiologic mechanism for its association with poor outcome has yet to be elucidated.13 This new vital sign may be programmable into currently used monitors, but its usefulness has yet to be confirmed. Hypotension has been traditionally set, arbitrarily, at 90 mm Hg and below. However, Eastridge and coworkers14 have suggested that hypotension be redefined as 110 mm Hg and below, because that BP is more predictive of death and hypoperfusion. They concluded that 110 mm Hg would be a more clinically relevant cutoff point for hypotension and hypoperfusion. In 2008, Bruns and colleagues15 confirmed that concept, showing that a prehospital BP lower than 110 mm Hg was associated with a sharp increase in mortality, and 15% of patients with that BP would eventually die in the hospital. As a result, they recommended redefining prehospital triage systems. Of note, especially in older patients, normal vital signs may miss occult hypoperfusion as indicated by increased lactate levels and base deficit.16 Lactate and Base Deficit Lactate has been a marker of injury, and possibly ischemia, and has stood the test of time.16 However, new data question the cause and role of lactate. Emerging information is confusing; it suggests that we may not understand lactate for what it truly implies. Lactate has long been thought to be a byproduct of anaerobic metabolism and is routinely perceived to be an end waste product that is completely unfavorable. Physiologists are now questioning this paradigm and have found that lactate behaves more advantageously than not. An analogy would be that firefighters are associated with fires, but that does not mean that firefighters are bad, nor does it mean that they caused the fires. Research has shown that lactate accumulates in muscle and blood during exercise; it is at its highest level at, or just after, exhaustion. Accordingly, it was assumed that lactate was a waste product. We also know that lactic acid appears in response to muscle contraction and continues in the absence of oxygen. In addition, accumulated lactate disappears when oxygen is present in tissues. Recent evidence has indicated that lactate is an active metabolite, capable of moving among cells, tissues, and organs, where it may be oxidized as fuel or reconverted to form pyruvate or glucose. It now appears that increased lactate production and concentration, as a result of anoxia or dysoxia, are often the exception rather than the rule. Lactate seems to be a shuttle for energy; the lactate shuttle is now the subject of much debate. The end product of glycolysis is pyruvic acid. Lack of oxygen is thought to convert pyruvate into lactate. However, lactate formation may allow carbohydrate metabolism to continue through glycolysis. It is postulated that lactate is transferred from its site of production in the cytosol to neighboring cells and to various organs (e.g., heart, liver, kidney), where its oxidation and continued metabolism can occur. Lactate is also being studied as a pseudohormone because it seems to regulate the cellular redox state through exchange and conversion into pyruvate and through its effects on the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide (reduced)—the NAD+/NADH ratio. It is released into the systemic circulation and taken up by distal tissues and organs, where it also affects the redox state in those cells. Further

Shock, Electrolytes, and Fluid Chapter 5 75

Compensatory Mechanisms When needed, blood flow to less critical tissues is diverted to more critical tissues. The earliest compensatory mechanism in response to a decrease in intravascular volume is an increase in sympathetic activity. Such an increase is mediated by pressure receptors or baroreceptors in the aortic arch, atria, and carotid bodies. A decrease in pressure inhibits parasympathetic discharge while norepinephrine and epinephrine are liberated and causes adrenergic receptors in the myocardium and vascular smooth

muscle to be activated. Heart rate and contractility are increased; peripheral vascular resistance is also increased, resulting in an increased BP. However, the various tissue beds are not affected equally; blood is shunted from less critical organs (e.g., skin, skeletal muscle, splanchnic circulation) to more critical organs (e.g., brain, liver, kidneys). Then, the juxtaglomerular apparatus in the kidney—in response to the vasoconstriction and decrease in blood flow— produces the enzyme renin, which generates angiotensin I. The angiotensin-converting enzyme located on the endothelial cells of the pulmonary arteries converts angiotensin I to angiotensin II. In turn, angiotensin II stimulates an increased sympathetic drive, at the level of the nerve terminal, by releasing hormones from the adrenal medulla. In response, the adrenal medulla affects intravascular volume during shock by secreting catechol hormones—epinephrine, norepinephrine, and dopamine— which are all produced from phenylalanine and tyrosine. They are called catecholamines because they contain a catechol group derived from the amino acid tyrosine. The release of catecholamines is thought to be responsible for the elevated glucose level in hemorrhagic shock. Although the role of glucose elevation in hemorrhagic shock is not fully understood, it does not seem to affect outcome.21 Cortisol, also released from the adrenal cortex, plays a major role in that it controls fluid equilibrium. In the adrenal cortex, the zona glomerulosa produces aldosterone in response to stimulation by angiotensin II. Aldosterone is a mineralocorticoid that modulates renal function by increasing the recovery of sodium and excretion of potassium. Angiotensin II also has a direct action on the renal tubules, reabsorbing sodium. The control of sodium is a primary mechanism whereby the human body controls water absorption or secretion in the kidneys. One of the problems in shock is that the release of hormones is not infinite; the supply can be exhausted. This regulation of intravascular fluid status is further affected by the carotid baroreceptors and atrial naturetic peptides. Signals are sent to the supraoptic and paraventricular nuclei in the brain. Antidiuretic hormone (ADH) is released from the pituitary, causing retention of free water at the level of the kidney. Simultaneously, volume is recruited from the extravascular and cellular spaces. A shift of water occurs as hydrostatic pressures fall in the intravascular compartment. At the capillary level, hydrostatic pressures are also reduced, because the precapillary sphincters are vasoconstricted more than the postcapillary sphincters. Lethal Triad The triad of acidosis, hypothermia, and coagulopathy is common in resuscitated patients who are bleeding or in shock from various factors. Our basic understanding is that inadequate tissue perfusion results in acidosis caused by lactate production. In the shock state, the delivery of nutrients to the cells is thought to be inadequate, so adenosine triphosphate (ATP) production decreases. The human body relies on ATP production to maintain homeostatic temperatures; ATP is the source of heat in all homeothermic (warm-blooded) animals. Thus, if ATP production is inadequate to maintain body temperature, the body will trend toward the ambient temperature. For most patients, this is 22° C (72° F), the temperature inside typical hospitals. The resulting hypothermia then affects the efficiency of enzymes, which work best at 37° C. For surgeons, the critical problem

SECTION I SURGICAL BASIC PRINCIPLES

evidence has shown that it affects wound regeneration, with the promotion of increased collagen deposition and neovascularization. Lactate may also induce vasodilation and catecholamine release and stimulate fat and carbohydrate oxidation. Lactate levels in blood are highly dependent on the equilibrium between production and elimination from the bloodstream. The liver is predominantly responsible for clearing lactate; acute or chronic liver disease affects lactate levels. Lactate was always thought to be produced from anaerobic tissues, but it now seems that various tissue beds that are not undergoing anaerobic metabolism produce lactate when signaled of distress. In canine muscle, lactate is produced by moderate-intensity exercise when the oxygen supply is ample. A high adrenergic stimulus also causes a rise in lactate level as the body prepares or responds to stress. A study of climbers of Mount Everest has shown that the resting PO2 on the summit was approximately 28 mm Hg and decreased even more during exercise.17 The blood lactate level in those climbers was essentially the same as at sea level. These studies have allowed us to question lactate and its true role. In humans, lactate may be the preferred fuel in the brain and heart; infused lactate is used before glucose at rest and during exercise. Because it is glucose sparing, lactate allows glucose and glycogen levels to be maintained. However, some data point to lactate’s protective role in TBIs.18 Lactate fuels the human brain during exercise. The level of lactate, whether it is a waste product or source of energy, seems to signify tissue distress, from anaerobic conditions or other factors.19 Release of epinephrine and other catecholamines will result in higher lactate levels. Base deficit, a measure of the number of millimoles of base required to correct the pH of 1 liter of whole blood to 7.4, seems to correlate well with lactate level, at least in the first 24 hours after an injury. Rutherford, in 1992, showed that a base deficit of 8 is associated with a 25% mortality rate in patients older than 55 years without a head injury or in patients younger than 55 with a head injury. When base deficit remains elevated, most clinicians believe that it is an indication of ongoing shock. One of the problems with base deficit is that it is commonly influenced by the chloride from various resuscitation fluids, resulting in a hyperchloremic nongap acidosis. In patients with renal failure, base deficit can also be a poor predictor of outcome. In the acute stage of renal failure, a base deficit lower than 6 mmol/liter is associated with a poor outcome.20 With the use of hypertonic saline (HTS), which has three to eight times the sodium chloride concentration as normal saline, depending on the concentration used, in trauma patients, the hyperchloremic acidosis has been shown to be relatively harmless. However, when HTS is used, the base deficit should be interpreted with caution.

76 SECTION I SURGICAL BASIC PRINCIPLES with hypothermia is that the coagulation cascade depends on enzymes affected by hypothermia; if enzymes are not functioning optimally because of hypothermia, coagulopathy worsens, which in surgical patients can contribute to uncontrolled bleeding from injuries or the surgery itself. Further bleeding continues to fuel the triad. The optimal method to stop the vicious cycle of death is to stop the bleeding and the causes of hypothermia. In most typical scenarios, hypothermia is not spontaneous from ischemia but is induced because of using room temperature fluid or cold blood products. Acidosis

Bleeding causes a host of responses. During the resuscitative phase, the lethal triad (acidosis, hypothermia, and coagulopathy) is frequent, most likely because of two major factors. First, tissue ischemia from the lack of blood flow results in lactic acidosis. Some believe that the acidotic state is not necessarily undesirable, because the body tolerates acidosis better than alkalosis. Oxygen is more easily offloaded from the hemoglobin molecules in the acidotic environment; many who try to preserve tissue have found that cells live longer in an acidotic environment. Correcting acidosis with sodium bicarbonate has classically been avoided because it is treating a number or symptom when the cause needs to be addressed. Treating the pH alone has shown no benefit, but it can lead to complacency; patients appear to be better resuscitated, but the underlying cause of their acidosis has not been adequately addressed. It is also argued that rapidly injecting sodium bicarbonate can worsen intracellular acidosis because of the diffusion of the converted CO2 into the cells. The best fundamental approach to metabolic acidosis from shock is to treat the underlying cause of shock. However, some clinicians believe that treating the pH has advantages, because the enzymes necessary for the coagulation cascade work better at an optimal temperature and optimal pH. Coagulopathy can contribute to uncontrolled bleeding, so some have recommended treating acidosis for patients in dire scenarios. Treating acidosis with sodium bicarbonate may have a benefit in an unintended and unrecognized way. Rapid infusion is usually accompanied by a rise in BP in hypotensive patients, which is usually attributed to correcting the pH. However, sodium bicarbonate in most urgent situations is given in ampules. The 50-mL ampule of sodium bicarbonate has 1 mEq/mL—in essence, similar to giving a hypertonic concentration of sodium, which quickly draws fluid into the vascular space. Given its high sodium concentration, a 50-mL bolus of sodium bicarbonate has physiologic results similar to those of 325 mL of normal saline or 385 mL of LR. Essentially it is like giving small doses of HTS. Sodium bicarbonate quickly increases CO2 levels by its conversion in the liver, so if the minute ventilation is not increased, respiratory acidosis can result. THAM (tromethamine; tris[hydroxymethyl]aminomethane) is a biologically inert amino alcohol of low toxicity that buffers CO2 and acids. It is sodium-free and limits the generation of CO2 in the process of buffering. At 37° C, the pKa of THAM is 7.8, making it a more effective buffer than sodium bicarbonate in the physiologic range of blood pH. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system by generating sodium bicarbonate and decreasing the partial pressure of CO2. It rapidly distributes to the extracellular space and slowly penetrates the intracellular space, except

in the case of erythrocytes and hepatocytes, and is excreted by the kidney. Unlike sodium bicarbonate, which requires an open system to eliminate CO2 to exert its buffering effect, THAM is effective in a closed or semiclosed system and it maintains its buffering ability during hypothermia. THAM acetate (0.3 M; pH, 8.6) is well tolerated, does not cause tissue or venous irritation, and is the only formulation available in the United States. THAM may induce respiratory depression and hypoglycemia, which may require ventilatory assistance and the administration of glucose. The initial loading dose of THAM acetate (0.3 M) for the treatment of acidemia may be estimated as follows: THAM (in mL of 0.3 M solution ) = lean body weight (in kg ) × the base deficit (in mmol / liter ) The maximal daily dose is 15 mmol/kg/day for an adult (3.5 liters of a 0.3-M solution in a patient weighing 70 kg). It is indicated in the treatment of respiratory failure (acute respiratory distress syndrome [ARDS ] and infant respiratory distress syndrome) and has been associated with the use of hypothermia and permissive hypercapnia (controlled hypoventilation). Other indications are diabetic and renal acidosis, salicylate and barbiturate intoxication, and increased intracranial pressure associated with brain trauma. It is used in cardioplegic solutions and during liver transplantation. Despite these features, THAM has not been documented clinically to be more efficacious than sodium bicarbonate. Hypothermia

Hypothermia can be beneficial and detrimental. A fundamental knowledge of hypothermia is of vital importance in the care of surgical patients. The beneficial aspects of hypothermia are mainly because of decreased metabolism. Injury sites are often iced, creating vasoconstriction and decreasing inflammation through decreased metabolism. This concept of cooling to slow metabolism is also the rationale behind using hypothermia to decrease ischemia during cardiac, transplantation, pediatric, and neurologic surgery. Also, amputated extremities are iced before reimplantation. Cold water near-drowning victims have higher survival rates thanks to the preservation of the brain and other vital organs. The Advanced Life Support Task Force of the International Liaison Committee of Resuscitation now recommends cooling (to 32° to 34° C) unconscious adults, who have spontaneous circulation after out of hospital cardiac arrest caused by ventricular fibrillation, for 12 to 24 hours. Induced hypothermia is vastly different from spontaneous hypothermia, which is typically from shock, inadequate tissue perfusion, or cold fluid infusion. Medical or accidental hypothermia is also very different from trauma-associated hypothermia (Table 5-2). The survival rates after accidental hypothermia range from approximately 12% to 39%; the average temperature drop is to approximately 30° C (range, 13.7° to 35.0° C). The lowest recorded temperature in a survivor of accidental hypothermia (13.7° C [56.7° F]) was in an extreme skier in Norway; she was trapped under the ice and eventually fully recovered neurologically. The data in patients with trauma-associated hypothermia differ. Their survival rate falls dramatically with their core temperature, reaching 100% mortality when it reaches 32° C at any point—whether in the emergency room, operating room, or

Shock, Electrolytes, and Fluid Chapter 5 77

DEGREE

Cause TRAUMA

ACCIDENT

Mild

36°-34° C

35°-32° C

Moderate

34°-32° C

32°-28° C

Severe

>40

30.5

RISK CLASS

15.3

Adapted from Arozullah AM, Khuri SF, Henderson WG, et al: Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med 135:847–857, 2001; and Arozullah AM, Daley J, Henderson WG, Khuri SF: Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 232:242–253, 2000.

Patients with chronic end-stage renal disease undergo dialysis before surgery to optimize their volume status and control the potassium level. Intraoperative hyperkalemia can result from surgical manipulation of tissue or transfusion of blood. Such patients are often dialyzed on the day after surgery as well. In the acute setting, patients who have a stable volume status can undergo surgery without preoperative dialysis, provided that no other indication exists for emergency dialysis.12 Prevention of secondary renal insults in the perioperative period include the avoidance of nephrotoxic agents and maintenance of adequate intravascular volume throughout this period. In the postoperative period, the pharmaco*kinetics of many drugs may be unpredictable, and adjustments in dosage need to be made according to pharmacy recommendation. Notably, narcotics used for postoperative pain control may have prolonged effects despite hepatic clearance, and nonsteroidal agents are avoided in patients with renal insufficiency. Hepatobiliary System Hepatic dysfunction may reflect the common pathway of a number of insults to the liver, including viral-, drug-, and toxinmediated disease. A patient with liver dysfunction requires

careful assessment of the degree of functional impairment, as well as a coordinated effort to avoid additional insult in the perioperative period (Fig. 11-2).13 A history of any exposure to blood and blood products or exposure to hepatotoxic agents is obtained. Patients frequently know whether hepatitis has been diagnosed and need to be questioned about when the diagnosis was made and what activity led to the infection. Although such a history may not affect further patient evaluation, it is important to obtain in case an operative team member is injured during the planned surgical procedure. A review of systems specifically inquires about symptoms such as pruritus, fatigability, excessive bleeding, abdominal distention, and weight gain. Evidence of hepatic dysfunction may be seen on physical examination. Jaundice and scleral icterus may be evident with serum bilirubin levels higher than 3 mg/dL. Skin changes include spider angiomas, caput medusae, palmar erythema, and clubbing of the fingertips. Abdominal examination may reveal distention, evidence of fluid shift, and hepatomegaly. Encephalopathy or asterixis may be evident. Muscle wasting or cachexia can be prominent. A patient with liver dysfunction should undergo standard liver function tests. Elevations in hepatocellular enzyme levels

SECTION II PERIOPERATIVE MANAGEMENT

Table 11-5 Risk Factors for Development of Postoperative Pneumonia and Respiratory Failure—cont’d

220 SECTION II PERIOPERATIVE MANAGEMENT

Acute hepatitis

Postpone elective surgery at least until liver function tests have normalized

Patient with liver disease facing surgery

Chronic hepatitis

Surgery is generally considered safe in these patients

Obstructive jaundice 1. Perioperative fluid management to prevent renal dysfunction 2. No dopamine or mannitol 3. Lactulose may be helpful 4. Antibiotic prophylaxis 5. No routine preoperative biliary drainage 6. Check for abnormal coagulation parameters

Cirrhosis Child’s A and B: Treat ascites, coagulopathy and proceed to surgery Child’s C: Postpone until the patient’s Child’s class could be improved or cancel surgery for conservative management Encephalophathy 1. Treat with lactulose 2. Prevent by treating precipitating conditions such as GI bleeding, alkalosis, uremia, avoidance of sedatives

Coagulophathy Target PT—no more than 2 sec above normal 1. Vitamin K—10 mg SQ 2. FFP if no improvement with Vit K 3. Give cryoprecipitate as needed Ascites 1. Fluid restriction 2. Diuretics—furosemide and/or spironolactone 3. Paracentesis—may be diagnostic or therepeutic with simultaneous administration of albumin

FIGURE 11-2 Approach to a patient with liver disease. FFP, fresh-frozen plasma; GI, Gastrointestinal; SQ, subcutaneous. (Adapted from Rizvon MK, Chou CL: Surgery in the patient with liver disease. Med Clin North Am 87:211–227, 2003.)

may suggest a diagnosis of acute or chronic hepatitis, which can be investigated by serologic testing for hepatitis A, B, and C. Alcoholic hepatitis is suggested by lower transaminase levels and an aspartate aminotransferase-to-alanine transaminase ratio (AST/ALT) higher than 2. Laboratory evidence of chronic hepatitis or clinical findings consistent with cirrhosis is investigated with tests of hepatic synthetic function, notably serum albumin, prothrombin, and fibrinogen levels. Patients with evidence of impaired hepatic synthetic function also have a CBC and serum electrolyte analysis. Type and screen are indicated for any procedure in which blood loss could be more than minimal. In the event of an emergency situation requiring surgery, such an investigation may not be possible. A patient with acute hepatitis and elevated transaminase levels is managed nonoperatively, when feasible, until several weeks beyond normalization of laboratory values. Urgent or emergency procedures in these patients are associated with increased morbidity and mortality. A patient with evidence of chronic hepatitis may often safely undergo surgery. A patient with cirrhosis may be assessed with the Child-Pugh classification, which stratifies operative risk according to a score based on abnormal albumin and bilirubin levels, prolongation of the prothrombin time (PT), and degree of ascites and encephalopathy (Table 11-7). This scoring system

was initially used to predict mortality in cirrhotic patients undergoing portacaval shunt procedures, although it has been shown to correlate with mortality in cirrhotic patients undergoing a wider spectrum of procedures as well. Data generated more than 25 years ago showed that patients with Child class A, B, and C cirrhosis had mortality rates of 10%, 31%, and 76%, respectively, during abdominal operations; these figures have been validated more recently.8 Although the figures may not represent current risk for all types of abdominal operations, little doubt exists that the presence of cirrhosis confers additional risk for abdominal surgery, proportional to the severity of disease. Other factors that affect outcomes in these patients are the emergency nature of a procedure, prolongation of the PT more than 3 seconds above normal and refractory to correction with vitamin K, and presence of infection. Two common problems requiring surgical evaluation in a cirrhotic patient are hernia (umbilical and groin) and cholecystitis. An umbilical hernia in the presence of ascites is a difficult management problem because spontaneous rupture is associated with increased mortality rates. Elective repair is best after the ascites has been reduced to a minimum preoperatively, although the procedure is still associated with mortality rates as high as 14%. Repair of groin hernias in the presence of ascites is less risky in terms of recurrence and mortality.

Principles of Preoperative and Operative Surgery Chapter 11 221

ONSET OF ACTION

PEAK EFFECT

DURATION OF ACTION

Rapid acting (Lispro, NovoLog, Apidra)

10-30 min

30-90 min

3-4 hr

Short-acting (Regular, Humulin, Novolin)

30-60 min

2-5 hr

6-10 hr

Intermediate-acting (NPH, Lente)

1-4 hr

4-12 hr

12-24 hr

Long-acting (Glargine [Lantus])

1-2 hr

3-20 hr

24-30 hr

>2.3

Adapted from Ahmed Z, Lockhart CH, Weiner M, et al: Advances in diabetic management: Implications for anesthesia. Anesth Analg 100:666–669, 2005.

PARAMETER

Points 1

Encephalopathy

None

Stage I or II

Stage III or IV

Ascites

Absent

Slight (controlled with diuretics)

Moderate despite diuretic treatment

Bilirubin (mg/dL)

Albumin (g/liter)

>3.5

2.8-3.5

48 hr (days 1-4) and Any systemic antibiotic (days 1-3 of the ICU stay) and Central venous catheter (days 1-3) and At least one of the following: • Total parenteral nutrition (days 1-3) • Any renal replacement therapy (days 1-3) • Any major surgery (days −7 to 0) • Pancreatitis (days −7 to 0) • Any steroid or other immunosuppression (days −7 to 0)

Shorr Candidemia Score282 A simple, equal-weight score (1 point each) differentiated reasonably well among patients admitted with a bloodstream infection, with a C statistic of 0.70. Age 95%), C. glabrata (95%), C. parapsilosis (>95%), C. krusei (>95%), C. tropicalis (99%), C. guillermondi, C. lusitaniae Variable activity: Aspergillus spp., ferrous Trichosporon beigelii, Fusarium spp., Blastomyces dermatidis

IV: 0.5-1.0 mg/kg/day over 2-4 hr Oral: 1 mL oral suspension, swish and swallow 4× daily, ×2 wk

Amphotericin B liposomal (less nephrotoxicity)

C. albicans (>95%), C. glabrata (>95%), C. parapsilosis (>95%), C. krusei (>95%), C. tropicalis (99%), C. guillermondi, C. lusitaniae Variable activity: Aspergillus spp.

IV: 3-5 mg/kg/day

Amphotericin B colloidal dispersion

C. albicans (>95%), C. glabrata (>95%), C. parapsilosis (>95%), C. krusei (>95%), C. tropicalis (99%), C. guillermondi, C. lusitaniae Variable activity: Aspergillus spp.

IV: 3-5 mg/kg/day

Amphotericin B lipid complex

C. albicans (>95%), C. glabrata (>95%), C. parapsilosis (>95%), C. krusei (>95%), C. tropicalis (99%), C. guillermondi, C. lusitaniae Variable activity: Aspergillus spp.

IV: 5 mg/kg/day

Ketoconazole

C. albicans

PO: 200-400 mg/daily

Voriconazole

Aspergillus spp., Fusarium spp., C. albicans (99%), C. glabrata (99%), C. parapsilosis (99%), C. tropicalis (99%), C. krusei (99%), C. guillermondi (>95%), C. lusitaniae (95%)

IV: 6 mg/kg q12h ×2, then 4 mg/kg IV every 12 hr PO: >40 kg, 200 mg every 12 hr; 38.5° C [101.3° F]) or hypothermia (105 CFU/mL of Candida spp. in BAL fluid, in addition to the appearance of a new infiltrate on CXR. Invasive fungal infections in non-neutropenic ICU patients are treated if histology or cytopathology shows yeast cells or pseudohyphae from a needle aspiration or biopsy (excluding mucous membranes), a positive culture obtained aseptically from a normally sterile and clinically or radiologically abnormal site consistent with

infection (excluding urine, sinuses, and mucous membranes), or a positive percutaneous blood culture in patients with temporally related clinical signs and symptoms compatible with the relevant organism. Survival is more likely from candidemia than from other forms of invasive candidiasis, and is strongly influenced negatively by critical illness.304 The repertoire of antifungal agents has expanded with the introduction of less toxic formulations of amphotericin B, improved triazoles, echinocandins, and other agents that target the fungal cell wall.305 Table 12-10 lists available antifungal agents. Amphotericin B is a natural polyene macrolide that binds primarily to ergosterol, the principal sterol in the fungal cell membrane, leading to disruption of ion channels, production of oxygen free radicals, and apoptosis. It is active against most fungi, including in cerebrospinal fluid. Because of its high level of protein binding, tissue concentrations are not usually affected by hemodialysis. Infusion-related reactions can occur in up to 73% of patients with the first dose and often diminish

Surgical Infections and Antibiotic Use Chapter 12 271

CANDIDA SPP.

FLUCONAZOLE

ITRACONAZOLE

VORICONAZOLE (NOT STANDARDIZED)

AMPHOTERICIN B

CASPOFUNGIN (NOT STANDARDIZED)

C. albicans

C. tropicalis

C. parapsilosis

S to I (?R)

C. glabrata

S-DD to R

S to I

C. krusei

S-DD to R

S to I

C. lusitaniae

S to R

I, Intermediate; R, resistant; S, susceptible; S-DD, susceptible dose-dependent (increased MIC may be overcome by higher dosing, such as 12 mg/kg/day fluconazole).

during continued therapy. Amphotericin B–associated nephrotoxicity can lead to azotemia and hypokalemia, although acute potassium release with rapid infusion can occur and lead to cardiac arrest. Amphotericin B lipid formulations allow for higher dose administration with lessened nephrotoxicity, but whether outcomes are enhanced is unproved. Nystatin is a polyene similar in structure to amphotericin B, and is currently used topically for C. albicans. Flucytosine is a fluorinated pyrimidine analogue that is converted to 5-fluorouracil, which causes RNA miscoding and inhibits DNA synthesis. It is available in the United States in oral form only and has been used with amphotericin B for synergism against Candida spp. But, in general, there is scant evidence that dual-agent therapy for fungal infections is beneficial.306 The azoles inhibit the cytochrome P450–dependent enzyme, 14-alpha reductase, altering fungal cell membranes through the accumulation of abnormal 14-alpha-methyl sterols. Ketoconazole is available only in tablet form and is indicated for candidiasis and candiduria. Fluconazole and itraconazole are available in oral and parenteral formulations and are active against Candida spp., except C. krusei, and Fusarium spp. Itraconazole is active against Aspergillus spp. As noted, C. glabrata and C. krusei resistance has been observed with fluconazole. The tissue concentration of both drugs is influenced by many agents such as antacids, H2 antagonists, isoniazid, phenytoin, and phenobarbital. Biofilms produced by Candida spp. are penetrated by fluconazole and most other antifungal agents.307,308 Second-generation antifungal triazoles include posaconazole, ravuconazole, and voriconazole. They are active against Candida spp., including fluconazole-resistant strains, and Aspergillus spp. For the latter, voriconazole is emerging as the treatment of choice.309,310 The echinocandins include caspofungin, micafungin, and anidulafungin, each of which is approved therapy for candidiasis and candidemia but is third-line treatment for invasive aspergillosis.311 Because of their distinct mechanism of action, disrupting the fungal cell wall by inhibiting (1 → 3)-β-D-glucan synthesis, the echinocandins can theoretically be used in combination with other standard antifungal agents.306 The echinocandins have activity against Candida and Aspergillus spp., but are not reliably active against other fungi. Echinocandin activity is excellent against most Candida spp., but moderate against C. parapsilosis, C. guillermondi, and C. lusitaniae. Echinocandins exhibit no cross-resistance with azoles or polyenes.312 Prospective randomized trials have demonstrated that micafungin is noninferior to caspofungin for therapy of invasive candidiasis313 and

as effective as liposomal amphotericin B.314 Micafungin may be cost-effective in comparison to fluconazole therapy. With the proliferation of non-albicans Candida infections caused by the widespread use of fluconazole, empirical therapy regimens recommend an echinocandin or lipid formulation of amphotericin B as the first-line agent for therapy of seriously or critically ill patients (see Box 12-14 and Table 12-10).303,315 Once the pathogen has been identified as Candida, therapy may be de-escalated to fluconazole, except for C. glabrata and C. krusei, for which continuation therapy with an echinocandin may be indicated (Table 12-11). REFERENCES 1. Desborough JP: The stress response to trauma and surgery. Br J Anaesth 85:109–117, 2000. 2. Napolitano LM, Faist E, Wichmann MW, et al: Immune dysfunction in trauma. Surg Clin North Am 79:1385–1416, 1999. 3. Gardner EM, Murasko DM: Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology 3:271– 290, 2002. 4. Latham R, Lancaster AD, Covington JF, et al: The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol 22:607–612, 2001. 5. Cheadle WG: Risk factors for surgical site infection. Surg Infect (Larchmt) 7(Suppl 1):S7–11, 2006. 6. Zerr KJ, Furnary AP, Grunkemeier GL, et al: Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 63:356–361, 1997. 7. Pomposelli JJ, Baxter JK, 3rd, Babineau TJ, et al: Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr 22:77–81, 1998. 8. Yendamuri S, Fulda GJ, Tinkoff GH: Admission hyperglycemia as a prognostic indicator in trauma. J Trauma 55:33–38, 2003. 9. Bochicchio GV, Bochicchio KM, Joshi M, et al: Acute glucose elevation is highly predictive of infection and outcome in critically injured trauma patients. Ann Surg 252:597–602, 2010. 10. Griesdale DE, de Souza RJ, van Dam RM, et al: Intensive insulin therapy and mortality among critically ill patients: A metaanalysis including NICE-SUGAR study data. CMAJ 180:821– 827, 2009. 11. Eachempati SR, Hydo LJ, Shou J, et al: Implementation of tight glucose control for critically ill surgical patients: A process improvement analysis. Surg Infect (Larchmt) 10:523–531, 2009.

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Table 12-11 Usual Susceptibilities of Candida Species to Selected Antifungal Agents

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124. Pieracci FM, Barie PS: Strategies in the prevention and management of ventilator-associated pneumonia. Am Surg 73:419–432, 2007. 125. Antonelli M, Conti G, Rocco M, et al: A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 339:429–435, 1998. 126. Holzapfel L, Chevret S, Madinier G, et al: Influence of long-term oro- or nasotracheal intubation on nosocomial maxillary sinusitis and pneumonia: Results of a prospective, randomized, clinical trial. Crit Care Med 21:1132–1138, 1993. 127. Kress JP, Pohlman AS, O’Connor MF, et al: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471–1477, 2000. 128. Marelich GP, Murin S, Battistella F, et al: Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses: Effect on weaning time and incidence of ventilator-associated pneumonia. Chest 118:459– 467, 2000. 129. Zanella A, Scaravilli V, Isgro S, et al: Fluid leakage across tracheal tube cuff, effect of different cuff material, shape, and positive expiratory pressure: A bench-top study. Intensive Care Med 37:343–347, 2011. 130. Drakulovic MB, Torres A, Bauer TT, et al: Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: A randomised trial. Lancet 354:1851–1858, 1999. 131. Heyland DK, Dhaliwal R, Drover JW, et al: Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 27:355–373, 2003. 132. Berne JD, Norwood SH, McAuley CE, et al: Erythromycin reduces delayed gastric emptying in critically ill trauma patients: A randomized, controlled trial. J Trauma 53:422–425, 2002. 133. van Nieuwenhoven CA, Buskens E, van Tiel FH, et al: Relationship between methodological trial quality and the effects of selective digestive decontamination on pneumonia and mortality in critically ill patients. JAMA 286:335–340, 2001. 134. Verwaest C, Verhaegen J, Ferdinande P, et al: Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med 25:63–71, 1997. 135. Lingnau W, Berger J, Javorsky F, et al: Changing bacterial ecology during a five-year period of selective intestinal decontamination. J Hosp Infect 39:195–206, 1998. 136. Chlebicki MP, Safdar N: Topical chlorhexidine for prevention of ventilator-associated pneumonia: A meta-analysis. Crit Care Med 35:595–602, 2007. 137. Earley AS, Gracias VH, Haut E, et al: Anemia management program reduces transfusion volumes, incidence of ventilatorassociated pneumonia, and cost in trauma patients. J Trauma 61:1–5, 2006. 138. Sawyer RG, Crabtree TD, Gleason TG, et al: Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections. Clin Transplant 13:260–265, 1999. 139. Neuhauser MM, Weinstein RA, Rydman R, et al: Antibiotic resistance among gram-negative bacilli in US intensive care units: Implications for fluoroquinolone use. JAMA 289:885– 888, 2003.

276 SECTION II PERIOPERATIVE MANAGEMENT 158. Clinical and Laboratory Standards Institute: Principles and procedures for blood cultures; approved guideline, 2007 (http:// www.clsi.org/source/orders/free/m47-a.pdf ). 159. Mermel LA, Farr BM, Sherertz RJ, et al: Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 32:1249–1272, 2001. 160. Tambyah PA, Maki DG: Catheter-associated urinary tract infection is rarely symptomatic: A prospective study of 1,497 catheterized patients. Arch Intern Med 160:678–682, 2000. 161. Golob JF, Jr, Claridge JA, Sando MJ, et al: Fever and leukocytosis in critically ill trauma patients: It’s not the urine. Surg Infect (Larchmt) 9:49–56, 2008. 162. Safdar N, Slattery WR, Knasinski V, et al: Predictors and outcomes of candiduria in renal transplant recipients. Clin Infect Dis 40:1413–1421, 2005. 163. Bryan CS, Reynolds KL: Hospital-acquired bacteremic urinary tract infection: Epidemiology and outcome. J Urol 132:494– 498, 1984. 164. Quintiliani R, Klimek J, Cunha BA, et al: Bacteraemia after manipulation of the urinary tract. The importance of pre-existing urinary tract disease and compromised host defences. Postgrad Med J 54:668–671, 1978. 165. Ksycki MF, Namias N: Nosocomial urinary tract infection. Surg Clin North Am 89:475–481, ix–x, 2009. 166. Laupland KB, Bagshaw SM, Gregson DB, et al: Intensive care unit-acquired urinary tract infections in a regional critical care system. Crit Care 9:R60–65, 2005. 167. Schwartz DS, Barone JE: Correlation of urinalysis and dipstick results with catheter-associated urinary tract infections in surgical ICU patients. Intensive Care Med 32:1797–1801, 2006. 168. Schiotz HA: The value of leucocyte stix results in predicting bacteriuria and urinary tract infection after gynaecological surgery. J Obstet Gynaecol 19:396–398, 1999. 169. Solomkin JS, Hemsell DL, Sweet R, et al: Evaluation of new anti-infective drugs for the treatment of intra-abdominal infections. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 15(Suppl 1):S33–S42, 1992. 170. Merlino JI, Yowler CJ, Malangoni MA: Nosocomial infections adversely affect the outcomes of patients with serious intraabdominal infections. Surg Infect (Larchmt) 5:21–27, 2004. 171. Nathens AB, Rotstein OD, Marshall JC: Tertiary peritonitis: Clinical features of a complex nosocomial infection. World J Surg 22:158–163, 1998. 172. Pacelli F, Doglietto GB, Alfieri S, et al: Prognosis in intraabdominal infections. Multivariate analysis on 604 patients. Arch Surg 131:641–645, 1996. 173. Roehrborn A, Thomas L, Potreck O, et al: The microbiology of postoperative peritonitis. Clin Infect Dis 33:1513–1519, 2001. 174. Sturkenboom MC, Goettsch WG, Picelli G, et al: Inappropriate initial treatment of secondary intra-abdominal infections leads to increased risk of clinical failure and costs. Br J Clin Pharmacol 60:438–443, 2005. 175. Montravers P, Gauzit R, Muller C, et al: Emergence of antibioticresistant bacteria in cases of peritonitis after intra-abdominal surgery affects the efficacy of empirical antimicrobial therapy. Clin Infect Dis 23:486–494, 1996. 176. Barie PS, Hydo LJ, Shou J, et al: Efficacy and safety of drotrecogin alfa (activated) for the therapy of surgical patients with severe sepsis. Surg Infect (Larchmt) 7(Suppl 2):S77–S80, 2006.

177. Barie PS, Vogel SB, Dellinger EP, et al: A randomized, doubleblind clinical trial comparing cefepime plus metronidazole with imipenem-cilastatin in the treatment of complicated intraabdominal infections. Cefepime Intra-abdominal Infection Study Group. Arch Surg 132:1294–1302, 1997. 178. Farthmann EH, Schoffel U: Principles and limitations of operative management of intraabdominal infections. World J Surg 14:210–217, 1990. 179. Garcia-Sabrido JL, Tallado JM, Christou NV, et al: Treatment of severe intra-abdominal sepsis and/or necrotic foci by an ‘openabdomen’ approach. Zipper and zipper-mesh techniques. Arch Surg 123:152–156, 1988. 180. Marshall JC, Maier RV, Jimenez M, et al: Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med 32:S513–S526, 2004. 181. 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 14:218–226, 1990. 182. Ohmann C, Wittmann DH, Wacha H: Prospective evaluation of prognostic scoring systems in peritonitis. Peritonitis Study Group. Eur J Surg 159:267–274, 1993. 183. Gajic O, Urrutia LE, Sewani H, et al: Acute abdomen in the medical intensive care unit. Crit Care Med 30:1187–1190, 2002. 184. DiPiro JT, Edmiston CE, Jr, Bohnen JM: Pharmacodynamics of antimicrobial therapy in surgery. Am J Surg 171:615–622, 1996. 185. Anstead GM, Owens AD: Recent advances in the treatment of infections due to resistant Staphylococcus aureus. Curr Opin Infect Dis 17:549–555, 2004. 186. Kashuba AD, Bertino JS, Jr, Nafziger AN: Dosing of aminoglycosides to rapidly attain pharmacodynamic goals and hasten therapeutic response by using individualized pharmaco*kinetic monitoring of patients with pneumonia caused by gram-negative organisms. Antimicrob Agents Chemother 42:1842–1844, 1998. 187. Thomas JK, Forrest A, Bhavnani SM, et al: Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agents Chemother 42:521–527, 1998. 188. Benko AS, Cappelletty DM, Kruse JA, et al: Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections. Antimicrob Agents Chemother 40:691–695, 1996. 189. Lau WK, Mercer D, Itani KM, et al: Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother 50:3556–3561, 2006. 190. Velmahos GC, Toutouzas KG, Sarkisyan G, et al: Severe trauma is not an excuse for prolonged antibiotic prophylaxis. Arch Surg 137:537–541, 2002. 191. Al-Ghnaniem R, Benjamin IS, Patel AG: Meta-analysis suggests antibiotic prophylaxis is not warranted in low-risk patients undergoing laparoscopic cholecystectomy. Br J Surg 90:365– 366, 2003. 192. Lewis RT: Oral versus systemic antibiotic prophylaxis in elective colon surgery: A randomized study and meta-analysis send a message from the 1990s. Can J Surg 45:173–180, 2002. 193. Centers for Medicare & Medicaid Services: Anticipated public reporting of National Hospital Quality Measure SIP-2 (SCIP

Surgical Infections and Antibiotic Use Chapter 12 277

195.

196. 197.

198. 199. 200.

201. 202. 203. 204. 205.

206. 207.

208. 209.

CATEGORY

FACTORS

Respiratory rate

70 mm Hg (FIO2 of 40%)

PaCO2

110 mm Hg) is significantly associated with cardiac complica tions and systolic hypertension (>160 mm Hg) is associated with an increased risk for stroke and death. In patients with new-onset or severe perioperative hypertension and patients with a hypertensive emergency, treatment with agents that have a rapid onset of action, short half-life, and few autonomic side effects to lower blood pressure is essential. Medications most commonly used in this setting include nitroprusside and nitro glycerin (vasodilators), labetalol and esmolol (beta blockers), enalaprilat (useful for patients receiving long-term ACE inhibi tors), and nicardipine (calcium channel blocker). It is crucial in the acute setting not to decrease blood pressure more than 25% to avoid ischemic strokes and hypoperfusion injury to other organs.

SECTION II PERIOPERATIVE MANAGEMENT

high. The presence of leg ulcers and peripheral vascular disease precludes the use of mechanical devices. Anticoagulation is the standard of care treatment for VTE. It prevents clot propagation and allows endogenous fibrinolytic activity to dissolve existing thrombi, a process that occurs over weeks and months. Incomplete resolution is not uncommon and predisposes to recurrent VTE. The initial treatment is with LMWH, UFH, or fondaparinux, followed by VKA, which is administered on the same day as LMWH or UFH, with overlap for 5 days or longer until the target INR is achieved. In patients with VTE and active cancer, anticoagulation is continued indef initely. Surgical patients within 24 hours of surgery may be considered for a retrievable inferior vena cava filter until antico agulation is initiated. In patients with a contraindication to anticoagulation, placement of an inferior vena cava filter pro tects against PE. UFH is given intravenously (a weight-adjusted bolus of 70 U/kg is followed by 1000 U/hr) to achieve a partial throm boplastin time 1.5 to 2 times the control value. aPTT is deter mined 6 hours after the loading dose and then on a daily basis, and the dose of heparin is adjusted accordingly. UFH is easily reversible and hence the agent of choice. LMWH is given SC once or twice daily (enoxaparin, 1.5 mg/kg/day, or dalteparin, 10,000 to 18,000 U/day, depending on weight). Monitoring of LMWH is not necessary. Both UFH and LMWH may be asso ciated with HITT, and therefore the platelet count is monitored between days 3 and 5. Warfarin is given orally and this therapy is allowed to overlap with heparin therapy until the INR is therapeutic for 2 consecutive days before heparin is discontin ued. Therapy is continued for more than 3 months, with the goal to reach an INR of 2.5. In massive PE, the goal of therapy is to maintain hemody namic stability, enhance coronary flow, and minimize right ven tricular ischemia. Once suspected, resuscitation is initiated, oxygen administered, and IV UFH therapy started. In the hemodynamically unstable, IV vasoactive medications are required. Thrombolytic therapy, if not contraindicated, has the advantage of dissolving the clot rapidly, with rapid improvement in pulmonary perfusion, hemodynamic alterations, gas exchange, and right ventricular function. The role of surgical embolectomy is controversial. The transcatheter technique (with or without low-dose thrombolytic therapy) is another therapeutic approach. Placement of an inferior vena cava filter reduces the risk for recurrence of PE. Novel anticoagulants under investigation include factor Xa inhibitors (direct inhibitor [hypermethylated derivative of fondaparinux with a long half-life given IV or SC] or indirect inhibitor mediated by antithrombin [given orally or parenter ally]) and direct thrombin inhibitors.

