Conn's Current Therapy 2008: Text with Online Reference

Rakel & Bope: Conn's Current Therapy 2008, 60th ed. Copyright © 2008 Saunders, An Imprint of Elsevier CONN'S Current T...

Author: Robert E. Rakel MD | Edward T. Bope MD

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Rakel & Bope: Conn's Current Therapy 2008, 60th ed. Copyright © 2008 Saunders, An Imprint of Elsevier

CONN'S Current Therapy 2008 Text with Online Reference Robert E. Rakel, MD Professor, Department of Family and Community Medicine, Baylor College of Medicine, Houston, Texas Edward T. Bope, MD Director, Riverside Family Practice Residency Program Clinical Professor, Department of Family Medicine, The Ohio State University College of Medicine, Columbus, Ohio LATEST APPROVED METHODS OF TREATMENT FOR THE PRACTICING PHYSICIAN SAUNDERS ELSEVIER 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CONN'S CURRENT THERAPY 2008 ISBN: 978-1-4160-4435-2 Copyright © 2008 by Saunders, an imprint of Elsevier, Inc. 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. Some material was previously published. Permissions may be sought directly from Elsevier's Rights Department: phone: (+1) 215 239 3804 (US) or . You may (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected] also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions .

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. 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 the practitioner, relying on his or her experience and knowledge of the patient, 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 Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data

Current therapy; latest approved methods of treatment for the practicing physician. Editors: H. F. Conn and others v. 28 cm. annual ISBN 978-1-4160-4435-2 1. Therapeutics. 2. Therapeutics, Surgical. 3. Medicine—Practice. I. Conn, Howard Franklin, 1908-1982 ed. RM101.C87 616.058 49-8328 rev* Acquisitions Editor: Druanne Martin Developmental Editor: Lucia Gunzel Publishing Services Manager: Frank Polizzano Project Manager: Jeff Gunning Design Direction: Steve Stave

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com


Contributors Charles S. Abrams, MD Associate Professor of Medicine, University of Pennsylvania School of Medicine Staff Physician, Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Platelet-Mediated Bleeding Disorders Mark J. Abzug, MD Professor of Pediatrics (Infectious Diseases), University of Colorado School of Medicine Staff Pediatrician, The Children's Hospital, Denver, Colorado Viral Meningitis and Encephalitis Suraj Achar, MD Assistant Clinical Professor, Department of Family and Preventive Medicine, and Associate Director, Sports Medicine Fellowship, University of California, San Diego, School of Medicine, La Jolla Staff Physician, UCSD Thornton Hospital, La Jolla, and UCSD Medical Center, Hillcrest, California Common Sports Injuries Sujeet S. Acharya, MD Resident Physician, The University of Chicago Medical Center, Chicago, Illinois Renal Calculi Tod C. Aeby, MD Residency Program Director, Department of Obstetrics, Gynecology, and Women's Health, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii Uterine Leiomyomas Carl M. Allen, DDS, MSD Professor, Department of Oral Pathology, The Ohio State University College of Dentistry Director, Oral & Maxillofacial Surgery and Pathology, University Hospital Professor, Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Diseases of the Mouth Antonio Almeida, MD Assistant Professor, Universidade Nova de Lisboa School of Medicine Consultant Hematologist, Instituto Portugès de Oncologia, Lisbon, Portugal Sickle Cell Disease Tina S. Alster, MD

Clinical Professor of Dermatology, Georgetown University School of Medicine Director, Washington Institute of Dermatologic Laser Surgery, Washington, DC Keloids Navin M. Amin, MD Professor of Family Medicine, University of California, Irvine, School of Medicine, Irvine Associate Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles Associate Professor of Medicine, Stanford University School of Medicine, Stanford, California Infective Endocarditis Girish Anand, MD Fellow in Gastroenterology, Albert Einstein Medical Center, Philadelphia, Pennsylvania Dysphagia and Esophageal Obstruction Deverick J. Anderson, MD Clinical Associate, Duke University Medical Center, Durham, North Carolina Rickettsial and Ehrlichial Infections Vinicius C.S. Antao, MD, MSc, PhD Adjunct Assistant Professor, Community Medicine Department, West Virginia University College of Medicine, Morgantown, West Virginia Silicosis and Asbestosis Karim Aoun, MD Associate Professor, University of Tunis Faculty of Medicine Attending Physician, Pasteur Institute of Tunis, Tunisa, Tunisia Leishmaniasis Baha M. Arafah, MD Professor of Medicine, Case Western Reserve University School of Medicine Attending Physician, Division of Endocrinology, University Hospitals/Case Medical Center, Cleveland, Ohio Hyperprolactinemia Paul M. Arguin, MD Captain, U.S. Public Health Service Chief, Domestic Malaria Unit, Centers for Disease Control and Prevention, Atlanta, Georgia Malaria Aydin Arici, MD Professor of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut Dysfunctional Uterine Bleeding Isao Arita, MD

Chairman, Agency for Cooperation in International Health, Kumamoto, Kumamoto City, Japan Smallpox Noel A. Armenakas, MD Clinical Associate Professor, Department of Urology, Cornell Weill Medical School Attending Surgeon, Lenox Hill Hospital and New York–Presbyterian Hospital, New York, New York Trauma to the Genitourinary Tract Ramesh Ayyala, MD Associate Professor; Director, Residency Program in Ophthalmology Director, Glaucoma Service, Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana Conjunctivitis Claus Bachert, MD, PhD Professor, University of Ghent Faculty of Medicine Chief of Clinics, Ear-Nose-Throat Department, University Hospital of Ghent, Ghent, Belgium Nonallergic Perennial Rhinitis Gopal H. Badlani, MD Vice Chairman, Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York Benign Prostatic Hyperplasia Adrianne Williams Bagley, MD Clinical Associate Professor, Johns Hopkins University School of Medicine Associate Staff, Johns Hopkins Hospital, Baltimore, Maryland Pelvic Inflammatory Disease David A. Baker, MD Professor, Department of Obstetrics, Gynecology, and Reproductive Medicine, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook, New York Vulvovaginitis David M. Bamberger, MD Professor of Medicine and Vice-Chair of Educational Affairs, Department of Medicine, University of Missouri–Kansas City School of Medicine Chief, Infectious Diseases Section, Truman Medical Center, Kansas City, Missouri Gonorrhea Raymond L. Barnhill, MD Clinical Professor of Dermatology and Pathology, University of Miami Miller School of Medicine, Miami Staff Pathologist, University of Miami Medical Group and Sylvester Comprehensive Cancer Center, Coral Gables, Florida Nevi

James C. Barton, MD Clinical Professor, Department of Medicine, University of Alabama at Birmingham School of Medicine Medical Director, Southern Iron Disorders Center, Birmingham, Alabama Iron Deficiency Nurcan Baykam, MD Associate Professor of Infectious Diseases, University of Ankara Faculty of Medicine Staff, Infectious Diseases and Clinical Microbiology Clinic, Ankara Numune Education and Research Hospital, Ankara, Turkey Brucellosis Carolyn E. Beck, MD, MSc Assistant Professor, University of Toronto Faculty of Medicine Staff Paediatrician, Division of Paediatric Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Parenteral Fluid Therapy for Infants and Children Meg Begany, RD, CSP, LDN Clinical Neonatal Dietitian, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Normal Infant Feeding Jerome Belinson, MD Staff, Department of Obstetrics and Gynecology, Taussig Cancer Institute Director, Gynecologic Oncology Fellowship Program, Cleveland Clinic, Cleveland, Ohio Ovarian Cancer Nicholas P. Bell, MD Clinical Assistant Professor, Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston, Houston, Texas Glaucoma Pelayo C. Besa, MD Radiation Oncology Head, Santiago, Chile Hodgkin's Disease: Radiation Therapy Karl R. Beutner, MD, PhD Associate Clinical Professor of Dermatology, University of California, San Francisco, School of Medicine, San Francisco, California Condyloma Acuminatum (Genital Warts) Zulfiqar A. Bhutta, MB, BS, PhD Husein Lalji Dewraj Professor of Pediatrics, Aga Khan University and Medical Center, Karachi, Pakistan Typhoid Fever

Joseph Biederman, MD Professor of Psychiatry, Harvard Medical School Chief of Clinical and Research in Pediatric Psychopharmacology, Massachusetts General Hospital, Boston, Massachusetts Attention Deficit Hyperactivity Disorder John P. Bilezikian, MD Professor of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons Attending Physician, NewYork–Presbyterian Hospital, New York, New York Primary Hyperparathyroidism and Hypoparathyroidism Warren P. Bishop, MD Professor of Pediatrics, University of Iowa Carver College of Medicine Director, Division of Gastroenterology, University of Iowa Children's Hospital, Iowa City, Iowa Constipation Soenke Boettger, MD Fellow, Memorial Sloan-Kettering Cancer Center, New York, New York Delirium Jonathan Bond, MB, MRCPI Specialist Registrar in Hematology, The Adelaide and Meath Hospital, Dublin, Ireland Chronic Leukemias Herbert L. Bonkovsky, MD Professor, University of Connecticut School of Medicine, Farmington, Connecticut Professor, University of North Carolina College of Medicine Vice President for Research, Carolinas Health Care System, Charlotte, North Carolina Porphyria Patrick Borgen, MD Chief, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York Diseases of the Breast Harisios Boudoulas, MD, PhD Professor of Medicine and Pharmacy Emeritus, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Director, Center of Clinical Research, Academy of Athens, Athens, Greece Mitral Valve Prolapse: The Floppy Mitral Valve, Mitral Valve Prolapse, and Mitral Valvular Regurgitation Aida Bouratbine, MD Professor, University of Tunis Faculty of Medicine

Head, Laboratory of Parasitology, Pasteur Institute of Tunis, Tunis, Tunisia Leishmaniasis Krystene I. Boyle, MD Clinical Instructor, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine Clinical Fellow, Department of OB/GYN, Division of Reproductive Endocrinology, University of Cincinnati Medical Center, Cincinnati, Ohio Menopause Robert Bradsher, MD Richard V. Ebert Professor of Medicine, University of Arkansas College of Medicine Program Director, Internal Medicine Residency and Infectious Diseases Fellowship Training Program Vice-Chairman, Department of Internal Medicine Director, Division of Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas Blastomycosis Daniel M. Brailita, MD Fellow in Gastroenterology, University of Texas Southwestern Medical Center, Dallas, Texas Acute and Chrunic Hepatitis Marc Brand, MD Assistant Professor of Surgery, Rush Medical College Attending Surgeon, Rush University Medical Center, Chicago, Illinois Tumors of the Rectum and Colon Chad M. Braun, MD Assistant Professor, Department of Family Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois Nausea and Vomiting Mark E. Brecher, MD Professor and Vice Chair, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine Director, McLendon Clinical Laboratories, Chapel Hill, North Carolina Therapeutic Use of Blood Components Patricia D. Brown, MD Associate Professor of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine Chief of Medicine, Detroit Receiving Hospital, Detroit, Michigan Pyelonephritis J. James Bruno II, MD Lenox Hill Hospital, New York, New York Trauma to the Genitourinary Tract

John Brusch, MD Assistant Professor of Medicine, Harvard Medical School, Boston Associate Chief of Medicine, Cambridge Health Alliance, Cambridge, Massachusetts Streptococcal Pharyngitis Peter Buckley, MD Professor of Psychiatry, Medical College of Georgia Staff Psychiatrist, MCG Medical Center, Augusta, Georgia Schizophrenia Cathy L. Budman, MD Associate Professor of Psychiatry, New York University School of Medicine, New York Director, Movement Disorders Program in Psychiatry, North Shore–Long Island Jewish Health System, Manhassett, New York Gilles de la Tourette Syndrome Irina Burd, MD, PhD Instructor, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine Staff, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Menopause Kevin A. Bybee, MD Assistant Professor of Medicine, University of Missouri–Kansas City School of Medicine Consulting Cardiologist, Mid-America Heart Institute, Cardiovascular Consultants, PA, Kansas City, Missouri Acute Myocardial Infarction John Byrne, MCh Assistant Professor of Surgery, Albany Medical College Member, The Vascular Group, Albany Medical Center, Albany, New York Acquired Diseases of the Aorta Alexander Bystritsky, MD, PhD Professor, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA Director, Anxiety Disorder Program, The Semel Institute for Neuroscience and Human Behavior, Los Angeles, California Panic Disorder Diego Cadavid, MD Associate Professor, Department of Neurology and Neuroscience, UMDNJ–New Jersey Medical School, Newark, New Jersey Relapsing Fever

Grant R. Caddy, MD Consultant Physician and Gastroenterologist, Ulster Hospital, Belfast, Northern Ireland Cholelithiasis and Cholecystitis Thomas R. Caraccio, PharmD Associate Professor of Emergency Medicine, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Assistant Professor of Pharmacology and Toxicology, New York College of Osteopathic Medicine, Old Westbury, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions Enrique V. Carbajal, MD Associate Clinical Professor of Medicine, University of California, San Francisco, School of Medicine, San Francisco Staff Physician–Cardiology, VA Central California Health Care System, Fresno, California Premature Beats Stephen D. Cassivi, MD, MSc, FRCSC, FACS Associate Professor of Surgery, Mayo Clinic College of Medicine Director of Lung Transplantation, Division of General Thoracic Surgery, Mayo Clinic, Rochester, Minnesota Pleural Effusion and Empyema Thoracis Serguei A. Castaneda, MD Research Associate, Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts Thalassemia Frank R. Cerniglia Jr., MD Director of Pediatric Urology, Urologic Institute of New Orleans, New Orleans, Louisiana Childhood Enuresis Joumana T. Chaiban, MD Fellow in Endocrinology, Case Western Reserve University School of Medicine and University Hospitals/Case Medical Center, Cleveland, Ohio Hyperprolactinemia Sarah L. Chamlin, MD Assistant Professor of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine Staff Physician, Children's Memorial Hospital, Chicago, Illinois Atopic Dermatitis Miriam M. Chan, RPh, PharmD Clinical Assistant Professor of Family Medicine, College of Medicine, and Clinical Assistant Professor of Pharmacy, College of Pharmacy, The Ohio State University Director of Pharmacy Education, Riverside Family Medicine Residency Education, Riverside Methodist Hospital,

Columbus, Ohio Popular Herbs and Nutritional Supplements; New Drugs Sam S. Chang, MD Associate Professor of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee Malignant Tumors of the Urogenital Tract Gary C. Chen, MD Resident Physician, Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California Bleeding Esophageal Varices Stella T. Chou, MD Instructor in Pediatrics, University of Pennsylvania School of Medicine Attending Physician, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Nonimmune Hemolytic Anemia Bart L. Clarke, MD Assistant Professor of Medicine, Mayo Clinic College of Medicine Consultant, Mayo Clinic, Rochester, Minnesota Osteoporosis Claus-Frenz Claussen, MD Professor Extraordinarius in Neuro-otology, Julius-Maximilaus University Faculty of Medicine, Wuerzburg, Germany Acting Director, Neuro-otological Research Institute of 4GF, Bad Kissingen, Germany Tinnitus Harris R. Clearfield, MD Professor of Medicine, Drexel University College of Medicine Section Chief, Gastroenterology, Hahnemann University Hospital, Philadelphia, Pennsylvania Diverticula of the Alimentary Tract Donald Clemons, MD Clinical Assistant Professor, Department of Family Practice, Quillen School of Medicine, Johnson City, Tennessee Premalignant Lesions Melanie W. Conway, MD Attending Psychiatrist, Texarkana Living Hope, Texarkana; Dardanelle Hospital, Dardanelle; Levi Hospital, Hot Springs; and White River Medical Center, Batesville, Arkansas Mood Disorders Michael S. Cookson, MD

Associate Professor of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee Malignant Tumors of the Urogenital Tract John F. Coyle II, MD Clinical Professor, Department of Medicine, University of Oklahoma College of Medicine–Tulsa, Tulsa, Oklahoma Disturbances Caused by Heat Lester M. Crawford, PhD Former Research Professor, Georgetown University School of Medicine, Washington, DC Former Head, Department of Physiology, University of Georgia College of Medicine, Athens, Georgia Foodborne Illness Burke A. Cunha, MD Professor of Medicine, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Chief, Infectious Disease Division, Winthrop-University Hospital, Mineola, New York Viral and Mycoplasmal Pneumonias; Urinary Tract Infections in Women Stella Dantas, MD Physician, Department of Obstetrics and Gynecology, Beaverton Medical Office, Northwest Permanente PC Physicians and Surgeons, Beaverton, Oregon Uterine Leiomyomas R. Clement Darling III, MD Professor of Surgery, Albany Medical College Chief, Division of Vascular Surgery, Albany Medical Center Hospital, The Vascular Group, PLLC, Albany, New York Acquired Diseases of the Aorta Andre Dascal, MD, FRCPC Associate Professor of Medicine, Microbiology and Immunology, McGill University Faculty of Medicine Senior Infectious Disease Physician, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada Acute Infectious Diarrhea; Toxic Shock Syndrome Susan Davids, MD, MPH Assistant Professor of Medicine, Medical College of Wisconsin Associate Program Director, Internal Medicine Residency, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin Acute Bronchitis Susan A. Davidson, MD Associate Professor, University of Colorado School of Medicine Chief, Gynecologic Oncology, University of Colorado Hospital, Denver, Colorado

Neoplasms of the Vulva Prakash C. Deedwania, MD Professor of Medicine, University of California, San Francisco, School of Medicine, San Francisco Chief, Cardiology Section, VA Central California Health Care System, Fresno, California Premature Beats Albert A. Del Negro, MD Clinical Assistant Professor of Medicine, Georgetown University School of Medicine, Washington, DC Medical Director, Cardiac Pacemaker Clinic, and Cardiac Electrophysiologist, Inova Fairfax Hospital, Fairfax, Virginia Heart Block Marie-France Demierre, MD Associate Professor of Dermatology and Medicine, Boston University School of Medicine Director, Skin Oncology, and Director, Photopheresis Program, Boston Medical Center, Boston, Massachusetts Cutaneous T Cell Lymphoma Stephen R. Deputy, MD Assistant Professor of Neurology, Louisiana State University School of Medicine Staff Neurologists, Children's Hospital, New Orleans, Louisiana Traumatic Brain Injury in Children Sarah E. Dick, MD Senior Dermatology Resident, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Bullous Diseases Ram Dickman, MD Research Fellow, Southern Arizona VA Health Care System, Neuro-Enteric Clinical Research Group, Tucson, Arizona Gaseousness and Indigestion Alice N. Do, DO Research Fellow, Solano Clinical Research, Division Dow Pharmaceutical Sciences, Vallejo, California Condyloma Acuminatum (Genital Warts) Sunil Dogra, MD, DNB, MNAMS Assistant Professor, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Leprosy Basak Dokuzoguz, MD Chief, Infectious Diseases and Clinical Microbiology Clinic, Ankara Numune Education and Research Hospital,

Ankara, Turkey Brucellosis Douglas A. Drevets, MD, DTM&H Associate Professor of Medicine, University of Oklahoma School of Medicine Staff Physician, Oklahoma City VA Medical Center, Oklahoma City, Oklahoma Plague Jean Dudler, MD Associate Professor of Medicine, Division of Rheumatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Rat-Bite Fever Kamryn T. Eddy, PhD Clinical Fellow, Massachusetts General Hospital, and Research Fellow, Harvard Medical School, Boston, Massachusetts Bulimia Nervosa Libby Edwards, MD Associate Clinical Professor of Dermatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill Chief, Division of Dermatology, Carolinas Medical Center and Southeast Vulvar Clinic, Charlotte, North Carolina Pruritus Ani and Vulvae George E. Ehrlich, MD Adjunct Professor, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Adjunct Professor of Clinical Medicine, New York University School of Medicine, New York, New York Osteoarthritis Kimberly May Eickhorst, MD Chief Resident, St. Luke's–Roosevelt Hospital Center, New York, New York Diseases of the Hair Brandon D. Einstein, BA Medical Student, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Nevi Julian Elliott, MB, BS, FRACP Conjoint Senior Lecturer, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney Infectious Diseases Physician, Alfred Hospital, Melbourne HIV Clinical Advisor, International Health Research Group, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia

Psittacosis John M. Embil, MD, FRCP(C), FACP Associate Professor, Department of Medicine and Medical Microbiology, Section of Infectious Diseases, University of Manitoba Faculty of Medicine Director, Infection Prevention and Control Unit, Health Science Centre, Winnipeg, Manitoba, Canada Necrotizing Skin and Soft Tissue Infections Elizabeth D. Ennis, MD Clinical Assistant Professor, Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham School of Medicine Vice President of Medical Education and Research, Baptist Health System–Birmingham Director, Internal Residency Program, Baptist Health System, Birmingham, Alabama Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome Helen Enright, MD Department of Haematology, Adelaide and Meath Hospitals, Tallaght, Dublin, Ireland Chronic Leukemias Alexander Espinoza, MD University of California, Los Angeles School of Medicine, Los Angeles, California Common Sports Injuries Chukwuemeka N. Etufugh, MD Resident, Department of Pathology, Baylor University Medical Center, Dallas, Texas Venous Stasis Ulcers Amanda Nickles Fader, MD Clinical Fellow in Gynecologic Oncology, Cleveland Clinic, Cleveland, Ohio Ovarian Cancer Ruth Falik, MD Associate Professor of Medicine, Baylor College of Medicine Attending Physician, Ben Taub General Hospital, Houston, Texas Pain; Atrial Fibrillation Ronnie Fass, MD Professor of Medicine, University of Arizona School of Medicine Director, GI Motility Laboratories, University of Arizona Health Sciences Center and Southern Arizona VA Health Care System, Tucson, Arizona Gaseousness and Indigestion Fred G. Fedok, MD, FACS

Professor, Department of Surgery, Chief, Division of Otolaryngology—Head and Neck Surgery, Penn State Hershey Medical Center, Hershey, Pennsylvania Bell's Palsy (Idiopathic Acute Peripheral Facial Paralysis) Seth I. Felder, BA Medical Student, University of South Florida College of Medicine, Tampa, Florida Nevi Steven R. Feldman, MD, PhD Professor of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Acne Vulgaris and Rosacea Eve S. Ferdman, BA Managing Editor, Brachytherapy, Memorial Sloan-Kettering Cancer Center, New York, New York Brain Tumors L. Jaime Fitten, MDS Professor of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA Director, Geriatric Psychiatry, Greater Los Angeles Veterans Administration, Sepulveda Campus, Los Angeles, California Alzheimer's Disease Alan B. Fleischer Jr., MD Professor and Chair, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Acne Vulgaris and Rosacea Adriana Foster, MD Assistant Professor, Department of Psychiatry and Health Behavior, Medical College of Georgia Staff Psychiatrist, MCG Medical Center, Augusta, Georgia Schizophrenia Melvin H. Freedman, MD Professor Emeritus, Department of Pediatrics, University of Toronto Faculty of Medicine Honorary Consultant, Hematology-Oncology Senior Scientist Emeritus, Research Institute Chair, Research Ethics Board (IRB), The Hospital for Sick Children, Toronto, Ontario, Canada Neutropenia Ellen W. Freeman, PhD Research Professor, Department of Obstetrics/Gynecology and Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Premenstrual Syndrome

Eugene P. Frenkel, MD Professor of Internal Medicine and Radiology, University of Texas Southwestern Medical School at Dallas; Patsy R. & Raymond D. Nasher Distinguished Chair in Cancer Research; Elaine Dewey Sammons Distinguished Chair in Cancer Research in honor of Eugene P. Frenkel, M.D.; and A. Kenneth Pye Professorship in Cancer Research, Harold C. Simmons Comprehensive Cancer Center, Southwestern Medical Center, Dallas, Texas Pernicious Anemia and Other Megaloblastic Anemias Jermy N. Friedman, MB, ChB Associate Professor, Department of Paediatrics, University of Toronto Faculty of Medicine Head, Division of Paediatric Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Parenteral Fluid Therapy for Infants and Children Neil J. Friedman, MD Adjunct Clinical Associate Professor, Department of Ophthalmology, Stanford University School of Medicine, Stanford Private Practice, Mid-Peninsula Ophthalmology, Palo Alto, California Vision Correction Procedures Deborah K. Froh, MD Associate Professor of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia Cystic Fibrosis Maisie M. Fung, MD Staff Physician, Camino Medical Group, Mountain View, California Peripheral Arterial Disease Joseph M. Furman, MD, PhD Professor, Departments of Otolaryngology and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Episodic Vertigo Steven L. Galetta, MD Ruth Wagner Van Meter and Ray Van Meter Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Optic Neuritis R. Michael Gallagher, DO Director, Headache Center of Central Florida, Melbourne, Florida Headache Andrea Gallina, MD Vita-Salute University; Resident in Training, San Raffaele Hospital, Milan, Italy Prostatitis

Juan Armando Garcia, MD Staff-Intensivist, Cardiovascular ICU, The Methodist Hospital, Houston, Texas Management of Chronic Obstructive Pulmonary Disease Christopher S. George, MD Attending Physician, Department of Hematology and Medical Oncology, Riverside Methodist Hospital, Columbus, Ohio Primary Lung Cancer James N. George, MD George Lynn Cross Professor of Medicine, University of Oklahoma College of Medicine; Hematology-Oncology Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Thrombotic Thrombocytopenic Purpura Teresa M. George, MD Assistant Program Director, Internal Medicine Residency Program, Riverside Methodist Hospital, Columbus, Ohio Primary Lung Cancer Glenn S. Gerber, MD Associate Professor of Surgery/Urology, Director of Endourology, and Director of Residency Program and Student Clerkship, University of Chicago Pritzker School of Medicine, Chicago, Illinois Renal Calculi Paul L.F. Giangrande, MD Senior Lecturer in Haematology, University of Oxford Consultant Haematologist, Oxford Haemophilia Centre and Thrombosis Unit, Churchill Hospital, Oxford, United Kingdom Venous Thrombosis David B.K. Golden, MD Associate Professor of Medicine, Johns Hopkins University School of Medicine Director, Allergy-Immunology, Sinai Hospital, Baltimore, Maryland Allergic Reactions to Insect Stings Monica Peterson Gordon, MD Geriatric Psychiatry Fellow, David Geffen School of Medicine at UCLA, Los Angeles, California Alzheimer's Disease E. Ann Gormley, MD Professor of Surgery (Urology), Dartmouth Medical School Staff Urologist, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

Urinary Incontinence Eduardo Gotuzzo, MD Principal Professor of Medicine, Universidad Peruana Cayetano Heredia Chief, Department of Infectious, Tropical, and Dermatologic Diseases, Hospital National Cayetano Heredia, Lima, Peru Cholera John E. Gough, MD, FACEP Professor, Department of Emergency Medicine, Brody School of Medicine at East Carolina University Attending Physician, Emergency Department, Pitt County Memorial Hospital, Greenville, North Carolina Marine Trauma, Envenomations, and Intoxications Mark A. Granner, MD Associate Professor of Neurology, University of Iowa Carver College of Medicine Director, Iowa Comprehensive Epilepsy Program, University of Iowa Hospitals and Clinics, Iowa City, Iowa Seizures and Epilepsy in Adolescents and Adults Charles S. Greene, DDS Clinical Professor and Director of Orofacial Pain Studies, University of Illinois College of Dentistry Orofacial Pain Consultant, Illinois Masonic Hospital, Chicago, Illinois Temporomandibular Disorders Joseph Greensher, MD Professor of Pediatrics, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Medical Director and Associate Chair, Department of Pediatrics, Long Island Regional Poison and Drug Information Center, Winthrop-University Hospital, Mineola, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions Charles Grose, MD Professor of Pediatrics, University of Iowa Carver College of Medicine Director of Infectious Diseases Division, Children's Hospital of Iowa, Iowa City, Iowa Varicella (Chickenpox) Marlon A. Guerrero, MD Chief Surgical Resident, St. Luke's Episcopal Health System, Houston, Texas Thyroid Cancer Abdo Haddad, MD Fellow, Hematology and Medical Oncology, Cleveland Clinic Foundation, Cleveland, Ohio Aplastic Anemia

Frank G. Haluska, MD, PhD Tufts University School of Medicine Deputy Director and Clinical Director, Cancer Center, Tufts-New England Medical Center, Boston, Massachusetts Melanoma Rashidul Haque, MB, PhD Scientist, Laboratory Sciences Division, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B), Dhaka, Bangladesh Amebiasis Rachel Haroz, MD Assistant Professor of Emergency Medicine, UMDNJ–Robert Wood Johnson Medical School at Camden Attending Physician, Department of Emergency Medicine, Cooper University Hospital Camden, New Jersey Spider Bites and Scorpion Stings E. John Harris Jr., MD Professor of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California Peripheral Arterial Disease Umur Hatipoglu, MD Clinical Assistant Professor of Medicine, University of Illinois at Chicago College of Medicine Section Chief, Pulmonary and Critical Care Medicine, Mercy Hospital and Medical Center, Chicago, Illinois Bacterial Pneumonia Dana M. Hayden, MD, MPH General Surgery Resident, Rush University Medical Center, Chicago, Illinois Tumurs of the Rectum and Colon Emil R. Heinze, MD Assistant Clinical Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles Senior Rheumatology Fellow, UCLA San Fernando Valley Program, Olive View–UCLA Medical Center, Sylmar, California Bursitis, Tendinitis, Myofascial Pain, and Fibromyalgia J. Claude Hemphill III, MD, MAS Associate Professor of Clinical Neurology and Neurological Surgery, University of California, San Francisco, School of Medicine Director, Neurocritical Care, San Francisco General Hospital, San Francisco, California Intracerebral Hemorrhage William Henderson, MD Clinical Assistant Professor, University of British Columbia Faculty of Medicine, Vancouver Attending Physician, Royal Columbia Hospital, New Westminister, British Columbia, Canada

Acute Respiratory Failure David B. Herzog, MD Professor of Psychiatry (Pediatrics), Harvard Medical School, Cambridge Director, Eating Disorders Unit—Child Psychiatry Service, and Director, Harris Center for Education and Advocacy in Eating Disorders, Massachusetts General Hospital, Boston, Massachusetts Bulimia Nervosa Camile Hexsel, MD Research Fellow, Department of Dermatology, Henry Ford Hospital, Detroit, Michigan Sunburn David G. Hill, MD Waterbury Pulmonary Associates, Waterbury; Yale University School of Medicine, New Haven, Connecticut Cough Christopher D. Hillyer, MD Transfusion Medicine Program, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia Adverse Effects of Blood Transfusion Darryl T. Hiyama, MD Professor of Clinical Surgery, David Geffen School of Medicine at UCLA Staff Surgeon, UCLA Center for Health Sciences, Los Angeles, California Parenteral Nutrition in Adults Brian D. Hoit, MD Professor of Medicine, Physiology and Biophysics, Case School of Medicine Director, Echocardiography, University Hospitals of Cleveland, Cleveland, Ohio Pericarditis M. Ekramul Hoque, MBBS, MPH (Hons), PhD Research Fellow, School of Population Health, University of Auckland, Auckland, New Zealand Giardiasis Duane R. Hospenthal, MD, PhD Associate Professor of Medicine, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, Maryland Clinical Professor of Medicine, University of Texas Medical School at San Antonio, San Antonio Chief, Infectious Disease Service, Brooke Army Medical Center, Fort Sam Houston, Texas Coccidioidomycosis Tamara Salam Housman, MD

Procedural Dermatology/Mohs Micrographic Surgery Fellow, Dermatologic Surgery, University of Washington Medical Center, Seattle, Washington Warts (Verrucae) Samuel S. Hsu, MD Assistant Professor, University of Maryland School of Medicine, Baltimore, Maryland Tetanus Katherine Hughes, MB, ChB Specialist Registrar in Endocrinology and Diabetes, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom Thyroiditis Scott A. Hundahl, MD Professor of Clinical Surgery, University of California, Davis, School of Medicine Chief of Surgery, VA Northern California Health Care System, Sacramento VA Medical Center, Sacramento, California Tumors of the Stomach Nader Husseinzadeh, MD Professor, University of Cincinnati School of Medicine, Cincinnati, Ohio Cancer of the Uterine Cervix Neil H. Hyman, MD Samuel B. and Michlle D. Labow Professor of Surgery, University of Vermont College of Medicine Chief, Division of General Surgery, Fletcher Allen Health Care, Burlington, Vermont Hemorrhoids, Anal Fissure, and Anorectal Abscess and Fistula Robert D. Inman, MD Professor of Medicine and Immunology, University of Toronto Faculty of Medicine Director, Arthritis Center of Excellence, University Health Network, Toronto, Ontario, Canada Ankylosing Spondylitis Matilde lorizzo, MD Department of Dermatology, University of Bologna, Bologna, Italy Diseases of the Nails Jon E. Isaacson, MD Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, Penn State University College of Medicine, Hershey, Pennsylvania Bell's Palsy (Idiopathic Acute Peripheral Facial Paralysis) Alan C. Jackson, MD, FRCPC

Professor of Medicine (Neurology) and Medical Microbiology, University of Manitoba Faculty of Medicine Head, Section of Neurology, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada Rabies Aleda A. Jacobs, MD Mohs Fellow, Procedural Dermatology, Baylor College of Medicine/Baylor Clinic, Houston, Texas Cancers of The Skin Robert M. Jacobson, MD Professor of Pediatrics, Mayo Clinic College of Medicine Chair, Department of Pediatric and Adolescent Medicine, and Consultant in Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota Office-Based Immunization Practices Mamta K. Jain, MD, MPH Assistant Professor, University of Texas Southwestern Medical School at Dallas, Dallas, Texas Acute and Chronic Hepatitis James J. James, MD, DrPH, MHA Director, Center for Disaster Preparedness and Emergency Response, American Medical Association, Chicago, Illinois Toxic Chemical Agents Reference Chart: Symptoms and Treatment; Biologic Agents Reference Chart—Symptoms, Tests, and Treatment Stephen G. Jenkinson, MD Chief, Pulmonary Diseases Section, Audie Murphy VA Medical Center, San Antonio, Texas Management of Chronic Obstructive Pulmonary Disease Gordon L. Jensen, MD, PhD Professor and Head, Department of Nutritional Sciences, and Professor of Medicine, Pennsylvania State University, Hershey, Pennsylvania Obesity Jeffrey Jim, MD, MS Resident Physician, Department of Surgery, UCLA Medical Center Los Angeles, California Parenteral Nutrition in Adults Michael Johns, MD Assistant Professor of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia Hoarseness and Laryngitis Candice E. Johnson, MD, PhD Clinical Professor of Pediatrics, University of Colorado Health Sciences Center School of Medicine

Volunteer Faculty, The Children's Hospital, Denver, Colorado Bacterial Infections of the Urinary Tract in Girls James F. Jones, MD Research Medical Officer, Chronic Viral Diseases Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Chronic Fatigue Syndrome Michael P. Jones, MD Associate Professor of Medicine, Division of Gastroenterology, Northwestern University Feinberg School of Medicine Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Irritable Bowel Syndrome Joseph L. Jorizzo, MD Professor, Founding and Former Chair, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Cutaneous Vasculitis Rome Jutabha, MD Associate Professor of Medicine, David Geffen School of Medicine at UCLA Director, UCLA Center for Small Bowel Diseases, UCLA Medical Center, Los Angeles, California Bleeding Esophageal Varices S. Patrick Kachur, MD Commander, U.S. Public Health Service Chief, Malaria Strategic Applied Science Unit, Centers for Disease Control and Prevention, Atlanta, Georgia Malaria Tamilarasu Kadhiravan, MD Senior Resident, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India Management of the Patient with HIV Disease Pierre I. Karakiewicz, MD Associate Professor, Department of Urology, University of Montreal Faculty of Medicine Urologic Oncologist and Director, Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada Prostatitis Matthew E. Karlovsky, MD Staff Urologist (Voiding Dysfunction/Female Urology), Private Practice, Center for Urological Services, PC, Phoenix, Arizona Benign Prostatic Hyperplasia

Andreas Katsambas, MD, PhD Professor and Chairman, 1st Department of Dermatology, University of Athens School of Medicine Attending Physician, “Andreas Sygros” Hospital for Skin and Venereal Diseases, Athens, Greece Parasitic Diseases of the Skin Philip O. Katz, MD Clinical Professor of Medicine, Jefferson Medical College of Thomas Jefferson University Chairman, Division of Gastroenterology, Albert Einstein Medical Center, Philadelphia, Pennsylvania Dysphagia and Esophageal Obstruction Andrew M. Kaunitz, MD Professor, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, Florida Contraceptive Methods Sean Keenan, MD Clinical Assistant Professor of Medicine, University of British Columbia Faculty of Medicine, Vancouver Head, Department of Critical Care Medicine, Royal Columbia Hospital, New Westminister, British Columbia, Canada Acute Respiratory Failure Jennifer Kelly, DO Assistant Professor of Medicine, Division of Endocrinology, SUNY Upstate Medical University, Syracuse, New York Diabetes Insipidus Rebecca Lewis Kelso, MD Assistant Professor, Department of Dermatology, University of Texas Medical Branch School of Medicine, Galveston, Texas Fungal Diseases of the Skin Stephen F. Kemp, MD Associate Professor of Medicine and Assistant Professor of Pediatrics, University of Mississippi School of Medicine Director, Allergy and Immunology Fellowship Program, University of Mississippi Medical Center, Jackson, Mississippi Anaphylaxis and Serum Sickness James W. Kendig, MD Professor of Pediatrics, Pennsylvania State University School of Medicine Staff Pediatrician, Division of Newborn Medicine, Penn State Children's Hospital, Hershey, Pennsylvania Hemolytic Disease of the Newborn

Sripathi R. Kethu, MD Assistant Professor of Medicine, Brown University School of Medicine, Providence, Rhode Island Gastric and Peptic Ulcer Disease Sundeep Khosla, MD Professor of Medicine, Mayo Clinic College of Medicine Consultant, Mayo Clinic, Rochester, Minnesota Osteoporosis Craig S. Kitchens, MD Professor of Medicine, University of Florida College of Medicine Associate Chief of Staff for Education, Malcolm Randall VA Medical Center, Gainesville, Florida Snakebite Joel D. Klein, MD, FAAP Professor of Pediatrics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Chief, Division of Pediatric Infectious Diseases, Alfred I. duPont Hospital for Children, Wilmington, Delaware Mumps Jonathan Kolitz, MD Associate Professor of Medicine, New York University School of Medicine, New York Director, Leukemia Service, Monter Cancer Center, North Shore University Hospital, Lake Success, New York Acute Leukemias in Adults Luciano Kolodny, MD Endocrinologist, HealthPartners Medical Group, Woodbury, Minnesota Erectile Dysfunction Gerald B. Kolski, MD, PhD, FAAAAI, FAAP Clinical Professor of Pediatrics, Temple University School of Medicine Adjunct Clinical Professor of Pediatrics, Drexel University School of Medicine, Philadelphia Chairman, Department of Pediatrics, Crozer Chester Medical Center, Upland, Pennsylvania Asthma in Children John Koo, MD Professor and Vice Chairman, Department of Dermatology, University of California, San Francisco, School of Medicine Director, UCSF Psoriasis Treatment Center, Phototheraphy Unit and Clinical Research Unit, University of California San Francisco Medical Center, San Francisco, California Papulosquamous Disorders Stephen L. Kopecky, MD Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota Acute Myocardial Infarction

Frederick K. Korley, MD Robert E. Meyerhoff Assistant Professor of Emergency Medicine, Johns Hopkins University School of Medicine Staff, Johns Hopkins Medical Institutions, Baltimore, Maryland Disturbances Due To Cold Milind J. Kothari, DO Professor of Neurology and Vice Chair of Education and Training, Pennsylvania State College of Medicine, Hershey, Pennsylvania Myasthenia Gravis and Related Disorders Jeffrey A. Kraut, MD Chief of Dialysis, Veterans Affairs Greater Los Angeles Healthcare System Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California Chronic Renal Failure Robert A. Kreisberg, MD Distinguished Professor Emeritus, University of South Alabama, Mobile Clinical Professor of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham Teaching Faculty, Baptist Health System, Birmingham, Alabama Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome Jacques Kremer, PhD Post-Doctoral Program, Institute of Immunology, National Laboratory of Health, Luxembourg, Luxembourg Measles (Rubeola) John N. Krieger, MD Professor of Urology, University of Washington School of Medicine and Public Health Attending Surgeon, University of Washington Medical Center and Hanborview Medical Center Chief of Urology, VA Puget Sound, Seattle, Washington Epididymitis; Nungonococcal Urethritis Leonard R. Krilov, MD Professor of Pediatrics, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Chief, Pediatric Infectious Disease, and Vice-Chairman of Pediatrics, Winthrop-University Hospital, Mineola, New York Infectious Mononucleosis Michael Kroll, MD Associate Professor of Medicine, Baylor College of Medicine Staff Hematologist-Oncologist, Michael E. DeBakey VA Medical Center, Houston, Texas Polycythemia Vera

Bhushan Kumar, MD, MNAMS Former Professor and Head, Department of Dermatology, Post-Graduate Institute of Medical Education and Research, Chandigarh, India Leprosy Paul Y. Kwo, MD Associate Professor of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana Cirrhosis Norman J. Lacayo, MD Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, Stanford University School of Medicine, Stanford Attending Physician, Lucile Packard Children's Hospital, Palo Alto, California Acute Leukemia in Children Lori M.B. Laffel, MD, MPH Associate Professor of Pediatrics, Harvard Medical School Chief, Pediatric, Adolescent, and Young Adult Section, and Investigator, Section on Genetrics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts Diabetes Mellitus in Children and Adolescents Gabriella Lakos, MD, PhD Visiting Assistant Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois Connective Tissue Disorders Paul R. Lambert, MD Professor and Chairman, Department of Otolaryngology, Medical University of South Carolina, Charleston, South Carolina Ménière's Disease Barbara A. Latenser, MD Clara L. Smith Professor of Burn Treatment and Clinical Professor of Surgery, University of Iowa Carver College of Medicine Medical Director, Burn Treatment Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa Burn Treatment Guidelines Yung R. Lau, MD Associate Professor of Pediatric Cardiology, University of Alabama of Birmingham School of Medicine, Bimingham, Alabama Congenital Heart Disease Mark Layton, MD

Reader, Imperial College Consultant, Hammersmith Hospital, London, United Kingdom Sickle Cell Disease Luca Lazzarini, MD Department of Infectious Diseases and Tropical Medicine, San Bortolo Hospital, Vicenza, Italy Osteomyelitis Andrew G. Lee, MD Professor of Opthalmology, Neurology, and Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, Iowa Optic Neuritis Chai Sue Lee, MD Assistant Professor, Department of Dermatology, University of California, Davis, School of Medicine, Davis Director, Psoriasis and Phototherapy Treatment Center, UC Davis Medical Center, Sacramento, California Papulosquamous Disorders Jason T. Lee, MD Assistant Professor of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California Peripheral Arterial Disease Julie Leegwater-Kim, MD, PhD Fellow in Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, New York Parkinsonism Jerrold B. Leikin, MD Professor of Emergency Medicine, Northwestern University Feinberg School of Medicine Professor of Medicine, Rush Medical College, Chicago Director of Medical Toxicology, Evanston Northwestern Healthcare–Omega, Glenbrook Hospital, Glenview, Illinois Disturbance Due to Cold Marcel Levi, MD Professor of Medicine, University of Amsterdam Faculty of Medicine Chairman, Department of Medicine, Academic Medical Center, Amsterdam, The Netherlands Disseminated Intravascular Coagulation Moshe Levi, MD Professor of Medicine, University of Colorado School of Medicine Nephrology Fellow, University of Colorado Hospital, Aurora, Colorado Hyponatremia

Eyal Levit, MD Assistant Clinical Professor of Dermatology, Columbia University College of Physicians and Surgeons Director of Dermatologic and Cosmetic Surgery, St. Luke's Hospital Director, Procedural Dermatology Fellowship, New York–Presbyterian Hospital and St. Luke's–Roosevelt Hospital, New York, New York Diseases of the Hair Henry W. Lim, MD Chairman and C.S. Livingood Chair, Department of Dermatology, Henry Ford Hospital, Detroit, Michigan Sunburn Gary H. Lipscomb, MD Professor and Vice Chairman, University of Tennessee College of Medicine Director, Division of Gynecologic Specialties, University of Tennessee Health Science Center, Memphis, Tennessee Ectopic Pregnancy James A. Litch, MD, DTMH Clinical Assistant Professor, University of Washington School of Medicine and School of Public Health, Seattle, Washington High-Altitude Illness Virginia Litle, MD Assistant Professor of Surgery, Mount Sinai School of Medicine Assistant Attending, Department of CT Surgery, Mount Sinai Medical Center, New York, New York Primary Lung Abscess Jonathan S. Lopresti, MD, PhD Associate Professor of Clinical Medicine, Keck School of Medicine at USC Attending Physician, LAC/USC Medical Center, Los Angeles, California Hypothyroidism Jacqueline M. Losi-Sasaki, MD Private Practice, The Dermatology Clinic, PLLC, Gulfport, Mississippi Viral Diseases of the Skin James M. Lyznicki, MS, MPH Senior Scientist, Center for Disaster Preparedness and Emergency Response, American Medical Association, Chicago, Illinois Toxic Chemical Agents Reference Chart: Symptoms and Treatment; Biologic Agents Reference Chart—Symptoms, Tests, and Treatment

Jaroslaw P. Maciejewski, MD, PhD Staff, Hematologic Oncology and Blood Disorders Section Head, Experimental Hematology and Hematopoiesis Associate Professor, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio Aplastic Anemia Douglas W. MacPherson, MD, MSc (CTM) Professor, Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton President, Migration Health Consultants Inc., Cheltenham, Ontario, Canada Intestinal Parasites Carl D. Malchoff, MD, PhD Professor of Internal Medicine, University of Connecticut School of Medicine, Farmington, Connecticut Adrenocortical Insufficiency Brian F. Mandell, MD, PhD Professor of Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Vice Chairman of Medicine, Department of Rheumatic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio Hyperuricemia and Gout Susan Manzi, MD, MPH Associate Professor of Medicine and Epidemiology and Co-Director, Lupus Center of Excellence, University of Pittsburgh School of Medicine Attending, UPMC Magee and UPMC Presbyterian, Pittsburgh, Pennsylvania Connective Tissue Disorders Ali J. Marian, MD Center for Cardiovascular Genetic Research and The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center Staff Physician, The Methodist Hospital Professional Staff, St. Luke's Episcopal Hospital/Texas Heart Institute, Houston, Texas Hypertropic Cardiomyopathy Vickie Martin, MD Resident, Department of Obstetrics and Gynecology, Kingston General Hospital, Kingston, Ontario, Canada Amenorrhea Maria Mascarenhas, MBBS Associate Professor of Pediatrics, University of Pennsylvania School of Medicine Section Chief, Nutrition Division of Gastroenterology and Nutrition Director, Nutrition Support Service, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Normal Infant Feeding

Wissam E. Mattar, MD Indiana University School of Medicine, Indianapolis, Indiana Cirrhosis Eric L. Matteson, MD, MPH Professor of Medicine, Mayo Clinic College of Medicine Consultant in Rheumatology, Mayo Clinic, Rochester, Minnesota Rheumatuid Arthritis Martin J. McCaffrey, MD Associate Professor of Pediatrics, Division of Neonatal and Perinatal Medicine, University of North Carolina at Chapel Hill School of Medicine; North Carolina Children's Hospital, Chapel Hill, North Carolina Resuscitation of the Newborn Anthony L. McCall, MD, PhD James M. Moss Professor of Diabetes, University of Virginia School of Medicine Endocrinologist, University of Virginia Health Care System, Charlottesville, Virginia Diabetes Mellitus in Adults Michael T. McCann, MD Clinical Assistant Professor, Baylor College of Medicine, Houston, Texas Spine Pain Laura J. McCloskey, PhD Assistant Professor of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University Associate Director, Clinical Laboratories, and Director, Jefferson Hospital for Neurosciences Laboratory, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Reference Intervals for the Interpretation of Laboratory Tests Jacqueline Carinhas McGregor, MD Director, Baylor Child Psychiatry Clinic Associate Professor, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas Anxiety Disorders Michael McGuigan, MD Medical Director, Long Island Regional Poison and Drug Information Center, Winthrop-University Hospital, Mineola, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions Stephen H. McKellar, MD Chief Resident, Cardiothoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota

Pleural Effusion and Empyema Thoracis Dilcia McLenan, MD Assistant Professor of Pediatrics, Baylor College of Medicine, Pearland, Texas Care of the High-Risk Neonate D. Scott McMeekin, MD Presbyterian Foundation Presidential Professor, University of Oklahoma College of Medicine Section Chief, Gynecologic Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Cancer of the Endometrium J. Scott McMurray, MD Associate Professor of Pediatric Otolaryngology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Otitis Media Donald McNeil, MD Associate Professor of Clinical Medicine, Department of Immunology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Allergic Reactions to Drugs Anupama Menon, MD, MPH Assistant Professor of Medicine, Division of Infectious Diseases, University of Arkansas for Medical Sciences Staff Physician, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas Blastomycosis Ted A. Meyer, MD, PhD Assistant Professor, Department of Otolaryngology, Medical University of South Carolina, Charleston, South Carolina Ménière's Disease Merry N. Miller, MD Professor and Chair, Department of Psychiatry and Behavioral Sciences, Quillen College of Medicine, East Tennessee State University Attending Psychiatrist, Woodridge Psychiatric Hospital, Johnson City, Tennessee Mood Disorders Paul D. Miller, MD Distinguished Clinical Professor of Medicine, University of Colorado School of Medicine Medical Director, Colorado Center for Bone Research, Lakewood, Colorado Paget's Disease of Bone

Peter A. Millward, MD Assistant Professor of Pathology, Pennsylvania State College of Medicine Medical Director, Blood Bank and Apheresis Service, Milton S. Hershey Medical Center, Hershey, Pennsylvania Therapeutic Use of Blood Components Howard C. Mofenson, MD Professor of Pediatrics and Emergency Medicine, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Professor of Pharmacology and Toxicology, New York College of Osteopathic Medicine, Old Westbury, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions Alladi Mohan, MD Adjunct Professor, Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Andhra Pradesh, India Sarcoidosis; Tuberculosis and Other Mycobacterial Diseases Robert M. Moldwin, MD Assistant Professor of Urology, Albert Einstein College of Medicine of Yeshiva University, Bronx Director, Interstitial Cystitis Center, North Shore–Long Island Jewish Health Care System, New Hyde Park, New York Bacterial Infections of the Urinary Tract in Males Eugene W. Monroe, MD Assistant Clinical Professor of Dermatology, Medical College of Wisconsin Staff, Advanced Healthcare, Milwaukee, Wisconsin Urticaria and Angioedema Angela Yen Moore, MD Arlington Center for Dermatology, Arlington, Texas Viral Diseases of the Skin Terry L. Moore, MD Professor of Internal Medicine, Pediatrics, and Molecular Microbiology and Immunology, Saint Louis University School of Medicine Director, Division of Pediatric Rheumatology and Adult Rheumatology, Saint Louis University Medical Center, St. Louis, Missouri Juvenile Idiopathic Arthritis Enrique Morales, MD Attending Nephrologist, Hospital 12 de Octubre, Madrid, Spain Primary Glomerular Diseases John F. Moran, MD

Professor of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois Angina Pectoris Arnold M. Moses, MD Professor of Medicine, State University of New York Upstate Medical University College of Medicine Attending Physician, University Hospital, Syracuse, New York Diabetes Insipidus Scott Moses, MD Medical Staff, Fairview Lakes Regional Medical Center, Wyoming, Minnesota Pruritus Alan C. Moss, MD Instructor, Harvard Medical School Fellow in Gastroentrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Inflammatory Bowel Disease Steven F. Moss, MD Associate Professor of Medicine, The Warren Alpert Medical School of Brown University Director, Gastroenterology Fellowship Training Program, Rhode Island Hospital, Providence, Rhode Island Gastric and Peptic Ulcer Disease Claude P. Muller, MD Immunology, University of Trier Faculty of Medicine; Experimental Medicine, University of Horburg, Germany HOD Institute of Immunology, National Laboratory of Health, Luxembourg, Luxembourg Measles (Rubeola) Tashanna K.N. Myers, MD Fellow in Gynecologic Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Cancer of the Endometrium Ashwatha Narayana, MD Associate Professor, Department of Radiology, New York University School of Medicine Residency Program Director and Associate Chair of Clinical Research, Department of Radiation Oncology, New York University Medical Center, New York, New York Brain Tumors Lisa R. Nash, DO Assistant Professor, Department of Family Medicine, University of Texas Medical Branch School of Medicine, Galveston, Texas Postpartum Care Laeth S. Nasir, MBBS

Professor, Department of Family Medicine, University of Nebraska College of Medicine Staff Physician, University of Nebraska Medical Center, Omaha, Nebraska Dysmenorrhea Gideon Nesher, MD Start Clinical Associate Professor of Medicine, The Hebrew University Medical School Head, Department of Internal Medicine A, Share-Zedek Medical Center, Jerusalem, Israel Polymyalgia Rheumatica and Giant-Cell Arteritis David N. Neubauer, MD Assistant Professor, Johns Hopkins University School of Medicine Associate Director, Johns Hopkins Sleep Disorders Center, Baltimore, Maryland Sleep Disorders Ronald Lee Nichols, MD William Henderson Professor of Surgery–Emeritus and Professor of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana Bacterial Diseases of the Skin Electra Nicolaidou, MD, PhD Lecturer in Dermatology, 1st Department of Dermatology, University of Athens School of Medicine Lecturer in Dermatology, “Andreas Sygros” Hospital for Skin and Venereal Diseases, Athens, Greece Parasitic Diseases of the Skin John T. Nicoloff, MD Professor of Medicine and Senior Associate Chair for Research, Department of Medicine, Keck School of Medicine at USC Attending Physician, LAC/USC Medical Center, Los Angeles, California Hypothyroidism Maureen M. O'Brien, MD Instructor, Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford Staff, Lucile Packard Children's Hospital, Palo Alto, California Acute Leukemia in Children David L. Olive, MD Professor of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Endometriosis Brian Olshansky, MD Professor of Medicine, University of Iowa Carver College of Medicine Cardiologist, University of Iowa Hospitals and Clinics, Iowa City, Iowa Tachycardias