298 SECTION II PERIOPERATIVE MANAGEMENT Perioperative Ischemia and Infarction Cause

Approximately 30% of all patients taken to the operating room have some degree of CAD. Older patients, patients with periph eral artery disease, and those undergoing vascular, thoracic, major orthopedic, or upper abdominal procedures are at high risk for an acute coronary syndrome in the postoperative period. Major risk factors for developing CAD are smoking, family history, adverse lipid profiles, diabetes mellitus, and elevated blood pressure.22 Although management of nonoperative MI has improved, the mortality associated with perioperative MI remains approximately 30%. Perioperative myocardial compli cations result in at least 10% of all perioperative deaths. In the 1970s, the risk for recurrence of MI within 3 months of an MI was reported to be 30% and, if a patient underwent surgery within 3 to 6 months of infarction, the reinfarction rate was 15%; 6 months postoperatively the reinfarction rate was only 5%. However, improved preoperative assessment, advances in anesthesia and intraoperative monitoring, and the availability of more sophisticated intensive care unit monitoring have resulted in improvement in the outcome of patients at risk for an acute cardiac event. Individuals undergoing an operation within 3 months of an infarction have an 8% to 15% reinfarction rate; between 3 and 6 months postoperatively, the reinfarction rate is only 3.5%. The general mortality associated with MI in patients without a surgical procedure is 12%. Myocardial ischemia and MI result from the imbalance between myocardial oxygen supply and demand. Primary causes that reduce myocardial perfusion and therefore oxygen supply include coronary artery narrowing caused by a thrombus that develops on a disrupted atherosclerotic plaque, dynamic obstruction caused by spasm of an epicardial coronary artery or diseased blood vessel, and severe narrowing caused by progres sive atherosclerosis. Secondary causes that increase myocardial oxygen requirements, usually in the presence of a fixed restricted oxygen supply (limited myocardial perfusion), are extrinsic cardiac factors that include fever and tachycardia (increased myocardial oxygen demand), hypotension (reduced coronary blood flow), and anemia and hypoxemia (reduced myocardial oxygen delivery). The increased circulating catecholamines asso ciated with surgical stress further increase myocardial oxygen demand. Presentation and Diagnosis

Acute coronary syndrome refers to a constellation of clinical symptoms that are compatible with myocardial ischemia and encompasses MI: ST-segment elevation myocardial infarction (STEMI) and depression (Q wave and non–Q wave), and unsta ble angina (UA)/non–ST-segment elevation myocardial infarc tion (NSTEMI). UA/NSTEMI is defined as ST-segment depression or prominent T wave inversion and/or positive bio markers of myonecrosis in the absence of ST-segment elevation and in an appropriate clinical setting. The risk for myocardial ischemia and MI is greatest in the first 48 hours after surgery, and it may be difficult to make the diagnosis. The classic mani festation, chest pain radiating into the jaw and left arm region, is often not present. Patients may have shortness of breath, increased heart rate, hypotension, or respiratory failure. Periop erative myocardial ischemia and MI are often silent and, when they occur, are marked by shortness of breath (heart failure,

respiratory failure), increased heart rate (arrhythmias), change in mental status, or excessive hyperglycemia in diabetics. Many perioperative MIs are non–Q wave NSTEMI. Periprocedural MI is associated with the release of biomarkers of necrosis, such as MB isoenzymes of creatinine kinase (CK-MB) and troponins, into the circulation. The troponin complex consists of three subunits, T (TnT), I (TnI), and C (TnC). TnT and TnI are derived from heart-specific genes and are referred to as cardiac troponins (cTns). cTns are not present in healthy individuals; their early release is attributable to the cytosolic pool and late release to the structural pool. Patients considered to have acute coronary syndrome should have a 12-lead ECG and placed in an environment with continuous electrocardiographic monitoring and defibrillator capability. Biomarkers of myocardial necrosis are measured. CK-MB has a short half-life and is less sensitive and less specific than cTns. Troponins can be detected in blood as early as 2 to 4 hours but elevation may be delayed for up to 8 to 12 hours. The timing of elevation of cTns is similar to CK-MB but cTns persist longer, for up to 5 to 14 days. Elevated cTn levels above the 99th percentile of normal in two or more blood samples collected at least 6 hours apart indicates the presence of myo cardial necrosis. Equivalent information is obtained with cTnI and cTnT, except in patients with renal dysfunction, in whom cTnI has a specific role. Each patient should have a provisional diagnosis of acute coronary syndrome with UA (electrocardio graphic changes of ischemia and no biomarkers in the circula tion), STEMI, or NSTEMI. The distinction has therapeutic implications because patients with STEMI may be considered for immediate reperfusion therapy (fibrinolysis or percutaneous intervention).22 Treatment Preventing coronary ischemia is a function of identifying patients prospectively at risk for a perioperative cardiac complication. This will allow improvement of the condition of the patient, possibly lowering the risk, selection of patients for invasive or noninvasive cardiac testing, and identifying patients who will benefit from more intensive perioperative monitoring. Preop erative cardiac risk assessment includes adequate history taking, physical examination, and basic diagnostic tests. The history is important to identify patients with cardiac disease or those at risk for cardiac disease, including previous cardiac revasculariza tion, history of MI or stroke, and presence of valvular heart disease, heart failure, arrhythmia, hypertension, diabetes, lung disease, and renal disease. Unstable chest pain, especially cre scendo angina, warrants careful evaluation and probable post poning of an elective operation. Physical examination may reveal uncontrolled hypertension, evidence of peripheral artery disease, arrhythmia, or clinical stigmata of heart failure (HF). The CXR may show pulmonary edema, ECG may show an arrhythmia, blood gas analysis may reveal hypercapnia or a low PaO2, and blood tests may show abnormal kidney function. The patient who is found to have HF on physical examination or by history must have the problem treated before consideration for an elec tive operative procedure. Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery, published by the American College of Cardiology (ACA) and American Heart Association (AHA), have stratified clinical predictors of increased perioperative cardiovascular risk leading to MI, CHF, or death into major, intermediate, and minor risks (Table 13-6) and

Surgical Complications Chapter 13 299

Table 13-7 Cardiac Risk Stratification for Noncardiac Surgical Procedures LEVEL OF RISK

RISK FACTOR

LEVEL OF RISK

RISK FACTOR

Major

Unstable coronary syndromes Acute or recent MI with evidence of considerable ischemic risk as noted by clinical symptoms or noninvasive studies Unstable or severe angina (Canadian class III or IV) Decompensated heart failure Significant arrhythmias High-grade atrioventricular block Symptomatic ventricular arrhythmias in the presence of underlying heart disease Supraventricular arrhythmias with an uncontrolled ventricular rate Severe valve disease

High (cardiac risk often >5%)

Emergency major operations, particularly in the elderly Aortic and other major vascular surgery Peripheral vascular surgery Anticipated prolonged surgical procedures associated with large fluid shifts and blood loss

Intermediate (cardiac risk generally 50 mOsm/liter

Fractional excretion of sodium

Variable

Urine, plasma creatinine leve

>40

80-90 mg/dL Persistent metabolic acidosis Acute fluid overload Uremic symptoms (pericarditis, encephalopathy, anorexia) Removal of toxins Platelet dysfunction causing bleeding Hyperphosphatemia with hypercalcemia

corticosteroid secreted from the adrenal cortex, is under the influence of adrenocorticotropic hormone (ACTH) released from the pituitary gland, which in turn is under the influence of hypothalamic corticotropin-releasing hormone; both hor mones are subject to negative feedback by cortisol itself. Cortisol is a stress hormone. Chronic adrenal insufficiency may result from primary destruction of the adrenal gland or be secondary to a disease state or disorder involving the hypothalamus or anterior pitu itary gland. Primary adrenal insufficiency is most frequently caused by autoimmune adrenalitis (Addison’s disease), in which the adrenal cortex is destroyed by cytotoxic lymphocytes. Sec ondary adrenal insufficiency is most commonly caused by longterm administration of pharmacologic doses of glucocorticoids. Chronic use of glucocorticoids causes suppression of the hypothalamic-pituitary-adrenal axis, induces adrenal atrophy, and results in isolated adrenal insufficiency. Acute adrenal insufficiency may occur as a result of abrupt cessation of pharmacologic doses of chronic glucocor ticoid therapy, surgical excision or destruction of the adrenal gland (adrenal hemorrhage, necrosis, or thrombosis in patients with sepsis or antiphospholipid syndrome), or surgi cal excision or destruction (postpartum necrosis) of the pitu itary gland. In addition, so-called functional or relative acute adrenal insufficiency may develop in critically ill and septic patients. Presentation and Diagnosis

The clinical manifestations of adrenal insufficiency depend on the cause of the disease and associated endocrinopathies.29 Symptoms and signs of chronic primary and secondary adrenal insufficiency are similar and nonspecific—fatigue, weakness, anorexia, weight loss, orthostatic dizziness, abdominal pain, diarrhea, depression, hyponatremia, hypoglycemia, eosinophilia,

Surgical Complications Chapter 13 305

• Determine baseline serum cortisol level. • Give 250 µg cosyntropin IV (or IM). • Measure serum cortisol levels 30 to 60 min after cosyntropin is given. • Results • Normal adrenal function: Basal or postcorticotropin plasma cortisol concentration is at least 18 µg/dL (500 nmol/liter) or preferably 20 µg/dL (550 nmol/ liter). • Primary adrenal insufficiency: Cortisol secretion is not increased. • Severe secondary adrenal insufficiency: Cortisol levels increase a little or not at all because of adrenocortical atrophy.

decreased libido and potency. Patients with primary hypoadre nalism also show manifestations of elevated plasma levels of corticotropin and hyperpigmentation of the skin and mucous membranes. Patients with secondary disease, in contrast, ini tially have neurologic or ophthalmologic symptoms (headaches, visual disturbances) before showing signs of hypothalamicpituitary-adrenal axis disease (hypopituitarism). Manifestations of hypothalamic-pituitary-adrenal axis suppression include hypoadrenalism, decreased levels of corticotropin, and manifes tations of other hormone deficiencies (e.g., pallor, loss of hair in androgen-dependent areas, oligomenorrhea, diabetes insipidus, hypothyroidism). Laboratory test abnormalities, including hyponatremia, hyperkalemia, acidosis, hypoglycemia or hyperglycemia, normo cytic anemia, eosinophilia, and lymphocytosis, are present to a variable extent. The diagnosis, however, is established by measur ing the morning plasma cortisol concentration. A level higher than 19 µg/dL (525 nmol/liter) rules out adrenal insufficiency and less than 3 µg/dL (83 nmol/liter) indicates its presence. A basal plasma corticotropin level exceeding 100 pg/mL (22 nmol/ liter), low or low-normal basal aldosterone level, and increased renin concentration are indicative of primary hypoadrenalism. The rapid corticotropin stimulation test to determine adrenal responsiveness is the diagnostic procedure of choice when testing for primary adrenal insufficiency (Box 13-10). To confirm the diagnosis of secondary adrenal insuffi ciency, the metyrapone test is performed. An insufficient increase in plasma 11-deoxycortisol and a low plasma cortisol concentration ( 36 cm H2O). Treatment

The prevention of primary ACS entails leaving the peritoneal cavity open in patients at risk for IAH and after high-risk surgi cal procedures. Patients at risk for secondary ACS receiving crystalloid resuscitation must be monitored closely and, when given more than 6 liters of crystalloid in a 6-hour period, IAP must be measured. In addition to blood pressure and urine output, monitoring APP (APP = mean arterial pressure − IAP) by continuously measuring IAP throughout resuscitation is a helpful indicator of the resuscitation end point. Routine mea surement of IAP must also be considered in critically ill patients because IAH is the leading cause of chest wall impairment in ARDS. Monitoring gastric pH can detect cases of secondary ACS early after admission to the intensive care unit. A high incidence of suspicion is paramount, especially in cases of sec ondary ACS in which the onset is insidious and manifestations are subtle. Patients exhibiting the prodromal phase of ACS benefit from timely intervention to relieve the IAH and prevent progression to ACS (Box 13-13). Conservative fluid resuscita tion, administration of analgesia, sedatives and pharmacologic paralysis, patient positioning, drainage of intra-abdominal fluid, escharotomy, renal placement therapy, and diuretics are mea sures that may prevent progression to ACS. Optimizing treatment and identifying patients with IAH-ACS likely to benefit from decompression is a challenging task. The decision to intervene surgically is not based on IAH alone but rather on the presence of organ dysfunction in asso ciation with IAH. Few patients with a pressure of 12 mm Hg have any organ dysfunction, whereas IAP higher than 15 to 20 mmHg is significant in every patient. With grade III IAH,

BOX 13-13 Prevention of Abdominal Compartment Syndrome Patients at risk for IAH and abdominal compartment syndrome are identified (e.g., major trauma, complex abdominal procedure). Organ function is monitored and assessed: • Lungs: Hypercapnia, hypoxia, difficult ventilation, elevated pulmonary artery pressure, drop in Pao2/Fio2 ratio, decreased compliance, intrapulmonary shunt, increased dead space • Heart: Decreased cardiac output and cardiac index and need for vasopressors • Kidneys: Oliguria unresponsive to fluid therapy • Central nervous system: Glasgow coma scale score 5 cm of mesentery

Table 13-12 Factors Associated With Increased Risk for Clostridium difficile Colitis CATEGORY

RISK FACTORS

Patient-related factors

Increasing age Preexisting renal disease Preexisting chronic obstructive lung disease Impaired immune defense Underlying malignancy Underlying gastrointestinal disease

Treatment-related factors

Preoperative bowel cleansing Antibiotic use Immunosuppressive therapy Surgery Prolonged hospital stay

Facility-related factors

Intensive care units Caregivers Long-term facilities

Maturation Primary maturation of end stoma or afferent limb of loop ileostomy Avoidance of traversing skin with sutures during maturation

Other Maneuvers* Tunneling of bowel through extraperitoneal space of abdominal wall Mesenteric-peritoneal closure Fixation of mesentery or bowel to fascial ring Use of supportive rod with loop stomas *May be performed but have not been proved to be effective in preventing postoperative complications.

stomal prolapse can be achieved locally by making a circumfer ential incision at the mucocutaneous junction, excision of redundant bowel, and rematuration. Repair of loop stomal pro lapse is achieved by local revision to an end stoma. Laparotomy may be required for the treatment of recurrent prolapse and prolapse associated with a parastomal hernia. Large permanent or complicated parastomal hernias are treated by relocating the stoma or reinforcing the fascia ring with mesh (synthetic or biomaterial). Treatment of a peristomal fistula entails resection of the diseased or involved segment of bowel and relocation of the stoma. Treatment of mucosal islands ranges from ablation with electrocautery to relocation of the stoma. Treatment of chemical dermatitis entails cleaning the damaged skin, the use of barriers, and a properly fitting stomal management system. Candida dermatitis is best treated with nystatin powder. Allergic dermatitis is treated by removal of the offending item and symptomatic relief is produced by oral anti histamine or topical or oral steroid therapy. Traumatic dermati tis is treated by patient education and application of a skin barrier under the tape is used to secure the faceplate in place. Occasionally, in cases of severe dermatitis, the patient will have to be admitted to the hospital and placed on TPN while the skin around the stoma heals enough to allow subsequent place ment of an appliance. Clostridium difficile Colitis Causes

C. difficile colitis (CDC) is an inflammatory bowel disease caused by toxins produced by unopposed proliferation of the

bacterium C. difficile. Several factors are associated with increased risk for CDC (Table 13-12). There has been an increased inci dence and diagnosis rate of C. difficile infection (CDI) in hos pitalized patients, as well as an increase in severity, requiring admission to the intensive care unit, treatment failure of the disease, colectomies, and 30-day mortality (4.7% in 1992 to 13.8% in 2003).36,37 These changes are caused by increased awareness of the disease, advanced age of inpatients, with numer ous comorbidities, ubiquitous use of antibiotics, and emergence and spread of a hypervirulent strain. Historically, cephalospo rins, clindamycin, and ampicillin-amoxicillin were most com monly associated with CDI. Fluoroquinolones, as a class of antibiotics, have emerged as the most prone and at increased risk to cause CDI, and the increased use of newer generation fluo roquinolones is implicated in outbreaks of a fluoroquinoloneresistant strain. Since 2000, a hypervirulent toxinotype III strain of C. difficile (designated BI/NAP1/027 strain) has been identi fied in Canada, the United States, and England. Virulence of the wild-type C. difficile bacteria is related to enterotoxin A and cytotoxin B encoded by the genes tcdA and tcdB. Polymorphisms or partial deletions (18-base pair deletion) in tcdC may lead to increased production of toxins A and B at levels 16 and 23 times higher than the wild type. Antibiotic use continues to precede almost all cases of infection. Of patients contracting CDC, 90% have received antibiotic therapy and 70% have been treated with multiple antibiotics. Patients receiving prolonged courses of antibiotic therapy are particularly susceptible, and those receiving prophy laxis are also at risk. Prolonged hospital stay allows exposure to contaminated environmental surfaces by more susceptible people. Intensive care and long-term facility units are not only sites of heavy environmental contamination, but also house critically ill and vulnerable patients. Impaired host immune defense as a result of advanced age, surgery, immunosuppressive medications, HIV, and chemotherapy are major risk factors. The proportion of immunocompromised patients infected with C. difficile has increased from 20% to 30% in the past decade. Surgical patients account for 45% to 55% of CDC, and the highest rates of infection are noted in patients undergoing general and vascular surgery. C. difficile is a gram-positive anaer obic spore-forming bacillus; approximately 5% to 35% of bac teria do not produce toxins and thus do not cause colitis. The

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BOX 13-15 Technical Aspects of Stoma Construction

314 SECTION II PERIOPERATIVE MANAGEMENT organism produces a capsule that resists degradation by phago cytes. The spore is heat-resistant, persists in the environment for months and years in a dormant phase, and survives on inanimate objects. Approximately 3% to 5% of the general population has the organism in their stool. This increases to 8.6% of patients with hematologic malignancies and 10% to 25% of adults during hospitalization. Antibiotic use leads to a disturbance in the microflora of the colon and allows the nosocomial organism to grow, prolifer ate, and produce toxins. Toxin A, an enterotoxin, causes cell rounding, mucosal damage and inflammation, and release of inflammatory mediators. Toxin B is a potent cytotoxin that causes identical cell rounding and activates the release of cyto kines from human monocytes. The toxins translocate to the portal circulation. Phagocytosis of toxins by macrophages in the liver results in the elaboration of several cytokines that act in the propagation of the systemic septic response.

more prominent and are associated with systemic signs of toxic ity. Diarrhea may be absent in 5% to 12% of cases; the WBC count may be depressed but is most commonly increased with a rapid elevation (>20,000 cells/mm3) and bandemia (>30%). A leukemoid reaction is a prominent feature that may suggest CDC or herald the onset of fulminant disease. Frank peritoneal signs and toxic megacolon may develop and rapidly progress to shock. Toxic megacolon usually develops slowly and is charac terized by obstipation, a dilated colon, and systemic toxicity. In fulminant disease, the toxin assay is negative in 12.5% of cases. CT scanning is diagnostic and typically shows a boggy, edema tous, and thickened colon wall (>3 mm) in 88%, pancolitis in 50%, serous ascites in 35%, pericolic inflammation in 35%, a clover leaf or accordion sign in 20%, and megacolon (transverse colon >8 cm) in 25% of cases. Sigmoidoscopy shows pseudo membranes in 90% of cases versus 23% in mild cases.

Presentation and Diagnosis

Treatment of CDC starts with prevention. However, this is dif ficult because disinfectants may eliminate C. difficile but not the highly resistant spores, antibiotics are ineffective in clearing stools of carriers and although effective, steam sterilization is expensive. Judicious use of antibiotics, application of standard hygiene measures to hospital staff, use of disposable gloves and single-use disposable thermometers, and ward closure and decontamination in case of outbreaks are important for decreas ing the mortality and morbidity associated with CDC. Once a diagnosis of CDC is made, medical therapy and timely surgical intervention improve recovery and lower the mortality rate. Death is related to delay in diagnosis, reliance on negative toxin assay, less than total abdominal colectomy, and additional patient-related factors. Infections with C. difficile usually follow a benign course. Although some patients respond to discontinuation of antibiotic therapy, others require treat ment and respond within 3 to 4 days, and symptoms resolve in 95% to 98% within 10 days. Vancomycin (125 mg, four times/ day) is given orally, down the NG tube or given or as an enema, or metronidazole (Flagyl) is given orally (250 mg, four times/ day) or IV (500 mg, three times/day) for 2 weeks. Antimotility agents and narcotics are avoided. IV fluid therapy is instituted to correct dehydration. In the absence of ileus, oral intake is allowed. Approximately 25% to 30% of patients develop recur rent disease as a result of reinfection with a second strain or reactivation of toxigenic spores that persist in the colon. Treat ment of relapse is similar to that of the primary infection. In patients with recurrent attacks, pulsed vancomycin therapy, combination therapy with vancomycin and rifampicin, or the administration of competitive organisms (e.g., Lactobacillus acidophilus and Saccharomyces cerevisiae) may be tried. Most patients with CDI respond to medical treatment but, occasionally, the disease progresses to a more severe form, such as fulminant colitis, despite appropriate and timely medical treatment. Fulminant colitis is characterized by severe systemic inflammatory response (fever, hypotension, tachycardia, leuco cytosis, and/or requirement for volume resuscitation), shock, multiple organ failure, and death caused by toxin-induced inflammatory mediators (e.g., IL-8, macrophage inflammatory protein-2, substance P, tumor necrosis factor-α [TNF-α]) released locally in the colon. Hypotension that requires vasopres sor support despite adequate volume resuscitation, lactate level 5 mmol/liter or higher, respiratory failure and ventilator support,

Overgrowth of the toxigenic strain of C. difficile results in a variety of disease states, with varied clinical courses. Watery diarrhea is the hallmark symptom and usually starts during or shortly after antibiotic use. One dose of antibiotic can result in the disease, but the incidence with prophylactic antibiotics increases with extended use of antibiotics beyond the recom mended period. Approximately 25% to 40% of patients become symptomatic 10 weeks after completion of antibiotic therapy. The stools are foul-smelling and may be positive for the presence of occult blood. In mild to moderate cases, systemic signs of infection are absent or present to a mild degree. In severe colitis, the diarrhea becomes associated with abdominal cramps and anorexia, abdominal tenderness, dehydration, tachycardia, a raised leukocyte (white blood cell [WBC]) count, and bandemia (>10%). Pseudomembranous colitis is the more dramatic form of the disease and develops in 40% of patients who are signifi cantly symptomatic. Cell cytotoxin assay in tissue culture is a highly sensitive and specific test for the detection of toxin B (rounding effect) and is the gold standard diagnostic test for CDC. ELISA that detects toxin A or B in stool is highly sensitive and specific. Unlike the stool cytotoxic test, which requires 24 to 48 hours, results with ELISA are obtained within hours, the test is less expensive, and does not require specific training. Endoscopy reveals nonspecific colitis in moderate disease (mucosal edema and patchy erythema) or pseudomembranes in severe disease. The presence of pseudomembranes may be limited to the prox imal colon in 10% of cases and the rectum may be spared in 60% of cases. Radiographs of the abdomen may be normal or show adynamic ileus, colonic dilation, thumb printing, or haus tral thickening. CT scans may show a thickened and edematous colon wall and free peritoneal fluid. Approximately 2% to 5% of patients develop fulminant colitis, despite timely medical therapy, and may succumb to cytokine-mediated cardiovascular collapse and death. This fre quently develops in hospitalized and postoperative patients but may occur in the out of hospital setting. At-risk patients are the immunocompromised or those taking multiple antibiotics, patients with a previous diagnosis of C. difficile infection, those with vasculopathy, older adults, those with chronic obstructive pulmonary disease, and those in renal failure. In fulminant colitis, abdominal cramps, distention, and tenderness become

Treatment

Surgical Complications Chapter 13 315

Anastomotic Leak Causes

Numerous factors can cause or are associated with an increased risk for anastomotic leak (Table 13-13). Mechanical bowel prep aration has long been considered a critical factor in preventing infectious complications after elective colorectal surgery. In emergencies, surgeons have resorted to on-table colonic lavage to cleanse the colon and primary anastomosis, with good results. With decreased morbidity rates as a result of effective antibiotic Table 13-13 Risk Factors Associated With Anastomotic Leak DEFINITIVE FACTORS

IMPLICATED FACTORS

Technical aspects: Blood supply Tension on the suture line Airtight and watertight anastomosis

Mechanical bowel preparation Drains Advanced malignancy Shock and coagulopathy

Location in the GI tract: Pancreaticoenteric Colorectal Above the peritoneal reflection Below the peritoneal reflection

Emergency surgery Blood transfusion Malnutrition Obesity Gender

Local factors: Septic environment Fluid collection

Smoking Steroid therapy Neoadjuvant therapy

Bowel-related factors: Radiotherapy Compromised distal lumen Crohn’s disease

Vitamin C, iron, zinc, and cysteine deficiency Stapler-related factors: Forceful extraction of the stapler Tears caused by anvil or gun insertion Failure of the stapler to close

prophylaxis, modern surgical techniques, and advances in patient care, the need for mechanical bowel preparation has been questioned. Studies have shown that mechanical bowel prepara tion results in adverse physiologic changes and structural altera tions in the colonic mucosa and inflammatory changes in the bowel wall. Furthermore, some studies have suggested that its use in elective cases is not only unnecessary but also associated with increased anastomotic leaks, intra-abdominal and wound infections, and reoperation.39 Proponents of intraoperative lavage have also become content with simply decompressing the dilated colon and milking away fecal matter in the area of the anastomosis instead of aggressive cleansing. Although there is a trend toward elimination of cleansing of the colon in elective and emergent colon resection, one must be cautioned against abandoning the practice completely, especially for anterior resec tions, in which the presence of stool in the rectum poses a problem with the use of staplers. The level of the anastomosis in the GI tract is important. Although small bowel, ileocolic, and ileorectal anastomoses are considered safe, esophageal, pancreaticoenteric, and colorectal anastomoses are considered high risk for leakage. In the esopha gus, lack of serosa appears to be a significant contributing factor. In the pancreas, the texture of the gland and size of the pancre atic duct, presence of pancreatic duct obstructive lesions, experi ence of the operating surgeon, and probably the type of enteric anastomosis are implicated (see later). In the rectum, the highest leak rate is found in anastomoses in the distal rectum, 6 to 8 cm from the anal verge. Adequate microcirculation at the resection margins is crucial for the healing of any anastomosis. Factors interfering with the perianastomotic microcirculation include smoking, hypertension, locally enhanced coagulation activity as a result of surgical trauma, perianastomotic hematoma, and presence of macrovascular disease. In colorectal anastomoses, relative isch emia in the rectal remnant is a factor because its blood supply is derived from the internal iliac artery via the inferior hemor rhoidal vessels, contribution from the middle hemorrhoidal artery is minimal and, at best, variable because the vessels are mostly absent and, when present, are unilateral. Total mesorec tal excision, neoadjuvant therapy, and extended lymphadenec tomy with high ligation of the inferior mesenteric artery are additional contributing factors. Intraluminal distention is believed to be responsible for rupture of an anastomosis. The mechanical strength of the anas tomosis is important and, in the early period, is dependent on sutures or staples, with endothelial cells and fibrin-fibrinonectin complex additionally contributing to the tension force. Con struction of a watertight and airtight anastomosis is therefore essential. Antiadhesive agents may predispose to leaks because they isolate the anastomosis from the peritoneum and omentum and, as found in animal studies, decrease anastomotic bursting pressure and hydroxyproline levels.40 Intra-abdominally placed open rubber drains are not helpful and, if left for more than 24 to 48 hours, are associated with an increased risk of infection. In the pelvis, drains have been shown in some studies to be associated with a higher leak rate. Conversely, drains may remove blood, cellular debris, and serum that act as good culture media for perianastomotic sepsis or abscess formation. Local sepsis affects the integrity of the anastomosis negatively as it reduces collagen synthesis and increases collagenase activity, which results in increased lysis of

SECTION II PERIOPERATIVE MANAGEMENT

and an increase in organ dysfunction are alarming premortem signs.36,38 Colectomy is indicated when medical treatment fails or when the patient develops hemodynamic instability, fulminant disease, toxic megacolon, or peritonitis. The timing of interven tion is not well established. Although the end point of failure of medical therapy is not known, a 24- to 48-hour trial is consid ered minimal. Early intervention commits the patient to a major surgical procedure and an ileostomy, and a delayed intervention is associated with high mortality (35% to 75%).36-38 Once the patient develops fulminant CDC, multiple organ failure, and hypotension, surgical intervention is less likely to be beneficial. Mortality is also increased with advanced age (>65 years), prolonged duration of CDI, length of medical treatment, and elevated serum lactate levels.36-38 Consequently, to lower mortality of severe CDI, patients at risk for fulminant disease are identified and the clinical features of the disease must be recognized. Most importantly, surgical intervention must be considered during a critical window that precedes the onset of multiple organ failure and hemodynamic collapse from prolonged septic shock. Early surgical intervention noted in recent years (2000-2006 versus 1995-1996) has changed the outcome, with a decrease in mortality from 65% to 32%.36,37 The procedure of choice is total abdominal colectomy and ileos tomy. Lesser procedures are less effective and associated with high mortality (70%) compared with 11% with abdominal colectomy.

316 SECTION II PERIOPERATIVE MANAGEMENT collagen at the anastomosis. Defunctioning or protective stomas do not decrease the overall leak rate but rather minimize the severity and sequelae of perianastomotic contamination and decrease the reoperation rate. Defunctioning stomas, however, deprive the colon of short-chain fatty acids, resulting in exclu sion colitis and delay in epithelialization of the anastomosis, and are associated with altered collagen metabolism observed in leftsided anastomoses. Bevacizumab, an angiogenesis inhibitor, is associated with increased risk for surgical site complications. It is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). VEGF is a critical factor for the survival of endothelial cells and is selectively present in the neovasculature of growing tumors. Bevacizumab binds with high specificity and affinity to VEGF, inhibiting the binding of VEGF to its recep tors and negatively affecting angiogenesis and/or the remodeling of the existing network of blood vessels. Bevacizumab is used in combination with standard chemotherapy IFL (irinotecan, 5-fluorouracil [FU], and leucovorin) in the treatment of patients with metastatic colorectal cancer. In animal studies, antiangio genic cancer therapy inhibits dermal wound healing in a doserelated fashion and compromises healing of colonic anastomoses. In patients with metastatic colorectal cancer, it increases the risk of surgical site complications—spontaneous dehiscence of primary anastomosis and colocutaneous fistula formation from an anastomosis. Such complications may occur up to 2 years after surgery.41 The mechanism is probably related to micro thromboembolic disease leading to bowel ischemia, inhibition of angiogenesis in the microvascular bed of the new anastomosis, inhibition of neoangiogenesis in postradiated tissue, and reduc tion in the number of newly formed vessels in granulation tissue surrounding anastomotic sites. Risk factors for delayed anasto motic complications include a history of anastomotic complica tions, radiotherapy, and rectal location of anastomoses. Emergency bowel surgery is associated with high morbidity and mortality, in part because of sepsis and anastomotic leakage. This is related to the poor nutritional status of the patient, pres ence of underlying malignancy, immunocompromised state, presence of intra-abdominal contamination or sepsis, and hemo dynamic instability. Transfusion, on the one hand, causes impaired cell-mediated immunity and predisposes to infection and, on the other hand, alleviates anemia and improves the oxygen-carrying capacity of red blood cells that may have a positive impact on healing. Obesity increases the difficulty and complexity of the surgery, has been shown to be associated with increased postoperative complications, and is an independent risk factor for an increasing leakage rate, especially after a low colorectal anastomosis. Steroids affect healing by decreasing col lagen synthesis, delaying the appearance of the inflammatory reaction, and reducing the production of transforming growth factor-β and insulin-like growth factor in wounds, which are essential for wound healing. Presentation and Diagnosis

Anastomotic leak is a dreadful complication to encounter. It results in sepsis and enteric fistula formation, leads to reopera tion and a possible permanent stoma, and is associated with decreased survival and increased local recurrence rate after cura tive resection of cancer, and possibly leads to death.42 The clinical manifestations are the result of a cascade of events that start with loss of integrity of the anastomosis and

leakage of intestinal contents. The leakage may be diffuse throughout the peritoneal cavity (uncontrolled leak) or become walled off by omentum, abdominal wall, and contiguous loops of bowel, pelvic wall or adhesions from prior operations. If a surgical drain is present, intestinal contents are discharged onto the skin. Intra-abdominal fluid collections may contain intesti nal contents, frank pus, or pus mixed with intestinal contents. If the fluid collection is drained surgically or percutaneously, there is an initial discharge of purulent material followed by feculent material heralding the formation of an enterocutaneous fistula (controlled fistula). If allowed to drain through the surgi cal incision or abdominal wall, surgical wound infection and dehiscence with evisceration or an abdominal wall abscess may occur. If the fluid collection burrows into a contiguous structure such as the urinary bladder or vagin*, spontaneous drainage occurs, with the formation of an enterovesical or enterovagin*l fistula. Hence, after the index surgery, a patient may have an initial normal postoperative course or may not have been progressing as expected. The early warning signs of anastomotic leak are malaise, fever, abdominal pain, ileus, localized erythema around the surgical incision, and leukocytosis. Patients may also develop bowel obstruction, induration, and erythema in the abdominal wall, rectal bleeding, or suprapubic pain. There may be an initial excessive drainage from the surgical wound or surgical wound dehiscence and/or evisceration. An intra-abdominal fluid collec tion or abdominal wall abscess may be identified and drained surgically or percutaneously. Patients may also experience pneu maturia, fecaluria, and pyuria. Once a fistulous communication is established, problems related to the loss of intestinal contents, perifistula skin, surgical wound, and malnutrition soon ensue. Sepsis is a prominent feature of anastomotic leakage and results from diffuse peritonitis or localized abscess, abdominal wall infection, or contamination of a sterile site with intestinal contents. Abdominal wall infection develops as a result of contact of purulent material with the muscle and subcutaneous tissue, tissue necrosis associated with fascial sutures, and/or contact of corrosive intestinal juices with the abdominal wall, resulting in chemical erosion and extension of the infectious process. Nonclostridial necrotizing infections of the abdominal wall occur, particularly with fistulas of the lower GI tract that contain high concentrations of Enterobacteriaceae, nongroup A beta-hemolytic streptococci, and anaerobic cocci or penicillin-sensitive Bacteroides spp. Contamination of the urinary bladder with intestinal contents (enterovesical fistula) results in urosepsis. Treatment

Treatment of anastomotic leakage starts with prevention. In elective cases, nutritional support for 5 to 7 days is appropriate for patients who are malnourished or have lost significant amounts of weight. Mechanical and chemical bowel prepara tions are still recommended by many surgeons prior to colorec tal resection. In patients receiving or who have received bevacizumab, the appropriate interval between the last dose administered and the surgery is not known. The terminal halflife of the medication is long—20 days—so wound healing complications are documented up to 56 days after treatment. It is advisable to delay elective surgery for at least 4 to 8 weeks or, preferably, three half-lives (60 days) after treatment. In patients with newly constructed anastomoses who are candidates for

Surgical Complications Chapter 13 317 Drains and octreotide can be used when an anastomosis is per formed to a soft pancreas with a small duct and in lower surgi cal volume centers or centers with a high leak rate (>10%). Pancreatic duct stents (placed intraoperatively) continue to be used, despite the lack of data to suggest that they decrease the leak rate.43 A pancreatic stent placed prior to a distal pancreatec tomy decompresses the pancreatic duct by abolishing the pres sure gradient between the pancreatic duct and duodenum and may decrease the risk of fistula formation, thus allowing the site of a leak to seal. Once an anastomotic leak is suspected or diagnosed, resuscitation is started immediately because patients are in the postoperative period and have been without nutrition. Further more, they have a contracted intravascular volume because of third spacing and lost intestinal contents, and may have an electrolyte imbalance. Intravascular volume is restored with crystalloid fluids and a blood transfusion if anemia is present and electrolyte imbalances are corrected. Oral intake is stopped and the bowel is put at rest to decrease luminal contents and GI stimulation and secretion. A NG tube is placed if obstruc tive symptoms are present. Infected surgical wounds are opened, and any abdominal wall abscesses are incised and drained. Reoperation is indicated if there is diffuse peritonitis, intraabdominal hemorrhage, suspected intestinal ischemia, major wound disruption, or evisceration. Reoperation is a major undertaking and is associated with significant mortality and morbidity. The procedure is bloody and carries the risk of bowel injury. Primary closure of the leaking point only is avoided because failure is certain. The management of duodenal and proximal jejunal leaks is a challenging task. In these situations, transgastric placement of a jejunal tube helps divert gastric and biliopancreatic secre tions and placement of drains in close proximity to the leak allows external drainage of the intestinal contents. Pyloric exclu sion and gastrojejunostomy should be used judiciously in these situations. Management of jejunal, ileal, and colorectal leaking anastomoses depends on the severity and duration of contamina tion, condition of the bowel, and hemodynamic stability of the patient. In a critically ill and unstable patient, especially one with fecal peritonitis, a damage control type of procedure is performed—the anastomosis is taken down, the ends of the bowel are stapled, peritoneal lavage is performed, and the inci sion is left open. A second-look laparotomy with stomal forma tion is performed in 24 to 48 hours or once the patient is more stable. Otherwise, in the small bowel, an anastomosis may be performed or the ends of the bowel are delivered as stomas; in the colon, the proximal end of the colon is brought out as a colostomy and the distal end closed or brought out as a mucous fistula; and, in the rectum, the distal end is closed and the proximal end of the colon delivered as a stoma. A proximal diverting stoma with drainage of the pelvis is not adequate treat ment of leaking colorectal anastomoses associated with diffuse peritonitis. If the abdomen is left open, covering the bowel with the greater omentum (if available) or a biologic implant protects the bowel and prevents desiccation and spontaneous fistula for mation. Negative-pressure wound therapy is best avoided when bowel is exposed, especially in the presence of unprotected suture or staple line.44 In the absence of diffuse peritonitis and evisceration, a CT scan may identify single or multiple abscesses, pneumoperito neum, ascites and, at times, extravasation of oral contrast into

SECTION II PERIOPERATIVE MANAGEMENT

bevacizumab therapy, evaluation of the anastomosis prior to initiation of therapy with fine-cut CT scanning, barium enema, and colonoscopy allows identification of patients at risk for anastomotic complications. In emergencies, especially in hemo dynamically unstable, immunocompromised, and nutritionally depleted patients, in the presence of fecal peritonitis, significant bowel dilation, and edema, an anastomosis is best avoided because a leak may prove fatal. Construction of an anastomosis that is at low risk for dis ruption requires the following: 1. Adequate exposure, gentle handling of tissues, aseptic precaution, and meticulous, careful dissection 2. Adequate mobilization so that the two attached organs have a tension-free anastomosis 3. Correct technical placement of sutures or staples with little variance 4. Matching of the lumina of the two organs to be con nected, which can be done by various techniques 5. Preservation of the blood supply to the ends of struc tures to be anastomosed Sufficient microcirculation is essential for healing of the anastomosis. In intestinal anastomoses, the marginal artery of the colon and last vascular arcade of small bowel mesentery must be preserved. The small bowel serosa must not be denuded of mesentery more than 3 to 4 cm for hand-sewn anastomoses. In the distal colon, to ensure a tension-free anastomosis, the fol lowing maneuvers may be required: inferior mesenteric artery may be divided at its origin, windows created in the mesentery of the small bowel up to the third portion of the duodenum, and small branches interrupted between the arcades, creating mesenteric windows and dividing the ileocolic vessels at their origin. For intestinal and colorectal anastomoses, there is no difference in the rate of anastomotic leakage between hand-sewn and stapled anastomoses and among various stapling techniques, provided that sound surgical technique is followed. The decision to construct a one- or two-layer intestinal anastomosis is a matter of preference. A colorectal anastomosis is easier to perform in one layer. However, since the advent of stapling devices, an anastomosis deep in the pelvis has most commonly been stapled. The technique is not only faster but also improves asepsis because the anastomosis is performed in a closed fashion compared with a hand-sewn anastomosis, which is considered an “open anastomosis” and allows for more contamination. In low anterior resection, the omentum may be advanced to the pelvis and placed around the colorectal anastomosis. This maneuver may lower the rate of anastomotic leak or disruption but mostly appears to decrease the severity of the complication. Drainage of a colorectal anastomosis is advisable in difficult cases and when technical problems are encountered, or when neoad juvant therapy has been used. Defunctioning stomas are used for extraperitoneal anastomoses, when technical difficulties are encountered, or after neoadjuvant therapy. When constructing a pancreaticoenteric anastomosis, a pancreaticojejunostomy is equivalent to pancreaticogastrostomy. An end to side–duct to mucosa pancreaticojejunostomy is asso ciated with a lower leak rate compared with an end-to-end invagin*ting pancreaticojejunostomy; obliteration of the main pancreatic duct with protamine gel or human fibrin sealant, or suture closure of the remnant pancreas without an anastomosis, is associated with the highest leak rate.43 The routine placement of drains in proximity to pancreatic anastomoses is controversial.

318 SECTION II PERIOPERATIVE MANAGEMENT the peritoneal cavity. Multiple abscesses require open drainage, a single intra-abdominal abscess can be drained percutaneously, and a pelvic abscess can be drained transrectally or transvagi nally. Following drainage, an external fistula may develop. The management of a controlled fistula is outlined in the next section. If percutaneous drainage fails to control sepsis, reopera tion is indicated. At the time of open drainage of a pelvic abscess, if there is any doubt about the origin of the abscess (de novo abscess versus abscess secondary to a small anastomotic leak that has sealed), a defunctioning stoma is constructed unless there is complete disruption of the anastomosis. In that case, the ends of the bowel are exteriorized as a stoma. A pancreaticojejunos tomy leak, if small, can be treated by placing a drain next to the leak. However, for an anastomosis that has almost fallen apart, the patient will probably require completion pancreatectomy. A patient who has a bile duct leak will require drainage of the infection and placement of a drain next to the leak or, in the case of a large leak, may require bile duct reconstruction.

A fistula represents an abnormal communication between two epithelialized surfaces, one of which is a hollow organ. In the GI tract, a fistula may develop between any two digestive organs or between a hollow organ and the skin and may be develop mental or acquired. Acquired fistulas account for most GI fistu las and can be traumatic, spontaneous, or postoperative in nature. GI fistulas are most commonly iatrogenic, develop after an operation, and may occur anywhere in the GI tract. Esophageal, aortoenteric, and rectal fistulas are not discussed in this section. In the past, acquired GI fistulas most commonly developed as a result of a difficult appendectomy. At present, they commonly occur as the result of anastomotic breakdown, dehiscence of a surgically closed segment of stomach or bowel, unrecognized iatrogenic bowel injury following adhesiolysis, or during closure of a laparotomy incision. Occasionally, they develop after instru mentation or drainage of a pancreatic, appendiceal, or diver ticular fluid collection or abscess. The presence of intrinsic intestinal disease, such as Crohn’s disease, radiation enteritis, distal obstruction, or a hostile abdominal environment, such as an abscess or peritonitis, are predisposing factors for fistula for mation. The risk is also higher in emergencies when the patient may be malnourished or poorly prepped. Gastric fistulas are uncommon and frequently occur after resection for cancer and less frequently after resection for peptic ulcer disease, necrotizing pancreatitis, an antireflux procedure, or bariatric surgery. Pancreatic fistulas develop as a result of disruption of the main pancreatic duct or its branches secondary to trauma or postoperatively following pancreatic biopsy, distal pancreatectomy, pancreaticoduodenectomy, pancreatic necro sectomy, and surgery on the stomach, biliary tree, or spleen. Intestinal fistulas develop after resection for cancer, diverticular disease, inflammatory bowel disease, or closure of a stoma.

course. They then start showing the manifestations of leakage of intestinal contents (see earlier). The seriousness and severity of these manifestations depend on the surgical anatomy and phys iology of the fistula. Anatomically, the fistula may originate from the stomach, duodenum, small bowel (proximal or distal), or large bowel. The tract of the fistula may erode into another portion of the intestines (enteroenteric fistula) or another hollow organ (enterovesical), thus forming an internal fistula, or into the body surface (enterocutaneous and pancreatic fistula) or vagin* (enterovagin*l fistula), thus forming an external fistula. A mixed fistula describes an internal fistula associated with an external fistula. A superficial fistula drains on top of an open or granulating wound; in a deep fistula, the tract traverses the abdominal cavity and drains onto the skin. Physiologically, the fistula is classified as high or low output on the basis of the volume of discharge in 24 hours. The exact definition of low and high output varies from 200 to 500 mL/24 hr. However, three different categories are recognized—low output (500 mL/24 hr). The ileum is the site of the fistula in 50% of high-output fistulas. The discussion in this section focuses mainly on external fistulas. Sepsis is a prominent feature of postoperative intestinal fistulas and is present in 25% to 75% of cases. As noted earlier, sepsis is the result of diffuse peritonitis or localized abscess, abdominal wall or necrotizing infection, or contamination of a sterile hollow organ with intestinal contents. Loss of intestinal contents through the fistula results in hypovolemia and dehydration, electrolyte and acid-base imbal ance, loss of protein and trace elements, and malnutrition. In a high intestinal fistula, it also results in loss of the normal inhibi tory effect on gastric secretion, thus resulting in a gastric hyper secretory state. With high-output enterocutaneous fistulas, there is also intrahepatic cholestasis related to the loss of bile salts, disruption of enterohepatic circulation, and bacterial overgrowth in the defunctionalized intestine. Malnutrition results from loss of protein-rich secretions, lack of nutrient intake, loss of absorp tion caused by bypass of the gut (e.g., gastrocolic, duodenocolic, high enterocutaneous fistulas), and sepsis that sets the stage for nutritional deficiency and rapid breakdown of body muscle mass. In gastroduodenal and proximal small bowel fistulas, the output is high and the fluid loss, electrolyte imbalance, and malabsorp tion are profound. In distal small bowel and colonic fistulas, the output is low and dehydration, acid-base imbalance, and malnu trition are uncommon. Significant electrolyte imbalance occurs in 45% of patients and malnutrition occurs in 55% to 90%. Skin and surgical wound complications develop as a result of contact of GI effluent with skin or the wound. Effluent der matitis results from the corrosive effect of intestinal contents, which cause irritation, maceration, excoriation, ulceration, and infection of the skin. Fecal dermatitis is marked by erythema and desquamation and may encourage skin sepsis. Superficial and deep surgical wound and necrotizing infections also develop. Pain and itching by contact of effluent with unprotected skin is intolerable and affects the morale of the patient.

Presentation and Diagnosis

Treatment

Intestinal Fistulas Causes

Enterocutaneous fistulas are usually associated with a triad of sepsis, fluid and electrolyte imbalance, and malnutrition. Patients are usually in the postoperative period and may not be progress ing as expected or may have an initial normal postoperative

Postoperative intestinal fistulas are not a new problem but rather continue to be a challenging clinical scenario. Their etiogenesis has changed and their management continues to evolve. In the past, the main focus of management involved suctioning of the

Surgical Complications Chapter 13 319

FACTORS

FAVORABLE

UNFAVORABLE

Surgical anatomy of the fistula

Long tract, >2 cm Single tract No other fistulas Lateral fistula Nonepithelialized tract Origin (jejunum, colon, duodenal stump, and pancreaticobiliary) No adjacent large abscess

Short tract, 10 lb Weak grip strength Low energy expenditure Self-reported exhaustion Slow walking speed

aged 65 to 69 years is approximately 18 years, whereas the life expectancy for similarly aged patients with dementia is closer to 10 years. In older persons with congestive heart failure, 20% die within 1 year and 75% within 5 years of initial hospitalization. Understanding the impact of comorbidity on life expectancy is therefore essential in risk-benefit determinations. Of all comorbid conditions, cardiovascular disease is the most prevalent, and cardiovascular events are a leading cause of severe perioperative complications and death. Therefore, the main thrust of preoperative evaluation in most patients, regardless of age, has focused on identifying patients at risk for cardiac complications. The American College of Cardiology (ACC) and American Heart Association (AHA) Task Force on Practice Guidelines first published an in-depth set of guidelines for preoperative cardiac evaluation in 1996, with updates in 2002 and 2007.20 These guidelines provide a stepwise Bayesian strategy for determining which patients will need further testing to clarify risk or further treatment to minimize risk. Stratification is based on factors related to the patient and type of surgery. For older patients with known cardiac disease, rigorous workup may be necessary. For most patients, assessment of exercise tolerance and functional capacity is an accurate method of predicting the adequacy of cardiac and pulmonary reserves (see later). Although the main focus of preoperative evaluation has been cardiac status, pulmonary complications in older patients are at least as common as cardiac complication, if not more so. Risk factors for pulmonary complications are not as well studied as those for cardiac complications, although many of the same issues apply to both. Poor exercise capacity and poor general health predict pulmonary and cardiac complications. In a systematic review of the literature for risk factor for pulmonary complications after noncardiac surgery (not limited to older adults) both patient and procedural factors were identified (Table 14-3).21 Age older than 80 years was associated with the highest odds ratio (OR) of a pulmonary complication, even after adjusting for comorbidity. Indicators of impaired function, nutrition, and cognition, among others, were also important.

Surgery in the Geriatric Patient Chapter 14 337

PATIENTRELATED FACTORS

ODDS RATIO

Age (years)

PROCEDURERELATED FACTORS

ODDS RATIO

Aortic aneurysm repair

6.90

70-79

3.90

Thoracic surgery

4.24

≥80

5.63

Abdominal surgery

3.01

ASA class ≥ II

3.12-4.87

Upper abdominal surgery

2.91

Abnormal CXR

4.81

Neurosurgery

2.53

CHF

2.93

Prolonged surgery

2.26

Functionally dependent

1.62-2.51

Head and neck surgery

2.21

COPD

2.36

Emergency surgery

2.21

Weight loss

1.62

Vascular surgery

2.10

Medical Comorbidity

1.48

General anesthesia

1.83

Cigarette use

1.40

Perioperative transfusion

1.47

Impaired sensorium

1.39

Alcohol use

1.21

Adapted from Smetana GW, Lawrence VA, Cornell JE: Preoperative pulmonary risk stratification for noncardiothoracic surgery: Systematic review for the American College of Physicians. Ann Intern Med 144:581–595, 2006.

Aortic aneurysm and thoracic and abdominal operations were the strongest procedure-related factors, but others, such as abdominal surgery, prolonged surgery, and emergency surgery, were also important. Additional comorbid conditions, such as prior stroke, gastroesophageal reflux disease (GERD), and poor dentition, also place older patients at increased risk of aspiration. Subtle changes in cognitive and swallowing function are similarly common in older adults and are associated with aspiration pneumonia and other negative outcomes. Initial screening for aspiration risk can be accomplished easily with a simple 3-ounce water swallow test, which has been shown to have high sensitivity and negative predictive value. This test is accomplished by asking the patient to swallow 90 mL of water without stopping. Choking, coughing, wet quality to the voice after swallowing, or failure to complete the test indicates that a more thorough swallowing examination may be in order. Passing this test indicates a low risk for aspiration; however, the false-positive rate is high. Aspiration precautions, however, should be instituted for all older patients with any risk factors for aspiration In a recent review of strategies to reduce postoperative pulmonary complications, only lung expansion interventions, such as incentive spirometry, were shown by good evidence to have an effect.22 The selective use of nasogastric decompression (rather than routine use) and short-acting (as opposed to longacting) intraoperative neuromuscular blockade was supported by fair evidence. Evidence supporting smoking cessation,

epidural anesthesia and analgesia, laparoscopic versus open approaches, and nutritional supplementation was insufficient or conflicting. Function Postoperative outcome in the geriatric surgical patient is largely determined by the impact of physiologic decline and comorbidity on an individual’s functional reserves. Limited preoperative functional reserves also contribute to postoperative immobility, which in turn leads to complications such as atelectasis and pneumonia, venous stasis and pulmonary embolism, and multisystem deconditioning (see later). Function can be assessed in many ways. American Society of Anesthesiologists Classification

For decades, the physical status classification of the American Society of Anesthesiologists (ASA) has been used successfully to stratify operative risk. This simple classification ranks patients according to the functional limitations imposed by coexisting disease. When curves for mortality versus ASA class are examined with regard to age, there is little difference between younger and older patients, which indicates that mortality is a function of coexisting disease rather than chronologic age. ASA classification has been shown to predict postoperative mortality accurately, even in patients older than 80 years. In a large multicenter Department of Veterans Affairs study (National Surgical Quality Improvement Program [NSQIP]), surgical patients were assessed prospectively for operative risk and risk-adjusted models were then created to allow comparison of the quality of surgical care among different institutions. Of the 68 variables studied, the ASA functional classification was the factor most predictive of postoperative morbidity and the second most predictive of mortality.23 Activities of Daily Living

The ability to perform ADLs (e.g., feeding, continence, transferring, toileting, dressing, bathing) and instrumental ADLs (IADLs; e.g., telephone use, transportation, meal preparation, shopping, housework, medication management, managing finances) have also been shown to correlate with postoperative mortality and morbidity.24 Inactivity, defined as the inability to leave the home on one’s own at least twice per week, has been associated with a higher incidence of all major surgical complications. Postoperative mortality in severely limited patients has been reported to be almost 10 times higher than mortality in active patients. In another study of functional recovery after major elective open abdominal operations, better recovery and shorter time to recovery of ADLs and IADLs were almost always predicted by a better preoperative physical performance status, as measured by three simple tests of strength and mobility.25 Exercise Tolerance

Of all the methods of assessing overall functional capacity, exercise tolerance is the most sensitive predictor of postoperative cardiac and pulmonary complications in older adults. In an older but frequently quoted study comparing exercise tolerance and other assessment techniques, Gerson and associates demonstrated that an inability to raise the heart rate to 99 beats/min while performing 2 minutes of supine bicycle exercise was the most sensitive predictor of postoperative cardiac and pulmonary complications and death.26

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Table 14-3 Potential Risk Factors for Postoperative Pulmonary Complications

338 SECTION II PERIOPERATIVE MANAGEMENT

ESTIMATED ENERGY REQUIREMENTS FOR VARIOUS ACTIVITIES* 1 MET

4 METs

Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level ground at 2–3 mph or 3.2–4.8 km/h?

4 METs

Climb a flight of stairs or walk up hill? Walk on level ground at 4 mph or 6.4 km/h? Run a short distance? Do heavy work around the house like scrubbing floors or lifting or moving heavy furniture?

Do light work around the house like dusting or washing dishes?

Participate in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football? Participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing? 10 METs

*MET, metabolic equivalent (see text). FIGURE 14-9 Estimated energy requirements for various activities. With increasing activity, the number of METs increases. An inability to function above 4 METs has been associated with increased perioperative cardiac events and long-term risk. (From Eagle KA, Berger PB, Calkins H, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery]: ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery]. Circulation 105:1257– 1267, 2002.)

Formal exercise testing, however, is not necessary in every older patient. The metabolic requirements for many routine activities have already been determined and are quantitated as metabolic equivalents (MET). One MET, defined as 3.5 mL/ kg/min, represents the basal oxygen consumption of a 70-kg, 40-year-old man at rest. Estimated energy requirements for various activities are shown in Figure 14-9. An inability to function above 4 METs has been associated with increased perioperative cardiac events and long-term risk. By asking appropriate questions about the level of activity, functional capacity can be accurately determined without the need for additional testing. Cognition Many people experience healthy aging without significant impairments, but a number of sensory, cognitive, and functional declines can occur with age, threatening independence. In cases of extreme sensory or cognitive loss, as seen with vascular and Alzheimer’s dementia, the capacity to perform ADLs can be compromised. These age-associated changes in cognitive function may have profound effects on postsurgical recovery and outcome. Additionally, worse biologic functioning is often associated with lower cognitive performance. The importance of preoperative cognitive status as a risk factor for negative postoperative outcomes in older patients is often overlooked. Cognitive assessment is rarely a part of the preoperative history and physical examination, and there are no widely accepted guidelines for such evaluation in surgical patients. However, preoperative cognitive deficits can have significant short- and long-term consequences in the postoperative period; preoperative cognitive deficits are the greatest risk factor for postoperative delirium and cognitive changes discovered postoperatively can persist for as long as 6 months after surgery. It is most important to recognize that a change in mental status in older patients following surgery is often the earliest

sign of a postoperative complication. Therefore, some form of assessment for mental status should be part of the routine postoperative evaluation. If an adequate preoperative cognitive evaluation has been conducted, postoperative assessment only requires brief observations of behavior and a comparison to baseline. There are several methods for evaluating baseline cognitive function. The Folstein Mini- Mental State Examination (MMSE) has traditionally been used because of its ease of administration and reliability. It has been suggested that the Mini-Cog test detects clinically significant cognitive impairment as well as, if not better than, the MMSE in multiethnic older individuals.27 It is easier to administer to non–English-speaking patients and is less biased by low education and literacy levels. The Mini-Cog test combines a three-item word learning and recall task (0 to 3 points; each correctly recalled word, 1 point), with a simple clock-drawing task (abnormal clock, 0 points; normal clock, 2 points) used as a distraction before word recall. Total possible Mini-Cog scores range from 0 to 5 points, with 0 to 2 suggesting high and 3 to 5 suggesting a low likelihood of cognitive impairment. Nutritional Status Surgeons recognize the value of optimal nutritional status to minimize perioperative mortality and morbidity. However, older patients are at particular risk for malnutrition and therefore at increased risk for adverse perioperative events. It remains imperative for surgeons to continue to assess nutritional status and attempt to correct malnutrition to achieve optimal results. Although this may be difficult in any patient, detection plus correction of malnutrition in older patients is crucial. The impact of poor nutrition as a risk factor for perioperative mortality and morbidity such as pneumonia and poor wound healing has long been appreciated. A variety of

Surgery in the Geriatric Patient Chapter 14 339

Recent Weight Loss Limited Ability to Get Food Immobility Poverty

Disinterest in Eating Depression Isolation Cognitive impairment Decreased appetite Decreased taste

Difficulty Eating Poor dentition Swallowing disorder GERD

Increased Gastrointestinal Losses Diarrhea Malabsorption

Systemic Diseases Chronic lung Liver Cardiac Renal Cancer

Drugs and Medications EtOH Suppressed appetite Block nutrient metabolism

psychosocial issues and comorbid conditions common to older adults place this population at high risk for nutritional deficits. Malnutrition is estimated to occur in approximately 0% to 15% of community-dwelling older persons, 35% to 65% of older patients in acute care hospitals, and 25% to 60% of institutionalized older adults. Factors that lead to inadequate intake and uptake of nutrients in this population include the ability to obtain food (e.g., financial constraints, availability of food, limited mobility), desire to eat food (e.g., living situation, mental status, chronic illness), ability to eat and absorb food (e.g., poor dentition, chronic gastrointestinal disorders such as GERD or diarrhea), and medications that interfere with appetite or nutrient metabolism (Box 14-7). In the frail older adult, a number of factors contribute to neuroendocrine dysregulation of the signals that control appetite and satiety and lead to what is termed the anorexia of aging. Although the anorexia of aging is a complex interaction of many interrelated events and systems, the result is chronic undernutrition and loss of muscle mass (sarcopenia). Malnutrition has also been associated with increased risk of falls and hospital admission. Measurement of nutritional status in older adults, however, is difficult. Standard anthropomorphic measures do not take into account the changes in body composition and structure that accompany aging. Immune measures of nutrition are influenced by age-related changes in the immune system in general. Furthermore, criteria for the interpretation of biochemical markers

in this age group have not been well established. Complicated markers and indices of malnutrition exist but are not necessary in the routine surgical setting. Subjective assessment by history and physical examination, in which risk factors and physical evidence of malnutrition are evaluated, has been shown to be as effective as objective measures of nutritional status. Several screening tools may be used, including the Subjective Global Assessment (SGA), Mini Nutritional Assessment (MNA), and Malnutrition Screening Tool (MST). The SGA is a relatively simple, reproducible tool for assessing nutritional status from the history and physical examination. SGA ratings are most strongly influenced by loss of subcutaneous tissue, muscle wasting, and weight loss. The SGA has been validated in older and critically ill patients, and has been related to the development of postoperative complications.28 The MNA, which measures 18 factors, including body mass index (BMI), weight history, cognition, mobility, dietary history, and self-assessment, is also a reliable method for assessing nutritional status. Nutritional status, as determined by the SGA and MNA, has been shown to predict outcome in outpatient and hospitalized geriatric medical patients. The MST is also a simple screening tool and has been validated in older patients in hospital and residential settings.29 Maintenance of adequate nutritional status in older residents of chronic residential facilities is improved with a nutritional coordinator program. The serum albumin level has been implicated as a strong predictor of outcome, both perioperative mortality and morbidity, in surgical patients. Recent evidence has demonstrated that low serum albumin levels in older patients correlate with increased length of stay, increased rates of readmission, unfavorable disposition, and increased all-cause mortality. In the Veterans Affairs NSQIP study (see earlier),23 a low serum albumin level was the most important predictive factor for mortality. This suggests that a low serum albumin level is a sensitive marker of outcome, regardless of whether it is directly related to poor nutritional status or to unidentified complex chronic illness; effects on outcome may correlate to a better extent with inflammation, at least in dialysis patients. More recently, albumin also has been shown to correlate with infection and in-hospital death. Although there is no definitive evidence from large randomized trials on preoperative nutritional restoration, amelioration of malnutrition with protein or immune-enhancing supplementation may improve outcome in some groups of older patients. Frailty

Although recognizing an individual who is frail may seem easy, defining the physiologic components that describe the frail phenotype has proven more difficult. Frailty is primarily a geriatric syndrome in which declines in reserves across many organ systems leave the individual with a decreased ability to respond to many stressors. The frail individual typically has loss of muscle mass (sarcopenia), chronic undernutrition, weakness, and decreased exercise tolerance. For study purposes, the frail phenotype is currently defined by five characteristics: weight loss, weak grip strength, self-reported exhaustion, slow walking speed, and low energy expenditure.30 The presence of frailty is associated with many poor health outcomes, such as falls, disability, hospitalization, and death. Recent evidence has also suggested that frailty in surgical patients independently predicts higher postoperative complication rates,

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BOX 14-7 Factors Associated With Increased Risk of Malnutrition

340 SECTION II PERIOPERATIVE MANAGEMENT longer lengths of stay, and more frequent discharges to nursing facilities. The degree of frailty also predicts the magnitude of the increased risk with those classified as frail (four or five characteristics) having worse outcomes than those classified as intermediately frail (two or three characteristics).31 SPECIFIC POSTOPERATIVE COMPLICATIONS Although older surgical patients with comorbid disease are at higher risk for many of the same surgical complications that occur in patients of all ages, several serious complications are more specific to this age group. These likely reflect an overall decline in physiologic capacity and reserve. Delirium Delirium, a disturbance of consciousness and cognition that presents over a short period of time, with a fluctuating course, is among the most common and potentially devastating postoperative complication seen in older patients. Postoperative delirium is associated with higher rates of morbidity (30 days) and mortality (6 months), longer intensive care unit (ICU) length of stay, longer hospital length of stay, higher rates of institutionalization after discharge, and higher overall hospital costs.32 The incidence of postoperative delirium in older patients varies with the type of procedure: less than 5% after cataract surgery, 35% after vascular surgery, and 40% to 60% after hip fracture repair. The incidence in older patients requiring treatment in an ICU is over 50%. Postoperative delirium is usually the result of an interaction between preexisting conditions (risk factors) and postoperative events or complications (precipitating factors). The onset of delirium maybe the first indication of a serious postoperative complication. Identifying risk factors preoperatively, and minimizing precipitating factors intraoperatively and postoperatively, is currently the best strategy to prevent delirium (Table 14-4).

Table 14-4 Risk Factors and Precipitating Factors for Delirium RISK FACTORS

PRECIPITATING FACTORS

Advanced age

Infection

Cognitive impairment

Medications

Functional impairment

Hypoxemia

Poor nutrition

Electrolyte abnormalities

Comorbidity

Under treated pain

Alcohol abuse

Neurologic events

Psychotropic medications

Dehydration

Sensory impairment

Sensory deprivation

Type of surgery

Sleep disruption

Severe illness

Use of bladder catheters Unfamiliar environment Use of physical restraints

Adapted from Lagoo-Deenadayalan SA, Newell MA, Pofahl WE: Common perioperative complications in older patients. In Rosenthal RA, Zenilman ME, Katlic MR (eds): Principles and practice of geriatric surgery, ed 2, New York, 2011, Springer, pp 361–376.

Risk Factors

The most important risk factor for postoperative delirium in older patients is a preexisting cognitive deficit, so some form of cognitive assessment is an essential part of the preoperative workup. Other risk factors include poor functional status, undernutrition or malnutrition, serious coexisting illness, sensory deficits, depression, alcohol consumption, preoperative psychotropic drug use, severity of illness, and magnitude of surgical stress. In a large prospective study of patients older than 50 years undergoing elective, noncardiac surgery, Marcantonio and coworkers33 have determined the relative importance of some of these factors in predicting delirium and developed a quantitative predictive rule to identify patients at risk. Precipitating Factors

Precipitating factors for delirium in the postoperative setting include common postoperative complications (e.g., hypoxia, sepsis, metabolic disturbances), untreated or undertreated pain, medications (e.g., certain antibiotics, analgesics, antihypertensives, beta blockers, benzodiazepines), situational issues (e.g., unfamiliar environment, immobility, loss of sensory assist devices such as glasses and hearing aids), use of bladder catheters and other indwelling devices or restraints, and disruption of the normal sleep-wake cycle (e.g., medications and treatments given during usual sleep hours). No association has been found with the route of anesthesia (epidural versus general) or the occurrence of intraoperative hemodynamic complications. However, intraoperative blood loss, need for blood transfusion, and postoperative hematocrit level lower than 30% are associated with a significantly increased risk for postoperative delirium. Although delirium is common in older patients following surgery, the diagnosis is frequently not appreciated. Agitation and confusion are usually recognized but depressed levels of consciousness may also be present. The Confusion Assessment Model (CAM) developed by Wei and colleagues34 is a simple, well-validated tool to diagnose delirium. A positive CAM requires the following: (1) acute onset with waxing and waning course and (2) inattention, with (3) disordered thinking or (4) altered level of consciousness. The best treatment for delirium is prevention. Strategies that focus on maintaining orientation (e.g., family at the bedside, sensory devices available), encouraging mobility, maintaining normal sleep-wake cycles (no medications during sleep hours), and avoiding dehydration and inappropriate medications have been shown to decrease the number and duration of episodes of delirium in hospitalized patients.35 Pharmacologic prevention trials have not yet shown consistently positive results. Once delirium is diagnosed, a thorough search for precipitating factors such as infections, hypoxia, metabolic disturbances, inappropriate medications, and undertreated pain should be conducted. Invasive devices and catheters should be removed as soon as possible and restraints should be avoided. A thorough review of the history should also be conducted and the family queried about possible predisposing factors, such as unrecognized alcohol consumption. Aspiration Aspiration is a common cause of morbidity and mortality in older patients in the postoperative period. The incidence of

Surgery in the Geriatric Patient Chapter 14 341

Incidence of aspiration pneumonia (%)

Table 14-5 Organ System Effects of Bed Rest

2.5 2 1.5

SYSTEM

EFFECT

Cardiovascular

↓ Stroke volume, ↓ cardiac output, orthostatic hypotension

Respiratory

↓ Respiratory excursion, ↓ oxygen uptake, ↑ potential for atelectasis

Muscles

↓ Muscle strength, ↓ muscle blood flow

Bone

↑ Bone loss, ↓ bone density

Gastrointestinal

Malnutrition, anorexia, constipation

Genitourinary

Incontinence

Skin

Sheering force, potential for skin break down

Psychological

Social isolation, anxiety, depression, disorientation

1 0.5 0 20s

30s

40s

50s

60s

70s

80+

Age group (in years) FIGURE 14-10 There is almost an exponential increase in postoperative aspiration pneumonia with increasing age. (From Kozlow JH, Berenholtz SM, Garrett E, et al: Epidemiology and impact of aspiration pneumonia in patients undergoing surgery in Maryland, 1999-2000. Crit Care Med 31:1930–1937, 2003.)

postoperative aspiration pneumonia increases almost exponentially with increasing age, with patients older than 80 years having a 9- to 10-fold greater risk than those 18 to 29 years of age (Fig. 14-10).36 Swallowing is a complex, coordinated interaction of many neuromuscular events. As many as one third of independent functioning older persons report some difficulty with swallowing. With age, there is a decline in several of the elements of normal swallowing that predispose to aspiration. These include loss of teeth, decrease in the strength of the muscles of mastication, slowing of the swallow time, decreased laryngopharyngeal sensation, and decreased cough strength. Poor oral hygiene and the edentulous state are also associated with an overgrowth of pathologic organisms, which predispose to pneumonia following aspiration. In general, other risk factors for aspiration in older patients can be categorized as disease- related (e.g., stroke, dementia, neuromuscular disorders such as Parkinson’s disease, GERD), medication-related (e.g., drugs that cause dry mouth or altered mental status), and iatrogenic factors. The last of these is particularly relevant to surgical patients. The presence of devices crossing the oropharynx (e.g., nasogastric tubes [NG], endotracheal tubes [ET], esophageal thermometers, transesophageal echocardiographic [TEE] probes), has been shown to disrupt the swallowing mechanism further. The need for prolonged intubation is associated with swallowing dysfunction and aspiration, as is the use of enteral feeding tubes. The routine use of NG tubes in patients undergoing colon resection has been correlated with an increased risk of aspiration pneumonia, as has the use of TEEs in patients undergoing cardiac surgery. The occurrence of postoperative ileus also predisposes to aspiration. Aspiration risk should be assessed preoperatively in all older patients with risk factors for aspiration and in those with any report of a swallowing abnormality (see earlier, “Preoperative Assessment”). Aspiration precautions should be ordered for any patient thought to be at risk. These include 30- to 45-degree upright positioning, careful evaluation of gastrointestinal function prior to starting feeding and frequently thereafter, careful monitoring of gastric residuals in patients with feeding tubes,

From Kleinpell RM, Fletcher K, Jennings BM: Reducing functional decline in hospitalized elderly. In Hughes RG (ed): Patient safety and quality: An evidence-based handbook for nurses, AHRQ Publ No. 08-0043, Rockville, MD, 2008, Agency for Healthcare Research and Quality, pp 251–265.

and upright position during meals and for 30 to 45 minutes after meals in those on an oral diet. Deconditioning In older patients, the prolonged period of immobility that follows hospitalization for a major surgical procedure often results in functional decline and overall deconditioning. Functional decline has been observed after as little as 2 days of immobility. Deconditioning is a distinct clinical entity, characterized by specific changes in function of many organ systems (Table 14-5).37 Deconditioned individuals have ongoing functional limitations, despite improvement in the original acute illness. The period for functional recovery may be as much as three times longer than the period of immobility. Prolonged bed rest also leads to other postoperative complications, such as pressures ulcers and falls. A major risk factor for deconditioning during hospitalization is a preexisting functional limitation. For example, patients requiring ambulation assist devices such as canes or walkers prior to hospitalization are more likely to suffer significant further functional decline. Other less obvious functional limitations, such as the inability to perform activities such as walking up a flight of steps carrying a bag of groceries (4 METs), are also associated with higher rates of postoperative complications and greater chances of functional decline. Other risk factors include two or more comorbidities, five or more medications, and a hospitalization or emergency room visit in the preceding year.37 Patients who develop delirium while in the hospital are also at greater risk of developing serious functional decline and of requiring placement in short-term rehabilitation or long-term care facilities. Assessment of functional capacity is an essential part of the preoperative assessment (see earlier). In patients identified at risk for functional decline, a plan for early directed methods to promote mobility, including early physical therapy consultation, should be establish prior to surgery. The “out of bed” order may be the most important of all routine postoperative orders for older patients.

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342 SECTION II PERIOPERATIVE MANAGEMENT Structured models for the in-hospital care of geriatric patients have been developed for patients hospitalized for medical illnesses. Adaptation of these models for surgery patients could promote improvements in functional and cognitive status. Preoperative conditioning to improve function prior to surgery, termed prehabilitation or prehab, has theoretical merit, although evidence to support its usefulness is still lacking. SURGERY OF MAJOR ORGAN SYSTEMS Endocrine Surgery Thyroid Disease

Hypothyroidism occurs in 10% of women and 2% of men older than 60 years; hyperthyroidism occurs in 0.5% to 6% of persons older than 55. Hypothyroidism is caused by autoimmune disease, previous radioablation or surgery, and drugs that interfere with the synthesis of thyroid hormone, such as amiodarone. Hyperthyroidism is usually caused by toxic multinodular goiter, with Graves’ disease being less common than in younger persons. Medical treatment of hypothyroidism in older adults is similar to that in younger patients. Surgical treatment of hyperthyroidism may be necessary for large goiters compressing the trachea. It is most important to remember that as with disorders of many other organ systems, symptoms of hypothyroidism and hyperthyroidism in this age group are easily overlooked or attributed to other causes. Failure to recognize the presence of either can result in serious perioperative problems. The incidence of thyroid nodules increases throughout life, whether detected by physical examination, ultrasound, or autopsy, although physical examination is less sensitive because of fibrosis of the soft tissues of the neck and the gland. The incidence of nodules in autopsy series is 50%. Thyroid nodules are four times more common in females, but the risk for cancer in a nodule is higher in males. Most thyroid nodules are single when detected. Thyroid nodules change slowly over the short term. Prospective studies have shown, however, that up to 25% of colloid nodules can shrink over a period of 2 to 3 years and may disappear. Well-differentiated thyroid cancer is divided into papillary and follicular subtypes. Sporadic papillary thyroid cancer has an almost bell-shaped distribution of age at diagnosis, with a decreasing trend in patients older than 60 years. Age is a negative prognostic factor for survival and other outcomes; patients older than 60 years have an increased risk for local recurrence, and patients younger than 20 and older than 60 have a higher risk for the development of distant metastasis. Similar results have been noted for follicular cancer. Increasing patient age correlates with increased risk for death by approximately twofold over a span of 20 years. Guidelines for the management of thyroid nodules and well-differentiated cancers can be found in the 2006 report of the American Thyroid Associations Guidelines Task Force.38 When thyroidectomy is indicated, it can usually be performed safely, even in patients much older than 80 years. However, older age does confer a higher risk of complications, longer hospital stays, more likely discharge to a location other than home, and higher rate of perioperative mortality. Surgical outcomes in older patients with multiple comorbidities have been shown to be better when the operative volume of the surgeon is more than 30 thyroidectomies/year.

Parathyroid Disease

The incidence of primary hyperparathyroidism increases with age; it affects approximately 2% of older persons, with a 3 : 1 female preponderance (1 in 1000 postmenopausal women). The disease is characterized by elevated serum calcium levels, often within 1 mg of normal, in the presence of elevated parathyroid hormone (PTH) to levels 1.5 to 2.0 times normal. Most cases in older adults are solitary adenomas. Until the 1970s, the disease was often symptomatic with nephrolithiasis (stones), overt skeletal disease (bones), and neuropsychiatric complaints (psychic groans) on presentation. With the advent of routine calcium testing as part of automated chemistry analysis, this pattern has changed, and now 80% of cases are asymptomatic. A careful history, however, will frequently reveal the presence of less obvious psychological and emotional symptoms. Other subtle symptoms in older persons include memory loss, personality changes, inability to concentrate, exercise fatigue, and back pain. Several studies have shown that only 5% to 8% of patients are truly asymptomatic. In response to the controversy regarding treatment of asymptomatic hyperparathyroidism, the National Institutes of Health (NIH) consensus conference in 1990 offered parameters for care. Participants agreed that truly asymptomatic patients, with serum calcium levels only mildly elevated, no previous history of life-threatening hypercalcemia, and normal renal, bone, and mental status, can be safely observed without surgery. Patients with CrCl decreased by 30% over age-matched controls, 24-hour urinary calcium excretion of more than 400 mg, and decreased bone mass more than 2 standard deviations (SDs) from age- and race-matched controls are offered surgical treatment. Further indications for surgery include primary hyperparathyroidism in patients younger than 50 years and hyperparathyroidism in patients for whom close follow-up would be difficult or for whom significant concomitant illness complicates management. At a more recent NIH workshop in 2002, a panel reconsidered therapy for asymptomatic primary hyperparathyroidism. The threshold for parathyroidectomy was reduced to include patients with a serum calcium level more than 1 mg/dL above the upper limits of normal. This definition still leaves uncertain whether weakness and depression indicate symptomatic disease, although approximately 40% of patients with hyperparathyroidism have one or both complaints. Because the risk for morbidity and mortality associated with surgery is low, even in older patients, parathyroidectomy remains the treatment of choice unless other comorbid conditions preclude surgery. Minimally invasive parathyroid surgery has gained acceptance with the adoption of sestamibi-directed surgery, intraoperative parathyroid hormone (PTH) assay, and videoscopic surgery. Cure rates in patients older than 70 years at one center have risen from 84% in the pre–minimally invasive era (before 2001) to 98% after the introduction of radioguided minimally invasive surgery under regional anesthesia.39 Breast Disease Epidemiology Increasing age is a major risk factor for developing

breast cancer. Worldwide, almost one third of breast cancer cases occur in patients older than 65 years. In the United States, more than 50% of new cases of breast cancer and approximately two thirds of breast cancer–related deaths occur in patients older than 65 years. Breast cancer incidence increases with age, peaking

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Presentation and Screening The presentation of breast cancer is

similar in older and younger populations. The painless mass represents the most common symptom of breast cancer. In older women, a new breast lump is likely to represent a malignancy. Breast pain, skin thickening, breast swelling, or nipple discharge or retraction should be vigorously pursued with biopsy in older women. Breasts become less dense with aging, making the clinical examination easier in older women. This difference also translates into an improved positive predictive value of an abnormal mammogram in women older than 65 years. The American Cancer Society recommends monthly breast self-examination, annual clinical breast examination, and annual mammography beginning at age 40, with no upper age limit as long as a woman remains in good health. If a woman’s life expectancy is estimated to be less than 3 to 5 years, has severe functional limitations, or has multiple comorbidities that are likely to impair survival, discontinuation of screening is appropriate. The American Geriatrics Society Position Statement recommends annual or at least biennial mammography to age 75 years. Beyond the age of 75, mammography should be biennial or at least every 3 years if life expectancy is more than 4 years.41

Pathology and Treatment Overview Overall, breast cancers in older patients tend to be associated with more favorable pathologic prognostic factors. As patients’ ages increase, their breast tumors are associated with more favorable tumor biology, as indicated by increased hormone sensitivity, attenuated epidermal growth factor receptor 2 (erb-b2) overexpression, and lower grades and proliferative indices. However, older patients are more likely to present with larger and more advanced tumors, and recent reports have suggested that the involvement of lymph nodes increases with age. Despite these differences, stage per stage, survival for older women with breast cancer is similar to that seen in younger women. Older women are less likely to receive definitive surgery, breast-conserving surgery, postlumpectomy radiotherapy, adjuvant hormonal therapy, and adjuvant chemotherapy. Breast cancer trials in the United States have a disproportionately low enrollment of older women. Women 65 years and older are less likely than stage- and physician-matched younger women to be offered participation in breast cancer trials. Therefore, most recommendations for the treatment of older women with breast cancer have been derived from studies done in women younger than 70 years. Unlike the treatment of younger women with breast cancer, a central concept in decision making in older patients with breast cancer is that of life expectancy. Accurate predictions and knowledge of life expectancy are inherently important in decisions regarding screening older populations using mammography, treatment of the primary lesion, and use of systemic adjuvant therapy. Currently available treatment options often carry short-term risks and toxicities in older women that are not mitigated by long-term survival gains. Surgery Surgical resection of the primary tumor is recommended for all older patients unless they are poor surgical candidates, and breast-conserving therapy should be recommended

when possible. Despite evidence that age is not a contraindication to breast-conserving surgery, older women have historically had lower rates of breast-conserving cancer surgery than younger women. Recent studies have indicated that the proportion of older women undergoing breast-conserving therapy is increasing. Omitting surgery exposes patients to a higher risk of local relapse and therefore is considered a suboptimal option, even for unfit older women. Tamoxifen alone had been previously recommended for the treatment of patients unfit for surgery and with short life expectancies, because tamoxifen antagonizes the estrogen receptor; in contrast to premenopausal women in whom the ovaries are responsible for estrogen production, the adrenal gland produces estrogen in postmenopausal women. Recent evidence42 has indicated that the response to aromatase inhibitors, which block the synthesis of estrogen, is higher than tamoxifen in the neoadjuvant setting. Therefore, these agents may be more effective primary treatment for unfit older patients. Aromatase inhibitors are also associated with less thromboembolic complications than tamoxifen; however, the use of aromatase inhibitors in patients with severe osteoporosis is cautioned. The role of axillary lymph node dissection (ALND) in the management of women with breast cancer has evolved over the last 10 to 15 years. ALND should be used when there is clinical suspicion of axillary lymph node involvement or a high-risk tumor. Biopsy of sentinel lymph nodes is a safe alternative to ALND in patients with clinically node-negative tumors. Older patients with tumor size smaller than 2 to 3 cm and no clinical evidence of axillary involvement should be offered a sentinel lymph node biopsy.40 Radiation Therapy For women 70 years of age or older who have early, estrogen-receptor–positive breast cancer, the addition of adjuvant radiation therapy to tamoxifen does not significantly decrease the rate of mastectomy for local recurrence, increase the survival rate, or increase the rate of freedom from distant metastases. Therefore, tamoxifen alone is a reasonable choice for adjuvant treatment in such women. For older women with small, node-negative tumors, the decision to include breast irradiation after lumpectomy should be made on a case-by-case basis after careful discussion of the risks of locoregional recurrence and the side effects of radiation therapy. Alternatively, partial-breast irradiation with multicatheter interstitial brachytherapy, balloon catheter brachytherapy, three dimensional conformal externalbeam radiotherapy, and intraoperative radiotherapy can be an option in selected older patients. Older women treated with mastectomy should be offered chest wall irradiation if they have tumors greater that 5 cm or more than four involved axillary lymph nodes.40 Chemotherapy Tamoxifen and aromatase inhibitors, such as anastrozole, improve overall survival, reduce local recurrence, and reduce the risk of contralateral breast cancer for hormonesensitive tumors in older women. Tamoxifen and anastrozole have side effects that can reduce their tolerance. Tamoxifen is associated with deep vein thrombosis, pulmonary emboli, cerebrovascular events, endometrial carcinoma, vagin*l discharge and bleeding, and hot flashes. There are considerably more musculoskeletal complaints, including arthralgias and fractures, with anastrozole. The added value of chemotherapy in older women who receive endocrine therapy is influenced greatly by