Steven M. Opal, MD Professor of Medicine, The Warren Alpert Medical School of Brown University, Providence Director, Infectious Disease Service, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island Severe Sepsis and Septic Shock Ida F. Orengo, MD Professor of Dermatology, Baylor College of Medicine Chief of Mohs Surgery, Baylor Clinic and VA Medical Center, Houston, Texas Cancers of the Skin Richard R. Orlandi, MD Associate Professor, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine Associate Director, Center for Therapeutic Biomaterials, University of Utah Health Sciences Center, Salt Lake City, Utah Sinusitis Finbar D. O'Shea, MB, MRCPI Spondylitis Fellow, Arthritis Center of Excellence, Toronto Western Hospital, Toronto, Ontario, Canada Ankylosing Spondylitis Matthew T. Oughton, MD, FRCPC Post-Doctoral Research Fellow, Department of Medicine, McGill University Faculty of Medicine, Montreal, Quebec, Canada Acute Infectious Diarrhea Gary D. Overturf, MD Professor of Pediatrics and Pathology University of New Mexico College of Medicine Medical Director, Infectious Diseases, TriCore Reference Laboratories, Albuquerque, New Mexico Bacterial Meningitis Paul M. Palevsky, MD Professor of Medicine, University of Pititsburgh School of Medicine Chief, Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Acute Renal Failure Charles J. Parker, MD Professor of Medicine, University of Utah School of Medicine, Salt Lake City, Utah Autoimmune Hemolytic Anemia John E. Parker, MD Professor of Medicine, West Virginia University of College of Medicine Section Chief, Pulmonary and Clinical Care Medicine, WVU Health Sciences Center, Morgantown, West Virginia

Silicosis and Asbestosis Manisha J. Patel, MD Clinical Instructor, Johns Hopkins University School of Medicine, Baltimore, Maryland Cutaneous Vasculitis Eleni Patrozou, MD Teaching Fellow in Medicine Infectious Diseases, The Warren Alpert Medical School of Brown University, Providence Infectious Disease Fellow, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island Severe Sepsis and Septic Shock Ian M. Paul, MD, MSc Associate Professor of Pediatrics and Health Evaluation Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania Fever Mark A. Peppercorn, MD Professor of Medicine, Harvard Medical School Senior Consultant, Center of Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts Inflammatory Bowel Disease Nancy D. Perrier, MD Associate Professor, University of Texas M.D. Anderson Cancer Center, Houston, Texas Thyroid Cancer Andrew C. Peterson, MD Assistant Professor of Surgery, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Maryland Urology Residency Program Director, Madigan Army Medical Center, Tacoma, Washington Management of Urethral Stricture Disease William A. Petri, MD, PhD Chief, Division of Infectious Disease and International Health, University of Virginia Medical Center, Charlottesville, Virginia Amebiasis; Travel Medicine Tania J. Phillips, MD Professor of Dermatology, Boston University School of Medicine Consulting Dermatologist, Boston Medical Center, Boston, Massachusetts Venous Stasis Ulcers

Michael E. Pichichero, MD Professor of Microbiology and Immunology, Pediatrics, and Medicine, Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York Pertussis Bianca Maria Piraccini, MD, PhD Department of Dermatology, University of Bologna, Bologna, Italy Diseases of the Nails Pierre-François Plouin, MD Professor of Cardiovascular Medicine, Université Paris-Descartes Head, Hypertension Unit, Hôpital Emopeen G. Pompladh, Paris, France Pheochromocytomas Michael J. Pollack, MD Gastroentrology Fellow, University Hospitals of Cleveland, Cleveland, Ohio Hiccups Susan P. Perrine, MD Professor of Pediatrics, Medicine, and Pharmacology and Experimental Therapeutics, Boston University School of Medicine Hematologist, Boston Medical Center, Boston, Massachusetts Thalassemia Uday Popat, MD Associate Professor of Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas Non-Hodgkin's Lymphoma Lawrie W. Powell, MD, PhD Professor Emeritus, School of Medicine, The University of Queensland Faculty of Health Sciences Director of Research, Teaching and Research Unit, Royal Brisbane and Women's Hospitals, Brisbane, Queensland, Australia Hemochromatosis Manuel Praga, MD Associate Professor of Medicine, Universidad Complutense Head, Nephrology Department, Hospital 12 de Octubre, Madrid, Spain Primary Glomerular Diseases Richard A. Prinz, MD Professor of Surgery, Rush Medical College Chief, General Surgery, Rush University Medical Center, Chicago, Illinois Acute and Chronic Pancreatitis

L. Michael Prisant, MD Professor of Medicine, Medical College of Georgia Director of Hypertension and Clinical Pharmacology, MCG Medical Center, Augusta, Georgia Hypertension Gregory Proctor, MD Nephrology Fellow, University of Colorado School of Medicine/University of Colorado Hospital, Aurora, Colorado Hyponatremia Beth W. Rackow, MD Assistant Professor, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut Dysfunctional Uterine Bleeding Sharow S. Raimer, MD Professor and Chair, Department of Dermatology, University of Texas Medical Branch School of Medicine, Galveston, Texas Fungal Diseases of the Skin Kirk D. Ramin, MD Associate Professor and Director, Maternal-Fetal Medicine Fellowship Program, Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota Antepartum Care Julio A. Ramirez, MD Professor of Medicine, University of Louisville School of Medicine Chief, Division of Infectious Diseases, Department of Veterans Affairs Medical Center, Louisville, Kentucky Legionellosis Didier Raoult, PhD Faculty of Medicine, Rickettsial Unit, Université de la Mediterranée, Marseille, France Q Fever Susan E. Reef, MD Centers for Disease Control and Prevention, Atlanta, Georgia Rubella and Congenital Rubella Syndrome Adam Reich, MD, PhD Assistant Professor, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland Pigmentary Disorders

Robert L. Reid, MD Professor, Department of Obstetrics and Gynecology, Queen's University Faculty of Medicine Chair, Division of Reproductive Endocrinology and Infertility, Kingston General Hospital, Kingston, Ontario, Canada Amenorrhea Martin Reite, MD Professor of Psychiatry, University of Colorado School of Medicine Medical Staff, University Hospital, Denver, Colorado Treatment of Insomnia Robert W. Rho, MD Assistant Professor of Medicine, Division of Cardiology, University of Washington School of Medicine, Seattle, Washington Cardiac Arrest: Sudden Cardiac Death Lawrence Rice, MD Professor of Medicine and Professor of Thrombosis Research, Baylor College of Medicine Staff Physician, The Methodist Hospital, Houston, Texas Non-Hodgkin's Lymphoma James R. Roberts, MD Professor of Emergency Medicine and Senior Consultant of Medical Toxicology, Drexel University College of Medicine Chairman of Emergency Medicine and Director, Division of Toxicology, Mercy Hospital of Philadelphia, Philadelphia, Pennsylvania Spider Bites and Scorpion Stings Jenice Robinson, MD Assistant Professor of Neurology, Pennsylvania State College of Medicine, Hershey, Pennsylvania Myasthenia Gravis and Related Disorders Robb L. Romp, MD Assistant Professor of Pediatric Cardiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Congenital Heart Disease Leon Rosenthal, MD Sleep Medicine Associates of Texas, Dallas, Texas Sleep Apnea Richard N. Rosenthal, MD Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons Chairman, Department of Psychiatry, St. Luke's–Roosevelt Hospital Center, New York, New York

Alcoholism Michael B. Rothberg, MD, MPH Assistant Professor of Medicine, Tufts University School of Medicine, Boston Director of Scholarly Activities, Internal Medicine Residency Program, Baystate Medical Center, Springfield, Massachusetts Influenza Israel Rubinstein, MD Professor of Medicine and Biopharmaceutical Sciences, University of Illinois at Chicago College of Medicine, Chicago, Illinois Bacterial Pneumonia Chirag Sandesara, MD Electrophysiology Fellow, University of Iowa Hospitals and Clinics, Iowa City, Iowa Tachycardias Karl J. Sandin, MD, MPH Adjunct Professor of Sociology, Westmont College, Santa Barbara, California Rehabilitation of the Stroke Patient J. Terry Saunders, PhD Assistant Professor of Medical Education in Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia Diabetes Mellitus in Adults Peter C. Schalock, MD Instructor in Dermatology, Harvard Medical School Assistant in Dermatology, Massachusetts General Hospital, Boston, Massachusetts Contact Dermatitis Ralph M. Schapira, MD Professor and Vice Chair, Department of Medicine, Medical College of Wisconsin Staff Physician, Milwaukee Veterans Affairs Medical Center, Milwaukee, Wisconsin Histoplasmosis; Acute Bronchitis Randall T. Schapiro, MD Clinical Professor of Neurology, University of Minnesota Medical School, Minneapolis Director, The Schapiro Center for Multiple Sclerosis at The Minneapolis Clinic of Neurology, Golden Valley, Minnesota Multiple Sclerosis Michael Schatz, MD, MS

Clinical Professor, Department of Medicine, University of California, San Diego, School of Medicine Chief, Department of Allergy, Kaiser Permanente, San Diego, California Asthma in Adolescents and Adults Stacey A. Scheib, MD Resident Physician, Department of Obstetrics and Gynecology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Menopause Lawrence R. Schiller, MD Clinical Professor of Internal Medicine, University of Texas Southwestern College of Medicine at Dallas Attending Physician, Digestive Health Associates of Texas Program Director, Gastroenterology Fellowship, Baylor University Medical Center, Dallas, Texas Malabsorption Kerrie Schoffer, MD, FRCPC Assistant Professor in Neurology, Dalhousie University Faculty of Medicine Neurologist, QEII Health Sciences Centre, Halifax, Nova Scotia Peripheral Neuropathies Craig Michael Schramm, MD Associate Professor, Department of Pediatrics, University of Connecticut School of Medicine, Farmington Chief, Pediatric Pulmonary Division, Connecticut Children's Medical Center, Hartford, Connecticut Atelectasis Kathryn G. Schuff, MD Associate Professor of Endocrinology and Clinical Research Compliance Manager, General Clinical Research Center, Oregon Health and Science University School of Medicine, Portland, Oregon Cushing's Syndrome W. Cooper Scurry Jr., MD Fellow, McCollough Plastic Surgery Clinic, Gulf Shores, Alabama Bell's Palsy (Idiopathic Acute Peripheral Facial Paralysis) Carlos Seas, MD Associate Professor of Medicine, Universidad Peruana Cayetano Heredia Chief, Inservice Department, Hospital National Cayetano Heredia, Lima, Peru Cholera Daniel J. Sexton, MD Professor, Duke University School of Medicine, Durham, North Carolina Rickettsial and Ehrlichial Infections

Mrunal Shah, MD Clinical Assistant Professor of Family Medicine, The Ohio State University College of Medicine Assistant Program Director, Riverside Family Practice Residency Program, Riverside Methodist Hospital, Columbus, Ohio Syphilis Rupali Shah, MD Resident Physician, UNC Hospitals, Chapel Hill, North Carolina Hoarseness and Laryngitis Prateek Sharma, MD Professor of Medicine and Fellowship Program Director, University of Kansas School of Medicine/Medical Center, Kansas City Missouri Gastroesophageal Reflux Disease Surendra K. Sharma, MD, PhD Chief, Division of Pulmonary and Critical Care Medicine, All India Institute of Medical Sciences, New Delhi, India Management of the Patient with HIV Disease; Sarcoidosis; Tuberculosis and Other Mycobacterial Diseases Chelsea A. Sheppard, MD Transfusion Medicine Program, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia Adverse Effects of Blood Transfusion Raj D. Sheth, MD Director, Comprehensive Epilepsy Program Professor, University of Wisconsin–Madison School of Medicine, Madison, Wisconsin Epilepsy in Infancy and Childhood Marc A. Silver, MD Clinical Professor of Medicine, University of Illinois at Chicago College of Medicine, Chicago Adjunct Professor, Department of Biomedical Engineering, Illinois Institute of Technology, Chicago Chairman, Department of Medicine, and Director, Heart Failure Institute, Advocate Christ Medical Center, Oak Lawn, Illinois Heart Failure Peter A. Singer, MD Professor of Clinical Medicine, Keck School of Medicine of USC Chief, Clinical Endocrinology, Department of Medicine, LAC–USC Medical Center, Los Angeles, California Hyperthyroidism Arti Sinha, MB, BS Guy's, King's and St. Thomas' School of Medicine; Foundation Year 2 Physician, St. Thomas' Hospital; London, United Kingdom

Conjunctivitis Michael J. Smith, MD Instructor, Department of Pediatrics, University of Pennsylvania School of Medicine Fellow, Division of Infectious Diseases, The Children's Hospital of Philadelphia, Pennsylvania Cat-Scratch Disease Cynthia B. Snider, MD, MPH Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia Travel Medicine Carmen C. Solorzano, MD Assistant Professor of Surgery, University of Miami Miller School of Medicine Chief, Endocrine Surgery, University of Miami/Sylvester Cancer Center, Miami, Florida Acute and Chronic Pancreatitis Suman Sood, MD Instructor in Medicine, Hematology-Oncology, University of Pennsylvania School of Medicine Staff, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Platelet-Mediated Bleeding Disorders Thomas Spencer, MD Associate Professor of Psychiatry, Harvard Medical School Assistant Director of Clinical and Research Program in Pediatric Psychopharmacology and Director of Depression and Tourette's Clinic, Massachusetts General Hospital, Boston, Massachusetts Attention Deficit Hyperactivity Disorder Stanley M. Spinola, MD David H. Jacobs Professor and Director, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana Chancroid Richard K. Sterling, MD Professor of Medicine, Medical College of Virginia–Virginia Commonwealth University School of Medicine, Richmond, Virginia Cirrhosis Catherine Stevens-Simon, MD Associate Professor of Pediatrics, Division of Adolescent Medicine, University of Colorado School of Medicine Staff Physician, Children's Hospital, Denver, Colorado Chlamydia trachomatis A. Keith Stewart, MB, ChB

Senior Associate Consultant, Mayo Clinic Arizona, Scottsdale, Arizona Multiple Myeloma Christopher D. Still, DO Medical Director, Center for Nutrition and Weight Management, Department of Gastroenterology and Nutrition, Geisinger Health Care System, Danville, Pennsylvania Obesity Erik K. St. Louis, MD Assistant Professor of Neurology, University of Iowa Carver College of Medicine Co-Director, Iowa Comprehensive Epilepsy Program, University of Iowa Hospitals and Clinics, Iowa City, Iowa Seizures and Epilepsy in Adolescents and Adults Mark W.J. Strachan, MD Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh, United Kingdom Thyroiditis David J. Straus, MD Professor of Clinical Medicine, Weill Cornell Medical College Attending Physician, Memorial Sloan-Kettering Cancer Center, New York, New York Hoogkin's Disease: Chemotherapy Paniti Sukumvanich, MD Fellow, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York Diseases of the Breast Scott Swanson, MD Professor of Surgery, Mount Sinai School of Medicine Attending Surgeon, Mount Sinai Medical Center, New York, New York Primary Lung Abscess Jessica P. Swartout, MD Fellow in Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota Antepartum Care Misha F. Syed, MD Assistant Professor, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch School of Medicine, Galveston, Texas Glaucoma Jacek C. Szepietowski, MD, PhD Professor and Vice Chair, Department of Dermatology, Venereology and Allergology, Wroclaw Medical

University Director, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland Pigmentary Disorders Mahsa Tehrani, MA Medical Student, George Washington University School of Medicine and Health Sciences, Washington, DC Keloids Marty S. Teltscher, MD, CM Infections Diseases and Medical Microbiology Fellow, McGill University Faculty of Medicine/SMED–Jewish General Hospital, Montreal, Quebec, Canada Toxic Shock Syndrome Victor J. Test, MD, FCCP Assistant Professor of Clinical Medicine, Division of Pulmonary Medicine and Critical Care, University of California, San Diego, School of Medicine, La Jolla, California Pulmonary Embolism Manish Thapar, MD Instructor, University of Missouri College of Medicine Attending Physician, University Hospital, Columbia, Missouri Porphyria David R. Thomas, MD Professor of Medicine, Saint Louis University School of Medicine Attending Physician, Saint Louis University Hospital, St. Louis, Missouri Pressure Ulcers Rodger E. Tiedemann, MB, ChB, PhD Clinical Senior Lecturer in Medicine, University of Auckland Faculty of Medicine, School of Medicine, Auckland, New Zealand Research Associate, Mayo Clinic Arizona, Scottsdale, Arizona Multiple Myeloma Joyce A. Tinsley, MD Associate Professor, Department of Psychiatry Director of Psychiatric Residency Training and Director of Addiction Psychiatry Training, University of Connecticut School of Medicine, Farmington, Connecticut Drug Abuse Lama L. Tolaymat, MD, MPH Assistant Professor, Department of Obstetrics and Gynecology, University of Florida College of Medicine Director of Ultrasound and Prenatal Diagnosis, UF Health Science Center Jacksonville, Jacksonville, Florida Contraceptive Methods

Linus H. Santo Tomas, MD, MS Assistant Professor of Pulmonary Critical Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Histoplasmosis Marcia G. Tonnesen, MD Associate Professor of Dermatology and Medicine, State University of New York at Stony Brook Health Sciences Center School of Medicine, Stony Brook Chief of Dermatology, Veterans Affairs Medical Center, Northport, New York Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis Peter P. Toth, MD, PhD Chief of Medicine, CGH Medical Center Visiting Clinical Associate Professor, University of Illinois at Chicago College of Medicine, Chicago Director of Preventive Cardiology, Sterling Rock Falls Clinic, Sterling, Illinois Dyslipoproteinemias Maria Trent, MD, MPH Assistant Professor of Pediatrics, Johns Hopkins University School of Medicine Active Staff, Johns Hopkins Hospital Children's Center, Baltimore, Maryland Pelvic Inflammatory Disease Arvid E. Underman, MD, FACP, DTMH Clinical Professor of Medicine and Microbiology, Keck School of Medicine of USC, Los Angeles Director of Graduate Medical Education, Huntington Hospital, Pasadena, California Salmonellosis Nicholas Van Bruaene, MD ENT in Training, Department of Oto-Rhino-Laryngology, University Hospital Ghent, Ghent, Belgium Nonallergic Perennial Rhinitis Mary Lee Vance, MD Professor of Medicine and Neurosurgery, University of Virginia School of Medicine Attending Physician, University of Virginia Hospital, Charlottesville, Virginia Acromegaly; Hypopituitarism Brian A. VanderBrink, MD Chief Resident, North Shore–Long Island Jewish Health Care System, New Hyde Park, New York Bacterial Infections of the Urinary Tract in Males John Varga, MD Gallagher Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois Connective Tissue Disorders

Donald C. Vinh, MD, FRCP(C), Dip(ABIM) Division of Infectious Diseases, Department of Medicine, and Department of Medical Microbiology, McGill University Health Center, Montreal General Hospital, Montreal, Quebec, Canada Necrotizing Skin and Soft Tissue Infections Todd W. Vitaz, MD Assistant Professor, Department of Neurological Surgery, University of Louisville School of Medicine Director of Neurosurgical Oncology Co-Director, Neurosciences ICU, Norton Hospital, Louisville, Kentucky Management of Head Injuries Jeffery T. Vrabec, MD Associate Professor, Department of Otolaryngology–Head and Neck Surgery, Baylor College of Medicine Clinical Associate Professor, Department of Head and Neck Surgery, M.D. Anderson Cancer Center Active Staff, Otolaryngology–Head and Neck Surgery, The Methodist Hospital Courtesy Staff, Otolaryngology Service, Texas Children's Hospital, and Head and Neck Surgery, M.D. Anderson Cancer Center, Houston, Texas Chair, Facial Nerve Disorders Committee, and Member, SIPac Committee, American Academy of Otolaryngology–Head and Neck Surgery Chair, ByLaws Committee, American Neurotology Society Membership Committee Otitis Externa Sachin Wani, MD Gastroenterology and Hepatology Fellow, University of Kansas School of Medicine/VA Medical Center, Kansas City, Missouri Gastroesophageal Reflux Disease Shobha Wani, MD Fellow, Section of Rheumatology, Washington Hospital Center, Washington, DC Lyme Disease Thomas T. Ward, MD Associate Professor of Medicine, Oregon Health and Science University School of Medicine Chief, Infectious Diseases, Portland Veterans Affairs Medical Center, Portland, Oregon Toxoplasmosis Cheryl Waters, MD Albert and Judith Glickman Professor, Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York Parkinsonism Richard W. Weber, MD Professor of Medicine, University of Colorado School of Medicine and National Jewish Medical and Research

Center, Denver, Colorado Allergic Rhinitis Caused by Inhalant Factors Arthur Weinstein, MD, FACP, FACR Professor of Medicine, Georgetown University School of Medicine Associate Chairman, Department of Medicine, and Director, Section of Rheumatology, Washington Hospital Center, Washington, DC Lyme Disease Steven D. Weisbord, MD, MSc Assistant Professor of Medicine, University of Pittsburgh School of Medicine Staff Physician, Renal Section, and Core Faculty Member, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Acute Renal Failure David G. Weismiller, MD Associate Professor and Vice Chair for Academic Affairs, Department of Family Medicine, Brody School of Medicine at East Carolina University, Greenville, North Carolina Hypertensive Disorders of Pregnancy Mitchell J. Weiss, MD, PhD Associate Professor of Pediatrics, University of Pennsylvania School of Medicine; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Nonimmune Hemolytic Anemia Robert C. Welliver Sr., MD Professor, University at Buffalo State University of New York School of Medicine Co-Director, Division of Infectious Diseases, Women and Children's Hospital of Buffalo, Buffalo, New York Viral Respiratory Infections Victoria Werth, MD Professor, Department of Dermatology, University of Pennsylvania School of Medicine Chief, Dermatology, Philadelphia VA Medical Center, Philadelphia, Pennsylvania Bullous Diseases Derek S. Wheeler, MD Assistant Professor of Clinical Pediatrics, University of Cincinnati College of Medicine Associate Medical Director, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio Resuscitation of the Newborn Timothy Wilens, MD Associate Professor of Psychiatry, Harvard Medical School Director of Substance Abuse Services, Clinical and Research Pediatric Psychopharmacology, Massachusetts

General Hospital, Boston, Massachusetts Attention Deficit Hyperactivity Disorder Kira Williams, MD Chief Resident in Psychiatry, Anxiety Disorders Clinic, Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Hospital, Los Angeles, California Panic Disorder Steven R. Williams, MD Clinical Assistant Professor, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Infertility Phillip M. Williford, MD Associate Professor of Dermatology and Director of Mohs Micrographic Surgery, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Warts (Verrucae) Elzbieta Wirkowski, MD Associate Professor of Clinical Neurology, SUNY at Stony Brook, Long Island Director of Cerebrovascular Disorders and Co-Director of Neurological Intensive Care Unit, Withrop University Hospital, Mineola, New York Ischemic Cerebrovascular Disease Andrew L. Wong, MD Professor of Clinical Medicine, David Geffen School of Medicine at UCLA, Los Angeles Chief of Rheumatology, Olive View–UCLA Medical Center, Sylmar, California Bursitis, Tendinitis, Myofascial Pain, and Fibromyalgia Wing-Yen Wong, MD Associate Professor of Pediatrics, Keck School of Medicine at USC Voluntary Faculty/Attending Staff Physician, Children's Hospital Los Angeles, Los Angeles Medical Director, Clinical Research and Development, Baxter BioScience, Baxter Health Care Corp., Westlake Village, California Hemophilia and Related Disorders Jamie R.S. Wood, MD Instructor in Pediatrics, Harvard Medical School Research Associate, Sections on Genetics and Epidemiology and Vascular Cell Biology, and Staff Physician, Pediatric, Adolescent, and Young Adult Section, Joslin Diabetes Center, Boston, Massachusetts Diabetes Mellitus in Children and Adolescents Jon B. Woods, MD Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences F. Edward Hébert

School of Medicine, Bethesda, Maryland Pediatric Infectious Diseases, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas Anthrax Charles F. Wooley, MD Professor of Medicine Emeritus, Division of Cardiology, Heart and Lung Research Institute/The Ohio State University School of Medicine and Public Health, Columbus, Ohio Mitral Valve Prolapse: The Floppy Mitral Valve, Mitral Valve Prolapse, and Mitral Valvular Regurgitation Jennifer Wright, MD Fellow in Hematology/Oncology, Baylor College of Medicine, Houston, Texas Polycythemia Vera Ronald F. Young, MD Director of Neurosurgery, California Neuroscience Institute, St. John's Regional Medical Center, Oxnard, California Trigeminal Neuralgia William F. Young Jr., MD, MSc Professor of Medicine, Mayo Clinic College of Medicine Consultant, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota Primary Aldosteronism Michael C. Zacharisen, MD Associate Professor of Pediatrics and Medicine (Allergy/Immunology), Medical College of Wisconsin Staff Physician, Children's Hospital of Wisconsin, Milwaukee, Wisconsin Hypersensitivity Pneumonitis Jami Star Zeltzer, MD Associate Professor, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts Vaginal Bleeding in Late Pregnancy Kathryn A. Zug, MD Associate Professor of Medicine(Dermatology), Dartmouth Medical School, Hanover Staff Physician, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire Contact Dermatitis



Preface Starting in 1949, Conn's Current Therapy has provided a yearly update on the practical treatment of nearly 400 diseases and disorders. Howard Conn was the initial developer and author, who set out to provide a concise and up-to-date reference on the most recent advances in therapy for conditions most commonly encountered in practice. Some less common conditions also are included, because certain disorders can have serious consequences if not diagnosed early and managed appropriately. Well-known scholar and clinician Robert Rakel, MD, took over editorship in 1984 after Dr. Conn's death and remains today as the editor. Edward Bope, MD, joined him in 2001 to share the editor responsibilities. Each year, new experts are chosen to write on the topics. They are selected on the basis of recommendations from other authorities, or scholarly activity and/or research. Changing authors with each edition keeps the book crisp in coverage, fresh in tone, and brimming with the latest in practical advice. The authors give references for their discussions but also tell you how they manage the problem in their own clinical practice. Such practical wisdom is of immense value to today's physician, who typically is inundated with sometimes conflicting information from multiple sources. New topics are included every year, so the book remains current with the problems likely to be encountered in practice. Now with the purchase of Conn's Current Therapy 2008 you also can have your favorite or commonly referenced topics available on your computer or handheld device. In fact, you will have access to the 2006, 2007, and 2008 editions for downloading your favorite articles from the book. Readers are encouraged to compare the treatments presented in these editions to see how different experts manage the same problem. Conn's Current Therapy is indeed an international book. Contributing authors from around the world offer advice about the diagnosis and management of conditions not common to the United States. The contribution of these international experts adds greatly to the comprehensive nature of the book, and given the amount of international travel, it is quite possible to see unusual disorders far from the homeland of their origin. Each chapter includes Key Diagnostic and Key Therapeutic boxes for quick reference. As always, tables, graphs, and figures are used when possible to present in-depth data in a convenient format. References for further reading provide some options for additional information if needed. In keeping with today's emphasis on evidence-based medicine, the clinician is pointed toward good evidence, when available, for treatment success. Careful attention is given to ensuring that the information included is correct and up to date. All of the material is reviewed by a pharmacist, Dr. Rakel or Dr. Bope, and multiple copy editors for accuracy and readability. Trade names are included alongside the generic drug names to help the clinician identify the medicines by whatever name is most familiar. The treatments recommended are those found to work best in the experience of the author. When a drug is not FDA approved for that use, this is indicated by a footnote; such notations may merely reflect that approval for that indication was never requested. We greatly appreciate the assistance of the very capable editorial staff at Elsevier and particularly the contribution of our pharmacist reviewers, Miriam Chan, RPH, PharmD, and Grace Kuo, PharmD.

Robert E. Rakel, MD Edward T. Bope, MD



SECTION 1 – Symptomatic Care Pending Diagnosis

Chapter 1 – Pain

Method of: Ruth Falik, MD Pain is one of the most common patient complaints. According to population-based surveys, it has been estimated that 75 million American adults experience chronic pain. Of these, one third report a significant impact on their quality of life. The annual cost in direct medical expenditures, informal costs, and lost productivity has been estimated at greater than $100 billion. Chronic pain is the most common cause of long-term disability—more than 5 million American workers receive disability compensation for chronic pain. Pain is subjective. The physician depends on the patient's description to determine intensity, quality, location, and duration of pain. The patient's perception of pain is the best available tool for evaluation. Intellectual, emotional, and cultural variables affect the patient's experience and description of pain. Pain is commonly underappreciated by the physician and hence undertreated. Whether pain is acute or chronic, inadequate treatment can slow recovery, impair patient functioning, and adversely affect the quality of life. Definitions Pain can be considered a successful adaptive response to a hostile environment. The experience of pain provides protective information that contributes to survival either by preventing injury or by promoting attention to healing when injury has occurred. Pain becomes maladaptive when it is divorced from noxious stimuli and instead represents a pathologic process of the nervous system. Several distinct types of pain have been described. Nociceptive pain is defined as transient pain in response to a noxious stimulus; it is protective and confers a survival benefit. Inflammatory pain is defined as spontaneous pain and hypersensitivity to pain in response to inflammation and the resulting damage to tissue. Neuropathic pain is the result of damage to the nervous system itself, such as lesions to the peripheral nervous system seen in patients with diabetic or AIDS neuropathy. Functional pain is the result of abnormal central processing of normal input; no neurologic deficit or peripheral abnormality can be identified. Functional pain is maladaptive; it is a dysfunctional amplification in the responsiveness of the nervous system. Inflammatory, neuropathic, and functional pain share some characteristics. Pain can arise spontaneously in the absence of any apparent peripheral stimulus (allodynia) or it can arise in response to normally innocuous stimuli (hyperalgesia), such as light touch. Spontaneous pain and changes in sensitivity to stimuli are basic to the disease entity of chronic pain. Current research tries to define the underlying neurobiological mechanisms so that therapy can be targeted to the particular mechanism. The aim is to move from mere

symptom control to mechanism-specific modalities that can eradicate or even abort the development of pain. Epidemiology There are at least 600 identifiable pain syndromes, ranging from fibromyalgia to low back pain. Risk factors for developing chronic pain include trauma, surgery, a prior history of back or breast surgery, cholecystectomy, thoracotomy, and advanced age. Among the noninstitutionalized elderly, 25% to 65% report chronic pain. For those in long-term care facilities, more than 80% have chronic pain. Sensitivity to pain changes with aging. The elderly might not manifest the classic symptoms of such painful syndromes as myocardial infarction or appendicitis. Although the response to acute pain can diminish with age (possibly due to deterioration of peripheral C-fibers), the elderly have an increased incidence of chronic pain, possibly due to age-related reduction in the functioning of the antinociceptive pathways and reduced levels of endorphins and enkephalins.

CURRENT DIAGNOSIS Pain is subjective. The physician is dependent on the patient's description to determine intensity, quality, location, and duration of pain. Intellectual, emotional, and cultural variables affect the patient's experience and description of pain. Nociceptive pain is transient pain in response to a noxious stimulus; it is protective and confers a survival benefit. Inflammatory, neuropathic, and functional pain can arise spontaneously in the absence of apparent noxious stimulus (allodynia) or in response to normally innocuous stimuli (hyperalgesia). Chronic pain persists despite attempts to alleviate it. The duration of pain is not the criterion by which chronic pain is distinguished from acute pain; it is the inability to restore the pain-free state. Chronic pain is not merely a symptom but is itself a disease. Addiction is rare in patients who first use opioids for pain relief. Tolerance and dependency are likely with long-term use. Close follow-up is mandatory. Perception of pain may be gender specific. Women seek treatment for chronic pain more often than do men. Many clinical entities with chronic pain as a major component (fibromyalgia, temporomandibular disorder, interstitial cystitis) are far more prevalent in women. For the most part, the published literature shows that women a have a lower pain threshold and a lower tolerance of painful stimuli. Researchers have postulated that differences in women's experience of pain are linked to primitive survival strategies. Cultural, emotional, and behavioral influences also affect gender differences in the experience of pain. Recent studies have shown that there are gender differences in the opioid receptor system; this might someday provide the basis for gender-based therapy. Treatment PHARMACOLOGIC TREATMENT

Nonopioid Analgesics

The goal of treatment for any pain is to remove the cause. Correct diagnosis is essential. Acute pain, typically caused by tissue injury or infection, requires only temporary therapy. Treating the underlying condition might not immediately ameliorate the pain for some conditions (e.g., burns, trauma, and sickle cell crisis). Analgesic medications are then the first line of therapy. In treating acute mild pain, aspirin, acetaminophen, and nonsteroidal anti-inflammatory agents (NSAIDs) are the drugs of choice. Currently, more than 20 NSAIDs are available. Aspirin and NSAIDS inhibit cyclooxygenase (COX), thereby preventing the subsequent formation of prostaglandins responsible for inflammation. Aspirin and NSAIDs are also antipyretic and analgesic. Acetaminophen has antipyretic and analgesic actions, but it does not have anti-inflammatory properties. These over-the-counter medications alleviate common types of pain, such as headache and musculoskeletal pain. Gastrointestinal absorption is excellent, and side effects are minimal with occasional use.

CURRENT THERAPY Aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line choices in the treatment of mild to moderate pain. If pain persists despite optimal dosing, then opioid drugs should be given. Administer orally whenever possible. Although opioid effects are dose-related, there is great variability among patients. Optimal pain relief with minimal side effects requires titration of both dose and interval. Side effects can be anticipated and should be treated proactively. Adjuvant drugs may be used in addition to traditional analgesic medication. Adjuvant drugs can enhance the analgesic effect of opioid and nonopioid medications, allowing a lower dose of the opioid or nonopioid drug and a lower incidence of side effects. Nonpharmacologic modalities, such as exercise and cognitive behavior therapy, can improve functioning and the quality of life. Address the four A s of pain management outcomes (analgesia, activities of daily living, adverse side effects, and aberrant drug-taking behavior) at each encounter. NSAIDS and aspirin, by inhibiting COX-1, undermine gastric mucosal integrity and can lead to bleeding. Aspirin also irreversibly acetylates platelets, impairing their aggregative function. NSAIDs, when used chronically, can impair renal function and, in some persons, increase blood pressure. Acetaminophen does not impair platelet function or cause gastric irritation. Acetaminophen is hepatotoxic at large doses (>4 g/day), and at not-so-large doses (>2.5 g/day) in patients with impaired liver function. Ketorolac tromethamine (Toradol), a parenteral NSAID, extends the usefulness of this class of compounds in managing acute severe pain, for example, postoperatively. Because it is more nephrotoxic than orally

administered NSAIDs, it is recommended for short-term use only. A lower dose should be given to patients who weigh less than 50 kg or who are older than 65 years. COX-2 inhibitors have been marketed as more selective NSAIDs. These drugs act primarily on COX-2, which is an inducible form of COX and an important mediator of inflammation and pain. They were thought to have little or no effect on platelets or gastric mucosa, but because of an increased incidence of cardiovascular events noted in patients taking some COX-2 inhibitors, rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market. Celecoxib (Celebrex) is still available, as is meloxicam (Mobic), a less selective COX-2 inhibitor. Opioid Analgesics

Opioids are the most powerful analgesic medications available. They are pharmacologically similar to opium or morphine and are the drugs of choice when aspirin, NSAIDS, and acetaminophen fail. They have the broadest range of efficacy. They are rapid acting and reliable. For the most part, side effects are mild and well tolerated. Respiratory depression, the most serious side effect, can be readily reversed with the narcotic antagonist naloxone (Narcan). Oral opioids typically prescribed in the ambulatory care setting include codeine, oxycodone (OxyContin, Roxicodone), and hydrocodone (typically in combination with acetaminophen [e.g., Vicodin]). The choice and dose of opioid medication vary depending on the route of administration, severity of pain, known side effects, and cost. These drugs are often given in combination with aspirin or acetaminophen for additive analgesia, but doses of these combination medications are limited by the nonopioid component. When this occurs, the opioid and nonopioid medications should be given separately to allow further upward titration of the opioid. Oral dosing is preferred but might not be feasible in the setting of nausea, vomiting, dysphagia, or abnormal gastrointestinal absorption. Rapid pain relief requires parenteral administration. Intravenous administration is preferred; intramuscular injection should be avoided if possible. Acute side effects include nausea, vomiting, and sedation; the most serious side effect is respiratory depression. Patients receiving parenteral opioids should be closely monitored, preferably with an oxygen saturation monitor, and naloxone should be readily available. Opioid effects are dose related, but there is great variability among patients. Optimal pain relief with minimal side effects requires titration of both dose and interval. Side effects can be anticipated and should be treated proactively. It is imperative that pain relief and side effects be assessed frequently and the dose adjusted accordingly. Morphine remains the standard against which all other opioids are measured. Constant pain requires continual (around-the-clock) analgesic medication, preferably with a longer-acting drug, as well as a supplementary, shorter-acting medication for breakthrough pain. If frequent supplementation is required, then the maintenance dose of the long-acting analgesic should be increased or the dosing interval decreased. If adequate pain relief cannot be achieved at the maximum recommended dose of one narcotic preparation (or if side effects become intolerable), the patient should be switched to another opioid medication starting at the equivalent dosage ( Table 1 ).

TABLE 1 -- Equianalgesic Doses of Selected Opioids Route Drug

Parenteral Oral

Morphine[*]

10 mg

Duration

60 mg[*] 3-6 h

Extended release morphine (MS Contin, Kadian) NA

15 mg

8-12 h

Codeine

60 mg

120 mg 4-6 h

Oxycodone (OxyContin, Roxicodone)

NA

20 mg

4-6 h

Methadone

10 mg

15 mg

6-8 h

Fentanyl injectable (Sublimaze)

100 µg

NA

1-2 h

Fentanyl patch (Duragesic Transdermal)

25 µg/h

Hydromorphone (Dilaudid)

1.5 mg

7.5 mg

Meperidine (Demerol)

75 mg

300 mg 2-4 h

Hydrocodone[†] (Vicodin, Lortab)

NA

30 mg

1 patch/72 h 2-4 h

3-4 h

Abbreviation: NA = not applicable.

* For single or intermittent dosing. For chronic or scheduled dosing, 30 mg. † Combined with acetaminophen at varying doses of component drugs.

Codeine is usually given in combination with aspirin or acetaminophen. It provides excellent analgesia for mild to moderate pain as well as excellent cough suppression (particularly useful for pleuritic pain management). Oxycodone and propoxyphene (Darvon) are given for moderate to severe pain. Immediaterelease and sustained-release morphine sulfate preparations (MS Contin, Kadian) are available as pills or liquid. Methadone (Dolophine) is very effective when taken orally and suppresses the symptoms of withdrawal from other opioids because of its extended half-life (8-59 hours) and slow release from liver and other tissues. Its analgesic duration (6-8 hours) is much shorter. Tramadol (Ultram) is not an opioid but has similar analgesic properties and is thought to be less addictive. It comes in pill form only. Hydromorphone (Dilaudid) is a morphine derivative that can be given orally, intramuscularly, subcutaneously, or, with caution, intravenously. It also comes in a rectal suppository formulation. Fentanyl (Sublimaze, Duragesic) can be given parenterally as well as transdermally (Duragesic patch) and transmucosally (Actiq) using a lollipop for drug delivery. Meperidine (Demerol) is contraindicated in patients with impaired renal function or those taking MAO inhibitors. Meperidine should not be used for more than 48 hours or at doses greater than 600 mg/24 hours

because accumulation of the toxic metabolite, normeperidine, can result in seizures. Patient-controlled analgesia (PCA) has been successfully used in postoperative and terminally ill patients. PCA typically delivers drug via a continuous infusion of an opioid. An agent with a short half-life should be used. Additional doses can be given when the patient pushes a button. The system is set up to limit the total hourly dose that can be delivered to prevent overdosing. PCA can also be provided subcutaneously, intrathecally, or epidurally. It requires an alert, oriented patient who can understand the dosing principle and who can physically push the button. Early studies have shown better pain relief than with conventional analgesic therapy without an increase in the total amount of drug used. Adjuvant Analgesics

Successful relief of pain can require more than opioid and nonopioid drugs. In addition to traditional analgesic medications, adjuvant drugs may be used. Antidepressants, anticonvulsants, systemically administered local anesthetics, corticosteroids, neuroleptics, N-methyl-d-aspartate (NMDA) antagonists, and bisphosphonates are often used to enhance pain relief. The choice of adjuvant drug should be directed at the specific type of pain. Adjuvant analgesics are standard therapy for treating diabetic neuropathy, postherpetic neuralgia, and trigeminal neuralgia. Antidepressant drugs are commonly used to treat neuropathic pain. Tricyclic antidepressants have been widely used for diabetic neuropathy. Low-dose amitriptyline (Elavil) can provide significant relief for some patients. At higher doses, serious side effects including cardiac dysrhythmias can occur, limiting the usefulness of this group of drugs. Currently, the FDA has approved medications for only two neuropathic pain syndromes: gabapentin (Neurontin) and 5% lidocaine patch (Lidoderm) for postherpetic neuralgia and carbamazepine (Tegretol) for trigeminal neuralgia ( Table 2 ).

TABLE 2 -- Adjuvant Drug-Dosing Regimens Medication Starting Dose Maximum Dose

Comments

Gabapentin (Neurontin)

300 mg hs

3600 mg/day (1200 Can increase by 100-300 mg/d every 7 days mg q8h) Adjust dose amount and frequency when renal function is impaired

5% Lidocaine (Lidoderm)

1 patch daily for 12 h

3 patches daily for 12 h

Do not apply to broken or inflamed skin; caution in patients with impaired liver function

Amitriptyline (Elavil)

10-25 mg hs

150 mg/day

Start at lowest dose in elderly given anticholinergic side effects; monitor QRS duration

Carbamazepine (Tegretol)

100 mg bid

600 mg bid

Take with food; therapeutic levels 4-12 µg/mL

Bisphosphonates are used for bone pain in cancer patients: pamidronate (Aredia) and zoledronic acid (Zometa) are parenteral formulations that are also useful for treating hypercalcemia. Corticosteroids are also used in cancer patients who have bone, visceral, or neuropathic pain. Additional benefits of corticosteroids include an antiemetic effect, mood elevation, and appetite stimulation. Adjuvant pharmacologic therapy can

boost the analgesic effect of opioid and nonopioid medication. This allows a lower dose of the opioid or nonopioid and a lower incidence of their side effects. NONPHARMACOLOGIC TREATMENT Physical Therapy

Although medications can diminish pain and its concomitant symptoms (fatigue, depression), nonpharmacologic therapies can improve the dysfunction induced by chronic pain. The two most studied nonpharmacologic modalities studied are exercise and cognitive behavior therapy. For musculoskeletal pain, massage, guided mobilization and manipulation, stretching, strengthening, thermotherapy, and neurostimulatory modalities are of value in alleviating pain and maintaining function. Biofeedback, individual counseling, group therapy, and relaxation techniques can provide support and improve the patient's sense of well-being. The challenge is to improve long-term adherence and compliance. The role of complementary and alternative medicine in managing chronic pain is an area of ongoing research; the original funding in 1992 for the National Institutes of Health Office of Alternative Medicine was $2 million; currently it is more than $115 million. Issues in Chronic Pain Management Chronic pain is seen with chronic disease (e.g., arthritis, AIDS). It can also be seen with one-time injury to the central or peripheral nervous system (e.g., stroke, varicella zoster infection). Chronic pain persists despite attempts to alleviate it. The duration of pain is not the criterion by which chronic pain is distinguished from acute pain; the criterion is the inability to restore the pain-free state. Chronic pain is not merely a symptom but is itself a disease. The original tissue injury heals, but either central or peripheral sensitization occurs, and there is persistent pain in the absence of apparent damage. The International Association for the Study of Pain defines chronic pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”; the pain experienced might not correlate well with tissue damage. Some patients experience both acute and chronic pain; cancer patients, for example, can have chemotherapy-induced neuropathy along with acute pain caused by procedures or metastatic spread of disease. Patients with chronic pain can undergo surgery or experience significant trauma, and the acute pain superimposed on chronic pain is challenging to manage. The long-term use of opioids to treat pain caused by malignant disease is accepted, but there is still resistance to such therapy for pain of nonmalignant origin. Addiction is rare in patients who first use opioids for pain relief. Tolerance and physical dependency are likely with long-term use. Close follow-up is mandatory. Patients with pain can have concomitant aberrant drug-taking behavior. Addiction manifests as out-of-control behavior, with compulsive and harmful drug use. This needs to be distinguished from pseudoaddiction, which occurs when pain is inadequately treated, driving the patient to unilateral dose increases or use of alcohol or street drugs. Patients with comorbid conditions can benefit from a multidisciplinary approach that

includes physical and occupational therapy, social service support, and psychological counseling. The four A s of pain management outcomes are analgesia (pain relief), activities of daily living (psychosocial functioning), adverse side effects, and aberrant drug-taking behavior (addiction-related activities). These domains should be explicitly assessed, discussed, and documented at each encounter.



REFERENCES American Academy of Pain Medicine. American Academy of Pain Medicine : Home page. (accessed July 12, 2007). Available at http://www.painmed.org Furlan et al., 2006. Furlan AD, Sandoval J, Mailis-Gagnon A, Tunks E: Opioids for chronic noncancer pain: A meta-analysis of effectiveness and side effects. CMAJ 2006; 174(11):1589-1594. Gilron et al., 2006. Gilron I, Watson CPN, Cahill CM, Moulin DE: Neuropathic pain: A practical guide for the clinician. CMAJ 2006; 175(3):265-275. Loeser and Medzack, 1999. Loeser JD, Medzack R: Pain: An overview. Lancet 1999; 353(9164):16071609. MedlinePlus. MedlinePlus : Pain. (accessed July 12, 2007). Available at http://www.nlm.nih.gov/medlineplus/pain.html Olorunto and Galankiuk, 2006. Olorunto WA, Galankiuk S: Managing the spectrum of surgical pain: Acute management of the chronic pain patient. J Am Coll Surg 2006; 202(1):169-175. Passik and Weinreb, 2000. Passik SD, Weinreb HJ: Managing chronic nonmalignant pain: Overcoming obstacles to the use of opioids. Adv Ther 2000; 17(2):70-83. Schnitzer, 1998. Schnitzer TJ: Non-NSAID pharmacologic treatment options for the management of chronic pain. Am J Med 1998; 105(1B):45S-52S. Wilson, 2006. Wilson JF: The pain divide between men and women. Ann Intern Med 2006; 144(6):461-464. Woolf, 2004. Woolf CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140(6):441-451.



Chapter 2 – Nausea and Vomiting

Method of: Chad M. Braun, MD Nausea and vomiting are protective reflexes caused by a wide range of etiologies spanning from benign conditions to emergent disorders. Nausea and vomiting can occur independently but most often are associated. Usually nausea precedes vomiting and is often accompanied by skin pallor, increased sweating, and feeling flushed. It is also described as the urge to vomit. Vomiting (emesis) is the forceful oral expulsion of the contents of the stomach. Retching is the repetitive contraction of the muscles of the diaphragm and abdominal wall that often precede or accompany vomiting. Nausea and vomiting are mediated by efferent stimuli from the vomiting center in the brain to the musculature in the abdomen and chest. The neurotransmitters commonly associated with nausea and vomiting are acetylcholine, histamine, serotonin, and dopamine. These neurotransmitters are important in the treatment of persistent or severe nausea and vomiting. Most episodes of nausea and vomiting are acute, self-limited, and easily diagnosed based on the clinical picture. Chronic nausea and vomiting (1 month or more) is a diagnostic and therapeutic challenge for the clinician. Differential Diagnosis Causes of nausea and vomiting are numerous and varied ( Table 1 ). Of these causes, one of the most common is an adverse reaction to a medication. Nonsteroidal anti-inflammatories, chemotherapeutic agents, antidepressants, narcotics, antibiotics, and oral contraceptives are all commonly associated with nausea and vomiting. It is important to note, however, that almost any medication can cause nausea. An accurate medication history thus is very important.

TABLE 1 -- Differential Diagnosis of Nausea and Vomiting Medications Analgesics—acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), rheumatologic and antigout drugs, opioids (codeine, morphine, oxycodone [Roxicodone]) Anesthetic agents—halothane, fentanyl (Sublimaze) Antiasthmatics—theophylline Anticonvulsants—phenobarbital, phenytoin (Dilantin) Antidepressants—selective serotonin reuptake inhibitors (SSRIs) Antimicrobials—acyclovir (Zovirax), erythromycin, itraconazole (Sporanox), metronidazole (Flagyl), sulfonamides, tetracycline Antiparkinsonian drugs—levodopa (Dopar), carbidopa (Lodosyn) Cancer chemotherapy—cisplatin (Platinol-AQ), cyclophosphamide (Cytoxan), dacarbazine (DTIC-Dome), nitrogen mustard

Cardiovascular agents—antiarrhythmics, antihypertensives, ß-blockers, calcium channel antagonists, digoxin, diuretics Corticosteroids—prednisone Diabetic drugs—sulfonylureas, metformin (Glucophage) Ergot alkaloids—dihydroergotamine (Migranal), ergotamine (Ergomar), methysergide (Sansert) Gastrointestinal agents—azathioprine (Imuran), sulfasalazine (Azulfidine) Hormonal agents—estrogen, progesterone, oral contraceptives Iron replacement—ferrous sulfate Substance abuse—alcohol, nicotine Infectious Causes Gastroenteritis—viral, bacterial, parasitic Other—otitis media, systemic sepsis Gastrointestinal Disorders Functional disorders—chronic intestinal pseudoobstruction, gastroparesis, irritable bowel syndrome, nonulcer dyspepsia Mechanical obstruction—gastric outlet obstruction, small bowel obstruction Organic gastrointestinal disorders Appendicitis Hepatobiliary disease—biliary colic, cholecystitis, hepatitis, neoplasia Inflammatory bowel disease—Crohn's disease Mesenteric ischemia Peptic diseases—esophagitis, Helicobacter pylori, nonulcer dyspepsia, peptic ulcer disease Pancreatic disease—pancreatitis, pancreatic adenocarcinoma Paralytic ileus Peritoneal irritation—peritonitis, metastases Postoperative gastric surgery Retroperitoneal fibrosis Central Nervous System (CNS) Disorders Increased intracranial pressure—abscess, hemorrhage, hydrocephalus, infarction, malignancy, meningitis, pseudotumor cerebri Demyelinating disorders Labyrinthine disorders—labyrinthitis, Méniére's disease, motion sickness Migraine headaches Parkinsonian disorders

Seizures—complex partial Psychologic/Psychiatric Disorders Anxiety Depression Eating disorders—anorexia nervosa, bulimia nervosa Pain Psychogenic vomiting Medical Conditions Cardiac—acute myocardial infarction, congestive heart failure Genitourinary—acute nephritis, nephrolithiasis, ovarian torsion, pyelonephritis, testicular torsion Endocrinologic and metabolic conditions—acute intermittent porphyria, Addison's disease, diabetic ketoacidosis, hypercalcemia, hyperparathyroidism, hyperthyroidism, hypoparathyroidism, uremia Pregnancy—hyperemesis gravidarum, morning sickness Postoperative Nausea and Vomiting Radiation Therapy Idiopathic Conditions Cyclic vomiting syndrome Gastric dysrhythmias

Viral and bacterial infections are another common cause of nausea and vomiting. This manifestation is often as an acute syndrome with fever and diarrhea. Common viral agents are rotavirus, enterovirus, and adenovirus. Bacterial causes such as Salmonella, Campylobacter, and Shigella are usually seen with the consumption of tainted food or water and can be associated with bloody diarrhea. Disorders of the gastrointestinal tract can cause nausea and vomiting. Common examples of this are peptic ulcer disease, gastroparesis, dyspepsia, and irritable bowel disease. In addition, gastrointestinal emergencies such as acute appendicitis, acute cholecystitis, mesenteric ischemia, and intestinal obstruction can be associated with nausea and vomiting. Nausea and vomiting are also exhibited during pregnancy. This is usually most frequent in the first trimester and manifested as “morning sickness.” It is most common in the first pregnancy and is usually self-limited. Rarely seen is hyperemesis gravidarum, a condition characterized by intractable vomiting and weight loss that is often accompanied by fluid and electrolyte abnormalities.

CURRENT DIAGNOSIS Acute and chronic nausea and vomiting must be differentiated. Nausea and vomiting have a wide range of possible causes. Control patient symptoms and then look for an underlying etiology. Few evidence-based therapy guidelines exist outside of postchemotherapy and postoperative nausea and vomiting. Psychological disorders are also associated with nausea and vomiting. These can be seen in anxiety, depression, eating disorders such as anorexia and bulimia, and in psychogenic vomiting. Note that patients with psychogenic vomiting usually maintain a normal level of nutrition because they vomit only a small amount of the ingested food. Other causes of nausea and vomiting not to be overlooked include central nervous system (CNS) disorders such as acute labyrinthitis, Méniére's disease, and motion sickness. In addition, any condition that causes increased intracranial pressure can cause nausea and vomiting. Further, approximately three fourths of all surgical procedures are complicated by postoperative nausea and vomiting. Most of this is thought to be anesthesia related. Clinical Assessment To narrow the wide differential associated with nausea and vomiting, it is important for the clinician to use a thoughtful approach to determine the underlying cause. Assessment begins with the differentiation of these symptoms from regurgitation (passive retrograde flow of gastric or esophageal contents into the mouth) and rumination (an effortless regurgitation of recently digested food into the mouth followed by spitting or reswallowing). With a thorough history and physical examination, the clinician can determine whether the patient can be effectively treated as an outpatient or requires hospitalization for treatment and further evaluation. To do this, the clinician must effectively characterize the patient's symptoms with special attention to the onset, duration, frequency, and severity of the symptoms. Some sample questions and scenarios follow. When did the symptoms begin? How long have they been present? Acute causes of nausea and vomiting such as gastroenteritis or an adverse reaction to a medication has a much different course than chronic causes such as gastroparesis or irritable bowel syndrome. When does the vomiting occur? Is it in the morning or after meals? The temporal course is important. Early morning vomiting is often associated with pregnancy and uremia, whereas nausea and vomiting after meals can be seen with a motility disorder or an obstruction. It is also important to explore the character of the vomitus, specifically if it contains food, bile, or blood. In addition, the clinician should query the patient about any exacerbating or alleviating factors and whether or not the patient has experienced any weight loss or recently traveled. After completing the history, the clinician should perform a focused physical examination. Here the key is to search for any consequences or complications of vomiting and to identify any signs that may point to the cause of the symptoms. Areas to be highlighted would be as follows. Vital signs, mucous membranes, and skin turgor should be examined for signs of dehydration. Bowel sounds should be quantified as normal,

hyperactive, or hypoactive. The abdomen should be evaluated for distention and tenderness because specific sites of discomfort can give a clue to a diagnosis. Any visible hernias, surgical scars, or peristalsis should be noted. A neurologic exam should also be performed, including an assessment of the patient's optic fundus and gait. The teeth should be inspected for signs of enamel breakdown. A brief screening for any signs of psychological disease such as anxiety or depression should also be undertaken. Diagnostic Testing The history and physical examination guides the clinician to any further diagnostic testing that is required. Many cases of nausea and vomiting do not require any further testing. If necessary, screening laboratory testing should include serum chemistries, which may detect electrolyte abnormalities, dehydration or uremia, and a complete blood count, which may detect signs of infection. Depending on the clinical picture, an erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone, and liver and pancreatic function testing can be considered. All women of childbearing age should have a pregnancy test. Stool studies can also be considered (e.g., giardiasis). Serum drug levels for toxicity should be considered in appropriate patients. Further diagnostic testing is dictated by the patient presentation. If any obstruction or perforation is suspected, flat and upright abdominal radiographs can be obtained. Note that these can be normal in early or intermittent obstruction. Further studies such as an upper gastrointestinal barium study or a small bowel followthrough can be helpful if obstruction is considered. Esophagogastroduodenoscopy (EGD) is used to evaluate the mucosa of the esophagus, stomach, and duodenum for signs of inflammation. Additional testing that may be helpful depending on symptomatology includes an abdominal ultrasound, abdominal computed tomography (CT) scan, enteroclysis, and electrogastrography. For hypothesized gastric motility disorders, a gastric emptying study and antroduodenal manometry can be pursued. If nausea and vomiting are persistent or severe and a gastrointestinal cause is not found, other etiologies such as systemic disease, CNS disorders, and psychological causes must be considered. CNS causes are best evaluated by head CT or magnetic resonance imaging (MRI). MRI provides better visibility of a posterior fossa lesion if that is of concern. Patients with chronic unexplained nausea and vomiting should also be screened for psychiatric disorders. If the clinician has pursued this diagnostic evaluation and is still unsure of the cause of persistent symptoms, consultation with a specialist should be obtained. Most often this would begin with a gastroenterologist but would depend on the symptom picture. Treatment Effective treatment of nausea and vomiting depends on identification and correction of the underlying cause. Most cases of nausea and vomiting require no specific treatment. However, patients may require evaluation for fluid and electrolyte disorders associated with nausea and vomiting. Symptomatic therapy should be based on symptom severity and the clinical presentation. Except in the case of pregnancy or drug overdose, antiemetic agents are often used empirically for relief. Oral rehydration, or intravenous if necessary, can then be pursued. If abdominal pain is also present, surgical consultation may be warranted. With mild nausea and vomiting, dietary changes may be sufficient. Patients should be counseled to try small amounts (1-4 ounces/serving) of cool, clear liquids and advance as tolerated. A goal of 1 to 2 liters of fluid a day is a good one. If the patient successfully tolerates clear liquids, addition of small portions of easily digested foods such as bananas, rice, bouillon, and toast are in order. Dietary fat content should be reduced.

Dairy products should be avoided. The diet can gradually be advanced with easily tolerated foods such as plain chicken or turkey and vegetables, bland soups, and fruit. Food should be consumed deliberately, and the patient should take care not to overeat. Increased physical activity around times of eating should be avoided. Note that nausea and vomiting associated with pregnancy can very often be treated with dietary changes alone.

CURRENT THERAPY Most cases of nausea and vomiting do not require any therapy except dietary change. Hydration status must be monitored. Depending on symptom severity, antiemetics can be given by a variety of routes: oral, intravenous, and rectal. Use of medications is often limited by adverse effects. With persistent or severe nausea and vomiting, antiemetic agents may be warranted. Most of these agents are centrally acting and can be divided into nine families ( Table 2 ). By using medications from different families as needed or in combination, the likelihood of adverse drug reactions can be lessened. Because these agents work in the CNS, most adverse effects are also central, such as sedation, lethargy, and extrapyramidal effects. Outside of postoperative and postchemotherapy nausea and vomiting, there are few trials that identify an antiemetic of choice. Commonly used antiemetics are prochlorperazine (Compazine), promethazine (Phenergan), metoclopramide (Reglan), and trimethobenzamide (Tigan).

TABLE 2 -- Commonly Used Medications for Nausea and Vomiting Class/Medication

Usual Dosage

Route(s)

Adverse Effects

Anticholinergic Scopolamine (Transderm Scop)

1 patch every 3 d

Transdermal Dry mouth, drowsiness, impaired eye accommodation; rare: disorientation, memory disturbance, dizziness, hallucinations

Diphenhydramine (Bendadryl)

25-50 mg q4-6h

IM, IV, PO

Hydroxyzine (Atarax, Vistaril)

25-100 mg q6h

IM, PO

Meclizine (Antivert)

25-50 mg q6h

PO

Promethazine (Phenergan)

12.5-25 mg IM, IV, PO, q4-6h PR

Antihistamines

Benzamides

Sedation, dry mouth, constipation, confusion, blurred vision, urinary retention

Class/Medication

Usual Dosage

Metoclopramide (Reglan)

5-15 mg q6h

Trimethobenzamide (Tigan)

250 mg q6- IM, PO, PR 8h

Route(s)

Adverse Effects

IM, IV, PO

Sedation, restlessness, diarrhea, agitation, central nervous depression, extrapyramidal effects, hypotension, neuroleptic syndrome, supraventricular tachycardia

Benzodiazepines Lorazepam (Ativan)[1]

0.5-2.5 mg q8-12h

IM, IV, PO

Sedation, amnesia, respiratory depression, ataxia, blurred vision, hallucinations, emotional reactions

Butyrophenones Droperidol (Inapsine)

0.625-1.25 IM, IV mg q3-4h[3]

Sedation, hypotension, tachycardia, extrapyramidal effects, dizziness, blood pressure increase, hallucinations, chills, QT prolongation, torsade de pointes

Haloperidol (Haldol)[1]

05.-5 mg q8h

IM, IV, PO

2.5-5 mg q8h

PO

Drowsiness, euphoria, vision difficulties, somnolence, vasodilation, abnormal thinking, dysphoria, diarrhea, flushing, tremor, myalgias

4 mg q6h

IM, IV, PO

Gastrointestinal upset, anxiety, insomnia, hyperglycemia, facial flushing, euphoria, peritoneal itching

Chlorpromazine (Thorazine)

10-25 mg q4-6h

IM, PO, PR

Prochlorperazine (Compazine)

5-10 IM, IV, PO, (25PR) mg PR q6h

Sedation, lethargy, skin irritation, cardiovascular effects, extrapyramidal effects, cholestatic jaundice, hyperprolactinemia, neuroleptic malignant syndrome, blood abnormalities

Thiethylperazine (Torecan)

10-20 mg q6h[3]

Cannabinoids Dronabinol (Marinol)

Corticosteroids Dexamethasone (Decadron)[1] Phenothiazines

IM, IV, PO

5-HT3 Serotonin Antagonists Ondansetron (Zofran)

8 mg q8h

IV, PO

Granisetron (Kytril)

2 mg per 24 h

IV, PO

Dolasetron (Anzemet)

100 mg per IV, PO 24 h

Headache, constipation, fever, asthenia, arrhythmias, diarrhea, dizziness, ataxia, tremor, somnolence, thirst, nervousness, elevated hepatic transaminases

Abbreviations: IM = intramuscular; IV = intravenous; PO = orally; PR = per rectum.

1 Not FDA approved for this indication. 3 Exceeds dosage recommended by manufacturer.

Antiemetic Drugs SEROTONIN ANTAGONISTS Ondansetron (Zofran), granisetron (Kytril), and dolasetron (Anzemet), especially when introduced prior to treatment, are effective in the prevention of chemotherapy- and radiation-associated emesis. They are also effective in postoperative nausea and vomiting, but less expensive options (e.g., droperidol [Inapsine] and dexamethasone [Decadron][1]) are equally effective. The serotonin antagonists are usually well tolerated. 1 Not FDA approved for this indication.

DOPAMINE ANTAGONISTS The phenothiazines, butyrophenones, and substituted benzamides are all examples of antiemetics that work through dopaminergic blockade. Phenothiazines are often not effective for severe vomiting and have a high incidence of side effects including sedation, hypotension, and extrapyramidal effects. Metoclopramide (Reglan) is more effective for severe nausea and vomiting but again has a high incidence of adverse effects. This agent has been especially effective in treating gastroparesis. It should be noted that droperidol (Inapsine) has been associated with QT prolongation and electrocardiogram (EKG) monitoring is recommended with administration. ANTIHISTAMINES AND ANTICHOLINERGICS Antihistamines and anticholinergics are of value in the prevention of nausea and vomiting associated with inner ear disturbances, motion sickness, vertigo, and migraines. They often cause drowsiness. BENZODIAZEPINES These medications can be helpful in psychogenic and anticipatory vomiting. CORTICOSTEROIDS Dexamethasone (Decadron)[1] is commonly used in combination with other antiemetics. Use of steroids and serotonin antagonists is effective in chemotherapy-associated nausea and vomiting, and steroids and lowdose droperidol (Inapsine) is useful in postoperative nausea and vomiting. CANNABINOIDS Marijuana is used as an antiemetic and an appetite stimulant. Its efficacy is increased when combined with prochlorperazine (Compazine). Dronabinol (Marinol) is a synthetic cannabinoid available by prescription. CNS side effects are very common with these drugs.

NONPHARMACOLOGIC OPTIONS Note that both ginger and acupressure are effective in the treatment of nausea and vomiting. Special Circumstances CHEMOTHERAPY INDUCED Attempt to treat patients prophylactically to avoid nausea and vomiting. Use combination therapy. Try to avoid using medications from the same family to decrease the chance of adverse reactions. Note that chemotherapy-induced emesis may begin as long as 24 hours post treatment and may require therapy for 4 to 7 days. DIABETES Use promotility agents such as metoclopramide (Reglan) for gastroparesis-associated nausea and vomiting. PREGNANCY Morning sickness is common in the first trimester of pregnancy but usually resolves by the second. Reassurance, frequent small meals, and dietary changes are usually sufficient. For some patients, pyridoxine (vitamin B6)[1] is helpful. In most cases, antiemetics are avoided in pregnancy. In severe cases involving protracted symptoms and fluid and electrolyte abnormalities (hyperemesis gravidarum), hospitalization and intravenous hydration may be required. No antiemetics are approved for use in pregnancy. Selection of any medication to be used in pregnancy should be with careful consideration of the severity of symptoms and potential risk to the fetus. Meclizine (Antivert) and promethazine (Phenergan) are used in pregnancy but neither is FDA-approved for this indication. MOTION SICKNESS Anticholinergics and antihistamines are effective here. Transdermal scopolamine patches (Transderm Scop) are convenient for those exposed to motion for long periods (cruise ships). POSTOPERATIVE Approximately 80% of patients who undergo anesthesia experience nausea and vomiting in the perioperative or postoperative period. Serotonin antagonists or combination therapy with dexamethasone (Decadron)[1] and droperidol (Inapsine) are effective here.



REFERENCES American Gastroenterological Association, 2001. American Gastroenterological Association : Medical position statement: Nausea and vomiting. Gastroenterology 2001; 120(1):261-262. Anthony, 2004. Anthony L: Nausea and vomiting. Conn's Current Therapy 2004; Hasler and Chung, 2005. Hasler WL, Chung O: Approach to the patient with gastrointestinal disease. Harrison's Principles of Internal Medicine, 16th ed. 2005. McQuaid, 2006. McQuaid KR: Nausea and vomiting. Current Medical Diagnosis and Treatment 2006; Miser, 2005. Miser WF: Nausea and vomiting. Conn's Current Therapy 2005; Pasricha, 2005. Pasricha PJ: Treatment of disorders of bowel motility and water flux; antiemetics; agents used in biliary and pancreatic disease. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th ed. 2005.



Chapter 3 – Gaseousness and Indigestion

Method of: Ram Dickman, MD Ronnie Fass, MD Gaseousness Gaseousness includes bloating, belching, and flatulence, which are among the most common gastrointestinal symptoms reported by patients who seek their physician's advice and especially by those with functional bowel disorders. Despite the clinical importance of gaseousness, the pathophysiology of this disorder is not fully understood. Bloating and flatulence are frequently attributed to excess gas within the gut lumen; however, gas transit studies in patients with bloating have not demonstrated an increased amount of gas within the gut. The current mainstays of treatment of gaseousness include lifestyle and diet modifications. BLOATING Abdominal bloating is a sensation of a swollen or distended abdomen. The term is sometimes used to describe a sensation of excess gas or a full belly. Abdominal bloating may affect between 10% and 30% of the general population. Bloating is a very common complaint, especially in patients with functional bowel disorders, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD). Objective Evidence

The gastrointestinal lumen of a normal subject contains less than 200 mL of gas, which is a combination of swallowed air (N2, O2) and gases that are produced during acid neutralization (CO2) and bacterial fermentation (H2, methane, CO2). Measurement of a patient's abdominal girth using abdominal impedance plethysmography allows objective assessment of reports of bloating. Studies in IBS patients show a greater 24-hour fluctuation in abdominal girth as compared to healthy controls. Abdominal distention (objective parameter) peaks 4 to 6 hours before bedtime and was correlated with bloating (subjective parameter) only in the subgroup of patients with constipation-predominant IBS. However, in other subgroups of IBS patients, there was no association between symptoms and changes in abdominal girth. Interestingly, studies that assessed intestinal gas dynamics found that IBS patients have delayed transit of gas along the gut and a significant increase in gas retention as compared to controls. Specifically, gas retention within the jejunum seems to be the main cause for the patients' symptoms. However, other studies found that the total amount of gas within the gut in symptomatic patients (mainly IBS) who complained of

bloating was the same as in asymptomatic controls. In one study, for example, during gas infusion into the gut, patients with IBS and bloating complained of greater discomfort and gaseousness than did controls. Thus, it appears that the key mechanism for bloating in patients with functional bowel disorders is an abnormal perception of intestinal gas.

CURRENT DIAGNOSIS Gaseousness

History: drugs (narcotics, calcium channel blockers, anticholinergics), surgery (vagotomy, adhesions, Nissan fundoplication), diabetes, celiac sprue, intestinal myopathies, diet (consumption of starch, lactose, fructose, sorbitol, beans, cabbage, cauliflower, Brussels sprouts) Alarm symptoms: weight loss, anemia, anorexia, fever, and gastrointestinal bleeding Blood tests: complete blood count, glucose and electrolytes, thyroid-stimulating hormone Upper or lower endoscopy and/or 24-hour pH monitoring Breath testing for lactose and fructose intolerance Indigestion

Upper endoscopy with biopsies for Helicobacter pylori 24-hour pH monitoring Gastric emptying rate measurement Water-load test Psychological evaluation BELCHING Belching is the expulsion of gas from the stomach while retaining solid and fluid material. Occasional belching is a normal physiologic process aimed to remove air from the stomach, typically during or after meals. The air is commonly swallowed during meals or introduced into the stomach through carbonated beverages and other food products. Repetitive belching not related to meals is secondary to esophageal air aspiration. Excessive belching is almost always associated with functional gastrointestinal disorders (functional dyspepsia and aerophagia) and with gastroesophageal reflux disease (GERD). Patients may also complain of an inability to belch. Common causes of the latter include esophageal achalasia and postNissan fundoplication (“gas-bloat syndrome”). In one large study, 17% of 8351 healthy subjects reported having excessive belching with a similar frequency in men and women. Patient Evaluation

Evaluation of patients with excessive belching is appropriate only if an underlying organic cause is suspected and should include an upper endoscopy, esophageal pH monitoring, and esophageal manometry (the latter to rule out achalasia). Radiographic studies of the esophagus and stomach may also be helpful in

patients with co-morbid factors. FLATULENCE Studies of healthy subjects found that the frequency of flatus passed per day ranges from 10 to 14 times. Flatus volume is difficult to measure in clinical practice. Thus, clinicians should rely on their patient's reported average frequency of flatus episodes per day over a predetermined period of time (1 to 2 weeks). Increased flatus production (more than 22 times per day) may be caused by malabsorption of carbohydrates in patients with celiac sprue, pancreatic insufficiency, and short bowel syndrome. Additionally, in susceptible patients, malabsorption of lactose, fructose, sorbitol, and starch can result in excessive flatus production because of colonic bacterial fermentation of these unabsorbable carbohydrates. CLINICAL ASSESSMENT The clinical assessment of gaseousness is aimed to rule out more serious conditions that have clinical manifestations similar to benign functional bowel disorders. TREATMENT Treatment of gaseousness includes recommendations to reduce ingestion of gas-forming food products and drugs that facilitate intestinal passage. Patients need to reduce air swallowing (aerophagia) by avoidance of carbonated beverages, gum chewing, and smoking and by drinking from a straw. Dietary modifications include avoidance of dietary fibers, caffeine, cabbage, Brussels sprouts, beans, broccoli, and cauliflower. Loperamide (Imodium) may increase intestinal fluid absorption in patients with rapid transit. Tegaserod (Zelnorm) may improve bloating in constipation-predominant IBS patients. Antibiotics may be beneficial in the case of bloating caused by bacterial overgrowth. Indigestion (Dyspepsia) Dyspepsia is a persistent or recurrent pain or discomfort in the epigastrium associated with a feeling of fullness, early satiety, bloating, belching, and nausea. It is estimated that up to 40% of the adults in the United States experience dyspeptic symptoms at least once a year.

CURRENT THERAPY Gaseousness

Bloating and flatulence Reduce air swallowing (avoidance of carbonated beverages, gum chewing, smoking; drinking from a straw) Dietary modifications (avoidance of dietary fibers, caffeine, beans, cabbage, broccoli, cauliflower) Loperamide (Imodium), 2 mg PO 1-2/d, for malabsorption because of rapid transit Tegaserod (Zelnorm), 6 mg PO 2/d, for constipation-predominant irritable bowel syndrome Short courses of antibiotics for bacterial overgrowth Simethicone (Mylicon) Belching Reduce air swallowing Indigestion Dyspepsia

Prokinetics Metoclopramide (Reglan),[1] 10 mg PO 1-3/d Tegaserod (Zelnorm),[1] 6 mg PO 3/d Domperidone (Motilium),[*] 40 mg PO 3/d Proton pump inhibitors (PPIs) Omeprazole (Prilosec),[1] 20 mg PO 1-2/d Rabeprazole (AcipHex),[1] 20 mg PO 1-2/d Pantoprazole (Protonix),[1] 40 mg PO 1-2/d Lansoprazole (Prevacid),[1] 30 mg PO 1-2/d Esomeprazole (Nexium),[1] 40 mg PO 1-2/d Combination PO therapy for H. pylori infection: 10-14 d: PPI 2/d + 1 g amoxicillin 2/d + 500 mg clarithromycin 2/d Functional Dyspepsia

Antidepressants Nortriptyline (Aventyl/Pamelor),[1] amitriptyline (Elavil/Endep),[1] Doxepin (Sinequan), 50 mg PO qhs Trazodone (Desyrel), 100-150 mg PO 1/d Hypnotherapy Psychological treatments

Abbreviation: PO = orally. 1 Not FDA approved for this indication. * Investigational drug in the United States.

ETIOLOGY In most of the patients with dyspepsia (60%), no significant organic finding underlies patients' symptoms. These patients are defined as having functional dyspepsia. Other causes include peptic ulcer disease (15% to 25%), Helicobacter pylori infection (30% to 60%), GERD, gastric cancer, and nonsteroidal antiinflammatory drug (NSAID) use. The underlying mechanisms for functional dyspepsia include antral hypomotility, impaired gastric accommodation, disordered gastric electrical activity, and visceral hypersensitivity. Additionally, studies found that psychological co-morbidity (anxiety, neuroses, and depression) are more common in FD than in controls. CLINICAL ASSESSMENT Because of the many symptoms included in the category of dyspepsia, the clinical evaluation of dyspeptic patients implies that many other conditions are included in the differential diagnosis such as gastroesophageal reflux disease, H. pylori infection, and gastric cancer. Consequently, an appropriate workup for patients with dyspepsia may include upper endoscopy, 24-hour esophageal pH monitoring, H. pylori assessment, gastric emptying studies, and the water-load test. In patients with functional dyspepsia, psychological consultation is an important part of the patient's evaluation. TREATMENT Physicians should tailor their treatment approach to dyspepsia according to the severity and frequency of the patient's symptoms. Evaluation for psychosocial abnormalities may be essential in a significant subset of dyspeptic patients. Although not systematically validated, therapeutic recommendations include dietary and lifestyle modifications such as eating smaller and frequent meals and avoiding foods with high fat and fiber content. Antisecretory medications, promotility drugs, and pain modulators should be considered in the proper clinical scenario. Hypnotherapy is more effective in FD patients as compared to medical therapy. Psychological intervention is an essential therapeutic modality in patients with psychological disturbances.



REFERENCES Kellow et al., 2003. Kellow J, Lee OY, Chang FY, et al: An Asia-Pacific, double blind, placebo controlled randomised study to evaluate the efficacy, safety, and tolerability of Tegaserod in patients with irritable bowel syndrome. Gut 2003; 52:671-676. Mertz et al., 1998. Mertz H, Fass R, Krodner A, et al: Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol 1998; 93:160-165. Moayyedi et al., 2000. Moayyedi P, Forman D, Braunholtz D, et al: The proportion of upper gastrointestinal symptoms in the community associated with Helicobacter pylori, lifestyle factors, and nonsteroidal antiinflammatory drugs. Leeds HELP Study Group. Am J Gastroenterol 2000; 95:1448-1455. Salvioli et al., 2005. Salvioli B, Serra J, Azpiroz F, et al: Origin of gas retention and symptoms in patients with bloating. Gastroenterology 2005; 128:574-579. Serra et al., 2001. Serra J, Azpiroz F, Malagelada JR, et al: Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut 2001; 48:14-19. Talley et al., 2005. Talley NJ, Vakil NB, Moayyedi P: American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005; 129:1756-1780.



Chapter 4 – Hiccups

Method of: Michael J. Pollack , MD Hiccups are a common and usually benign phenomenon that affects nearly everyone at some time. It is more accurately termed singultus , derived from the Latin word singult , which means the act of catching one's breath while sobbing. Hiccups are caused by synchronous contractions of the diaphragmatic and intercostal muscles followed by the immediate and sudden closure of the glottis. The forcefully inspired air meeting the closed glottis creates the hiccup sound. Most episodes are transient and resolve without medical therapy. Rarely, hiccups are the only symptom of a serious systemic illness. The role of the practitioner is to know when to initiate the appropriate workup and how to treat the hiccups until the underlying problem, if identified, is resolved. Classification Hiccups can be classified as transient, persistent, or chronic. An episode of hiccups that lasts less than 1 day is transient. This type of episode is usually a benign, often physiologic phenomenon. An episode lasting up to 1 month is deemed persistent. Beyond this time it is considered chronic. Practically speaking, hiccups should be viewed as either transient or chronic. Most people experience some form of hiccups throughout their lives. The majority of these episodes are a transient nuisance. Chronic hiccups are quite rare with an estimated prevalence of approximately 1 in 100,000 people but can lead to significant adverse effects including malnutrition, weight loss, fatigue, and generalized debilitation. Those patients who present to their practitioner with hiccups most often experience them chronically. Hiccups can occur in utero, but they have no known physiologic function. Chronic hiccups occur more often in males, but transient hiccups affect both males and females equally. Mechanism The precise mechanism of hiccups is unknown. Three neural pathways are described in the hiccup reflex: afferent (phrenic and vagus nerves); a poorly characterized hiccup center in the brainstem; and efferent (phrenic, vagus, cervical, and thoracic nerves). The hiccup center is thought to involve a complex interaction among the brainstem, respiratory centers, phrenic nerve nuclei, the reticular activating center, and the hypothalamus. Theoretically, pathology in or around any of these areas can trigger hiccups. The frequency of hiccups is known to increase with a decline in arterial PCO2 and to decrease as PCO2 rises. This is the physiologic basis for the home remedy of breathing into a paper bag to stop hiccups. Etiology Transient hiccups are usually caused by overdistention of the stomach by air (such as during endoscopy), overeating, eating too fast, or alcohol or tobacco use; these typically resolve without medical therapy. Other benign causes include sudden changes in ambient or gastrointestinal temperature, sudden excitement, or emotional stress. Chronic hiccups may be caused by many underlying processes ( Table 1 ). Processes

affecting either the vagus or the phrenic nerve are the most common cause. Examples of precipitating irritants include foreign bodies in contact with the tympanic membrane (auricular branch of the vagus), pharyngitis, laryngitis or neck tumors (recurrent laryngeal nerve of the vagus), mediastinal masses, subdiaphragmatic abscesses, and gastroesophageal reflux (phrenic nerve).

TABLE 1

-- Selected Causes of Persistent Hiccups

Pharyngitis Laryngitis Pneumonia Esophagitis Aortic aneurysm Mediastinal tumors Pancreatitis Peptic ulcer disease Subphrenic abscess Myocardial infarction Gallbladder disease Gastric distention

Meningitis Encephalitis Cerebrovascular accident Arteriovenous malformation Brain abscess Neoplasms Trauma Temporal arteritis

Multiple sclerosis Hydrocephalus Ventriculoperitoneal shunts

Alcohol Uremia Hypoglycemia Hyponatremia Hypocalcemia Septicemia

General anesthesia Tracheal intubation Neck extension Gastric distention Organ manipulation Barbiturates Steroids Benzodiazepine Methyldopa Stress Excitement Malingering Conversion

Abbreviation: CNS = central nervous system.

Phrenic/Vagus Nerve Irritation

CNS Disorders

Toxic-Metabolic Disorders

Postoperative Factors

Psychogenic Drugs Factors


Central nervous system (CNS) disorders, toxic-metabolic disorders, and psychogenic factors are also implicated, to some extent, in the etiology of hiccups. CNS disorders include structural, vascular, and infectious processes. Toxic-metabolic disorders include uremia, alcoholic intoxication, and general anesthetic agents. Psychogenic factors associated with both transient and persistent hiccups include stress, anxiety, and even malingering. Medical Evaluation The approach to the patient with an attack of hiccups depends on its duration. Transient hiccups are both common and benign and do not require investigation. However, chronic hiccups may be the only symptom of an underlying medical condition, and they require a thorough evaluation. The initial approach to identify the cause of chronic hiccups is a complete patient history and comprehensive physical examination, with a focus on the duration, frequency, alleviating factors, and aggravating factors. CURRENT DIAGNOSIS

Hiccups are usually transient and benign.

The hiccup reflex arc, which consists of afferent/efferent phrenic and vagus nerves as well as a poorly characterized hiccup center in the brainstem, is key in understanding the underlying cause.

Chronic hiccups may be a symptom of a serious underlying condition and warrant a thorough medical evaluation. Laboratory tests should start with a complete blood count and renal function with full electrolyte panel. A chest radiograph is important to aid in the detection of possible anatomic irritants to the phrenic or vagus nerves. An electrocardiogram helps detect pericardial disease or even pacemaker dysfunction. If the radiograph and electrocardiogram are unrevealing, second-level testing should be pursued guided by the relevant history and clinical findings, including a computed tomography of the head, chest, and abdomen; lumbar puncture; upper endoscopy; or bronchoscopy. Further testing, if required, would include magnetic resonance imaging of the head, an electroencephalogram, pulmonary function tests, and esophageal manometry. Treatment Because chronic hiccups are usually a sign of an underlying systemic disease, priority should be given to

treating the condition. For example, proton pump inhibitors can be used if gastroesophageal reflux is implicated, or systemic chemotherapy can be administered if a neoplasm is detected. When a cause cannot be determined and hiccups persist, empirical therapy is warranted. It can be used to palliate chronic, transient, or persistent hiccups while treatment of the underlying condition is ongoing. No single modality or agent is universally accepted as the treatment of choice. Interventions can be divided into pharmacologic ( Table 2 ) and nonpharmacologic therapies ( Table 3 ). Examples of nonpharmacologic treatments include the age-old and well-known home remedies that include breath holding, breathing into a paper bag, swallowing a teaspoon of sugar, the Valsalva maneuver, and gargling with ice water. Some of these maneuvers have a physiologic basis because they are based on an attempt to interrupt the vagally mediated afferent limb of the hiccup reflex arc.

TABLE 2

-- Pharmacotherapy for Persistent Hiccups

Chlorpromazine (Thorazine) Haloperidol (Haldol)[1 ] Phenytoin (Dilantin)[1 ] Carbamazepine (Tegretol)[1 ] Valproic acid (Depakene)[1 ] Gabapentin (Neurontin)[1 ] Baclofen (Kemstro)[1 ] Cyclobenzaprine (Flexeril)[1 ] Metoclopramide (Reglan)[1 ] Amitriptyline (Elavil)[1 ] Antipsychotics Anticonvulsants Muscle Relaxants Dopamine Antagonists Antidepressants 1 Not FDA approved for this indication.

TABLE 3 -- Home Remedies to Treat Hiccups Breath holding Forcible traction on the tongue Direct pharyngeal stimulation Biting on a lemon Valsalva maneuver Ice-water gargles Swallowing granulated sugar Fright Breathing into a bag

Rubbing back of neck (C5 dermatome)

Several drugs are successful anecdotally in the treatment of hiccups. The most widely used agent is chlorpromazine (Thorazine), a phenothiazine antipsychotic. It is the only agent that has achieved U.S. Food and Drug Administration (FDA) approval for treatment of hiccups. Chlorpromazine is a centrally acting agent whose precise mechanism in terminating hiccups is unknown. Intravenous administration is considered to be most effective and frequently used in an emergency department setting. Its side effects include hypotension, dystonic reactions, and excessive drowsiness. These are usually rare occurrences and avoidable if the drug is administered slowly. Oral formulations in doses of 25 to 50 mg three to four times daily as needed can be used up to 7 to 10 days. Metoclopramide (Reglan),[1 ] a dopamine antagonist and promotility agent, is often used when chlorpromazine does not alleviate the hiccups. It has a more favorable side-effect profile but is not as effective as chlorpromazine. The usual dose is 10 mg three to four times a day. Baclofen (Kemstro),[1 ] an analogue of -aminobutyric acid, has shown some success in limited case series, and it has fewer side effects than the other agents used to treat hiccups. The usual dosage is 10 mg three times a day. Various anticonvulsants, antidepressants, and CNS agents are all reported to terminate intractable hiccups. When the therapies just cited fail, both nonconventional and invasive modalities may be successful. Both hypnosis and acupuncture have been tried, and case reports laud their success. Phrenic nerve blocking and crushing are successful as well. Diaphragmatic pacing ameliorates those afflicted with chronic hiccups. CURRENT THERAPY

Most transient hiccups resolve spontaneously.

Numerous nonpharmacologic and pharmacologic therapies are proposed for treating chronic hiccups.

Although symptom control is important, a search for an underlying etiology is essential. In summary, hiccups are a common annoyance that most people experience at some point in their lives. Their self-limiting nature usually obviates the need for medical intervention. Hiccups rarely are chronic and can be the sole symptom of a serious underlying condition. The approach to the management of patients with symptomatic hiccups is the search for and treatment of the underlying problem as well as the implementation of the numerous methods known to resolve hiccups. 1 Not FDA approved for this indication.

Copyright © 2008 Elsevier Inc . All rights reserved. - www.mdconsult.com


REFERENCES Friedman, 1996. Friedman NL: Hiccups: A treatment review. Pharmacotherapy 1996; 16:986-995. Kolodzik and Eilers, 1991. Kolodzik PW, Eilers MA: Hiccups: Review and approach to management. Ann Emerg Med 1991; 20:565-573. Lewis, 1985. Lewis JH: Hiccups: Causes and cures. J Clin Gastroenterol 1985; 7:539-552. Rousseau, 1995. Rousseau P: Hiccups. South Med J 1995; 88:175-181. Souadjian and Cain, 1968. Souadjian J, Cain J: Intractable hiccups: Etiological factors in 220 cases. Postgrad Med 1968; 43:72-77.



Chapter 5 – Acute Infectious Diarrhea

Method of: Matthew T. Oughton, MD, FRCPC Andre Dascal, MD, FRCPC Diarrhea is defined as production of at least 200 g of stool per day. However, accurate measurement of stool mass is impractical and is most often used only in clinical trials. A more functional definition of diarrhea is an increase in stool frequency and liquidity compared to the patient's usual bowel habit. Diarrhea is generally classified as acute if it lasts no more than 14 days, persistent if longer than 14 days, and chronic if longer than 30 days. Clinically, there are two major types of diarrhea. Secretory diarrhea is watery, is usually produced in large volumes, and contains little or no blood or leukocytes. Inflammatory diarrhea is bloody, usually has leukocytes, and is produced in smaller volumes. Recognizing the class of diarrhea can be useful in suggesting etiologies and in managing the diarrhea. The precise cause of a case of diarrhea is usually difficult to ascertain, because diarrhea is a nonspecific reaction by the intestine to numerous insults, including infections, toxins, and autoimmune disorders. Acute infectious diarrhea, by definition, is caused by a microbial pathogen. Although infections are the leading cause of diarrhea, many different pathogens cause acute infectious diarrhea, and the likelihood of any particular agent depends on the patient's age, symptoms, and epidemiologic risk factors (Boxes 1 and 2 [1] [2]). In immunocompetent adults in the developed world, acute infectious diarrhea is most often a minor and selfresolving ailment. Recent data for the United States estimate an annual burden of between 211 million and 375 million cases, with more than 900,000 hospitalizations and 6000 deaths. However, acute infectious diarrhea can cause severe illness in infants, immunocompromised patients, and malnourished patients; it remains a major cause of global morbidity and mortality. The World Health Organization (WHO) estimates that more than 4 billion cases of acute infectious diarrhea occur each year worldwide and attributes 2 million deaths (5% of all deaths) to diarrheal diseases annually. Most of these deaths are in children who are younger than 5 years and live in developing countries. Thorough investigation of a patient with acute diarrhea should include a detailed history, physical examination, and laboratory tests (see Boxes 1 and 2 [1] [2]). In general, clinical investigation of an individual case of acute infectious diarrhea is more useful in identifying sequelae of diarrhea, such as dehydration, than it is in revealing the exact etiologic agent. However, identification of the causative organism can sometimes reveal the existence of a common-source outbreak. One well-known example occurred in 1994, when the state public health laboratory in Minnesota noted an increase in Salmonella serotype enteritidis detected in submitted samples; this ultimately led to the recognition of a multistate Salmonella outbreak related to improperly cleaned ice cream trucks.

BOX 1 Clinical History for Acute Infectious Diarrhea •

•

Description of diarrhea •

Duration

•

Frequency

•

Presence of blood, pus, “grease” in stool

•

Symptoms of fever, tenesmus, dehydration

•

Weight loss

Other GI symptoms •

Anorexia

•

Cramping

•

Emesis

•

Nausea

•

Previous episodes with similar symptoms

•

Ill contacts with similar symptoms

•

Recent antibiotic exposure

•

Other medication exposure

•

•

•

•

Anticholinergics

•

Antimotility agents

•

Aspirin (ASA)

•

Proton pump inhibitors (PPIs)

Recent dietary history •

Shellfish

•

Undercooked meat (chicken)

•

Unsanitary water

Animal contacts •

Turtles

•

Other reptiles

Travel history •

Travel to endemic or epidemic areas

•

Sexual history

•

Vaccination history

•

Contact with institutions, e.g., hospitals, nursing homes, daycare facilities

•

Employment history

•

Immune status •

Presence of HIV

•

Presence of other congenital or acquired immunodeficiencies

BOX 2 Physical Examination for Acute Infectious Diarrhea •

•

Vital signs •

Blood pressure (look for postural changes)

•

Heart rate (look for postural changes)

•

Respiratory rate

•

Temperature

•

Weight (particularly useful to assess effects of rehydration)

Cardiovascular examination •

Volume status (jugular venous pressure)

•

Respiratory examination

•

Rule out hyperventilation (compensatory respiratory alkalosis for metabolic acidosis due to dehydration and loss of bicarbonate)

•

Abdominal examination

•

•

Focal tenderness

•

Guarding

•

Hepatosplenomegaly

•

Consider rectal examination (look for bloody stool)

Integument examination •

Lymphadenopathy

•

Rashes (rose spots)

Etiology It is uncommon to identify the exact etiologic agent in a case of acute infectious diarrhea. However, in some clinical situations, exact identification is important for determining optimal management or possible sequelae. The treatment of inflammatory diarrhea varies depending on the causative organism, and some diseases require alterations in therapy (e.g., suspected Campylobacter resistance to fluoroquinolones) or even avoidance of antibiotic therapy (e.g., enterohemorrhagic Escherichia coli, in which antibiotic therapy

has been associated with more frequent adverse outcomes) (Boxes 3 and 4 [3] [4]). BOX 3 Etiologic Agents of Predominantly Secretory Diarrhea Bacterial

•

Enteroaggregative Escherichia coli (EAEC)

•

Enterotoxigenic E. coli (ETEC)

•

Vibrio cholerae

Viral

•

Adenovirus (types 40 and 41)

•

Astrovirus

•

Caliciviruses (Norwalk, Sapporo)

•

Rotavirus

Protozoal

•

Cryptosporidium

•

Cyclospora

•

Dientamoeba fragilis

•

Giardia lamblia

•

Isospora belli

•

Microspora species (especia lly Enterocytozoon bieneusi)

BOX 4

Etiologic Agents of Predominantly Inflammatory Diarrhea Bacterial

•

Aeromonas sp.

•

Bacteroides fragilis (enterotoxigenic strains)

•

Campylobacter sp. (particularly FQ-resistant strains)

•

Clostridium difficile (toxigenic strains)

•

Escherichia coli (enterohemorrhagic, enteroinvasive)

•

Pleisomonas sp.

•

Shigella sp.

•

Salmonella enterica serotypes typhi and paratyphi

•

Nontyphoid Salmonella species

•

Noncholera Vibrio species

•

Yersinia

Protozoal

•

Entamoeba histolytica

BACTERIA Escherichia coli

E. coli is a versatile pathogen that causes a wide spectrum of disease affecting numerous organ systems. This is illustrated by the wide variety of diarrheagenic E. coli, including enterotoxigenic (ETEC), enteroaggregative (EAEC), enterohemorrhagic (EHEC), enteropathogenic (EPEC), and enteroinvasive (EIEC) strains. In general, people are exposed to diarrheagenic E. coli by consuming contaminated food and water. ETEC is a major cause of infantile diarrhea and traveler's diarrhea. Infantile diarrhea affects infants usually in developing countries, particularly during warm and wet conditions, and traveler's diarrhea affects the immunologically naive tourist under similar conditions. In both cases, a large inoculum is required to cause disease. Major virulence factors of ETEC strains include species-specific fimbriae for enterocyte adherence, as well as heat-stable and heat-labile plasmid-encoded enterotoxins. After a relatively brief incubation period of 1 to 2 days, the infected patient develops a secretory diarrhea that lasts up to 5 days. The cornerstones of management are prevention (through dietary hygiene) and adequate rehydration. Antibiotics use is controversial and usually reserved for moderate to severe disease. EAEC is recognized as a major cause of children's and traveler's diarrhea. Since the initial identification of EAEC in 1985, studies have identified numerous putative virulence factors, including specific aggregative adherence fimbriae. However, no one factor has been identified in all EAEC strains. This suggests that apart

from their aggregative adherence to enterocytes, EAEC strains are probably a heterogeneous collection. However, the clinical disease caused by EAEC is relatively consistent and includes persistent secretory diarrhea with low-grade fever. Management of disease from EAEC requires adequate rehydration; the role of antibiotics remains controversial. The notorious virulence of EHEC (also known as Shiga-like toxin–producing E. coli) has led to frequent media reports of “hamburger disease.” E. coli O157:H7 is the most common strain of EHEC, although several others have been documented. Unlike most other categories of diarrheagenic E. coli, EHEC can cause disease with an infectious dose as low as 10 to 100 organisms. Sequelae of EHEC infection include hemorrhagic diarrhea, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. The primary virulence factor is Shiga-like toxin, which damages ribosomes. The gene for Shiga-like toxin is transmitted between EHEC strains by a bacteriophage vector. A separate virulence plasmid has been identified in certain strains of EHEC, but its significance is uncertain. Management of EHEC disease is supportive, because some evidence suggests that antibiotics can enhance the release of Shiga-like toxin and increase the risk of developing hemolytic-uremic syndrome. EPEC has been associated most strongly with pediatric diarrhea in both epidemic and sporadic forms. EPEC adheres to enterocytes, causing the pathognomic attaching and effacing lesion seen on pathologic section. It then secretes proteins that initiate signal transduction within the enterocyte, ultimately resulting in secretory diarrhea. Because EPEC causes persistent diarrhea that can lead to significant dehydration, rehydration and antibiotic therapy are usually indicated. As its name implies, EIEC invades enterocytes, where it then replicates and spreads to adjacent cells. The resulting diarrhea may be secretory or inflammatory and lasts up to 7 days. EIEC is closely related to Shigella genetically and in the clinical disease that they both cause. As with Shigella, antibiotic treatment reduces duration of symptomatic illness. Shigella Species

The genus Shigella consists of four serovars pathogenic to humans: Shigella sonnei (Group A), Shigella flexneri (Group B), Shigella boydii (Group C), and Shigella dysenteriae (Group D). S. sonnei, the most commonly isolated species, typically causes secretory diarrhea, and the remaining Shigella species cause bacillary dysentery with fever, bloody diarrhea, cramping, and tenesmus. As with the typhoid group of Salmonella, humans are the sole host for Shigella species; however, the low infectious dose required by Shigella species to cause disease is more similar to the nontyphoid Salmonella species. Salmonella Species

For clinical purposes, the genus Salmonella can be divided into two broad groups: typhoid and nontyphoid. The typhoid group, consisting of Salmonella enterica serotypes typhi and paratyphi, causes typhoid (enteric) fever. These organisms exclusively infect human hosts and are transmitted via contaminated food or water. A large inoculum of typhoid group bacteria is required to experimentally produce infection. Some infected persons become chronic carriers who can transmit infection to others, such as the infamous Typhoid Mary. Typhoid fever is endemic in the developing world. The classic presentation of typhoid fever evolves over 3

weeks: a stepwise fever with temperature-pulse dissociation in the first week, abdominal pain and rose spots on the trunk in the second week, and hepatosplenomegaly with intestinal bleeding in the third week. Because these species are only transmitted between human hosts, identification of one case of typhoid fever becomes a public health issue that mandates contact tracing. Possible complications include bacteremia, gastrointestinal bleeding or perforation, cholangitis, pneumonia, and osteomyelitis. The nontyphoid group consists of all Salmonella species except S. enterica serotypes typhi and paratyphi. These species generally incubate in animals and are transmitted to humans through consumption of contaminated food or water; direct human-to-human transmission is exceedingly rare. In contrast to the typhoid group, nontyphoid Salmonella species can cause disease with inocula as low as 10 to 100 colonyforming units (CFU). The disease that results is most often a gastroenteritis with fever, emesis, and diarrhea that can be secretory or inflammatory, lasting up to 7 days. Possible complications include bacteremia, endovascular infection from seeding of atherosclerotic plaques or prosthetic grafts, and Reiter's syndrome Campylobacter Species

Campylobacter species are common bacterial causes of acute infectious diarrhea; Campylobacter jejuni is the major species that causes human disease. Infection is contracted through consumption of contaminated poultry, milk, or water. After an incubation period of 2 to 7 days, the patient develops bloody diarrhea. Campylobacter diarrhea is also notable for its manifold extraintestinal complications, including autoimmune phenomena such as reactive arthritis and Guillain-Barré syndrome. Antibiotic therapy is usually reserved for severe disease or immunocompromised patients, in whom recurrent disease is more frequent. Vibrio cholerae

Vibrio cholerae is the prototype of an enterotoxic bacterium that causes secretory diarrhea. It is almost exclusively a disease of developing countries with poor sanitation. There have been several pandemics in the last century, with the most recent affecting South America and Central America as well the more typical regions in Africa and Asia. The only two serotypes to cause human disease are O1 and O139; serotype O1 is divided into biotypes cholerae and eltor. Cholera toxin affects enterocytes to produce a secretory diarrhea described as rice-water stools. Disease severity ranges from mild to severe with profound dehydration. Rehydration is the cornerstone of treatment, via oral or intravenous routes as dictated by clinical severity. Clostridium difficile

Clostridium difficile has been recognized as one cause of antibiotic-associated diarrhea and the leading cause of pseudomembranous colitis since the late 1970s. C. difficile–associated diarrhea was conventionally thought to only be a health issue for institutionalized patients who have had recent exposure to antibiotics or chemotherapy. In the last 3 years, however, significant expansions in C. difficile–associated diarrhea disease severity and host range have been described by researchers in North America and Europe. Disease severity ranges broadly from asymptomatic colonization to mild diarrhea to fulminant pseudomembranous colitis. Other Bacteria

Several other bacteria are less-common causes of acute infectious diarrhea. They merit some discussion

because of their specific clinical presentations or potential for causing severe disease. Vibrio parahemolyticus

Vibrio parahemolyticus causes gastrointestinal illness associated with consumption of raw or undercooked oysters and other seafood. The spectrum of illness varies widely. Immunocompetent patients usually develop self-limited secretory diarrhea or gastroenteritis with fever lasting from 1 to 3 days, and immunocompromised patients present with severe diarrhea, septicemia, and a profound hemolytic anemia. Staphylococcus aureus

Staphylococcus aureus causes a variety of gastrointestinal illnesses. It is a common cause of enterotoxinmediated foodborne illness, manifesting with emesis, watery diarrhea, and cramping after a brief incubation period of 1 to 6 hours. S. aureus, particularly methicillin-resistant S. aureus (MRSA), is also an uncommon but recognized cause of pseudomembranous colitis. Bacteroides fragilis

Although Bacteroides fragilis is recognized as part of the normal flora of the large intestine, certain strains produce a metalloprotease that has been associated with diarrhea in several studies of human and animal populations. Some studies have suggested that these enterotoxigenic B. fragilis strains may be more likely than nontoxigenic strains to cause blood infections. Clostridium perfringens

Clostridium perfringens is a ubiquitous pathogen that is a common cause of enterotoxin-mediated secretory diarrhea. Its specific enterotoxin (CPE) has been found in all five toxinotypes of C. perfringens. Gastrointestinal disease can result from ingestion of preformed toxin, with a short incubation period before clinical disease, or ingestion of a large bacterial inoculum, requiring a longer incubation before disease. Treatment is usually supportive. PROTOZOA Giardia lamblia

Giardia lamblia is a protozoan pathogen that causes diarrhea that can be chronic and refractory to treatment. The infectious cyst form is ingested in contaminated food or water, and the trophozoite then attaches to the intestinal wall. Giardia has expanded its environmental niche in recent years from the beaver fever endemic to isolated rivers and lakes, becoming a global pathogen. Entamoeba histolytica

Entamoeba histolytica can cause amoebic dysentery, which can manifest as acute, subacute, or chronic diarrhea. Diagnosis of E. histolytica is complicated by the highly similar but nonpathogenic Entamoeba dispar. Other than the rare situation where microscopy of stool detects ingested erythrocytes (pathognomic of E. histolytica), the two species are morphologically identical and can only be distinguished by

methodologies such as serology, antigen detection, or nucleic acid testing. VIRUSES Rotavirus

Rotavirus primarily affects infants and children from 3 to 36 months of age, resulting in a spectrum of disease from asymptomatic shedding to severe gastroenteritis with dehydration. Globally, it is the leading viral cause of severe gastroenteritis. Other groups affected include travelers, the immunocompromised, and patients in hospitals or other institutions. Calicivirus

Norwalk virus is the most well-known member of the calicivirus family. Outbreaks of Norwalk often occur in long-term care facilities, cruise ships, and hospitals. It is highly contagious, with attack rates often greater than 10%. The clinical syndrome of Norwalk infection usually features rapid onset of severe nausea and emesis along with varying degrees of diarrhea. Differential Diagnosis OTHER INFECTIONS Infections that cause diarrhea are not necessarily primarily gastrointestinal ( Box 5 ). Systemic infections that result in diarrhea are probably underrecognized as a distinct etiology; however, the astute clinician should usually be able to recognize a systemic infection after a proper history, physical examination, and appropriate laboratory tests. Bacterial infections such as Group A streptococcosis, legionellosis, leptospirosis, and some tick-borne infections (including borreliosis, ehrlichosis, tularemia, and Rocky Mountain spotted fever) can manifest with diarrhea as an initial symptom. Septicemia, caused by a variety of pathogens such as gram-negative enteric organisms, can also cause diarrhea and other gastrointestinal symptoms. Viremia is another cause of diarrhea; the most common cause is probably influenza, but other viruses including severe acute respiratory syndrome–associated coronavirus (SARS-CoV), hantaviruses, dengue virus (Flavivirus sp.), and hemorrhagic fever viruses should be considered in the presence of correlating exposures. Plasmodium falciparum malaria can result in diarrhea severe enough to mimic bacillary dysentery, and severe diarrhea has been associated with poor outcome. BOX 5

Diseases That Can Mimic Acute Infectious Diarrhea Infectious Etiologies

•

Dengue fever

•

Francisella sp.

•

Hantavirus

•

Legionella sp.

•

Leptospirosis

•

Lyme borreliosis

•

Malaria

•

SARS

Noninfectious Etiologies

•

Antibiotic-associated diarrhea

•

Bacterial overgrowth

•

Brainerd diarrhea (infectious etiology suspected but unproved)

•

Endocrinopathies (e.g., VIPoma)

•

Inflammatory bowel disease

•

Irritable bowel syndrome

•

Other medications

Abbreviations: SARS = severe acute respiratory syndrome; VIP = vasoactive intestinal peptide. OTHER NONINFECTIOUS ETIOLOGIES A variety of noninfectious causes can result in acute diarrhea (see Box 5 ). For instance, diarrhea is a common adverse effect of antimicrobial agents and other medications. The mechanism varies by antibiotic, but common reasons include direct stimulation of gut motility, increased gut osmolality, and disruption of the normal gut flora. Although not strictly an infection, diarrhea is one of the most common symptoms of bacterial overgrowth. This disease occurs after disruption of host mechanisms that normally regulate bacterial intestinal colonization, such as pancreatitis or intestinal dysmotility. Definitive treatment should address the underlying condition, but broad-spectrum antibiotics can result in a long-lasting cure. Brainerd diarrhea was initially described after an outbreak in Brainerd, Minnesota, in 1983. It manifests as an acute secretory diarrhea that can last for several months. Its etiology remains unknown, but several outbreaks have demonstrated epidemiologic links to consumption of unpasteurized milk and undertreated

water. Some endocrinopathies, such as VIPoma, can cause profuse diarrhea. Inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) can manifest with an inflammatory diarrhea and constitutional symptoms. Irritable bowel syndrome can result in periods of diarrhea; however, there are alternating periods of constipation and a lack of constitutional symptoms. Special Cases TRAVELER'S DIARRHEA According to the Centers for Disease Control and Prevention (CDC), 20% to 50% of international travelers develop diarrhea related to their travels. The etiologic agents vary by exposure, geographic region, and local outbreaks. Bacteria are the most commonly implicated pathogens, with ETEC being the most commonly identified cause. Other etiologic agents include the other common bacterial, viral, and protozoal enteric pathogens described earlier. Diarrhea is usually mild to moderate and self-limited; 90% of patients report resolution of symptoms after 1 week, and 98% after 4 weeks. Although it is usually a nuisance rather than a severe threat to health, diarrhea can significantly limit the traveler's activities. Because traveler's diarrhea is self-limited, investigations of the cause are usually reserved for diarrhea that is prolonged or manifests with higher-risk features such as fever or bloody stool. Stool should be examined for ova and parasites (O&P) if the travel history is supportive. The focus for management should be supportive care. People seen for travel medicine advice should be counseled to avoid consuming water or food not known to be safe. The safest diet for travelers consists of freshly prepared foods served thoroughly heated, fruits and vegetables that are peeled or are washed with safe water, and beverages that are bottled or boiled before consumption. Ice and tap water should be considered contaminated. Patients for whom diarrhea could be catastrophic should be advised to avoid traveling unless it is strictly necessary. After the traveler has developed diarrhea, a variety of medications are available for treatment. See the discussion of management of acute infectious diarrhea later in this chapter. IMMUNOCOMPROMISED STATES Gastrointestinal illness is a common problem in immunocompromised patients. Apart from the infectious etiologies of diarrhea described earlier, other causes found in immunocompromised patients include the agent causing the immunocompromised state (such as HIV or chemotherapeutic agents), opportunistic organisms, adverse effects of medications, dysfunction of intestinal absorption, and idiopathic enteropathies. Opportunistic organisms that can cause diarrhea include parasites (e.g., Cryptosporidium parvum, Cyclospora cayetanensis, Isospora belli, microsporidia), fungi (e.g., disseminated fungal infections from Histoplasma capsulatum and Cryptococcus neoformans), bacteria (e.g., Mycobacterium avium-intracellulare complex), and viruses (e.g., cytomegalovirus, herpes simplex virus). In general, treatment requires prolonged courses of antimicrobial agents and can be complicated by concomitant medications or diseases;

consultation with an appropriate specialist is suggested. Prevention Methods of prevention are listed in Box 6 . BOX 6 Prevention of Acute Infectious Diarrhea •

Avoidance

•

Hygiene

•

Prophylactic antibiotics

•

Probiotics

•

Vaccines •

Cholera/ETEC (Dukoral)[2]

•

Rotavirus (RotaTeq)

•

Salmonella typhi (Vivotif Berna, Typhim Vi)

Abbreviation: ETEC = enterotoxigenic Escherichia coli. 2 Not available in the United States.