SECTION II PERIOPERATIVE MANAGEMENT

at age 75 and declining slightly thereafter. It is expected that as life expectancy continues to improve in Western countries, the proportion and absolute numbers of women with breast cancer will rise dramatically.40

344 SECTION II PERIOPERATIVE MANAGEMENT comorbidity and life expectancy. Models for estimating the benefits of chemotherapy in hormone receptor–positive older women have been developed, which demonstrate that a high risk of recurrence is needed to achieve a small survival benefit with adjuvant chemotherapy. For example, to reduce mortality risk at 10 years by 1% with chemotherapy, the risk of breast recurrence at 10 years has to be at least 25% for a 75-year-old woman in average health. These data suggest that chemotherapy for older women with hormone receptor–positive breast cancer should be offered only to node-positive patients who are in reasonable health, with a high risk of recurrence, and a life expectancy of more than 5 years. Older node-negative patients are unlikely to benefit from chemotherapy unless they have large hormone receptor–positive tumors with adverse pathologic characteristics or hormone receptor–negative tumors larger than 2 cm. An Internet based tool that incorporates age, health status, and tumor characteristics can help determine the potential benefit of adjuvant chemotherapy for breast cancer patients (http://www.adjuvantonline.com).40,41 Gastrointestinal Surgery Esophagus

The esophagus undergoes characteristic changes with aging. Dysfunction of the proximal aspects of swallowing is noted during normal aging. Resting upper esophageal sphincter pressure and relaxation are decreased in the older normal population compared with a younger control population. The duration of oropharyngeal swallowing and sensory threshold for initiating a swallow are increased with advancing age. These factors increase the risk of pharyngeal stasis and potential for aspiration. Dysmotility of the cricopharyngeus (upper esophageal sphincter) with increasing age can result in Zenker’s diverticulum (see Chapter 43). It appears that in normal healthy individuals, the physiologic function of the esophagus is preserved with increasing age, except for those older than 80 years. In the very old, the amplitude of esophageal contractions is decreased. It has been suggested that there is an association with GERD with the peristaltic dysfunction that occurs with aging. Although the lower esophageal sphincter resting pressure is normal and relaxes appropriately after deglutition, the sphincter fails to contract rapidly back to baseline, resulting in prolonged decreased tone. There is also an increased incidence of sliding hiatal hernia with aging, likely caused by laxity at the gastroesophageal junction. These conditions, in addition to delayed gastric emptying in older patients, predispose them to GERD. It is also important to remember that many medications prescribed for older patients increase the relaxation of the lower esophageal sphincter.43 The complications of GERD, including erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma, are seen with an increased frequency in older patients. However, recent studies have demonstrated that symptoms may be attenuated in older adults. Specifically, older patients with severe esophagitis are least likely to have severe heartburn. Instead, they present with more nonspecific symptoms, such as dysphagia, anorexia, anemia, weight loss, and vomiting.32 This absence of classic symptoms may be the result of an age-related decreased esophageal sensitivity to pain. Therefore, more aggressive diagnosis and/ or treatment of GERD may be warranted for older patients, regardless of their presenting symptoms. The success of laparoscopic Nissen fundoplication for the correction of GERD in

FIGURE 14-11 Scout film for a CT scan showing a giant paraesophageal hernia with the entire stomach in the chest, rotated in an organoaxial direction.

older patients provides a viable alternative to lifelong medications, which may also be less effective in older patients. As many as 90% of older patients report relief of symptoms, particularly vomiting and aspiration, after a Nissen procedure. Paraesophageal hernias also increase with advancing age and can reach enormous size without symptoms (Fig. 14-11). In the past, the fear of gastric volvulus, with subsequent strangulation, mandated immediate repair of paraesophageal hernias, even in the absence of symptoms. Watchful waiting is recommended, rather than immediate surgery for asymptomatic hernias, with a 1.1% annual probability of requiring an emergency operation. Dysphagia is a frequent symptom in the older population that can cause significant problems in the perioperative period. Dysphagia in older adults can be divided into two categories— abnormalities affecting the neuromuscular mechanisms controlling movement of the tongue, pharynx, and upper esophageal sphincter (oropharyngeal dysphagia), and disorders affecting the esophagus itself (esophageal dysphagia). Causes of oropharyngeal dysphagia include stroke, Parkinson’s disease, myasthenia gravis, diabetes, carcinomas, Zenker’s diverticulum, and osteophytes. Causes of esophageal dysphasia can be divided into problems with motility, such as achalasia, diffuse esophageal spasm, and scleroderma, and structural problems, such as carcinoma, benign stricture, webs, and vascular compression. Esophageal resection remains the only established curative treatment for cancer of the esophagus and gastric cardia. A major problem is that the surgery required is extensive, with a considerable risk of complications. Although the short-term mortality

Surgery in the Geriatric Patient Chapter 14 345

Stomach

A progressive cephalad migration of the antral-fundic junction occurs with age. Studies have shown that between 25% and 80% of older persons have fasting achlorhydria. This is caused by progressive loss of parietal cells and decreased antral and serum concentrations of gastrin. Achlorhydria results in derangements in folate, iron, and vitamin B12 absorption.43 The incidence of peptic ulcer disease increases with age. Up to 80% of peptic ulcer–related deaths occur in patients older than 65 years. Other factors that increase the risk of peptic ulcer disease in older adults are the use of nonsteroidal antiinflammatory drugs (NSAIDs) and infection with Helicobacter pylori. NSAID use has increased markedly over the past few years, especially in older adults. The use of NSAIDs increases the risk of developing complicated peptic ulcer disease in older when compared with younger patients. Actual NSAID use is also a useful prognostic indicator; the mortality rate from peptic ulcer disease in older patients who take NSAIDs is twice that of those who do not. Similarly, 80% of all ulcer-related deaths are in patients taking NSAIDs. Despite this finding, NSAIDs are frequently prescribed to older patients, even those with previous gastrointestinal problems. H. pylori infections are believed to occur at a rate of 1%/year, yielding a substantial percentage of older adults harboring infections. Older patients typically present for surgical correction of peptic ulcer disease in a delayed fashion and with more advanced disease. This translates to statistically significant increases in operative mortality for older patients undergoing surgery for complicated peptic ulcer disease. Age alone has not been shown to be an independent predictor of surgical risk. Multivariate analysis reveals three risk factors for operative mortality in perforated ulcer—the presence of concomitant disease, preoperative shock, and more than 48 hours of perforation. Age, amount of peritoneal soilage, and length of history of ulcer disease do not appear to be significant risks. The incidence of gastric cancer rises progressively with age, with most patients between the ages of 50 and 70 years at presentation. Risks include dietary (e.g., pickled vegetables, salted fish, nitrates, nitrites), occupational (e.g., metal, asbestos, rubber workers), and geographic (Asia versus Western Hemisphere) factors. Chronic atrophic gastritis, previous gastric surgery, and chronic H. pylori infection, more frequently found in older patients, are associated with an increased risk of gastric cancer. Chronic atrophic gastritis and H. pylori infection are also risk factors for gastric lymphoma and its precursor, mucosalassociated lymphoid tissue. These patients typically present in the sixth decade of life. The presentation of gastric cancer is changing in older persons, leading to the need for more aggressive surgery. Older patients present with a predominance of intestinal type tumors rather than the more aggressive diffuse

type. There is also a progression of the location of the tumor to more proximal areas of the stomach. As a result, total gastrectomy for cure in this population is now required in 13% to 34% of cases. No difference in resectability or the rate of positive lymph nodes found at surgery (60% to 70%) has been noted between younger and older patients.45 Biliary Tract Disease

In almost all populations, and both genders, the prevalence of gallstones increases with increasing age, although the magnitude of this increase varies with the population. It is not surprising, therefore that biliary tract disease is the single most common cause of acute abdominal complaints in patients older than 65 years in the United States and accounts for approximately one third of all abdominal surgeries in this age group. In 2006, persons older than 65 years accounted for 50% of the hospital discharges for primary diagnosis cholelithiasis and one third of the over 400,000 inpatient cholecystectomies performed that year. The increased frequency of gallstones in older adults is thought to result from changes in the composition of bile and impaired biliary motility. Alterations in the composition of bile with advancing age include an increase in the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA, the ratelimiting enzyme in the synthesis of cholesterol) and a decrease in the activity of 7α-hydroxylase (the rate-limiting enzyme in the synthesis of bile salts from cholesterol). This results in the supersaturation of bile with cholesterol and a decrease in the primary bile salt pool. The ratio of secondary to primary bile salts also increases. It is postulated that these secondary bile salts promote cholesterol gallstone formation by enhancing cholesterol synthesis, increasing the protein content of bile, decreasing nucleation time, and increasing the production of specific phospholipids that are thought to affect the production of mucin. It has also been suggested that the increase in secondary bile salts in older adults may promote the recycling of bilirubin, which in turn leads to the unconjugated bilirubin supersaturation necessary for pigment stone formation. Alterations in gallbladder motility and bile duct motility are thought to be central to the development of cholesterol and brown pigment stones, respectively. The role of motility in black pigment stone formation, however, is less clear. Biliary motility is a complex interaction of hormonal and neural factors, but the major stimulus for gallbladder emptying is cholecystokinin (CCK). The sensitivity of the gallbladder wall to CCK has been shown to decrease with increasing age in animal models. In humans, gallbladder sensitivity to CCK is also decreased. However, there is a compensatory increase in the production of CCK in response to a stimulus that results in normal gallbladder contraction. The significance of this observation with regard to gallstone formation, however, is undetermined. The indications for treatment of gallstone disease in older persons are the same as in younger patients, although complications of the disease, rather than biliary colic, are more common in those of advanced age. Older patients admitted to the hospital for cholecystectomy are more likely to have multiple biliary diagnoses, carry a concomitant diagnosis of cholangitis, undergo open operation, and require additional procedures such as endoscopic retrograde cholangiopancreatography (ERCP) or CBD exploration. The increased rate of complicated disease seen in older patients may be attributable to the increased severity of

SECTION II PERIOPERATIVE MANAGEMENT

has decreased in recent years, the complication rate remains high. Recent studies have suggested that survival after resection of esophageal cancer is improving; however, this is may be partly the result of detection and treatment of earlier stage tumors. It appears that there is no difference in surgical complication rates between younger and older esophagectomy patients; however, overall morbidity and mortality rates are higher in older patients. This is most likely because of an increase in cardiopulmonary complications seen in the older age group undergoing esophageal resection.44

346 SECTION II PERIOPERATIVE MANAGEMENT prelaparoscopic era, bile duct stones were addressed at the time of cholecystectomy. Although open CBD exploration was extremely successful in clearing the bile duct of stones, it was associated with a significant increase in operative mortality and morbidity over simple cholecystectomy alone. Most clinicians now agree that if CBD stones are suspected from a dilated duct on ultrasound or from abnormal liver or pancreatic test results, a preoperative attempt at sphincterotomy and extraction via endoscopic retrograde cholangiopancreatography should be carried out. Successful duct clearance by this approach is reported in more than 90% of cases. Recurrence of CBD stones after sphincterotomy, however, even with antecedent or subsequent cholecystectomy, is higher in older than in younger patients (20% versus 4%). Risk factors for recurrence include a dilated CBD, duodenal diverticulum, angulation of the CBD, and previous cholecystectomy. Management of the gallbladder after successful endoscopic treatment of CBD stones in patients without coincident acute cholecystitis is still controversial. Several studies have indicated that a complication related to the gallbladder will eventually develop in 4% to 24% of patients managed by endoscopic sphincterotomy alone and that 5.8% to 18% will require subsequent cholecystectomy. Unfortunately, because patients managed in this fashion are frequently the oldest and frailest patients, the mortality related to subsequent acute cholecystitis in these patients can be as high as 25%. Special consideration must be given to the treatment of gallstones found at the time of laparotomy for an unrelated condition. The addition of cholecystectomy to the primary procedure usually adds little increased morbidity or mortality. Although some controversy still exists, many surgeons would proceed with incidental cholecystectomy if the patient were stable, exposure was appropriate, and the cholecystectomy added

the disease, an increased prevalence of comorbid illnesses, or both. However, it is more likely to be a combination of factors, including delays in diagnosis and treatment caused by the frequent absence of typical biliary tract symptoms. Biliary colic, or episodic right upper quadrant pain radiating to the back, precedes the development of a complication only half as often in older as in younger patients. Even in the presence of acute cholecystitis, as many as 25% of older patients may have no abdominal tenderness, one third have no elevation in temperature or WBC count, and up to 59% have no peritoneal signs in the right upper quadrant. Unfortunately, the outcome of biliary tract surgery in older patients hospitalized for treatment has not improved much over the past several decades. Older patients still have more complicated disease at the time of surgery, longer lengths of stay, higher rates of in-hospital mortality, and much higher rates of discharge to sites other than home (Fig. 14-12).46 Until predictors of impending complications other than symptoms are identified, improving the outcome of biliary tract disease in older adults will be difficult. Increased awareness of the atypical manifestations of gallstone-related illness in this age group is essential. Treatment of acute cholecystitis in older adults is somewhat controversial. Whereas considerable evidence supports the safety and efficacy of early laparoscopic cholecystectomy for acute cholecystitis in general, some authors favor percutaneous drainage, followed by delayed cholecystectomy, in older adults. Recent evidence has suggested that as many as 25% of older patients admitted to the hospital with a diagnosis of acute cholecystitis do not undergo cholecystectomy on the initial admission. However, readmission rates in this group are high, and 2-year survival is worse, even after adjustment for comorbidities and other patient risk factors.47 The presence of CBD stones increases the likelihood of postoperative complications and death. In the

p 2 to 3 cm in diameter) have a high recurrence rate if closed primarily and are repaired with a prosthesis.34 Recurrence rates vary between 10% and 50% and are typically reduced by more than 50% with the use of prosthetic mesh.35 Prosthetic material may be placed as an onlay patch to buttress a tissue repair, interposed between the fascial defect, sandwiched between tissue planes, or put in a sublay position. Depending on its location, several important properties of the mesh must be considered. Prosthetic Materials for Ventral Hernia Repair Synthetic Materials Various synthetic mesh products are available.

Desirable characteristics of a synthetic mesh include being chemically inert, resistant to mechanical stress while maintaining compliance, sterilizable, noncarcinogenic, inciting minimal inflammatory reaction, and hypoallergenic. The ideal mesh has yet to be defined. When selecting the appropriate mesh, the surgeon must consider the position of the mesh, whether it will be in direct contact with the viscera, and the presence or risk of infection. Mesh constructs can be classified based on weight of the material, pore size, water angle (hydrophobic or hydrophilic), and whether there is an antiadhesive barrier present. When placing a mesh in the extraperitoneal position without the risk of bowel erosion, a macroporous unprotected mesh is appropriate. Both polypropylene and polyester mesh have been successfully placed in the extraperitoneal position. Polypropylene mesh is a hydrophobic macroporous mesh that allows for the ingrowth of native fibroblasts and incorporation into the surrounding fascia. It is semirigid, somewhat flexible, and porous. Placing polypropylene mesh in an intraperitoneal position directly apposed to the bowel is avoided because of unacceptable rates of enterocutaneous fistula formation.36 Recently, lighter weight polypropylene mesh has been introduced to address some of the long-term complications of heavyweight polypropylene mesh. The definition of lightweight mesh was arbitrarily chosen at less than 50 g/m2, with heavyweight mesh weighing more than 80 g/m2. These lightweight mesh

SECTION X ABDOMEN

normal decussation of fibers from all three lateral abdominal muscles. Strangulation is unusual in most patients; however, strangulation or rupture can occur in chronic ascitic conditions. Small asymptomatic umbilical hernias barely detectable on examination need not be repaired. Adults who have symptoms, a large hernia, incarceration, thinning of the overlying skin, or uncontrollable ascites should have hernia repair. Spontaneous rupture of umbilical hernias in patients with ascites can result in peritonitis and death. Classically, repair was done using the vest over pants repair proposed by Mayo, which uses imbrication of the superior and inferior fascial edges. Because of increased tension on the repair and recurrence rates of almost 30% with long-term follow-up, however, the Mayo repair is rarely performed today. Instead, small defects are closed primarily after separation of the sac from the overlying umbilicus and surrounding fascia. Defects larger than 3 cm are closed using prosthetic mesh.33 There are a number of techniques to place this mesh and no prospective data have conclusively found clear advantages of one technique over another. Options for mesh implantation include bridging the defect, placing a preperitoneal underlay of mesh reinforced with suture repair, and placing it laparoscopically. The laparoscopic technique requires general anesthesia and is reserved for large defects or recurrent umbilical hernias.34 There is no universal consensus on the most appropriate method of umbilical hernia repair.

1132 SECTION X ABDOMEN

Table 46-2 Biologic Mesh for Abdominal Wall Reconstruction and Postharvesting Processing Techniques PRODUCT

SOURCE

CROSS-LINKED

STERILIZATION METHOD

Alloderm (Lifecell, Branchburg, NJ)

Human dermis

Ionic

Allomax (Davol, Warwick, RI)

Human dermis

E beam

Flex HD (Ethicon, Sommerville, NJ)

Human dermis

Ethanol

Strattice (Lifecell, Branchburg, NJ)

Porcine dermis

Gamma irradiation

Permacol (Covidien, Norwalk, CT)

Porcine dermis

Yes

Ethanol

Collamend (Davol, Warwick, RI)

Porcine dermis

Yes

Ethanol

Xenmatrix (Davol, Warwick, RI)

Porcine dermis

Gamma irradiation

Surgimend (TEI Biosciences, Boston, MA)

Bovine fetal dermis

Ethanol

Veritas (Synovis, St. Paul, MN)

Bovine

Periguard (Synovis, St. Paul, MN)

Bovine

Yes

Surgisis (Cook, Bloomfield, IN)

Porcine intestine

products often have an absorbable component of material that provides initial handling stability, typically composed of Vicryl (polyglactin 910) or Monocryl (poliglecaprone 25; Ethicon, Somerville, NJ). Whether lightweight mesh results in improved patient outcomes is controversial. Two prospective randomized trials evaluating the incidence of postoperative pain after open inguinal hernia repair have shown mixed results.37 In a randomized controlled trial evaluating lightweight versus heavy weight polypropylene mesh for ventral hernia repair, the recurrence rate was more than twice that in the lightweight group (17% versus 7% for heavyweight mesh), which approached statistical significance (P = .052).38 Polyester mesh is composed of polyethylene terephthalate and is a hydrophilic, heavyweight, macroporous mesh. This mesh has several different weaves that can yield a two-dimensional flat screen–like mesh and a three-dimensional multifilament weave. Unprotected polyester mesh should not be placed directly on the viscera because unacceptable rates of erosion and bowel obstruction have been reported.36 When placed in the preperitoneal position in complex ventral hernia repairs, complication rates are low.7,39 When placing mesh in an intraperitoneal position, several options are available. A single sheet of mesh with both sides constructed to reduce adhesions, or a composite-type mesh with one side made to promote tissue ingrowth and the other to resist adhesion formation, are available. Single-sheet mesh is composed of expanded PTFE (polytetrafluoroethylene). This prosthetic has a visceral side that is microporous (3 µm) and an abdominal wall side that is macroporous (17 to 22 µm) and promotes tissue ingrowth. This product differs from other synthetic meshes in that it is flexible and smooth. Some fibroblast proliferation occurs through the pores, but PTFE is impermeable to fluid. Unlike polypropylene, PTFE is not incorporated into the native tissue. Encapsulation occurs slowly and infection can occur during the encapsulation process. When infected, PTFE almost always must be removed. To promote better tissue integration, composite mesh was developed. This product combines the attributes of polypropylene and PTFE by layering the two substances on top of one another. The PTFE surface serves as a permanent protective

Ethanol

interface against the bowel and the polypropylene side faces superficially, to be incorporated into the native fascial tissue. These materials have variable rates of contraction and, when placed together, can result in buckling of the mesh and visceral exposure to the polypropylene component. Recently, other composite meshes have been developed that combine a macroporous mesh with a temporary, absorbable antiadhesive barrier. Basic constructs of these mesh materials include heavyweight or lightweight polypropylene, or polyester. Absorbable barriers are typically composed of oxidized regenerated cellulose, omega-3 fatty acids, or collagen hydrogels. A number of small animal studies have validated the antiadhesive properties of these barriers, but currently no human trials exist evaluating the ability of these composite materials to resist adhesion formation. Biologic Materials The newest development in prostheses for ventral hernia repair is nonsynthetic or natural tissue mesh. There are numerous biologic grafts available for abdominal wall reconstruction (Table 46-2). These products can be categorized based on the source material (e.g., human, porcine, bovine), postharvesting processing techniques (e.g., cross-linked, non– cross-linked) and sterilization techniques (e.g., gamma radiation, ethylene oxide gas sterilization, nonsterilized). These products are largely composed of acellular collagen and theoretically provide a matrix for neovascularization and native collagen deposition. These properties provide distinct advantages in infected or contaminated cases in which synthetic mesh is thought to be contraindicated. Ideal placement techniques are yet to be defined for these relatively new products; however, some general principles apply. These products function best when used as a fascial reinforcement rather than as a bridge or interposition repair.40 Unfortunately, the long-term durability of biologic mesh is currently unknown. There are no data comparing the effectiveness of these natural tissue alternatives with that of synthetic mesh repairs. Operative Technique Ventral Hernias It is generally agreed that all but the smallest

incisional hernias can be repaired with mesh, and the surgeon has various options for placing the mesh. The onlay technique involves primary closure of the fascia defect and placement of a

Hernias Chapter 46 1133

Intraperitoneal Mesh Placement After reopening the prior incision, and with the use of available dual-type mesh or composite mesh, the mesh can be placed in an intraperitoneal position at least 4 cm beyond the fascial margin and secured with interrupted mattress sutures. This technique requires raising subcutaneous flaps and the mesh may be in direct contact with the abdominal contents. The laparoscopic approach for ventral hernia repair relies on the same principles as the retrorectus repair; however, the mesh is placed within the peritoneal cavity. This repair is useful, particularly for large defects. Trocars are placed as far laterally as feasible based on the size and location of the hernia. The hernia contents are reduced and adhesions are lysed. The surface area of the defect is measured, and a barrier-coated mesh is fashioned with at least 4 cm of overlap around the defect. The mesh is rolled, placed into the abdomen, and deployed. It is secured to the anterior abdominal wall with preplaced mattress sutures that are passed through separate incisions; tacking staples are placed between these sutures to secure the mesh 4 cm beyond the defect. The advantage of this approach is a quicker recovery time. There are fewer incisional complications with the laparoscopic approach because large incisions and subcutaneous under mining are avoided. Retromuscular Mesh Placement This technique involves placing prosthetic mesh in the extraperitoneal position in the preperitoneal space or retrorectus position. This technique was initially described by Stoppa.7 A large piece of mesh is placed in the retromuscular space on top of the posterior rectus sheath or peritoneum. This space must be dissected laterally on both sides of the linea alba to a distance of 8 to 10 cm beyond the defect. The prosthetic mesh extends 5 to 6 cm beyond the superior and inferior borders of the defect. With smaller defects, the mesh does not need to be sutured because it is held in place by intraabdominal pressure (Pascal’s principle), allowing eventual incorporation into the surrounding tissues. Alternatively, in larger defects, the mesh can be secured laterally with several sutures. This approach avoids contact between the mesh and abdominal viscera and has been shown in long-term studies to have a

Mesh placement options

Inlay Mesh

Overlay

Underlay (intraperitoneal)

Retrorectus Posterior sheath and peritoneum can be approximated and closed with suture

Preperitoneal Peritoneum

Posterior rectus and peritoneal layer

Intermuscular FIGURE 46-11 Mesh placement options for abdominal wall reconstruction.

respectable recurrence rate (14%) in large incisional hernias. The retrorectus space is bordered laterally by the linea semilunaris. In very large hernias or in those patients with atrophic rectus muscles, this might prevent adequate mesh overlap. Alternatively, the preperitoneal plane can be accessed by incising the posterior rectus sheath approximately 1 cm medial to the linea semilunaris. Once the preperitoneal space is accessed, the dissection can be carried laterally to the psoas muscle, if necessary.42 Very large sheets of prosthetic mesh can be placed in this location with wide defect coverage. A retrospective review from the Mayo Clinic, with a median follow-up of 5 years, has documented a 5% overall hernia recurrence rate in 254 patients who underwent complex ventral hernia repair over a 13-year period.43 Component Separation Another option for the repair of complex

or large ventral defects is the component separation technique (Fig. 46-12). This involves separating the lateral muscular layers of the abdominal wall to allow their advancement. Primary

SECTION X ABDOMEN

mesh over the anterior fascia. The major advantage of this approach is that the mesh is placed outside the abdominal cavity, avoiding direct interaction with the abdominal viscera. However, disadvantages include the large subcutaneous dissection, increased likelihood of seroma formation, superficial location of the mesh, which places it in jeopardy of contamination if the incision becomes infected, and the repair is usually under tension. Prospective analysis of this technique is not available, but a retrospective review has reported recurrence rates of 28%.41 Interposition prosthetic repairs involve securing the mesh to the fascial edge without overlap. This results in a predictably high recurrence rate because the synthetic often pulls away from the fascial edge because of increased intra-abdominal pressure. A sublay or underlay technique involves placing the prosthetic below the fascial components. The mesh can be placed intraperitoneally, preperitoneally, or in the retrorectus (retromuscular) space. It is highly desirable to have the mesh placed beneath the fascia. With a wide overlap of mesh and fascia, the natural forces of the abdominal cavity act to hold the mesh in place and prevent migration. This can be accomplished using several techniques (Fig. 46-11).

1134 SECTION X ABDOMEN

1 2 3 4

3 2 1

3 4

1 2

3 4

1 2

FIGURE 46-12 Component separation technique. A, The skin and subcutaneous fat are dissected free from the anterior sheath of the rectus abdominis muscle and the aponeurosis of the external abdominal oblique muscle. B, The external abdominal oblique is incised 1 to 2 cm lateral to the rectus abdominis muscle. C, The external abdominal oblique is separated from the internal abdominal oblique. D, The dissection is carried to the posterior axillary line. E, Additional length can be achieved by incising the posterior rectus sheath above the arcuate line. F, Care must be taken to avoid damaging the nerves and blood supply that enter the rectus abdominis posteriorly. (deVries Reilingh TS, van Goor H, Rosman C, et al: Components separation technique for the repair of large abdominal wall hernias. J Am Coll Surg 196:32–37, 2003.)

fascial closure at the midline is often possible. The procedure is performed by raising large subcutaneous flaps above the external oblique fascia. These flaps are carried laterally past the linea semilunaris. This dissection itself can provide some advancement of the abdominal wall. Large perforating subcutaneous vessels can be preserved to prevent ischemic necrosis of the skin flaps. A relaxing incision is made 2 cm lateral to the linea semilunaris on the lateral external oblique aponeurosis from several centimeters above the costal margin to the pubis. The external oblique is then bluntly separated in the avascular plane, away from the internal oblique, allowing its advancement. Further relaxing incisions have been described to the aponeurotic layers of the internal oblique or transversus abdominis but this can result in problematic lateral bulges or herniation at this site. Additional release can be safely achieved by incising the posterior rectus sheath. These techniques, when applied to both sides of the abdominal wall, can yield up to 20 cm of mobilization. Although this technique often allows tension-free closure of these large defects, recurrence rates as low as 20% have been reported with the use of prosthetic reinforcement in large hernias.44 It is important that patients understand that a lateral bulge can occur after releasing the external oblique aponeurosis. Recognizing the high recurrence rates with component separation alone, several authors have reported small series of biologic mesh

reinforcement of these repairs.40 To date, no randomized controlled trials have supported a lower recurrence rate with biologic prosthetic reinforcement. If a bioprosthetic is placed, it can be secured with an underlay or onlay technique. No comparative data exist demonstrating the superiority of either repair technique.45 Endoscopic Component Separation One of the major limitations

of open component separation is that large skin flaps are necessary to access the lateral abdominal wall musculature. Recognizing these limitations, innovative, minimally invasive approaches to component separation have been described.46 The basic principle of a minimally invasive component separation is to gain direct access to the lateral abdominal wall without creating a lipocutaneous flap. Typically, this is performed by a direct cut down through a 1-cm incision off the tip of the 11th rib over lying the external oblique muscle (Fig. 46-13). The external oblique is split in the line of its fibers and a standard bilateral inguinal hernia balloon dissector is placed in between the external and internal oblique muscles, toward the pubis. Three laparoscopic trocars are placed in the space created and the dissection is carried from the pubis to several centimeters above the costal margin. The linea semilunaris is carefully identified and the external oblique is incised from beneath the muscle, at least

Hernias Chapter 46 1135

SECTION X ABDOMEN

Aponeurosis of external oblique

External oblique Dissecting balloon Rectus Transversus abdominis

Internal oblique

Cranial Aponeurosis Caudal Camera port

External oblique Instrument port

Rectus Transversus abdominis

Internal oblique

2 cm lateral to the linea semilunaris. The muscle is released from the pubis to several centimeters above the costal margin. This procedure is performed bilaterally. Synthetic or biologic mesh can be used to reinforce the repair of the midline closure. These relatively new techniques are feasible, but long-term data demonstrating equivalency to open techniques are lacking. Results of Incisional Hernia Repairs Several prospective randomized trials have compared laparoscopic and open ventral hernia repairs (Table 46-3).47-51 Although most of these studies were small, with fewer than 100 patients, the results tend to favor a laparoscopic approach. The incidences of postoperative complications and recurrence were less in hernias repaired laparoscopically. Several retrospective reports have demonstrated similar advantages for a laparoscopic approach. Based on the comparative trials listed in Table 46-3, laparoscopic incisional hernia repair results in fewer postoperative complications, lower infection rate, and decreased hernia recurrence.42-48 Until an appropriately powered prospective randomized trial is performed, the ideal approach will largely be based on surgeon expertise and preference. UNUSUAL HERNIAS There are a number of hernias that occur infrequently, of various types.

FIGURE 46-13 Endoscopic component separation: port placement and surgical technique.

Types Spigelian Hernia

A spigelian hernia occurs through the spigelian fascia, which is composed of the aponeurotic layer between the rectus muscle medially and semilunar line laterally. Almost all spigelian hernias occur at or below the arcuate line. The absence of posterior rectus fascia may contribute to an inherent weakness in this area. These hernias are often interparietal, with the hernia sac dissecting posterior to the external oblique aponeurosis. Most spigelian hernias are small (1 to 2 cm in diameter) and develop during the fourth to seventh decades of life. Patients often present with localized pain in the area without a bulge because the hernia lies beneath the intact external oblique aponeurosis. Ultrasound or CT of the abdomen can be useful to establish the diagnosis. A spigelian hernia is repaired because of the risk for incarceration associated with its relatively narrow neck. The hernia site is marked before operation. A transverse incision is made over the defect and carried through the external oblique aponeurosis. The hernia sac is opened, dissected free of the neck of the hernia, and excised or inverted. The defect is closed transversely by simple suture repair of the transversus abdominis and internal oblique muscles, followed by closure of the external oblique aponeurosis. Larger defects are repaired using a mesh prosthesis. Recurrence is uncommon.

127

Lomanto et al. (2006)49

31 39

233

PTFE or PP

PTFE

ePTFE

Polyester + collagen Polyester + collagen

ePTFE or polyester + collagen ePTFE, PP, or ePTFE

OPEN

Mesh Used LAP

Lap, Laparoscopic, LOS, length of stay; PP, polypropylene.

Asencio et al. (2009)60

Pring et al. (2008)

Olmi et al. (2007)47

Bingener et al. (2007)

McGreevy et al. (2003)48

STUDY (YEAR)

No. of Patients LAP OPEN

6.70

N/A

Intraoperative Complications (%) LAP OPEN

3.46

2.7

N/A

2.74

1.1

3.33

9.9

N/A

4.7

1.5

LOS (days) LAP OPEN

Table 46-3 Comparative Randomized Studies Between Open and Laparoscopic Ventral Hernia Repair

5.20

16.50

33.10

7.70

33.30

29.40

43.30

21.10

Postoperative Complications (%) LAP OPEN

19.6

N/A

Follow-up (mo) LAP OPEN

9.70

3.30

N/A

7.90

4.20

N/A

Recurrence (%) LAP OPEN

1136 SECTION X ABDOMEN

Hernias Chapter 46 1137

The obturator canal is formed by the union of the pubic bone and ischium. This canal is covered by a membrane pierced at the medial and superior border by the obturator nerve and vessels. Weakening of the obturator membrane may result in enlargement of the canal and formation of a hernia sac, which can lead to intestinal incarceration and strangulation. The patient can present with evidence of compression of the obturator nerve, which causes pain in the anteromedial aspect of the thigh (Howship-Romberg sign) that is relieved by thigh flexion. Almost 50% of patients with obturator hernia present with complete or partial bowel obstruction. An abdominal CT scan can establish the diagnosis, if necessary. A posterior approach, open or laparoscopic, is preferred. This approach provides direct access to the hernia. After reduction of the hernia sac and contents, any preperitoneal fat within the obturator canal is reduced. If necessary, the obturator foramen is opened posterior to the nerve and vessels. The obturator nerve can be manipulated gently with a blunt nerve hook to facilitate reduction of the fat pad. The obturator foramen is repaired with prosthetic mesh, taking care to avoid injury to the obturator nerve and vessels. Patients with compromised bowel usually require laparotomy. Lumbar Hernia

Lumbar hernias can be congenital or acquired after an operation on the flank and occur in the lumbar region of the posterior abdominal wall. Hernias through the superior lumbar triangle (Grynfeltt’s triangle) are more common. The superior lumbar triangle is bounded by the 12th rib, paraspinal muscles, and internal oblique muscle. Less common are hernias through the inferior lumbar triangle (Petit’s triangle), which is bounded by the iliac crest, latissimus dorsi muscle, and external oblique muscle. Weakness of the lumbodorsal fascia through either of these areas results in progressive protrusion of extraperitoneal fat and a hernia sac. Lumbar hernias are not prone to incarceration. Small lumbar hernias are frequently asymptomatic. Larger hernias may be associated with back pain. CT is useful for diagnosis. Both open and laparoscopic repairs are useful. Satisfactory suture repair is difficult because of the immobile bony margins of these defects. Repair is best done by placement of prosthetic mesh, which is sutured beyond the margins of the hernia. There is usually sufficient fascia over the bone to anchor the mesh. Interparietal Hernia

Interparietal hernias are rare and occur when the hernia sac lies between layers of the abdominal wall. These hernias most frequently occur in previous incisions. Spigelian hernias are almost always interparietal. The correct preoperative diagnosis of interparietal hernia can be difficult. Many patients with complicated interparietal hernias present with intestinal obstruction. Abdominal CT can assist in the diagnosis. Large interparietal hernias usually require placement of prosthetic mesh for closure. When this cannot be done, the component separation technique may be useful to provide natural tissues to obliterate the defect. Sciatic Hernia

The greater sciatic foramen can be a site of hernia formation. These hernias are extremely unusual and difficult to diagnose and frequently are asymptomatic until intestinal obstruction

occurs. In the absence of intestinal obstruction, the most common symptom is the presence of an uncomfortable or slowly enlarging mass in the gluteal or intragluteal area. Sciatic nerve pain can occur, but sciatic hernia is a rare cause of sciatic neuralgia. A transperitoneal approach is preferred if bowel obstruction or strangulation is suspected. Hernia contents can usually be reduced with gentle traction. Prosthetic mesh repair is usually preferred. A transgluteal approach can be used if the diagnosis is certain and the hernia is reducible, but most surgeons are not familiar with this approach. With the patient prone, an incision is made from the posterior edge of the greater trochanter across the hernia mass. The gluteus maximus muscle is opened, and the sac is visualized. The muscle edges of the defect are reapproximated with interrupted sutures or the defect is obliterated with mesh. Perineal Hernia

Perineal hernias are caused by congenital or acquired defects and are quite uncommon. These hernias may also occur after abdominoperineal resection or perineal prostatectomy. The hernia sac protrudes through the pelvic diaphragm. Primary perineal hernias are rare, occur most commonly in older multiparous women, and can be quite large. Symptoms are usually related to protrusion of a mass through the defect that is worsened by sitting or standing. A bulge is frequently detected on bimanual rectal-vagin*l examination. Perineal hernias are generally repaired through a transabdominal approach or combined transabdominal and perineal approaches. After the sac contents are reduced, small defects may be closed with nonabsorbable suture, whereas large defects are repaired with prosthetic mesh. Loss of Domain Hernias

Loss of domain implies a massive hernia in which the herniated contents have resided for so long outside the abdominal cavity that they cannot simply be replaced into the peritoneal cavity. We typically classify loss of domain hernias into patients with and without preoperative contamination. Each group is then subcategorized into two groups. Patients with a small hernia defect and a massive hernia sac (e.g., large inguinoscrotal hernias) require restoration of peritoneal cavity domain, whereas patients with a large defect and a massive hernia sac (open abdomen with skin graft) require restoration of peritoneal domain and reconstruction of the abdominal wall. Prior to repair of these complex defects, the patient must undergo careful preoperative evaluation. A clear understanding of the morbidity and mortality associated with these reconstructive procedures is critical. Weight reduction, smoking cessation, optimization of nutrition, and glucose control are all important aspects of complex abdominal wall reconstruction. Previously, methods to stretch the abdominal wall gradually were used to allow for the restoration of abdominal domain and closure. This was accomplished by insufflation of air into the abdominal cavity to create a progressive pneumoperitoneum. Repeated administrations of increasing volumes of air over 1 to 3 weeks allowed the muscles of the abdominal wall to become lax enough for primary closure of the defect. This technique is particularly suited for small defects and massive hernia sacs.52 For large defects, we prefer a staged approach using expanded PTFE (ePTFE) dual mesh for patients with loss of abdominal domain

SECTION X ABDOMEN

Obturator Hernia

1138 SECTION X ABDOMEN and lateral retraction of the abdominal wall musculature. The initial stage involves reduction of the hernia and placement of a large sheet of ePTFE dual mesh secured to the fascial edges with a running suture. Subsequent stages involve serial elliptical excision of the mesh until the fascia can be approximated in the midline without tension. Finally, the mesh is completely excised and the fascia is reapproximated with component separation and a biologic underlay patch, if necessary.53 Parastomal Hernia Repair Parastomal hernia is a common complication of stoma creation. In fact, the creation of a stoma by strict definition is an abdominal wall hernia. The incidence of parastomal hernias is highest for colostomies and occurs in up to 50% of stomas. Fortunately, most patients remain asymptomatic and life-threatening complications, such as bowel obstruction and strangulation, are rare. Unlike midline incisional hernia repair, routine repair of parastomal hernias is not recommended. Surgical repair should be reserved for patients experiencing symptoms of bowel obstruction, problems with pouch fit, or cosmetic issues. Three general approaches are available for parastomal hernia repair. These techniques include primary fascial repair, stoma relocation, and prosthetic repair. Primary fascial repair involves hernia reduction and primary fascial reapproximation through a peristomal incision. This technique carries a predictably high recurrence rate. The advantage of this approach is that the abdomen often is not entered, making the operation less complex. Because of the high recurrence rate with this technique, it should be reserved for patients who will not tolerate a laparotomy. Stoma relocation improves results; however, it requires a laparotomy and predisposes to another parastomal hernia in the future. To reduce the rate of recurrent herniation, some surgeons reinforce the repair with biologic mesh in a keyhole fashion around the new stoma site. Early results are promising but long-term outcomes have not yet been reported.54 Prosthetic repairs of parastomal hernias can provide excellent long-term results with a lower rate of hernia recurrence, but a higher rate of prosthetic complications must be accepted. Regardless of the technique, a permanent foreign body placed in apposition to the bowel can result in erosion, obstruction, and disastrous complications. Several approaches to prosthetic mesh placement have been described. The mesh can be placed as an onlay patch, intra-abdominally, or in the retrorectus position. When placing the mesh intraperitoneally, a keyhole is fashioned around the stoma site or placed as a flat sheet, lateralizing the stoma as it exits the abdomen, as described by Sugarbaker.55 Several authors have described laparoscopic approaches to parastomal hernia repair, including keyhole and Sugarbakertype repairs56,57 (Fig. 46-14). All these series are small and have reported only short-term follow-up, limiting our ability to make clear recommendations for this difficult problem. Complications Mesh Infection

Mesh infections are serious complications that can be difficult to treat. If ePTFE becomes infected, it requires removal with the resultant morbidity of another defect, which often must be closed under tension, leading to inevitable recurrence. In open ventral hernia repair, incisional and mesh infections are not infrequent. Using the laparoscopic technique and placing a large

A. Sugarbaker

Rectus Posterior sheath B. Keyhole

C. Reciting with mesh reinforcement

FIGURE 46-14 Surgical approaches for parastomal hernia repair.

piece of mesh without undermining large subcutaneous tissue flaps avoids wound complications. In a series of almost 1000 patients who had laparoscopic ventral hernia repair, mesh infections occurred in less than 1% of cases.58 Perhaps the greatest advantage of the laparoscopic approach for repairing ventral hernias is this reduction in infectious complications. Two randomized controlled trials have compared laparoscopic and open ventral hernia repair.59,60 Seromas

Seroma formation can occur after laparoscopic and open ventral hernia repair. In open ventral hernia repair, drains are often placed in an attempt to obliterate the dead space caused by the hernia and tissue dissection. These drains can cause mesh contamination and seromas can form after drain removal. With laparoscopic repair, the hernia sac is not resected and a seroma cavity will result. Most of these seromas will resolve over time as the mesh becomes incorporated on the hernia sac. Preoperative discussions with the patient describing the expectations of a temporary seroma are imperative before laparoscopic ventral hernia repair. We reserve aspiration for symptomatic or persistent seromas after 6 to 8 weeks. Enterotomy

Intestinal injury during adhesiolysis can be catastrophic. Management of an enterotomy during a hernia repair is controversial and depends on the segment of intestine injured (small versus large bowel) and amount of spillage. Options include aborting the hernia repair, using a primary tissue or biologic tissue repair, and performing a delayed repair using prosthetic mesh in 3 to 4 days. When there is gross contamination, the use of synthetic mesh is contraindicated. SELECTED REFERENCES Anson BJ, McVay CB: Inguinal hernia: The anatomy of the region. Surg Gynecol Obstet 66:186–191, 1938. Condon RE: Surgical anatomy of the transversus abdominis and transversalis fascia. Ann Surg 173:1–5, 1971.