AVOIDANCE

An effective method for preventing acute infectious diarrhea is to eliminate exposures that put one at risk. This applies particularly to patients who would be at high risk for contracting acute infectious diarrhea or having adverse outcomes, for example, patients who are immunocompromised or physically debilitated. Exposure avoidance is usually situational and patient-specific, such as suggesting that travel be postponed to a region currently undergoing a cholera epidemic or cautioning against consumption of raw seafood. HYGIENE

Proper handwashing by health care workers caring for patients with acute diarrhea is essential to prevent institutional transmission, and its importance cannot be overstated. Barrier precautions are also commonly implemented, particularly if the patient is incontinent of stool. Other precautions, such as tailoring environmental cleaning practices to specific pathogens during outbreaks, are also proven effective. PROPHYLACTIC ANTIBIOTICS

There is a limited role for antibiotics in preventing acute infectious diarrhea, particularly traveler's diarrhea. The normally mild severity and self-limited nature of the disease, along with the risk of adverse effects from antibiotics, means that prophylactic antibiotics are most often reserved for brief durations in patients at high

risk for contracting acute infectious diarrhea or for experiencing adverse outcomes. PROBIOTICS

There has been a surge of publications concerning the role of probiotics in preventing diarrhea of varying etiologies. Although individual studies have produced varied results for diarrhea caused by C. difficile–associated diarrhea and traveler's diarrhea, a recent meta-analysis of 34 studies supported a role for probiotics in preventing diarrhea, with an overall risk reduction of at least 21%. Stratification by type of diarrhea found a much larger reduction in antibiotic-associated (52%) than traveler's (8%) diarrhea. Protective effects seemed relatively conserved despite different probiotic organisms being used, which might imply a common protective mechanism shared between organisms or a common host response. The variety of probiotic organisms and dosing regimens described in the literature has not yet led to a standardized formulation.

CURRENT DIAGNOSIS History

Duration and frequency of diarrhea Other gastrointestinal symptoms (emesis, tenesmus, abdominal pain) Presence of bloody stool, fever Medication use, including recent antibiotic use Recent contact with ill persons, travel, and animal contact Consumption of raw or undercooked poultry or seafood Immunocompromised state (rule out) Physical Examination

Hydration status Gastrointestinal examination Other systems as indicated by symptoms Laboratory Tests

For limited secretory diarrhea: usually none For bloody diarrhea: complete blood count (CBC), stool for culture (rule out O157:H7); consider ova and parasites test (O&P) For chronic diarrhea: consider C. difficile assay, O&P For traveler's diarrhea: CBC, stool for culture and O&P For immunocompromised patients: CBC, stool for culture and O&P

VACCINES Rotavirus

A live human-bovine reassortant rotavirus oral vaccine (RotaTeq) has been licensed since February 2006 in the United States for infants 6 to 32 weeks of age. The vaccine appears efficacious in preventing rotaviral gastroenteritis, and consequently it reduces the need for outpatient and inpatient assessment. A large phase III trial demonstrated no increased risk over placebo of intussusception, an adverse effect that led to the withdrawal of a previous rotavirus vaccine. Vibrio Cholerae and ETEC

An oral inactivated cholera vaccine (Dukoral), available in Canada but not in the United States, has demonstrated some efficacy in preventing traveler's diarrhea. The B subunit of V. cholerae toxin used in this vaccine has sufficient structural homology with ETEC heat-labile toxin to provide moderate short-term protection against this common cause of traveler's diarrhea, lasting up to 3 months. This vaccine is limited to patients with high-risk medical conditions, such as immunodeficiencies. Salmonella typhi

Enteral and parenteral vaccines are available to prevent typhoid. The enteral form (Vivotif Berna) is a live attenuated strain of S. typhi, which is taken as four capsules over 7 days and confers immunity for approximately 5 years. The parenteral form (Typhim Vi) is purified capsular polysaccharide that is given as a single intramuscular injection. This is the preferred route for patients with contraindications to live attenuated vaccines, such as immunocompromised status. Neither vaccine is completely protective, and neither provides protection against S. paratyphi. Treatment Management of acute infectious diarrhea is listed in Box 7 . BOX 7

Management of Acute Infectious Diarrhea Rehydration

•

•

Enteral •

World Health Organization formulation

•

Commercially available rehydration solutions

•

Home remedies

Parenteral •

Intravenous

•

Intraosseus

•

Enteroclysis

Medications

•

Antidiarrheals •

Bismuth subsalicylate

•

Morphine derivatives

•

Antibiotics

•

Probiotics

REHYDRATION Maintaining adequate hydration is usually the cornerstone of management for acute diarrhea. The route of administration depends on the patient's hydration status and disease severity; enteral hydration is preferred to parenteral, if possible.

CURRENT THERAPY Supportive care Rehydration (always replace previous losses and provide maintenance) Enteral Parenteral (intravenous, intraosseus, enteroclytic) Antidiarrheal medications (only if patient is afebrile and stools are not bloody) Morphine derivatives Bismuth subsalicylate (Pepto-Bismol) Antibiotics (only if necessary as indicated by symptoms, severity, and risk factors) Empiric therapy Adults Ciprofloxacin (Cipro) 500 mg PO bid for 3-5 d Levofloxacin (Levaquin)[1] 500 mg PO qd for 3-5 d Children Azithromycin (Zithromax) [1] 5-10 mg/kg PO qd for 3-5 d Trimethoprim-sulfamethoxazole (Septra) 5-25 mg/kg/d PO in two equally divided doses for 3-5 d plus Erythromycin 10 mg/kg/d PO qid for 5 d Specific therapy as directed by pathogen identification and susceptibilities Probiotics 1 Not FDA approved for this indication.

In 2003 the WHO reformulated their well-known oral rehydration solution (ORS). The new lower-osmolarity formula has been found to reduce stool volume, emesis, and the need for switching to intravenous therapy in children with diarrhea. This new formulation has 75 mmol/L sodium, 75 mmol/L glucose, and a total osmolarity 245 mOsm/L, which can be achieved with a recipe of 2.6 g sodium chloride, 13.5 g anhydrous glucose, 1.5 g potassium chloride, 2.5 g sodium bicarbonate and 1.5 g trisodium citrate dihydrate per liter of water. A homemade solution can be prepared with 40 mL sugar and 5 mL table salt per liter of clean water; however, this preparation lacks potassium. Furthermore, commercially prepared rehydration solutions should be preferred to homemade in order to minimize the chance of errors in preparing the solution. Most sports drinks are not equivalent to actual rehydration solutions, because sports drinks often have higher carbohydrate and lower electrolyte loads. Parenteral rehydration is usually intravenous, although intraosseus administration can be used for infants in

whom intravenous access cannot be obtained and enteroclysis can be used in adult patients with difficult vascular access who do not require large volumes of replacement fluid. Sufficient volumes of fluid should be given to replace preexisting fluid deficits as well as ongoing losses and maintenance requirements. ANTIDIARRHEAL MEDICATIONS Some medications reduce intestinal motility by affecting the myenteric motor plexus to inhibit peristalsis. Opioid derivatives, such as loperamide (Imodium), are the class of medications most commonly used for this purpose. Although licensed for use with acute, chronic, and traveler's diarrhea, loperamide is contraindicated in the presence of fever or bloody stool or in situations where inhibition of peristalsis is otherwise undesirable or potentially harmful. Other medications are classified as antidiarrheal but have different mechanisms of action. Bismuth subsalicylate (Pepto-Bismol) appears to function by multiple mechanisms including intestinal secretion reduction, intestinal reabsorption of fluids and electrolytes, toxin binding, and direct antimicrobial effects. It has proven efficacy in the management of traveler's diarrhea, although its dosing frequency may be difficult for some patients. Racecadotril (or acetorphan) [2] is a new synthetic enkephalinase inhibitor that acts by the same mechanism as the opioid derivatives and has been studied for its antidiarrheal effect in pediatric patients. ANTIBIOTICS Antibiotics should be used cautiously in the treatment of acute infectious diarrhea. Most clinical cases adequately resolve without antibiotic therapy. Furthermore, their use can sometimes cause diarrhea (such as antibiotic-associated diarrhea or C. difficile–associated diarrhea), and indiscriminate use can contribute to selective pressures that favor development of antibiotic-resistant organisms. Recommendations in the empiric and pathogen-specific treatment of acute infectious diarrhea are given in Tables 1 and 2 [1] [2].

TABLE 1 -- Empiric Therapy of Diarrheal Disease Clinical Syndrome Adult Patients Febrile dysenteric diarrhea in industrialized regions, or moderate to severe traveler's diarrhea

Pediatric Patients

Ciprofloxacin (Cipro) 500 mg PO bid or levofloxacin (Levaquin)[1] 500 mg PO qd for 3-5 d

Azithromycin (Zithromax) [1] 5-10 mg/kg PO qd for 3-5 d or trimethoprim-sulfamethoxazole (Septra) 525 mg/kg/d PO in two divided doses for 3-5 d plus erythromycin[1] 10 mg/kg PO qid for 5 d

Persistent diarrhea (=14 d in Consider anti-Giardia duration) in industrialized therapy: metronidazole countries (Flagyl)[1] 250 mg PO tid for 7d

Consider anti-Giardia therapy: metronidazole (Flagyl)[1] 20 mg/kg/d PO in three divided doses for 7d

Adapted from Montes M, DuPont HL: Enteritis, enterocolitis and infectious diarrhea syndromes. In Cohen J, Powderly WD: Infectious Diseases, 2nd ed. St Louis: Mosby, 2004, pp 477-489.

TABLE 2 -- Pathogen-Specific Therapy of Diarrheal Disease

Pathogen

Adult Patients

Campylobacter jejuni

Azithromycin (Zithromax) [1] 500 mg PO qd for Erythromycin stearate[1] 40 mg/kg/d in four 3d divided doses for 5 d or azithromycin[1] 10 mg/kg/d

Clostridium difficile

Initial disease: metronidazole (Flagyl) 250 mg Initial disease: metronidazole 20 mg/kg/d in PO qid for 10-14 d or vancomycin (Vancocin) three divided doses for 10-14 d or 125-500 mg PO qid for 10-14 d vancomycin 125-500 mg PO qid for 10-14 d

EAEC, EIEC, EPEC, ETEC

Same as empiric therapy for febrile dysentery Azithromycin[1] 10 mg/kg/d. and traveler's diarrhea (see Table 1 ) If resistance is suspected, use ceftriaxone (Rocephin),[1] cefixime (Suprax),[1] or cefotaxime (Claforan)[1]

EHEC[*]

No antimicrobial therapy (increased risk of increasing toxin release and hemolyticuremic syndrome)

No antimicrobial therapy (increased risk of increasing toxin release and hemolyticuremic syndrome)

Entamoeba histolytica

Metronidazole 500 mg PO tid for 10 d or tinidazole (Tindamax) 1 g PO bid for 3 d

Metronidazole 50 mg/kg/d IV in three divided doses plus diiodohydroxyquin (Yodoxin) 40 mg/kg/d in three divided doses for 20 d

Follow with paromomycin (Humatin) 500 mg PO tid for 7 d

Pediatric Patients

Giardia lamblia

Metronidazole[1] 250 mg PO tid for 7 d or Metronidazole[1] 20 mg/kg/d in three divided albendazole (Albenza)[1] 400 mg PO qd for 5 doses for 7 d or furazolidone (Furoxone) 6 d or tinidazole 2 g PO in one dose mg/kg/d divided in four doses for 7 d

Shigella sp.

Ciprofloxacin (Cipro) 500 mg PO bid for 3-5 d Azithromycin[1] 10 mg/kg/d If resistance is or levofloxacin (Levaquin)[1] 500 mg PO qd suspected, use ceftriaxone,[1] cefixime,[1] or for 3-5 d cefotaxime[1]

Salmonella sp. non-typhoid group

Asymptomatic or mild: no antimicrobial therapy At risk for complications: ciprofloxacin[1] 500 mg PO bid or levofloxacin [1] 500 mg PO qd for 5-7 d Alternatives: azithromycin[1] or erythromycin stearate (Erythrocin stearate)[1] 500 mg PO bid for 5 d

=6 mo old: ceftriaxone[1] 50 mg/kg IV qd >6 mo old and healthy, and asymptomatic or with mild illness: no antimicrobial therapy

At risk for complications: ceftriaxone[1] 50 mg/kg IV qd (not to exceed 2 g/d)

typhoid group

Ciprofloxacin (Cipro) 500 mg PO bid for 7-10 Ceftriaxone 75-100 mg/kg IVq24h for 14 d d or levofloxacin (Levaquin)[1] 500 mg PO OD (not to exceed 4 g/d) or azithromycin 20 for 7-10 d or ceftriaxone 2 g IV q 24h for 14 d mg/kg PO OD for 5-7 d (not to exceed 1 g/d)

Vibrio cholerae

Doxycycline 300 mg PO for one dose or ciprofloxacin[1] 1 g PO for one dose

TMP-SMX (Septra)[1] 1 DS tab PO bid for 3 d or azithromycin[1] 20 mg/kg PO for one dose (not to exceed 1 g)

Adapted from Montes M, DuPont HL: Enteritis, enterocolitis and infectious diarrhea syndromes. In Cohen J, Powderly WD: Infectious Diseases, 2nd ed. St Louis: Mosby, 2004, pp 477-489.

Pathogen

Adult Patients

Pediatric Patients

Recurrent disease can require prolonged courses of antibiotics or adjunctive therapy (e.g., IVIG,[1] resins[1]) Adapted from Montes M, DuPont HL: Enteritis, enterocolitis and infectious diarrhea syndromes. In Cohen J, Powderly WD: Infectious Diseases, 2nd ed. St Louis: Mosby, 2004, pp 477-489. Abbreviations: DS = double strength; EAEC = enteroaggregative E. coli; EHEC = enterohemorrhagic E. coli; EIEC = enteroinvasive E. coli. EPEC = enteropathogenic E. coli; ETEC = enterotoxigenic E. coli; IVIG = intravenous immunoglobulin; TMP-SMX = trimethoprim-sulfamethoxazole.

1 Not FDA approved for this indication. 2 Not available in the United States. * Shiga toxin and Shiga-like toxin–producing E. coli.

PROBIOTICS As with the prevention of diarrhea, a growing body of evidence supports the use of probiotics for treating acute infectious diarrhea. One of the major limitations to using probiotics is the variation in species and doses used in different clinical trials. However, there seems to be a class effect that is most likely a combination of competition for intestinal binding sites or nutritional resources, elaboration of antibacterial compounds, and immune stimulation. Another recognized limitation is the rare but serious case of blood infection from the probiotic organism; documented cases have occurred not only in recipients but also in other patients being cared for in close proximity to the recipient.



REFERENCES Aranda-Michel and Giannella, 1999. Aranda-Michel J, Giannella RA: Acute diarrhea: A practical review. Am J Med 1999; 106:670-676. DuPont, 2005. DuPont HL: What's new in enteric infectious diseases at home and abroad. Curr Opin Infect Dis 2005; 18:407-412. Dupont and the Practice Parameters Committee of the American College of Gastroenterology, 1997. Dupont HL, the Practice Parameters Committee of the American College of Gastroenterology : Guidelines on acute infectious diarrhea in adults. Am J Gastroenterol 1997; 92(11):1962-1975. Guerrant et al., 2001. Guerrant RL, Van Gilder T, Stiner TS, et al: Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001; 32:331-350. Hahn et al., 2001. Hahn S, Kim Y, Garner P: Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhea in children: Systematic review. Br Med J 2001; 323:81-85. Helton and Rolson, 2004. Helton T, Rolson DD: Which adults with acute diarrhea should be evaluated?. What is the best diagnostic approach?. Cleve Clin J Med 2004; 71(10):778-785. Musher and Musher, 2004. Musher DM, Musher BL: Contagious acute gastrointestinal infections. N Engl J Med 2004; 351(23):2417-2427. Reisinger et al., 2005. Reisinger EC, Fritzsche C, Krause R, Krejs GJ: Diarrhea caused by primarily nongastrointestinal infections. Nat Clin Practice Gastroenterol Hepatol 2005; 2(5):216-222. Sazawal et al., 2006. Sazawal S, Hiremath G, Dhingra U, et al: Efficacy of probiotics in prevention of acute diarrhoea: A meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis 2006; 6:374-382. Thielman and Guerrant, 2004. Thielman NM, Guerrant RL: Acute infectious diarrhea. N Engl J Med 2004; 350:38-47. World Health Organization. World Health Organization : Oral rehydration salts: Production of the new ORS. 2006. (accessed April 5, 2007). PDF available at http://www.who.int/child-adolescenthealth/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_06.1.pdf



Chapter 6 – Constipation

Method of: Warren P. Bishop, MD Constipation is not as easily defined as one might imagine. Patients may report being constipated in response to several different symptoms. Decreased defecation frequency is perhaps the most common symptom. What is normal bowel frequency? This varies throughout life. In infants who are exclusively breast-fed, initial bowel frequency can be more than 10 stools per day. After several weeks of age, breast-fed infants can produce less than one stool per week without any evident distress or distention. In bottle-fed infants and throughout childhood, one or two stools per day is typical. Stool frequency remains stable throughout most of adult life, varying between one stool every 3 days and three stools per day. Fewer than three stools per week is considered to be abnormal in adults, as defined by the Rome II Committee on Functional Gastrointestinal Disorders in 1999. Other criteria for constipation defined by this committee are listed in Box 1 . At least two of the listed criteria must be met to make the diagnosis. BOX 1 Diagnostic Criteria for Constipation At least 12 wk, which need not be consecutive, in the preceding 12 mo of two or more of: •

Straining in >1 of 4 defecations

•

Lumpy or hard stools in >1 of 4 defecations

•

Sensation of incomplete evacuation in >1 of 4 defecations

•

Sensation of anorectal obstruction or blockage in >1 of 4 defecations

•

Manual maneuvers to facilitate >1 of 4 defecations (e.g., digital evacuation, support of the pelvic floor) plus

•

Fewer than three defecations per wk

•

Loose stools are not present, and there are insufficient criteria for diagnosis of irritable bowel syndrome

Etiology and Physiology The major physiologic causes of constipation include slow colonic transit and blocked defecation. The first requirement for normal defecation is normal colonic motility, or transit. Slow colonic transit can be caused by many factors, such as neuromuscular disorders, hypothyroidism, diabetes mellitus, conditions obstructing

the colon, and medications ( Box 2 ). The act of defecation itself is a complex process requiring normal rectal sensation, reflex relaxation of the internal anal sphincter, voluntary relaxation of the external sphincter, and contraction of pelvic floor muscles. Interference with this sequence of events leads to obstructed defecation. Many interacting factors can contribute, including poor-quality diet, physical inactivity, low calorie intake, poor social situation, cultural taboos, fear of painful stools (especially in young children), sexual abuse, medications, and physical ailments that reduce muscle strength, reduce CNS control, or block the anal canal. BOX 2 Causes of Slow Colonic Transit Functional

•

Irritable bowel syndrome

Endocrine or Metabolic

•

Anticholinergics

•

Antipsychotics

•

Diabetes mellitus

•

Hypercalcemia

•

Hypokalemia, hypomagesemia

•

Hypothyroidism

•

Renal failure

Medications

•

Aluminum antacids

•

Antidiarrheal agents

•

Antiparkinson drugs

•

Calcium channel blockers

•

Cholestyramine (Questran)

•

Diuretics

•

Opiates

•

Tricyclic antidepressants

Neuromuscular

•

Amyloidosis

•

Botulism

•

Chagas' disease

•

Dysautonomia

•

Hirschsprung's disease

•

Pseudo-obstruction

•

Sarcoidosis

Obstructive

•

Colon cancer

•

External compression

•

Strictures

Blocked defecation in children is most commonly the result of voluntarily withholding stool. This usually occurs during toilet training, and the resultant large, hard stools cause pain and continued fecal withholding. Congenital anorectal anomalies typically result in blocked defecation in infants. In older persons, cancers, sigmoid and rectal intussusception, solitary rectal ulcer syndrome, poor pelvic floor function, and pregnancy may be responsible ( Box 3 ). BOX 3 Causes of Blocked Defecation Congenital (Infants)

•

Anal stenosis

•

Anteriorly displaced anus

•

Hirschsprung's disease

•

Imperforate anus

•

Spinal cord dysraphism

Acquired Structural Conditions

•

Pregnancy

•

Rectocele

•

Sigmoid or rectal intussusception

•

Solitary rectal ulcer syndrome

•

Strictures

Functional

•

Anal fissure or painful defecation

•

Pelvic floor dysfunction

•

Voluntary stool withholding (functional fecal retention)

Evaluation After a careful history of the onset, characteristics, and associated symptoms of constipation (see Box 1 ), the physical examination must include careful evaluation of the abdomen. Care should be taken not to mistake abdominal or pelvic tumors for fecal masses. Rectal examination must be performed in all cases. The rectal evaluation should include documenting perianal lesions, tenderness, anal stenosis, pelvic mass lesions, perineal descent when bearing down, strength of external sphincter and perineal ascent during voluntary clenching, the force of expulsion when asked to expel the examiner's finger, evidence of fecal soiling, and the presence or absence of rectal dilation. History of difficult defecation with excessive straining, sensation of incomplete emptying, or use of manual assistance will serve to differentiate blocked defecation from slow colonic transit. Patients with these symptoms can benefit from further evaluation by a gastroenterologist, who might consider further diagnostic testing such as anorectal manometry, colonic motility studies, or defecography. Patients with suspected slow transit constipation can be further evaluated by selective use of colonic transit studies (using radiopaque markers or scintiscan) or barium enema, or both. Most patients with constipation do not require specialized studies and can be treated empirically as outlined next.

CURRENT DIAGNOSIS Constipation can be defined in several ways. Stools that are hard, infrequent, or pebbly are common symptoms. Other criteria include excessive straining, need for manual assistance during defecation, or a sensation of incomplete emptying. History must include the symptoms listed above, painful defecation, rectal bleeding, fecal soiling, and a detailed history of laxatives used. The presence of abdominal pain relieved by defecation suggests irritable bowel syndrome. Rectal examination must always be performed to evaluate for obstruction, inflammation, and function of pelvic floor and sphincter muscles. Etiologic categories include blocked defecation (physical obstruction, voluntary retention due to pain or fear of defecation, anismus), slow-transit constipation, and irritable bowel syndrome with constipation. Treatment EDUCATION Patients need to understand the physiology of defecation, including the importance of using the toilet in response to the urge to defecate and toilet-sitting immediately on awakening and after meals, times when

propulsive colonic activity is most likely. The mechanism of action, safety, and precautions of all prescribed drugs should be discussed. Patients are often unduly afraid that even nonabsorbable osmotics like polyethylene glycol (e.g., MiraLax) may be habitforming, and thus deny themselves adequate therapy.

CURRENT THERAPY Increased fiber should be taken orally, generally given as a twice-daily fiber supplement. A saline or osmotic laxative, such as milk of magnesia or polyethylene glycol (MiraLax or GlycoLax), should be used if fiber alone is not sufficient. Saline laxatives containing phosphate carry a risk of electrolyte disturbance and should be used with caution. Fermentable osmotic agents, such as sorbitol and lactulose, can cause cramping, flatulence, and perianal skin irritation. Stimulant laxatives such as bisacodyl and senna derivatives are of questionable safety for long-term use, but they are reasonable for acute relief. MEDICAL THERAPY If a fecal impaction is present on rectal examination, it should be evacuated immediately before beginning maintenance therapy. Enemas should be used only when absolutely necessary and with caution; complications have occurred, especially with repeated administration or poor expulsion of the solution. Potential complications include intestinal perforation, hyperphosphatemia, hypocalcemia, hypovolemic shock, and sepsis. Oral polyethylene glycol solutions (MiraLax, GlycoLax, GoLYTELY[1], CoLyte[1]), taken over several days, are gentle and effective disimpaction agents. After disimpaction for adult patients, most authorities recommend beginning maintenance therapy with fiber supplements, some of which are listed in Table 1 . Often, fiber alone is simply not adequate. Milk of magnesia is a relatively inexpensive next step and works well for most adult patients, but palatability limits its use in children. Electrolyte-free polyethylene glycol with an average molecular weight of 3350 (e.g., MiraLax, GlycoLax) is now the standard laxative therapy in many centers, especially for children, due to its excellent efficacy, safety, and palatability. The average effective pediatric dose is around 0.8 g/kg/day. It is generally mixed at a hypotonic strength of around 2 g/30 mL, which allows some water absorption while also increasing fecal water content. Adult dosing has been variously reported between 17 and 68 g/day.

TABLE 1 -- Fiber Therapy Products Fiber Type Brand Name Fiber Content Bran

All Bran

10.4 g per ½ cup

Psyllium

Metamucil

3.4 g/Tbs

Konsyl

6 g/tsp

Citrucel

2 g/Tbs

Methycellulose

Fiber Type

Brand Name Fiber Content

Calcium polycarbophil FiberCon

1 g/2 tabs

Guar gum

3 g/Tbs

Benefiber

Abbreviations: tabs = tablets; Tbs = tablespoon (5 mL); tsp = teaspoon (15 mL).

For all patients, response to the chosen initial dose should be evaluated and then adjustments made as appropriate. Phosphate-based laxatives and nonabsorbable disaccharides are less desirable because of potential side effects and poor palatability. Stimulants such as bisacodyl (Dulcolax) or senna (Senokot) can be very effective for occasional use to treat exacerbations or as part of a disimpaction regimen. Chronic use of these agents should be limited to patients unresponsive to adequate doses of osmotic laxatives such as polyethylene glycol. Medical therapies for constipation are summarized in Table 2 .

TABLE 2 -- Medical Treatment of Constipation Type

Example

Usual Dose

Fermentable osmotic agents

Lactulose, sorbitol

15-30 mL bid

Fiber supplements

See Table 1

Start 2-3 g bid, increase for effect

Lubricant

Mineral oil

Usual dose: 15-45 mL qd-bid

Nonfermentable osmotic agent PEG 3350 (MiraLax)

Adult 17-68 g/d[*] Child 0.5-1.5 g/d[*]

Saline laxatives

Milk of magnesia

Adult: 15-30 mL bid Child: 2-4 mL/kg/d

Stimulants

Bisacodyl (Dulcolax)

One 10-mg suppository up to 3 × per wk

Surfactant stool softener

Docusate sodium (Colace) 100 mg bid

Abbreviation: PEG = polyethylene glycol.

* Start with lower dose and adjust for effect.

1 Not FDA approved for this indication.

SURGICAL THERAPY Very few cases of constipation merit consideration of surgery. Obvious candidates are patients with congenital anorectal malformations, strictures, or cancer. Cecostomy for antegrade enemas is helpful in spinal cord injury and meningomyelocele patients, who cannot provide the voluntary muscle contractions required for efficient defecation. Colectomy is reserved for the most severe cases of colonic inertia

unresponsive to maximum medical management. Placement of a stoma is a reversible action that can benefit some patients with distal colonic dysmotility.



REFERENCES DiPalma et al., 2000. DiPalma JA, DeRidder PH, Orlando RC, et al: A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000; 95:446-450. Heaton et al., 1992. Heaton KW, Radvan J, Cripps H, et al: Defecation frequency and timing, and stool form in the general population: A prospective study. Gut 1992; 33:818-824. Mollen et al., 1997. Mollen RM, Claassen At, Kuijpers JH: The evaluation and treatment of functional constipation. Scand J Gastroenterol 1997; 223:8-17. Pashankar and Bishop, 2001. Pashankar DS, Bishop WP: Efficacy and optimal dose of daily polyethylene glycol 3350 for treatment of constipation and encopresis in children. J Pediatr 2001; 139:428-432. Sandler et al., 1990. Sandler RS, Jordan MC, Shelton BJ: Demographic and dietary determinants of constipation in the U.S. population. Am J Pub Health 1990; 80:185-189. Smith, 1973. Smith B: Pathologic changes in the colon produced by anthraquinone laxatives. Dis Colon Rectum 1973; 16:455-458. Thompson et al., 1999. Thompson WG, Longstreth GF, Drossman DA, et al: Functional bowel disorders and functional abdominal pain. Gut 1999; 45(suppl 2):II43-II47.



Chapter 7 – Fever

Method of: Ian M. Paul, MD, MSc Fever is both sign and symptom of an underlying disease process that often produces anxiety for patients, parents, and health care providers. This so-called fever phobia can cause inappropriate management of the illness and fever. Fever is typically a transient phenomenon that only requires treatment when it is accompanied by discomfort or otherwise compromises a patient's health. Definitions Fever is characterized by an elevated core body temperature that occurs as a protective response to a pathogen. Observations by Wunderlich in 1868 defined normal body temperature at 37°C (98.6°F) and febrile temperature at 38°C (100°F) or higher. Studies also show diurnal variation and differences in temperature based on temperature site (mouth, rectum, ear, or temporal artery), but most clinicians classify a temperature of 38°C (100.4°F) or greater as fever.

CURRENT DIAGNOSIS Temperatures taken by oral, rectal, tympanic, or temporal artery thermometers of 38.0°C (100.4°F) or more are consistent with fever. Fever is a normal physiologic response but can cause dehydration and increase metabolic rate. Benign febrile seizures can occur in young children with fevers. The other symptoms accompanying a fever help determine the severity of the febrile illness. Fever in infants younger than 3 months or in neutropenic patients is considered a medical emergency until proved otherwise. Fevers lasting 8 or more days without a clear cause are considered a fever of unknown origin (FUO). They may warrant more extensive evaluation. Many clinicians, patients, and parents also use the term high fever, although this is not based on consistent objective criteria. Nonetheless, a temperature of 40°C (104°F) or greater is considered by many to be a high fever because nearly universally, patients are uncomfortable when experiencing a body temperature of this magnitude. Some worry that without treatment body temperature continues to rise during fever. This fear is unjustified, however, because only rarely do temperatures exceed 41.1°C (106°F), the temperature considered to be the physiologic limit of the febrile response. If a temperature recorded is greater than 41.1°C (106°F), superimposed hyperthermia is probable. Hyperthermia is distinguished from fever and characterized by a temperature above the hypothalamic set point. This is related to a hypothalamic insult or a disruption in normal homeostatic mechanisms that balance heat production and dissipation.

Two other definitions related to fever are fever without a source and fever of unknown origin (FUO). Both terms are used when no cause is determined for the fever and/or its associated illness. The majority of cases in both have infectious etiologies; the difference relates to duration of the fever. Fever without a source is used in the first week of an illness, whereas FUO is used for a fever lasting 8 or more days or occurring at intervals over weeks or months. Physiology and Pathophysiology Fever begins with an inciting stimulus that triggers an inflammatory response. Most often this stimulus is infectious and causes leukocytes to release cytokines including interleukin-1ß, tumor necrosis factor-a, interleukin-6, and interferon- . These and other cytokines interact with the temperature regulatory tissues in the anterior hypothalamus and release prostaglandin E2 (PGE2). PGE2 then alters the firing rate of neurons in the preoptic area of the anterior hypothalamus, increasing the thermoregulatory set point. Other systems respond to increase body temperature as this set point rises. Examples of these responses include shivering to increase heat production and peripheral vasoconstriction to reduce heat loss. Behavioral responses such as wearing warm clothes or covering up with a blanket may also occur. The febrile response to an antigenic challenge is a beneficial one. Numerous studies show improved outcomes in those who manifest proper febrile responses and that many components of the immune system function better at higher temperatures (e.g., enhanced neutrophil migration, increased T-cell proliferation, and production of interferon). Clinical studies supporting this concept show treatment with acetaminophen prolonged the duration of active varicella in children, and aspirin therapy prolonged the shedding of rhinovirus in adults. Fever Phobia and the Complications of Fever Fever phobia, the fear surrounding fever, termed by Dr. Barton Schmitt, has been recognized for several decades. Schmitt found some startling results when questioning parents about fever. His study shows that 56% of parents gave antipyretics for temperatures less than 37.8°C (100°F), and 58% thought temperatures less than 38.9°C (102°F) constituted a “high fever.” Further, 62% thought fever caused permanent harm, with “brain damage” a common concern. In 2001, a similar study found equally troubling results. These authors found that 85% of parents woke their child to give antipyretics, 52% checked their child's temperature every hour or less, and most worrisome, 58% gave antipyretics too often. Fever is the normal physiologic process previously described. Complications are rare and usually well tolerated. Common adverse events are dehydration and, in children 6 months to 6 years of age, benign febrile seizures, which are a common occurrence in young children without subsequent focal findings. The belief that seizures are caused by a rapid rise in temperature has been contradicted. In addition, no evidence suggests that aggressive use of antipyretics prevents a febrile seizure. Fever is generally a protective physiologic response, but under some circumstances, it is harmful. For example, the metabolic rate steadily increases as body temperature rises. Further, myocardial depression, orthostatic dysfunction, and increases in oxygen consumption, respiratory minute volume, and respiratory

quotient may not be tolerated by patients, especially those with chronic conditions. Severe complications such as death or so-called brain damage occurring during febrile illness are related to the underlying disease process, not fever. Treatment of Fever It is important to overcome the desire to focus on a thermometer's reading when treating a fever by evaluating and treating the underlying illness and treating the discomfort associated with the febrile illness. The underlying condition may be age or disease specific. For example, infants younger than 3 months and neutropenic patients with fever are considered medical emergencies and require aggressive evaluation. Fever in the absence of a condition like one of these requires treatment only when accompanied by discomfort or other morbidity.

CURRENT THERAPY Treat the underlying illness and the discomfort associated with the febrile illness, not the number on the thermometer. If antipyretic/analgesic medications are used, appropriate choices for children are: Acetaminophen (Tylenol) 15 mg/kg every 4 to 6 h up to five times per d as needed for children older than 3 mo. Ibuprofen (Motrin, Advil) 10 mg/kg every 6 h as needed for children older than 6 mo. If antipyretic/analgesic medications are used, appropriate choices for adolescents and adults are: Acetaminophen (Tylenol), 650 to 1000 mg every 4 to 6 h as needed (maximum 4000 mg per d). Ibuprofen (Motrin, Advil), 200 to 400 mg every 6 h as needed. Aspirin, 325 to 650 mg every 6 h as needed. Sponge bathing, if chosen, should use tepid water with an antipyretic medication and no alcohol. ACETAMINOPHEN Acetaminophen (Tylenol) is the most commonly used medication to treat fever. This drug is well absorbed from oral and rectal routes and widely available in liquid and tablet preparations around the world. Acetaminophen produces its antipyretic effect by inhibiting the release of PGE2 yet does not possess the anti-inflammatory properties of nonsteroidal anti-inflammatory agents. Children at least 3 months or older may be given acetaminophen at a dose of 15 mg/kg every 4 to 6 hours up to a maximum of 75 mg/kg per day. Remember that children less than 3 months of age require evaluation when presenting with fever, and acetaminophen should be used with caution so as not to miss a serious bacterial infection. Doses of 650 to 1000 mg every 4 to 6 hours with a maximum daily dose of 4000 mg may be given to adolescents and adults. An extended-release preparation of 1300 mg maximum every 8 hours is also available for adolescents and adults. IBUPROFEN

Ibuprofen (Motrin, Advil) is a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic and antiinflammatory properties in addition to its antipyretic effects. This drug is highly effective and generally well tolerated with short-term administration when given orally. Ibuprofen's antipyretic mechanism of action blocks prostaglandin synthesis through inhibition of cyclooxygenase. This converts arachidonic acid to cyclic endoperoxides. Ibuprofen may be given to febrile children 6 months or older at a dose of 10 mg/kg every 6 to 8 hours. This dose has similar efficacy to that of acetaminophen. Adolescents and adults may take doses of 200 to 400 mg every 6 hours as needed. ASPIRIN Aspirin (acetylsalicylic acid) is used less than it was in recent years. This drug was the standard treatment of fever for many years but is no longer used with children because of an association with Reye's syndrome. It has anti-inflammatory, analgesic, and antipyretic properties similar to ibuprofen and remains an effective treatment for adults. Adults may be given doses of 325 to 650 mg every 4 to 6 hours as needed. Bleeding commonly occurs with aspirin therapy because of its antiplatelet effect (e.g., in the gastrointestinal tract). MEDICATION COMBINATIONS Combinations or alternating regimens of antipyretics should be used with caution, although studies show that aspirin and acetaminophen combinations are more effective. The American Academy of Pediatrics (AAP) cautions against using multiple antipyretics because of an increase in the likelihood of dosing errors. The AAP also cites a lack of evidence to support the joint use of acetaminophen with ibuprofen. NONPHARMACOLOGIC TREATMENT External cooling, most commonly sponge bathing, is used to reduce fever. Some have advised against its use because it can cause discomfort. Discomfort is less likely to occur during sponging when using tepid water and antipyretic administration, but the efficacy of this treatment is questioned. Alcohol should not be a component of the bath because it may cause dehydration and hypoglycemia.



REFERENCES Acetaminophen toxicity in children, 2001. Acetaminophen toxicity in children. Pediatrics 2001; 108(4):10201024. Aronoff and Neilson, 2001. Aronoff DM, Neilson EG: Antipyretics: Mechanisms of action and clinical use in fever suppression. Am J Med 2001; 111(4):304-315. Bouchama and Knochel, 2002. Bouchama A, Knochel JP: Heat stroke. N Engl J Med 2002; 346(25):19781988. Crocetti et al., 2001. Crocetti M, Moghbeli N, Serwint J: Fever phobia revisited: Have parental misconceptions about fever changed in 20 years?. Pediatrics 2001; 107(6):1241-1246. Doran et al., 1989. Doran TF, De Angelis C, Baumgardner RA, Mellits ED: Acetaminophen: More harm than good for chickenpox?. J Pediatr 1989; 114(6):1045-1048. Kluger, 1991. Kluger MJ: Fever: Role of pyrogens and cryogens. Physiol Rev 1991; 71(1):93-127. Kluger, 1992. Kluger MJ: Fever revisited. Pediatrics 1992; 90(6):846-850. Mackowiak and Worden, 1994. Mackowiak PA, Worden G: Carl Reinhold August Wunderlich and the evolution of clinical thermometry. Clin Infect Dis 1994; 18(3):458-467. Schmitt, 1980. Schmitt BD: Fever phobia: Misconceptions of parents about fevers. Am J Dis Child 1980; 134(2):176-181. Sharber, 1997. Sharber J: The efficacy of tepid sponge bathing to reduce fever in young children. Am J Emerg Med 1997; 15(2):188-192. Simons et al., 2005. Simons SHP, Anderson BJ, Tibboel D: Analgesic agents. In: Yaffe SJ, Aranda JV, ed. Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice, 3rd ed.. Philadelphia: Lippincott Williams & Wilkins; 2005:638-662. Stanley et al., 1975. Stanley ED, Jackson GG, Panusarn C, et al: Increased virus shedding with aspirin treatment of rhinovirus infection. JAMA 1975; 231(12):1248-1251.



Chapter 8 – Cough

Method of: David G. Hill, MD Cough is among the most common presenting complaints of outpatients in the United States. It serves as a protective reflex against foreign material and as a method to clear secretions from the airway. The cough center is located in the medulla, and the cough reflex is mediated by way of multiple nervous system pathways including the trigeminal, glossopharyngeal, vagus, and phrenic nerves. Cough is mediated by separate neural pathways from bronchoconstriction. When cough occurs there is a synchronized activation of muscles, the glottis opens, and the lungs expand. At the peak of inspiration the glottis closes and expiratory muscles contract. This results in increased intrathoracic pressure; when the glottis opens airflow can reach 500 miles per hour. The cough reflex varies in different patient populations. Women have a more sensitive cough reflex than men. Smokers' cough reflexes are depressed despite the increased frequency of cough in this population. Patients who have a decreased cough sensitivity following cerebral vascular accidents have an increased incidence of pneumonia. Angiotensin-converting enzyme (ACE) inhibitors increase cough reflex sensitivity and have been shown to decrease the risk of pneumonia in patients with cerebrovascular accidents. The evaluation of cough as a patient complaint may best be pursued by examining the duration of the symptoms. Cough can be subcategorized into acute and chronic cough. Cough that occurs following an acute respiratory infection may narrow the differential diagnosis and is addressed separately. Acute Cough Acute cough may be defined as cough that has been present for less than 8 weeks. Because all causes of chronic coughs initially cause acute symptoms, patients with acute cough may actually have cough caused by one of the etiologies discussed later in this section; however, acute cough more commonly is the result of a less indolent process ( Box 1 ). Infectious etiologies are a frequent cause of acute cough. Most acute cough is the result of viral infections, specifically the common cold. Most cough resulting from the common cold is self-limited and lasts less than 3 weeks. Most episodes of sinusitis are of viral etiology; however, bacterial sinusitis can also result in acute cough. The presence of a significant smoking history raises the possibility of an acute exacerbation of chronic obstructive pulmonary disease (COPD) as the cause of acute cough, especially in patients with previously documented COPD. Bordetella pertussis infection may also be the etiology of an acute episode of cough. Noninfectious processes that lead to acute cough include allergic rhinitis, congestive heart failure, asthma, and aspiration. The clinical history, physical examination, and diagnostic testing are of particular importance in differentiating these disease states and often point to the diagnosis. BOX 1

Causes of Acute Cough •

Viral upper respiratory infections (the common cold)

•

Acute sinusitis (usually viral, occasionally bacterial)

•

Exacerbation of chronic obstructive pulmonary disease

•

Allergic rhinitis

•

Bordetella pertussis infection

Postinfectious Cough Postinfectious cough begins with an acute upper respiratory tract infection but persists following the resolution of the other acute symptoms ( Box 2 ). Postnasal drip syndrome may present following the common cold or sinusitis. Bronchospasm may lead to postinfectious cough either as a result of a single episode of postinfectious wheezing or an exacerbation of underlying asthma. Postinfectious cough may be the initial presentation of asthma. Recurrent episodes of airflow obstruction are required to confirm the diagnosis of this chronic illness. Because B. pertussis can present with an indolent course, this infection can be confused with a postinfectious cough. Similarly, bacterial sinusitis can be confused with postinfectious cough. Both of these etiologies of cough are the result of ongoing infection rather than true postinfectious cough. Mycoplasma pneumoniae and Chlamydia pneumoniae infections may also result in postinfectious cough likely because of persistent airway inflammation and increases in cough reflex sensitivity. BOX 2 Causes of Postinfectious Cough •

Postnasal drip syndrome

•

Bronchospasm

•

Bordetella pertussis infection

•

Bacterial sinusitis

•

Mycoplasma pneumoniae/Chlamydia pneumoniae infection

Chronic Cough Chronic cough presents the most difficult diagnostic dilemma for the health care practitioner. Cough of greater than 8 weeks' duration can be considered chronic. Lesser duration of symptoms may still be indicative of one of the etiologies discussed in this section, but such cough is more likely the result of one of the infectious or postinfectious etiologies described previously. In patients who have never smoked, chronic cough is most likely the result of asthma, postnasal drip syndrome, or gastroesophageal reflux. These three etiologies are the most common cause of chronic cough regardless of patient age. In nonsmokers with a normal chest radiograph who are not taking an ACE inhibitor, these three etiologies alone or in combination are the cause of more than 85% of chronic cough ( Box 3 ). Postnasal drip syndrome is the most common of these etiologies. Cough may be the sole presenting symptom of any of these conditions; they are not mutually exclusive and may coexist, particularly in the patient with troublesome, persistent symptoms. Most patients with problematic, persistent cough have multiple etiologies contributing to their symptoms. COPD

must be considered in current smokers and in those patients with a significant smoking history. Smokers can have a cough of any etiology, however, and it should not be assumed that their cough is the result of smoking or COPD. Although smokers frequently admit to cough when a history is taken, they infrequently seek medical attention for this symptom. Cough resulting from the use of ACE inhibitors must be considered in all patients being treated with these medications. Less common, yet frequent causes of cough include chronic bronchitis from irritants other than tobacco smoke and eosinophilic bronchitis. Occasionally, chronic cough may be the result of: •

Bronchogenic carcinoma

•

Metastatic carcinoma

•

Bronchiectasis

•

Sarcoidosis

•

Pulmonary fibrosis

•

Pneumoconiosis

•

Hypersensitivity pneumonitis

•

Congestive heart failure

•

Chronic infection, such as tuberculosis or Mycobacterium avium complex

•

Recurrent aspiration because of pharyngeal or esophageal abnormalities

BOX 3 Causes of Chronic Cough •

Postnasal drip syndrome

•

Asthma

•

Gastroesophageal reflux disease (GERD)

•

Eosinophilic bronchitis

•

Angiotensin-converting enzyme inhibitors

Key Diagnostic Points The evaluation of acute cough should focus on the history and physical examination. Most acute cough will be the result of self-limited viral upper respiratory infections. More thorough evaluation is necessary in the workup of cough of longer duration particularly if the cough has been present for more than 2 months. The history of onset of the cough and whether it was associated with an acute infectious episode should be elicited. Exposure to sick contacts particularly to a known case of B. pertussis are important historic considerations. The timing and nature of the cough and any associated sputum must be described. Factors that mitigate or worsen the cough should be examined, and prior history of episodic cough, allergies, wheezing, asthma, and gastroesophageal reflux should be questioned. A thorough medication history particularly regarding use of ACE inhibitors must be obtained. Environmental factors both at home and in the work place should be reviewed. Although smoking history is important, it is again noted that smoking-related cough is an infrequent reason for a patient to seek medical attention. The physical examination should focus most on the head, neck, and thorax with a thorough examination of the upper respiratory tract including the

auditory canal, nose, and oropharynx. The cardiopulmonary examination should also be thorough to elicit signs of less common illnesses. Acute cough associated with an acute respiratory illness and prominent upper airway symptoms can be assumed to be secondary to the common cold. Diagnostic testing is not indicated in such patients; a chest radiograph would be normal and is thus not recommended. Patients who have abnormal sinus transillumination, purulent nasal secretions, sinus pain or tenderness, or maxillary toothache could possibly have bacterial sinusitis. Again, a viral etiology of sinusitis is more likely than bacterial sinusitis, and antibiotic therapy should be initiated only in patients with persistent symptoms despite symptomatic therapy. Patients with documented COPD who present with acute cough, purulent sputum, dyspnea, and wheezing have an exacerbation of their underlying COPD and should be treated appropriately. Allergic rhinitis usually presents with a clear clinical history of episodic nasal and other allergy symptoms, and allergen avoidance can be initiated. It is important to note that allergic rhinitis can present with perennial symptoms. Postinfectious cough should be evaluated with thorough history and physical examinations followed by limited diagnostic evaluation and empiric therapies. Patients should be treated for postnasal drip syndrome, particularly in the setting of described rhinitis, postnasal drip, or frequent throat clearing. The presence of nasal inflammation and congestion, cobblestoning of the pharyngeal mucosa, or mucus in the oropharynx should also lead to empiric therapy for postnasal drip syndrome. If cough persists in the patients with suspected postnasal drip syndrome, evaluation of the sinuses with imaging and treatment of those patients with evidence of bacterial sinusitis should be pursued. Computed tomography (CT) imaging of the sinuses is the gold standard for diagnosing bacterial sinusitis. Patients with postinfectious cough and an abnormal respiratory examination should have a chest radi ograph. Patients with a normal radiograph and evidence of bronchospasm can be empirically treated for airway hyperreactivity. Again, the diagnosis of asthma requires recurrent airflow obstruction and cannot be made on the basis of a single episode of postinfectious wheezing or airway hyperreactivity. In subjects with cough and vomiting, known exposure to a case of B. pertussis, or in the presence of a B. pertussis epidemic in the community, empiric therapy for this illness should be pursued. Before the vaccine era, B. pertussis was an endemic disease, which occurred in cyclic epidemics. It has been documented that B. pertussis continues to circulate in the adult population despite control of the disease in the pediatric population by vaccination. Immunity to B. pertussis, whether as a result of primary infection or immunization, is shortlived. The longer the elapsed interval since prior infection or immunization and repeat infection, the more likely repeat infection will be symptomatic. Perhaps repeat adolescent and adult booster immunization programs should be implemented to effectively control or eliminate this infection. History and physical examinations remain paramount in the patient presenting with chronic cough. The majority of patients should have a chest radiograph obtained as part of their evaluation. If the history and physical examination suggest that postnasal drip, asthma, or gastroesophageal reflux is the etiology of a patient's symptoms, empiric therapy for these conditions should be initiated. Cough triggered by environmental factors or changes may be secondary to rhinitis and postnasal drip or airway hyperreactivity and asthma. Substernal burning or a sour taste in the mouth, particularly when triggered by supine positioning or bending, should increase the suspicion of gastroesophageal reflux. If asthma is suspected, spirometry should be performed to document whether airflow obstruction is present. Response to inhaled bronchodilator with normal spirometry is indicative of airway hyperreactivity.

Improvement in symptoms and spirometry with empiric asthma therapy even in the setting of normal baseline flow rates also confirms an asthmatic etiology. A methacholine challenge can be performed to confirm airway hyperreactivity. If cough in the setting of a positive methacholine challenge shows absolutely no response to empiric asthma therapy with inhaled corticosteroids and bronchodilators, consider a trial of systemic steroids. If the cough does not respond to aggressive asthma therapy, the methacholine challenge test results were probably false positive; asthma therapy can be discontinued and diagnostic efforts focused elsewhere. Cough patients being treated with ACE inhibitors should cease these medications. Up to 30% of patients treated with ACE inhibitors will develop a persistent cough, more commonly in women, nonsmokers, and patients of Chinese ancestry. It may take 4 weeks or more for cough caused by ACE inhibitors to resolve following cessation of these medications. In the presence of ACE inhibitor use, further evaluation of dry cough should not be pursued until the patient has been withdrawn from these medications for 1 month. An abnormal chest radiograph can direct further diagnostic studies and therapies, whereas a normal chest radiograph makes less common etiologies of chronic cough such as carcinoma, congestive heart failure, sarcoidosis, or interstitial lung disease unlikely. Evidence of basilar infiltrates or fibrosis may suggest interstitial lung disease or chronic aspiration. Severe gastroesophageal reflux must be considered in those patients with radiographic evidence of chronic aspiration. Chronic cough without a definitive etiology can be troubling to both patient and health care provider. A systematic approach can simplify both diagnosis and treatment ( Figure 1 ). It is again stressed that such a cough may be the result of multiple etiologic factors. In the absence of specific factors that help to point to an etiology of chronic cough, empiric treatment for postnasal drip syndrome should be pursued. Methacholine challenge testing will rule out asthma if it is negative and should also be performed early in the evaluation of chronic cough. Cough may be the sole manifestation of asthma in nearly 60% of patients presenting with chronic cough. A positive methacholine challenge does not have 100% predictive value but should lead to empiric asthma therapy.

FIGURE 1 Approach to chronic cough of uncertain origin. ACE = angiotensin-converting enzyme; CT = computed tomography

CURRENT DIAGNOSIS All Patients Presenting With Cough

Perform thorough history and physical examination. Review timing and nature of cough along with exacerbating or mitigating factors. Review prior history of cough, allergies, asthma, or gastroesophageal reflux. Take medication history, particularly use of ACE inhibitors. Focus physical examination on head, neck, and thorax. Patients With Postinfectious or Chronic Cough

Obtain chest radiograph, particularly in patients with an abnormal respiratory examination. Evaluate airflow obstruction with spirometry. Stop ACE inhibitors and assess for improvement. Administer empiric therapy for postnasal drip, asthma, or gastroesophageal reflux. Consider methacholine challenge testing to evaluate for airway hyperreactivity. Induce sputum for eosinophils or empiric trial of corticosteroids for eosinophilic bronchitis. If cough persists, consider esophagoscopy, 24-hour pH probe monitoring, high-resolution chest CT, or bronchoscopy. Abbreviations: ACE = angiotensin-converting enzyme; CT = computed tomography.

Empiric therapy for silent gastroesophageal reflux should be initiated in those who do not respond to treatment for postnasal drip syndrome and do not have evidence of or respond to treatment for asthma. Cough may be the only manifestation of gastroesophageal reflux up to 30% of the time. Definitive diagnosis of gastroesophageal reflux requires invasive testing and may require more than one testing modality. Therefore it is recommended that empiric therapy for reflux be pursued before diagnostic testing. Reflux therapy should include conservative approaches such as dietary and lifestyle changes, bed positioning, and pharmacologic treatment. Gastroesophageal reflux–related cough can be particularly troublesome and persistent and may take weeks or months to respond to appropriate and intensive antireflux therapy. This may include higher-than-normal doses of proton pump inhibitors and promotility agents. Surgical treatment of reflux may be necessary to effectively treat reflux related cough in some patients. In patients with persistent cough, the common etiologies of cough often coexist and exacerbate one another. Therapy should often be additive, for instance treating both asthma and reflux, rather than mutually exclusive. Persistent cough should result in further diagnostic evaluation including sputum studies, esophagoscopy, 24-hour pH probe esophageal monitoring, high-resolution chest CT, and possibly bronchoscopy. In the presence of normal chest imaging, bronchoscopy is unlikely to yield beneficial diagnostic information in the patient with chronic cough.

CURRENT THERAPY Treatment of Acute Cough

Common cold: Supportive care with dexbrompheniramine, 6 mg, and pseudoephedrine, 120 mg (Drixoral Cold and Allergy Tablets); or ipratropium nasal spray (Atrovent, 0.06%), two 42-mcg sprays in each nostril 3 times daily for 4 to 7 d depending on duration of symptoms. Acute sinusitis: Treat as a common cold. Add oxymetazoline (Afrin), two sprays twice daily for three days. If symptoms persist, consider antibiotic therapy directed against Haemophilus influenzae and Streptococcus pneumoniae such as azithromycin (Zithromax), 500 mg daily for 3 d. Exacerbation of chronic obstructive pulmonary disease: Antibiotics directed against H. influenzae and S. pneumoniae for 3 to 7 d such as clarithromycin (Biaxin), 500 mg twice daily for 7 d; systemic corticosteroids such as prednisone (Deltasone), 40 mg tapered over 10 d; inhaled anticholinergics such as tiotropium (Spiriva), one inhalation daily; and short-acting ß-agonists such as albuterol (Proventil), two inhalations every 4 h as needed; smoking cessation. Allergic rhinitis: Nasal corticosteroids such as mometasone (Nasonex), two sprays in each nostril daily; nonsedating antihistamines such as fexofenadine (Allegra), 180 mg daily; allergen avoidance if possible. Bordetella pertussis: Erythromycin 500 mg four times daily for 14 d or trimethoprim 160 mg/sulfamethoxazole (Bactrim DS),[1] 800 mg twice daily for 14 d. Other macrolide antibiotics such as azithromycin (Zithromax)[1] or clarithromycin (Biaxin)[1] are likely effective and may be better tolerated. Treatment of Postinfectious Cough

Postnasal drip syndrome: Dexbrompheniramine, 6 mg, and pseudoephedrine (Drixoral Cold and Allergy Tablets), 120 mg for up to 3 wk; ipratropium (Atrovent), 0.06% nasal spray for up to 3 wk; azelastine (Astelin) nasal spray (137 mcg), two sprays each nostril twice daily for up to 3 wk. Bronchospasm: Inhaled corticosteroid such as budesonide (Pulmicort),[1] two inhalations daily with or without inhaled long-acting ß-agonist such as formoterol (Foradil), two inhalations twice daily; shortacting ß-agonist such as albuterol (Ventolin), two puffs every 4 h as needed. Oral steroids such as prednisone (Deltasone), 40 mg tapered over 10 d. Bordetella pertussis: Erythromycin, 500 mg four times daily for 14 d, or trimethoprim 160 mg/sulfamethoxazole, 800 mg (Bactrim DS)[1] twice daily for 14 d. Other macrolide antibiotics such as azithromycin (Zithromax)[1] or clarithromycin (Biaxin)[1] are likely effective and may be better tolerated. Bacterial sinusitis: Dexbrompheniramine, 6 mg, and pseudoephedrine (Drixoral Cold and Allergy Tablets), 120 mg for up to 3 wk; oxymetazoline (Afrin), two sprays twice daily for 3 d; azithromycin (Zithromax), 500 mg daily for 3 d. Chlamydia/mycoplasma: Clarithromycin (Biaxin), 500 mg twice daily for 14 d. Treatment of Chronic Cough

Postnasal drip syndrome Nonallergic: Dexbrompheniramine, 6 mg, and pseudoephedrine (Drixoral Cold and Allergy Tablets), 120 mg for up to 3 wk; ipratropium (Atrovent), 0.06% nasal spray for up to 3 wk; azelastine (Astelin) nasal spray (137 mcg), two sprays each nostril twice daily for up to 3 wk. Allergic: Fluticasone (Flonase) (50 mcg), two sprays each nostril daily; fexofenadine (Allegra), 180 mg daily; allergen avoidance. Asthma: Albuterol (Proventil), two puffs every 4 hours as needed; inhaled corticosteroid such as budesonide (Pulmicort), two inhalations daily with or without inhaled long-acting ß-agonist such as formoterol (Foradil), two inhalations twice daily; combination of long-acting ß-agonist and inhaled steroid such as fluticasone/salmeterol (Advair) (100/50 mcg), inhaled twice daily; montelukast (Singulair), 10 mg daily; prednisone (Deltasone), 40 mg daily with tapering dose over 10 d. Gastroesophageal reflux: Dietary and lifestyle modifications, lansoprazole (Prevacid), 30 mg daily for up to 3 mo; metoclopramide (Reglan), 10 mg before meals and sleep. Eosinophilic bronchitis: Fluticasone (Flovent)[1] (110 mcg), two inhalations twice daily; prednisone (Deltasone), 30 mg daily for 3 wk. ACE inhibitor: Discontinue medication. 1 Not FDA approved for this indication.

Eosinophilic bronchitis in the absence of asthma is also a frequent cause (up to 13% of cases) of chronic cough. Patients with eosinophilic bronchitis will have normal spirometry and a negative methacholine challenge. The disease may be diagnosed by appropriate induced sputum analysis showing at least 3% eosinophils. Alternatively it can be empirically treated with a course of inhaled corticosteroids. Most patients appear to respond to inhaled corticosteroids within 3 weeks. Systemic corticosteroids may be required to improve the symptoms in some cases. There may be an association of gastroesophageal reflux with eosinophilic bronchitis. Patients with gastroesophageal reflux have been found to have increased sputum eosinophilia. Bronchiectasis may infrequently result in chronic cough. Bronchiectasis is characterized by the abnormal dilatation of one or more branches of the bronchial tree. It can effectively be diagnosed by high resolution CT scan of the thorax. Bronchiectasis may occur following a severe infection, distal to an area of airway obstruction, congenitally, from chronic inflammatory processes, and as a result of chronic parenchymal scarring and traction. Patients with bronchiectasis may present with productive or nonproductive coughs. They may have recurrent episodes of infection resulting from persistent colonization of the abnormal bronchial segment. Infectious agents may include routine bacterial organisms and typical or atypical mycobacterium. Bronchiectasis may be seen in a variety of chronic illnesses. The presence of bronchiectasis in a patient without a known predisposing cause should prompt the clinician to look for appropriate clinical states. such as:

•

Primary or acquired immunodeficiencies

•

Abnormalities of ciliary function, such as ciliary dyskinesia or cystic fibrosis

•

Postinfectious inflammatory processes, such as allergic bronchopulmonary aspergillosis

•

Collagen vascular diseases

•

Inflammatory bowel disease

•

Sarcoidosis

•

Yellow nail syndrome

The presence of localized bronchiectasis may be an indication to pursue flexible fiberoptic bronchoscopy to rule out an obstructing lesion and to obtain appropriate culture specimens. Treatment of bronchiectasis is aimed at the underlying disease state if one can be identified. Infections should be treated with appropriate antibiotics. Clearance of bronchial secretions can be aided with mucolytics and chest physiotherapy including use of percussive devices. In some cases surgical therapy to remove the bronchiectatic segment can be considered. Treatment The key treatments for cough are best described based on the suspected etiology. Acute cough therapy should focus on supportive treatment of the underlying suspected etiology, which will likely be a viral upper respiratory infection. Therapy for exacerbation of chronic obstructive pulmonary disease, allergic rhinitis, bacterial sinusitis, or B. pertussis infection is more specific. Postinfectious cough should focus on therapy for postnasal drip syndrome or airways reactivity if suspected. In chronic cough of uncertain etiology (see Figure 1 ), cough therapy should begin with empiric treatment of postnasal drip syndrome, evaluation and treatment of asthma, empiric treatment of gastroesophageal reflux syndrome, and finally evaluation or empiric therapy for eosinophilic bronchitis. Cough is a frequent and troublesome symptom for both patient and health care provider. Acute cough although at times troubling is usually self-limiting. Postinfectious cough and chronic cough are more problematic, but can effectively be evaluated and treated by performing a thorough history and physical examination and pursuing a systematic approach to diagnostic evaluation and both empiric and guided therapies. The resolution of chronic troubling cough is a therapeutic relief for the patient and a gratifying experience for the caregiver.



REFERENCES Barnes et al., 2004. Barnes TW, Afessa B, Swanson KL, Lim KG: The clinical utility of flexible bronchoscopy in the evaluation of chronic cough. Chest 2004; 126:268-272. Breitling et al., 1999. Breitling CE, Ward R, Goh KL: Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999; 160:406-410. Cherry, 1999. Cherry JD: Epidemiological, clinical, and laboratory aspects of pertussis in adults. Clin Infect Dis 1999; 28(suppl2):S112-S117. Cohen and Sahn, 1999. Cohen M, Sahn SA: Bronchiectasis in systemic diseases. Chest 1999; 116:10631074. Irwin and Madison, 2001. Irwin RS, Madison JM: Symptom research on chronic cough: A historical perspective. Ann Intern Med 2001; 134:809-814. Irwin and Madison, 2000. Irwin RS, Madison JM: The diagnosis and treatment of cough. N Engl J Med 2000; 343:1715-1721. Irwin and Madison, 2002. Irwin RS, Madison JM: The persistently troublesome cough. Am J Respir Crit Care Med 2002; 165:1469-1474. Kiljander, 2003. Kiljander TO: The role of proton pump inhibitors in the management of gastroesophageal reflux disease-related asthma and chronic cough. Am J Med 2003; 115(3A):S65-S71.



Chapter 9 – Treatment of Insomnia

Method of: Martin Reite, MD Three things should be remembered when considering treatment of an insomnia complaint. First, insomnia is more often a symptom, than a specific disorder. Second, it is important to perform a systematic differential diagnosis, keeping in mind the possibility that there will be very likely more than one cause of an insomnia complaint. Finally, the cause of the complaint usually can be determined, and most patients complaining of insomnia can be helped. Also, insomnia must not be trivialized. Insomnia is among the most frequent complaints in the population; untreated insomnia is associated with increases in new-onset anxiety and depression, increased daytime sleepiness, and increased health-related concerns. Insomnia can include difficulty in getting to sleep (sleep-onset insomnia), difficulty staying asleep (sleepmaintenance insomnia), or early morning awakening (terminal insomnia). Because such subtypes are not stable over time, this method of subtyping may have little clinical usefulness. As a rule, insomnia complaints are more frequent in women, elderly persons, and patients of lower socioeconomic status. Screening for Sleep Complaints Three routine questions, illustrated in Box 1 , will detect most significant sleep problems. A positive answer to any of these questions merits consideration of a more detailed sleep history to determine whether in fact a sleep disorder is present. Box 2 outlines the items to be covered in a sleep history. BOX 1 Detection of Specific Sleep Disorders Are you content with your sleep? (identifies most insomnia complaints) Are you excessively sleepy during the day? (identifies most disorders of excessive sleepiness) Does your bed partner complain about your sleep? (identifies most parasomnia disorders)

BOX 2

Sleep History Questionnaire When did the symptoms start, and what was going on at the time? What has been the symptom pattern across time? Are symptoms stress or situationally related? What is your typical daily schedule, hour by hour? What medications and treatments have been and are currently being used to date? Is there a presence of familial sleep-related symptoms?

Sources of diagnostic information should include the bed partner whenever possible because many sleeprelated symptoms are apparent only to the bed partner. A several-week daily sleep diary also can be useful at this stage of the evaluation because it can provide a detailed daily description of sleep/wake activity patterns. Transient and Short-Term Insomnia Transient (1 to several days) and short-term (up to 3 weeks) insomnias are typically stress related, and respond well to pharmacologic (short-term hypnotic) intervention. They should be considered for active treatment, because untreated short-term insomnia can lead to a state of “conditioned arousal” resulting in a chronic insomnia. Differential Diagnosis of the Chronic Insomnia Complaint The differential diagnosis of a chronic insomnia complaint can represent a more challenging task and requires a thorough differential diagnostic evaluation, which includes systematically considering the conditions or combinations of conditions that are most likely to result in insomnia complaints. General practice parameters for the evaluation of chronic insomnia complaints can be found at: http://www.aasmnet.org/PDF/ChronicParameter.pdf . Box 3 lists the common causes of insomnia (not necessarily listed in order of frequency). Each cause is briefly discussed. BOX 3

Common Causes of Insomnia Medical conditions and/or pharmacologic treatment of medical conditions Psychiatric disorders (especially depression, anxiety, and post-traumatic stress disorder [PTSD]) Substance abuse disorders Circadian rhythm disorders presenting as insomnia Periodic limb movements in sleep (PLMS) Central sleep apnea The primary insomnia, conditioned insomnia, and sleep-state misperception group MEDICAL CONDITIONS AND TREATMENT Medical conditions, and in susceptible patients, many pharmacologic treatments of medical conditions, can result in insomnia complaints. The endocrinopathies are notorious for being associated with sleep-related complaints, as are conditions associated with chronic pain, breathing difficulties, cardiac arrhythmias, arthritis, renal failure, and central nervous system (CNS) disorders. Box 4 lists the more commonly used medications that can result in insomnia complaints. BOX 4 Medications Often Associated with Insomnia Anticholinergics Antidepressants Antihypertensives Antineoplastic agents Bronchodilators CNS stimulants

Corticosteroids Decongestants Diuretics Histamine-2 (H2) blockers Smoking cessation aids

The treatment of insomnia associated with medical conditions is first to isolate and appropriately treat the medical condition and the symptoms (e.g., pain) causing the insomnia. If the insomnia complaint persists, evaluate the possibility of an additional cause for the sleep complaint. Supplementary use of a short half-life hypnotic agent [e.g., zolpidem (Ambien), 5-10 mg at bedtime] may be helpful. Insomnia associated with fibromyalgia and chronic fatigue syndrome is frequently resistant to treatment, although small doses of amitriptyline (Elavil)[1] (10-50 mg at bedtime) or cyclobenzaprine (Flexeril)[1] (10 mg three times a day) have been reported to be helpful; occasionally, zolpidem (5-10 mg) will help with the associated insomnia complaints. Dementing illnesses are often associated with severe insomnia complaints that are quite disruptive to patients and families and often are the factors precipitating institutional care. Sleep is often disturbed in such disorders on the basis of disease-associated CNS lesions, and different specific pathophysiologies (not yet well understood) may respond to different treatments. Until such specific treatments can be based on specific pathophysiology, we should adhere to optimal environmental circadian principles (quiet, dark nocturnal environment; bright, socially stimulating daytime environment). Appropriate use of hypnotics may be helpful, although responses may be variable. 1 Not FDA approved for this indication.

PSYCHIATRIC DISORDERS Psychiatric disorders, especially those associated with anxiety or depression, frequently include insomnia (delayed sleep onset, frequent awakening, or early morning awakening) as an associated symptom. Effective treatment of the psychiatric condition will often relieve the insomnia complaint, although a supplemental hypnotic might be indicated early in treatment. Different antidepressant agents have quite different effects on sleep as illustrated in Table 1 , and the initial choice of an antidepressant might profitably take such effects into account.

TABLE 1 -- Effect of Antidepressants on Sleep Scale[*] Effects on EEG Sleep Drug TCAs

Trade Name Continuity SWS

REM

Sedation Effects

Effects on EEG Sleep Drug

Trade Name Continuity SWS

REM

Sedation Effects

Amitriptyline

Elavil

I (3)

I (1)

D (3)

4

Doxepin

Sinequan

I (3)

I (2)

D (2)

4

Imipramine

Tofranil

I (0-1)

I (1)

D (2)

2

Nortriptyline

Pamelor

I (1)

I (1)

D (2)

2

Desipramine

Norpramin

(0)

I (1)

D (2)

1

Clomipramine

Anafranil

I (0-1)

I (1)

D (4)

0

Nardil

D (1)

(0)

D (4)

0

D (2)

(0)

D (4)

0

MAOIs Phenelzine

Tranylcypromine Parnate SSRIs Fluoxetine

Prozac

D (1)

D (0-1) D (0-1) 0

Paroxetine

Paxil

D (1)

D (0-1) D (2)

0

Sertraline

Zoloft

(0)

(0)

D (2)

0

Citalopram

Celexa

D (1)

(0)

D (1)

ND

Fluvoxamine

Luvox

D (1)

(0)

D (1)

ND

Escitalopram

Lexapro

(0)

(0)

D (2)

0

Bupropion

Wellbutrin

D (0-1)

(0)

I (1)

0

Venlafaxine

Effexor

D (1)

D (1)

D (3)

2

Trazodone

Desyrel

I (3)

I (0-1)

D (1)

4

Mirtazapine

Remeron

I (3)

I (2)

(0)

3

Nefazodone

Serzone

I (1)

(0)

I (1)

1

Other

Abbreviations: EEG = electroencephalogram; MAOIs = monoamine oxidase inhibitors; REM = rapid eye movement; SSRIs = selective serotonin reuptake inhibitors; SWS = slow-wave sleep; TCAs = tricyclic antidepressants.

* Scale 0-4: 0 = no significant effect; I = increase and D = decrease.

If, for a patient already complaining of insomnia, an antidepressant with a known high incidence of insomnia side effects is chosen, it may be useful to augment it with a hypnotic agent early in the course of treatment. SUBSTANCE USE SLEEP DISORDERS

Alcohol abuse remains a significant problem in the etiology of sleep complaints, as do stimulants and other drugs of abuse. Treatment includes withdrawal of the offending substance, with long-term abstinence as the goal. Treatment of substance abuse-related insomnia should emphasize behavioral treatment strategies to the fullest extent possible, because psychoactive agents have already proved to be a problem. CIRCADIAN RHYTHM DISORDERS Disturbances in the regulation of the circadian system frequently present as sleep-related complaints, although the source of the problem lies in the circadian system rather than sleep pathology. Sleep per se may be adequate, but it occurs at the wrong time. Delayed sleep-phase syndrome (DSPS) is the most common, and is likely a genetically based disorder with frequent onset in adolescence or early adulthood. These individuals cannot get to sleep (because of phase delay in the body temperature rhythm) until 3 to 4 a.m., and if allowed to sleep, 8 to 9 hours may do well. If they have to arise at 7 a.m. for school or work, they will be sleep deprived and complain of insomnia. Early morning bright-light exposure, with restriction of light exposure in the evening, has been found to be effective for phase-advancing the circadian system in DSPS. Evening bright-light treatment is effective in treating advanced sleep-phase syndrome. Low-dose (1-3 mg) melatonin[*] at bedtime may help regulate circadian rhythms in some individuals. Jet lag and shift-work–related sleep problems also fall in the category of circadian rhythm problems. A detailed discussion of these problem areas is beyond the scope of this article, but recently emerging data suggest that properly timed bright-light exposure, supplemented with melatonin[1],[*] administration and appropriate hypnotic use, can significantly reduce associated symptoms. * Available as a dietary supplement.

PERIODIC LIMB MOVEMENTS OF SLEEP AND RESTLESS LEGS SYNDROME Both restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) are associated with a variety of medical conditions, including iron deficiency, but they may occur in otherwise healthy individuals (especially the elderly). A polysomnogram (PSG) is usually required for accurate diagnosis of a PLMS disorder, quantifying both the number of events and their association with awakenings or arousals. Table 2 lists the drugs currently used in the treatment of PLMS and RLS.

TABLE 2 -- Beginning Dose Schedules for PMLS and RLS Drug Dose (mg) Administration Dopa Agonists Carbidopa/Levodopa

25/100-50/200 Bedtime/(Sinemet)[1] symptom onset

Controlled-release

25/100-50/200 Bedtime/Carbidopa/Levodopa symptom onset (Sinemet CR)[1]

Bromocriptine (Parlodel)[1]

2.5-5

Bedtime

Baclofen (Lioresal)[1]

20-40

Bedtime

Drug

Dose (mg)

Administration

Pergolide (Permax)[1]

0.05

Bedtime/symptom onset

Pramipexole (Mirapex)[1]

0.125

Bedtime

Ropinirole (Requip)[1]

0.25

Bedtime

Oxycodone (Roxicodone)[1] 5-15

Bedtime

Codeine[1]

10-60

Bedtime

Triazolam (Halcion)[1]

0.125-0.25

Bedtime

Temazepam (Restoril)[1]

15-30

Bedtime

Clonazepam (Klonopin)[1]

0.5-1.5

Bedtime

Gabapentin (Neurontin)[1]

100-300

Bedtime

Other Agents


CENTRAL SLEEP APNEA Central sleep apnea with frequent arousals is a relatively rare cause of chronic insomnia except at higher altitudes, and may require a PSG for accurate diagnosis. Both oxygen and continuous positive airway pressure (CPAP) can be used in the treatment of central apnea in patients with medical disorders. The efficacy of pharmacologic agents in the treatment of central sleep apnea has yet to be clearly established in well-controlled studies. Acetazolamide (Diamox)[1] (250 mg twice a day) may be effective for the prevention of high altitude-induced central apnea. THE PRIMARY INSOMNIA, CONDITIONED INSOMNIA, AND SLEEP-STATE MISPERCEPTION SYNDROME GROUP Although there are several more rare causes of a chronic insomnia complaint, most often it is generally safe to assume that once the aforementioned specific causes have been systematically excluded or appropriately treated (and the insomnia complaints remain), we are in all probability left with either a primary insomnia disorder (DSM-IV 307.42), a conditioned insomnia, a sleep-state misperception syndrome (SSMS), or some combination thereof. A treatment approach that combines both behavioral and pharmacologic approaches is generally recommended. Such a combined treatment approach offers the advantage of a pharmacologic agent that can produce rapid relief of the sleep complaint, along with behavioral strategies, which take longer to become effective but provide long-term results that are under a patient's control. Active and continued involvement of the patient is important for any chronic insomnia treatment. Sleep Laboratory Studies All night PSGs, which monitor multiple physiologic variables during sleep, are rarely needed in the evaluation of insomnia complaints, except for symptoms associated with PLMS or for a sleep-related

breathing disorder, where a PSG is usually required for accurate diagnosis. A recent review of the use of PSGs in the insomnia complaints can be found at: http://www.aasmnet.org/PDF/260616.pdf .

The 24-hour recording of activity (Actigraphy) can also be useful in the diagnosis of circadian rhythm-based sleepcomplaints (e.g., see: http://www.aasmnet.org/PDF/260315.pdf ). Treatment After completing the evaluation of a chronic insomnia complaint and arriving at a diagnostic formulation, a treatment plan should be developed addressing all likely contributing causes. The treatment plan will likely include both behavioral and pharmacologic components, and should be discussed in detail with the patient. Patients might be encouraged to visit the web pages of the American Sleep Disorders Association ) and the National Sleep Foundation (www.nsf.org ) to learn more about factors (www.asda.org influencing sleep. Patient education facilitates effective treatment. BEHAVIORAL TREATMENTS Behavioral treatment strategies are aimed at (a) breaking bad sleep habits and replacing them with sleeppromoting habits; (b) directly decreasing physiologic arousal levels using cognitively based or learned strategies; and (c) providing the patient with several types of cognitive strategies to deal with sleep difficulties, thus promoting a sense of competence and diminishing anxiety about sleep. First and foremost among the behavioral strategies is good sleep hygiene—the behaviors and habits that foster good sleep. Box 5 highlights the principles of good sleep hygiene. It is helpful to prepare a handout for patients summarizing good sleep hygiene practices that they can take with them. Box 6 lists additional behavioral strategies. BOX 5 Good Sleep Hygiene Establish a regular sleep schedule that does not vary by more than 1 hour. Maintain a state of good aerobic fitness with regular exercise (but not within 3 hours of sleep onset). Do not use caffeine or alcohol to excess. Ensure a quiet, dark, cool bedroom. Provide a time to wind down in the evening before sleeping. Consider a high-tryptophan snack (milk, cookies, banana) before bed. Use the bedroom for sleep and sex but not for reviewing or thinking about the affairs of the day.

Minimize exposure to late evening bright light to avoid phase-delaying the circadian system.

BOX 6 Other Behavioral Strategies for the Treatment of Insomnia Biofeedback (EMG and EEG): teaches subjects to decrease autonomic arousal Progressive relaxation: training in systematic total body relaxation Sleep restriction: good for subjects spending excessive time in bed with poorly consolidated sleep Yoga, transcendental meditation (TM): self-control strategies Cognitive behavioral therapy (several types): improved self-confidence and self-control PHARMACOLOGIC TREATMENTS Benzodiazepine (BZ) compounds and newer nonbenzodiazepine agents active at the level of the BZ receptor are the most commonly used hypnotic agents. Older hypnotic agents (chloral hydrate, paraldehyde [Paral], barbiturates) may have limited usefulness for very short-term use in specific patients, but they cannot be recommended for the treatment of chronic insomnia. BZ agents activate all BZ receptors (hypnotic, anxiolytic, muscle relaxant, anticonvulsant), and different agents demonstrate relatively little receptor specificity. The BZ compounds differ substantially in terms of half-life and are illustrated in Table 3 . The clinician can choose the agent with a half-life most appropriate for the clinical situation.

TABLE 3 -- Benzodiazepines Name

Dose (mg)

Generic

Trade Name Adult

Triazolam

Halcion

0.125–0.25 0.125–0.25 Rapid

1.5–5.5

Estazolam

ProSom

1–2

0.5–1

Rapid

20–30

Temazepam Restoril

15–30

7.5–15

Intermediate 8–20

Quazepam

7.5–15

7.5

Intermediate 15–120

15–30

7.5

Intermediate 36–250

Doral

Flurazepam Dalmane

Elderly

Onset

Half-Life (Hours)

Long half-life BZ agents may be associated with residual daytime sedation and impairments in psychomotor performance. All BZ agents interfere with memory consolidation, the more potent agents (e.g., triazolam [Halcion]) most prominently. All BZ agents are prone to the development of tolerance, dependence, and rebound insomnia in response to rapid withdrawal. BZ agents also tend to decrease stages 3 to 4 sleep, and increase fast activity in the waking and sleeping electroencephalogram (EEG). These results may continue after drug discontinuation. Clearly useful for the treatment of insomnia associated with anxiety, the use of long-term BZ treatment of primary insomnia is problematic, especially in light of the research and development of new, apparently safe and effective nonbenzodiazepine agents designed to be selectively more active on the hypnotic receptor. Newer non-BZ agents selectively active at the omega1BZ receptor include zolpidem and zolpidem-MR (Ambien and Ambien-CR), zaleplon (Sonata), and eszopiclone (Lunesta). These agents do not appear to alter sleep architecture, and appear less prone to induce significant tolerance, dependence, or withdrawal compared to conventional benzodiazepines. All have relatively rapid onset of action, but differ in half life and duration of action. Approximate half lives are zaleplon ~1 hr, zolpidem ~1-3 hr, zolpidem MR ~2-4 hr, and eszopiclone ~6 hr. Neither zolpidem-MR or eszopiclone have restrictions on duration of use. The melatonin receptor agonist ramelteon (Rozerem) has also been recently released for the treatment of insomnia (possibly most effective in circadian regulation problems), and has no duration of use restriction. Antidepressant agents, especially sedative tricyclics, are frequently used at low doses to manage chronic insomnia despite the relative lack of well-controlled double-blind studies demonstrating efficacy. These agents are clearly indicated in insomnia that accompanies depressive disorders, where their effectiveness is clear. These agents are normally taken about one hour before bedtime so their sedative effects have time to emerge. This effectively teaches the patient to take a pill to sleep, which is counterproductive for treating insomnia. The new non-BZ hypnotics with their rapid onset of action can be placed at the bedside and are taken if the patient has not fallen asleep within 30 minutes. Several agents more directly involved in modulating -aminobutyric acid (GABA) activity, such as tiagabine (Gabitril)[1] and sodium oxybate (Xyrem),[1] have been used in limited studies to promote slow-wave sleep, but there are insufficient published data to make specific recommendations as to their potential usefulness in insomnia at this time. LONG-TERM USE OF HYPNOTIC AGENTS Current thinking suggests we might best conceptualize primary insomnia as a chronic disorder that will likely require long-term treatment. Considering the known adverse effects of chronic sleep loss, in the context of the present availability of relatively safe and effective hypnotic agents, there would appear to be no reason to withhold or severely limit pharmacologic treatment in those responsible patients for whom a comprehensive and thorough diagnostic evaluation has established the presence of a primary insomnia disorder. It should go without saying, however, that behavioral treatment also should be actively implemented in those patients who are being considered for long-term pharmacologic management.



Chapter 10 – Pruritus

Method of: Scott Moses, MD Because pruritus is the most common symptom in dermatology, clinicians are often asked to reduce its distressing effect on comfort and sleep. Left untreated, itch and its associated persistent scratching increases risk of chronic skin changes and secondary infection. Although pruritus is most often caused by a dermatologic condition, it can also be a symptom of underlying systemic disease. The sensation of itch starts in the skin's free nerve endings, travels via unmyelinated C-fibers to the spine, and finally travels via the spinothalamic tract to the brain. Histamine, commonly associated with allergic rhinitis and urticaria, is only one of several chemical mediators of pruritus. Serotonin is integral to the pruritus of uremia, cholestasis, polycythemia vera, lymphoma, and morphine-associated pruritus. In atopic dermatitis, proinflammatory mediators (e.g., cytokines) are released in an immune-mediated response. Pruritus has been attributed to neuropathy in a wide variety of conditions including herpes zoster, brachioradial pruritus, notalgia paresthetica, spinal tumors, and multiple sclerosis. Diagnosis History is the key to identifying the cause of pruritus. Most causes are evident from the associated dermatitis ( Box 1 ), distribution ( Figure 1 ), or exogenous exposure history ( Box 2 ). Clinicians should focus on the timing of pruritus and associated rash development, food and medication exposures, possible allergen and irritant exposures, pet exposure, and travel history. BOX 1 Dermatitis-Associated Causes of Pruritus Allergic Contact Dermatitis

•

Sharply demarcated erythematous lesion with overlying vesicles

•

Reaction within 2-7 d of exposure (see Box 4 )

Atopic Dermatitis

•

Atopic patients (allergic rhinitis, asthma) with the itch that rashes

•

Affects flexor wrists and ankles, antecubital and popliteal fossa

Bullous Pemphigoid

•

Initially pruritic urticarial lesions, often in intertriginous areas

•

Tense blisters form after urticaria

Cutaneous T-Cell Lymphoma (Mycosis Fungoides)

•

Oval eczematous patch on non–sun-exposed skin (e.g., buttocks)

•

Can also manifest as erythroderma (exfoliative dermatitis)

•

Can also manifest as a new eczematous disorder in older adults

Dermatitis Herpetiformis

•

Rare vesicular dermatitis affects lumbosacral spine, elbows, knees

Folliculitis

•

Pruritus out of proportion to appearance of dermatitis

•

Papules and pustules at follicular sites on chest, back, or thighs

Lichen Planus

•

Lesions often on the flexor wrists

•

6 Ps: pruritus, polygonal, planar, purple papules and plaques

Lichen Simplex Chronicus

•

Complication of chronic scratching (e.g., atopic dermatitis)

•

Thickened plaques over lower legs, posterior neck, and groin

Parasitic Skin Infections Insects

•

Chigger bites (harvest mite): Southeastern United States

•

Cutaneous myiasis (bot fly): Central and South America, Africa

•

Leishmaniasis (sand fly): Central and South America, Africa, Asia

Pediculosis (lice)

•

Occiput of school-aged child

•

Genitalia affected in adults (STD)

Scabies

•

Burrows at hand web spaces, axillae, and genitalia

•

Hyperkeratotic plaques, pruritic papules or scale present

•

Face and scalp affected in children but not adults

Prurigo nodularis

•

Complication of chronic scratching (variant of lichen simplex)

•

1-2 cm nodules on extensor arms and legs

Psoriasis

•

Plaques on extensor extremities, low back, palms, soles, and scalp

Sunburn

•

Consider photosensitizing causes (e.g., NSAIDs, cosmetics)

Xerotic Eczema

•

Intense itching during winter in northern climates

•

Involves back, flanks, abdomen, waist, and distal extremities

Abbreviations: NSAIDs = nonsteroidal anti-inflammatory drugs; STD = sexually transmitted disease.

FIGURE 1 Causes of pruritus (by distribution). Adapted from Moses S: Pruritus. Am Fam Physician 2003;68:1135-1146.

BOX 2

Exposure-Related Pruritus Allergic Contact Dermatitis

•

Topical medications: Neomycin, benzocaine (Americaine)

•

Nickel, latex, cosmetics, black hair dye

•

Laundry detergents or fabric softeners

•

Paint-on tattoos (paraphenylenediamine)

•

Tattoo dye: cadmium yellow, mercuric sulfide (red)

•

Ointments highly concentrated in inert oil

Heat Exposure

•

Miliaria rubra (prickly heat)

•

Cholinergic urticaria (response to hot bath, fever, exercise)

Occupational Exposure

•

Dyes (e.g., glyceryl monothioglycolate)

•

Potassium dichromate in cements and dyes

•

Rosins or epoxy resins in adhesives

•

Rubber, methyl methacrylate, fiberglass

Systemic Medications

•

Drug hypersensitivity (rifampin [Rifadin], vancomycin [Vancocin])

•

Itraconazole (Sporanox), fluconazole, ketoconazole (Nizoral)

•

Niacinamide (niacin), B vitamins, aspirin, quinidine (Quinidex)

•

Nitrates (food preservatives)

•

Spinal narcotics (pruritus affects face, neck, and upper chest)

Water Exposure

•

Aquagenic pruritus (associated with polycythemia vera)

•

Cholinergic urticaria (response to warm water)

•

Itching within 15 min of any water contact

•

Polycythemia vera

•

Swimmer's itch (7-d eruption after freshwater swimming)

In children, pruritus rarely has a systemic cause. However, clinicians should be alert for children who demonstrate red flag symptoms such as growth failure, anorexia, fatigue, associated bowel or bladder changes, and nighttime awakenings due to pruritus.

CURRENT DIAGNOSIS Reassuring findings that suggest a nonorganic cause include recent onset, localized itch, pruritus limited to exposed skin, household members also with pruritus, and recent travel history. Underlying systemic disease is responsible for up to 50% of pruritus in older adults and is uncommon in children. Laboratory testing to consider in atypical cases includes a complete blood count, ferritin, thyroidstimulating hormone, serum bilirubin, alkaline phosphatase, serum creatinine, blood urea nitrogen, HIV test, and skin scrapings, biopsy, and culture. Underlying systemic disease is responsible for up to 50% of pruritus in older adults and should be considered in refractory cases and where skin findings are absent. Reassuring findings that suggest a nonsystemic cause include recent onset, localized itch, pruritus limited to exposed skin, household members also with pruritus, and recent travel history. Dermatitis distribution and appearance often indicate the cause. The examination can also reveal the chronicity of pruritus. Excoriations and impetigo are seen acutely, and postinflammatory pigment changes and lichenification are seen with chronic scratching. Clinicians should be alert for findings consistent with thyroid disease, renal disease, liver disease, anemia, and hematologic malignancy. Examination should include careful palpation of the lymph nodes, liver, and spleen. Systemic causes of pruritus are listed in Box 3 . Pruritic conditions specific to pregnancy are summarized in Box 4 . BOX 3 Systemic Causes of Pruritus Cholestasis

•

Intense itching, worse at night

•

Affects hands, feet, and pressure sites

•

Reactive hyperpigmentation spares midback (butterfly appearance)

Chronic Renal Failure

•

Severe paroxysms of generalized itching

•

Worse in summer

Delusions of parasitosis

•

Focal erosions on exposed areas of arms and legs

Human Immunodeficiency Virus

•

Pruritus is a common presenting symptom due to secondary causes

•

Causes: Eczema, drug reaction, eosinophilic folliculitis, seborrhea

Hodgkin's Lymphoma

•

Prolonged generalized pruritus often precedes diagnosis

Hyperthyroidism

•

Skin is warm and moist

•

Pretibial edema may be present

•

Onycholysis, hyperpigmentation, and vitiligo have been associated

Iron-Deficiency Anemia

•

Other dermatologic signs include glossitis and angular cheilitis

Malignant Carcinoid

•

Intermittent head and neck flushing

•

Explosive diarrhea

Multiple Myeloma

•

Affects elderly with bone pain, headache, cachexia, anemia, and renal failure

Neurodermatitis or Neurotic Excoriations

•

Bouts of intense itching that can awaken the patient from a sound sleep

•

Affects scalp, neck, wrist, extensor elbow, outer leg, ankle, perineum

Parasitic Infection (usually in returning travelers or immigrants)

•

Filariasis: Tropical parasite responsible for lymphedema

•

Onchocerciasis: Transmitted by black fly in Africa, Latin America

•

Schistosomiasis: Fresh water exposure in Africa, Mediterranean, South America

•

Trichinosis: Undercooked pork, bear, wild boar, or walrus meat

Parvovirus B19

•

Slapped cheek appearance in children

•

Arthritis in some adults

Peripheral Neuropathy

•

Brachioradial pruritus: Affects lateral arms of white patients in the tropics

•

Notalgia paresthetica: Midback pruritus with hyperpigmented patch

•

Herpes zoster: Accompanies painful prodrome 2 d before rash

Polycythemia Rubra Vera

•

Pricking-type itch persists for hours after hot shower or bath

Scleroderma

•

Nonpitting extremity edema, erythema, and intense pruritus

•

Edema phase with pruritus precedes fibrosis of the skin

Urticaria

•

Response to allergen, cold, heat, exercise, sunlight, or direct pressure

Weight Loss (Rapid) in Eating Disorders

•

Other signs include hair loss or fine lanugo hair on back and cheeks

•

Also yellow skin discoloration and petechiae

BOX 4 Causes of Pruritus in Pregnancy Pruritic Urticarial Papules and Plaques of Pregnancy

•

Common in the third trimester

•

Intense pruritus involves abdomen

•

Spreads to thighs, buttocks, breasts, and arms

Prurigo of Pregnancy

•

Common in second half of pregnancy

•

Extensor arms and abdomen with excoriated papules and nodules

•

Associated with atopic dermatitis

Herpes Gestationis or Pemphigoid Gestationis

•

Uncommon

•

Autoimmune condition associated with Graves' disease

•

Vesicles and bullae on abdomen and extremities in second half of pregnancy

•

Responds to prednisone[1] 0.5 mg/kg (Level A)

Intrahepatic Cholestasis of Pregnancy

•

Uncommon

•

Trunk and extremity itching without rash in late pregnancy

•

Jaundice not present in the mild form (prurigo gravidarum)

•

Responds to cholestyramine (Questran) and Vitamin K1 (Aquamephyton)[1](Level B)

Pruritic Folliculitis of Pregnancy

•

Uncommon, occurs in second half of pregnancy

•

Erythematous follicular papules over trunk, with spread to extremities

•

May be a variant of prurigo of pregnancy

Other Common Pruritic Conditions Exacerbated in Pregnancy

•

Atopic dermatitis

•

Contact dermatitis

Levels of evidence: Level A: Evidence from high-quality randomized controlled clinical trials or metaanalyses; Level B: Evidence from nonrandomized clinical studies or nonquantitative systematic reviews. 1 Not FDA approved for this indication.

In cases refractory to 2 weeks of symptomatic therapy or in which an underlying systemic cause is considered, a limited laboratory evaluation is indicated and is summarized in Table 1 . When itch persists or is refractory to general measures, remember that up to one half of older adults have pruritus caused by an underlying systemic problem.

TABLE 1 -- Diagnostic Evaluation of Pruritus for Atypical, Persistent, or Refractory Cases

Tests

Findings

Complete blood count,[*] serum ferritin[*]

Iron deficiency anemia, polycythemia rubra vera, Hodgkin's lymphoma, multiple myeloma, parasitic infection

Serum bilirubin, alkaline phosphatase[*]

Cholestasis (e.g., cirrhosis)

Serum creatinine, blood urea nitrogen[*]

Uremia (e.g., chronic renal failure)

Thyroid stimulating hormone[*]

Hyperthyroidism

Microscopy of skin scrapings, skin culture, skin biopsy

Dermatophytes, scabies; skin bacterial, fungal or viral infection; mastocytosis, mycosis fungoides, bullous pemphigoid

HIV test

HIV infection

Chest radiograph

Hodgkin's lymphoma, multiple myeloma

Stool tests

Parasites, Helicobacter pylori Children: pinworms, perianal streptococcus

* Denotes a first-line test. Unmarked tests are performed if history indicates.

Treatment Pruritus is usually self-limited and responds well to nonspecific measures such as liberal use of skin lubricants and avoidance of provocative factors ( Box 5 ). Oral antihistamines are not uniformly effective in all causes of pruritus. Specific management of dermatitis, as with atopic dermatitis, scabies, and contact dermatitis, can relieve symptoms. BOX 5 Nonspecific Management of Pruritus •

•

•

Use skin lubricants liberally •

Petrolatum or skin lubricant cream at bedtime

•

Apply alcohol-free, hypoallergenic lotions frequently during day

Avoid excessive bathing •

Briefly pat dry after bath and immediately apply skin lubricants

•

Decrease bathing frequency

•

Limit bathing to brief exposure to tepid water

Limit soap use •

Use mild, unscented, hypoallergenic soap 2 or 3 times per wk

•

Daily use of soap only in groin and axillae; spare legs, arms, and torso

•

Minimize dryness •

•

•

Choose clothing that does not irritate the skin •

Doubly rinsed cotton clothes and silk are best

•

Add bath oil (e.g., Alpha Keri) to rinse cycle when washing sheets

•

Avoid heat-retaining fabrics (synthetics)

•

Avoid wool and smooth-textured cotton clothes

Avoid vasodilators •

•

•

•

•

•

Humidify dry indoor environment (especially in winter)

Avoid caffeine, alcohol, spices, hot water, and excessive sweating

Avoid provocative topical medications •

Avoid prolonged topical corticosteroids (risk of skin atrophy)

•

Avoid topical anesthetics and antihistamines

•

May sensitize exposed skin and risk contact dermatitis

Standard antipruritic topical agents •

Menthol and camphor (e.g., Sarna Lotion)

•

Oatmeal baths (e.g., Aveeno)

•

Pramoxine[1] (e.g., PrameGel [pramoxine + menthol], Pramosone [pramoxine + hydrocortisone])

•

Calamine lotion (Use on weeping lesions only, not on dry skin)

Antipruritic topical agents for refractory cases (used in severe atopic dermatitis) •

Doxepin 5% cream (Zonalon)

•

Burow's solution (wet dressings with aluminum acetate 5% in water)

•

Unna's boot[1] (zinc oxide paste bandages)

•

Coal tar emulsion[1] (Zetar)

Systemic antipruritic agents (used in allergic and urticarial disease) •

Doxepin (Sinequan)[1] 1 mg/kg up to 25 mg at bedtime (Level A)

•

Hydroxyzine (Atarax) 0.5 mg/kg up to 25-50 mg at bedtime

•

Nonsedating antihistamines (e.g., Fexofenadine [Allegra], Level A)

Prevent complications of scratching •

Keep fingernails short and clean

•

Rub skin with palms if urge to scratch is irresistible

Level A: Evidence from high-quality randomized controlled clinical trials or meta-analyses.

CURRENT THERAPY Pruritus is usually self-limited and responds well to nonspecific measures such as liberal use of skin lubricants and avoidance of provocative factors. Antihistamines are not uniformly effective in reducing itch. Left untreated, itch and its associated persistent scratching increases risk of impetigo and cellulitis in the short term and lichen simplex chronicus and prurigo nodularis in chronic cases. In the atypical case, where these measures fail, a systemic condition may be uncovered. In these patients, the itch should be alleviated by treating the underlying condition, as with thyroid replacement in hypothyroidism or iron supplementation in iron deficiency anemia. Uremia and cholestasis-related pruritus have established effective therapies beyond treating the causative chronic renal or hepatic insufficiency ( Box 6 ). BOX 6 Specific Management of Pruritic Conditions Cholestasis

•

Cholestyramine (Questran) (Level B) •

Adult: 4 g 30 min before meals

•

Child: 240 mg/kg/d divided tid (up to 6 g/d)

•

Ursodiol (Actigall)[1] 15 mg/kg/d divided before meals

•

Ondansetron (Zofran)[1] 4-8 mg IV, then 4 mg PO q8h (Level B)

•

Opioid receptor antagonist (Level A) •

Naloxone (Narcan)[1] 0.002 mcg/kg/h IV, titrate to max 0.25 mcg/kg/h

•

Naltrexone (Revia)[1] 12.5 mg PO qd (advance to 50 mg PO qd)

•

Rifampin (Rifadin)[1] 10 mg/kg/d divided bid (max: 300 mg bid) (Level B)

•

Bile duct stenting from extrahepatic cholestasis (Level A)

•

Lidocaine (Xylocaine)[1] IV has been used

•

Bright light therapy (Level B)

•

Plasmapheresis

Neurotic Excoriation

•

Pimozide (Orap)[1] for delusions of parasitosis

•

Selective serotonin reuptake inhibitor (SSRI)

Notalgia Paresthetica

•

Topical capsaicin (Zostrix)[1] applied 4-6 times per d for several wk (Level B)

Polycythemia Vera

•

Aspirin[1] 500 mg PO q8-24h (Level B)

•

Paroxetine (Paxil)[1] 10-20 mg PO qd (Level B)

•

Interferon-a (Intron A)[1] 3-35 million IU/wk (Level B)

Spinal Opioid–Induced Pruritus

•

Ondansetron (Zofran)[1] 8 mg IV concurrent with opioid (Level A)

•

Nalbuphine (Nubain)[1] 5 mg IV concurrent with opioid (Level B)

Uremia

•

UV B phototherapy twice weekly for 1 mo (Level A)

•

Activated charcoal[1] 6 g/d (Level A)

•

Topical capsaicin[1] 0.025% cream to localized areas (Level A)

•

Ondansetron and naltrexone are not efficacious in uremia (Level A)

Levels of evidence: Level A: Evidence from high-quality randomized controlled clinical trials or metaanalyses; Level B: Evidence from nonrandomized clinical studies or nonquantitative systematic reviews. Complications Itch and the scratch it induces are not benign. When scratching is left unchecked, fingernails introduce bacteria into abraded skin, and impetigo or cellulitis can ensue. Lichen simplex chronicus and prurigo nodularis are chronic skin changes seen with long-term scratching and in particular with atopic dermatitis. Medications to treat pruritus are also not without adverse effects. Antihistamines can affect alertness and learning if used during the day, and with chronic use, the associated dry mouth can predispose to tooth decay. Follow-Up General measures to treat pruritus should be reviewed at each visit. Consistent practice of these simple home strategies can prevent sleepless nights, frequent evaluations, unnecessary medications, and the complications of scratching.



REFERENCES Belsito, 2000. Belsito DV: The diagnostic evaluation, treatment and prevention of allergic contact dermatitis in the new millennium. J Allergy Clin Immunol 2000; 105:409-420. Bender, 2003. Bender BG: Sedation and performance impairment of diphenhydramine and secondgeneration antihistamines: A meta-analysis. J Allergy Clin Immunol 2003; 111:770-776. Bergasa, 2004. Bergasa NV: An approach to the management of the pruritus of cholestasis. Clin Liver Dis 2004; 8:55-66. Berger and Gilchrest, 1998. Berger R, Gilchrest BA: Skin disorders. In: Duthie EH, Katz PR, ed. Practice of Geriatrics, 3rd ed.. Philadelphia: WB Saunders; 1998:467-472. Boiko and Zeiger, 2000. Boiko S, Zeiger R: Diagnosis and treatment of atopic dermatitis, urticaria, and angioedema during pregnancy. Immunol Allergy Clin North Am 2000; 20:839. Callen et al., 2000. Callen JP, Bernardi DM, Clark RAF, Weber DA: Adult-onset recalcitrant eczema: A marker of noncutaneous lymphoma or leukemia. J Am Acad Dermatol 2000; 43:207-210. Correale et al., 1999. Correale CE, Walker C, Lydia M, Craig TJ: Atopic dermatitis: A review of diagnosis and treatment. Am Fam Physician 1999; 60:1191-1210. Cyr and Dreher, 2001. Cyr PR, Dreher GK: Neurotic excoriations. Am Fam Physician 2001; 64:1981-1984. Diehn and Tefferi, 2001. Diehn F, Tefferi A: Pruritus in polycthaemia vera: Prevalence. laboratory correlates and management 2001; 115:619-621. Fagan, 1999. Fagan EA: Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999; 3:603-632. Finn et al., 1999. Finn AF, Kaplan AP, Fretwell R, et al: A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999; 103:10711078. Fisher, 1993. Fisher AA: Aquagenic pruritus. Cutis 1993; 51:146-147. Gelfand and Rudikoff, 2001. Gelfand JM, Rudikoff D: Evaluation and treatment of itching in HIV-infected patients. Mt Sinai J Med 2001; 68:298-308. Ghent, 1999. Ghent CN: The pruritus of cholestasis. Hepatology 1999; 29:1003-1006. Gupta et al., 1992. Gupta MA, Gupta AK, Voorhees JJ: Starvation-associated pruritus: A clinical feature of eating disorders. J Am Acad Dermatol 1992; 27:118-120. Habif, 1996. Habif TP: Clinical Dermatology, 3rd ed.. Chicago, Mosby–Year Book, 1996. Harrigan and Rabinowitz, 1999. Harrigan E, Rabinowitz LG: Atopic dermatitis. Immunol Allergy Clin North Am 1999; 19:383-396. Heymann, 1999. Heymann WR: Chronic urticaria and angioedema associated with thyroid autoimmunity:

Review and therapeutic implications. J Am Acad Dermatol 1999; 40:229-232. Koblenzer, 1999. Koblenzer CS: Itching and atopic skin. J Allergy Clin Immunol 1999; 104:S109-S113. Krajnik and Zylicz, 2001. Krajnik M, Zylicz Z: Understanding pruritus in systemic disease. J Pain Symptom Manage 2001; 21:151-168. Kroumpouzos and Cohen, 2001. Kroumpouzos G, Cohen LM: Dermatoses of pregnancy. J Am Acad Dermatol 2001; 45:1-19. Leung, 1998. Leung AKC: Pruritus in children. J Roy Soc Health 1998; 118:280-286. Lidofsky and Scharschmidt, 1998. Lidofsky S, Scharschmidt BF: Jaundice. In: Feldman M, Scharschmidt BF, Sleisenger MH, Fordtran JS, ed. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th ed.. Philadelphia: WB Saunders; 1998:230-231. Moses, 2003. Moses S: Pruritus. Am Fam Physician 2003; 68:1135-1146. Parker, 2000. Parker F: Structure and function of skin. In: Goldman L, Bennett JC, ed. Cecil Textbook of Medicine, 21st ed.. Philadelphia: WB Saunders; 2000:2266. Paus et al., 2006. Paus R, Schmeiz M, Biró T, Steinhoff M: Frontiers in pruritus research: Scratching the brain for more effective itch therapy. J Clin Invest 2006; 116:1174-1185. Robinson-Bostom and DiGiovanna, 2000. Robinson-Bostom L, DiGiovanna JJ: Cutaneous manifestations of end-stage renal disease. J Am Acad Dermatol 2000; 43:975-986. Shellow, 2000. Shellow WVR: Evaluation of pruritus. In: Goroll AH, Mulley AG, ed. Primary Care Medicine, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2000:1001-1004. Stambuk and Colvin, 2002. Stambuk R, Colvin R: Dermatologic disorders. In: Gabbe SG, Niebyl JR, Simpson JL, ed. Obstetrics: Normal and Problem Pregnancies, 4th ed.. New York: Churchill Livingstone; 2002:1283-1290. Tennyson, 2001. Tennyson H: Neurotropic and psychotropic drugs in dermatology. Dermatol Clin 2001; 19:179-197. Tormey and Chambers, 1994. Tormey WP, Chambers JPM: Pruritus as the presenting symptom in hyperthyroidism. Br J Clin Pract 1994; 48:224. Valsecchi and Cainelli, 1983. Valsecchi R, Cainelli T: Generalized pruritus: A manifestation of iron deficiency. Arch Dermatol 1983; 119:630. Veien et al., 2001. Veien NK, Hattel T, Laurberg G: Spaun E: Brachioradial pruritus. J Am Acad Dermatol 2001; 44:704-705. Villamil et al., 2005. Villamil AG, Bandi JC, Galdame OA, et al: Efficacy of lidocaine in the treatment of pruritus in patients with chronic cholestatic liver disease. Am J Med 2005; 118:1160-1163. Waxler et al., 2005. Waxler B, Dadabhoy Z, Stojiljkovic L, Rabito SF: Primer of postoperative pruritus for anesthesiologists. Anesthesiology 2005; 103:168-178.