Hernias Chapter 46 1139

These three references are classic descriptions of the anatomy of the groin. All are well illustrated.

Bisgaard T, Bay-Nielsen M, Kehlet H: Re-recurrence after operation for recurrent inguinal hernia. A nationwide 8-year follow-up study on the role of type of repair. Ann Surg 247:707–711, 2008. This long term population-based study provides useful information about the results of recurrent inguinal hernia repairs.

de Vries Reilingh TS, van Goor H, Charbon JA, et al: Repair of giant midline abdominal wall hernias: “Components separation technique” versus prosthetic repair: Interim analysis of a randomized controlled trial. World J Surg 31:756–763, 2007. This is a prospective randomized trial evaluating outcomes of open ventral hernia repair with synthetic mesh versus component separation without reinforcement.

Forbes SS, Eskicioglu C, McLeod RS, et al: Meta-analysis of randomized controlled trials comparing open and laparoscopic ventral and incisional hernia repair with mesh. Br J Surg 96:851–858, 2009. This is a meta-analysis evaluating eight prospective randomized trials comparing laparoscopic with open ventral hernia repair.

Itani KM, Hur K, Kim LT, et al: Veterans Affairs Ventral Incisional Hernia Investigators: Comparison of laparoscopic and open repair with mesh for the treatment of ventral incisional hernia: A randomized trial. Arch Surg 145:322–328, 2010. This is a prospective randomized trial evaluating laparoscopic versus open ventral hernia repairs.

Neumayer L, Giobbie-Hurder A, Jonasson O, et al: Open mesh versus laparoscopic mesh repair of inguinal hernia. N Engl J Med 350:1819– 1827, 2004. Excellent prospective randomized trial comparing these two types of hernia repairs in Veterans Administration hospitals.

Zhao G, Gao P, Ma B, et al: Open mesh techniques for inguinal hernia repair: A meta-analysis of randomized controlled trials. Ann Surg 250:35–42, 2009. Excellent meta-analysis of various techniques of tension-free repairs.

REFERENCES 1. Bradley M, Morgan D, Pentlow B, et al: The groin hernia—an ultrasound diagnosis? Ann R Coll Surg Engl 85:178–180, 2003. 2. Della Santa V, Groebli Y: [Diagnosis of non-hernia groin masses.] Ann Chir 125:179–183, 2000. 3. Fitzgibbons RJ, Jr, Giobbie-Hurder A, Gibbs JO, et al: Watchful waiting vs repair of inguinal hernia in minimally symptomatic men: A randomized clinical trial. JAMA 295:285–292, 2006.

4. Lichtenstein IL, Shulman AG, Amid PK, et al: The tension-free hernioplasty. Am J Surg 157:188–193, 1989. 5. Gilbert AI: Sutureless repair of inguinal hernia. Am J Surg 163: 331–335, 1992. 6. Kugel RD: Minimally invasive, nonlaparoscopic, preperitoneal, and sutureless, inguinal herniorrhaphy. Am J Surg 178:298–302, 1999. 7. Stoppa RE: The treatment of complicated groin and incisional hernias. World J Surg 13:545–554, 1989. 8. Malangoni MA, Condon RE: Preperitoneal repair of acute incarcerated and strangulated hernias of the groin. Surg Gynecol Obstet 162:65–67, 1986. 9. Voyles CR, Hamilton BJ, Johnson WD, et al: Meta-analysis of laparoscopic inguinal hernia trials favors open hernia repair with preperitoneal mesh prosthesis. Am J Surg 184:6–10, 2002. 10. Bisgaard T, Bay-Nielsen M, Kehlet H: Re-recurrence after operation for recurrent inguinal hernia. A nationwide 8-year follow-up study on the role of type of repair. Ann Surg 247:707–711, 2008. 11. Nordin P, Haapaniemi S, van der Linden W, et al: Choice of anesthesia and risk of reoperation for recurrence in groin hernia repair. Ann Surg 240:187–192, 2004. 12. Neumayer L, Giobbie-Hurder A, Jonasson O, et al: Open mesh versus laparoscopic mesh repair of inguinal hernia. N Engl J Med 350:1819–1827, 2004. 13. Amato B, Moja L, Panico S, et al: Shouldice technique versus other open techniques for inguinal hernia repair. Cochrane Database Syst Rev (4):CD001543, 2009. 14. van Veen RN, Wijsmuller AR, Vrijland WW, et al: Long-term follow-up of a randomized clinical trial of non-mesh versus mesh repair of primary inguinal hernia. Br J Surg 94:506–510, 2007. 15. Zhao G, Gao P, Ma B, et al: Open mesh techniques for inguinal hernia repair: A meta-analysis of randomized controlled trials. Ann Surg 250:35–42, 2009. 16. Schroder DM, Lloyd LR, Boccaccio JE, et al: Inguinal hernia recurrence following preperitoneal Kugel patch repair. Am Surg 70:132–136, 2004. 17. EU Hernia Trialists Collaboration: Repair of groin hernia with synthetic mesh: Meta-analysis of randomized controlled trials. Ann Surg 235:322–332, 2002. 18. Wake BL, McCormack K, Fraser C, et al: Transabdominal preperitoneal (TAPP) vs totally extraperitoneal (TEP) laparoscopic techniques for inguinal hernia repair. Cochrane Database Syst Rev (1):CD004703, 2005. 19. Mikkelsen T, Bay-Nielsen M, Kehlet H: Risk of femoral hernia after inguinal herniorrhaphy. Br J Surg 89:486–488, 2002. 20. Kald A, Fridsten S, Nordin P, et al: Outcome of repair of bilateral groin hernias: A prospective evaluation of 1,487 patients. Eur J Surg 168:150–153, 2002. 21. Aufenacker TJ, van Geldere D, van Mesdag T, et al: The role of antibiotic prophylaxis in prevention of wound infection after Lichtenstein open mesh repair of primary inguinal hernia: A multicenter double-blind randomized controlled trial. Ann Surg 240:955–960, 2004. 22. Grant AM, Scott NW, O’Dwyer PJ: Five-year follow-up of a randomized trial to assess pain and numbness after laparoscopic or open repair of groin hernia. Br J Surg 91:1570–1574, 2004. 23. Nienhuijs SW, Boelens OB, Strobbe LJ: Pain after anterior mesh hernia repair. J Am Coll Surg 200:885–889, 2005. 24. Nienhuijs SW, van Oort I, Keemers-Gels ME, et al: Randomized trial comparing the Prolene Hernia System, mesh plug repair and

SECTION X ABDOMEN

Nyhus LM: An anatomic reappraisal of the posterior inguinal wall, with special consideration of the iliopubic tract and its relation to groin hernias. Surg Clin North Am 44:1305, 1960.

1140 SECTION X ABDOMEN

25.

26. 27. 28. 29. 30. 31. 32.

33. 34. 35. 36. 37.

38.

39. 40. 41. 42.

Lichtenstein method for open inguinal hernia repair. Br J Surg 92:33–38, 2005. Picchio M, Palimento D, Attanasio U, et al: Randomized controlled trial of preservation or elective division of ilioinguinal nerve on open inguinal hernia repair with polypropylene mesh. Arch Surg 139:755–758, 2004. Shulman AG, Amid PK, Lichtenstein IL: The “plug” repair of 1402 recurrent inguinal hernias. 20-year experience. Arch Surg 125:265–267, 1990. Haapaniemi S, Gunnarsson U, Nordin P, et al: Reoperation after recurrent groin hernia repair. Ann Surg 234:122–126, 2001. Karthikesalingam A, Markar SR, Holt PJ, et al: Meta-analysis of randomized controlled trials comparing laparoscopic with open mesh repair of recurrent inguinal hernia. Br J Surg 97:4–11, 2010. Sevonius D, Gunnarsson U, Nordin P, et al: Repeated groin hernia recurrences. Ann Surg 249:516–518, 2009. Rucinski J, Margolis M, Panagopoulos G, et al: Closure of the abdominal midline fascia: Meta-analysis delineates the optimal technique. Am Surg 67:421–426, 2001. Carlson MA, Ludwig KA, Condon RE: Ventral hernia and other complications of 1000 midline incisions. South Med J 88:450– 453, 1995. Seiler CM, Deckert A, Diener MK, et al: Midline versus transverse incision in major abdominal surgery: A randomized, double-blind equivalence trial (POVATI: ISRCTN60734227). Ann Surg 249:913–920, 2009. Luijendijk RW, Hop WC, van den Tol MP, et al: A comparison of suture repair with mesh repair for incisional hernia. N Engl J Med 343:392–398, 2000. Wright BE, Beckerman J, Cohen M, et al: Is laparoscopic umbilical hernia repair with mesh a reasonable alternative to conventional repair? Am J Surg 184:505–508; discussion 508–509, 2002. Anthony T, Bergen PC, Kim LT, et al: Factors affecting recurrence following incisional herniorrhaphy. World J Surg 24:95–100, 2000. Leber GE, Garb JL, Alexander AI, et al: Long-term complications associated with prosthetic repair of incisional hernias. Arch Surg 133:378–382, 1998. Koch A, Bringman S, Myrelid P, et al: Randomized clinical trial of groin hernia repair with titanium-coated lightweight mesh compared with standard polypropylene mesh. Br J Surg 95:1226– 1231, 2008. Conze J, Kingsnorth AN, Flament JB, et al: Randomized clinical trial comparing lightweight composite mesh with polyester or polypropylene mesh for incisional hernia repair. Br J Surg 92: 1488–1493, 2005. Rosen MJ: Polyester-based mesh for ventral hernia repair: Is it safe? Am J Surg 197:353–359, 2009. Jin J, Rosen MJ, Blatnik J, et al: Use of acellular dermal matrix for complicated ventral hernia repair: Does technique affect outcomes? J Am Coll Surg 205:654–660, 2007. de Vries Reilingh TS, van Geldere D, Langenhorst B, et al: Repair of large midline incisional hernias with polypropylene mesh: Comparison of three operative techniques. Hernia 8:56–59, 2004. Novitsky YW, Porter JR, Rucho ZC, et al: Open preperitoneal retrofascial mesh repair for multiply recurrent ventral incisional hernias. J Am Coll Surg 203:283–289, 2006.

43. Iqbal CW, Pham TH, Joseph A, et al: Long-term outcome of 254 complex incisional hernia repairs using the modified Rives-Stoppa technique. World J Surg 31:2398–2404, 2007. 44. de Vries Reilingh TS, van Goor H, Charbon JA, et al: Repair of giant midline abdominal wall hernias: “Components separation technique” versus prosthetic repair: Interim analysis of a randomized controlled trial. World J Surg 31:756–763, 2007. 45. Ewart CJ, Lankford AB, Gamboa MG: Successful closure of abdominal wall hernias using the components separation technique. Ann Plast Surg 50:269–273, 2003. 46. Rosen MJ, Jin J, McGee MF, et al: Laparoscopic component separation in the single-stage treatment of infected abdominal wall prosthetic removal. Hernia 11:435–440, 2007. 47. Olmi S, Scaini A, Cesana GC, et al: Laparoscopic versus open incisional hernia repair: An open randomized controlled study. Surg Endosc 21:555–559, 2007. 48. McGreevy JM, Goodney PP, Birkmeyer CM, et al: A prospective study comparing the complication rates between laparoscopic and open ventral hernia repairs. Surg Endosc 17:1778–1780, 2003. 49. Lomanto D, Iyer SG, Shabbir A, et al: Laparoscopic versus open ventral hernia mesh repair: A prospective study. Surg Endosc 20:1030–1035, 2006. 50. Bingener J, Buck L, Richards M, et al: Long-term outcomes in laparoscopic vs open ventral hernia repair. Arch Surg 142:562– 567, 2007. 51. DeMaria EJ, Moss JM, Sugerman HJ: Laparoscopic intraperitoneal polytetrafluoroethylene (PTFE) prosthetic patch repair of ventral hernia. Prospective comparison to open prefascial polypropylene mesh repair. Surg Endosc 14:326–329, 2000. 52. McAdory RS, Cobb WS, Carbonell AM: Progressive preoperative pneumoperitoneum for hernias with loss of domain. Am Surg 75:504–508, 2009. 53. Lipman J, Medalie D, Rosen MJ: Staged repair of massive incisional hernias with loss of abdominal domain: A novel approach. Am J Surg 195:84–88, 2008. 54. Taner T, Cima RR, Larson DW, et al: The use of human acellular dermal matrix for parastomal hernia repair in patients with inflammatory bowel disease: A novel technique to repair fascial defects. Dis Colon Rectum 52:349–354, 2009. 55. Sugarbaker PH: Peritoneal approach to prosthetic mesh repair of paraostomy hernias. Ann Surg 201:344–346, 1985. 56. Byers JM, Steinberg JB, Postier RG: Repair of parastomal hernias using polypropylene mesh. Arch Surg 127:1246–1247, 1992. 57. Janes A, Cengiz Y, Israelsson LA: Randomized clinical trial of the use of a prosthetic mesh to prevent parastomal hernia. Br J Surg 91:280–282, 2004. 58. Heniford BT, Park A, Ramshaw BJ, et al: Laparoscopic repair of ventral hernias: Nine years’ experience with 850 consecutive hernias. Ann Surg 238:391–399; discussion 399–400, 2003. 59. Pring CM, Tran V, O’Rourke N, et al: Laparoscopic versus open ventral hernia repair: A randomized controlled trial. ANZ J Surg 78:903–906, 2008. 60. Asencio F, Aguilo J, Peiro S, et al: Open randomized clinical trial of laparoscopic versus open incisional hernia repair. Surg Endosc 23:1441–1448, 2009.

CHAPTER 47

ACUTE ABDOMEN Ronald A. Squires and Russell G. Postier

anatomy and physiology history evaluation and diagnosis preparation for emergency operation atypical patients algorithms in the acute abdomen summary

The term acute abdomen refers to signs and symptoms of abdominal pain and tenderness, a clinical presentation that often requires emergency surgical therapy. This challenging clinical scenario requires a thorough and expeditious workup to determine the need for operative intervention and initiate appropriate therapy. Many diseases, some of which are not surgical or even intra-abdominal,1 can produce acute abdominal pain and tenderness. Therefore, every attempt should be made to make a correct diagnosis so that the therapy selected, often a laparoscopy or laparotomy, is appropriate. The diagnoses associated with an acute abdomen vary according to age and gender.2 Appendicitis is more common in younger individuals, whereas biliary disease, bowel obstruction, intestinal ischemia and infarction, and diverticulitis are more common in older adults. Most surgical diseases associated with an acute abdomen result from infection, obstruction, ischemia, or perforation. Nonsurgical causes of an acute abdomen can be divided into three categories, endocrine and metabolic, hematologic, and toxins or drugs (Box 47-1).3 Endocrine and metabolic causes include uremia, diabetic crisis, addisonian crisis, acute intermittent porphyria, acute hyperlipoproteinemia, and hereditary Mediterranean fever. Hematologic disorders include sickle cell crisis, acute leukemia, and other blood dyscrasias. Toxins and drugs causing an acute abdomen include lead and other heavy metal toxins, narcotic withdrawal, and black widow spider poisoning. It is important to consider these possibilities when evaluating a patient with acute abdominal pain. Because of the potential surgical nature of the acute abdomen, an expeditious workup is necessary (Box 47-2). The workup proceeds in the usual order—history, physical examination, laboratory tests, and imaging studies. Although imaging studies have increased the accuracy with which the correct diagnosis can be made, the most important part of the evaluation

remains a thorough history and careful physical examination. Laboratory and imaging studies are usually needed, but are directed by the findings on history and physical examination. ANATOMY AND PHYSIOLOGY Abdominal pain is divided into visceral and parietal components. Visceral pain tends to be vague and poorly localized to the epigastrium, periumbilical region, or hypogastrium, depending on its origin from the primitive foregut, midgut, or hindgut (Fig. 47-1). It is usually the result of distention of a hollow viscus. Parietal pain corresponds to the segmental nerve roots innervating the peritoneum and tends to be sharper and better localized. Referred pain is pain perceived at a site distant from the source of stimulus. For example, irritation of the diaphragm may produce pain in the shoulder. Common referred pain sites and their accompanying sources are listed in Box 47-3. Determining whether the pain is visceral, parietal, or referred is important and can usually be done with a careful history. Introduction of bacteria or irritating chemicals into the peritoneal cavity can cause an outpouring of fluid from the peritoneal membrane. The peritoneum responds to inflammation by increased blood flow, increased permeability, and formation of a fibrinous exudate on its surface. The bowel also develops local or generalized paralysis. The fibrinous surface and decreased intestinal movement cause adherence between the bowel and omentum or abdominal wall and help localize inflammation. As a result, an abscess may produce sharply localized pain, with normal bowel sounds and gastrointestinal function, whereas a diffuse process, such as a perforated duodenal ulcer, produces generalized abdominal pain, with a quiet abdomen. Peritonitis may affect the entire abdominal cavity or part of the visceral or parietal peritoneum. Peritonitis is peritoneal inflammation of any cause. It is usually recognized on physical examination by severe tenderness to palpation, with or without rebound tenderness, and guarding. Peritonitis is usually secondary to an inflammatory insult, most often a gram-negative infection with an enteric organism or anaerobe. It can result from noninfectious inflammation; a common example is pancreatitis. Primary peritonitis occurs more commonly in children and is most often caused by Pneumococcus or hemolytic Streptococcus spp.4 Adults with end-stage renal disease on peritoneal dialysis can develop infections of their peritoneal fluid, with the most common organisms being grampositive cocci. Adults with ascites and cirrhosis can develop primary peritonitis and, in these cases, the organisms are usually Escherichia coli and Klebsiella spp. 1141

1142 SECTION X ABDOMEN BOX 47-1 Nonsurgical Causes of the Acute Abdomen

BOX 47-2 Surgical Acute Abdominal Conditions

Endocrine and Metabolic Causes

Hemorrhage

Uremia Diabetic crisis Addisonian crisis Acute intermittent porphyria Hereditary Mediterranean fever

Solid organ trauma Leaking or ruptured arterial aneurysm Ruptured ectopic pregnancy Bleeding gastrointestinal diverticulum Arteriovenous malformation of gastrointestinal tract Intestinal ulceration Aortoduodenal fistula after aortic vascular graft Hemorrhagic pancreatitis Mallory-Weiss syndrome Spontaneous rupture of spleen

Hematologic Causes Sickle cell crisis Acute leukemia Other blood dyscrasias

Toxins and Drugs Lead poisoning Other heavy metal poisoning Narcotic withdrawal Black widow spider poisoning

HISTORY A detailed and organized history is essential to formulating an accurate differential diagnosis and subsequent treatment regimen. Current technologic advances in imaging cannot and will never replace the need for a skilled clinician’s bedside examination. The history must not only focus on the investigation of the pain complaints, but on past problems and associated symptoms as well. Questions should be open-ended whenever possible, and structured to disclose the onset, character, location, duration, radiation, and chronology of the pain experienced. It is tempting to ask questions about whether the pain is sharp or whether eating makes it worse. This specific yes or no style can facilitate the history taking by not allowing the patient to narrate, but it can miss vital details and potentially skew the response. A much better questioning style would be to determine how the pain feels to the patient or whether anything makes the pain better or worse. Often, additional information can be gained by observing how the patient describes the pain that is experienced. Pain identified with one finger is often more localized and typical of parietal innervation or peritoneal inflammation as compared with indicating the area of discomfort with the palm of the hand, which is more typical of the visceral discomfort of bowel or solid organ disease. The intensity and severity of the pain are related to the underlying tissue damage. Sudden onset of excruciating pain suggests conditions such as intestinal perforation or arterial embolization with ischemia, although other conditions, such as biliary colic, can present suddenly as well. Pain that develops and worsens over several hours is typical of conditions of progressive inflammation or infection such as cholecystitis, colitis, and bowel obstruction. The history of progressive worsening versus intermittent episodes of pain can help differentiate infectious processes that worsen with time compared with the spasmodic colicky pain associated with bowel obstruction, biliary colic from cystic duct obstruction, or genitourinary obstruction (Figs. 47-2 to 47-4). Equally as important as the character of the pain is its location and radiation. Tissue injury or inflammation can trigger visceral and somatic pain. Solid organ visceral pain in the abdomen is generalized in the quadrant of the involved organ, such as liver pain across the right upper quadrant of the abdomen.

Infection Appendicitis Cholecystitis Meckel’s diverticulitis Hepatic abscess Diverticular abscess Psoas abscess

Perforation Perforated gastrointestinal ulcer Perforated gastrointestinal cancer Boerhaave’s syndrome Perforated diverticulum

Blockage Adhesion induction small/large bowel obstruction Sigmoid volvulus Cecal volvulus Incarcerated hernias Inflammatory bowel disease Gastrointestinal malignancy Intussusception

Ischemia Buerger’s disease Mesenteric thrombosis/embolism Ovarian torsion Ischemic colitis Testicular torsion Strangulated hernias

BOX 47-3 Locations and Causes of Referred Pain Right Shoulder Liver Gallbladder Right hemidiaphragm

Left Shoulder Heart Tail of pancreas Spleen Left hemidiaphragm

Scrotum and testicl*s Ureter

Acute Abdomen Chapter 47 1143

Esophagus, trachea, bronchi Heart and aortic arch

SEGMENTAL INNERVATIONS

Vagus T1-T3 or T4

NERVES

C1 2 3 4 5 6 7 8 T1

Sup. cardiac* Middle cardiac Inf. cardiac

Stomach

T5-T7

Biliary tract

T6-T8

Small intestine

T8-T10

2 3 4 5 6 7 8

Kidney

T10-L1

9 10

Maj. splanchnic

Colon

T10-L1

Min. splanchnic

Uterine fundus

T10-L1

Least splanchnic

Bladder

Thoracic cardiac

L1 2 3 4 5

Uterine cervix S2-S4

Rectum

S1 2 3 4 5

PLEXUSES

Sacral Parasympathetic Bladder Cervix Rectum

Cardiac Pulmonary*

Celiac and adrenal* Renal Spermatic* Ovarian* Preaortic Inf. mesenteric Sup. hypogastric Bladder* Prostate* Uterus

* No known sensory fibers in sympathetic rami. FIGURE 47-1 Sensory innervation of the viscera. (From White JC, Sweet WH: Pain and the neurosurgeon, Springfield, Ill, 1969, Charles C Thomas, p 526.)

Small bowel pain is perceived as poorly localized periumbilical pain, whereas colon pain is centered between the umbilicus and pubis symphysis. As inflammation expands to involve the peritoneal surface, parietal nerve fibers from the spine allow for focal and intense sensation. This combination of innervation is responsible for the classic diffuse periumbilical pain of early appendicitis that later shifts to become an intense focal pain in the right lower abdomen at McBurney’s point. If the physician focuses on the character of the current pain and does not thoroughly investigate its onset and progression, he or she will miss these strong historical clues (Figs. 47-5 and 47-6). Pain may also extend well beyond the diseased site. The liver shares some of its innervation with the diaphragm and may create referred pain to the right shoulder from the C3-C5 nerve roots. Genitourinary pain is another source of pain that commonly has a radiating pattern. Symptoms are primarily in the flank region, originating from the splanchnic nerves of T11-L1, but pain often radiates to the scrotum or labia via the hypogastric plexus of S2-S4.

Activities that exacerbate or relieve the pain are also important. Eating will often worsen the pain of bowel obstruction, biliary colic, pancreatitis, diverticulitis, or bowel perforation. Food can provide relief from the pain of nonperforated peptic ulcer disease or gastritis. Clinicians will often recognize that they are evaluating peritonitis while taking the history. Patients with peritoneal inflammation will avoid any activity that stretches or jostles the abdomen. They describe worsening of the pain with any sudden body movement and realize that there is less pain if their knees are flexed. The car ride to the hospital can be agonizing, with the patient feeling every bump along the way. Associated symptoms can be important diagnostic clues. Nausea, vomiting, constipation, diarrhea, pruritis, melena, hematochezia, and/or hematuria can all be helpful symptoms if present and recognized. Vomiting may occur because of severe abdominal pain of any cause or as a result of mechanical bowel obstruction or ileus. Vomiting is more likely to precede the onset of significant abdominal pain in many medical conditions,

SECTION X ABDOMEN

VISCUS

1144 SECTION X ABDOMEN

Cholecystitis Hepatitis

Pancreatitis

Ureteral colic (may be constant)

Appendicitis Tubo-ovarian abcess or ectopic pregnancy

Perforated ulcer

Diverticulitis

FIGURE 47-2 Character of pain—gradual, progressive pain.

Ruptured aortic aneurysm

FIGURE 47-4 Character of pain—sudden, severe pain.

Biliary colic Perforated ulcer Ureteral colic (kidney stones) Small bowel obstruction

Pyelonephritis, renal or ureteral colic

Colonic obstruction

FIGURE 47-3 Character of pain—colicky, crampy, intermittent pain.

FIGURE 47-5 Referred pain. Solid circles are primary or most intense sites of pain.

whereas the pain of an acute surgical abdomen presents first and stimulates vomiting via medullary efferent fibers that are triggered by visceral afferent pain fibers. Constipation or obstipation can be a result of mechanical obstruction or decreased peristalsis. It may represent the primary problem and require laxatives and prokinetic agents, or merely be a symptom of an underlying condition. A careful history should include whether the patient is continuing to pass any gas or stool from the rectum. A complete obstruction is more likely to be associated with subsequent bowel ischemia or perforation caused by the massive distention

that can occur. Diarrhea is associated with several medical causes of acute abdomen, including infectious enteritis, inflammatory bowel disease or parasitic contamination. Bloody diarrhea can be seen in these conditions, as well as in colonic ischemia. The past medical history could be more helpful than any other single part of the patient’s evaluation. Previous illnesses or diagnoses can greatly increase or decrease the likelihood of certain conditions that would otherwise not be strongly considered. Patients may, for example, report that the current pain is similar to the kidney stone passage that they experienced a

Acute Abdomen Chapter 47 1145

Pancreatitis

Appendicitis

FIGURE 47-6 Referred pain. Solid circles are primary or most intense sites of pain.

decade previously. On the other hand, a prior history of appendectomy, pelvic inflammatory disease, or cholecystectomy can significantly influence the differential diagnosis. During the abdominal examination, all scars on the abdomen should be accounted for by the medical history obtained. A history of medications and the gynecologic history of female patient are also important. Medications can both create acute abdominal conditions or alternatively mask their symptoms. Although a thorough discussion of the impact of all medications is beyond the scope of this chapter, several common drug classes deserve mention. High-dose narcotic use can interfere with bowel activity and lead to obstipation and obstruction. Narcotics can also contribute to spasm of the sphincter of Oddi and exacerbate biliary or pancreatic pain. They can also suppress pain sensation and alter mental status, which can impair the ability to diagnose the condition accurately. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with an increased risk of upper gastrointestinal inflammation and perforation; steroids can block protective gastric mucous production by chief cells and reduce the inflammatory reaction to infection, including advanced peritonitis. As a class, immunosuppressive agents increase a patient’s risk of acquiring various bacterial or viral illnesses and also blunt the inflammatory response, diminishing the pain that is present and the overall physiologic response. Anticoagulants are more prevalent in our emergency patients as the population ages. These drugs may be the cause of gastrointestinal bleeds, retroperitoneal hemorrhages, or rectus sheath hematomas. They can also complicate the preoperative preparation of the patient and be the cause of substantial morbidity if their use goes unrecognized. Finally, recreational drugs can play a role in patients with an acute abdomen. Chronic alcoholism is strongly associated with coagulopathy and portal hypertension from liver impairment. Cocaine and methamphetamine can create an intense vasospastic reaction, which can create lifethreatening hypertension and cardiac and intestinal ischemia.

PHYSICAL EXAMINATION An organized and thoughtful physical examination is critical to the development of an accurate differential diagnosis and the subsequent treatment algorithm. Despite newer technologies, including high-resolution computed tomography (CT) scanning, ultrasound, and magnetic resonance imaging (MRI), the physical examination remains a key part of a patient’s evaluation and must not be minimized. Skilled clinicians will be able to develop a narrow and accurate differential diagnosis in most of their patients at the conclusion of the history and physical examination. Laboratory and imaging studies can then be used to confirm the suspicions further, reorder the proposed differential diagnosis or, less commonly, suggest unusual possibilities not yet considered. The physical examination should always begin with a general inspection of the patient, to be followed by inspection of the abdomen itself. Patients with peritoneal irritation will experience worsened pain with any activity that moves or stretches the peritoneum. These patients will typically lie very still in bed during the evaluation and often maintain flexion of their knees and hips to reduce tension on the anterior abdominal wall. Disease states that cause pain without peritoneal irritation, such as ischemic bowel or ureteral or biliary colic, typically cause patients to shift and fidget in bed continually while trying to find a position that lessens their discomfort (Fig. 47-7). Other important clues such as pallor, cyanosis, and diaphoresis may also be observed during the general inspection. Abdominal inspection should address the contour of the abdomen, including whether it appears distended or scaphoid or whether a localized mass effect is observed. Special attention should be paid to all scars present and, if surgical in nature, should correlate with the surgical history provided. Fascial hernias may be suspected and can be confirmed during palpation of the abdominal wall. Evidence of erythema or edema of skin may suggest cellulitis of the abdominal wall, whereas ecchymosis is sometimes observed with deeper necrotizing infections of the fascia or abdominal structures, such as the pancreas.

SECTION X ABDOMEN

Cholecystitis

Gynecologic health, specifically the menstrual history, is crucial in the evaluation of lower abdominal pain in a young woman. The likelihood of ectopic pregnancy, pelvic inflammatory disease, mittelschmerz, and/or severe endometriosis are all heavily influenced by the details of the gynecologic history. Little has changed in the technique or goals of history taking since Dr. Zachary Cope first published his classic paper on the diagnosis of acute abdominal pain in 1921.5 An exception is the application of computers to history taking, which has been extensively studied in Europe.6-10 Data were collected by physicians on detailed standardized forms during history and physical examinations and entered into computers programmed with a medical database of diseases and their associated signs and symptoms. The computer-generated diagnosis, based on mathematical probabilities, was as much as 20% more accurate than physicians who didn’t use computers to help arrive at a diagnosis. Statistically significant improvement was identified in regard to a timely laparotomy, shortened hospital stay, and reduced need for surgery and hospitalization. However, it should be noted that statistically significant improvements in accuracy and efficiency can be realized without computer assistance if similar standardized forms are used for data collection. This has also been observed in the settings of trauma and critical care.

1146 SECTION X ABDOMEN

Gallbladder

Renal

Stomach Pancreas

Small bowel

Colon Uterine

FIGURE 47-7 Common locations for visceral pain.

Auscultation can provide useful information about the gastrointestinal tract and vascular system. Bowel sounds are typically evaluated for their quantity and quality. A quiet abdomen suggests an ileus, whereas hyperactive bowel sounds are found in enteritis and early ischemic intestine. The pitch and pattern of the sounds are also considered. Mechanical bowel obstruction is characterized by high-pitched tinkling sounds that tend to come in rushes and are associated with pain. Far away, echoing sounds are often present when significant luminal distention exists. Bruits heard within the abdomen reflect turbulent blood flow in the vascular system. These are most frequently encountered in the setting of high-grade arterial stenoses (70% to 95% but can also be heard if an arteriovenous fistula is present). The clinician can also perform a subtle test for the location and degree of pain during the auscultatory examination by varying the position and amount of pressure applied with the stethoscope. These data can then be compared with the findings during palpation and evaluated for consistency. Even though few patients will try to deceive their physician intentionally, some may exaggerate their pain complaints so as not to be disregarded or taken lightly. Percussion is used to assess for gaseous distention of the bowel, free intra-abdominal air, degree of ascites, and/or presence of peritoneal inflammation. Hyperresonance, commonly termed tympany to percussion, is characteristic of underlying gas-filled loops of bowel. In the setting of bowel obstruction or ileus, this tympany is heard throughout all but the right upper quadrant, where the liver lies beneath the abdominal wall. If localized dullness to percussion is identified anywhere other than the right upper quadrant, an abdominal mass displacing the bowel should be considered. When liver dullness is lost and resonance is uniform throughout, free intraabdominal air should be suspected. This air rises and collects beneath the anterior abdominal wall when the patient is in a supine position. Ascites is detected by looking for fluctuance

of the abdominal cavity. A fluid wave or ripple can be generated by a quick firm compression of the lateral abdomen. The resulting wave should then travel across the abdominal wall. Movement of adipose tissue in the obese abdomen can be mistaken for a fluid wave. False-positive examinations can be reduced by first pressing the ulnar surface of the examiner’s open palm into the midline soft tissue of the abdominal wall to minimize any movement of the fatty tissue while generating the wave with the opposite hand. Peritonitis is also assessed by percussion. Older, traditional writings have presented a technique of deep compression of the abdominal wall, followed by abrupt release. This practice is excruciating in the setting of peritoneal inflammation and can create significant discomfort, even in its absence. More sensitive and reliable methods can and should be used. Firmly tapping the iliac crest, flank, or heel of an extended leg will jar the abdominal viscera and elicit characteristic pain when peritonitis is present. The final major step in the abdominal examination is palpation. Palpation typically provides more information than any other component of the abdominal examination. In addition to revealing the severity and exact location of the abdominal pain, palpation can further confirm the presence of peritonitis and identify organomegaly or an abnormal mass lesion. Palpation should always begin gently and away from the reported area of pain. If considerable pain is induced at the outset of palpation, the patient is likely to guard voluntarily and will continue to do so, limiting the information obtained. Involuntary guarding, or abdominal wall muscle spasm, is a sign of peritonitis and must be distinguished from voluntary guarding. To accomplish this, the examiner applies consistent pressure to the abdominal wall, away from the point of maximal pain, while asking the patient to take a slow deep breath. In the setting of voluntary guarding, the abdominal muscles will relax during the act of inspiration; if involuntary, they remain spastic and tense. Pain, when focal, suggests an early or well-localized disease process, whereas diffuse pain on palpation is present with extensive inflammation or a late presentation. If pain is diffuse, careful investigation should be carried out to determine where the pain is greatest. Even in the setting of extreme contamination from perforated peptic ulcers or colonic diverticula, the site of maximal tenderness often indicates the underlying source. Numerous unique physical findings have come to be associated with specific disease conditions and are well described as examination signs (Table 47-1). Murphy’s sign of acute cholecystitis results when inspiration during palpation of the right upper quadrant results in sudden worsening of pain because of descent of the liver and gallbladder toward the examiner’s hand. Several signs help localize the site of under lying peritonitis, including obturator, psoas, and Rovsing’s signs. Others, such as the Fothergill and Carnett signs, help distinguish intra-abdominal disease from that of the abdominal wall. A digital rectal examination needs to be performed in all patients with acute abdominal pain, checking for the presence of a mass, pelvic pain, or intraluminal blood. A pelvic examination should be included for all women when evaluating pain located below the umbilicus. Gynecologic and adnexal processes are best characterized by a thorough speculum and bimanual evaluation.

Acute Abdomen Chapter 47 1147

SIGN

DESCRIPTION

DIAGNOSIS OR CONDITION

Aaron

Pain or pressure in epigastrium or anterior chest with persistent firm pressure applied to McBurney’s point

Acute appendicitis

Bassler

Sharp pain created by compressing appendix between abdominal wall and iliacus

Chronic appendicitis

Blumberg

Transient abdominal wall rebound tenderness

Peritoneal inflammation

Carnett

Loss of abdominal tenderness when abdominal wall muscles are contracted

Intra-abdominal source of abdominal pain

Chandelier

Extreme lower abdominal and pelvic pain with movement of cervix

Pelvic inflammatory disease

Charcot

Intermittent right upper abdominal pain, jaundice, and fever

Choledocholithiasis

Claybrook

Accentuation of breath and cardiac sounds through abdominal wall

Ruptured abdominal viscus

Courvoisier

Palpable gallbladder in presence of jaundice

Periampullary tumor

Cruveihier

Varicose veins at umbilicus (caput medusa)

Portal hypertension

Cullen

Periumbilical bruising

Hemoperitoneum

Danforth

Shoulder pain on inspiration

Hemoperitoneum

Fothergill

Abdominal wall mass that does not cross midline and remains palpable when rectus contracted

Rectus muscle hematomas

Grey Turner

Local areas of discoloration around umbilicus and flanks

Acute hemorrhagic pancreatitis

Iliopsoas

Elevation and extension of leg against resistance creates pain

Apppendicitis with retrocecal abscess

Kehr

Left shoulder pain when supine and pressure placed on left upper abdomen

Hemoperitoneum (especially from splenic origin)

Mannkopf

Increased pulse when painful abdomen palpated

Absent if malingering

Murphy

Pain caused by inspiration while applying pressure to right upper abdomen

Acute cholecystitis

Obturator

Flexion and external rotation of right thigh while supine creates hypogastric pain

Pelvic abscess or inflammatory mass in pelvis

Ransohoff

Yellow discoloration of umbilical region

Ruptured common bile duct

Rovsing

Pain at McBurney’s point when compressing the left lower abdomen

Acute appendicitis

Ten Horn

Pain caused by gentle traction of right testicl*

Acute appendicitis

BOX 47-4 Laboratory Studies for the Acute Abdomen Hemoglobin level White blood cell count with differential Electrolyte, blood urea nitrogen, creatinine levels Urinalysis Urine human chorionic gonadotropin level Amylase, lipase levels Total and direct bilirubin levels Alkaline phosphatase level Serum aminotransferase Serum lactate levels Stool for ova and parasites C. dificile culture and toxin assay

EVALUATION AND DIAGNOSIS Laboratory Studies A number of laboratory studies are considered routine in the evaluation of a patient with an acute abdomen (Box 47-4). They help confirm that inflammation or infection is present and also aid in the elimination of some of the most common nonsurgical conditions. A complete blood count with differential is valuable

because most patients with an acute abdomen will have a leukocytosis or bandemia. Measurement of serum electrolyte, blood urea nitrogen, and creatinine levels will assist in evaluating the effect of factors such as vomiting or third space fluid losses. In addition, they may suggest an endocrine or metabolic diagnosis as the cause of the patient’s problem. Serum amylase and lipase level determinations may suggest pancreatitis as the cause of the abdominal pain but can also be elevated in other disorders, such as small bowel infarction or duodenal ulcer perforation. Normal serum amylase and lipase levels do not exclude pancreatitis as a possible diagnosis caused by the effects of chronic inflammation on enzyme production and timing factors. Liver function tests, including determination of total and direct bilirubin, serum aminotransferase, and alkaline phosphatase levels are helpful in evaluating potential biliary tract causes of acute abdominal pain. Lactate levels and arterial blood gas determinations can be helpful in diagnosing intestinal ischemia or infarction. Urine testing, such as urinalysis, is helpful in the diagnosis of bacterial cystitis, pyelonephritis, and certain endocrine abnormalities, such as diabetes or renal parenchymal disease. Urine culture can confirm a suspected urinary tract infection and direct antibiotic therapy but cannot be done in time to be helpful in the evaluation of an acute abdomen. Urinary measurements of human chorionic gonadotropin level can suggest pregnancy as a confounding factor in the patient’s presentation or aid in decision

SECTION X ABDOMEN

Table 47-1 Abdominal Examination Signs

1148 SECTION X ABDOMEN

FIGURE 47-8 Appendicitis. A, CT scan of uncomplicated appendicitis. A thick-walled, distended, retrocecal appendix (arrow) is seen with inflammatory change in the surrounding fat. B, CT scan of complicated appendicitis—a retrocecal appendiceal abscess (A) with an associated phlegmon posteriorly found in a 3-week postpartum, obese woman. Inflammatory change extends through the flank musculature into the subcutaneous fat (arrow).

FIGURE 47-9 Small bowel infarction associated with mesenteric venous thrombosis. A, Note the low-density thrombosed superior mesenteric vein (solid arrow) and incidental gallstones (open arrow). B, Thickening of proximal small bowel wall (arrow) coincided with several feet of infarcting small bowel at time of operation.

making regarding therapy. The fetus of a pregnant patient with an acute abdomen is best protected by providing the best care to the mother, including surgery, if indicated.11 Stool testing for occult blood can be helpful in the evaluation of these patients but is nonspecific. Testing stool for ova and parasite evaluation, as well as culture and toxin assay for Clostridium difficile, can be helpful if diarrhea is a component of the patient’s presentation. Imaging Studies Improvements in imaging techniques, especially multidetector CT, have revolutionized diagnosis of the acute abdomen. The most difficult diagnostic dilemmas of the past—appendicitis in young women and ischemic bowel in older adults—can now be diagnosed with greater certainty and speed (Figs. 47-8 and 47-9).12-14 This has resulted in more rapid operative correction of the problem, with less morbidity and mortality. Despite its usefulness, CT is not the only imaging technique available and is also not the first step in imaging for most patients. In addition, no imaging technique can replace a careful history and physical examination.