Zirwas and Seraly, 2001. Zirwas MJ, Seraly MP: Pruritus of unknown origin: A retrospective study. J Am Acad Dermatol 2001; 45:892-896.



Chapter 11 – Tinnitus

Method of: Claus-Frenz Claussen, MD Tinnitus is noise(s) in the ear, which is usually subjective and can be extremely disturbing and frustrating to those affected. According to studies of the American Tinnitus Association, approximately 36 million Americans older than 40 years suffer from tinnitus. Tinnitus has been regarded as a disease entity for many centuries. During the second half of the 20th century, physicians were able to discriminate among several different kinds of tinnitus including bruits, maskable tinnitus, and nonmaskable tinnitus. Under the influence of Shulman and his team, the term tinnitology was coined. The present interest of researchers in the field of tinnitology is split into two fields of action: suggestions for improvement of objective and quantitative differential diagnostics in tinnitus and research and development to improve various types of treatment for different kinds of tinnitus. General Phenomena of Tinnitus A noise without any human information function, a tinnitus, can be a normal as well as a pathologic function of human hearing. On the one hand, tinnitus can be regarded as a problem of acoustic resolution of the inner ear microphone, that is, the cochlear noise-to-signal ratio. In a well-dampened soundproof chamber, most normal-hearing persons experience a sizzling sound in their ears because of their perception of molecular vibrations from inner ear fluids (as known from thermodynamics). Yet this underlying percept is masked in everyday life by normal environmental noise. On the other hand, tinnitus patients regularly tell their physicians about subjective ear noises that they describe, for example, as pulsating, humming, roaring, whistling, hissing, fullness of the ear, and pressure and/or pain in the ear. Table 1 presents the subjective sensational qualities of tinnitus in 823 tinnitus patients (77.52% male and 22.48% female with a mean age of 50.87 years ± 8.68 years) from Bad Kissingen, Germany, who underwent clinical inpatient rehabilitation therapy for several weeks for severe disabling tinnitus.

TABLE 1 -- Subjective Classification of Ear Noises in 823 (= 100%) Tinnitus Patients Complaints Right Ear (%) Left Ear (%) Pulsating

1.94

1.94

Humming

7.41

6.93

Complaints

Right Ear (%) Left Ear (%)

Roaring

14.10

14.22

Whistling

50.67

51.76

Hissing

9.96

10.81

Pressure in the ear 6.32

5.83

Pain in the ear

14.22

14.10

In these same patients, we looked for descriptions of different time/intensity patterns of their tinnitus ( Table 2 ), and the subjective background of discomfort was investigated as shown in Table 3 . Additionally, the patients named the most irritating factors related to their tinnitus ( Table 4 ).

TABLE 2 -- Subjective Classification of Different Time/Intensity Patterns of Tinnitus in 823 (= 100%) Patients Time/Intensity Patterns

%

Permanent

59.17

Intermittent

19.97

Swelling up and going down 43.26

TABLE 3 -- Subjective Classification of Subjective Background of Discomfort in 823 (= 100%) Patients Subjective Complaints About Factors of Discomfort

%

Headache

69.02

Migraine

4.13

Exhaustion

59.99

Lacking in drive

42.16

Feeling of weakness

55.29

Forgetfulness

68.41

Disorientation

0.49

Daze

44.84

Tiredness

63.91

Insomnia

69.50

TABLE 4 -- Subjective Classification of Most Irritating Factors Related to Their Tinnitus in 823 (= 100%) Patients

Most Irritating Factors Related to Tinnitus

%

All patients with specific additional statements 25.76 Difficulties in going to sleep

10.69

Difficulties in sleeping through the night

11.06

Depression

0.24

Abnormal sounds (also hallucinations)

2.67

Acute hearing loss

8.38

Sleep disturbance is a common and frequent complaint. Scientific studies report decreased tolerance and increased discomfort when insomnia and depression are associated with tinnitus. In 1991, a sample of 338 New Zealanders regularly experiencing tinnitus completed and returned questionnaires to associations for people with tinnitus or hearing impairment. Nearly half the sample was sometimes depressed because of tinnitus. Those reporting depression and those reporting more severe problems as a consequence of the tinnitus saw more health care professionals and used more coping strategies. Most respondents did not remember exactly when they first noticed the tinnitus.

CURRENT DIAGNOSIS Irritating subjective or objective perception of irritating acoustic noise or sound in the ear, head, or body that may be described, for example, as: Pulsating Humming Roaring Whistling Hissing A questionnaire investigation comprising 1091 patients from Bispebjerg Hospital, Copenhagen (1993), concerning “tinnitus-incidence and handicap,” was conducted at a hearing center. A majority of patients, 59%, claimed that they were troubled by tinnitus. Neither a greater degree of hearing loss nor a longer duration of tinnitus was associated with more severe tinnitus. Among patients with both subjective hearing loss and tinnitus, 23% stated that tinnitus was the greater problem, and 38% said that tinnitus and hearing loss were equally troublesome. The corresponding figures for patients with hearing impairment of such a degree that a hearing aid was deemed necessary were 9% and 41%, respectively. Stress symptoms such as headache, tension of facial muscles, and sleep disturbances were correlated to tinnitus. Of patients with tinnitus, 83% were interested in obtaining treatment for it. The so-called Copenhagen Male Study reported on the results from a 10-year follow-up examination concerning hearing and factors known to cause hearing problems. The original sample comprised 5050

subjects, and at the present examination, 3387 (67%) men at a median of 63 years of age (range, 53 to 75 years) participated. An increasing prevalence of 30% to 40% of hearing problems was demonstrated with increasing age. A prevalence of 17% of tinnitus of more than 5 minutes' duration was found; 3% indicated that tinnitus was so annoying that it interfered with sleep, reading, and/or concentration. The prevalence of tinnitus increased up to 70 years of age and seemed to remain constant thereafter. In Norway, 15% of the adult population has experienced shorter or longer periods of tinnitus. Three percent of these, in total approximately 7000 to 10,000 persons, suffer from continuous tinnitus followed by symptoms that represent a handicap or occupational disability. Similar observations were reported from many other countries. Clinical Types Tinnitus is no longer considered to be a syndrome or a single disease. Because of improvements in neurootometry, several different types of tinnitus can be differentiated. By means of modern audiometry, the framework for normal hearing can be described objectively and quantitatively. Therefore, in any tinnitus case, a thorough analysis of the hearing function and pathways needs to be performed including threshold audiometry, audiometric tinnitus masking (if possible), acoustic dynamics between the measurable thresholds of hearing and acoustic discomfort, speech audiometry, otoacoustic emissions, acoustic brainstem-evoked potentials, and acoustic late-evoked potentials. Thereby signs of pathology within the hearing pathways between the ear and the human brain cortex can be measured. Thus, we know from thorough neuro-otologic studies that approximately 24% of cases of disabling tinnitus have their source within the otoacoustic periphery (i.e., inner ear and the eighth cranial nerve). Approximately 35% originate from the acoustic pathways within the brainstem. Approximately 41% have their cause within supratentorial structures and/or functions. These pathologies also should serve as basic information for planning systematic pharmacotherapy directed to the central nervous system (CNS) focus of dysfunction. At least four different kinds of tinnitus ( Figure 1 ) can be discriminated, which can be determined by the physician using a simple question-and-answer procedure as follows.

FIGURE 1 Categories of physiologic and clinical types of tinnitus.

BRUITS

Q:

Has someone informed you that he or she could hear a noise coming from your head?

A:

Yes. Their description of what they heard listening from outside my head is similar to what I perceive.

By means of auscultation through a stethoscope or a microphone, a real sound can be objectively heard emanating from the patient's skull. Patients frequently report, for example, a bubbling, hissing, or pulsating sound. The cause can be vascular in origin, that is, abnormal curling of blood caused by atheromas, vascular dissections, scars, compressions, or high blood pressure amplitudes, for example. Bruits also can originate from the middle ear and its connections toward the epipharynx: middle ear

inflamma tions with bubbling sounds of gas from within the effusions, whizzing middle ear muscles, or an open eustachian tube. Cracking sounds, which are misinterpreted as tinnitus, are reported from arthritic and other mandibular joint disorders. Also, sounds can be transferred from the cervical spine and its joints as well as its vessels into the cranial structures so that they become misinterpreted as tinnitus. ENDOGENOUS TINNITUS

Q:

Where is your feeling of well-being better, in a busy and noisy environment or in cavelike silence?

A:

I much prefer a busy and noisy environment. The patient with a maskable or endogenous tinnitus prefers covering it with external sounds. When using masking procedures, easily three zones of tinnitus can be discriminated within the hearing field:

1.

Low-tone tinnitus (at and below 750 Hz)

2.

Middle-frequency tinnitus (1 to 2 kHz)

3.

High-frequency tinnitus (above 2 kHz until 10 kHz or even 12 kHz)

Low-tone tinnitus is more frequently found in Ménière's disease and some other cochlear-apical disorders, and middle-tone tinnitus is more frequently found in diseases such as otosclerosis. Most frequently tinnitus is matched in the high-tone range and is related, for example, to noise trauma, whiplash, head and skull trauma, cardiovascular failure, stress, acoustic neuromas, and toxic events including those associated with pharmaceutical, nicotine, or drug abuse. Also, several masking points may exist simultaneously. Dysfunctions of the inner ear contribute to the development of tinnitus. But tinnitus by itself depends on a cortical process of the human brain. A sleeping patient does not suffer from any kind of tinnitus. Since approximately 1985, the Würzburg neuro-otology group of Claussen et al. has been able to detect by means of vestibular evoked potentials (VestEP) and brain electrical activity mapping (BEAM) groups of patients suffering from a maskable or endogenous tinnitus that respond cortically in a typical, reproducible, and measurable manner: 1.

Location of the site of the potentials around the upper gyrus of the temporal lobe (Brodmann's area 41)

2.

Typical shortening of the latencies of evoked quantitative electroencephalograms (QEEGs) (i.e., VestEP waves I, II, III)

3.

Enlarged DC shift of the evoked QEEGs (i.e., difference between VestEU waves III and IV)

4.

Typical cortical electrical burst expansion in three phases on the brain surfaced

Since approximately 1990, the New York group of Shulman, Strashun, and Goldstein has followed a neuroradiologic path for deciphering the cortical modalities in tinnitus patients by using single-photon emission computer tomography (SPECT). They discovered remarkably elevated metabolic processes in the temporal lobes of patients suffering from a maskable tinnitus. Thereafter we were able to prove in therapeutic trials with pharmacotherapy (e.g., extractum ginkgo biloba

[EGB 761][*]), as well as with physiotherapy (competitive kinesthetic interaction therapy [KKIT]), that the subjective reduction or abolition of tinnitus goes together with an electrophysiologic measurable normalization of the VestEP with BEAM or QEEG. So the endogenous tinnitus could be proven to be a CNS network phenomenon. * Available as dietary supplement.

EXOGENOUS TINNITUS

Q:

Where is your feeling of well-being better, in a busy and noisy environment or in cavelike silence?

A:

I much prefer a cavelike silence because noise and/or a group of people speaking at the same time are most confusing. It provokes ringing and shrieking sounds within my ears.

Unlike endogenous tinnitus, patients suffering from exogenous tinnitus cannot benefit from masking noises from their surroundings. Some physicians wrongly call this condition hyperacusis, but these patients do not hear better as this term suggests. Seemingly better is the named syndrome of the hypersensitive ear. In exogenous tinnitus, pure-tone audiometry may be normal or exhibit regular deficits of the hearing threshold, but there is no maskable tinnitus. However, when measuring the acoustic dynamics by adding the audiometrically recorded discomfort threshold, the discomfort level, which is usually between 1 and 8 kHz below 95 dB, rises below this level to values of 90 to 60 dB or even 50 dB. The person being exposed to sound exceeding the level of his low discomfort threshold experiences a loss of understanding together with subjective pain and noise in the ears accompanied by possible vegetative reactions. Hearing aids can adjust the incoming sounds by filtering, peak clipping, and cleaning of the sound signals so they fit optimally into the remaining acoustic dynamics of the individually existing hearing field. Thus, hearing aids are the first choice for treating exogenous tinnitus. Some other methods for treating this type of tinnitus are physiotherapy, psychotherapy, stress reduction, and supportive pharmacotherapy. TINNITUS IN SLOW BRAINSTEM SYNDROME (CLAUSSEN)

Q:

How would you best describe your tinnitus?

A:

I am becoming increasingly more in a daze and more disoriented and hear ringing and other sounds, which I cannot really localize in my ears or my head. The noise disturbs me as much as my mental instability.

We regularly see older patients who complain about a hazy tinnitus in combination with vertigo, giddiness, and dizziness and also report a reduced state of alertness. These patients have a connected statoacoustic problem. Objectively, affected patients exhibit an increase in the latencies of the experimentally provoked vestibular nystagmus as well as of the acoustically evoked brainstem potentials. Especially in this group, we have noted by evaluating our therapeutic responses that a combination of cocculus[†] (picrotoxin), conium[†] (coneine), amber and petrol oil (Vertigoheel[†]) has a so-called tuning-up effect on the brainstem. Then the typical symptoms also disappear.

† Available as homeopathic remedy.

COMBINED ENDOGENOUS AND EXOGENOUS TINNITUS A combination of both types of subjective tinnitus, endogenous and exogenous, is also found in tinnitus patients. Affected patients report that the noise they hear is present during both the day and night; however, the noise fluctuates. Especially the intensity of the noise can be very increased, for example when the patient is in a noisy environment or busy place or in a conversation with several participants. Even though patients with combined endogenous and exogenous tinnitus have maskable tinnitus, they report that therapeutic acoustic maskers do not reduce their symptoms. They need a thorough audiometric and neuro-otologic workup. Contemporary and Practical Treatment Modern therapy of tinnitus appears to be complex and sometimes incomprehensible. But when talking about therapy of disabling tinnitus, we emphasize a main therapeutic approach in the sense that we have to break and inhibit the psychosomatic cycle of deterioration from tinnitus to stress, to insomnia, to panic. Some aspects of this reactional behavior are similar to pain. The steps for individual tinnitus therapy must be chosen according to the kind of tinnitus diagnosed. Tinnitus is frequently associated with conditions such as stress, hearing loss, noise trauma, otorhinolaryngologic disorders (e.g., Ménière's disease, otosclerosis, perilymphatic fistula, acoustic neuroma), high blood pressure, metabolic disorders, allergy, intoxications, whiplash and other head and neck traumas, functional disorders of the neck, burnout syndrome, mandibular joint problems, and extracranial and intracranial vascular problems. The Current Therapy box lists different therapeutic approaches to tinnitus. These ten therapies must be individually interrelated with the different types of tinnitus (see Figure 1 ). Besides the severe disabling types of tinnitus, minor forms of tinnitus also occasionally occur that may be event related or may be time limited. NOISE AVOIDANCE AND BASICS OF THERAPY Avoidance can help in noise-related tinnitus by the prevention of noise exposure or at least by wearing ear protection. The use of ototoxic drugs must be controlled and limited. Inflammatory ear disease needs specific treatment of the external and the middle ear with antibiotics and anti-inflammatory drugs. Control and maintenance of a satisfactory degree of aeration of the middle ear is necessary. Acoustic neuroma calls for surgical removal of the tumor. Surgery is also necessary in otosclerosis and perilymphatic fistula. Specific gnatholic therapy by a dentist is recommended in a temporomandibular joint syndrome. INSTRUMENTATIONS FOR THERAPY Instrumentations currently available and frequently used according to the type and the chronicity of tinnitus are as follows:

1.

Tinnitus maskers/tinnitus instruments, tapes/CDs for masking and relaxation

2.

Acoustic ultra-high-frequency stimulation

3.

Hearing aids

4.

External electrical stimulations

5.

External magnetic stimulation

PHARMACOTHERAPY Pharmacotherapy, that is, treatment with pharmaceutical agents, is important in the management of tinnitus. It may be the main therapy or may play only a supportive, palliative, or intermittent role. The four lines of therapeutic agents used in the treatment of tinnitus may overlap and may be combined. First-Line Agents

First-line therapeutic agents can relieve tinnitus either slowly or quickly. Lidocaine (Xylocaine),[1] a local anesthetic drug, only has a temporary effect in suppressing tinnitus. It is an aminoethylamide, which is well soluble in water. A daily intravenous dose of lidocaine of 1 mg per kg of body weight can temporarily alleviate the phenomenon of endogenous tinnitus. The duration, however, depends on the blood level. As soon as the level of lidocaine in the blood is lowered below a threshold, tinnitus returns. In tinnitus, lidocaine is best applied by iontophoresis through an electrical field with an active electrode in the external ear and a passive electrode at an arm, after instillation of a solution of lidocaine (1:100,000) into the external meatus. This therapy temporarily relieves the disturbing tinnitus, so that the patients at least get some hours of rest and sleep. However, the untoward side effects of lidocaine also have to be taken into consideration. Some forms of tinnitus also have an acoustic hallucinatory component, as in epilepsia. Therefore, carbamazepine (Tegretol),[1] which is an important antiepileptic agent used for bipolar affective disorders, is also used in tinnitus with a supratentorial focus. We have seen beneficial effects in very specific cases of endogenous tinnitus. Chemically, carbamazepine belongs to the tricyclic antidepressants. In adults, we give a daily dose of 200 mg. However, renal, hepatic, and hematologic parameters have to be monitored thoroughly. 1 Not FDA approved for this indication.

Second-Line Agents

This group of drugs is especially used to treat the emotional effects seen in endogenous tinnitus, exogenous tinnitus, and combined endogenous and exogenous tinnitus, which can lead via sleeplessness to anxiety and panic. Here we see an indication for alprazolam (Xanax)[1] and similar substances. Alprazolam is

administered to tinnitus patients in a daily dosage of 0.75 to 1.5 mg. Also chlordiazepoxide (Librium)[1] can alternatively be applied in a daily dosage of 15 to 30 mg. Even diazepam (Valium)[1] is used in a daily dosage of 4 to 30 mg.

CURRENT THERAPY Avoidance of noise, ototoxic drugs, allergens Treatment of bruits by medical or surgical measures Instrumental therapy Tinnitus maskers Hearing aids Electrostimulation Specific pharmacotherapy Lidocaine (Xylocaine)[1] Carbamazepine (Tegretol)[1] Calming pharmacotherapy Diazepam (Valium)[1] Amitriptyline (Elavil)[1] Nontropic pharmacotherapy Gingko[*] Flunarizine[2] Neurotransmitter-directed pharmacotherapy Betahistine[*] Gabapentin (Neurontin) Psychotherapy Retraining therapy (TRT) Physiotherapy Competitive kinesthetic interaction therapy (KKIT) Other therapies Hypnotherapy Counseling Acupuncture The mood changes associated with tinnitus can lead to psychosis and insomnia. Here a tricyclic

antidepressant such as amitriptyline (Elavil)[1] in a daily dosage of 75 to 150 mg can be helpful. Additionally, this agent has a desired sedative component. Other sedatives and psychotropic drugs are also used to treat the psychologic effects associated with tinnitus, but they must be applied very carefully. Third-Line Agents

Third-line therapeutic agents comprise the so-called nootropic drugs. These are pharmacologic agents that activate brain function through improved metabolism, leading to a better adaptation and interconnection. They were originally developed to treat senile dementia. Within this group, in Germany, we use piracetam (Nootrop, Normabraïn) in a daily dosage of 800 to 1200 mg. We have seen very beneficial effects from extract of ginkgo biloba (EGB 761[*]) (Tebonin, Rökan), which is administered in a daily dosage of 120 mg. We also use calcium channel antagonists, among which flunarizine (Sibelium), [*] in a daily dosage of 15 to 30 mg, is effective in tinnitus with irritative foci, especially in mesencephalic and diencephalic areas. Cinnarizin[*] was the predecessor. This holds especially for the endogenous tinnitus group. Fourth-Line Agents

The fourth line of therapy involves neurotransmitter-directed pharmacotherapy. According to the chemical structures of the neurotransmitters, we mainly use one system of the amines (i.e., the histamine mechanism) and one system of amino acids (i.e., -aminobutyric acid [GABA]). Because it is known that inner ear functions are regulated at the neurotransmission level of the histaminergic H1, H2, and H3 receptors, betahistine (Serc)[2] plays an important role in inner ear receptor-targeted therapy. The daily dosage that we administer in peripheral cochlear tinnitus is 16 to 48 mg. The inhibitory neurotransmitter GABA is extremely potent in its ability to alter neuronal discharges because of failures in the supratentorial CNS neurotransmission. According to recent findings, endogenous tinnitus with a supratentorial dysregulation can be influenced by gabapentin (Neurontin).[1] It is used in dosages starting with 300 mg daily and can be increased to 900 mg daily. Originally gabapentin was used as an additional therapy in partial epilepsia without secondary generalized seizures. Like with other antiepileptic drugs, the parameters from kidney, liver, and blood have to be supervised. 2 Not available in the United States.

ADAPTED PSYCHOTHERAPY Nowadays so-called tinnitus retraining therapy (TRT) is widely applied. It includes a therapeutic wide-band low-level noise generator. It is based on habituation, which is defined as a reduced response to a stimulus after repeated exposure. It is a state in which the tinnitus signal no longer elicits any response. Resetting or reprogramming neuronal networks involved in subcortical signal detection brings about habituation.

Also, in cases with a known interrelation of stress and tinnitus, a stress–diathesis model for tinnitus was proposed by Shulman et al. Stress management techniques require a counselor and the close cooperation of the patient, physician, biofeedback therapist, and psychologist. A cognitive therapy that provides significant support to the patient with severe disabling tinnitus, particularly for control of the effect, is strongly recommended and encouraged. ADAPTED PHYSIOTHERAPY A specific program of physiotherapy successfully applied in endogenous tinnitus is KKIT. This therapy uses expressive movements of body language. In a special rehabilitation program, different groups of muscles in the hand, arm, leg, foot, and body, rising from the feet up to the face, are activated, which guides the tinnitus patient into a situation of peaceful resting, reduction of tension, and finally into relaxation. This scheme was adapted from a program of treating pain. KKIT points toward mechanisms of interference of expressive gestural movements with facilitating tinnitus from around the basal ganglia of the brain. OTHER METHODS OF THERAPY Other methods of tinnitus therapy recommended in the literature include acupuncture, counseling, group therapy, and hypnotherapy.



REFERENCES Alster et al., 1993. Alster J, Shemesh Z, Ornan M, Attias J: Sleep disturbance associated with chronic tinnitus. Biol Psychiatry 1993; 34:84-90. Arnesen and Engdahl, 1996. Arnesen AR, Engdahl B: Tinnitus—etiology, diagnosis and treatment. Tidsskr Nor Laegeforen 1996; 116:2009-2012. Bergmann and Bertora, 1996. Bergmann JM, Bertora GO: Cortical and brainstem topodiagnostic testing in tinnitus patients—a preliminary report. Int Tinnitus J 1996; 2:151-158. Bertora and Bergmann, 2004. Bertora GO, Bergmann JM: Tinnitus: Supratentorial areas study through brain electric tomography (LORETA). ASN 2004; 2:2.ISSN 1612-3352. Claussen, 1985. Claussen CF: Treatment of the slow brainstem syndrome with Vertigoheel. Biol Med 1985; 3:447-470.4:510-514. Claussen. Claussen CF: Medical classification of tinnitus between bruits: Exogenous and endogenous tinnitus and other types of tinnitus. ASN 2004;2, ISSN 1612-3352. Available at http://www.neurootology.org

Claussen et al., 1991. Claussen CF, Kolchev C, Schneider D, Hahn A: Neurootological brain electrical activity mapping in tinnitus patients. Proceedings of the 4th International Tinnitus Seminar, Bordeaux 1991; 1092:351-355. Claussen et al., 1995. Claussen CF, Schneider D, Koltchev C: On the functional state of central vestibular structures in monaural symptomatic tinnitus patients. Int Tinnitus J 1995; 1:5-12. George and Kemp, 1991. George RN, Kemp S: A survey of New Zealanders with tinnitus. Br J Audiol 1991; 25:331-336. Jastreboff and Hazell, 1993. Jastreboff PJ, Hazell JWP: A neurophysiological approach to tinnitus: Clinical implications. Br J Audiol 1993; 27:1-11. Parving et al., 1993. Parving A, Hein HO, Suadicani P, et al: Epidemiology of hearing disorders. Some factors affecting hearing. The Copenhagen Male Study. Scand Audiol 1993; 22:101-107. Quaranta et al., 1996. Quaranta A, Assennato G, Sallustio V: Epidemiology of hearing problems among adults in Italy. Scand Audiol Suppl 1996; 42:9-13. Shulman, 1996. Shulman A: A final common pathway for tinnitus—the medial temporal lobe system. Tinnitus J 1996; 2:115-126. Shulman et al., 1991. Shulman A, Aran JM, Feldmann H, et al: Tinnitus diagnosis/treatment, Philadelphia, Lea & Febiger, 1991. Shulman et al., 1995. Shulman A, Strashun AM, Afriyie M, et al: SPECT imaging of brain and tinnitus—neurotologic/neurologic implications. Int Tinnitus J 1995; 1:13-29.



ACKNOWLEDGMENT Sponsored by grant Projekt D. 1417, durch die LVA Baden-Württemberg, Stuttgart, Germany.



Chapter 12 – Spine Pain

Method of: Michael T. McCann, MD Back pain is one of the most common musculoskeletal complaints seen in primary care practices; empirical treatment is frequently based on conjecture. Our understanding of the pathophysiology of spine and radicular pain has increased dramatically over the last decade as a result of new technology and more advanced diagnostic testing. Early and accurate diagnosis is imperative if we are to provide specific lesionbased treatment to optimize patient outcomes and health care spending. Although patients are satisfied with their care for most major illnesses, 20% to 25% of surveyed patients were dissatisfied with their care for back pain. Only headache treatment also received such poor scores. The top reason patients listed for dissatisfaction with their physician's care was inadequate explanation of why they hurt. Although muscle strain is the most common reason given to patients as the cause of their back pain, it is actually highly unlikely to be the etiology for back pain severe enough for a patient to seek medical care or for pain that lasts more than 2 weeks. An underlying spinal disorder is usually present, leading to overlying myofascial tenderness and tightness. Isolated back pain is not a neurologic problem. Rather, it is an orthopedic problem, as will be evident from the following discussion. Epidemiology Eighty percent of the U.S. population develops back pain, limiting day-to-day activities, at some time in their lives. The peak incidence of such pain is between 35 and 65 years of age, declining thereafter. Based on radiographic degeneration alone, we would expect the incidence to increase linearly with age. In 80% of patients, episodes are self-limited, but in 15% to 20%, the pain chronically restricts function. Direct and indirect economical costs are estimated to be between $80 and $100 billion per year in the United States and, from an insurer's standpoint, costs may exceed expenditures on pediatric and obstetrical care combined. The majority of treatment expenditures are on the 20% of patients whose pain does not resolve spontaneously: recurrent or chronic back pain sufferers. To limit expenditures and optimize patient outcomes, it is vital that we prevent progression to a chronic state. Such prevention can best be achieved by early and accurate diagnosis and treatment. Pathophysiology Somatic (nociceptive) pain is caused by noxious stimulation of nerve endings in the vertebrae, joints, ligaments and disks, whereas radicular (neuropathic) pain is produced by evoked ectopic impulses in the dorsal root ganglia ( Figure 1 ).

FIGURE 1 Spine cross section.

Somatic Pain In primary somatic back pain, we try diagnostically to separate the pain generators into two anatomic categories based on their relation to the spinal canal. Treatment is significantly different based on the site of the lesions. Note that primary spinal nerve or cord pathology does not in and of itself produce axial back pain. Pain generators in the anterior column are the disks and vertebral bodies. Only the outer third of a disk's annulus is innervated. Tears of these outer annular fibers produce exquisite pain and back spasm even without complete disruption of the disk. This is a frequent missed cause of nonspecific back pain because these internal disk disruptions are rarely visualized on routine spine magnetic resonance imaging (MRI) or

computer tomography (CT) scans. If noted on MRI, a high-intensity zone (HIZ) finding in a disk is highly suggestive of a painful internal annular tear. Definitive diagnosis is established with manometric provocative CT diskography. Diskitis, although rare, is also suggested by MRI findings, although aspiration may be necessary to establish an inflammatory or infectious etiology definitively. Vertebral compression fractures, whether osteoporotic, traumatic, or pathologic, also contribute to anterior column primary axial pain. CT scanning or plain radiographs generally confirm the diagnosis; however, bone scanning may be necessary to confirm acuteness of a finding and to help rule out metastatic foci. Osteomyelitis should also be considered in any fracture with associated fever or a recent septic source. The posterior column sources of back pain include the facet joints from the atlanto-occipital articulation caudad to the sacroiliac joints. All are true diarthrodial joints. The surfaces are capped with articular cartilage and lined with a synovial membrane. These paired innervated structures are subject to degeneration and painful traumatic injuries. In double-blind placebo controlled studies, the cervical facets appear to be the source of pain in 59% of patients with postwhiplash cervicalgia. Estimates regarding the lumbar spine place the incidence of facet-based low back pain between 15% and 40%, and the incidence increases significantly after 65 years of age. Spondylolisthesis refers to a shift in the alignment between two vertebrae. With associated stress fractures of the pars interarticularis (spondylolysis), it is another posterior column source of pain. In chronic cases, instability leads to associated fibrosis under the pars fractures that produce radicular compression and neuropathic extremity pain. The slippage may also lead to central and foraminal stenosis with neurogenic claudication. Neuropathic Pain The most common cause of lumbar radicular pain in young patients is disk herniation (98%). Nerve compression alone, however, does not offer a satisfactory explanation for the pain produced. In human studies, root compression alone produces distal extremity paresthesias and numbness but no pain. Isolated lumbar radiculopathy does not cause significant back pain, and disk herniation size does not correlate with severity of pain on straight leg raise testing. Nucleus pulposus placed within the epidural space produces extreme inflammation with a 100,000-fold increase in phospholipase-A2 immunoreactivity that can be directly correlated with mechanical hyperalgesia. In the complete absence of root compression, nucleus pulposus stimulates sustained discharges of Ad and Aß pain fibers in the dorsal root ganglia and causes a conduction delay in the roots. Intravenous methylprednisolone (Solu-Medrol)[1] prevents this conduction delay. Radicular pain appears to be caused by a combination of mechanical irritation in an otherwise chemically sensitized root. Other sources of radicular pain include central spinal and lateral recess stenosis caused by facet arthropathies, ligamentous hypertrophy, and spondylolisthesis. Even more etiologies include neuromeningeal anomalies, neoplasms, infections, and vascular malformations. Peripheral neuropathies, including thoracic outlet, cubital and carpal tunnel syndromes, piriformis syndrome, tarsal tunnel, and other primary mononeuropathies, may also mimic or exist in conjunction with radiculopathies. 1 Not FDA approved for this indication.

Assessment The goal of the initial assessment is to screen for emergent causes of back or radicular pain including aneurysms, infections, segmental instability, fractures, tumors, and myelopathy. A careful history and examination should help delineate referred cardiac, pulmonary, gastrointestinal, urologic, gynecologic, and vascular sources. History For all patients presenting with back or radicular pain, the screening history should include weight loss, recent fevers or infections, and significant change in bowel or bladder function, including incontinence. For patients with cervicothoracic or upper extremity radicular pain, a cardiac history should be added. Abdominal symptoms, hematuria, dysuria, or vaginal discharge should be included for lumbar pain. Radicular pain is lancinating with superficial and deep components that extend in distinct, but not necessarily dermatomal, distributions. Pain may extend partially or entirely in the distribution of the affected spinal nerve. Somatic referred pain is deep, aching, and diffuse. It can overlap with radicular symptoms in the proximal extremities. Proximal extremity pain can be radicular, whereas distal extremity pain is not necessarily always radicular. Diffuse distal symptoms with dysesthesia, complaints of bowel or bladder urgency or incontinence, and a history of balance difficulties are red flags for myelopathy. Most patients also give a history of cervicothoracic or associated radicular pain. If accompanied by severe low back pain and complaints of saddle numbness, consider cauda equina syndrome, a surgical emergency. Claudication symptoms are suggestive of spinal stenosis and usually there is little pain at rest. Differentiation from vascular claudication is sometimes difficult, but pain with neurogenic claudication is usually not worsened with supine positioning and leg elevation. Examination Although clinical exam may establish the presence of a radiculopathy or localize the segmental pain level, etiology must be established by other means. Tumors, cysts, stenosis spondylolisthesis, and disk herniations may all cause very similar clinical signs. Muscle pain and spasm should not be considered the primary source of the patient's back pain unless all other potential sources are ruled out and an objective rheumatologic etiology is identified pointing to a myositis. An antalgic gait from distal degenerative joint disease may cause lumbar muscular aching, but rarely is the back the site of greatest pain. This is not to say that muscles cannot be painful, but rather that in the majority of primary back pain cases, the muscles are simply reacting to an underlying derangement in the spine itself. More specifically, examination should note hyperreflexia and clonus and test for Babinski's and Hoffmann's signs to note upper motor neuron irritability. Screening cardiovascular and abdominal examination helps rule

out other sources of back pain.

CURRENT DIAGNOSIS Emergent or Urgent Conditions Associated with Back Pain (Red Flags)

ASSOCIATED SYMPTOMS

CONDITION

New onset bowel or bladder incontinence

Myelopathy

Balance difficulties

Myelopathy

Diffuse distal weakness or immobility

Myelopathy

Recent weight loss

Tumor

Severe chest or abdominal pain

Aortic aneurysm

HISTORY

CONDITION

Osteoporosis

Fracture

Recent trauma

Fracture

Intravenous drug use

Infection

Recent infection

Infection

Immunosuppressed state

Infection

AGE

CONDITION 60 y

Tumor suspicion

Male >55 y (M:F 4:1)

Aortic aneurysm

ASSOCIATED SIGNS

CONDITION

Tender abdomen

Aortic aneurysm

Saddle sensory loss

Cauda equina syndrome

Hyperreflexia with positive clonus, Babinski's sign, and Hoffmann's sign Myelopathy

Natural Course of the Disease

For lumbar radicular pain in patients treated conservatively, 50% of patients can expect to have resolution of radicular symptoms after 4 weeks. At 12 months, in 49% of males and 33% of females, radicular pain remains improved. Unfortunately, 60% to 70% of these patients developed back pain by 4 weeks that persisted at 12 months regardless of the radicular pain improvement. For patients treated surgically versus conservatively, at 10 years there appears to be little statistically significant difference in outcome for radicular pain, with both groups achieving approximately 60% good results and poor results in 7% to 8%. This only holds true if surgery is not applied randomly, but as a last resort for patients who fail to respond to conservative care. For cervical radiculopathic symptoms, 70% can be expected to improve with time and 20% become asymptomatic. In patients for whom surgery was an option, 90% are improved or only mildly incapacitated at long-term follow-up. Isolated recurrences are seen in 32% of cases, whereas 10% have moderate to severe persistent disability. Although studies exist detailing favorable outcomes overall for radicular symptoms, the same does not necessarily hold true for mechanical back pain. Although 80% of patients appear to have resolution of initial symptoms independent of their course of care, 20% develop progressive or unrelenting pain. It appears that approximately 35% of persons have intermittent recurrences that limit their activities. Management Take an algorithmic approach to the patient presenting with back and/or radicular symptoms of new onset. If initial history and examination suggest an emergent cause for these symptoms, appropriate additional diagnostic testing and referral should be made. Indications for urgent surgical interventions are few but include progressive motor deficit and cauda equina syndrome—progressive neurologic deterioration with loss of bowel and bladder function. Once an emergent source of pain is ruled out, studies show that primary care physicians who prescribe the least amount of analgesics and place the fewest restrictions on activities have the best patient outcomes. In many cases, a more aggressive approach may reinforce illness behavior and foster a fear of future debilitation. Radicular Pain Predominating If radicular pain predominates in a minimally distressed patient, simple reassurance and an explanation of the natural course of recovery may suffice. Avoiding bed rest and activity modification to prevent axial loading should be discussed (no lifting in a forward flexed position and no repetitive flexion activities). A 2week reassessment allows any insidious red flag conditions to be picked up, provides reassurance, and allows adjustment of treatment. For more significantly distressed patients with acute radicular pain, additional analgesics and more frequent follow-up may be required. Although no analgesic regimen alters the natural course of recovery, based on the inflammatory pathogenesis of radicular pain a pulse dose of prednisone or methylprednisolone with a

taper can be considered over a week. However, in randomized controlled trials, the nonsteroidal antiinflammatory drugs (NSAIDs) piroxicam (Feldene) and indomethacin (Indocin) did not offer any greater analgesia or enhance recovery more than placebo. A limited course of muscle relaxants and opioid analgesics may be prescribed but often provide little relief in cases of true neuropathic pain. The limited duration of these prescriptions should be explained to the patient at the outset. Despite ongoing pain, the goal is to avoid dependency and reliance on these medications for activities that may be detrimental to the natural course of the disorder. Currently, greater success may be found with early initiation and titration of gabapentin (Neurontin)[1] for radicular pain. With low toxicity and few side effects, tolerance is usually good. Initiate dosing at night with 100 to 300 mg (lower dosing in patients APV, fAPV = ATV > NVP > ABC, TPV[d]

Cotrimoxazole, sulfadiazine, dapsone, atovaquone, voriconazole

Antihistamines; continue offending drug; watch for progression of rash; if so, discontinue.

GI intolerance[e]

Anorexia, nausea, vomiting, epigastric pain

PIs, ddI, ZDV

Isoniazid, rifamycins, Administer with food (not pyrazinamide for ddI, unboosted IDV); antiemetics; switch to less emetogenic ARV.

Diarrhea

PIs, especially NFV, LPV/r, and buffered ddI formulations

Clindamycin, atovaquone

Jaundice, fever, vomiting, hepatic necrosis, encephalopathy

NVP

Isoniazid, rifamycins, Discontinue all ARVs and pyrazinamide any other possible drug; rule out viral hepatitis; supportive management; do not rechallenge NVP.

Symptomatic or subclinical hepatic enzyme elevations

NNRTIs, d4T, ddI, ZDV, PIs, especially TPV

Isoniazid, rifamycins, pyrazinamide, azithromycin, clarithromycin, all azole antifungals

If symptomatic, discontinue all ARVs and switch to nonhepatotoxic ARVs after normalization; if asymptomatic, monitor closely.

Hepatotoxicity[f]

Rule out OIs; antimotility agents, calcium salts, bulk forming agents; rehydration, if needed.

Lactic acidosis, fatty liver[g]

Nonspecific GI NRTIs especially symptoms, tachypnea, d4T, ddI, ZDV tachycardia, hepatomegaly, hyperlactatemia, multiorgan failure

Metformin

Discontinue all ARVs; hydration; supportive treatment; IV thiamine/riboflavin; switch to ABC/3TC/TDF or NRTI-sparing regimens.

Pancreatitis[g]

Epigastric painddI, d4T, ddC, postprandial, vomiting, RTV; 3TC (in fever, elevated children) amylase, lipase

Alcohol, cotrimoxazole, pentamidine

Discontinue offending drugs; manage like acute pancreatitis related to any other cause; do not rechallenge.

Peripheral neuropathy[g]

Numbness, paresthesia–often painful; recovery possibly incomplete

Isoniazid

Switch to ABC/3TC/TDF; gabapentin, tricyclic antidepressants, narcotic analgesics.

ddI, d4T, ddC

Causative Drug(s) Adverse Effect

Manifestations

Antiretroviral(s)

Other Drugs

Stepwise Action

Myopathy[g]

Myalgia, muscle tenderness, proximal weakness, elevated creatine kinase

ZDV

Statins, fibrates, steroids

Switch to another NRTI; improves in 3–4 wk after discontinuation; coenzyme-Q, L-carnitine (unproven).

Nephrolithiasis, crystalluria[h]

Flank pain, nondescript abdominal pain, dysuria, hematuria, renal dysfunction

IDV

Cotrimoxazole, sulfadiazine, acyclovir

Discontinue IDV; hydration and analgesics; IDV can be resumed with plenty of oral fluids; if recurs, consider switching.

Nephrotoxicity

Renal dysfunction; nephrogenic diabetes insipidus; Fanconi syndrome

IDV, TDF

Acyclovir, amphotericin B, cotrimoxazole, pentamidine

Discontinue offending drug; hydration; generally reversible.

Hematologic

Anemia, neutropenia[i] ZDV

Cotrimoxazole, dapsone, sulfadiazine, pyrimethamine, flucytosine, trimetrexate, amphotericin B, ganciclovir, valganciclovir, rifabutin

Discontinue concomitant marrow suppressant, if any; exclude marrow involvement by OIs/malignancy; erythropoietin or filgrastim; switch to another NRTI.

Bleeding tendency in hemophiliacs

PIs

Eosinophilia

Enfuvirtide (Fuzeon)

Factor VIII infusion; consider NNRTI-based regimens. Cotrimoxazole, dapsone, sulfadiazine

Exclude disseminated strongyloidiasis, malignancy; watch for hypersensitivity.

CNS symptoms[j] Drowsiness, insomnia, EFV vivid dreams, nightmares, hallucination, worsening of psychiatric disorders, suicidal ideation

Isoniazid, dapsone, steroids

Usually resolve in 2–4 wk; consider discontinuation, if persistent or exacerbates psychiatric illness.

Lipodystrophy

Steroids

Assess cardiac risk factors; lifestyle modification; metformin,

Loss of subcutaneous PIs (except ATV); fat, buffalo hump, NRTIs, especially double chin, d4T

Causative Drug(s) Adverse Effect

Manifestations double chin, dyslipidemia, insulin resistance, diabetes mellitus

Antiretroviral(s) d4T

Other Drugs

Stepwise Action modification; metformin, glitazones, statins, fibrates[k]; consider early switching to ATV- or NNRTI-based regimens.

Based on Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, U.S. Department of Health and Human Services, October 2005. Abbreviations: 3TC = lamivudine (Epivir); ABC = abacavir (Ziagen); APV = amprenavir (Agenerase); ATV = atazanavir (Reyataz); CNS = central nervous system; d4T = stavudine (Zerit); ddC = zalcitabine (Hivid); ddI = didanosine (Videx); DLV = delavirdine (Rescriptor); EFV = efavirenz (Sustiva); fAPV = fosamprenavir (Lexiva); FTC = emtricitabine (Emtriva); GI = gastrointestinal; IDV = indinavir (Crixivan); LPV/r = lopinavir/ritonavir (Kaletra); NFV = nelfinavir (Viracept); NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine (Viramune), OI = opportunistic infection; PI = protease inhibitor; RTV = ritonavir (Norvir); TDF = tenofovir (Viread); TPV = tipranavir (Aptivus); ZDV = zidovudine (Retrovir).

a Only common and serious side effects are dealt with; side effects such as osteoporosis, avascular osteonecrosis (PIs), unconjugated hyperbilirubinemia, retinoid-like effects (IDV) and cranial malformations (EFV) are also known to occur. b Approximately 0.3%-1% with NVP; a low dose, lead-in period for NVP (see Table 4 ) may decrease the risk; less common (0.1%) with DLV and EFV; occurs in the initial weeks after initiation; safety of replacing NVP with another NNRTI is unknown. c Approximately 5% with ABC; once daily dosing possibly increases the risk; If ABC-related, symptoms resolve within 48 hrs after discontinuation of ABC. d APV, fAPV, and TPV are sulfonamide derivatives; potential cross-hypersensitivity with sulfonamides. e Symptoms begin with first doses; might abate with time. f

Low-dose, lead-in period for NVP might reduce the risk; monitoring: see Table 3 ; onset within the first few weeks with NNRTIs, after weeks to months with PIs, and after months to years with NRTIs; discontinuation of 3TC, FTC, or TDF in HBV co-infected patients might cause acute flare-up of hepatitis; safety of replacing NVP with another NNRTI is unknown.

g Class-specific adverse effect of NRTIs, because of mitochondrial toxicity; do not combine ddI/d4T/ddC; ABC, 3TC, and TDF are less prone; all 4 syndromes can occur in variable combinations; symptomatic lactic acidosis is rare but is associated with high mortality. h Approximately 10% of patients taking IDV experience at least 1 episode of colic; monitoring: see Table 3 ; recurrence is seen in only 50%, if fluid intake is improved (at least 1.5–2 L of noncaffeinated fluid; water preferably). i

Almost all ZDV-treated patients have isolated macrocytosis; anemia and neutropenia occur in approximately 1%-4% and 2%-8% respectively; monitoring: see Table 3 .

j

Occurs during initial weeks of treatment; patients are to be warned to restrict risky activities.

k Only atorvastatin (Lipitor) and pravastatin (Pravachol) among statins, and gemfibrozil (Lopid) and fenofibrate (Triglide) among fibrates, can be co-administered with PIs.

Drug interactions are often the underlying cause of ADRs. PIs are metabolized by the hepatic cytochrome

P450 (CYP) enzymes. At the same time, PIs are potent inhibitors of CYP. Conversely, NNRTIs, especially efavirenz (Sustiva), are a potent inducer of CYP. When antiretrovirals are co-administered with other drugs metabolized by or affecting CYP (antihistamines, prokinetics, lipid-lowering agents, antifungals, antitubercular drugs, anticonvulsants, etc.), complex pharmacokinetic interactions occur; this can lead to potentially toxic or subtherapeutic drug levels. In a patient on HAART, unnecessary prescriptions are to be avoided, and it is prudent always to check the compatibility and the dose modifications needed before prescribing. Management of Opportunistic Conditions GENERAL CONSIDERATIONS OIs are the most common cause of disability and death in HIV-infected patients who are not receiving treatment. Hence, it is important that OIs are promptly recognized and treated. Different pathogens may cause similar disease patterns, and multiple OIs may occur concurrently. Although it is important to make a definitive diagnosis in these patients, diagnostic workup should not delay unduly the initiation of appropriate treatment. Empirical treatment based on clinical suspicion may be justified in acutely ill patients. In a patient with a severe OI as the initial manifestation of HIV disease, management of the OI takes precedence over immediate initiation of HAART. This avoids potential drug interactions and possibly decreases the occurrence of immune reconstitution inflammatory syndrome (IRIS). However, in patients with OIs for which no effective treatment is available (cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy, and Kaposi's sarcoma), HAART itself can result in improvement and hence should be initiated as soon as possible. IRIS manifests as the occurrence of a new OI or worsening of a preexisting OI following initiation of HAART, usually in the first 3 months. Symptoms include fever, lymphadenopathy, serosal effusions, worsening or fresh pulmonary infiltrates, vitreitis, uveitis, and intracranial lesions. Occasionally life-threatening complications like acute respiratory distress syndrome (ARDS) and acute renal failure develop. Most instances of IRIS respond well to nonsteroidal anti-inflammatory drugs. HAART and OI-specific treatment need to be continued without interruption. Steroids may be useful in patients with life-threatening complications. OIs can be prevented by timely initiation of primary chemoprophylaxis ( Table 8 ). It has to be stressed that OIs listed in the table can also occur, albeit less often, in patients with CD4+ counts above the cutoffs for initiation of prophylaxis. Following treatment for an episode of OI, lifelong secondary prophylaxis is needed to prevent relapse. However, if a sustained improvement in CD4+ count is achieved following HAART, secondary prophylaxis for most of the OIs and primary prophylaxis can be withdrawn safely. Table 9 presents the possible etiology of opportunistic conditions. Management of common potentially lifethreatening OIs is presented next.

TABLE 8 -- Primary Chemoprophylaxis for Opportunistic Infections in the HIV-Infected Patient[*],[†]

Opportunistic Pathogen

Preferred Criteria for Initiation Regimen

Pneumocystis jiroveci

CD4+ 200/µL for mg qd, or dapsone, 50 mg =3 mo qd, + pyrimethamine, 50 mg qw, + leucovorin, 25 mg qw, or atovaquone (Mepron), 1500 mg qd

Mycobacterium aviumintracellulare

CD4+ 200/µL for =3 mo

CD4+ >100/µL for =3 mo

Not applicable

Based on USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV, 2001. Abbreviations: biw = twice weekly; TMP-SMX = cotrimoxazole (Bactrim); TST = tuberculin skin test; qw = once a week; tiw = 3 times a week.

* Apart from chemoprophylaxis, annual influenza immunization in all, pneumococcal vaccination in those with CD4+ =200/µL, and hepatitis A and hepatitis B vaccinations in susceptible patients are recommended. † Primary chemoprophylaxis not recommended for cytomegalovirus, Cryptococcus neoformans, Histoplasmsa capsulatum, Coccidioides immitis, Salmonella species, herpes simplex, and Candida species ‡ Primary prophylaxis to be restarted if CD4+ falls again below levels recommended for initiation. § Not prophylaxis in strict sense. For isoniazid-susceptible M. tuberculosis only; if probability of exposure to isoniazid-resistant M. tuberculosis is high, rifampicin (Rifadin), 600 mg qd, or rifabutin (Mycobutin), 300 mg qd, for 4 mo.

TABLE 9 -- Etiology of Opportunistic Conditions in the HIV-Infected Patient

Etiology (Infectious as well as Noninfectious) System Affected Pulmonary

Very common PCP Streptococcus pneumoniae Haemophilus influenzae Myobacterium tuberculosisa

Somewhat common Pseudomonas aeruginosa Staphylococcus aureus Enteric GNB Histoplasma species Cryptococcus species Cytomegalovirus Kaposi's sarcoma Aspergillus species

Rare Nocardia species Legionella species Myobacterium avium complex Toxoplasma gondii Cryptosporidium Rhodococcus equi Strongyloides Primary pulmonary hypertension DILS

Pulmonary lymphoma Heart failure Central nervous system (CNS)

Cryptococcus species Toxoplasmosis ADRs Psychiatric illness HIV dementia PMLE CNS lymphoma

M. tuberculosisa

Nocardia species

Cytomegalovirus

Histoplasma species

Bacterial brain abscess

Coccidioides immitis Aspergillus species Listeria monocytogenes Varicella-zoster virus Herpes simplex virus Treponema pallidum Acanthamoeba species Trypanosoma cruzi DILS

Gastrointestinal (GI)

Cytomegalovirus Clostridium difficile Salmonella species M. avium complex Giardia lamblia ADRs

Etiology (Infectious as well as Noninfectious) System Affected Gastrointestinal (GI)

Very common

Somewhat common

Rare

Cytomegalovirus

Shigella species

Amebiasis

Clostridium difficile

Campylobacter species

Strongyloides

Salmonella species M. avium complex Giardia lamblia ADRs

Microsporum Cryptosporidium Isospora Cyclospora

GI lymphoma Kaposi's sarcoma Enteroaggregative Escherichia coli DILS

Cryptococcus species Histoplasma species Undifferentiated fever

M. avium complex

Endocarditis

M. tuberculosis[*]

Lymphoma

Cytomegalovirus ADRs Sinusitis Catheter-related Early PCP Acute HIV syndrome

Extrapulmonary Pneumocystis Bartonella henselae Coccidioides immitis Mycobacterium kansasii Penicillium marneffei Leishmania species Toxoplasma gondii

Adapted from Sax PE: Opportunistic infections in HIV disease: Down but not out. Infect Dis Clin North Am 2001;15:433-455. Abbreviations: ADR = adverse drug reaction; DILS = diffuse infiltrative lymphocytosis syndrome; GNB = gram-negative bacilli; PCP = Pneumocystis jiroveci pneumonia; PMLE = progressive multifocal leukoencephalopathy.

* Incidence of tuberculosis varies greatly depending on the local prevalence.

Pneumocystis Jiroveci Pneumonia (PCP) PCP is the most common OI in HIV-infected patients. Approximately 90% of cases occur among patients with CD4+ less than 200 cells/µL. Although the overall mortality is approximately 10% to 20%, it exceeds 50% in those requiring mechanical ventilation for respiratory failure. PCP manifests as a subacute febrile illness accompanied by nonproductive cough and progressive exertional dyspnea. In patients with mild disease, physical findings are often scanty, barring tachypnea and scattered so-called cellophane crackles. Hypoxemia is useful to assess the severity of disease, and moderate to severe hypoxemia (PaO2 less than

70 mm Hg or [A-a]DO2 more than 35 mm Hg while breathing ambient air) indicates severe disease. Chest radiograph demonstrates diffuse, bilateral, interstitial infiltrates in a perihilar distribution. Atypical radiographic appearances like upper lobe predominance (in patients on inhaled pentamidine [NebuPent] prophylaxis), nodular infiltrates, cysts, and pneumothorax are also seen. An apparently normal-looking radiograph in a patient with compatible clinical presentation does not rule out a diagnosis of PCP. Diagnosis is established by the demonstration of cysts and trophozoites of Pneumocystis in induced sputum (sensitivity, 50% to 90%), bronchoalveolar lavage (90% to 99%), and transbronchial lung biopsy (95% to 100%) specimens by Gomori methenamine silver, Giemsa, or calcofluor staining. Immunofluorescent staining has better sensitivity and specificity than the tinctorial stains. rRNA-PCR techniques are currently being evaluated and can be used on oral washings. Cotrimoxazole (TMP-SMX, Bactrim) is the drug of choice. Mild to moderately severe cases can be managed with oral TMP-SMX (two double-strength tablets [Bactrim DS] three times daily for 21 days) on an ambulatory basis. Patients developing PCP despite TMP-SMX (Bactrim) prophylaxis can also be effectively treated with standard doses of TMP-SMX. Intravenous therapy (15-20 [TMP]/75-100 [SMX] mg/kg/day every 6 to 8 hours for 21 days) is indicated for patients with severe hypoxemia. In addition, steroids (prednisone,[1] 40 mg orally twice daily for days 1 to 5, 40 mg every day for days 6 to 10, and 20 mg every day for days 11 to 21) improve the mortality and reduce the need for mechanical ventilation in severe cases and should be started within 72 hours of starting anti-PCP treatment. Lack of clinical improvement or worsening hypoxemia after at least 4 to 8 days of anti-PCP treatment indicates failure and warrants changing of treatment. Serious ADRs related to TMP-SMX (Bactrim) also often necessitate a treatment change. The preferred alternative treatments are pentamidine (Pentam, 4 mg/kg intravenously [IV] every day) or clindamycin (Cleocin, 600 to 900 mg IV every 6 to 8 hours) plus primaquine[1] (15 to 30 mg [base] orally every day). Dapsone (100 mg orally every day) plus trimethoprim (Trimpex,[1] 15 mg/kg/day orally thrice daily), atovaquone (Mepron, 750 mg orally twice daily), or trimetrexate (Neutrexin, 1.2 mg/kg IV every day with leucovorin, 0.5 mg/kg IV every 6 hours) can be used also as alternatives in mild to moderately severe PCP. Following treatment, patients should be administered secondary prophylaxis, which has to be discontinued if the CD4+ counts improve to more than 200 cells/µL for 3 months after initiating HAART. However, in those who develop PCP while their CD4+ counts were more than 200 cells/µL, it is prudent to continue the secondary prophylaxis lifelong. 1 Not FDA approved for this indication.

CRYPTOCOCCOSIS Cryptococcosis occurs mostly among patients with CD4+ less than 50 cells/µL. Although the route of infection is via the lungs, most often the disease manifests as meningitis. Disseminated infection is common in HIV-infected patients, and in fact approximately 60% of patients with AIDS-associated cryptococcal meningitis have fungemia. Pulmonary involvement occurs either as a part of disseminated disease or as primary pneumonia. Molluscoid skin lesions with central hemorrhagic crust may be seen. Patients typically present with subacute onset of fever, prominent headache, and vomiting. The classical signs of meningeal inflammation are often absent. Occasionally, cognitive decline and personality changes might be the only presenting symptoms. Cryptococcomas may present as a focal neurologic deficit. Diagnosis is readily established by the demonstration of yeast cells by India ink staining of cerebrospinal fluid (CSF). Fungal culture and latex agglutination for cryptococcal antigen have better sensitivity than the India ink stain. The antigen can also be detected in the blood in most patients with meningitis. Untreated disease is uniformly fatal. Amphotericin B deoxycholate (Fungizone, 0.7 mg/kg IV every day for 2 weeks) is

the preferred treatment. Infusion-related ADRs such as chills, rigors, and fever are common and can be reduced by premedicating with acetaminophen (Tylenol). Liposomal preparations of amphotericin B (AmBisome, 4 mg/kg/day) can be used also to reduce nephrotoxicity. Addition of flucytosine (Ancobon, 25 mg/kg orally four times a day for 2 weeks) sterilizes the CSF faster and reduces the rate of relapse but not mortality. Amphotericin B is to be followed by fluconazole (Diflucan, 400 mg orally every day) for at least 8 weeks or until the CSF cultures become sterile and then lifelong (200 mg every day) for secondary prophylaxis. In patients with immune recovery following HAART, secondary prophylaxis can be discontinued if the CD4+ count is more than 100 to 200 cells/µL for 6 months. Raised intracranial pressure is very common and associated with early deaths. If symptomatic, daily lumbar punctures to reduce the pressure are needed, and in refractory cases, CSF shunting should be performed. DISSEMINATED MYCOBACTERIUM AVIUM INFECTION Like cryptococcosis and CMV disease, disseminated atypical mycobacterial infections occur more commonly in patients with CD4+ less than 50 cells/µL. Most infections are caused by Mycobacterium aviumintracellulare. Infections by Mycobacterium kansasii and Mycobacterium haemophilum are also known to occur. Symptoms are nonspecific and include fever, weight loss, diarrhea, and abdominal pain. Peripheral and axial lymphadenopathy, hepatosplenomegaly, anemia, elevated alkaline phosphatase, and bone marrow infiltration are common features. Localized manifestations occur commonly as a manifestation of IRIS. Pulmonary lesions in the form of miliary nodules and air-space infiltrates may be seen. Diagnosis is established by demonstrating mycobacteremia or by isolating the organism from involved tissue specimens. Treatment should include at least two effective drugs, usually clarithromycin (Biaxin, 500 mg orally twice daily) and ethambutol (Myambutol,[1] 15 mg/kg orally every day). Addition of a third drug should be considered, especially when CD4+ is less than 50 cells/µL, effective HAART is unavailable, or the mycobacterial load is high (more than 2.0 log 10 colony-forming units/mL of blood). Rifabutin (Mycobutin,[1] 300 mg orally every day) is the preferred third drug. Fluoroquinolones and amikacin (Amikin)[1] can be used as alternative agents. Generally, if possible, HAART should be initiated within 1 to 2 weeks after initiating antimycobacterial therapy. Lack of clinical improvement accompanied by persisting mycobacteremia after 4 to 8 weeks of treatment indicates failure, and further selection of drugs should be guided by susceptibility testing. Treatment has to be continued lifelong for secondary prophylaxis. However, if the CD4+ count improves to more than 100 cells/µL for 6 months, it can be discontinued, provided the patient is asymptomatic and treatment has been given for at least 12 months. CYTOMEGALOVIRUS DISEASE Retinitis is the most common manifestation of CMV disease. It presents as progressive painless loss of vision, and patients often experience floaters. Funduscopy reveals focal necrotizing retinitis, characterized by perivascular fluffy infiltrates with hemorrhages. Lesions spread centrifugally from the periphery, and those adjacent to the macula are sight threatening. Visual loss, if it occurs, is irreversible. Other manifestations include colitis, esophagitis, meningoencephalitis, and pneumonitis. Colitis causes persistent diarrhea and may result in extensive hemorrhage, perforation, and bacterial sepsis. CNS disease presents as dementia, ventriculoencephalitis, or ascending polyradiculomyelopathy. Viremia in the absence of end-organ disease may be seen but does not warrant immediate therapy. Sight-threatening retinitis is treated with an intraocular ganciclovir implant (Vitrasert) along with valganciclovir (Valcyte, 900 mg orally every day) lifelong. For peripheral lesions, valganciclovir (Valcyte), 900

mg orally twice daily for 2 to 3 weeks is to be followed by 900 mg every day for life. Ganciclovir (Cytovene, 5 mg/kg IV every 12 hours), foscarnet (Foscavir, 60 mg/kg IV every 8 hours), or cidofovir (Vistide, 5 mg/kg IV every day) for 2 to 3 weeks can be used as alternatives. Colitis and esophagitis are treated with ganciclovir (Cytovene) or foscarnet (Foscavir) for at least 3 to 4 weeks or until symptoms resolve. A combination of ganciclovir (Cytovene) and foscarnet (Foscavir) until symptoms resolve is required for the treatment of neurologic disease. Secondary prophylaxis can be discontinued if CD4+ is more than 100 to 150 cells/µL for 6 months. However, regular ophthalmologic monitoring should be done to detect relapse early. IRIS occurs in most of the patients with CMV retinitis following initiation of HAART, resulting in vitreitis or uveitis. Periocular steroids or short courses of oral steroids often control the symptoms. TUBERCULOSIS IN HIV-INFECTED PATIENTS Tuberculosis is the most common OI in HIV-infected patients from developing countries. In contrast to other OIs, tuberculosis can occur at any level of CD4+ count. Extrapulmonary and disseminated forms become more common as the immunosuppression worsens. Meningeal and miliary dissemination often occurs. In advanced immunosuppression, typical cavitary and sputum-smear-positive pulmonary disease are seldom seen. Diagnostic and therapeutic approaches to tuberculosis remain the same as in a HIV-negative patient, except that once-weekly rifapentine (Priftin) and if CD4+ counts are less than 100 cells/mL, twice-weekly rifabutin (Mycobutin)[1] should not be used. Standard four-drug short-course regimens (see chapter on tuberculosis) are equally effective in HIV-infected patients with drug-susceptible tuberculosis. All patients should receive directly observed treatment, and thrice-weekly intermittent regimens can be used. Extensive interactions occur between rifamycins, PIs, and NNRTIs. If the patient is already on HAART, rifabutin (Mycobutin) is the preferred rifamycin, and HAART has to be continued with appropriate changes ( Table 10 ). If the patient is not on HAART, it is better started after the completion of the intensive phase in those with CD4+ more than 200 cells/mL. In those with CD4+ less than 200 cells/mL, it is preferable to initiate HAART early, after approximately 2 weeks of intensive-phase treatment.

TABLE 10 -- Pharmacokinetic Interactions between Antiretrovirals and Rifamycins Compatibility with Rifampicin Compatibility with Rifabutin (Rifadin) (Mycobutin) Rifampicin (Rifadin) dose change

Antiretroviral dose change

Rifabutin (Mycobutin) dosechange

Antiretroviral Drug


Saquinavir (Invirase, Fortovase)

Should not be used together

Saquinavir/ritonavir (Invirase Fortovase/Norvir)

( 400/ 400) mg bid

Indinavir (Crixivan)


1000 mg tid

150 mg qd[†]

Nelfinavir (Viracept)


1000 mg tid

150 mg qd[†]

Amprenavir (Agenerase)


Should not be used together None

None

None

150 mg qod[*]

150 mg qd[†]

Compatibility with Rifampicin (Rifadin)

Antiretroviral Drug


Rifampicin (Rifadin) dose change

Atazanavir (Reyataz)


Lopinavir/ritonavir (Kaletra)

(400/ 400) mg bid None

Efavirenz (Sustiva)

800 mg qd

Nevirapine (Viramune)

None

Delavirdine (Rescriptor)


None

Compatibility with Rifabutin (Mycobutin) Antiretroviral dose change

Rifabutin (Mycobutin) dosechange

150 mg qod[*] None

150 mg qod[*]

None

None

450 mg qd[‡]

None

None

None


Based on Centers for Disease Control and Prevention: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients, 2004. Note: Increase or decrease in the doses are indicated with appropriately directed arrows.

* Can be administered as 150 mg tiw. † Can be administered as 300 mg tiw. ‡ Can be administered as 600 mg tiw.

Management of the Pregnant HIV-Infected Woman Apart from the usual indications for initiating HAART, in a pregnant HIV-infected woman, an additional aim is to prevent perinatal transmission. This is most effectively achieved by suppressing viremia to undetectable levels with HAART. From this perspective, all pregnant HIV-infected women should be initiated on HAART, irrespective of the viral load, CD4+ count, and symptoms. Efavirenz (Sustiva), a combination of didanosine (Videx) and stavudine (Zerit), nevirapine (Viramune) in those with CD4+ more than 250 cells/µL, and oral liquid formulations of amprenavir (Agenerase) should be avoided. Although NRTIs and nevirapine (Viramune) can be administered in the usual adult doses, nelfinavir (Viracept) has to be given only twice daily ( Table 4 ). Initiation is better timed at the second trimester, to improve the tolerability and to avoid early fetal exposure to antiretrovirals. A detailed second-trimester fetal survey is indicated. The goal of treatment, follow-up assessment, and indications for resistance testing all remain the same as in a nonpregnant patient. HAART has to be continued without interruption through delivery. Intrapartum, zidovudine (Retrovir) has to be administered IV until the umbilical cord is clamped and other drugs can be continued by oral route. The option of elective cesarean delivery should be offered to patients with viral loads higher than 1000 copies/mL despite HAART. If opted for, elective cesarean delivery is performed at 38 weeks' gestation, avoiding an amniocentesis to document fetal lung maturity. Following delivery, the infant should receive zidovudine (Retrovir) for 6 weeks. To avoid transmission through breast milk, nursing the infant should be avoided completely, if resources permit. Where the sole indication for initiating HAART was

the prevention of perinatal transmission, HAART may be discontinued (in a staggered fashion, if nevirapine [Viramune] was included) after delivery. All infants exposed to antiretrovirals in utero should be followed up for possible adverse effects, regardless of the HIV status. Combined together, these interventions, namely HAART, cesarean delivery, and avoidance of breast-feeding, have brought down the risk of mother-to-child HIV transmission from approximately 25% to 1% to 2% in developed countries. In resource-limited settings and for HIV-infected women without prior HAART presenting in labor, peripartum prophylaxis with zidovudine (Retrovir), zidovudine with lamivudine (Combivir), nevirapine (Viramune), or zidovudine with nevirapine are acceptable alternatives. Postexposure Prophylaxis of HIV Infection The importance of adhering to universal precautions in preventing occupational transmission of HIV cannot be overstated. Administration of postexposure prophylaxis (PEP) can substantially reduce the risk of HIV transmission following accidental occupational exposure in the health care setting. However, PEP is associated with significant morbidity and potentially serious side effects. HIV testing of the health care personnel should be done at the time of exposure, at 6 weeks, 12 weeks, and 6 months after exposure. Generally, all grades of percutaneous, mucous membrane, and nonintact skin exposure to a known HIVinfected source warrant administration of PEP. In the case of mucosal or nonintact skin exposure to a small volume (a few drops) of body fluid from a known HIV-infected source, the decision to initiate PEP should be made on a case-to-case basis, after discussing with the exposed person the benefits as well as the risks of PEP. PEP should be initiated as soon as possible, preferably within hours following the exposure. The basic prophylaxis is with a two-drug regimen, usually a combination of two NRTIs (zidovudine + lamivudine [Combivir] or emtricitabine + tenofovir [Truvada]). If the exposure is more severe, three-drug regimens containing a PI are recommended. PEP is to be given for 4 weeks. If the source serostatus is unknown, administration of basic prophylaxis should be considered if the source is likely to be HIV infected and the exposure was percutaneous or involved a large volume of potentially infectious body fluid. The recommendations for PEP were extended recently to include nonoccupational exposures also (e.g., those reporting within 72 hours following an unanticipated sexual or injection drug use exposure to a known HIVinfected source).



REFERENCES Aberg et al., 2004. Aberg JA, Gallant JE, Anderson J, et al: Primary care guidelines for the management of persons infected with human immunodeficiency virus: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2004; 39:609-629. Carr and Cooper, 2000. Carr A, Cooper DA: Adverse effects of antiretroviral therapy. Lancet 2000; 356:1423-1430. Centers for Disease Control and Prevention, 2004. Centers for Disease Control and Prevention : Treating opportunistic infections among HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep 2004; 53(No. RR-15):1-112. Centers for Disease Control and Prevention, 2005. Centers for Disease Control and Prevention : Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposures to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Morb Mortal Wkly Rep 2005; 54(No. RR-2):1-19. Centers for Disease Control and Prevention, 2005. Centers for Disease Control and Prevention : Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep 2005; 54(No. RR-9):1-17. Chesney, 2000. Chesney MA: Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000; 30(Suppl 2):S171-S176. Grinspoon and Carr, 2005. Grinspoon S, Carr A: Cardiovascular risk and body fat abnormalities in HIVinfected adults. N Engl J Med 2005; 352:48-62. Hammer, 2005. Hammer SM: Management of newly diagnosed HIV infection. N Engl J Med 2005; 353:1702-1710. Panel on clinical practices for the treatment of HIV infection. Panel on clinical practices for the treatment of HIV infection, U. S. Department of Health and Human Services: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. (accessed February 1, 2006). Available at http://AIDSinfo.nih.gov October 6, 2005 Sax, 2001. Sax PE: Opportunistic infections in HIV disease: Down but not out. Infect Dis Clin North Am 2001; 15:433-455. Yeni et al., 2004. Yeni PG, Hammer SM, Hirsch MS, et al: Treatment of adult HIV infection. 2004 recommendations of the International AIDS Society—USA panel. JAMA 2004; 292:251-265.



Chapter 14 – Amebiasis

Method of: Rashidul Haque, MB, PhD William A. Petri Jr., MD, PhD Amebiasis, a disease caused by the protozoan parasite Entamoeba histolytica, is estimated to be the third leading parasitic cause of deaths worldwide in humans. There are noninvasive species of ameba including Entamoeba dispar and Entamoeba moshkovskii that are morphologically indistinguishable from E. histolytica by traditional light microscopy. Amebiasis is distributed worldwide, but the majority of cases are found in developing countries. The World Health Organization estimates that approximately 50 million people suffer from invasive amebiasis each year, resulting in 40,000 to 100,000 deaths annually. For example, a prospective study of preschool children in an urban slum of Dhaka, Bangladesh, demonstrated a 39% incidence of E. histolytica infection during the first year of observation. Human beings are the only known host of the parasite E. histolytica. Individuals become infected with E. histolytica when they ingest cysts in fecally contaminated food or water. When these cysts reach the intestine, they swell and release the motile, symptom-inducing form of E. histolytica, called the trophozoite. Trophozoites can remain in the intestine and even form new cysts without causing disease symptoms. They colonize the large intestine by adhering to colonic mucins via a galactose and N-acetyl-d-galactosamine (Gal/GalNAc)–specific lectin. Reproduction of trophozoites is without a recognized sexual cycle, and the overall population structure of E. histolytica appears to be clonal. Aggregation of amebae in the mucin layer likely signals encystation via the Gal/GalNAc lectin. Cysts excreted in stool perpetuate the life cycle by further fecal–oral spread. Invasive disease results when the trophozoite penetrates the intestinal mucus layer, which acts as barrier to invasion by inhibiting amebic adherence to the underlying epithelium and by slowing trophozoite motility. In addition, trophozoites can be carried through the blood to other organs, most commonly the liver, where they form life-threatening abscesses. Intestinal Amebiasis There are several clinical classifications of amebiasis based on the invasiveness and site of infection with different treatments. Intestinal amebiasis is a term that encompasses the entire spectrum of clinical intestinal disease, including amebic colitis. Patients with amebic colitis typically present with a several week history of cramping abdominal pain, weight loss, and watery or, less commonly, bloody diarrhea. The insidious onset and variable signs and symptoms make diagnosis difficult, with fever and grossly bloody stool absent in most cases. Differential diagnosis of a diarrheal illness with occult or grossly bloody stools should include Shigella, Salmonella, Campylobacter, and enteroinvasive and enterohemorrhagic Escherichia coli. Noninfectious causes include inflammatory bowel disease, ischemic colitis, diverticulitis, and arteriovenous malformation. Unusual manifestations of amebic colitis include acute necrotizing colitis, toxic megacolon, ameboma, and perianal ulceration with potential fistula formation. Acute necrotizing colitis is rare (40%

PCR/real-time PCR (abscess fluid) N/A

90%–100% (before therapy)

Laboratory Tests

Amebic Colitis Amebic Liver Abscess

Serology Acute

50%–70%

70%–90%

Convalescent

>90%

>90%

Abbreviation: PCR = polymerase chain reaction.

* Does not distinguish Entamoeba histolytica from the commensal parasites Entamoeba dispar and Entamoeba moshkovskii. † TechLab E. histolytica II antigen detection test.

Amebic liver abscess patients may reveal a mild to moderate leukocytosis and anemia. Patients with an acute presentation of amebic liver abscess tend to have a normal alkaline phosphatase and elevated aspartate transaminase with the opposite true for patients with a chronic presentation. Ultrasound, abdominal computed tomography scan, and magnetic resonance imaging of the liver are all excellent imaging modalities for detecting liver lesions (most commonly single and in the right lobe) but are not specific for amebic liver abscess. The differential diagnosis of a liver mass should include pyogenic liver abscess, necrotic hepatoma, and echinococcal cyst (usually an incidental finding that would not be the cause of fever and abdominal pain). Patients with amebic abscess are more likely than patients with pyogenic liver abscesses to be male and younger than age 50 years; have immigrated from or traveled to an endemic country; and lack jaundice, biliary disease, or diabetes mellitus. Fewer than half of patients with amebic liver abscess have parasites detected in their stool by antigen detection. Helpful clues to the diagnosis include the presence of epidemiologic risk factors for amebiasis and the presence of serum antiamebic antibodies (present in 70% to 80% of patients at the time of presentation; see Table 1 ). Occasionally, aspiration of the abscess is required to rule out a pyogenic abscess. Amebae are visualized in the abscess pus in a minority of patients with amebic liver abscess. Traditional PCR and real-time PCR tests can be used for the detection of E. histolytica DNA in the stool and liver abscess pus samples and have been found to be sensitive and specific (see Table 1 ). Therapy Therapy differs for invasive versus noninvasive infections ( Table 2 ). Noninvasive infections can be treated with lumen active agents such as paromomycin (Humatin) to eradicate cysts and lumen-dwelling trophozoites. Nitroimidazoles, particularly metronidazole (Flagyl), are the mainstay of therapy for invasive amebiasis (see Table 2 ). Nitroimidazoles with longer half-lives (namely tinidazole [Tindamax], secnidazole,[2] and ornidazole[2]) are better tolerated and allow shorter duration of treatment; they are recently available in the United States. Approximately 90% of patients presenting with mild to moderate amebic colitis or dysentery respond to nitroimidazole treatment. In the rare case of fulminant amebic colitis, it is prudent to add broad-spectrum antibiotics to treat intestinal bacteria that may spill into the peritoneum, with patients occasionally requiring surgical intervention for acute abdomen, gastrointestinal bleeding, or toxic megacolon. Parasites persist in the intestine in as many as 40% to 60% of metronidazole (Flagyl)treated patients. Therefore, metronidazole (Flagyl) treatment should be followed with paromomycin (Humatin) or the second-line agent diloxanide furoate (Furamide)2 to cure luminal infection (see Table 2 ). Do not treat with metronidazole (Flagyl) and paromomycin (Humatin) at the same time because the diarrhea, a common side effect of paromomycin, (Humatin) may make it difficult to assess response to therapy.

TABLE 2 -- Drug Therapy for the Treatment of Amebiasis[*] Type of Infection Drug Asymptomatic intestinal colonization

Adult Dosage

Pediatric Dosage

25–35 mg/kg/d in 3 doses × 7 d


500 mg tid × 10 d

20 mg/kg/d in 3 doses × 10 d

750 mg tid × 7–10 d in 3 doses × 7–10 d

35–50 mg/kg/d

Tinidazole (Tindamax) followed by luminal agent

800 mg tid × 5 d[3] in 3 doses × 5 d

60 mg/kg/d[3]

Paromomycin (Humatin)



Diloxanide furoate (Furamide)[5]

500 mg tid × 10 d in 3 doses × 10 d

20 mg/kg/d

Metronidazole (Flagyl) followed by luminal agent (similar to amebic liver abscess)

500–750 mg tid × 7–10 35–50 mg/kg/d d in 3 doses × 7–10 d

Paromomycin (Humatin) or Diloxanide furoate (Furamide)[*]

Amebic liver abscess[†] Metronidazole (Flagyl) or

Amebic colitis [†]

* The information is updated annually by the Medical Letter on Drugs and Therapeutics at http://www.medletter.com/htmlprm.htm#Parasitic . † Treatment of amebic liver abscess and amebic colitis should be followed by a treatment with a luminal agent. 3 Exceeds dosage recommended by the manufacturer. 5 Investigational drug in the United States.

Therapeutic aspiration of an amebic liver abscess is occasionally required as adjunctive treatment to antiparasitic therapy. Abscess drainage should be considered in patients who fail to clinically respond to drug therapy within 5 to 7 days or those with high risk of abscess rupture as defined by cavity size greater than 5 cm or location in the left lobe. Bacterial coinfection of amebic liver abscess has been occasionally observed (both prior to and as a complication of drainage), and it is reasonable to add antibiotics or drainage, or both, to the treatment regimen if a prompt response to nitroimidazole therapy is not observed. Imaging-guided percutaneous treatment (needle aspiration or catheter drainage) has replaced surgical intervention over more recent years as the procedure of choice for therapeutically reducing abscess size. 2 Not available in the United States.



REFERENCES Diamond and Clark, 1993. Diamond LS, Clark CG: A redescription of Entamoeba histolytica Schaudin 1903 (amended Walker 1911) separating it from Entamoeba dispar (Brumpt 1925). J Eukaryot Microbiol 1993; 40:340-344. Haque et al., 2000. Haque R, Mollah NU, Ali IKM, et al: Diagnosis of amebic liver abscess and intestinal infection with the TechLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol 2000; 38:3235-3239. Haque et al., 1998. Haque R, Ali IKM, Akther S, Petri Jr WA: Comparison of PCR, isoenzyme analysis, and antigen detection for diagnosis of Entamoeba histolytica infection. J Clin Microbio 1998; 36:449-452. Haque et al., 2001. Haque R, Ali IKM, Sack RB, et al: Amebiasis and mucosal IgA antibody against the Entamoeba histolytica adherence lectin in Bangladeshi children. J Infect Dis 2001; 183:1787-1793. Haque et al., 2003. Haque R, Huston CD, Hughes M, et al: Current concepts: Amebiasis. N Engl J Med 2003; 348:1565-1573. Petri et al., 2000. Petri Jr WA, Haque R, Lyerly D, Vine RR: Estimating the impact of amebiasis on health. Parasitol Today 2000; 16:320-321. Petri and Singh, 1999. Petri Jr WA, Singh U: State of the art: Diagnosis and management of amebiasis. Clin Infect Dis 1999; 29:1117-1125. Stanley, 2003. Stanley Jr SL: Amoebiasis. Lancet 2003; 361(9362):1025-1034.361 Tanyuksel and Petri, 2003. Tanyuksel M, Petri Jr WA: Laboratory diagnosis of amebiasis. Clin Microbiol Rev 2003; 16:713-729. World Health Organization, 1997. World Health Organization : Amoebiasis. Wkly Epidemiol Rec 1997; 72:97-100.



Chapter 15 – Giardiasis

Method of: M. Ekramul Hoque, MBBS, MPH (Hons), PhD Background Giardiasis is a parasitic infection of the upper small intestine caused by a flagellated protozoan, Giardia lamblia (also called Giardia intestinalis and Giardia duodenalis). This ubiquitous parasite is a major cause of intestinal infection among adults and children in developing and developed countries. The existence of this parasite was reported in the prehistoric era across the continents. However, pathogenicity of the organism among humans was known only in the latter part of the last century. Organism Giardia is a microscopic organism that exists in two life forms. The trophozoite, which is environmentally unstable, causes clinical illness, and the resistant cysts are responsible for the transmission of infection. Trophozoites are binucleated, flagellated, and pear shaped, measuring 12 to 15 µm long and 6 to 8 µm wide. They have a pair of claw-shaped median bodies and a concave ventral disk used for nourishment and attachment on the wall of the small intestine of vertebrate hosts. Cysts are smaller and oval, usually 8 to 12 µm long and 7 to 10 µm wide, and contain four nuclei. Epidemiology Giardiasis is one of the most common intestinal infections in the world. More than 200 million people are reported to have symptoms of giardiasis, and some 500,000 new cases are reported annually. Some estimates suggest the worldwide prevalence of giardiasis is 20% to 60%. Others report from 2% to 7% in industrialized countries and 20% to 30% in developing countries. In 2002, there were 21,300 giardiasis cases reported from 46 states of the United States, with an incidence rate of 7.6 cases per 100,000 population. The incidence varied by state from less than 0.1 to 23.5 cases per 100,000 population; rates were higher in northern states than southern states. Giardia infection is probably underreported by a factor of 10, and therefore the true burden of giardiasis in the United States is probably underestimated. Annually, 5,000 people are hospitalized in the United States due to severe giardiasis. New Zealand reports more than 30 cases of giardiasis per 100,000 population every year, which is one of the highest among the industrialized countries. Giardia infection is reported to be more prevalent in urban areas than in rural populations. Humans are the primary reservoir of the parasite. Other possible hosts are farm, wild, and domestic animals. Polymerase chain reaction (PCR) testing of samples of human feces from different geographic locations has so far associated G. intestinalis genotypes (assemblages) A and B with human infections. The role of animals in transmitting G. intestinalis to humans and the most likely routes of infection remain unclear.

Transmission of the Giardia infection is through the fecal-oral route following direct or indirect contact with cysts of Giardia. Cysts are infectious immediately after being excreted in feces. An infected person can excrete a maximum of 109 cysts per day for several months. Cysts may be killed by simple drying and heat, but they can survive for several weeks in cool and wet environments. Infectious dose is low; ingestion of as few as 10 cysts can cause infection. Commonly, the organism spreads by water or food or directly through person-to-person contact. Outbreaks of waterborne giardiasis have been reported year round, suggesting frequent contamination of water sources and longer survival of cysts in water. Giardiasis shows a bimodal pattern of age distribution, peaking in children younger than 5 years and in adults 25 to 44 years ( Figure 1 ). Incidence of infection varies by season, peaking in late summer and early autumn and dropping in winter. Persons at increased risk for infection include (among others) children of diaper age, children attending daycare centers, daycare workers, immunocompromised persons, pregnant women, institutionalized persons, travelers to endemic regions, people drinking contaminated water during outdoor activities, sewage and irrigation workers, and men who have sex with men.

FIGURE 1 Notification rate of giardiasis in New Zealand by age and gender.

It is not clear whether giardiasis causes malnutrition or malnutrition predisposes to Giardia infection. However, nutritional insufficiency can contribute to chronicity of the disease. Repeated exposure to the parasite can elicit an immune response, which might explain asymptomatic giardiasis cases. Breast-fed infants of immune mothers might acquire temporary protection against giardiasis, but this is not conclusive. Pathogenesis Clinical illness results from the interaction of Giardia organisms with the human host and the host's subsequent response to the parasite. Giardia isolates can vary in virulence, which might further explain the intensity of the symptoms.

After a person ingests Giarda cysts, excystation begins in the duodenum in the presence of gastric acid, pancreatic enzymes, and parasite-derived cysteine protease. Two tropozoites are formed from each cyst by binary fission (miotic division). The motility of parasites and the inflammatory cytokine response to parasitic attachment on the mucosal brush borders results in secretion of fluid and electrolytes, hence diarrhea and malabsorption. Trophozoites frequently slough off villi, which are swept into the fecal stream and replaced by new sets. After 4 to 15 days of colonization, some trophozoites encyst in the jejunum under an alkaline environment of bile secretion. Immotile cysts undergo a single cell division to form four nuclei, which are then passed intermittently in the feces. Giardia trophozoites remain adherent to the intestinal mucosa but are not invasive. This close association might directly affect the brush border and its enzyme system. Hospital-based investigation observed partial villous atrophy in up to 25% of patients. Malabsorption of vitamin B12 occurs in 20% to 40% cases. Parasites are also found in extraintestinal sites such as the gallbladder and the urinary tract. Clinical Features Clinical manifestations of giardiasis vary from asymptomatic infection to severe diarrhea. The incubation period for Giardia infection varies from 1 week to several weeks. However, a period of 5 to 25 days is average. Freshly exposed persons in an endemic area can present with acute symptoms that usually begin about 15 days (range, 1-46 days) following exposure. The symptoms include nausea, anorexia, upper abdominal discomfort, malaise, low-grade fever, and chills followed by the sudden onset of explosive, watery, foulsmelling diarrhea associated with foul flatulence and abdominal distention. Generally, the acute stage resolves spontaneously within 2 to 4 weeks. Some patients become asymptomatic passers of cysts for a period. Others have periodic brief recurrences of acute symptoms. About 30% to 50% of infected patients go on to a subacute or chronic stage. Overseas travelers to Giardiaendemic areas often do not recognize or remember the infection during their travel and subsequently present periodically with persistent or recurrent mild to moderate symptoms. Features of subacute to chronic Giardia infection include flatulence, mushy foul stools, upper abdominal cramps, abdominal distention, steatorrhea, marked weight loss, and fatigue. Uncommon manifestations are cholecystitis, pancreatitis, immunologic reactions (including arthritis, retinal arteritis, and iridocyclitis), and occasionally rash and urticaria, mostly in adults. In rare cases, symptoms persist for years, but most cases resolve spontaneously after a variable period of weeks or months. Generally, 10% to 30% of infected people remain symptom free, but the true percentage may be as high as 60%. The prevalence of asymptomatic infection is higher among children than among adults, especially among those in daycare. The duration of the asymptomatic cyst-passing state is not determined. Diagnosis Clinical signs and symptoms along with the history of risk behavior and exposure to Giardia risk factors can lead to a preliminary diagnosis of the disease. Laboratory diagnostic procedures are then applied to confirm the infection ( Figure 2 )

FIGURE 2 Diagnostic algorithm for giardiasis.

Traditionally, diagnosis is based on microscopic detection of Giardia cysts or trophozoites in the fecal specimens. At least three specimens of feces collected on consecutive days may be required to recover the parasite. The sensitivity of parasite detection is 50% to 70% in one specimen and 90% in three specimens.

CURRENT DIAGNOSIS Giardiasis is a common parasitic infection of the small intestine. Children, caregivers, travelers, and persons exposed to contaminated water are at greater risk for infection. Clinical manifestations vary widely. A large fraction of infected persons remain asymptomatic. Infective cysts pass intermittently with patients' feces. Diagnosis is by detection of Giardia parasites in feces by repeated microscopy or by immunologic assays. Assays can give false positives in recently cured persons. Infection can resolve spontaneously or can go into a chronic stage lasting for months with marked weight loss. Immunologic methods for detecting Giardia have superior sensitivity and specificity compared with other conventional methods of diagnosis. Widely used methods are enzyme immunoassay (EIA) detecting soluble antigens, direct fluorescent antibody (DFA) detecting intact organisms, and immunochromatographic lateralflow immunoassays or rapid assay. Sensitivity of immunoassay varies between 94% and 97%, and specificity varies between 99% and 100%. EIA and rapid assay can pick up antigens of recently cured cases; DFA detects Giardia cysts. Immunoassay tests are quick and costs are reasonable. Serologic tests do not have great diagnostic value in clinical practice because immunoglobulin G (IgG) persists even after infection; IgM, however, can indicate active infection. Negative serology does not exclude infection. Duodenal aspirates or string test and duodenal mucosal biopsy are costly and invasive. They should be reserved for situations when giardiasis is strongly suspected despite persistent negative feces tests. PCR is used mostly in epidemiologic studies. Treatment Giardiasis, if diagnosed, should be treated. There are unresolved debates on the significance of treatment of asymptomatic cases. However, asymptomatic cases can remain a potential source of infection and can turn symptomatic at any moment. PHARMACOLOGIC THERAPY A number of effective antigiardial drugs are available ( Table 1 ).

TABLE 1 -- Therapeutic Doses of Antigiardial Drugs

Drugs

Adult Dose[h]

Pediatric Dose[h]

Metronidazole (Flagyl)[a] 250 mg tid × 5-7 days

5 mg/kg tid × 5-7 days

Tinidazole (Fasigyn)[b]

2 g single dose

50 mg/kg single dose (max, 2 g)

Ornidazole (Tiberal)[c]

2 g single dose

40-50 mg/kg single dose (max, 2 g)

Quinacrine (Atabrine)[c] 100 mg tid × 5-7 days[f]

2 mg/kg tid × 5-7 days (max 300 mg/d)[f]

Furazolidone[b],[d]

100 mg qid × 7-10 days

1.25-2 mg/kg qid × 10 days

Paromomycin [a]

7-10 mg/kg tid × 5-10 days[g] 8-10 mg/kg tid × 5-10 days[g]

Paromomycin [a],[e]

7-30 mg/kg tid × 5-10 days[g]

Albendazole[a]

400 mg qd × 5 days

15 mg/kg/day × 5-7 days (max 400 mg/d)

a Not a U.S. FDA approved indication b Not available in the U.S. c No longer produced in the U.S. d Available in liquid formulation e In pregnancy f

After meal

g With meal h qd, once a day; bid, twice a day; tid, three times a day; qid, four times a day

Metronidazole (Flagyl)[1] is preferred and widely used because of its broad-spectrum coverage. It is not approved by the FDA for routine treatment of giardiasis in the United States. Metronidazole is effective and well tolerated and has a cure rate of 80% to 95%. The common side effects are gastrointestinal upset, headache, nausea, leukopenia, and metallic taste in the mouth. It is contraindicated in the first trimester of pregnancy due to its suspected carcinogenic, teratogenic, and mutagenic effects. Other minor side effects are peripheral neuropathy, seizures, depression, irritability, restlessness, and insomnia. Drug resistance is not yet widespread. Furazolidone (Furoxone)[2] is the primary drug choice in the United States. It is available in liquid form and is widely used to treat children. Cure rates are between 80% and 89%. It is not recommended in pregnancy. Side effects include gastrointestinal disturbances, hemolytic anemia, disulfiram-like reactions with alcohol, hypersensitivity reactions, brown discoloration of the urine, orthostatic hypotension, and hypoglycemia. Albendazole (Albenza)[1] is an anthelminthic whose efficacy is equal to that of metronidazole and with cure rates of 62% to 95%. Absence of anorexia in using this drug is an advantage for treating children. Notable side effects are gastrointestinal upset, abdominal pain, nausea, vomiting, diarrhea, dizziness, vertigo, fever, increased intracranial pressure, alopecia, and (reversible) increase in serum transaminases after prolonged use. Albendazole is contraindicated in pregnancy due to teratogenicity. Paromomycin (Humatin)[1] is a poorly absorbed aminoglycoside that is excreted in the feces without being metabolized. Its efficacy rate is between 60% and 70%. It is recommended for giardial infection in pregnant patients. Common side effects are nausea, increased gastrointestinal motility, abdominal pain, and diarrhea.5-Nitroimidazole compounds,

tinidazole (Tindamax) and ornidazole (Tiberal),[1],[2] are effective as first-line agents and have a cure rate of 90%. They are effective in single doses. Common side effects are gastrointestinal upset, vertigo, and bitter taste. Quinacrine[2] was one of the most effective drugs against giardial infection, with a cure rate of 92% to 95%. This drug is no longer produced in the United States and elsewhere in the world due a number of pharmacokinetic issues and adverse effects. Other potential drugs include benzimidazole derivatives such as mebendazole (Vermox)[1] and a 5-nitrothiazole derivative (Nitazoxanide), which are not used widely. Nitazoxanide (Alinia) has been used successfully in France in resistant giardiasis patients infected with HIV.

CURRENT THERAPY Metronidazole (Flagyl)[1] is widely used because of its broad-spectrum coverage, but it is contraindicated in the first trimester of pregnancy. Furazolidone (Furoxone)[2] is available in liquid form to treat children. Absence of anorexia with albendazole (Albenza)[1] is an advantage for treating children. Paromomycin (Humatin)[1] is recommended in pregnancy due to its poor absorption rate. Tinidazole (Tindamax) and ornidazole (Tiberal)[2] are effective in single doses. Nitazoxanide (Alinia) is used in drug-resistant giardiasis. Some diet modifications can reduce acute symptoms, improve host defense, and inhibit trophozoite replications. 1 Not FDA approved for this indication. 2 Not available in the United States.

OTHER MEASURES Diet modification can reduce acute symptoms, improve host defense mechanisms, and inhibit growth and replication of Giardia trophozoites in the lumen of the intestine. General advice is to consume a diet of whole foods that is high in fiber, low in simple carbohydrates, and low in fat. Follow-up Follow-up stool tests are advised to ensure resolution of infection. Hygiene practices should be enhanced during outbreaks. Symptomatic persons should be kept away from public contact. Prognosis Giardiasis is usually a self-limited intestinal infection. Effective antigiardial agents shorten the infection period. If untreated, giardiasis often resolves spontaneously in a few weeks. Prognosis is, therefore, generally excellent. Prevention

Eradication of giardiasis is not possible because the disease is endemic in the human population, animal population, and environment. Prevention and control methods are the way forward. Health departments in all countries, including the Centers for Disease Control and Prevention in the United States, publish recommendations for prevention and control of giardiasis. These include decontamination of water supplies and sanitary and hygiene practices. Potentially contaminated water may be treated by boiling for more than 1 minute or filtering through a pore size of 1 µm or smaller. Chlorination and iodination are unreliable. Laws and regulations to protect provisions of safe water should be enforced and monitored. Regular surveillance and reviews of sanitation can ensure quality. People involved in recreational water activities and persons traveling overseas must be informed about the possibility of exposure to the parasite. Persons with symptomatic cases should not swim in a pool until 2 weeks after the treatment. Other occupational groups (e.g., daycare workers, medical personnel, irrigation and sewage workers) need to be cautioned. In daycare centers, hand washing with soap after changing diapers and a separate diaper-changing area should be implemented. All symptomatic family members, daycare center teachers, and children in daycare should be treated for giardiasis. Treatment of asymptomatic cases should be considered if the infected person is suspected to be a potential source of transmission of the disease.



REFERENCES Cacciò et al., 2005. Cacciò SM, Thompson RCA, McLauchlin J, Smith HV: Unravelling Cryptosporidium and Giardia epidemiology. Trends Parasitol 2005; 21(9):430-437. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention : Parasitic disease information: Giardiasis fact sheet. (accessed April 5, 2007). Available at http://www.cdc.gov/ncidod/dpd/parasites/giardiasis/factsht_giardia.htm Gardner and Hill, 2001. Gardner TB, Hill DR: Treatment of giardiasis. Clin Microbiol Rev 2001; 14(1):114128. Hanson and Cartwright, 2001. Hanson KL, Cartwright CP: Use of an enzyme immunoassay does not eliminate the need to analyze multiple stool specimens for sensitive detection of Giardia lamblia. J Clin Microbiol 2001; 39(2):474-477. Hetsko et al., 1998. Hetsko ML, McCaffery JM, Svard SG, et al: Cellular and transcriptional changes during excystation of Giardia lamblia in vitro. Exp Parasitol 1998; 88(3):172-183. Hlavsa et al., 2005. Hlavsa MC, Watson JC, Beach MJ: Giardiasis surveillance—United States, 1998-2002. MMWR Surveill Summ 2005; 54(SS01):9-16. Hoque et al., 2002. Hoque ME, Hope VT, Scragg R: Giardia infection in Auckland and New Zealand: Trends and international comparison. The N Z Med J 2002; 115(1150):121-123. Islam et al., 1983. Islam A, Stoll BJ, Ljungstrom I, et al: Giardia lamblia infections in a cohort of Bangladeshi mothers and infants followed for one year. J Pediatr 1983; 103(6):996-1000. Kulda and Nohynkova, 1978. Kulda J, Nohynkova E: Flagellates of the human intestine and of intestines of other species. In: Kreier JP, ed. Protozoa of Veterinary and Medical Interest. Vol. II, New York: Academic Press; 1978:69-104. Lebwohl et al., 2003. Lebwohl B, Deckelbaum RJ, Green PHR: Giardiasis. Gastrointest Endosc 2003; 57(7):906-913. Mineno and Avery, 2003. Mineno T, Avery MA: Giardiasis: Recent progress in chemotherapy and drug development. Curr Pharm Des 2003; 9:841-855. New Zealand Ministry of Health, 1998. New Zealand Ministry of Health : Communicable disease control manual, Wellington, New Zealand Ministry of Health, 1998.



Chapter 16 – Severe Sepsis and Septic Shock

Method of: Eleni Patrozou, MD Steven M. Opal, MD Sepsis is defined as a deleterious systemic inflammatory response to an infection. The precise incidence of sepsis is unknown, owing to the lack of a readily available and consistently applied definition, but a variety of epidemiologic studies indicate that it is increasing in incidence. The Centers for Disease Control and Prevention (CDC) has reported a threefold increase in the incidence of sepsis since the 1990s. Using hospital discharge coding data, it is estimated that there are between 660,000 and 750,000 episodes of severe sepsis each year in the United States. Severe sepsis accounts for 1 of every 10 intensive care unit (ICU) admissions and represents 2% to 3% of all hospital admissions. Incidence of sepsis in the United States is projected to rise at a rate of 1.5% per year. The rising incidence of sepsis is primarily related to the aging of the population in developed countries, but the increased number of immunocompromised patients, the increased use of implantable devices in patient care, and the growing problem of antibiotic-resistant microorganisms probably contribute as well. Male patients are consistently and significantly more likely to develop sepsis than female patients. Since the late 1980s, gram-positive organisms have surpassed gram-negative bacterial pathogens as the predominant causative organisms that lead to sepsis. There has also been a remarkable increase in the number of episodes of fungal sepsis. This is an unfavorable trend because fungal sepsis is associated with a worse outcome than bacterial sepsis. Sepsis is now reported to be the tenth most common cause of death in the United States and is one of the most common causes of death in the noncoronary ICU. Systemic Inflammatory Response Syndrome and Sepsis A major clinical issue in the recognition and early management of sepsis is the imprecise definitions and vague terminology used to describe the septic process. There is no single clinical or laboratory test that verifies the diagnosis of sepsis, severe sepsis, and septic shock. A constellation of physiologic and laboratory studies are employed in concert to make a diagnosis of sepsis (see the Current Diagnosis box). The term systemic inflammatory response syndrome (SIRS) implies early evidence of an acute physiologic insult that may be induced by an infection. SIRS can result from a diverse group of insults such as trauma, severe drug reactions, burns, and pancreatitis. The term sepsis is used to define the SIRS response to a documented infection and generally implies a deleterious state in which the septic patient is at risk from both the infecting organism and the systemic host response itself. The lack of specificity in the clinical presentation of SIRS is problematic because the initial manifestations of sepsis mimic many other

inflammatory states. SIRS is operationally defined as the presence of two or more of the following: •

Temperature >38°C (100.4°F) or 90 beats per minute

•

Respiratory rate >20 breaths per minute or Paco2 12,000 cells/mm3, 10% immature band forms

Sepsis is the systemic inflammatory response to a documented infection. The diagnosis of sepsis requires the presence of at least two of the SIRS criteria as a response to an invasive infection in a normally sterile space (e.g., blood, lung parenchyma, renal interstitial space, cerebrospinal fluid). Uncomplicated sepsis can progress in a continuum of disease severity to severe sepsis and septic shock. Severe sepsis is defined as the presence of organ dysfunction or tissue hypoperfusion from the septic response. Perfusion abnormalities can include lactic acidosis, oliguria, or an acute alteration in mental status. Sepsis-induced hypotension occurs when the systolic blood pressure falls to less than 90 mm Hg or falls more than 40 mm Hg from baseline systolic blood pressure. Septic shock is a subset of severe sepsis with hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities. Patients who require vasopressor agents to maintain blood pressure yet continue to present with hypoperfusion abnormalities or organ dysfunction are still considered to be in septic shock. Multiple organ dysfunction syndrome (MODS) is sepsis-induced alteration of organ function. A gradation of organ dysfunction from mild biochemical abnormalities to complete organ failure necessitating interventional support exists in sepsis-related MODS. In 2001, the International Sepsis Definitions Conference reaffirmed the basic usefulness of these clinical definitions originally proposed in 1991 by the American College of Chest Physicians and Society of Critical Care Medicine. The consensus conference generated a series of common signs and symptoms of sepsis (see the Current Diagnosis box). The conference participants also proposed a new classification scheme called the PIRO system ( Box 1 ) to stratify septic patients on the basis of predisposing factors, the nature of the infection, the host response, and the pattern of organ dysfunction. The validity and practical usefulness of this proposed staging system to further the understanding of sepsis remain to be demonstrated. BOX 1

PIRO Staging of Sepsis Predisposition Premorbid conditions that influence likelihood of infection, sepsis, morbidity, survival (age, gender, hormonal state, genetic polymorphisms for immune response and coagulation proteins) Infection Organism associated with the sepsis response (type of organism, virulence potential, toxins, community or nosocomial acquisition) Response Clinical and immunologic manifestations of the septic response (either hyperinflammation or hypoinflammation) (e.g., procalcitonin, IL-6, HLA-DR, TNF, PAF) Organ Dysfunction Type and number of dysfunctional organs (reversible versus irreversible dysfunction), severity of dysfunction Abbreviations: HLA-DR = human leukocyte antigen-D related; IL = interleukin; PAF = platelet activating factor; TNF = tumor necrosis factor. From Levy MM, Fink MP, Marshall JE et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-1256. Pathogenesis Sepsis often begins as a physiologic host response as the microbial clearance mechanisms of the innate immune system are called into play to eliminate a microbial invader. Sepsis becomes evident as the host response becomes excessive or dysfunctional, culminating in diffuse endothelial injury, MODS, and septic shock. The molecular pathogenesis of sepsis begins when the host response becomes a disadvantageous process in which host-derived mediators and coagulation factors induce damage to tissues remote from the site of the initiating infectious process. Generalized release of a network of proinflammatory and antiinflammatory molecules and mediators produce a maladaptive state leading to dysfunctional cellular, tissue, and organ system injury. A complex and dynamic web of interacting inhibitors and activators of cell signaling events ensues, and these can deteriorate over time to refractory organ failure and shock unless appropriate interventions are instituted. As the process unfolds, anti-inflammatory events dominate and an immune refractory state evolves. This immunodepressed state is now well recognized in the later stages of sepsis, and it is characterized by excess anti-inflammatory mediators and cytokine inhibitors, cellular apoptosis of CD4+ lymphocytes, follicular dendritic cells, and tissue refractoriness to endotoxin or other inflammatory signals. This

paradoxically renders the patient susceptible to a variety of secondary infections by intrinsically less virulent pathogens such as fungal organisms, enterococcal pathogens, and a variety of antibiotic-resistant nosocomial pathogens. Host factors responsible for the important first line of defense against the infectious insult include epithelial barriers, antimicrobial peptides, mucociliary flow, pH of body fluids, urine volume, and secretory immunoglobulins. Once the integument and mucosal barriers are breached, the innate immune system of the host (neutrophils, monocytes, macrophages, dendritic cells, natural killer [NK] cells, alternate complement, and mannose-binding lectin pathways) provide key defenses against infectious insults. The adaptive arm of host immunity, composed of highly specific and clonal B cells and T cells, plays primarily a support role in sepsis. This adaptive response becomes more relevant to host defenses in repeated infection from the same or similar pathogens or as the septic process persists over days to weeks.

CURRENT DIAGNOSIS Infection (documented or suspected) plus some of the following. General Variables

Fever (core temperature >38.3°C [101°F]) Hypothermia (core temperature 90 bpm or >2 SD above the normal value for age Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg for longer than 24 h) Hyperglycemia (plasma glucose >120 mg/dL or 7.7 mmol/L in absence of diabetes) Inflammatory Variables

Leukocytosis (WBC count >12,000/µL) Leukopenia (WBC count 2 SD above the normal value Plasma procalcitonin >2 SD above the normal value Hemodynamic Variables

Arterial hypotension (systolic BP 3.5 L/min/m2 Organ dysfunction variables Arterial hypoxemia (Pao2/Fio2 < 300) Acute oliguria (urine output 1.5 or aPTT >60 sec) Ileus (absent bowel sounds) Thrombocytopenia (platelet count 4 mg/dL or >70 mmol/L) Tissue Perfusion Variables

Hyperlactatemia (>1 mmol/L) Decreased capillary refill or mottling Abbreviations: aPTT = activated partial thromboplastin time; bpm = beats per minute; INR = international normalized ratio; MAP = mean arterial pressure; SD = standard deviation; WBC = white blood cell. From Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-1256. The innate immune system recognizes highly conserved, essential, and unique structures found only in microbial pathogens. These PAMPs (pathogen-associated molecular patterns) are detected by cognate pattern-recognition receptors. These receptors include CD14, complement receptors for C3b, and a remarkable group of 10 human transmembrane receptors known as the Toll-like receptors (TLR). TLR4 is the recognition receptor of bacterial endotoxin from gram-negative bacteria. TLR2 partners with TLR1 or TLR6 to recognize a variety of microbial structures including bacterial lipopeptides, peptidoglycans, outer membrane proteins, and mycobacterial antigens. TLR5 detects bacterial flagella, and TLR9, TLR8, and TLR3 recognize prokaryotic DNA sequences, single-stranded RNA, and double-stranded RNA, respectively. Engagement of the TLRs initiates a series of intracellular phosphorylation events that terminate as transcriptional activators for a large number of genetic programs for inflammation, coagulation, and other acute-phase responses. Gram-positive organisms produce an array of potent exotoxins, some of which function as superantigens. Superantigens induce massive activation of mononuclear cells, macrophages, and T cells, leading to overproduction of inflammatory cytokines. The prototypic superantigenic disease entity is staphylococcal toxic shock syndrome caused by release of TSST-1 (toxic shock syndrome toxin-1). Streptococcal toxic shock from invasive group A streptococcal infections has now supplanted Staphylococcus aureus as the predominant superantigen-mediated form of toxic shock today.