Plain radiographs continue to play a role in imaging for patients with acute abdominal pain. Upright chest radiographs can detect as little as 1 mL of air injected into the peritoneal cavity. Lateral decubitus abdominal radiographs can also detect pneumoperitoneum effectively in patients who cannot stand; as little as 5 to 10 mL of gas may be detected with this technique.15 These studies are particularly helpful for patients suspected of having a perforated duodenal ulcer, because approximately 75% of these patients will have a large enough pneumoperitoneum to be visible (Fig. 47-10).16 This obviates the need for further evaluation in most patients, allowing for laparotomy with little delay. Plain films also show abnormal calcifications. Approximately 5% of appendicoliths, 10% of gallstones, and 90% of renal stones contain sufficient amounts of calcium to be radiopaque. Pancreatic calcifications seen in many patients with chronic pancreatitis are visible on plain films, as are the calcifications in abdominal aortic aneurysms, visceral artery aneurysm, and atherosclerosis in visceral vessels. Upright and supine abdominal radiographs are helpful in identifying gastric outlet obstruction, and obstruction of the

Acute Abdomen Chapter 47 1149

SECTION X ABDOMEN

FIGURE 47-11 Upright abdominal x-ray in a patient with an obstructing sigmoid adenocarcinoma. Note the haustral markings on the dilated transverse colon that distinguished this from small intestine.

FIGURE 47-10 Upright chest radiograph depicting moderate-sized pneumoperitoneum consistent with perforation of abdominal viscus.

proximal, mid, or distal small bowel. They can also aid in determining whether a small bowel obstruction is complete or partial by the presence or absence of gas in the colon. Colonic gas can be differentiated from small intestinal gas by the presence of haustral markings caused bythe taenia coli present in the colonic wall. An obstructed colon appears as distended bowel with haustral markings (Fig. 47-11). Associated distention of small bowel may also be present, especially if the ileocecal valve is incompetent. Plain films can also suggest volvulus of the cecum or sigmoid colon. Cecal volvulus is identified by a distended loop of colon in a comma shape, with the concavity facing inferiorly and to the right. Sigmoid volvulus characteristically has the appearance of a bent inner tube, with its apex in the right upper quadrant (Fig. 47-12). Abdominal ultrasonography is extremely accurate for detecting gallstones and assessing gallbladder wall thickness and presence of fluid around the gallbladder.17 It is also helpful for determining the diameter of the extrahepatic and intrahepatic bile ducts. Its usefulness in detecting common bile duct stones is limited. Abdominal and transvagin*l ultrasonography can aid in the detection of abnormalities of the ovaries, adnexa, and uterus. Ultrasound can also detect intraperitoneal fluid. The presence of abnormal amounts of intestinal air in most patients with an acute abdomen limits the ability of ultrasonography to evaluate the pancreas or other abdominal organs. There are important limits to the value of ultrasonography in the diagnosis of diseases that present as an acute abdomen. Ultrasound images are more difficult for most surgeons to interpret than plain radiographs and CT scans. Many hospitals have radiologic technologists available at all times to perform CT but this is often not the case with ultrasonography. As CT has become more widely available and less likely to be hindered by abdominal air,

FIGURE 47-12 Upright abdominal x-ray in a patient with a sigmoid colon volvulus. Note the characteristic appearance of a bent inner tube, with its apex in the right upper quadrant.

it is becoming the secondary imaging modality of choice in the patient with an acute abdomen, following plain abdominal radiography. A number of studies have demonstrated the accuracy and usefulness of CT of the abdomen and pelvis in the evaluation of acute abdominal pain.12-14 Many of the most common causes

1150 SECTION X ABDOMEN patients suffering a blunt abdominal trauma will have altered mental states from coexisting closed head injuries or from intoxicating substances. When a bowel injury is suspected, optimal CT scanning uses oral and IV contrast agents. Zissin and colleagues17 have reported an overall sensitivity of 64%, specificity of 97%, and accuracy of 82% when diagnosing small bowel injury following blunt trauma using dual-contrast CT scanning. Diagnostic clues include recognition of bowel wall thickening, identification of any gas outside the lumen of the intestine, and a moderate to large amount of intraperitoneal fluid without visible solid abdominal organ injury.

FIGURE 47-13 CT scan of a patient with a partial small bowel obstruction. Note the presence of dilated small bowel and decompressed small bowel. The decompressed bowel contains air, indicating a partial obstruction.

of the acute abdomen are readily identified by CT scanning, as are their complications. A notable example is appendicitis. Plain films and even barium enemas add little to the diagnosis of appendicitis; however, a well-performed CT using oral, rectal, and IV contrast is highly accurate for evaluating this disease. It is equally important that an experienced radiologist, accustomed to reading abdominal CT scans, interprets the study to maximize the sensitivity and specificity of the exam. A prospective study from the Netherlands15 has illustrated the variability of CT interpretation in the diagnosis of appendicitis. Three blinded groups of radiologists read CT scans of patients suspected of having appendicitis. All patients then underwent exploratory laparoscopy and 83% of patients were found to have appendicitis at surgery. Radiology group A was made up of radiology residents on call and trained in CT interpretation. Group B consisted of call staff radiologists; group C was composed of expert abdominal radiologists. For groups A, B, and C radiologists, the sensitivities of CT scanning for the diagnosis of acute appendicitis were 81%, 88%, and 95%, the specificities were 94%, 94%, and 100%, and the negative predictive values were 50%, 68%, and 81%, respectively. Differences between groups A and C were statistically significant. CT is also excellent for differentiating mechanical small bowel obstruction from paralytic ileus and can usually identify the transition point in mechanical obstruction (Fig. 47-13). Some of the most difficult diagnostic dilemmas, including acute intestinal ischemia and bowel injury following blunt abdominal trauma, can often be identified by this method. Traumatic small bowel injuries can be a clinical diagnosis challenge. Associated abdominal wall, pelvic, or spinal injuries can be significant distracters that could compromise an otherwise careful history and physical examination. In addition, many

INTRA-ABDOMINAL PRESSURE MONITORING An elevated intra-abdominal pressure can be a symptom of an acute abdominal process or can be the cause of the process. Abnormally increased intra-abdominal pressures diminish the blood flow to abdominal organs and decrease venous return to the heart while increasing venous stasis. Increased pressure in the abdomen can also press upward on the diaphragm, thereby increasing peak inspiratory pressures and decreasing ventilatory efficiency. Risk of esophageal reflux and pulmonary aspiration has also been associated with abdominal hypertension. It is important to consider the possibility of abdominal hypertension in any patient who presents with a rigid or significantly distended abdomen. Normal intra-abdominal pressure is considered to be 5 to 7 mm Hg for a relaxed individual of average body build lying in a supine position. Obesity and elevation of the head of the bed can increase the normal resting abdominal pressure. Morbid obesity has been shown to increase normal pressures by 4 to 8 mm Hg while elevation the head of the bed to 30 degrees raises the pressure by 5 mm Hg (average).18 Pressures are most commonly measured via the bladder by a pressure transducer attached to a Foley catheter. Pressure readings are obtained at end-expiration following instillation of 50 mL of saline into an otherwise empty bladder. Abnormally elevated pressures are those higher than 11 mm Hg and are graded 1 to 4 by severity (Table 47-2). Abdominal hypertension grades 1 and 2 can usually be treated adequately with medical interventions focusing on maintaining euvolemia, gut decompression with a nasogastric tube and/or laxatives and enemas, withholding enteral feedings, catheter aspiration of ascitic fluid, abdominal wall relaxation, and judicious use of hypotonic IV fluids. Grades 3 and 4 often require surgical decompression via laparotomy with open packing of the abdomen if the severe hypertension and organ dysfunction do not respond promptly to aggressive medical intervention. Diagnostic Laparoscopy A number of studies have confirmed the usefulness of diagnostic laparoscopy in patients with acute abdominal pain.19-21 Purported advantages include a high sensitivity and specificity, the ability to treat a number of the conditions causing an acute abdomen laparoscopically, and decreased morbidity and mortality, length of stay, and overall hospital costs. It may be particularly helpful in the critically ill, intensive care patient, especially if a laparotomy can be avoided.22 Diagnostic accuracy is high; the accuracy ranges from 90% to 100%, with the primary limitation being recognition of retroperitoneal processes. This compares favorably with other diagnostic studies showing superiority

Acute Abdomen Chapter 47 1151

DEGREE OF HYPERTENSION

MESENTERIC PRESSURE

CVP

PIP

GFR

PERFUSION

TREATMENT

Normal pressure

5-7 mm Hg

↔

None

Grade 1 hypertension

12-15 mm Hg

↔

↔,↑

↓

Maintain euvolemia

Grade 2 hypertension

16-20 mm Hg

↓

↑*

↑

↓

Nonsurgical decompression

Grade 3 hypertension

21-25 mm Hg

↓↓

↑↑*

↑↑

↓↓

Surgical decompression

Grade 4 hypertension

>25 mm Hg

↓↓↓

↑↑*

↑↑

↓↓↓

Surgical decompression; reexplore

CO, Cardiac output; CVP, central venous pressure; GFR, glomerular filtration rate; PIP, peak inspiratory pressure. *Misleadingly elevated and not reflective of intravascular volume.

to peritoneal lavage, CT scanning, or ultrasound of the abdomen.23 Because of advances in equipment and increased availability, this technique is being used more often in these patients. Differential Diagnosis The differential diagnosis for acute abdominal pain is extensive. Conditions range from the mild and self-limited to the rapidly progressive and fatal. All patients must therefore be seen and evaluated immediately on presentation and reassessed at frequent intervals for changes in condition. Although many acute abdomen diagnoses will require surgical intervention for resolution, it is important to remember that many causes of acute abdominal pain are medical in nature (see Figs. 47-2 and 47-4).24 Development of the differential diagnosis begins during the history and is further clarified during the physical examination. Refinements are then made with the assistance of laboratory analysis and imaging studies; typically, one or two diagnoses stand out. To be successful, this process requires a comprehensive knowledge of the medical and surgical conditions that create acute abdominal pain to allow individual disease features to be matched to patient demographics, symptoms, and signs. Certain physical examination, laboratory, and radiographic findings are highly correlated with surgical disease (Box 47-5). At times, some patients will be too unstable to undergo comprehensive evaluations that require transportat to other departments, such as radiology. In this setting, peritoneal lavage can provide information that suggests pathology requiring surgical intervention. The lavage can be performed under local anesthesia at the patient’s bedside. A small incision is made in the midline adjacent to the umbilicus and dissection is carried down to the peritoneal cavity. A small catheter or IV tubing is inserted and 1000 mL of saline is infused. A sample of fluid is allowed to siphon back out into the empty saline bag and is then analyzed for cellular or biochemical anomalies. This technique can provide sensitive evidence of hemorrhage or infection, as well as some types of solid or hollow organ injury. Patients having emergency or life-threatening surgical disease are taken for immediate laparotomy; urgent diagnoses allow time for stabilization, hydration, and preoperative preparation, as needed. The remaining acute abdominal patients are grouped similarly to those with surgical conditions that sometimes require surgery, those with medical diseases, and those who as yet remain unclear. Hospitalized patients who do not go urgently to the operating room must be reassessed frequently, preferably by the same examiner, to recognize potentially serious

BOX 47-5 Findings Associated With Surgical Disease in the Setting of Acute Abdominal Pain Physical Examination and Laboratory Findings Abdominal compartment pressures >30 mm Hg Worsening distention after gastric decompression Involuntary guarding or rebound tenderness Gastrointestinal hemorrhage requiring >4 U of blood without stabilization Unexplained systemic sepsis Signs of hypoperfusion (e.g., acidosis, pain out of proportion to examination findings, increasing liver function test results)

Radiographic Findings Massive dilation of intestine Progressive dilation of stationary loop of intestine (sentinel loop) Pneumoperitoneum Extravasation of contrast from bowel lumen Vascular occlusion on angiography Fat stranding, thickened bowel wall with systemic sepsis

Diagnostic Peritoneal Lavage (1000 mL) >250 white blood cells/mL >300,000 red blood cells/mL Bilirubin level higher than plasma level (bile leak) Particulate matter (stool) Creatinine level higher than plasma level (urine leak)

changes in condition that could alter the diagnosis or suggest development of complications. Although the goal of every surgeon is to make the correct diagnosis preoperatively and plan the best possible surgical procedure prior to entering the operating suite, it must be emphasized that a clear diagnosis will not be able to be determined in every patient. Surgeons must always be willing to accept uncertainly and commit to abdominal exploration when examination findings warrant. Laboratory and imaging studies, although helpful, should never replace the bedside clinical judgment of an experienced surgeon. Patients are more likely to be seriously or fatally harmed by delaying surgical treatment to perform confirmatory tests than by misdiagnoses discovered at operation. Laparoscopy has proved to be a valuable tool when the diagnosis is unclear. The presence of surgical disease can be confirmed in all but the most hostile abdominal environments and, as surgeon experience grows, more conditions will also be able to be treated

SECTION X ABDOMEN

Table 47-2 Abdominal Hypertension

1152 SECTION X ABDOMEN laparoscopically. Even when conversion to open technique is required, laparoscopic evaluation facilitates more accurate positioning of the laparotomy incision, thereby reducing its length. PREPARATION FOR EMERGENCY OPERATION Patients with an acute abdomen vary greatly in their overall state of health when the decision to operate is made. Regardless of the severity of illness, all patients require some degree of preoperative preparation. IV access should be obtained and any fluid or electrolyte abnormalities corrected. Almost all patients will require antibiotic infusions. The bacteria common in acute abdominal emergencies are gram-negative enteric organisms and anaerobes. Antibiotic infusion should be inititated once a presumptive diagnosis has been made. Patients with generalized paralytic ileus, as manifested by absent or hypoactive bowel sounds, benefit from a nasogastric tube to decrease the likelihood of vomiting and aspiration. Foley catheter bladder drainage to assess urine output, a measure of adequacy of fluid resuscitation, is indicated for most patients. Preoperative urine output of 0.5 mL/kg/hr, along a with systolic blood pressure of at least 100 mm Hg and a heart rate of 100 beats/min or less, are indicative of an adequate intravascular volume. A common electrolyte abnormality requiring correction is hypokalemia. If significant potassium repletion is necessary, a central venous line is required. The ability to administer potassium through a peripheral line is limited by the potential development of phlebitis. Preoperative acidosis may respond to fluid repletion and IV bicarbonate infusion. Acidosis caused by intestinal ischemia or infarction may be refractory to preoperative therapy. Significant anemia is uncommon and preoperative blood transfusions are usually unnecessary. However, most patients should have their blood typed, cross-matched, and available at operation. There is an inherent uncertainty in the operation that will be required for these patients, so having cross-matched blood available avoids transfusion delay if unexpected intraoperative events occur. The need for preoperative stabilization of patients must be weighed against the increased morbidity and mortality associated with delay in the treatment of some of the surgical diseases that present as an acute abdomen. The underlying nature of the disease process, such as infarcted bowel, may require surgical correction before stabilization of the patient’s vital signs and restoration of acid-base balance can occur. Deciding when the maximum benefit of preoperative therapy in these patients has been achieved requires good surgical judgment. ATYPICAL PATIENTS Pregnancy Acute abdominal pain presenting in the pregnant patient creates several unique diagnostic and therapeutic challenges. Special emphasis must be placed on the possibility of gynecologic and surgical diseases when acute abdominal pain develops during pregnancy because of their frequency and morbidity if left unrecognized. Laparoscopy has had a major impact on the diagnosis and treatment of the gravid female with acute abdominal pain and is now routinely used for many clinical situations. Shortterm follow-up has suggested equal or superior safety with the laparoscopic approach, but large series of long-term safety data are not available.25-28 The greatest threat facing the pregnant patient with acute abdominal pain is the potential for delayed diagnosis. Delays in receiving surgical treatment have proven far

8 mo 7 mo 6 mo

Umbilicus

5 mo 4 mo 3 mo McBurney’s point

FIGURE 47-14 Location of maternal normal appendix during fetal gestation.

more morbid than the surgery itself.11,29 Delays occur for several reasons. Often, symptoms are attributed to the underlying pregnancy, including abdominal pains, nausea, vomiting, and anorexia. Pregnancy can also alter the presentation of some disease processes and make the physical examination more challenging because of the enlarged uterus in the pelvis. The appendix rises out of the pelvis to within a few centimeters of the right anterolateral costal margin late in the third trimester (Fig. 47-14).30 Results of laboratory studies, such as white cell counts and other tests, are also altered in pregnancy, making recognition of disease more difficult. In addition, physicians may hesitate to perform typical imaging studies such as plain abdominal radio graphy or CT because of concern over radiation exposure to the developing fetus. The lack of radiologic information can take physicians out of their diagnostic routine and cause them to place extra emphasis on other modalities, such as monitoring vital signs and laboratory studies, which can confuse or underestimate the existing condition. Finally, physicians tend to be more conservative when treating pregnant patients. Surgery, especially in the pelvis, is associated with increased risks of spontaneous abortions in the first trimester and progressively increasing risk of preterm labor in the second and third trimesters. The overall risk attributed to surgery and anesthesia is estimated at 4% to 6%, but some have reported an incidence as high as 38%.28,31,32 Perioperative risk is minimized by maintaining physiologic O2 and CO2 levels during surgery, avoiding episodes of hypotension, and minimally manipulating the uterus. Appendicitis is the most common nonobstetric disease requiring surgery, occurring in 1 in 1500 pregnancies.27,33 Its symptoms typically consist of right lateral abdominal pain, nausea, and anorexia, but so-called typical presentations account for only 50% to 60% of cases.34 Fever is uncommon unless the appendix is perforated with abdominal sepsis. Symptoms can sometimes attributed to the underlying pregnancy and a high index of suspicion must be maintained. Laboratory studies can

Acute Abdomen Chapter 47 1153

FEATURE

Alvarado

Scoring

System

for

SCORE

Symptoms Right iliac fossa pain

Nausea, vomiting

Anorexia

Signs Right iliac fossa tenderness

Fever

Rebound tenderness

Tests WBC ≥10,000

Left shift of neutrophils

Score ≥7

Surgery recommended

From Brown MA, Birchard KR, Semelka RC: Magnetic resonance evaluation of pregnant patients with acute abdominal pain. Semin Ultrasound CT MR 26:206– 211, 2005.

also be misleading. Leukocytosis as high as 16,000 cells/mm3 is common in pregnancy, and labor can increase the count to 21,000/mm3. Many authors have suggested that a neutrophil shift more than 80% is suspicious for an acute inflammatory process, such as appendicitis; however, others have observed that only 75% of patients with proven appendicitis have a shift and as many as 50% of patients with a shift and pain are found to have a normal appendix.11,28,35 Scoring systems have been advocated that assign numeric scores to certain symptoms, signs, and laboratory values to predict the likelihood of appendicitis. Although systems such as the modified Alvarado scoring system (Table 47-3) help predict the need for surgical intervention, they have not been validated in a model of pregnancy.34 Ultrasound has been relied on as the first imaging tool in many centers. Graded compression ultrasound has been shown to have a sensitivity of 86% in the nonpregnant patient.27 In a case series of 42 pregnant women with suspected appendicitis, graded compression ultrasound was found to be 100% sensitive, 96% specific, and 98% accurate.36 Three women were excluded from the analysis because of a technically inadequate examination because of advanced gestational age (>35 weeks). Helical CT scanning has been established as a valuable tool for evaluation of the nonpregnant patient and shows promise as a second-line study in pregnancy. Compared with traditional CT scans, helical CT can provide a much faster study, with radiation exposures to the fetus of approximately 300 mrad.27 MRI is also beginning to play a role; it not only can demonstrate the normal appendix but it can also recognize an enlarged appendix, periappendiceal fluid, and inflammation.37 Large prospective series documenting the success of MRI diagnosis of appendicitis are lacking; however, one study has documented successful evaluation of 10 of 12 pregnant women while avoiding radiation exposure.38 The added difficulties in evaluating the pregnant patient with right lower quadrant abdominal pain have resulted in a significantly higher negative appendectomy rate as compared with their nonpregnant peers. False-positive diagnoses leading to negative appendectomies occur in 15% to 35% of pregnant

women presenting with lower abdominal pain.28 Although this diagnostic error rate would be unacceptable in a typical young healthy woman, it is widely accepted because of the fetal mortality suffered when appendicitis progresses to perforation prior to surgery. Perioperative fetal loss associated with appendectomy for early appendicitis is 3% to 5%, whereas it increases to more than 20% in the setting of perforation.39 The second and third most common surgical diseases seen in pregnancy are biliary tract disorders and bowel obstructions. Surgery for biliary disease occurs in 1 to 6 in 10,000 pregnancies.40 Symptoms of pain, nausea, and anorexia are the same as those in nonpregnant patients. Even though elevated estrogen levels should be more lithogenic, the incidence of disease is similar that for nongravid women.27 With few exceptions, the evaluation and treatment during pregnancy are similar to that for all patients with biliary disease. Ultrasound is the diagnostic test of choice. The alkaline phosphatase level is elevated secondary to an elevated estrogen level and normal values must be adjusted. Nuclear scans of the biliary tract pose minimal risk to the fetus but a Foley catheter should be placed so that isotope cleared by the kidneys does not collect adjacent to the uterus. Most surgeons try to treat simple biliary colic with conservative management in the first and third trimesters and plan elective laparoscopic cholecystectomy for the second trimester or the postpartum period to minimize fetal risk. Gallstone pancreatitis and acute cholecystitis should be managed more carefully. Gallstone pancreatitis has been associated with fetal loss as high as 60%.41 If a woman does not respond quickly to conservative treatment with hydration, bowel rest, analgesia, and judicious use of antibiotics, surgical treatment should be performed. Bowel obstructions are much less common, occurring in approximately 1 to 2 in 4000 deliveries; the underlying cause is adhesions in two thirds of cases. Volvulus is the second most common cause, occurring in 25% of cases compared with only 4% of the nonpregnant population.28 Signs and symptoms are typical but must not be attributed to morning sickness. Colicky abdominal pain with rapid abdominal distention should suggest the diagnosis to the clinician. Three periods during gestation are associated with an increased risk of obstruction and correlate with rapid changes in uterine size. The first is from 16 to 20 weeks, when the uterus grows beyond the pelvis. The second is from 32 to 36 weeks, when the fetal head descends, and the third is in the early postpartum period. The evaluation should be the same as for any patient and there should be no hesitation to obtain abdominal x-rays if the situation warrants. As with other acute inflammatory processes in the abdomen, maternal and fetal morbidity are most affected by delayed definitive treatment. Critically Ill Patients The critically ill patient with a potential acute abdomen is a difficult challenge for intensivists and surgeons. Many of the underlying diseases and treatments encountered in the intensive care unit (ICU) can predispose to acute abdominal disease. At the same time, unrecognized abdominal illness can be responsible for patients lingering in a critical state. Critically ill patients are often unable to appreciate symptoms to the same degree as their healthy peers because of nutritional or immune compromise, narcotic analgesia, or antibiotic use. Many of these patients have an altered mental status or are intubated and cannot provide detailed information to their providers.

SECTION X ABDOMEN

Table 47-3 Modified Appendicitis

1154 SECTION X ABDOMEN Cardiopulmonary bypass (CPB) has been associated with several acute abdominal illnesses. Mesenteric ischemia, paralytic ileus, Ogilvie’s syndrome, stress peptic ulceration, acute acalculous cholecystitis, and acute pancreatitis have all been linked to the low-flow state of CPB; their incidence appears to be linked to the duration of the cardiac procedure.42,43 Vasoactive medications and ventilator support have also been linked to hypoperfusion and similar abdominal processes. When an acute abdominal complication occurs in an ICU patient, it has a dramatic effect on outcome. Gajic and associates44 have studied 77 patients who experienced abdominal catastrophe while recovering in the medical ICU (MICU). Acute abdominal diagnoses included peptic ulcer, ischemic bowel, cholecystitis, bowel obstruction, and bowel inflammation. The APACHE III score on admission predicted an overall mortality of 31% in this group, yet they experienced an actual mortality of 63%. The development of a secondary acute abdominal illness doubled their observed mortality. Despite many of these patients having factors that could delay diagnosis, including antibiotics, analgesics, altered mental states, and intubations, 84% were still recognized as having abdominal pain, 95% as having abdominal tenderness, 73% as having abdominal distention, and 33% as having free intra-abdominal air. Inten sivists should maintain a high index of suspicion for the development of intra-abdominal disease and consult with surgeons early to maximize recovery potential. Surgeons must then work to exclude the possibility of abdominal disease using all the methods described in this chapter, as well as bedside ultrasound, paracentesis, or minilaparoscopy so that early surgical intervention can be undertaken appropriately. Immunocompromised Patients Immunocompromised patients have variable presentations with acute abdominal diseases. The variability is highly correlated to the degree of immunosuppression. There is no reliable test for determining the degree of immunosuppression experienced by a given patient so estimates are made by associations with certain disease states or medications. Mild to moderate compromise is experienced by older patients, malnourished individuals, diabetics, transplant recipients on routine maintenance therapy, cancer patients, renal failure patients, and HIV patients with CD4 counts higher than 200/mm3. Although patients in this group have the same types of illnesses and infections as those who are immunocompetent, they still can present in an atypical fashion. Abdominal pain and systemic signs and symptoms are often linked to the development of inflammation. These patients may not be able to mount a full inflammatory response and therefore may experience less abdominal pain and have delayed development of fever and a blunted leukocytosis. Severely compromised patients would typically include transplant recipients having received immunosuppressant therapy for rejection in the past 2 months, cancer patients on chemotherapy, especially those with neutropenia, and HIV patients with CD4 counts lower than 200/mm3. These patients present very late in their course, often with little or no pain, no fever, and vague constitutional symptoms, followed by an overwhelming systemic collapse. Pseudomembranous colitis has traditionally been associated with recent broad-spectrum antibiotic use, although it is increasingly seen in immunocompromised patients with diseases such as lymphoma, leukemia, and AIDS.45 Clinical manifestations commonly include diarrhea, dehydration, abdominal pain,

fever, and leukocytosis; however, immunocompromised patients may fail to exhibit many of these findings because of their inability to mount a normal inflammatory response. Imaging studies such as abdominal CT become increasingly important in making early accurate diagnoses when presentations are atypical. Characteristic findings on CT scans that suggest pseudomembranous colitis include bowel wall thickening (mean thickness, 11 to 15 mm),46 pancolonic distribution, and pericolonic standing. Other frequent findings include ascites, generalized mucosal enhancement, diffuse bowel dilation, and a double-halo sign, in which IV contrast enhances the mucosa and muscularis propria while edema in the submucosa creates an area of low attenuation in between (Table 47-4). These findings, when present, can greatly assist the clinician with forming the diagnosis of colitis. It is important to remember, however, that up to 14% of patients with proven pseudomembranous colitis will have had normal CT examinations and therefore the diagnosis should not be ruled out based solely on a negative scan.47 In addition, these patients may suffer from atypical infections, including peritoneal tuberculosis, fungal infections, including aspergillus and endemic mycoses, or viral infections, including cytomegalovirus and Epstein-Barr virus (Box 47-6). When an Table 47-4 Frequency of Common CT Findings in PseudoMembranous Colitis CT FINDINGS

FREQUENCY (%)

Bowel all thickening (>4 mm)

Pancolic distribution

Pericolic stranding

Ascites

Nodular/polypoid wall thickening

Mucosal enhancement

Bowel dilation

Accordion sign

From Tsiotos GG, Mullany CJ, Zietlow S, et al: Abdominal complications following cardiac surgery. Am J Surg 167:553–557, 1994.

BOX 47-6 Causes of Acute Abdominal Pain in the Immunocompromised Patient Opportunistic Infections Endemic mycoses (e.g., coccidiomycosis, blastomycosis, histoplasmosis) Tuberculin peritonitis Aspirgillosis Neutropenic colitis (typhlitis) Pseudomembranous colitis Cytomegalovirus colitis, gastritis, esophagitis, nephritis Epstein-Barr virus Hepatic abscess (fungal, pyogenic)

Iatrogenic Conditions Graft-versus-host disease with hepatitis or enteritis Peptic ulcer or perforation from steroid usage Pancreatitis caused by steroids or azathioprine Hepatic veno-occlusive disease (secondary to primary immunodeficiency or chemotherapy) Nephrolithiasis caused by indinavir treatment of HIV

Acute Abdomen Chapter 47 1155 intra-abdominal mass is also difficult because of the size and thickness of the abdominal wall. Abdominal imaging is also adversely affected by obesity. Plain abdominal radiography can require multiple images to view the entire abdomen, and clarity is reduced. CT and MRI may be impossible to perform as a patient’s girth or weight exceeds the size of the scanning aperture or weight limit of the mechanized bed. In these settings, a high index of suspicion and low threshold for surgical exploration must be maintained. Laparoscopy is a valuable tool in these patients. Specially designed trochars and hand-assist ports for the morbidly obese abdominal wall are now readily available and greatly facilitate minimally invasive exploration of the abdomen.

Morbidly Obese Patients Morbid obesity creates numerous challenges to the accurate diagnosis of acute abdominal processes. Many authors have described alterations in the signs and symptoms of peritonitis in the morbidly obese. Findings of overt peritonitis are often late and usually ominous, leading to sepsis, organ failure, and death.48Abdominal sepsis is a more subtle diagnosis in this population and may only be associated with symptoms such as malaise, shoulder pain, hiccups, and shortness of breath.49 Examination findings can also be difficult to interpret. Severe abdominal pain is not common and less specific findings such as tachycardia, tachypnea, pleural effusion, and fever may be the primary observation.50 Appreciation of distention or

ALGORITHMS IN THE ACUTE ABDOMEN Algorithms can aid in the diagnosis of the patient with an acute abdomen. As noted, computer-assisted diagnosis has been shown to be more accurate than clinical judgment alone in a number of acute abdominal disease states. Algorithms are the basis for computer diagnosis and can be useful when making clinical decisions. The algorithms shown are helpful in acute abdomen patients and can allow for a focused workup and expeditious therapy (Figs. 47-15 to 47-20).

History and physical

Acute onset

No peritoneal signs

Peritoneal signs

Acidosis, ↑lactate

Abdominal x-ray

Arterial ischemia

NL Consider angio

Mesenteric venous thrombosis

Pneumoperitoneum

No pneumoperitoneum

Water-soluble contrast swallow

or OR

Angio

Anticoagulation

Leak, not contained

Contained leak

NG + antibiotics

No leak

FIGURE 47-15 Algorithm for the treatment of acute-onset, severe, generalized abdominal pain. NG, Nasogastric tube; NL, normal study; OR, operation.

SECTION X ABDOMEN

abdominal infection does occur, it is less likely to be walled off as a localized infection because of the lack of inflammatory reaction. All severely immunocompromised patients require prompt and thorough evaluation for any persistent abdominal complaints. All patients requiring hospitalization should receive a surgical consult to aid in timely diagnosis and treatment. Highresolution CT can be of great benefit in these patients, but a low threshold for laparoscopy or laparotomy should be maintained for those with equivocal diagnostic test results and persistent symptoms that remain unexplained.

1156 SECTION X ABDOMEN

History and physical

Gradual onset

Amylase, lipase, LFTs

Pancreatitis

Fever, abnormal LFTs, cholangitis

Evaluate severity

Antibiotics, ? ERCP

Mild

Moderate

Severe

Supportive treatment

Consider CT

No shock

Shock, respiratory failure

Consider peritoneal lavage

FIGURE 47-16 Algorithm for the treatment of gradual-onset, severe, generalized abdominal pain. ERCP, Endoscopic retrograde cholangiopancreatography; LFTs, liver function tests.

History and physical

LFTs, amylase, lipase

↑ LFTs, NL amylase, lipase

Gallstones

Laparoscopy

Directed therapy

Dilated bile ducts

NL bile ducts

CT vs. ERCP

Directed therapy

History and physical

CT-directed therapy FIGURE 47-18 Algorithm for the treatment of left upper quadrant abdominal pain.

FIGURE 47-17 Algorithm for the treatment of right upper quadrant abdominal pain. ERCP, Endoscopic retrograde cholangiopan creatography; LFTs, liver function tests; NL, normal study; US, ultrasound.

SUMMARY Evaluation and management of the patient with acute abdominal pain remains a challenging part of a surgeon’s practice. Although advances in imaging techniques, use of algorithms, and computer assistance have improved the diagnostic accuracy for the conditions causing the acute abdomen, a careful history and physical examination remain the most important part of the evaluation. Even with these tools available, the surgeon must often make the decision to perform a laparoscopy or laparotomy with a good deal of uncertainty about the expected findings. Increased morbidity and mortality associated with a delay in the treatment of many of the surgical causes of the acute abdomen argue for an aggressive and expeditious surgical approach.

Acute Abdomen Chapter 47 1157

SECTION X ABDOMEN

History and physical

Female

Male

Gynecologic hx, ? UTI, ? appendicitis

Presentation consistent with appendicitis

Equivocal presentation

Laparotomy vs. laparoscopy

CT-directed therapy

Appendicitis

No appendicitis

Laparoscopy/laparotomy

CT-directed therapy

FIGURE 47-19 Algorithm for the treatment of right lower quadrant abdominal pain. hx, History; OR, operation; UTI, urinary tract infection.

History and physical

Peritonitis

No peritonitis

Contained abscess

Perforation

Antibiotics + percutaneous drainage

Laparotomy

Diverticulitis

Equivocal

Antibiotics

CT-directed therapy

Elective resection FIGURE 47-20 Algorithm for the treatment of left lower quadrant abdominal pain.

SELECTED REFERENCES Ahmad TA, Shelbaya E, Razek SA, et al: Experience of laparoscopic management in 100 patients with acute abdomen. Hepatogastro enterology 48:733–736, 2001.

Cademartiri F, Raaijmaker RHJM, Kuiper JW, et al: Multi-detector row CT angiography in patients with abdominal angina. Radiogra phics 24:969–984, 2004.

A description of the usefulness of laparoscopy in a large series of patients with acute abdomen. This is a good review of this important diagnostic and therapeutic tool.

A good review of the computerized tomographic characteristics of acute mesenteric ischemia. This outlines the radiographic findings that have greatly assisted in the diagnosis of this otherwise difficult condition.

1158 SECTION X ABDOMEN Graff LG, Robinson D: Abdominal pain and emergency department evaluation. Emerg Med Clin North Am 19:123–136, 2001. Good review of the spectrum of patients presenting with acute abdominal pain.

Macari M, Balthazar EJ: The acute right lower quadrant: CT evaluation. Radiol Clin North Am 41:1117–1136, 2003. A modern discussion of the role of CT in the evaluation of patients with right lower quadrant abdominal pain.

Silen W: Cope’s early diagnosis of the acute abdomen, ed 21, New York, 2005, Oxford University Press. This is a classic monograph stressing the importance of history and physical examination in the diagnosis of the acute abdomen. Almost all diseases presenting as an acute abdomen are presented. This is a mustread for the surgical resident.

Steinheber FU: Medical conditions mimicking the acute surgical abdomen. Med Clin North Am 57:1559–1567, 1973. This classic article reviews the various medical conditions that can present as an acute abdomen. It is well written and remains pertinent to the evaluation of these patients.

REFERENCES 1. Sethuraman U, Siadat M, Lepak-Hitch CA, et al: Pulmonary embolism presenting as acute abdomen in a child and adult. Am J Emerg Med 27:514 e511–515, 2009. 2. Graff LGT, Robinson D: Abdominal pain and emergency department evaluation. Emerg Med Clin North Am 19:123–136, 2001. 3. Steinheber FU: Medical conditions mimicking the acute surgical abdomen. Med Clin North Am 57:1559–1567, 1973. 4. Gilbert JA, Kamath PS: Spontaneous bacterial peritonitis: An update. Mayo Clin Proc 70:365–370, 1995. 5. Silen W: Cope’s early diagnosis of the acute abdomen, ed 21, New York, 2005, Oxford University Press. 6. Paterson-Brown S, Vipond MN: Modern aids to clinical decisionmaking in the acute abdomen. Br J Surg 77:13–18, 1990. 7. de Dombal FT: Computers, diagnoses and patients with acute abdominal pain. Arch Emerg Med 9:267–270, 1992. 8. Adams ID, Chan M, Clifford PC, et al: Computer aided diagnosis of acute abdominal pain: A multicentre study. Br Med J (Clin Res Ed) 293:800–804, 1986. 9. Wellwood J, Johannessen S, Spiegelhalter DJ: How does computeraided diagnosis improve the management of acute abdominal pain? Ann R Coll Surg Engl 74:40–46, 1992. 10. McAdam WA, Brock BM, Armitage T, et al: Twelve years’ experience of computer-aided diagnosis in a district general hospital. Ann R Coll Surg Engl 72:140–146, 1990. 11. Kort B, Katz VL, Watson WJ: The effect of nonobstetric operation during pregnancy. Surg Gynecol Obstet 177:371–376, 1993. 12. Macari M, Balthazar EJ: The acute right lower quadrant: CT evaluation. Radiol Clin North Am 41:1117–1136, 2003. 13. Cademartiri F, Raaijmakers RH, Kuiper JW, et al: Multi-detector row CT angiography in patients with abdominal angina. Radiographics 24:969–984, 2004.

14. Lee R, Tung HK, Tung PH, et al: CT in acute mesenteric ischaemia. Clin Radiol 58:279–287, 2003. 15. in’t Hof KH, Krestin GP, Steijerberg EW, et al: Interobserver variability in CT scan interpretation for suspected acute appendicitis. Emerg Med J 26:92–94, 2009. 16. Hanbidge AE, Buckler PM, O’Malley ME, et al: From the RSNA refresher courses: Imaging evaluation for acute pain in the right upper quadrant. Radiographics 24:1117–1135, 2004. 17. Zissin R, Osadchy A, Gayer G: Abdominal CT findings in small bowel perforation. Br J Radiol 82:162–171, 2009. 18. De Keulenaer BL, De Waele JJ, Powell B, et al: What is normal intra-abdominal pressure and how is it affected by positioning, body mass and positive end-expiratory pressure? Intens Care Med 35:969–976, 2009. 19. Ahmad TA, Shelbaya E, Razek SA, et al: Experience of laparoscopic management in 100 patients with acute abdomen. Hepatogastroenterology 48:733–736, 2001. 20. Perri SG, Altilia F, Pietrangeli F, et al: [Laparoscopy in abdominal emergencies. Indications and limitations.] Chir Ital 54:165–178, 2002. 21. Riemann JF: Diagnostic laparoscopy. Endoscopy 35:43–47, 2003. 22. Pecoraro AP, Cacchione RN, Sayad P, et al: The routine use of diagnostic laparoscopy in the intensive care unit. Surg Endosc 15:638–641, 2001. 23. Stefanidis D, Richardson WS, Chang L, et al: The role of diagnostic laparoscopy for acute abdominal conditions: an evidencebased review. Surg Endosc 23:16–23, 2009. 24. Hickey MS, Kiernan GJ, Weaver KE: Evaluation of abdominal pain. Emerg Med Clin North Am 7:437–452, 1989. 25. Lachman E, Schienfeld A, Voss E, et al: Pregnancy and laparoscopic surgery. J Am Assoc Gynecol Laparosc 6:347–351, 1999. 26. Fatum M, Rojansky N: Laparoscopic surgery during pregnancy. Obstet Gynecol Surv 56:50–59, 2001. 27. Sharp HT: The acute abdomen during pregnancy. Clin Obstet Gynecol 45:405–413, 2002. 28. Tarraza HM, Moore RD: Gynecologic causes of the acute abdomen and the acute abdomen in pregnancy. Surg Clin North Am 77:1371–1394, 1997. 29. Fallon WF Jr, Newman JS, Fallon GL, et al: The surgical management of intra-abdominal inflammatory conditions during pregnancy. Surg Clin North Am 75:15–31, 1995. 30. Baer J, Reis R, Arens R: Appendicitis in pregnancy with changes in position and axis of the normal appendix in pregnancy. JAMA 52:1359–1364, 1932. 31. Hunt MG, Martin JN Jr, Martin RW, et al: Perinatal aspects of abdominal surgery for nonobstetric disease. Am J Perinatol 6:412– 417, 1989. 32. Kammerer WS: Nonobstetric surgery in pregnancy. Med Clin North Am 71:551–560, 1987. 33. Mazze RI, Kallen B: Appendectomy during pregnancy: A Swedish registry study of 778 cases. Obstet Gynecol 77:835–840, 1991. 34. Brown JJ, Wilson C, Coleman S, et al: Appendicitis in pregnancy: An ongoing diagnostic dilemma. Colorectal Dis 11:116–122, 2009. 35. Tamir IL, Bongard FS, Klein SR: Acute appendicitis in the pregnant patient. Am J Surg 160:571–575, 1990. 36. Lim HK, Bae SH, Seo GS: Diagnosis of acute appendicitis in pregnant women: Value of sonography. AJR Am J Roentgenol 159:539–542, 1992.

Acute Abdomen Chapter 47 1159 45. Ramachandran I, Sinha R, Rodgers P: Pseudomembranous colitis revisited: Spectrum of imaging findings. Clin Radiol 61:535–544, 2006. 46. Fishman EK, Kavuru M, Jones B, et al: Pseudomembranous colitis: CT evaluation of 26 cases. Radiology 180:57–60, 1991. 47. Kawamoto S, Horton KM, Fishman EK: Pseudomembranous colitis: Spectrum of imaging findings with clinical and pathologic correlation. Radiographics 19:887–897, 1999. 48. Mehran A, Liberman M, Rosenthal R, et al: Ruptured appendicitis after laparoscopic Roux-en-Y gastric bypass: Pitfalls in diagnosing a surgical abdomen in the morbidly obese. Obes Surg 13:938–940, 2003. 49. Byrne TK: Complications of surgery for obesity. Surg Clin North Am 85, 2001. 50. Hamilton EC, Sims TL, Hamilton TT, et al: Clinical predictors of leak after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Surg Endosc 17:679–684, 2003.

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37. Brown MA, Birchard KR, Semelka RC: Magnetic resonance evaluation of pregnant patients with acute abdominal pain. Semin Ultrasound CT MR 26:206–211, 2005. 38. Cobben LP, Groot I, Haans L, et al: MRI for clinically suspected appendicitis during pregnancy. AJR Am J Roentgenol 183:671– 675, 2004. 39. Mahmoodian S: Appendicitis complicating pregnancy. South Med J 85:19–24, 1992. 40. Lanzafame RJ: Laparoscopic cholecystectomy during pregnancy. Surgery 118:627–631, 1995. 41. Printen KJ, Ott RA: Cholecystectomy during pregnancy. Am Surg 44:432–434, 1978. 42. Tsiotos GG, Mullany CJ, Zietlow S, et al: Abdominal complications following cardiac surgery. Am J Surg 167:553–557, 1994. 43. Welling RE, Rath R, Albers JE, et al: Gastrointestinal complications after cardiac surgery. Arch Surg 121:1178–1180, 1986. 44. Gajic O, Urrutia LE, Sewani H, et al: Acute abdomen in the medical intensive care unit. Crit Care Med 30:1187–1190, 2002.

CHAPTER 48

ACUTE GASTROINTESTINAL HEMORRHAGE Ali Tavakkolizadeh and Stanley W. Ashley

approach to the patient acute upper gastrointestinal hemorrhage acute lower gastrointestinal hemorrhage obscure causes of acute gastrointestinal hemorrhage

Acute gastrointestinal (GI) hemorrhage is a common clinical problem with diverse manifestations. This bleeding may range from trivial to massive and can originate from almost any region of the GI tract, including the pancreas, liver, and biliary tree. Although no demographic group is spared, the annual incidence of approximately 170 cases/100,000 adults increases steadily with advancing age, and is slightly more common in men than women.1 Furthermore, GI hemorrhage accounts for 1% to 2% of acute admissions, resulting in over 300,000 annual hospitalizations in the United States.2 It is also a common complication in patients hospitalized for other illnesses, especially surgical patients. Although the total economic burden of GI hemorrhage has not been formally assessed, annual estimates have suggested that diverticular bleeding alone costs the health care system in excess of 1.3 billion dollars.3 Management of these patients is frequently multidisciplinary, involving emergency medicine, gastroenterology, intensive care, surgery, and interventional radiology. The importance of early surgical consultation in the care of these patients cannot be overemphasized.4 In addition to aiding in the resuscitation of the unstable patient, in some settings the surgical endoscopist establishes the diagnosis and initiates therapy. Even when the gastroenterologist assumes this role, early collaboration with the surgeon permits the establishment of goals and limits for initial nonoperative therapy. Ultimately, 5% to 10% of patients hospitalized for bleeding require an operation intervention. Prompt surgical consultation permits more time for preoperative preparation and evaluation, as well as patient and family education, if urgent surgical intervention become necessary.1 Most patients with an acute GI hemorrhage stop bleeding spontaneously. This allows time for a more elective evaluation. However, in almost 15% of cases, major bleeding persists, requiring emergent resuscitation, evaluation, and treatment.5 Improvements in the management of such patients, primarily by means of early endoscopy and directed therapy, have significantly reduced the length of hospitalization. Despite this, mortality remains more than 5% and is significantly higher in those initially hospitalized for other reasons. This discrepancy between therapeutic advances and outcomes is probably related to the 1160

aging of the population, with an increase in comorbidity. Today, the patient requiring operative intervention is both older and sicker than in the past. Hemorrhage can originate from any region of the GI tract and is typically classified based on its location relative to the ligament of Treitz. Upper GI hemorrhage from proximal to the ligament of Treitz accounts for more than 80% of cases of acute bleeding.1 Peptic ulcer disease and variceal hemorrhage are the most common causes. Most lower GI bleeding is from the colon, with diverticula and angiodysplasias accounting for most cases. In less than 5% of patients, the small intestine in responsible.1 Obscure bleeding is defined as hemorrhage that persists or recurs after negative endoscopy. Occult bleeding is not apparent to patients until they present with symptoms related to the anemia. Determination of the site of bleeding is important for directing diagnostic interventions with minimal delay. However, attempts to localize the source should never precede appropriate resuscitative measures. APPROACH TO THE PATIENT In patients with GI bleeding, several fundamental principles of initial evaluation and management must be followed. A welldefined and logical approach to the patient with GI hemorrhage is outlined in Figure 48-1. On presentation, a rapid initial assessment permits determination of the urgency of the situation. Resuscitation is initiated with stabilization of the patient’s hemodynamic status and the establishment of a means for monitoring ongoing blood loss. A careful history and physical examination should provide clues to the cause and source of the bleeding and identify any complicating conditions or medications. Specific investigation should proceed to refine the diagnosis. Therapeutic measures are then initiated, bleeding is controlled, and recurrent hemorrhage is prevented. Initial Assessment Adequacy of the patient’s airway and breathing take first priority. Once these are ensured, the patient’s hemodynamic status becomes the dominant concern and forms the basis for further management. The presentation of GI bleeding is variable, ranging from hemoccult-positive stool on rectal examination to exsanguinating hemorrhage. Initial evaluation should focus on rapid assessment of the magnitude of the preexisting deficits and of ongoing hemorrhage. Continuous reassessment of the patient’s circulatory status determines the aggressiveness of subsequent evaluation and intervention. The history of the bleeding, its magnitude and frequency, should also provide some guidance.

Acute Gastrointestinal Hemorrhage Chapter 48 1161

History and exam Identify risk factors Previous surgery Medications

Localize bleeding Nasogastric tube aspirate Endoscopy Other studies as needed

Initiate therapy Pharmacologic Endoscopic Angiographic Surgical FIGURE 48-1 General approach to the patient with acute GI hemorrhage.

The severity of the hemorrhage can be generally determined based on simple clinical parameters. Obtundation, agitation, and hypotension (systolic blood pressure 60 yr Comorbid disease Renal failure Liver disease Respiratory insufficiency Cardiac disease Magnitude of the hemorrhage Systolic blood pressure 80 g/day of ethanol), and consumption of red meat or salt-cured foods.

radiologic studies. Of the remainder, pain, most often related to obstruction, is the most frequent complaint. Usually, obstruction is the result of intussusception, and benign small tumors are the most common cause of this condition in adults. Hemorrhage is the next most common symptom. Bleeding is usually occult; hematochezia or hematemesis may occur, although lifethreatening hemorrhage is uncommon. Diagnosis

Because of the insidious nature of many of the small bowel neoplasms, a high index of suspicion must be present for these neoplasms to be diagnosed. In most series, a correct preoperative diagnosis is made in only 20% to 50% of symptomatic patients. An upper gastrointestinal tract series with small intestinal followthrough yields an accurate diagnosis in 50% to 70% of patients with malignant neoplasms of the small intestine (Fig. 50-28). CT enteroclysis appears to be an even more sensitive technique, with a diagnostic accuracy of approximately 90%.7 Flexible endoscopy may be useful, particularly in diagnosing duodenal lesions, and often the colonoscope can be advanced into the terminal ileum for visualization and biopsy of ileal neoplasms. Push enteroscopy has not been used routinely to evaluate lesions in the small bowel because this test may take up to 8 hours to perform and may not visualize the entire small bowel. The use of swallowed radiotelemetry capsules (e.g., capsule endoscopy) that transmit images of the bowel wall may be of diagnostic value.

Clinical Manifestations

Symptoms associated with small bowel neoplasms are often vague and nonspecific and may include dyspepsia, anorexia, malaise, and dull abdominal pain, often intermittent and colicky. These symptoms may be present for months or years before surgery. Most patients with benign neoplasms remain asymptomatic, and the neoplasms are only discovered at autopsy or as incidental findings at laparotomy or upper gastrointestinal

FIGURE 50-28 Barium radiograph demonstrates a typical apple core lesion (arrows) caused by adenocarcinoma of the small bowel, producing a partial obstruction with dilated proximal bowel. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

Small Intestine Chapter 50 1257

Adenomas

FIGURE 50-29 CT scan of abdomen demonstrates a small bowel neoplasm (arrow). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

Plain films may confirm the presence of an obstruction; however, for the most part, they are useless in making a diagnosis of small bowel neoplasms. Angiography is of value in diagnosing and localizing tumors of vascular origin. CT of the abdomen can prove particularly useful in detecting extraluminal tumors, such as gastrointestinal stromal tumors (GISTs), and can provide helpful information regarding the staging of malignant cancers (Fig. 50-29). Ultrasonography has not proved to be effective in making the preoperative diagnosis of small bowel neoplasm. Despite sophisticated imaging and diagnostic modalities, diagnosis of a small bowel tumor is often achieved only at the time of surgical exploration, performed as an elective or emergency procedure. Benign Neoplasms The most common benign neoplasms include benign GISTs, adenomas, and lipomas. Adenomas are the most common benign tumors reported in autopsy series, but GISTs are the most common benign small bowel lesions that produce symptoms. In general, when a benign tumor is identified at operation, resection is indicated because symptoms, if not the reason for operation, are likely to develop over time. At operation, a thorough search of the remainder of the small bowel is warranted because multiple tumors are not uncommon. Leiomyomas

Leiomyomas, benign tumors of smooth muscle origin, are the most common symptomatic benign neoplasms of the small bowel. As the origin of these tumors has become clearer, pathologists have shifted from designations such as leiomyoma or leiomyosarcoma to the term stromal tumors (i.e., GISTs).27 Currently, these tumors are thought to arise from the interstitial cell of Cajal, an intestinal pacemaker cell of mesodermal descent. These tumors are made up of spindle (70%) and epithelioid (30%) cells, and benign GISTs are three to four times more common than malignant GISTs. Most (>90%) GISTs express CD117, the c-kit proto-oncogene protein that is a transmembrane receptor for the stem cell growth factor, and 70% to 80% express CD34, the human progenitor cell antigen. Less frequently, these tumors stain positive for actin and desmin. The

Adenomas account for approximately 15% of all benign small bowel tumors and are of three primary types: true adenomas, villous adenomas, and Brunner gland adenomas. Twenty percent of adenomas are found in the duodenum, 30% are found in the jejunum, and 50% are found in the ileum. Most of these lesions are asymptomatic, with most occurring singly and found incidentally at autopsy. The most common presenting symptoms are bleeding and obstruction. Villous adenomas of the small bowel are rare but do occur, are most commonly found in the duodenum, and may be associated with the familial polyposis syndrome. Both true and villous adenomas are thought to proceed along a similar adenoma-carcinoma sequence as colorectal adenomas and should be considered premalignant. Villous adenomas have a particular propensity for malignant degeneration and may be of relatively large size (>5 cm) in diameter. They are usually noted secondary to abdominal pain or bleeding; obstruction may also occur. The malignant potential of these lesions is reportedly between 35% and 55%. Treatment is determined by location and adenoma type. In the jejunum and ileum, the treatment of choice is segmental resection. Because of the potential morbidity associated with duodenal resection by pancreaticoduodenectomy or pancreas-preserving duodenectomy, the management of duodenal adenomas is different. For sporadic adenomas, endoscopic or open polypectomy can be performed if technically feasible. Although both these treatment strategies are associated with a recurrence rate of 30% to 50%, especially in adenomas larger than 3 cm, postpolypectomy surveillance remains possible.28 Invasive changes or a recurrence after polypectomy necessitate more of a definitive resection, such as a pancreaticoduodenectomy. Familial adenomas typically occur in the presence of familial adenomatous polyposis (FAP) syndrome and require a different algorithm. FAP-affected patients carry a 5% lifetime risk of developing duodenal adenocarcinoma, which represents the leading cause of cancer-related mortality in these kindreds. Typically, the adenoma burden is diffuse throughout the duodenum, making polypectomy impossible. To direct surveillance and treatment, patients are characterized by the Spigelman classification (Table 50-7). Screening endoscopy with a forward- and side-viewing endoscope is performed at regular intervals with biopsy of all suspicious, villous, or large (>3 cm) adenomas, in addition to random duodenal biopsies. Frequency of endoscopic screening is 1 to 3 years, depending on the Spigelman classification (I to III).28 Endoscopic or surgical polypectomy can be performed on large adenomas. Ablative therapy in the form of argon beam coagulation or photodynamic therapy has been

SECTION X ABDOMEN

incidence is equal in men and in women, and they are most frequently diagnosed in the fifth decade of life. Grossly, they are firm, gray-white lesions with a whorled appearance noted on cut surface; microscopic examination demonstrates welldifferentiated smooth muscle cells. These tumors may grow intramurally and cause obstruction. Alternatively, the tumors demonstrate intramural and extramural growth, sometimes achieving considerable size and eventually outgrowing their blood supply, resulting in bleeding manifestations, which is the most common indication for surgery in patients with benign stromal tumors. Surgical resection is necessary for appropriate treatment. Mitotic counts higher than 2/50 high-power fields imply an increased risk for local recurrence.

1258 SECTION X ABDOMEN

Table 50-7 Spigelman Adenomatosis

Classification

for

Duodenal

Points PARAMETER

No. of polyps

1-4

5-20

>20

Polyp size (mm)

1-4

5-10

>10

Histology

Tubular

Tubulovillous

Villous

Degree of dysplasia

Mild

Moderate

Severe

Stage 0, 0 points; stage 1, 1-4 points; stage 2, 5-6 points; stage 3, 7-8 points; stage 4, 9-12 points.

hemorrhage is uncommon but may occur. Although once considered a purely benign disease, adenomatous changes have been reported in 3% to 6% of hamartomas. Extracolonic cancers are common, occurring in 50% to 90% of patients (small intestine, stomach, pancreas, ovary, lung, uterus, and breast). The small intestine represents the most frequent site for cancer, compared with that of the general population. The treatment of complications of Peutz-Jeghers syndrome is directed mainly at the complication of obstruction or persistent bleeding. Resection should be limited to the segment of bowel that is producing complications and usually involves a limited resection. Because of the widespread nature of intestinal involvement, cure is not possible, and extensive resections are not indicated. Hemangiomas

attempted for these patients, but with disappointing results. The presence of high-grade dysplasia, carcinoma in situ, or a Spigelman IV classification necessitates pancreaticoduodenectomy or pancreas-preserving duodenectomy.28 Adenomas of the remaining small bowel also occur more frequently in FAP kindreds but are not as prevalent as the duodenal disease. Brunner gland adenomas represent benign hyperplastic lesions arising from the Brunner glands of the proximal duodenum. These adenomas may produce symptoms mimicking those of peptic ulcer disease. Diagnosis can usually be accomplished by endoscopy and biopsy, and symptomatic lesions in an accessible region should be resected by simple excision. There is no malignant potential for Brunner gland adenomas and a radical resection should not be used. Lipomas

Lipomas, which are also included in the category of stromal tumors, are most common in the ileum and present as single intramural lesions located in the submucosa. They usually occur in the sixth and seventh decades of life and are more frequent in men. Less than one third of these tumors are symptomatic and, of these, the most common manifestations are obstruction and bleeding from superficial ulcerations. The treatment of choice for symptomatic lesions is excision. Lipomas do not have malignant potential and therefore, when found incidentally, should be removed only if the resection is simple. Peutz-Jeghers Syndrome

Hamartomas of the small bowel occur as part of the PeutzJeghers syndrome, an inherited syndrome of mucocutaneous melanotic pigmentation and gastrointestinal polyps. The pattern of inheritance is simple mendelian dominant, with a high degree of penetrance. The classic pigmented lesions are small, 1- to 2-mm, brown or black spots located in the circumoral region of the face, buccal mucosa, forearms, palms, soles, digits, and perianal area. The entire jejunum and ileum are the most usual portions of the gastrointestinal tract involved with these hamartomas; however, 50% of patients may also have rectal and colonic lesions, and 25% of patients have gastric lesions. The most common symptom is recurrent colicky abdominal pain, usually as a result of intermittent intussusception. Lower abdominal pain associated with a palpable mass has been reported to occur in one third of patients. Hemorrhage as a result of autoamputation of the polyps occurs less frequently and is most commonly manifested by anemia. Acute life-threatening

Hemangiomas are developmental malformations consisting of submucosal proliferation of blood vessels. They can occur at any level of the gastrointestinal tract; the jejunum is the most commonly affected small bowel segment. Hemangiomas account for 3% to 4% of all benign tumors of the small bowel and are multiple in 60% of patients. Hemangiomas of the small bowel may occur as part of an inherited disorder known as OslerWeber-Rendu disease. In addition to the small bowel, hemangiomas may also be present in the lung, liver, and mucous membranes. Patients with Turner’s syndrome are likely also to have cavernous hemangiomas of the intestine. The most common symptom of small bowel hemangiomas is intestinal bleeding. Angiography and 99mTc–red blood cell scanning are the most useful diagnostic studies. If a hemangioma is localized preoperatively, resection of the involved segment of intestine is warranted. If not identified, intraoperative transillumination and palpation can be helpful Malignant Neoplasms Recent population-based analyses have shown that the incidence of malignant neoplasms of the small intestine has increased steadily over the past 3 decades. This increase has mirrored the increase in diagnosis of small bowel carcinoids, which have surpassed adenocarcinoma as the primary cause of small bowel malignancy. Based on both the Surveillance, Epidemiology and End Result (SEER) program and National Cancer Data Base (NCDB), small bowel malignancies, in order of frequency, include carcinoid, adenocarcinoma, lymphoma, and GIST.29 Surprisingly, treatment and outcome have changed little over the same time frame, which highlights the need for further investigation concerning the multidisciplinary management of these diseases. In contrast to benign lesions, malignant neoplasms almost always produce symptoms, the most common of which are pain and weight loss. Obstruction develops in 15% to 35% of patients and, unlike the intussusception produced by benign lesions, is usually the result of tumor infiltration and adhesions. Diarrhea with tenesmus and passage of large amounts of mucus may occur. Gastrointestinal bleeding, manifested by anemia and guaiac-positive stools or occasionally by melena or hematochezia, occurs to varying degrees with malignant lesions and is more common with leiomyosarcomas. A palpable mass may be felt in 10% to 20% of patients and perforations develop in approximately 10%, usually secondary to lymphomas and sarcomas. Although presentation may be similar, each tumor type has a distinct biology that dictates management and prognosis.

Small Intestine Chapter 50 1259

Carcinoids of the small bowel arise from enterochromaffin cells (Kulchitsky cells), found in the crypts of Lieberkühn30; these cells are also known as argentaffin cells because of their staining by silver compounds. These tumors were first described by Lubarsch in 1888; in 1907, Oberndorfer coined the term Karzinoide to indicate the carcinoma-like appearance and the presumed lack of malignant potential. Carcinoid tumors have been reported in a number of organs, including most commonly the lungs, bronchi, and gastrointestinal tract. Most patients with small bowel carcinoids are in their fifth decade of life. Carcinoids may be classified by the embryologic site of origin and secretory product. Carcinoid tumors may be derived from the foregut (respiratory tract, thymus), midgut (jejunum, ileum and right colon, stomach, proximal duodenum), and hindgut (distal colon, rectum). Foregut carcinoids characteristically produce low levels of serotonin (5-hydroxytryptamine) but may secrete 5-hydroxytryptophan (5-HTP) or adrenocorticotropic hormone. Midgut carcinoids are characterized by having high serotonin production. Hindgut carcinoids rarely produce serotonin but may produce other hormones, such as somatostatin and peptide YY. The gastrointestinal tract is the most common site for carcinoid tumors. After the appendix, the small intestine is the second most frequently affected site in the gastrointestinal tract. In the small intestine, carcinoids almost always occur within the last 2 feet of the ileum. Carcinoid tumors have a variable malignant potential and are composed of multipotential cells with the ability to secrete numerous humoral agents, the most prominent of which are serotonin and substance P (Table 50-8). In addition to these substances, carcinoid tumors have been found to secrete corticotropin, histamine, dopamine, neurotensin, prostaglandins, kinins, gastrin, somatostatin, pancreatic polypeptide, calcitonin, and neuron-specific enolase. The primary importance of carcinoid tumors is the malignant potential of the tumors themselves. Although the carcinoid syndrome, which is characterized by episodic attacks of cutaneous flushing, bronchospasm, diarrhea, and vasomotor collapse, can occur and is dramatic in its most florid form, it occurs in only a small percentage of patients with malignant carcinoids. Pathology Carcinoid tumors may arise in organs derived from

the foregut, midgut, and hindgut. Seventy percent to 80% of carcinoids are asymptomatic and found incidentally at the time of surgery. In the gastrointestinal tract, more than 90% of carcinoids are found in three sites—appendix (45%), ileum (28%), and rectum (16%; Table 50-9). The malignant potential (ability to metastasize) is related to location, size, depth of invasion, and growth pattern. Only approximately 3% of appendiceal carcinoids metastasize, but approximately 35% of ileal carcinoids are associated with metastasis. Most (≈75%) gastrointestinal carcinoids are smaller than 1 cm in diameter, and approximately 2% of these are associated with metastasis. In contrast, carcinoid tumors 1 to 2 cm in diameter and larger than 2 cm are associated with metastasis in 50% and 80% to 90% of cases, respectively. Grossly, these tumors are small, firm submucosal nodules that are usually yellow on cut surface (Fig. 50-30). They may be as subtle as a small whitish plaque seen on the antimesenteric border of the small intestine. Typically, they are associated with a larger mesenteric mass caused by nodal disease and

Table 50-8 Secretory Products of Carcinoid Tumors* AMINES

TACHYKININS

PEPTIDES

OTHER

5-HT

Kallikrein

Pancreatic polypeptide (40%)

Prostaglandins

5-HIAA (88%)

Substance P (32%)

Chromogranins (100%)

5-HTP

Neuropeptide K (67%)

Neurotensin (19%)

Histamine

HCG-α (28%)

Dopamine

HCG-β Motilin (14%)

*Values in parentheses represent percentage frequency. HCG, Human chorionic gonadotropin; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan.

Table 50-9 Distribution of Gastrointestinal Carcinoids: Incidence of Metastases and of Carcinoid Syndrome AVERAGE METASTASIS (%)

CASES OF CARCINOID SYNDROME

SITE

CASES

Esophagus

Stomach

93 (2%)

Duodenum

135 (4%)

Jejunoileum

1032 (28%)

Meckel’s diverticulum

42 (1%)

Appendix

1686 (45%)

Colon

91 (2%)

Rectum

592 (16%)

Ovary

Biliary tract

Pancreas

Total

3718

136

Adapted from Cheek RC, Wilson H: Carcinoid tumors. Curr Probl Surg (Nov):4–31, 1970.

desmoplastic invasion of the mesentery, which is often mistaken for the primary tumor. They tend to grow very slowly but, after invasion of the serosa, the intense desmoplastic reaction produces mesenteric fibrosis, intestinal kinking, and intermittent obstruction. Small bowel carcinoids are multicentric in 20% to 30% of patients. This tendency to multicentricity exceeds that of any other malignant neoplasm of the gastrointestinal tract. Another unusual observation is the frequent coexistence of a second primary malignant neoplasm of a different histologic type. This is usually a synchronous adenocarcinoma (most commonly in the large intestine) that can occur in 10% to 20% of patients with carcinoid tumors. Carcinoid tumors are associated with multiple endocrine neoplasia type 1 in approximately 10% of cases. Clinical Manifestations In the absence of carcinoid syndrome, symptoms of patients with carcinoid tumors of the small bowel

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Carcinoid Tumors

1260 SECTION X ABDOMEN

FIGURE 50-30 Gross pathologic characteristics of carcinoid tumor. A, Carcinoid tumor of the distal ileum demonstrates the intense desmoplastic reaction and fibrosis of the bowel wall. B, Mesenteric metastases from a carcinoid tumor of the small bowel. (Adapted from Evers BM, Townsend CM Jr, Thompson JC: Small intestine. In Schwartz SI [ed]: Principles of surgery, ed 7, New York, 1999, McGraw-Hill, p 1245.)

are similar to those of patients with small bowel tumors of other histologic types. The most common symptoms include abdominal pain, which is variably associated with partial or complete small intestinal obstruction. Obstructive symptoms can be caused by intussusception but usually occur secondary to a local desmoplastic reaction, apparently produced by humoral agents elaborated by the tumor. Diarrhea and weight loss may also occur. The diarrhea is a result of a partial bowel obstruction rather than the secretory diarrhea noted in patients with the malignant carcinoid syndrome. As mesenteric and nodal extension progress, local venous engorgement and ultimately ischemia of the affected segment of intestine contribute to most symptoms and complications related to the tumor. Malignant Carcinoid Syndrome The malignant carcinoid syn-

drome is a relatively rare disease, occurring in fewer than 10% of patients with carcinoid tumors. The syndrome is usually associated with carcinoid tumors of the gastrointestinal tract, particularly from the small bowel, but carcinoids in other locations, such as the bronchus, pancreas, ovary, and testes, have also been described in association with the syndrome. Because of the first-pass metabolism of the vasoactive peptides responsible for carcinoid syndrome, hepatic metastasis or extra-abdominal disease is necessary to elicit the syndrome. The classic description of the carcinoid syndrome typically includes vasomotor, cardiac, and gastrointestinal manifestations. A number of humoral factors are produced by carcinoid tumors, but those considered to contribute to the carcinoid syndrome include serotonin, 5-HTP (a precursor of serotonin synthesis), histamine, dopamine, kallikrein, substance P, prostaglandin, and neuropeptide K. Most patients who exhibit malignant carcinoid syndrome have massive hepatic replacement by metastatic disease. However, tumors that bypass the liver, specifically ovarian and retroperitoneal carcinoids, may produce the syndrome in the absence of liver metastasis.

Common symptoms and signs include cutaneous flushing (80%), diarrhea (76%), hepatomegaly (71%), cardiac lesions, most commonly right heart valvular disease (41% to 70%), and asthma (25%). Cutaneous flushing in the carcinoid syndrome may be of four varieties: 1. Diffuse erythematous, which is short-lived and normally affects the face, neck, and upper chest 2. Violaceous, which is similar to a diffuse erythematous flush except that the attacks may be longer and patients may develop a permanent cyanotic flush, with watery eyes and injected conjunctivae 3. Prolonged flushes, which may last up to 2 to 3 days and involve the entire body, and may be associated with profuse lacrimation, hypotension, and facial edema and 4. A bright-red patchy flushing, typically seen with gastric carcinoids The diarrhea associated with carcinoid syndrome is episodic (usually occurring after meals), watery, and often explosive. Increased circulating serotonin levels are thought to be the cause of the diarrhea because the serotonin antagonist methysergide effectively controls the symptom. Cardiac lesions of carcinoid tumors mainly involve the right side of the heart and are usually limited to the tricuspid and pulmonary valves. The three most common cardiac lesions are pulmonary stenosis (90%), tricuspid insufficiency (47%), and tricuspid stenosis (42%). Asthmatic attacks are usually observed during the flushing symptom, and serotonin and bradykinin have been implicated in this symptom. Malabsorption and pellagra (dementia, dermatitis, and diarrhea) are occasionally present and are thought to be caused by excessive diversion of dietary tryptophan. Diagnosis The elevation of various humoral factors forms the basis for diagnostic tests in patients with carcinoid tumors and the carcinoid syndrome. Carcinoid tumors produce serotonin,

Small Intestine Chapter 50 1261

SECTION X ABDOMEN

which is then metabolized in the liver and the lung to the pharmacologically inactive 5-hydroxyindoleacetic acid (5-HIAA). Elevated urinary levels of 5-HIAA measured over 24 hours with high-performance liquid chromatography are highly specific, although not sensitive. A potentially useful marker of neuroendocrine tumors is the plasma concentration of chromogranin A, a protein made in the secretory granules, which is elevated in more than 80% of patients with carcinoid tumors. Although recent reports have proposed chromogranin A levels to be the test of choice for the diagnosis of carcinoid, the lack of specificity for this test limits its usefulness as a sole marker. It appears that the combination of 24-hour urine 5-HIAA and serum chromogranin A levels provides the best biochemical diagnostic accuracy. In terms of surveillance after resection or as a marker to monitor response to therapy, chromogranin A levels have proven efficacy over urine 5-HIAA levels. Plasma serotonin, substance P, neurotensin, neurokinin A, and neuropeptide K levels can be measured, but these peptides may not be elevated in all patients. Provocative tests using pentagastrin, calcium, or epinephrine may be used to reproduce the symptoms of carcinoid tumors. The administration of pentagastrin is the safest, most reliable, and most frequently used; however, with the accuracy of current diagnostic tests, there are relatively few indications today for provocative tests. Carcinoid tumors of the small intestine are rarely diagnosed preoperatively. Barium radiographic studies of the small bowel may exhibit multiple filling defects as a result of kinking and fibrosis of the bowel (Fig. 50-31). There are a number of imaging techniques used to diagnose the extent and spread of carcinoid tumors. As CT technology has continued to progress, CT scanning has become the imaging modality of choice for identifying the site of disease and the presence of lymphatic or hematogenous metastases. CT angiography may be useful in cases associated with a large mesenteric process to identify encasem*nt and pseudoaneurysm formation, typical of a malignant process in the mesentery. A novel imaging study that takes advantage of the fact that many of these tumors possess somatostatin receptors is somatostatin receptor scintigraphy using 111 In-labeled pentetreotide. This scintigraphic localization study has shown encouraging results, with a higher reported sensitivity than conventional imaging techniques, such as CT, for delineating and localizing carcinoid tumors. In particular, somatostatin receptor scintigraphy is the test of choice to identify extra-abdominal metastatic disease or in cases in which the primary cannot be appreciated on CT scan. Although CT scanning and somatostatin receptor scintigraphy (SRS) are the predominant modalities for carcinoid tumor localization and staging, MRI is emerging as a potential adjunct to these current imaging techniques. When directly compared with CT or SRS, MRI has shown enhanced sensitivity for hepatic metastases evaluation. Unfortunately, MRI has not improved the ability to identify extrahepatic disease and remains constrained by institutional expertise. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, although important in the evaluation of other malignancies, has not proven beneficial for carcinoids. However, the addition of newer isotopes such as 11 C–5-HTP and 18F-L-dihydroxyphenylalanine (18F-DOPA) has dramatically improved the sensitivity of PET for neuroendocrine malignancies and, when fused with conventional CT scanning, may ultimately outperform the current accepted imaging modalities.31

FIGURE 50-31 Barium radiograph of a carcinoid tumor of the terminal ileum demonstrates fibrosis with multiple filling defects and highgrade partial obstruction (arrows). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

Treatment Surgical Therapy The treatment of patients with small bowel

carcinoid tumors is based on tumor size and site and presence or absence of metastatic disease.30 For primary tumors smaller than 1 cm in diameter without evidence of regional lymph node metastasis, a segmental intestinal resection is adequate. For patients with lesions larger than 1 cm, with multiple tumors, or with regional lymph node metastasis, regardless of the size of the primary tumor, wide excision of bowel and mesentery is required. Lesions of the terminal ileum are best treated by right hemicolectomy. Small duodenal tumors can be excised locally; however, more extensive lesions may require pancreaticoduodenectomy. In addition to treatment of the primary tumor, it is important that the abdomen be thoroughly explored for multicentric lesions. In cases in which the mesenteric disease appears to involve a large portion of the mesentery, dissection of the tumor off the mesenteric vessels, with preservation of the blood supply to unaffected bowel, is appropriate, albeit technically demanding. Not only does removal of the mesenteric disease provide a

1262 SECTION X ABDOMEN significant survival advantage, but also mesenteric debulking ensures the most durable palliation for the patient. Caution should be exerted in the anesthetic management of patients with carcinoid tumors because anesthesia may precipitate a carcinoid crisis characterized by hypotension, bronchospasm, flushing, and tachycardia predisposing to arrhythmias. The treatment of carcinoid crisis is IV octreotide given as a bolus of 50 to 100 µg, which may be continued as an infusion at 50 µg/hour. In addition, IV antihistamine and hydrocortisone may be of some benefit. In patients with carcinoid tumors and widespread metastatic disease, surgery is still indicated. In contrast to metastases from other tumors, there is a definite role for surgical debulking, which often provides beneficial symptomatic relief. In patients with limited hepatic involvement, metastasectomy has been shown to provide the most durable survival benefit when compared with other treatment modalities. Unfortunately, most patients are not candidates for liver resection because of extensive disease; recurrence after metastasectomy occurs in up to 75% of patients. In these cases, transarterial chemoembolization or radioembolization has been shown to provide liver-directed control of disease. Furthermore, resection of the primary tumor, with or without mesenteric resection, has been shown to improve survival and slow progression of hepatic metastases in patients with unresectable disease. Although there have been some small series of hepatic transplantation for extensive liver metastases from carcinoid, unacceptably high recurrence rates limit this approach. Medical Therapy Medical therapy for patients with malignant carcinoid syndrome is primarily directed toward the relief of symptoms caused by the excess production of humoral factors.30 Various long-acting analogues of somatostatin, such as octreotide (Sandostatin) or the slow-release formulation (Sandostatin LAR), relieve symptoms of the carcinoid syndrome (e.g., diarrhea, flushing) in most patients. In addition to the relief of symptoms using octreotide, tumor regression has been reported in some patients. A randomized controlled trial of 85 patients with unresectable metastatic midgut carcinoid compared treatment with Sandostatin LAR to placebo.32 A significant improvement in progression-free survival was seen and was most pronounced in patients with a resected primary tumor and/or low hepatic burden. Recently, second-generation right hemicolectomy somatostatin analogues have been developed to address the limitations of the current regimens. Pasireotide represents an important advance in current biologic therapy. With its broad somatostatin receptor inhibition and up to 40-fold increase in binding affinity, as compared with current somatostatin analogues, pasireotide my have a role as primary therapy or salvage therapy for patients who fail treatment on first-generation somatostatin therapy.33 Interferon-α (IFN-α) has also been shown to provide symptomatic relief in patients with carcinoid syndrome. A clinical trial that evaluated the use of IFN-α in more than 100 patients with carcinoid syndrome identified decreases in urinary 5-HIAA levels in 42% of patients and tumor regression in 15%. However, the increased incidence of side effects (e.g., fever, fatigue, anorexia, weight loss) precludes the widespread use of this drug. Serotonin receptor antagonists have been used with limited success. Methysergide is no longer used because of the increased

incidence of retroperitoneal fibrosis. Ketanserin and cyproheptadine have been shown to provide some control of symptoms and other antagonists, such as ondansetron, may be even more effective. Given the slow-growing nature of carcinoid, cytotoxic chemotherapy has had only limited success. The role of chemotherapy is confined predominantly to patients with metastatic disease who are symptomatic, unresponsive to other therapies, or have high tumor proliferation rates. The most frequent combination used is streptozotocin plus 5-fluorouracil or cyclophosphamide, which may result in some tumor regression in up to one third of the patients. The duration of response, however, is short-lived. The use of cisplatin and etoposide has shown some promise only in patients with well-differentiated carcinoids. Results using dacarbazine (DTIC) are conflicting. In summary, the treatment of metastatic carcinoid tumors requires a multidisciplinary approach and combined modalities may be the best option, including surgical debulking, hepatic artery embolization or chemoembolization, and medical therapy. In addition, newer and more targeted therapies are being developed that may be useful in the future. Targeted therapy has progressed down four separate pathways. Given the hypervascular nature of carcinoids, antiangiogenesis therapy (e.g., bevacizumab) is being investigated in combination with cytotoxic and somatostatin therapy.34 Based on the benefit of sunitinib seen in pancreatic neuroendocrine tumors, tyrosine kinase inhibitors have been evaluated as systemic therapy and as a liver-directed chemoembolization strategy for carcinoids as well. The PI3KAKT-mTOR pathway has also recently emerged as a potential target for systemic therapy. Agents such as everolimus, an mTOR inhibitor, although initially developed as immunosuppressant therapy, have redefined themselves as potent antitumor agents and remain under active investigation for carcinoid disease. Perhaps the most promising targeted therapy to date is radiolabeled somatostatin analogue therapy. In a series of over 500 patients with gastrointestinal neuroendocrine tumors including carcinoid, [177Lu-DOTA0,Tyr3]octreotate was well tolerated and provided significant improvements in response rates and overall survival when compared with historical controls.35 Prognosis Carcinoid tumors have the best prognosis of all small bowel tumors, whether the disease is localized or metastatic. Resection of a carcinoid tumor localized to its primary site approaches a 100% survival rate. Five-year survival rates are approximately 65% in patients with regional disease and 25% to 35% in those with distant metastasis. When widespread metastatic disease precludes cure, extensive resection for palliation is indicated. In fact, long-term palliation often can be obtained because these tumors are relatively slow-growing. A number of factors have been evaluated in an attempt to identify patients with carcinoid tumors who have a poor prognosis. Probably the most useful factor identified is an elevated level of chromogranin A, which was found to be an independent predictor of an adverse prognosis. Adenocarcinomas

Adenocarcinomas traditionally have constituted approximately 50% of the malignant tumors of the small bowel in most reported series, although the incidence has plateaued in recent years.29 The peak incidence is in the seventh decade of life, and most series show a slight male predominance. Most of these

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10 cm

10 cm Tumor

A FIGURE 50-32 Large circumferential mucinous adenocarcinoma of the jejunum. (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston.)

tumors are located in the duodenum and proximal jejunum (Fig. 50-32). Those arising in association with Crohn’s disease tend to occur at a somewhat younger age, and more than 70% arise in the ileum. Tumors of the duodenum tend to present somewhat earlier than those in the most distal intestine, with symptoms of jaundice and chronic bleeding. Adenocarcinomas of the jejunum and ileum usually produce symptoms that may be more nonspecific and include vague abdominal pain and weight loss. Intestinal obstruction and chronic bleeding can also occur. Perforation is uncommon. As with adenocarcinomas in other organs, survival of patients with small bowel adenocarcinomas is related to the stage of disease at the time of diagnosis. Unfortunately, diagnosis is often delayed, and the disease is advanced at the time of surgery, secondary to various factors (e.g., vagueness of symptoms, absence of physical findings, lack of clinical suspicion because of the rarity of these lesions). Treatment of small bowel adenocarcinoma is determined by location and stage. Duodenal adenocarcinomas are treated with pancreaticoduodenectomy or segmental resection if the tumor is in the third or fourth portion of the duodenum. Jejunal and ileal adenocarcinomas are treated with segmental resection with the associated mesentery (Fig. 50-33) or right colectomy for terminal ileal carcinomas. There is no standard adjuvant protocol for small bowel adenocarcinoma and adjuvant regimens are often dictated by location. Duodenal adenocarcinomas often receive a periampullary treatment protocol whereas midgut adenocarcinomas undergo a colorectal regimen. The prognosis of small bowel adenocarcinoma is poor, likely because of the delayed presentation and presence of advanced disease at diagnosis. Five-year survival rates are typically in the 15% to 20% range, although duodenal adenocarcinoma has a 5-year survival rate of 50%, probably because of the earlier symptom presentation and diagnosis. Lymphoma

Malignant lymphomas involve the small bowel primarily or as a manifestation of systemic disease. Primary gastrointestinal lymphomas, of which about one third occur in the small bowel, account for 5% of all lymphomas.36 Lymphomas constitute 7% to 25% of small bowel malignant tumors in the adult; in children younger than 10 years, they are the most common

FIGURE 50-33 Surgical management of carcinoma of the small bowel. A, Malignant tumors should be resected with a wide margin of normal bowel and a wedge of mesentery to remove the immediate draining lymph nodes. B, End-to-end anastomosis of the small bowel and repair of the mesentery. (Adapted from Thompson JC: Atlas of surgery of the stomach, duodenum, and small bowel, St Louis, Mosby–Year Book, 1992, p 299.)

FIGURE 50-34 Gross photograph of primary lymphoma of the ileum shows replacement of all layers of the bowel wall with tumor. (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston.)

intestinal neoplasm. Lymphomas are most commonly found in the ileum, where there is the greatest concentration of gutassociated lymphoid tissue. Increased risk for developing primary small bowel lymphomas has been reported in patients with celiac disease and immunodeficiency states (e.g., AIDS). Grossly, small intestine lymphomas are usually large, with most larger than 5 cm; they may extend beneath the mucosa (Fig. 50-34). Microscopically, there is often diffuse infiltration of the intestinal wall. Symptoms of small bowel lymphoma include pain, weight loss, nausea, vomiting, and change in bowel habits. Perforation may occur in up to 25% of patients (Fig. 50-35). Fever is uncommon and suggests systemic involvement. The treatment of small bowel lymphoma remains controversial. Traditionally, a combination of surgery, chemotherapy and radiation were used for all small bowel tumors. However, in the absence of symptoms, small bowel lymphomas may

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FIGURE 50-35 Small bowel lymphoma presents as perforation and peritonitis. (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston.)

respond to chemotherapy without the need for surgery. This can typically be predicted by cell type because B cell lymphomas are more chemosensitive than T cell lymphomas and have high remission rates with or without surgery. T cell lymphomas are traditionally more resistant to therapy and will progress to symptoms of obstruction or perforation if not resected. Regardless of cell type, resection is indicated at any onset of symptoms because progression to life-threatening hemorrhage or perforation portends a dismal prognosis. Five-year survival of 50% to 60% can be expected and is dictated by response to systemic therapy rather than the success of surgical resection. Gastrointestinal Stromal Tumors

Malignant GISTs, or leomyosarcomas, arise from mesenchymal tissue and constitute about 20% of malignant neoplasms of the small bowel (Fig. 50-36). These tumors are more common in the jejunum and ileum, typically are diagnosed in the fifth and sixth decades of life, and occur with a slight male preponderance. Malignant GISTs are larger than 5 cm at the time of diagnosis in 80% of patients. GISTs mostly arise from the muscularis propria and generally grow extramurally. Most common indications for surgery include bleeding and obstruction, although free perforation may occur as a result of hemorrhagic necrosis in large tumor masses. Typically, GISTs tend to invade locally and spread by direct extension into adjacent tissues and hematogenously to the liver, lungs, and bone; lymphatic metastases are unusual. The most useful indicators of survival and the risk for metastasis include the size of the tumor at presentation, mitotic index, and evidence of tumor invasion into the lamina propria. Treatment of GISTs continues to evolve and represents one of the first breakthroughs in signal transduction manipulation. Surgical management is straightforward, with segmental resection of the tumor containing segment to obtain negative margins. Wide resection of the mesentery with lymphadenectomy is not necessary. Until recently, adjuvant strategies for GIST were lacking and recurrence rates after resection were as high as 70%. However, the development of imatinib mesylate (Gleevec, formerly known as STI571) has altered previous treatment strategies. Imatinib mesylate is a tyrosine kinase inhibitor that blocks the unregulated mutant c-kit (CD117) tyrosine kinase and

FIGURE 50-36 Small bowel leiomyosarcoma (malignant gastrointestinal stromal tumor) with hemorrhagic necrosis. (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston.)

inhibits the BCR-ABL and platelet-derived growth factor (PDGF) tyrosine kinases. Previous randomized trials have verified its ability to control disease progression in patients with metastatic disease. However, a recent surgeon-initiated randomized trial has shown that 1 year of adjuvant imatinib mesylate, after complete resection of a GIST, significantly improved recurrence free survival.37 Adjuvant imatinib mesylate is now the standard of care for malignant GISTs, especially with size larger than 5 cm, high mitotic rate, or small bowel location. Further trials have suggested that neoadjuvant imatinib mesylate may help determine which patients with locally advanced or metastatic GIST may benefit from aggressive resection.38 Survival data are pending. The prognosis of malignant GIST has traditionally been poor because of the high recurrence rate. However, in the era of tyrosine kinase modulation therapy, the impact of these new therapies on overall survival remains to be determined. Metastatic Neoplasms Metastatic tumors involving the small bowel are much more common than primary neoplasms. The most common metastases to the small intestine are those arising from other intraabdominal organs, including the uterine cervix, ovaries, kidneys, stomach, colon, and pancreas. Small intestinal involvement is by direct extension or implantation of tumor cells. Metastases from extra-abdominal tumors are rare but may be found in patients with adenocarcinoma of the breast and carcinoma of the lung. Cutaneous melanoma is the most common extraabdominal source to involve the small intestine, with involvement of the small intestine noted in more than 50% of patients dying from malignant melanoma (Fig. 50-37). Common symptoms include anorexia, weight loss, anemia, bleeding, and partial bowel obstruction. Treatment is palliative resection to relieve symptoms or, occasionally, bypass if the metastatic tumor is extensive and not amenable to resection. DIVERTICULAR DISEASE Diverticular disease of the small intestine is relatively common. It may present as true or false diverticula. A true diverticulum contains all layers of the intestinal wall and is usually congenital.

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I 1

II 3

2 cm

53 15

III FIGURE 50-38 Distribution of 95 duodenal diverticula within the four portions of the duodenum. (From Eggert A, Teichmann W, Wittmann DH: The pathologic implication of duodenal diverticula. Surg Gynecol Obstet 154:62–64, 1982.)

diverticulum is the most common true congenital diverticulum of the small bowel. Duodenal Diverticula Incidence and Cause

B FIGURE 50-37 A, Barium radiograph shows target lesions consistent with metastatic melanoma of the small bowel (arrow). B, Gross specimen demonstrating metastatic melanoma to the small bowel. (A, Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex; B, courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston.)

False diverticula consist of mucosa and submucosa protruding through a defect in the muscle coat and are usually acquired defects. Small bowel diverticula may occur in any portion of the small intestine. Duodenal diverticula are the most common acquired diverticula of the small bowel, and Meckel’s

First described by Chomel, a French pathologist, in 1710, diverticula of the duodenum are relatively common, representing the second most common site for diverticulum formation after the colon. The incidence of duodenal diverticula varies, depending on the age of the patient and method of diagnosis. Upper gastrointestinal radiographic studies identify duodenal diverticula in 1% to 5% of all studies, whereas some autopsy series report the incidence as being as high as 15% to 20%. Duodenal diverticula occur twice as often in women as in men and are rare in patients younger than 40 years. They have been classified as congenital or acquired, true or false, and intraluminal or extraluminal. Two thirds to three fourths of duodenal diverticula are found in the periampullary region (within a 2-cm radius of the ampulla) and project from the medial wall of the duodenum (Fig. 50-38). Clinical Manifestations

The important thing to remember is that the overwhelming majority of duodenal diverticula are asymptomatic and are usually noted incidentally by an upper gastrointestinal series for an unrelated problem (Fig. 50-39). Diagnosis may also be obtained by upper gastrointestinal endoscopy or suggested by plain abdominal films showing an atypical gas bubble; CT can identify large diverticula. Less than 5% of duodenal diverticula will require surgery because of a complication of the diverticulum itself. Major complications of duodenal diverticula include obstruction of the biliary or pancreatic ducts that may contribute to cholangitis and pancreatitis, respectively, hemorrhage,

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FIGURE 50-39 Large diverticulum arises from the second portion of the duodenum. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

perforation and, rarely, blind loop syndrome. Unfortunately, asymptomatic duodenal diverticula often present as an acute perforation that occurs during endoscopic misadventure. Only those diverticula associated with the ampulla of Vater are significantly related to complications of cholangitis and pancreatitis. In these patients, the ampulla usually enters the duodenum at the superior margin of the diverticulum rather than through the diverticulum itself. The mechanism proposed for the increased incidence of complications of the biliary tract is the location of the perivaterian diverticulum, which may produce mechanical distortion of the common bile duct as it enters the duodenum, resulting in partial obstruction and stasis. Hemorrhage can be caused by inflammation, leading to erosion of a branch of the superior mesenteric artery. Perforation of duodenal diverticula has been described, but is rare. Finally, stasis of intestinal contents within a distended diverticulum can result in bacterial overgrowth, malabsorption, steatorrhea, and megaloblastic anemia (i.e., blind loop syndrome). Symptoms related to duodenal diverticula in the absence of any other demonstrable disease usually are nonspecific epigastric complaints that can be treated conservatively and may actually prove to be the result of another problem not related to the diverticulum itself. Treatment

As noted, most duodenal diverticula are asymptomatic and benign; when they are found incidentally, they should be left alone. Several operative procedures have been described for the treatment of the symptomatic duodenal diverticulum. The most common and effective treatment is diverticulectomy, which is most easily accomplished by performing a wide Kocher maneuver that exposes the duodenum. The diverticulum is then excised,

and the duodenum is closed in a transverse or longitudinal fashion, whichever produces the least amount of luminal obstruction. Because of the close proximity of the ampulla, careful identification of the ampulla is essential to prevent injury to the common bile duct and pancreatic duct. For diverticula embedded deep within the head of the pancreas, a duodenotomy is performed, with invagin*tion of the diverticulum into the lumen, which is then excised, and the wall is closed (Fig. 50-40A to C). Alternative methods that have been described for duodenal diverticula associated with the ampulla of Vater include an extended sphincteroplasty through the common wall of the ampulla in the diverticulum (see Fig. 50-40D to F). The treatment of a perforated diverticulum may require procedures similar to those described for patients with massive trauma-related defects of the duodenal wall. The perforated diverticulum should be excised and the duodenum closed with a serosal patch from the jejunal loop. If the surrounding inflammation is severe, it may be necessary to divert the enteric flow away from the site of the perforation with a gastrojejunostomy or duodenojejunostomy. Interruption of duodenal continuity proximal to the perforated diverticulum may be accomplished by pyloric closure with suture or a row of staples. If the diverticulum is posterior and perforates into the substance of the pancreas, operative repair may be difficult and dangerous. Wide drainage with duodenal diversion may be all that is feasible in such cases. Great care should be taken if the perforation is adjacent to the papilla of Vater. Intraluminal duodenal diverticula have been described but are highly uncommon and, if symptomatic, can be completely excised if they arise at a site distant from the ampulla. However, if a symptomatic intraluminal diverticulum is encountered associated with the ampulla of Vater, subtotal resection of the diverticulum should be carried out to protect the entry of the biliary pancreatic ducts. Jejunal and Ileal Diverticula Incidence and Cause

Diverticula of the small bowel are much less common than duodenal diverticula, with an incidence ranging from 0.1% to 1.4% in autopsy series and 0.1% to 1.5% in upper gastrointestinal studies. Jejunal diverticula are more common and are larger than those in the ileum. These are false diverticula, occurring mainly in an older age group (after the sixth decade of life). These diverticula are multiple, usually protrude from the mesenteric border of the bowel, and may be overlooked at surgery because they are embedded within the small bowel mesentery (Fig. 50-41). The cause of jejunoileal diverticulosis is thought to be a motor dysfunction of the smooth muscle or the myenteric plexus, resulting in disordered contractions of the small bowel, generating increased intraluminal pressure, herniation of the mucosa and submucosa through the weakest portion of the bowel (i.e., the mesenteric side). Clinical Manifestations

Jejunoileal diverticula are usually found incidentally at laparotomy or during an upper gastrointestinal study (Fig. 50-42); the great majority remain asymptomatic. Acute complications such as intestinal obstruction, hemorrhage, or perforation can occur but are rare. Chronic symptomatology includes vague chronic abdominal pain, malabsorption, functional pseudo-obstruction, and chronic low-grade gastrointestinal hemorrhage. Acute

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Retroduodenal diverticulum

Papilla in orifice of diverticulum

FIGURE 50-40 A-C, Treatment of a diverticulum protruding into the head of the pancreas. The duodenum is opened vertically. A clamp is used to invert the diverticulum into the lumen, where it is excised and the posterior wall defect is closed. D-F, Management of the unusual duodenal diverticula that arise in the periampullary location. A tube stent should be placed into the common bile duct and passed distally into the duodenum to facilitate identification and later dissection of the sphincter of Oddi. The diverticulum is inverted into the lumen of the duodenum. The round opening in the wall of the base of the diverticulum is the site at which the ampullary structures were freed by a circumferential incision. E, Line of division of the base of the diverticulum (heavy broken line), which is accomplished by free-hand dissection. After the diverticulum has been removed, the stent and enveloping papilla are protruded into the defect left by the division of the base of the diverticulum. The mucosa and muscle wall of the papilla are then sewn circumferentially to the wall of the duodenum. (Adapted from Thompson JC: Atlas of surgery of the stomach, duodenum, and small bowel. St Louis, 1992, Mosby–Year Book, pp 209–213.)

complications are diverticulitis, with or without abscess or perforation, gastrointestinal hemorrhage, and intestinal obstruction. Stasis of intestinal flow with bacterial overgrowth (blind loop syndrome), caused by the jejunal dyskinesia, may lead to deconjugation of bowel salts and uptake of vitamin B12 by the bacterial flora, resulting in steatorrhea and megaloblastic anemia, with or without neuropathy. Treatment

FIGURE 50-41 Multiple large jejunal diverticula located in the mesentery in an older patient presenting with obstruction secondary to an enterolith. (Adapted from Evers BM, Townsend CM Jr, Thompson JC: Small intestine. In Schwartz SI [ed]: Principles of surgery, ed 7, New York, 1999, McGraw-Hill, p 1248.)

For incidentally noted, asymptomatic jejunoileal diverticula, no treatment is required. Treatment of complications of obstruction, bleeding, and perforation is usually by intestinal resection and end-to-end anastomosis. Patients presenting with malabsorption secondary to the blind loop syndrome and bacterial overgrowth in the diverticulum can usually be given antibiotics. Obstruction may be caused by enteroliths that form in a jejunal diverticulum and are subsequently dislodged and obstruct the distal intestine. This condition may be treated by enterotomy and removal of the enterolith, or sometimes the enterolith can

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FIGURE 50-43 Omphalomesenteric remnant persisting as a fibrous cord from the ileum to the umbilicus.

FIGURE 50-42 Multiple jejunal diverticula demonstrated by a barium contrast upper gastrointestinal study. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

be milked distally into the cecum. When the enterolith causes obstruction at the level of the diverticulum, bowel resection is necessary. When a perforation of a jejunoileal diverticulum is encountered, resection with reanastomosis is required because lesser procedures such as simple closure, excision, and invagin*tion are associated with greater mortality and morbidity rates. In extreme cases, such as diffuse peritonitis, enterostomies may be required if judgment dictates that reanastomosis may be risky. Meckel’s Diverticulum Incidence and Cause

Meckel’s diverticulum is the most commonly encountered congenital anomaly of the small intestine, occurring in about 2% of the population. It was reported initially in 1598 by Hildanus and then described in detail by Johann Meckel in 1809. Meckel’s diverticulum is located on the antimesenteric border of the ileum 45 to 60 cm proximal to the ileocecal valve and results from incomplete closure of the omphalomesenteric, or vitelline, duct. An equal incidence is found in men and women. Meckel’s diverticulum may exist in different forms, ranging from a small bump that may be easily missed to a long projection that communicates with the umbilicus by a persistent fibrous cord (Fig. 50-43) or, much less commonly, a patent fistula. The usual manifestation is a relatively wide-mouthed diverticulum measuring about 5 cm in length, with a diameter of up to 2 cm (Fig. 50-44). Cells lining the vitelline duct are pluripotent; therefore, it is not uncommon to find heterotopic tissue within the Meckel diverticulum, the most common of which is gastric mucosa (present in 50% of all Meckel’s diverticula). Pancreatic mucosa is encountered in about 5% of diverticula; less commonly, these diverticula may harbor colonic mucosa.

FIGURE 50-44 Common presentation of a Meckel diverticulum projecting from the antimesenteric border of the ileum.

Clinical Manifestations

Most Meckel’s diverticula are entirely benign and are incidentally discovered during autopsy, laparotomy, or barium studies (Fig. 50-45). The most common clinical presentation of Meckel’s diverticulum is gastrointestinal bleeding, which occurs in 25% to 50% of patients who present with complications; hemorrhage is the most common symptomatic presentation in children 2 years of age or younger. This complication may present as acute massive hemorrhage, anemia secondary to chronic bleeding, or a self-limiting recurrent episodic event. The usual source of the bleeding is a chronic acid-induced ulcer in the ileum adjacent to a Meckel’s diverticulum that contains gastric mucosa.

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Meckel's diverticulum

Bladder

FIGURE 50-46 99mTc-pertechnetate scintigram from a child demonstrates a Meckel’s diverticulum clearly differentiated from the stomach and bladder. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

FIGURE 50-45 Barium radiograph demonstrates an asymptomatic Meckel’s diverticulum (arrow). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, Tex.)

Another common presenting symptom of Meckel’s diverticulum is intestinal obstruction, which may occur as a result of a volvulus of the small bowel around a diverticulum associated with a fibrotic band attached to the abdominal wall, intussusception or, rarely, incarceration of the diverticulum in an inguinal hernia (Littre’s hernia). Volvulus is usually an acute event and, if allowed to progress, may result in strangulation of the involved bowel. In intussusception, a broad-based diverticulum invagin*tes and then is carried forward by peristalsis. This may be ileoileal or ileocolic and present as acute obstruction associated with an urge to defecate, early vomiting and, occasionally, the passage of the classic currant jelly stool. A palpable mass may be present. Although reduction of an intussusception secondary to Meckel’s diverticulum can sometimes be performed by barium enema, the patient should still undergo resection of the diverticulum to negate subsequent recurrence of the condition. Diverticulitis accounts for 10% to 20% of symptomatic presentations. This complication is more common in adult patients. Meckel’s diverticulitis, which is clinically indistinguishable from appendicitis, should be considered in the differential diagnosis of a patient with right lower quadrant pain. Progression of the diverticulitis may lead to perforation and peritonitis. It is important to remember that when the appendix is found to be normal during exploration for suspected appendicitis, the distal ileum should be inspected for the presence of an inflamed Meckel’s diverticulum. Finally, much rarer complications of Meckel’s diverticula include neoplasms, with the most common benign tumors reported as leiomyomas, angiomas, and lipomas. Malignant neoplasms include adenocarcinomas, which generally originate from the gastric mucosa, sarcoma, and carcinoid tumor.

Diagnostic Studies

The diagnosis of Meckel’s diverticulum may be difficult. Plain abdominal radiography, CT, and ultrasonography are rarely helpful. In children, the single most accurate diagnostic test for Meckel’s diverticula is scintigraphy with sodium 99mTcpertechnetate. The 99mTc-pertechnetate is preferentially taken up by the mucus-secreting cells of gastric mucosa and ectopic gastric tissue in the diverticulum (Fig. 50-46). The diagnostic sensitivity of this scan has been reported as high as 85%, with a specificity of 95% and an accuracy of 90% in the pediatric age group. In adults, however, 99mTc-pertechnetate scanning is less accurate because of the reduced prevalence of ectopic gastric mucosa within the diverticulum. The sensitivity and specificity can be improved by the use of pharmacologic agents such as pentagastrin and glucagon or histamine 2 (H2) receptor antagonists (e.g., cimetidine). Pentagastrin indirectly increases the metabolism of mucus-producing cells, whereas glucagon inhibits peristaltic dilution and washout of intraluminal radionuclide. Cimetidine may be used to increase the sensitivity of scintigraphy by decreasing the peptic secretion, but not the radionuclide uptake, and retarding the release of pertechnetate from the diverticular lumen, thus resulting in higher radionuclide concentrations in the wall of the diverticulum. In adult patients, when nuclear medicine findings are normal, barium studies should be performed. In patients with acute hemorrhage, angiography is sometimes useful. Treatment

The treatment of a symptomatic Meckel’s diverticulum should be prompt surgical intervention with resection of the diverticulum or resection of the segment of ileum bearing the diverticulum. Segmental intestinal resection is required for treatment of patients with bleeding because the bleeding site is usually in the ileum adjacent to the diverticulum. Resection of the diverticulum for nonbleeding Meckel’s diverticula can be performed using a hand-sewn technique or stapling across the base of the

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Stomach

1270 SECTION X ABDOMEN diverticulum in a diagonal or transverse line to minimize the risk for subsequent stenosis. Reports have demonstrated the feasibility and safety of laparoscopic diverticulectomy. Longterm outcomes with this procedure, however, are lacking. Although the treatment of complicated Meckel’s diverticulum is straightforward, the optimal treatment of Meckel’s diverticulum noted as an incidental finding is still debated. It is generally recommended that asymptomatic diverticula found in children during laparotomy be resected. The treatment of Meckel’s diverticula encountered in the adult patient, however, remains controversial. In a landmark paper by Soltero and Bill,39 which formed the basis of the surgical management of asymptomatic Meckel’s diverticula in adults for a number of years, the likelihood of a Meckel’s diverticulum becoming symptomatic in the adult patient was estimated as 2% or less; morbidity rates from incidental removal, which were reported to be as high as 12% in some studies, far exceeded the potential for prevention of disease. This study was criticized, however, because it was not a population-based analysis. An epidemiologic population-based study by Cullen and associates40 has challenged the practice of ignoring an incidentally found Meckel’s diverticulum. A 6.4% rate of development of complications from the Meckel’s diverticulum was calculated to occur over a lifetime. This incidence of complications does not appear to peak during childhood, as originally thought. Therefore, the recommendation from this study was that an incidentally found Meckel’s diverticulum be removed at any age up to 80 years as long as no additional conditions (e.g., peritonitis) make removal hazardous. The rates of short- and long-term postoperative complications from prophylactic removal were low (~2%), and death was related to the primary operation or the general health of the patient and not to the diverticulectomy. Zani and coworkers41 have reviewed 244 articles evaluating the incidence and outcomes of Meckel’s diverticulum, including autopsy, population, and surgical series. They identified a clear incidence of increased morbidity associated with incidental resection over no treatment and determined that more than 700 patients with incidental Meckel’s diverticulum required resection to avoid one Meckel’s related death. In short, treatment of incidental Meckel’s diverticulum remains controversial, and conservative management of an incidental finding is a reasonable surgical approach. MISCELLANEOUS PROBLEMS Small Bowel Ulcerations Ulcerations of the small bowel are relatively uncommon and may be attributed to Crohn’s disease, typhoid fever, tuberculosis, lymphoma, and ulcers associated with gastrinoma (Table 50-10). Drug-induced ulcerations can occur and were, in the past, attributed to enteric-coated potassium chloride tablets and corticosteroids. In addition, ulcerations of the small intestine in which no causative agent can be identified have been described. It has been suggested that small bowel complications from nonsteroidal anti-inflammatory drugs (NSAIDs) may be more common than originally considered. NSAID-induced ulcers occur more commonly in the ileum, with single or multiple ulcerations noted. Complications necessitating operative intervention include bleeding, perforation, and obstruction. In addition to ulcerations, NSAIDs are known to induce an enteropathy characterized by increased intestinal permeability leading to protein loss and hypoalbuminemia, malabsorption, and anemia.

Table 50-10 Causes of Small Intestine Ulceration CAUSE

EXAMPLES

Infections

Tuberculosis, syphilis, cytomegalovirus, typhoid, parasites, Strongyloides hyperinfection, Campylobacter, Yersinia

Inflammatory

Crohn’s disease, systemic lupus erythematosus, celiac disease, ulcerative enteritis

Ischemia

Mesenteric insufficiency

Idiopathic

Primary ulcer, Behçet’s syndrome

Drug induced

Potassium, indomethacin, phenylbutazone, salicylates, antimetabolites

Radiation

Therapeutic, accidental

Vascular

Vasculitis, giant cell arteritis, amyloidosis (ischemic lesion), angiocentric lymphoma

Metabolic

Uremia

Hyperacidity

Zollinger-Ellison syndrome, Meckel’s diverticulum, stomal ulceration

Neoplastic

Lymphoma, adenocarcinoma, melanoma

Toxic

Acute jejunitis (β-toxin–producing Clostridium perfringens), arsenic

Mucosal lesions

Lymphocytic enterocolitis

Adapted from Rai R, Bayless TM: Isolated and diffuse ulcers of the small intestine. In Feldman M, Scharschmidt BF, Sleisenger MH (eds): Gastrointestinal and liver disease: Pathophysiology, diagnosis, management, Philadelphia, 1998, WB Saunders, pp 1771–1778.

Treatment of complications from small bowel ulcerations is segmental resection and intestinal reanastomosis. Ingested Foreign Bodies Ingested foreign bodies, which can lead to subsequent perforation or obstruction of the gastrointestinal tract, are swallowed, usually accidentally, by children or adults. These include glass and metal fragments, pins, needles, toothpicks, fish bones, coins, whistles, toys, and broken razor blades (Fig. 50-47). Intentional ingestion of foreign bodies is sometimes seen in the prison population and those who are mentally unstable. For most patients, treatment is observation, which allows the safe passage of these objects through the intestinal tract. If the object is radiopaque, progress can be followed by serial abdominal films. Cathartic agents are contraindicated. Sharp pointed objects such as needles, razor blades, or fish bones may penetrate the bowel wall. If abdominal pain, tenderness, fever, or leukocytosis occurs, immediate laparotomy and surgical removal of the offending object are indicated. Laparotomy is also required for intestinal obstruction. Small Bowel Fistulas Despite improvements in surgical nutrition and critical care, mortality from enterocutaneous fistulas remains high, 15% to 20% in recent reports.42 Improvements in outcome are focused on prevention and, when fistulas occur, prompt recognition and intervention. Enterocutaneous fistulas are most commonly iatrogenic, with 75% to 85% of cases attributed to surgical misadventure (e.g., anastomotic leakage, injury of the bowel or blood supply, erosion by suction catheters, laceration of the bowel by wire mesh or retention suture). The remaining 15%

Small Intestine Chapter 50 1271

High output (>500 mL/24 hr) Severe disruption of intestinal continuity (>50% of bowel circumference) Active inflammatory bowel disease of bowel segment Cancer Radiation enteritis Distal obstruction Undrained abscess cavity Foreign body in the fistula tract Fistula tract 20,000/mL) suggests complicated appendicitis with gangrene or perforation. A urinalysis can also be helpful in excluding pyelonephritis or nephrolithiasis. Minimal pyuria, frequently seen in older women, does not exclude appendicitis from the differential diagnosis because the ureter may be irritated adjacent to the inflamed appendix. Although microscopic hematuria is common in appendicitis, gross hematuria is uncommon and may indicate the presence of a kidney stone. Other blood tests are generally not helpful and are not indicated for the typical patient with suspected appendicitis.

The Appendix Chapter 51 1281

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Radiographic Studies

Computed tomography (CT) is commonly used in the evaluation of adult patients with suspected acute appendicitis. Improved imaging techniques, including the use of 5-mm sections, have resulted in increased accuracy of CT scanning,8 which has a sensitivity of approximately 90% and a specificity of 80% to 90% for the diagnosis of acute appendicitis in patients with abdominal pain. Results of a recent randomized study have suggested that the use of high-resolution multidetector CT (64MDCT) with or without oral or rectal contrast results in more than 95% accuracy in the diagnosis of acute appendicitis.9 In general, CT findings of appendicitis increase with the severity of the disease. Classic findings include a distended appendix more than 7 mm in diameter and circumferential wall thickening and enhancement, which may give the appearance of a halo or target (Fig. 51-1). As inflammation progresses, one may see periappendiceal fat stranding, edema, peritoneal fluid, phlegmon, or a periappendiceal abscess. CT detects appendicoliths in approximately 50% of patients with appendicitis and also in a

FIGURE 51-1 A, CT scan of the abdomen or pelvis in a patient with acute appendicitis may reveal an appendicolith (arrow). B, CT typically shows a distended appendix (arrow) with diffuse wall thickening and periappendiceal fluid (arrowhead). C, The appendix may be described as having mural stratification, referring to the layers of enhancement and edema within the wall (arrow); this may also be referred to as a target sign. C, Cecum; TI, terminal ileum.

small percentage of people without appendicitis. In patients with abdominal pain, the positive predictive value of the finding of an appendicolith on CT remains high (≈75%). Should CT be used routinely in the diagnostic evaluation of patients with suspected appendicitis? We do not recommend it, but one study has found that liberal use of CT scans is probably warranted because this has been credited with a declining incidence of negative appendectomy (i.e., the fraction of pathologically normal appendices that are removed).10 In the setting of typical right lower quadrant pain and tenderness with signs of inflammation in a young male patient, a CT scan is unnecessary, wastes valuable time, may be misinterpreted, and exposes the patient to risks for allergic contrast reaction, nephropathy, aspiration pneumonitis, and ionizing radiation. The latter carries increased risk in children in whom the rate of radiation-induced cancer has been estimated at 0.18% following an abdominal CT scan.11 CT has proved most valuable for older patients in whom the differential diagnosis is lengthy, clinical findings may be confusing, and appendectomy carries increased risk.12,13 In

1282 SECTION X ABDOMEN patients with atypical symptoms, CT scan may reduce the negative appendectomy rate. Liberal use of cross-sectional imaging seems most appropriate and, as always, the study needs to be performed only in settings in which it has a significant potential to alter management. Given the recent increased awareness of the risks of cumulative radiation exposure in young adults undergoing CT scanning,14 it remains to be seen whether magnetic resonance imaging (MRI) will replace CT as the preferred modality for the evaluation of the appendix in younger patients. The morbidity rate of perforated appendicitis far exceeds that of a negative appendectomy. Thus, the strategy has been to set a low enough threshold for removal of the appendix to minimize the cases of missed appendicitis. With increased use of CT, the frequency of negative explorations has declined in recent years, without an accompanying rise in the number of perforations. An analysis of more than 75,000 patients from 1999 to 2000 revealed a negative appendectomy rate of 6% in men and 13.4% in women.12 Among patients with abdominal pain, ultrasonography has a sensitivity of approximately 85% and a specificity of more than 90% for the diagnosis of acute appendicitis. Sonographic findings consistent with acute appendicitis include an appendix of 7 mm or more in anteroposterior diameter, a thick-walled, noncompressible luminal structure seen in cross section, referred to as a target lesion, or the presence of an appendicolith (Fig. 51-2). In more advanced cases, periappendiceal fluid or a mass may be found. Ultrasonography has the advantages of being a noninvasive modality requiring no patient preparation that also avoids exposure to ionizing radiation. Thus, it is commonly used in children and in pregnant patients with equivocal clinical findings suggestive of acute appendicitis. Ultrasonography has been shown to change the disposition of 59% of children with abdominal pain who had already been evaluated by the surgical team.15 Disadvantages of ultrasonography include

operator-dependent accuracy and difficulty interpreting the images by those other than the operator. Because performance of the study may require hands-on participation by the radiologist, ultrasonography may not be readily available at night or on weekends. Pelvic ultrasound can be especially useful in excluding pelvic pathology, such as tubo-ovarian abscess or ovarian torsion, which may mimic acute appendicitis. Although they are commonly obtained, the indiscriminate use of plain abdominal radiographs in the evaluation of patients with acute abdominal pain is unwarranted. In one study of 104 patients with acute onset of right lower quadrant pain, interpretation of plain x-rays changed the management of only six patients (6%) and, in one case, contributed to an unnecessary laparotomy.16 A calcified appendicolith is visible on plain films in only 10% to 15% of patients with acute appendicitis. Although its presence strongly supports the diagnosis in a patient with abdominal pain, the low sensitivity of this test renders it of little value in preoperative decision making. Plain abdominal films may be useful for the detection of ureteral calculi, small bowel obstruction, or perforated ulcer, but such conditions are rarely confused with appendicitis. Failure of the appendix to fill during a barium enema has been associated with appendicitis, but this finding lacks sensitivity and specificity because up to 20% of normal appendices do not fill. Diagnostic Laparoscopy

Although most patients with appendicitis will be accurately diagnosed based on history, physical examination, laboratory studies and, if necessary, imaging studies, there are a small number in whom the diagnosis remains elusive. For these patients, diagnostic laparoscopy can provide a direct examination of the appendix and a survey of the abdominal cavity for other possible causes of pain. We use this technique primarily for women of childbearing age in whom preoperative pelvic ultrasound or CT fails to provide a diagnosis. Concerns about the possible adverse effects of a missed perforation and peritonitis on future fertility sometimes prompt earlier intervention in this patient population. Special Patient Populations

FIGURE 51-2 Ultrasound of a normal appendix (top) illustrating the thin wall in coronal (left) and longitudinal (right) planes. In appendicitis, there is distention and wall thickening (bottom, right), and blood flow is increased, leading to the so-called ring of fire appearance. A, Appendix.

The diagnosis of appendicitis is particularly difficult in the very young and in older adults. It is in these groups that diagnosis is most often delayed and perforation occurs most frequently. Imaging studies are strongly considered here. Because of increasing concerns about radiation-induced cancers in children,11 ultrasonography is the preferred initial imaging modality for this group. For older patients, CT offers the ability to detect the broader array of conditions, such as diverticulitis and malignancy, found in the differential diagnosis. In infants, nonfocal findings such as lethargy, irritability, and anorexia may be present in the early stages of appendicitis, with vomiting, fever, and pain apparent as the disease progresses. Ultrasound is useful for the evaluation of appendicitis and other acute abdominal emergencies, such as pyloric stenosis, in infants. In preschool-aged children, the differential diagnosis includes intussusception, Meckel’s diverticulitis, and acute gastroenteritis. Intussusception may be distinguished by the colicky nature of the pain, with intervening pain-free periods, and the absence of peritonitis. Meckel’s diverticulitis is relatively uncommon, but its presentation is similar to that of appendicitis, except that the pain and tenderness typically localize in the

The Appendix Chapter 51 1283 Ultrasound is helpful for establishing the diagnosis and location of the inflamed appendix. In cases in which ultrasound has been equivocal, MRI has been used successfully, thereby avoiding ionizing radiation exposure to the developing fetus. The main challenge is to recognize the possibility of appendicitis in pregnant patients and intervene promptly, because peritonitis significantly increases the rate of fetal loss (2.6% to 10.9% in one meta-analysis).18 The challenge in the diagnosis is to balance this risk of perforation and risk of fetal demise and preterm labor from delayed diagnosis against the risk of a negative appendectomy. Laparoscopic appendectomy has been performed through the second trimester of pregnancy, although data are lacking comparing this approach to the open procedure. Appendicitis in older patients can be difficult to diagnose because many patients delay seeking care and the presentation may be atypical. Fever is uncommon, the white blood cell count may be normal, and many older patients with appendicitis do not experience right lower quadrant pain. Approximately 50% of older patients are incorrectly diagnosed at the time of admission and they have a much higher rate of perforation at the time of surgery because of delays in operative intervention.13 More than 50% of older patients with appendicitis are found to have perforated appendices, compared with fewer than 20% of younger patients. Diverticulitis and bowel obstruction are common misdiagnoses in older patients; the differential diagnosis also includes malignancies of the gastrointestinal tract and reproductive system, perforated ulcers, and cholecystitis. CT has become an invaluable tool for the evaluation of abdominal pain in older patients and its use has shortened preoperative hospital delays.13 Diagnostic Algorithm

Patients for whom the diagnosis of appendicitis is being considered should have a surgical evaluation (Fig. 51-3). Early involvement of the surgical team in the diagnostic evaluation of these patients may improve diagnostic accuracy and help avoid expensive and unnecessary diagnostic studies.19 Experienced clinicians accurately diagnose appendicitis based on a combination of history, physical examination, and laboratory studies approximately 80% of the time. We stratify patients based on their clinical findings starting with the extremes, which are easier to identify. Patients with a high probability of uncomplicated appendicitis undergo surgery. Patients suspected of having an appendiceal abscess undergo further imaging, typically ultrasonography for children or CT for adults. The next step in the evaluation of patients for whom the likelihood of appendicitis is believed to be low is determined by the probability and severity of alternate diagnoses under consideration. Some of these patients will be discharged with a planned follow-up visit or phone call the next day. Most older patients with abdominal pain undergo CT before discharge because of the high prevalence of surgical pathology in this patient population. The remaining patients are believed to have an intermediate probability of having appendicitis. Children and pregnant women in this category typically undergo abdominal ultrasonography. Women in their childbearing years may undergo pelvic ultrasonography, CT, or MRI, depending on the index of suspicion of pelvic pathology. Among patients who would otherwise be admitted to the hospital for observation, CT may reduce hospital costs by reducing length of stay. Following the completion of imaging studies, the patient is reexamined to determine

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periumbilical region. Gastroenteritis can be difficult to distinguish from acute appendicitis in any age group. Typically, diarrhea and vomiting occur early and persistently in gastroenteritis, and focal abdominal tenderness and peritoneal signs are uncommon. Sonography should be used liberally. It is advisable to discuss the importance of reevaluation within 12 to 24 hours with the parents of a child suspected of having gastroenteritis if the child develops worsening abdominal pain or other signs of clinical deterioration, because misdiagnosed appendicitis remains high on the list of considerations. In school-aged children, gastroenteritis often presents with abdominal pain and diarrhea, without fever or leukocytosis. The most common condition that mimics appendicitis in this population is mesenteric lymphadenitis, which may be caused by a wide variety of enteric infections.17 Ultrasonography may be helpful for identifying enlarged lymph nodes in the region of the ileal mesentery in conjunction with thickening of the ileal wall and a normal appendix, in which case appendectomy may be avoided. MRI may be helpful to resolve ambiguous sonographic or clinical findings. It is important to remember that enlarged mesenteric lymph nodes may also be the result of acute appendicitis. Inflammatory bowel disease is also considered in children, particularly if there is a history of recurrent episodes of abdominal pain. Constipation and functional pain are common in this age group. Although constipation may be associated with relatively severe pain, there are no peritoneal signs, fever, or leukocytosis, and the diagnosis is supported by a recent history of hard stools. Functional pain is usually somewhat milder, recurrent, and self-limited. In adults, it is important to consider other regional inflammatory conditions, such as pyelonephritis, colitis, and diverticulitis. The pain and tenderness of pyelonephritis are typically located in the flank and are accompanied by high fever and white blood cell count, as well as pyuria. Colitis is often accompanied by diarrhea and the location of the pain typically outlines the trajectory of the colon. In Crohn’s colitis, diarrhea is uncommon, but there is often a pattern of recurrent symptoms. The onset of right-sided diverticulitis is typically insidious, worsening over a period of days, and involving a larger area of tenderness in the right lower abdomen than appendicitis. CT scan is helpful for identifying the inflamed diverticula and enhancement of cecal wall thickening that accompanies this diagnosis. The differential diagnosis for appendicitis in women of childbearing age is broad and accounts for the higher incidence of false-positive diagnoses in this group. Pelvic pathology that may mimic acute appendicitis includes pelvic inflammatory disease (PID), tubo-ovarian abscess, ruptured ovarian cyst or ovarian torsion, and ectopic pregnancy. These conditions are typically distinguished from acute appendicitis by the absence of gastrointestinal symptoms. Pelvic ultrasound is especially helpful for these patients because of its high sensitivity and specificity for the diagnosis of pelvic pathology. If a normal appendix is also seen, appendicitis is unlikely. Appendicitis is the most common nonobstetric surgical disease of the abdomen during pregnancy. Diagnosis may be difficult because symptoms of nausea, vomiting, and anorexia, as well as elevated white blood cell count, are common during pregnancy. Moreover, the location of tenderness varies with gestation. After the fifth month of gestation, the appendix is shifted superiorly above the iliac crest and the appendiceal tip is rotated medially into the right upper quadrant by the gravid uterus.

1284 SECTION X ABDOMEN

Surgical consultation for acute abdominal pain

Clinical probability of acute appendicitis

High

Intermediate

Operate

CT or ultrasound and re-examine

+ Operate

Uncertain Diagnostic laparoscopy or admit/re-examine

Low

Elderly Unreliable Long distance

Reliable and local

CT re-examine

Discharge follow-up 4 to 6 cm) is drained percutaneously, if it is located in the iliac fossa, or transrectally, if it is in the lower pelvis. Patients who are systemically ill are treated with antibiotics and bowel rest and reevaluated. If they do not improve, we perform an open appendectomy. Similarly, sick patients with a phlegmon or small abscess are treated with antibiotics and bowel rest and reevaluated for signs of improvement, as described earlier. Some present during the recovery phase from the acute illness and may be managed as outpatients. Adults who are managed nonoperatively during their initial presentation may undergo colonoscopy 2 to 4 weeks after their acute illness to exclude colitis or neoplasms. We typically remove the appendix in these patients 6 to 8 weeks after the initial presentation. The procedure is performed laparoscopically as an outpatient. Outcomes The mortality rate after appendectomy is less than 1%. The morbidity of perforated appendicitis is higher than that of nonperforated cases and is related to increased rates of wound infection, intra-abdominal abscess formation, increased hospital stay, and delayed return to full activity. Surgical site infections and deep space infections or abscesses are the most common complications seen after appendectomy. Approximately 5% of patients with uncomplicated appendicitis develop wound infections after open appendectomy. Laparoscopic appendectomy is associated with a lower incidence of wound infections; this difference is magnified in groups of patients with perforated appendicitis (14% versus 26%).40 Patients with a fever and leukocytosis and a normalappearing wound after appendectomy undergo CT or ultrasonography to exclude an intra-abdominal abscess. Similarly, if pus emanates from a fascial opening during wound inspection, an imaging study is performed to identify any undrained intraabdominal fluid collections. In this situation, we place a percutaneous drain into the collection to divert the infected material away from the fascia and facilitate wound healing. For pelvic

abscesses that are located in proximity to the rectum or vagin*, we prefer ultrasound-guided transrectal or transvagin*l drainage, thereby avoiding the discomfort of a percutaneous perineal drain.31 Small bowel obstruction occurs in less than 1% of patients after appendectomy for uncomplicated appendicitis and in 3% of patients with perforated appendicitis who are followed for 30 years.41 Approximately 50% of these patients present with bowel obstruction during the first year. The risk for infertility following appendectomy in childhood appears to be small. A history of simple or perforated appendicitis was sought in a large cohort of infertile patients and compared with the frequency of appendicitis in pregnant women; no significant differences were found.42 There are rare reports of appendicocutaneous or appendicovesical fistulas after appendectomy, typically for perforated appendicitis. Fistulas to the skin generally close after any local infection is treated. Fistulas to the bladder have been successfully diagnosed and treated laparoscopically. NEOPLASMS Primary tumors of the appendix are rare. They are usually diagnosed after pathologic inspection of the appendix that was removed for suspected appendicitis. Although it was previously believed that carcinoid tumors were the most common appendiceal neoplasms, analysis of the Surveillance, Epidemiology, and End Results (SEER) database indicates that mucinous tumors of the appendix are more common.12 A mucocele of the appendix is the result of obstruction of the appendiceal orifice with distention of the appendix caused by intraluminal accumulation of mucoid material (Fig 51-9). A spectrum of histologic changes may be found in the mucosa of appendiceal mucoceles, ranging from benign epithelium to the invasive changes of mucinous adenocarcinoma.43 Intact mucoceles smaller than 2 cm are almost always benign.44 A retention cyst results from chronic obstruction of the proximal lumen, usually by fibrous tissue, which leads to a simple mucocele that is lined by flattened cuboidal epithelium and cured by appendectomy. Larger mucoceles are more likely to be neoplastic. Every effort is made to keep the mucocele intact during extraction, including placing the specimen in a bag or converting a laparoscopic procedure to an open procedure, if necessary.44 The mesoappendix is removed with the appendix to determine lymph node status, but a right hemicolectomy is not indicated unless there is invasion of the base of the appendix by tumor.45 Mucoceles that have ruptured are more likely to be associated with the spread of epithelial cells within mucoid fluid throughout the peritoneal cavity, so-called pseudomyxoma peritonei, or mucinous carcinomatosis of appendiceal origin. The appendix is the most common source of mucoid fluid collections in the abdomen. Patients may present with appendicitis or in a subacute fashion, with increased abdominal girth from intraperitoneal accumulation of mucoid material. Preoperative imaging studies may reveal enlargement of the ovaries caused by entrapment of mucinous tumor cells within ovarian tissue or focal mucinous fluid collections in the pelvis, left paracolic gutter, subhepatic space, splenic hilum, and/or omentum. Appendiceal mucinous neoplasms have several unique characteristics of which the surgeon needs to be aware. Many patients have peritoneal dissemination of tumor cells at the time of diagnosis, but most of these neoplasms are noninvasive.45 Nodal and liver

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in older patients with appendicitis.37 Older people have an increased incidence of cardiovascular, renal, and pulmonary complications after appendectomy. Analysis of a large administrative database has shown that the laparoscopic approach is associated with a shorter hospitalization and higher probability of discharge to home, rather than a skilled nursing facility, than open appendectomy for older patients with perforated or nonperforated appendicitis.38 Following risk adjustment among groups, the benefits of laparoscopic appendectomy appear to be more pronounced for older patients than for their younger counterparts.39

1290 SECTION X ABDOMEN

Treatment of appendicitis

Early/simple (

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