Some of the more commonly recognized primary pro- and anti-inflammatory molecules and mediators are listed in Box 2 . Included in the list of proinflammatory cytokines are tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, and interferon- (IFN- ). BOX 2 Potential Molecules Involved in the Pathogenesis of Severe Sepsis and Septic Shock Proinflammatory Molecules

•

Arachidonic acid metabolites: Prostaglandins, prostacyclin, thromboxane, leukotrienes

•

CD14, MD2

•

Clotting factors, PAI-1

•

Complement and activation of the complement cascade

•

Cytokines and chemokines (ILs-1, -2, -6, -8, -12, TNF, IFN- , G-CSF, MCP-1)

•

Elastase and lysosomal enzymes

•

Endorphins

•

Endotoxin and other microbial toxins and mediators

•

High mobility group box 1 (HMGB1)

•

Histamine and serotonin

•

Kinases: Protein kinases, tyrosine kinases, serine/theonine kinases

•

Kinins (e.g., bradykinin)

•

Mannose-binding lectin

•

Monocyte migration inhibitory factor (MIF)

•

Neopterin

•

NF-kB

•

PAF, oxidized phospholipids

•

Proteolytic enzymes

•

Reactive nitrogen intermediates: Nitric oxide, peroxynitrite

•

Soluble adhesion molecules

•

Toll-like receptors (1-10)

•

Toxic oxygen metabolites: Superoxide, hydroxyl radical, hydrogen peroxide

•

Vasoactive neuropeptides

Potential Anti-inflammatory Molecules

•

BPI

•

Epinephrine

•

Glucocorticoids and glucocorticoid receptors

•

IL-1ra

•

IL-1 receptor type II

•

IL-4, IL-10, IL-13

•

IkB

•

Leukotriene B4 receptor antagonist

•

Soluble CD14

•

sTNFr type 1 and type 2

•

TGF-ß

Abbreviations: BPI = bactericidal/permeability increasing protein; G-CSF = granulocyte colonystimulating factor; IFN- = interferon- I B = inhibitor of NF B; IL = interleukin; IL-ra = interleukin-1 receptor antagonist; MCP = monocyte chemoattractant protein; NF B = nuclear factor B; PAF = plateletactivating factor; PAI-1 = plasminogen activator inhibitor-1; sTNFr = soluble TNF receptor; TGF-ß = transforming growth factor-ß TNF = tumor necrosis factor.

An overwhelming systemic inflammatory response results when the host is unable to contain the proinflammatory response locally at the site of microbial invasion. The massive, uncontrolled production of inflammatory signals induces diffuse endothelial dysfunction and systemic activation of the coagulation system. The result is microvascular thrombi and up-regulation of endothelial adhesion molecules, causing increased microvascular permeability, vasodilation, organ dysfunction, and shock. Treatment In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock based on the best available published evidence. These guidelines, produced by the Surviving Sepsis Campaign, were published in 2004 and updated in 2006 as new clinical trials data became available. Management of sepsis and septic shock begins with prompt recognition of the process. Along with determination of the probable site of infection and causative microorganism, the initial management begins with an assessment of physiologic derangements. The general management strategy involves source control, restoration and maintenance of normal hemodynamic function, adequate oxygenation, ventilation, tissue oxygen delivery, and prevention of complications. The Current Therapy box outlines the general management principles. SOURCE CONTROL Prompt and effective management of the source of the infection is the cornerstone of sepsis management.

Necessary specimens should be sent for culture and susceptibility testing as early as possible and before antimicrobial therapy is initiated. This information will guide subsequent antimicrobial therapy to eradicate the causative pathogen(s). Recommendations for the initial antimicrobial regimen based on the source and likely pathogen are given in Table 1 .

TABLE 1 -- Suggested Empiric Antibiotic Choices in Severe Sepsis Likely Source of Antimicrobial Choice Infection Community-acquired pneumonia

Third-generation cephalosporin with a macrolide Alternative: fluoroquinolones

Hospital-acquired pneumonia

Third- or fourth-generation cephalosporins, extended-spectrum penicillins ± an aminoglycoside Alternatives: fluoroquinolones, carbapenems, ß-lactam–ß-lactamase inhibitors

Urinary tract infections

Extended-spectrum ß-lactam agent ± an aminoglycoside Add vancomycin (Vancocin) if MRSA is suspected Add linezolid (Zylox) if VRE is suspected

Intraabdominal infections Third- or fourth-generation cephalosporins with metronidazole (Flagyl) or clindamycin (Cleocin) or Extended-spectrum penicillins or ß-lactam–ß-lactamase inhibitor ± an aminoglycoside or fluoroquinolones and metronidazole Biliary tract infections

Extended-spectrum penicillin ± an aminoglycoside or fluoroquinolones

Neutropenic patients

Extended-spectrum ß-lactam agent Add vancomycin if MRSA is suspected Add aminoglycoside or fluoroquinolone if Pseudomonas aeruginosa is suspected Add a triazole antifungal or a ß-glucan inhibitor if candidemia is suspected

Abbreviations: MRSA = methicillin-resistant Staphylococcus aureus VRE = vancomycin-resistant enterococci.

Intravenous antibiotic therapy should be started within an hour of recognizing severe sepsis. Effective antimicrobial administration within the first hour of documented hypotension has been associated with increased survival to hospital discharge in adult patients with septic shock. For every additional hour to effective antimicrobial initiation in the first 6 hours after onset of hypotension, survival drops an average 7.6%.

After the likely pathogen is identified, antibiotic selection should be guided by the susceptibility patterns of causative microorganisms. The antimicrobial therapy should then be appropriately tailored with the aim of using a narrow-spectrum antibiotic to prevent the development of resistance, reduce toxicity, and reduce costs. Once a causative agent is identified, there is no evidence that combination therapy is more effective than monotherapy. However, most experts recommend combination therapy for patients with Pseudomonas infections and for neutropenic patients with severe sepsis or septic shock. The duration of therapy should typically be 7 to 10 days and guided by clinical response. All patients with severe sepsis should be evaluated for the presence of a focus of infection amenable to source-control measures, specifically drainage of an abscess or local focus of infection, débridement of necrotic tissue, removal of a potentially infected device, or definite control of a source of ongoing microbial contamination. The source-control objective should be accomplished with the least invasive method; for example, percutaneous rather than surgical drainage should be used for abscess drainage, if possible.

CURRENT THERAPY Identify the Cause and Source of Infection

Obtain suitable material for cultures, Gram stains, serologies, antigenic assays, and other diagnostic studies. Implement percutaneous or surgical drainage where appropriate. Initiate Appropriate Antibiotic Therapy

Initial therapy is empiric, but tailored therapy should begin as soon as microbiological data are available. Survival is improved when the initial antibiotic therapy is effective against the isolated organism(s) and started early. Restore and Maintain Hemodynamic Function

Implement an early goal-directed therapeutic approach. Fluids are the initial choice for volume resuscitation and may include crystalloids, colloids, volume expanders, or blood products. If hypotension and poor perfusion persist, then vasoactive agents should be used as necessary to ensure adequate hemodynamic function. Hemodynamic monitoring is often used to ensure the adequacy and effectiveness of therapy (arterial line, CVP, PA catheter). Physiologic dose corticosteroid replacement therapy may be beneficial for vasopressor-dependent patients who have an inadequate cortisol response. Provide Antithrombotic, Profibrinolytic, Anti-inflammatory Therapy

Use drotrecogin alfa (activated) (Xigris) per package insert recommendations. Provide Metabolic Support

Maintain early nutritional support. Maintain intestinal mucosa barrier function by the enteral route, the preferred method. Maintain tight glycemic control to decrease infectious complications; patient might need IV insulin therapy. Prevent Complications of Critical Illness

Provide DVT prophylaxis. Prevent stress-related gastrointestinal bleeding. Prevent organ system dysfunction. Prevent nosocomial and secondary infections. Recognize critical illness polyneuropathy and myopathy. Anticipate anemia of critical illness. Abbreviations: CVP = central venous pressure; DVT = deep vein thrombosis; PA = pulmonary artery. HEMODYNAMIC MANAGEMENT Sepsis is characterized by vasodilative or distributive shock, and there is an increase in vascular capacitance along with the decrease in the systemic vascular resistance. Septic patients are functionally volume depleted in the intravascular space from increased permeability as a result of endothelial cell injury. Early recognition of significant hemodynamic derangements and restoration of normal tissue perfusion are vital to prevent organ dysfunction and failure. The goal of hemodynamic resuscitation should be to raise the mean arterial pressure above 65 mm Hg. The resuscitative efforts and the adequacy of tissue perfusion can be assessed at the bedside by monitoring heart rate, BP, orthostatic BP changes, mental status, hourly urine output, and skin perfusion. The initial hemodynamic resuscitation should take the form of fluid for volume replacement. Debate continues regarding the appropriateness of colloid versus crystalloid fluids. Because the volume of distribution is much larger for crystalloids than for colloids, resuscitation with crystalloids requires about three times more fluid to achieve the same endpoints, and it results in more edema. The recent SAFE (Saline versus Albumin Fluid Evaluation) study indicated that albumin administration was indeed safe and as effective as crystalloid fluids. There was a nonsignificant decrease in mortality rates in a subset analysis of septic patients (P = 0.09). Previous meta-analyses of small studies of ICU patients had demonstrated no difference between crystalloid and colloid resuscitation. The lack of clear evidence of the benefit of colloid agents (albumin, dextran, and plasma expanders) and their high cost have generally resulted in the use of saline solutions for volume expansion.

A delicate balance is required between maintaining tissue perfusion and preventing fluid overload, with its attendant risk of lung injury. Bolus infusions are typically administered using the clinical response or measurements of central venous pressure (CVP) or pulmonary capillary wedge pressure (PCWP) as a guide. A CVP of 8 to 12 mm Hg or a PCWP of 12 mm Hg is generally considered a reasonable resuscitation target. Optimal fluid management in patients with acute lung injury is unknown. A recent large prospective, randomized study was performed to determine whether a liberal or a conservative strategy of fluid management was more effective in patients with established lung injury. Although there was no difference in 60-day mortality between the two treatment groups, patients in the group treated according to a conservative strategy of fluid management had significantly improved lung function and central nervous system function and a decreased need for sedation, mechanical ventilation, and intensive care. Invasive vascular monitoring may be used to aid in determining adequate hemodynamic resuscitation. If a central venous catheter is present, the CVP can be measured to assess the adequacy of the intravascular volume status. In select patients with hemodynamic insufficiency, insertion of pulmonary artery catheters to measure the left-sided and right-sided filling pressures and the various hemodynamic parameters may be beneficial. The use of pulmonary artery catheters has declined because multiple randomized trials now indicate that pulmonary artery catheters are not useful for routine hemodynamic monitoring in critically ill patients and are associated with more complications than the CVC. In shock states, estimation of blood pressure using a sphygmomanometer is commonly inaccurate. Insertion of an arterial line may be required, especially if the patient is unresponsive to initial volume resuscitation and requires the addition of vasopressor therapy for hemodynamic resuscitation. VASOPRESSOR MANAGEMENT If adequate fluid resuscitation is insufficient to restore adequate hemodynamic function, then vasopressor or inotropic therapy, or both, will be necessary. There are a wide variety of vasoactive medications that are useful in the hemodynamic resuscitation of septic shock. Table 2 highlights the differences and advantages of some of the more commonly used agents. Despite a wide range of possible agents, dopamine (Intropin) and norepinephrine (Levophed) are typically used in most clinical units. Some centers prefer to use phenylephrine (Neo-Synephrine) in patients with tachycardia or a history of arrhythmias because this pure aadrenergic agent causes less tachycardia and arrhythmia.

TABLE 2 -- Vasoactive Agents Commonly Used in Managing Severe Sepsis[1] Vasoactive Agent/Receptor Activity a 1 a 2 ß 1 ß 2 V1 V2 Dopamine (Intropin)

3+ 3+ 3+ 2+

10 µ g/kg/min

Vasoconstriction

a-Adrenergic effects predominate

Dobutamine (Dobutrex)

1+

3+ 2+

1+ 2-20 µ g/kg/min

Inotropy and chronotropy

25% increase in CI decreases PAOP

Epinephrine

3+ 3+ 3+ 2+

1+ 0.1-0.5 µ g/kg/min

Stroke volume and CI

Decrease splanchnic blood flow Increase oxygen consumption

Norepinephrine (Levophed)

3+ 2+ 2+

Vasoconstriction

Minimal change in heart rate or CI

0.03-1.5µ g/kg/min

Can decrease lactate Phenylephrine (NeoSynephrine)

3+

Vasopressin

(Pitressin)[1]

1+

0.5-8 µ g/kg/min

Vasoconstriction

Increases MAP CI can decrease

0.01-0.04

Vasoconstriction

Vasoconstrictor effect on the up-regulated V1, splanchnic vasoconstriction

U/min

Abbreviations: CI = cardiac index; GFR = glomerular filtration rate; MAP = mean aortic pressure; PAOP = pulmonary artery occluded pressure.


Unfortunately, there is a lack of large, prospective, randomized, protocol-controlled clinical trials that have compared dopamine and norepinephrine for managing patients who have septic shock. Dopamine has been the preferred agent in many units, in part because of its ease of use, the concept that it improves splanchnic and renal perfusion, and its safety record. Recent clinical trial results have revealed that there is no specific beneficial effect of renal dose dopamine in preventing the development of renal failure. A recent European observational study suggested that dopamine administration might actually be associated with increased mortality rates. Norepinephrine is a potent vasoconstrictor that also has some increased inotropic and chronotropic effects on the heart. A large observational study of French septic shock patients who required high doses of vasopressor therapy demonstrated a significant improvement in survival with the use of norepinephrine as compared with high doses of dopamine with or without the addition of epinephrine. There has been renewed interest in the use of vasopressin (Pitressin)[1] in patients with vasodilative shock.

The initial release of stored vasopressin from the posterior pituitary during hypotension depletes the body's store of the hormone. Unlike dopamine and epinephrine, vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects. Vasopressin can lead to decreased cardiac output and hepatosplenic flow. Most published reports exclude patients from vasopressin treatment if the cardiac index is less than 2 to 2.5 L/min/m2. Vasopressin should be used with caution in patients with cardiac dysfunction. Some patients with severe sepsis and septic shock have a reversible biventricular myocardial dysfunction, which has been attributed to circulating TNF-a, IL-1, or nitric oxide that are elaborated as part of the SIRS response. Ventricular dilation and a reduced ejection fraction are the components of this myocardial depression. Inotropic agents such as dobutamine (Dobutrex) or epinephrine can improve the myocardial contractility and hemodynamic function in these patients. By increasing stroke volume and heart rate, dobutamine increases the cardiac index. Although epinephrine can also increase the cardiac index, its use should be limited in the septic patient because it can impair splanchnic blood flow and increase systemic and regional lactate concentrations. 1 Not FDA approved for this indication.

SUPPORT OXYGENATION AND VENTILATION Abnormalities of the respiratory system are some of the most common evidence of organ system involvement in sepsis. Septic patients should be assessed for adequacy of oxygenation, oxygen delivery, ventilation, and the ability to protect the airway. Septic patients commonly have abnormalities of oxygenation and increased work of breathing. Patients who are hypoxemic should be given supplemental oxygen with a goal of achieving arterial oxygen saturation of at least 90%. Another decision to make in caring for the septic patient is the need and timing for endotracheal intubation and ventilatory support. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are relatively common manifestations of pulmonary dysfunction in the patient with severe sepsis and septic shock. Up to 35% of septic patients present with ARDS. The goal of mechanical ventilation is to maintain the Pao2 in the 55 to 70 mm Hg range while keeping the inspired oxygen concentration (Fio2) below 60%. The traditional approach to mechanically ventilating patients who have ALI and ARDS has been to employ tidal volumes in the 10 to 15 mL/kg range. The Acute Respiratory Distress Syndrome Network (ARDSNet) trial used low tidal volume ventilation of 6 mL/kg ideal body weight, coupled with maintaining an end-inspiratory plateau pressure up to 30 cm H2O and a nomogram for positive end-expiratory pressure (PEEP) titration based on Fio2 and oxygenation goals. This combination demonstrated an overall decrease in hospital mortality along with an increase in ventilator-free and organ failure–free days. The risk of infection and ventilator-associated complications increases with the duration of ventilatory support. Patients should be removed from the ventilator as soon as they no longer need mechanical ventilatory support. The use of weaning protocols implemented by trained ICU support staff have been shown to speed the weaning process and improve the overall process of extubating the critically ill patient. It is also important to use sedation and analgesia appropriately in this critically ill population. Excessive sedation and analgesia have been linked to prolonged stays on mechanical ventilatory support and increased complications. In a large multicenter controlled trial conducted in critically ill patients without ischemic cardiac disease or

acute blood loss, the restrictive practice of packed red blood cell (RBC) transfusions in the management of anemia and low hemoglobin levels (7.0-9.0 g/dL) was shown to provide adequate oxygen delivery to the tissues. In a subgroup of younger patients and less ill patients, it was found to be associated with a lower mortality rate compared with a more liberal transfusion policy with hemoglobin levels maintained between 10.0 and 12.0 g/dL. Banked, stored RBCs are less deformable, are less efficient at releasing oxygen from their 2,3-diphosphoglycerate–depleted hemoglobin stores, and might have immunosuppressive effects. Aggressive use of packed RBC transfusions in an effort to achieve supernormal oxygen delivery states should be discouraged. The use of weekly recombinant erythropoietin (Epogen) [1] reduces the need for transfusions in critically ill patients but with no effect on clinical outcome, and therefore erythropoietin is not recommended as a standard treatment for anemia associated with severe sepsis. SUPPORTIVE CARE FOR THE CRITICALLY ILL PATIENT Patients with severe sepsis and septic shock are critically ill and susceptible to the multiple complications common in the critically ill population. These complications include deep venous thrombosis (DVT) and pulmonary emboli, stress-related gastrointestinal bleeding, nosocomial infections, MODS, and critical illness polyneuropathy and myopathy. Patients in the ICU who have sepsis or septic shock should receive prophylaxis for DVT with unfractionated heparin or low-molecular-weight heparin, unless they have contraindications to their use. Pneumatic compression devices may be used in patients who have a coagulopathy or increased risk of bleeding. In patients at high risk, such as those with severe sepsis and a history of DVT, trauma, or orthopedic surgery, a combination of pharmacologic and mechanical therapies is recommended unless contraindicated. Prophylaxis for stress-related GI bleeding may be accomplished with H2-receptor blockers,[1] proton pump inhibitors,[1] sucralfate (Carafate),[1] or early enteral feeding. Proper nutrition is important for maintaining the necessary immune function during the septic metabolic process. Enteral administration of nutrition can prevent stress-related GI bleeding and might prevent the translocation of bowel organisms or endotoxin by maintaining the integrity of the GI tract's mucosal barrier function. Adequate nutrition is responsible for improved wound healing, decreased susceptibility of critically ill patients to infection, and optimized immune function. The following nutritional guidelines have been recommended for patients with sepsis: •

Daily caloric intake: 25 to 30 kcal/kg of usual body weight per day

•

Protein: 1.3 to 2.0 g/kg per day

•

Glucose: 30% to 70% of total nonprotein calories to maintain serum glucose lower than 150 mg/dL

•

Lipids: 15% to 30% of total nonprotein calories

•

Omega-6 polyunsaturated fatty acids: Reduce in septic patients, maintaining a level that prevents deficiency of essential fatty acids (7% of total calories)—generally 1 g/kg/day

Metabolic management also includes correction of electrolyte abnormalities as well as tight control of blood sugar, which might require constant insulin infusion. In medical and surgical ICU patients, tight glucose control aimed at keeping the blood sugar between 80 and 110 mg/dL was associated with a significant improvement in ICU and hospital survival. Tight glucose control should be the goal in critically ill patients if

careful monitoring for prevention of hypoglycemia can be maintained. INNOVATIVE THERAPIES Corticosteroid Therapy

Experimental studies in animal models of sepsis and septic shock have demonstrated improved survival using pretreatment or early treatment with high doses of corticosteroids. As a result of multiple failed trials of high-dose steroids in patients with severe sepsis, this treatment practice has largely been abandoned. Recently, the observation that basal cortisol levels and the cortisol response to the administration of adrenocorticotropic hormone (ACTH) [1] could predict survival in patients with severe sepsis and septic shock has renewed interest in steroid therapy. In a French study, patients who had septic shock and an intact pituitary-adrenal axis had a 74% survival rate. In comparison, patients who had impaired adrenal function, had a basal cortisol level of more than 34 µg/dL, and were unable to increase their cortisol level by at least 9 µg/dL had an 18% survival rate. Researchers hypothesized that patients with septic shock have a state of relative adrenal insufficiency and would benefit from the use of more physiologic corticosteroid replacement therapy. A recent multicenter prospective randomized, controlled trial of 300 patients with vasopressor-dependent septic shock demonstrated an improved survival rate in patients with impaired adrenal function who were given physiologic corticosteroid replacement therapy. Subjects were given a stress dose of 50 mg of hydrocortisone (Solu-Cortef)[1] intravenously every 6 hours for 7 days combined with a once-daily oral dose of 50 µg of fludrocortisone (Florinef). More recently, a randomized, double-blind clinical trial of patients with persistent ARDS found no beneficial effect of corticosteroids on survival in the hospital. Furthermore, the initiation of methylprednisolone (SoluMedrol)[1] 2 or more weeks after the onset of ARDS was associated with an increased mortality rate as compared with that in the placebo group. Patients in the methylprednisolone group were able to breathe without assistance earlier than were patients in the placebo group, but they were also more likely to resume assisted ventilation. Possible explanations for this effect include complications of corticosteroid therapy, such as neuropathy; complications related to the withdrawal of steroids, including shock; and pulmonary parenchymal causes of hypoxemic respiratory failure, such as recrudescence of fibroproliferation as a result of corticosteroid withdrawal. High-Volume Continuous Venovenous Hemofiltration Therapy

The use of high-volume, continuous hemofiltration (either continuous arteriovenous or venovenous) benefits the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. This form of management is expensive, requires defined expertise, and may be associated with metabolic and coagulation abnormalities. Further studies are needed to determine if this mode of therapy improves outcome in septic patients. Its use should probably be limited to patients with renal indications for hemofiltration. Antithrombotic Therapy

New therapies have been directed toward inhibitors of the coagulation system as a potential therapeutic strategy for patients with severe sepsis and septic shock. Among the therapies currently in use or under investigation are antithrombin tissue factor pathway inhibitor and recombinant human activated protein C. The protein C system is one of the endogenous antithrombotic agents. Drotrecogin alfa (activated) (Xigris) is the recombinant form of human activated protein C. Two international multicenter controlled trials of drotrecogin alfa, the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin alfa (activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. Drotrecogin alfa was approved on the basis of the favorable results of the PROWESS study, a phase III trial that demonstrated a significant survival benefit in 1690 patients with severe sepsis and septic shock. Treatment with a 96-hour infusion of drotrecogin alfa produced a 6.1% absolute risk reduction and a 19.4% relative risk reduction in the 28-day all-cause mortality in patients with severe sepsis (P = 0.005). The drotrecogin alfa–treated population experienced more serious bleeding complications (3.5%) compared with the placebo group (2.0%). The number needed to treat to save an additional life was 16. The U.S. Food and Drug Administration (FDA) and 19 other regulatory bodies in other countries (including the European Union) have approved drotrecogin alfa to treat severe sepsis in adult patients with a high risk of mortality. The FDA gives the example of using the Acute Physiology and Chronic Health Evaluation (APACHE) II to estimate the risk of death (APACHE II score 25), and other regulatory agencies use sepsisinduced multiorgan failure as an indication for its use. Drotrecogin alfa is contraindicated in patients with known sensitivity to drotrecogin alfa and in patients with a high risk of death from or significant morbidity associated with bleeding. However, the recently published ADDRESS trial demonstrated no evidence of benefit of drotrecogin alfa in patients with severe sepsis and at low risk of death. The results of the ADDRESS trial also failed to confirm the observation made in the PROWESS trial of a large reduction in mortality among patients with APACHE II scores of 25 or higher, although the number of patients (324) in this group was too small for a meaningful statistic comparison. Further trials of drotrecogin alfa in prospectively defined high-risk patients are required to clarify its optimal role in management of severe sepsis. Intensive Care of Patients with HIV Infection Antiretroviral therapy has increased the life expectancy of patients who are infected with HIV and has reduced the incidence of illnesses associated with AIDS. However, the incidence of pulmonary, cardiac, gastrointestinal, and renal diseases that are often not directly related to underlying HIV disease has increased. Although the guiding principles of management in the ICU pertain to critically ill patients with HIV infection, antiretroviral therapy and unresolved questions regarding its use in the ICU add an additional level of complexity to already complicated cases. Patients who are receiving antiretroviral therapy with evidence of virologic suppression (plasma HIV RNA below the limit of detection) before admission to the ICU should continue their antiretroviral regimen, if possible. Patients who continue to receive treatment should have no contraindications to continuation of treatment, such as major interactions between drugs used in the ICU and antiretroviral therapy. Drug interactions are particularly common and can be severe with hepatically metabolized agents via cytochrome P-450 3A (CYP 3A). In contrast, the benefits of continued antiretroviral therapy in the ICU are less clear for

patients with detectable plasma HIV RNA. For these patients, practitioners should consult with an HIV expert. Patients who did not receive antiretroviral therapy before ICU admission are the largest subgroup of patients with HIV infection admitted to the ICU. Initiation of antiretroviral therapy should be deferred in patients admitted to the ICU who have a condition that is not associated with AIDS. In these patients, the immediate prognosis is generally better than in those who have an AIDS-associated diagnosis, and the short-term outcome is most likely related to successful treatment of the underlying non-AIDS condition. However, antiretroviral therapy should be considered in patients whose CD4 cell count is less than 200 cells/mm3 and whose stay in the ICU is prolonged. The risk of opportunistic infection is increased in patients whose CD4 count is less than 200 cells/mm 3. For such patients, prophylaxis against opportunistic infections should also be prescribed (e.g., trimethoprim-sulfamethoxazole for Pneumocystis pneumonia), as recommended in current guidelines. In contrast, antiretroviral therapy should be considered for patients who are admitted to the ICU with an AIDS-associated diagnosis. This recommendation especially applies to patients whose physiologic condition is worsening despite optimal ICU management and treatment for the AIDS-associated condition. Patients who receive antiretroviral therapy should be followed for development of the immune reconstitution syndrome. Prognosis Despite the tremendous advances in the care of septic patients, the mortality rate for patients with severe sepsis and septic shock remains high. Mortality rates attributable to severe sepsis and septic shock remain in the 20% to 50% range. Factors associated with adverse outcome include advanced age, comorbid conditions, respiratory site of infection, virulent organisms, severity of illness, the number of organ system failures, and specific organ systems failing. In addition, a patient's genetic makeup or gender can have a dramatic impact on whether the patient develops sepsis as well as on the severity, clinical manifestations, and outcome of the sepsis. Survivors of sepsis have increased 6- and 12-month mortality rates compared with critically ill patients who do not have sepsis. Patients who have survived an episode of sepsis have a reduced quality of life and more health-related issues. These observations underscore the importance of early aggressive management of the septic patient and suggest that our future focus should also be directed toward prevention of sepsis.



REFERENCES Dellinger et al., 2004. Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32(3):858-873.(accessed April 18, 2007). Friedrich et al., 2006. Friedrich JO, Adhikari NK, Meade MO: Drotrecogin alfa (activated): Does current evidence support treatment for any patients with severe sepsis?. Crit Care 2006; 10(3):145. Huang et al., 2006. Huang L, Quartin A, Jones D, Havlir DV: Intensive care of patients with HIV infection. N Engl J Med 2006; 355(2):173-181. Kumar et al., 2006. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6):1589-1596. Martin et al., 2003. Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546-1554. Sakr et al., 2006. Sakr Y, Reinhart K, Vincent JL, et al: Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med 2006; 34(3):589-597. Steinberg et al., 2006. Steinberg KP, Hudson LD, Goodman RB, et al: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354(16):1671-1684. Van den Burghe et al., 2006. Van den Burghe G, Wilmer A, Hermans G, et al: Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449-461. Wheeler et al., 2006. Wheeler AP, Bernard GR, Thompson BT, et al: Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354(21):2213-2224. Wiedemann et al., 2006. Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354(24):2564-2575.



Chapter 17 – Brucellosis

Method of: Basak Dokuzoguz, MD Nurcan Baykam, MD Brucellosis is a common bacterial zoonotic disease. It has become more significant in recent years as a bioterrorism agent. Brucellosis is known as a historic disease, and the sequencing of the Brucella melitensis genome was completed in 2002. Etiology The disease is caused by bacteria of the genus Brucella, which are nonmotile, gram-negative, aerobic, unencapsulated cocci or short rods. Brucella species are divided into six subtypes based on the main host animals ( Table 1 ). Of these, B. abortus, B. melitensis, B. suis, and B. canis are known human pathogens. Two new species, provisionally called B. pinnipediae and B. cetaceae, have been shown to cause human diseases.

TABLE 1 -- Subtypes and Hosts of Brucella Species Species Host Animal

Human

B. abortus

Cows, camels, yaks, buffalo

+

B. melitensis

Goats, sheep, camels

+

B. suis

Pigs, wild hares, caribou, reindeer, wild rodents

+

B. canis

Canines

+

B. neotomae

Rodents

-

B. ovis

Sheep

-

B. pinnipediae Minke whales, dolphins

+

B. cetaceae

+

Seals

Epidemiology Brucellosis is one of the major zoonotic diseases and occurs all over the world. Some countries in Europe and North America have achieved control and prevention of the disease based on vaccination programs. However, brucellosis remains endemic in other parts of the world, especially in the Mediterranean, the Middle East, Central Asia, Africa, and Latin America. The real incidence of the disease is not known because underreporting of the disease is believed to be common.

The most common causes of human brucellosis are reported as B. melitensis followed by B. abortus. The biotypes of Brucella species vary by geographic region. The disease is transmitted to humans by direct contact with infected animals, by ingestion of raw or unpasteurized milk and milk products, through cuts and abrasions, or by inhalation of aerosols. It is an occupational disease of farmers, veterinarians, slaughterhouse workers, and health care workers, especially laboratory staff. Some individual cases occur as a result of ingesting contaminated dairy products, handling infected animal tissue or body fluids, or handling aborted animal fetuses and placentas. However, the transmission route for outbreaks is usually inhalation of aerosols. Human-to-human transmission of brucellosis is very rare, but there are a few case reports of humans infected through sexual contact, transplacental transmission, or transplantation. Pathogenesis The Brucella species are pathogenic for humans and animals. Brucella species prefer to survive and multiply within phagocytic cells of the host. Unlike other pathogenic bacteria, they do not have classic virulence factors such as exotoxins, cytolysins, capsules, fimbria, plasmids, and endotoxic lipopolysaccharides. Instead of these factors, the bacteria have molecular determinants that are necessary for cell invasion and survival in the cellular compartment. The major one of these molecular determinants is S lipopolysaccharide (S LPS). The bacteria are phagocytosed by M cells, macrophages, and neutrophils after invasion of mucosa. Fc receptors, complement, lectin, and fibronectin receptors mediate the bacteria for internalization. Most intracellular Brucella species are eliminated in phagolysosomes, but some of them reproduce in the acidic compartment. The intracellular mechanism of the organism is not completely described, but intracellular replication of bacteria does not destroy the cell or the cell's function. After they are taken up by local tissue lymphocytes, the bacteria disseminate into the circulation, and with tropism to the reticuloendothelial system, they become localized within bone marrow, liver, spleen, and lymph nodes. The characteristic feature of the disease is the formation of granulomas in these tissues. As a host humoral immune response to the disease, the titers of IgM antibodies increase within the first week of infection, and IgG synthesis follows after the second week. Cell-mediated immunity is probably the main mechanism for recovery from the infection. Clinical Features Human brucellosis is a multisystem disease that can manifest with a broad spectrum of clinical features. The musculoskeletal, genital, cardiac, respiratory, and nervous systems are involved. The definition and the classification of cases recommended by the World Health Organization (WHO) is presented in Box 1 . Some authors classify the disease course as acute, subacute, or chronic, but such a classification has no clinical significance. BOX 1

Recommended Case Definitions and Classifications by the World Health Organization Clinical Description An illness characterized by acute or insidious onset, with continued, intermittent, or irregular fever of variable duration; profuse sweating, particularly at night; fatigue; anorexia; weight loss; headache; arthralgia and generalized aching. Local infection of various organs can occur. Laboratory Criteria for Diagnosis

•

Isolation of Brucella spp. from clinical specimen or

•

Brucella agglutination titer (e.g., standard tube agglutination tests: STA>160) in one or more serum specimens obtained after onset of symptoms or

•

ELISA (IgA, IgG, IgM), 2-mercaptoethanol test, complement fixation test, Coombs' test, fluorescent antibody test (FAB), radioimmunoassay for detecting antilipopolysaccharide antibodies, counterimmunoelectrophoresis (CIE)

Case Classification Suspected A case that is compatible with the clinical description and is epidemiologically linked to suspected or confirmed animal cases or contaminated animal products. Probable A suspected case that has a positive rose bengal test. Confirmed A suspected or probable case that is laboratory confirmed. Abbreviations: ELISA = enzyme-linked immunosorbent assay; Ig = immunoglobulin.

The onset of symptoms can be insidious or acute after the incubation period, which is 2 to 8 weeks. A broad spectrum of symptoms such as fever, headache, back pain, weakness, profuse sweating, chills, depression, and joint pain can be observed. These symptoms can also mimic various infectious and noninfectious diseases. Usually an undulant fever pattern is accompanied by so much sweating that the patient needs to change clothes frequently. On the other hand, the physical examination might not reveal any specific finding ( Table 2 ). In children, the range of clinical signs and symptoms may be different than in adults, because children have fewer constitutional symptoms but more hepatic and splenic involvement.

TABLE 2 -- Clinical Presentation and Laboratory Findings of Human Brucellosis

Feature

Percentage

Signs and Symptoms Fever

72–91

Constitutive symptoms (e.g., malaise, arthralgias) 26–90 Hepatic involvement

17–31

Splenomegaly

14–16

Osteoarticular involvement

9–22

CNS disorder

3–13

Lymphadenopathy

2–7

Genitourinary involvement

1–5.7

Respiratory disorders

0.2–6

Cardiovascular disorders

0.4–1.8

Skin rashes

0.4–3

Laboratory Findings Hematologic Relative lymphocytosis

40

Anemia

31

Leukopenia

2–27

Thrombocytopenia

5–15

Pancytopenia

2

Biochemistry Elevated transaminase

24–31

Data derived from Aygen B, Doganay M, Sümerkan B, et al: Clinical manifestations, complications and treatment of brucellosis: An evaluation of 480 patients. Med Mal Infect 2002;32:485-493; Dokuzoguz B, Ergonul O, Baykam N, et al: Characteristics of B. melitensis versus B. abortus bacteremias. J Infect 2005;50(1):1-5; Pappas G, Akritidis N, Bosilkovski M, Tsianos E: Brucellosis. N Engl J Med 2005;352:2325-2336. Abbreviation: CNS, central nervous system.

Hepatomegaly, elevated transaminase levels, and granulomatous lesions are the presentations of hepatic involvement in brucellosis. The most common complication of brucellosis is osteoarticular disease, which occurs as peripheral arthritis, sacroiliitis, and spondylitis. This complication is reported in 10% to 80% of cases, and this range may be related to the age and genetic predisposition (HLA-B39) of patients and the infecting Brucella species. Genitourinary system involvements exist in 2% to 20% of patients with

brucellosis. Prostatitis, epididymo-orchitis, cystitis, pyelonephritis, interstitial nephritis, exudative glomerulonephritis, and renal abscess are the clinical manifestations of this complication. Neurobrucellosis can develop at any stage of disease and can have widely variable manifestations, including encephalitis, meningoencephalitis, radiculitis, myelitis, peripheral and cranial neuropathies, subarachnoid hemorrhage, and psychiatric manifestations. Brucellosis can cause a variety of ocular lesions and different types of skin rash that are nonspecific and reported rarely. Another rare (10% immature granulocytes

Hypotension (systolic BP 38.9°C

•

Hypotension •

Systolic blood pressure >90 mm Hg

•

Orthostatic drop in diastolic blood pressure >15 mm Hg

•

Orthostatic syncope or dizziness

•

Rash: Diffuse macular erythroderma, often involving palms and soles

•

Desquamation 1-2 wk after onset, particularly on the palms and soles

•

Multisystem organ involvement (=3)

•

•

CNS: Disorientation or altered level of consciousness without focal neurologic signs when fever and hypotension are absent

•

GI: Vomiting or diarrhea at onset of illness

•

Hematologic: Platelet count twice the upper limit of normal

•

Mucous membranes: Vaginal, oropharyngeal, or conjunctival hyperemia

•

Muscular: Severe myalgia or CK >twice the upper limit of normal

•

Renal: BUN or creatinine >twice the upper limit of normal or pyuria in the absence of UTI

Negative results of •

Blood, throat, or CSF cultures (blood cultures may be positive for S. aureus)

•

Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles

Revised Definition A revised definition seeks to incorporate laboratory findings confirming presence of an agent and susceptibility of the host.

•

Any of the following laboratory findings† •

Isolation of S. aureus from a mucosal or normally sterile site

•

Production of TSS-associated SAG by isolate

•

Lack of antibody to the implicated toxin at the time of acute illness

•

Development of antibody to the toxin during convalescence

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine phosphokinase; CNS = central nervous system; CSF = cerebrospinal fluid; GI = gastrointestinal; SAG = superantigen; TSS = toxic shock syndrome; UTI = urinary tract infection. Standard definition adapted from Reingold AL, Hargrett NT, Shands KN, et al: Toxic shock syndrome surveillance in the United States, 1980 to 1981. Ann Intern Med 1982;96:875-880. Revised definition from Parsonnet J: Case definition of staphylococcal TSS: A proposed revision incorporating laboratory findings. In Arbuthnott J, Furman B (eds). European Conference on Toxic Shock Syndrome. International Congress and Symposium Series 229. London: Royal Society of Medicine Press, 1997. BOX 2 Case Definitions for Group A Streptococcal Toxic Shock Syndrome A definite case is an illness that meets criteria IA and IIA. A probable case is an illness that meets criteria IB and IIB. I.

II.

Isolation of group A streptococcus A.

From a normally sterile site

B.

From a nonsterile site

Clinical signs of severity A.

Systolic blood pressure 177 µmol/L or elevation > twice over baseline

•

Coagulopathy: Platelets twice elevation or > twice upper limit of normal

•

ARDS

•

Generalized erythematous, macular rash that might desquamate

•

Soft tissue necrosis, including necrotizing fasciitis, myositis, or gangrene

Abbreviations: ALT = alanine aminotransferase; ARDS = acute respiratory distress syndrome; AST = aspartate aminotransferase; DIC = disseminated intravascular coagulation.

Adapted from the Working Group on Severe GAS Infections: Defining the group A streptococcal toxic shock syndrome. JAMA 1993;269:390-391. Onset of SA-TSS occurs 2 to 3 days after surgery or onset of menses. Early manifestations include a diffuse red, macular rash that does not spare soles or palms. The rash might involve the mucosa. In some severe cases petechiae, ulcerations, vesicles, and bullae occur. During the convalescent phase of the illness, 1 to 2 weeks after onset of symptoms, a nonspecific maculopapular rash with desquamation of the palms and soles can occur. A major review on the subject of TSS and superantigens in 2001 by McCormick and colleagues urges revision and modernization of the case definition by incorporating specific laboratory findings. The isolation of S. aureus from a mucosal or normally sterile site, production of TSS-associated SAG by isolated strains, lack of antibody to the implicated toxin at the time of acute illness, and development of antibody to the toxin during convalescence should contribute to the diagnosis of a likely case of SA-TSS. Although isolation of S. aureus from wounds and mucosal sites occurs in up to 90% of cases of SA-TSS, it is not required for the diagnosis. Bacteremia is present in only about 5% of cases. In GAS-TSS, infection can begin within 1 to 3 days after a minor local trauma. Suspicions should be raised in cases with rapidly progressive localized or diffuse pain that might indicate invasive streptococcal soft tissue infection. Soft tissue disease is present in 80% of cases. Invasive disease is present in 50% of cases. Repeated meticulous physical examination is necessary to detect the manifestation of initially unidentified invasive soft tissue disease. An influenza-like prodrome occurs before toxic presentation in 20% of cases. Bacteremia is present in 60% of patients with GAS-TSS. Titers of antibody to DNase B and antistreptolysin O can be measured to confirm exposure to GAS. The differential diagnosis of TSS includes septic shock, meningococcemia, Rocky Mountain spotted fever, scarlet fever, leptospirosis, ehrlichiosis, Kawasaki's disease, lupus erythematosus, measles, dengue fever, other viral exanthema, and adverse cutaneous drug eruption. Treatment Management of TSS requires early and definitive treatment. Critical care expertise early in the presentation of these patients is desirable. Treatment focuses on stabilizing the patient, eradicating the culprit organism, minimizing the toxin-mediated effects, and modulating the inflammatory immune response. Initial therapy includes large volumes of crystalloid intravenous fluids and vasopressor support to minimize hypotensioninduced end-organ damage. Blood products may be required to reverse coagulopathies and anemia. Surgical intervention in both GAS-TSS and SA-TSS should not be overlooked because it may be critical for exploration of affected tissues, débridement of necrotic tissues, and removal of foreign bodies. Antibiotics contribute to the management by reducing the number of toxin-producing organisms (ß-lactams and vancomycin [Vancocin]), as well as reducing production of toxin (clindamycin [Cleocin]) and possibly by modulating immune response (clindamycin).

CURRENT THERAPY Initial Management

Volume and crystalloid resuscitation Vasopressors and inotropic agents to support blood pressure as needed Correction of coagulopathy and anemia (frozen plasma, cryoprecipitate, and packed red blood cells) Initiation of appropriate antibiotic therapy Surgical consultation should be considered early in manifestation Critical care and infectious disease consultation Staphylococcal Toxic Shock Syndrome

Antibiotics One penicillinase-resistant penicillin: Oxacillin (Bactocill) 2 g IV q4h Nafcillin (Unipen) 2 g IV q4h Cloxacillin (Cloxapen) 2 g IV q4h[*] plus Clindamycin (Cleocin) 900 mg IV q8h plus Vancomycin (Vancocin) 2 g IV q12h [†] Adjust dose of penicillins and vancomycin for degree of renal dysfunction Streptococcal Toxic Shock Syndrome Antibiotics

Penicillin 4 million U IV q4h with or without Ceftriaxone (Rocephin) 2 g IV q12h plus Clindamycin (Cleocin) 900 mg IV q8h Adjust dose of penicillins and vancomycin for degree of renal dysfunction Intravenous Immunoglobulin[1] (IVIG)

1.0 g/kg d 1, 0.5 g/kg d 2 and 3 of treatment Data are not sufficient to recommend IVIG in all cases May be beneficial in streptococcal toxic shock Reasonable in some severe cases of staphylococcal toxic shock Staphylococcal toxic shock may require higher doses * Intravenous cloxacillin formulation is available only in Canada. † The addition of vancomycin should be based on prevalence of community-acquired methicillin-resistant S. aureus in the patient's population. Discontinue if appropriate when sensitivities are known. 1 Not FDA approved for this indication.

ANTIBIOTICS Antibiotics must be selected empirically, initially, and thereafter tailored to the specific resistance patterns of the organism. Penicillins and vancomycin should be appropriately adjusted for the degree of renal insufficiency. Patients who have allergies to ß-lactams and therefore cannot take penicillins and cephalosporins should be treated with vancomycin. Macrolides are not recommended due to resistance patterns, despite their superiority to penicillin in vitro and in animal studies. Minimal data are available about the use of fluoroquinolones, quinpristin-dalfopristin (Synercid), and linezolide (Zyvox) in TSS. Current recommendations for the treatment of SA-TSS include combination of a penicillinase-resistrant penicillin such as oxacillin (Bactocill), nafcillin (Unipen), or cloxacillin (Cloxapen) (2 g IV q4h) and high-dose clindamycin (900 mg IV q8h). Due to increasing rates of toxin-producing CA-MRSA, the addition of vancomycin (2 g/day IV in divided doses) is advised until sensitivity to penicillinase-resistant penicillins is confirmed. Current recommendations for the treatment of GAS-TSS include a combination of penicillin (4 million U q4h) and clindamycin (900 mg IV q8h). In severe GAS infections, ceftriaxone (Rocephin) (2 g IV q12h) should be considered. Although GAS is susceptible to penicillin, in large numbers of organisms the efficacy is reduced, likely due to reduction in the penicillin-targeted penicillin-binding proteins (PBPs) when GAS enters the stationary phase of growth. Ceftriaxone may have preferred activity, likely due to the increased expression of PBPs that it targets. Clindamycin affects protein synthesis rather than structural cell wall building factors, and the number of organisms has no bearing on efficacy. ADJUNCTIVE THERAPY Immunomodulatory Therapy

Adjunctive therapies include intravenous immunoglobulin (IVIg)[1] and other immunomodulators of the exaggerated inflammatory reaction initiated by toxic superantigens. Although there are minimal clinical trial data available on the use of IVIg in TSS, there is anecdotal and in vitro evidence supporting its early administration. It has been shown that polyclonal commercially available IVIg binds and inactivates toxins that mediate TSS; however, there is variability in efficacy from brand to

brand, as well as between batches within brands. In vitro studies have demonstrated increased potency of IVIg against GAS toxins as compared with S. aureus toxins, raising doubt about appropriate protective doses of IVIg. In a 2003 survey of infectious disease and critical care specialists across Canada, 76% of respondents reported that they would use IVIg in GAS-TSS, but only 26% would add it to therapy for SATSS. In a recent clinical trial, a trend toward a protective effect of IVIg (Endobulin) (1.0 g/kg on day 1, 0.5 g/kg on days 2 and 3) was elucidated. However, this trial was underpowered and halted prior to completion due to lack of enrollment. It is theorized that IVIg is particularly useful early in disease manifestation to minimize the inflammatory reaction until definitive antibiotic therapy is initiated. The use of IVIg is not without risk. There have been case reports of acute tubular necrosis, aseptic meningitis syndrome, central retinal vein obstruction, myocardial infarction, and thromboembolic diseases associated with IVIG use. Furthermore, patients with immunoglobulin A (IgA) deficiency can have severe anaphylactic reactions to IVIg infusion. In summary, due to lack of unequivocal objective data, IVIg therapy remains controversial, but it may be reasonable for treating TSS, especially GAS-TSS. Further research and well-formulated large-scale clinical trials are necessary. Immunomodulatory therapy focuses on inhibiting the signaling cascades induced by superantigens as well as the cytokines that are ultimately expressed. A combination of in vivo and in vitro data has been reported using a variety of agents demonstrating the effectiveness of suppressing SEB-mediated effects of TSS. Pentoxifylline (Trental)[1] is a TNF-a inhibitor that has been shown to dampen the inflammatory reaction, as has the corticosteroid dexamethasone (Decadron).[1] Other synthetic compounds and antibiotics have also been proposed. These therapies have not yet been approved for use in TSS, and inadequate data are available to recommend their use at this time. Chemoprophylaxis

Chemoprophylaxis remains a controversial issue. The rate of secondary cases among close contacts of patients with invasive GAS disease is 200 times that of the general population. Close contact has been defined as persons spending more than 4 hours a day or 20 hours a week together, sharing sleeping arrangements, or having direct mucous membrane contact within 7 days of illness of the index patient. In 1998, The CDC did not recommend antibiotic prophylaxis for all close contacts but rather individualization of prophylaxis for those exposed to patients with invasive GAS infection. The matter was revisited in a review in 2005 with a similar conclusion, stating that chemoprophylaxis was not warranted and that close contacts should be notified and urged to present for examination at the first signs of suspicious symptoms. Some public health authorities in Canada agree that close contacts should receive chemoprophylaxis with penicillin, first-generation cephalosporins, clindamycin, or erythromycin for 10 days. The official recommendations vary from province to province and depend on the type of invasive streptococcal disease. The theoretical risks of empiric antibiotic use in the select few exposed to patients with this rare disease are

probably negligible in the face of potentially new invasive GAS infections. Possible risks include antibioticassociated diarrhea and C. difficile colitis.



REFERENCES Darenberg et al., 2003. Darenberg J, Ihendyane N, Sjolin J, the StreptIg Study Group , et al: Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: A European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003; 37:333-340. Davies, 2001. Davies DH: Flesh-eating disease: A note on necrotizing fasciitis. Can J Infect Dis 2001; 12:136-140. Durand et al., 2006. Durand G, Bes M, Meugnier H, et al: Detection of new methicillin-resistant Staphylococcus aureus clones containing the toxic shock syndrome toxin 1 gene responsible for hospitaland community-acquired infections in France. J Clin Mircobiol 2006; 44:847-853. Gosbell, 2005. Gosbell IB: Epidemiology, clinical features and management of infections due to community methicillin-resistant Staphylococcus aureus (cMRSA). Intern Med J 2005; 35:S120-S135. Krakauer, 2005. Krakauer T: Chemotherapeutics targeting immune activation by staphylococcal superantigens. Med Sci Monit 2005; 11(9):RA290-RA295. Llewelyn and Cohen, 2002. Llewelyn M, Cohen J: Superantigens: Microbial agents that corrupt immunity. Lancet Infect Dis 2002; 2:156-162. McCormick et al., 2001. McCormick JK, Yarwood JM, Schlievert PM: Toxic shock syndrome and bacterial superantigens: An update. Annu Rev Microbiol 2001; 55:77-104. Reingold et al., 1982. Reingold AL, Hargrett NT, Shands KN, et al: Toxic shock syndrome surveillance in the United States, 1980 to 1981. Ann Intern Med 1982; 96:875-880. Schlievert, 2001. Schlievert PM: Use of intravenous immunoglobulin in the treatment of staphylococcal and streptococcal toxic shock syndromes and related illnesses. J Allergy Clin Immunol 2001; 108:S107-S110. Schlievert et al., 2005. Schlievert PM, Tripp TJ, Peterson ML: Reemergence of staphylococcal toxic shock syndrome in Minneapolis–St. Paul, Minnesota, during 2000-2003 surveillance period. J Clin Microbiol 2004; 42:2875-2876.Correspondence and reply:Tierno PM: Reemergence of staphylococcal toxic shock syndrome in the United States since 2000. J Clin Microbiol 2005; 43:2032-2033. Smith et al., 2005. Smith A, Lamagni TL, Olivier I, et al: Invasive group A streptococcal disease: Should close contacts routinely receive antibiotic prophylaxis?. Lancet Infect Dis 2005; 5:494-500. Stevens, 1999. Stevens DL: The flesh-eating bacterium: What's next?. J Infect Dis 1999; 179:S366-S374. Todd et al., 1978. Todd J, Fishaut M, Kapral F, Welch T: Toxic-shock syndrome associated with phagegroup-I Staphylococci. Lancet 1978; 2(8100):1116-1118.



Chapter 23 – Influenza

Method of: Michael B. Rothberg, MD, MPH Influenza is a viral respiratory infection that occurs in winter epidemics, affecting one tenth of the world's population each year. Among children and persons living in closed environments such as nursing homes or military bases, infection rates are as high as 40%. In the United States alone, influenza is estimated to cause 35,000 deaths and 200,000 hospitalizations each year, mostly among the elderly and those with serious comorbid illnesses. Direct medical costs exceed $3 billion, and indirect costs stemming from lost productivity total $15 billion yearly in the United States. Influenza types A and B cause illness in humans. Influenza A viruses are divided into subtypes based on the hemagglutinin (H) and neuraminidase (N) glycoproteins expressed on their surfaces. Currently circulating viruses include H3N2 and H1N1 subtypes. Minor variations in these glycoproteins (antigenic drift) occur almost yearly, resulting in new strains that cause localized outbreaks. Major variation (antigenic shift) occurs when two subtypes combine to create a new subtype, resulting in a global pandemic. Although infrequent, pandemics can have devastating consequences due to lack of immunity in the population. The H5N1 virus, or avian flu, has a mortality rate of 59%, but it cannot be considered a pandemic strain because it is not transmitted efficiently between humans. Because treatment is only modestly effective, influenza control efforts have focused on vaccination and prophylaxis, especially of high-risk groups. More recently, vaccination programs have expanded to include lower-risk adults and preschool children. National surveillance networks can now identify local outbreaks quickly and communicate the information efficiently via the Internet to individual providers, allowing timely diagnosis and treatment with antiviral therapy. As the use of antiviral drugs has increased, so has resistance, creating a challenge to find newer, more effective therapies, as we stand on the brink of a global pandemic. Clinical Features Influenza is spread via the respiratory route. Following an incubation period of 1 to 4 days, the virus typically causes abrupt onset of fever and dry cough, often accompanied by nasal congestion, headache, and myalgias. Fever can last for 3 to 5 days, during which time the patient is highly infectious. Recovery can last up to 2 weeks. Although the acute infection can cause a viral pneumonia, secondary bacterial infections—sinusitis, otitis media, bronchitis, and pneumonia—are more common. Elderly persons, infants, and those with comorbid conditions such as heart or lung disease are most susceptible to complications, accounting for the overwhelming majority of hospital admissions. Among community-dwelling elderly persons, there is considerable variability in the risk of hospitalization or death from influenza or pneumonia, ranging from 0.2% to 15% depending on age and comorbidities. Diagnosis

The signs and symptoms of influenza illness are nonspecific and cannot be reliably distinguished from those of other viral upper respiratory infections. One meta-analysis of diagnostic studies found that only fever (odds ratio [OR], 1.8) increased the likelihood of influenza, whereas absence of fever (OR, 0.40), cough (OR, 0.42), or headache (OR, 0.75) and lack of nasal congestion (OR, 0.49) all decreased it. Other symptoms typically associated with influenza, such as myalgia, malaise, and chills, had positive predictive value only for patients older than 60 years. Given the low odds ratios associated with clinical findings, signs and symptoms must be considered in the context of the local incidence of influenza at the time of presentation.

CURRENT DIAGNOSIS Influenza remains a clinical diagnosis based on the presence of fever, nasal congestion, and cough in the setting of local influenza activity. Rapid diagnostic testing can aid in diagnosis and surveillance early in the influenza season. Once influenza is detected, however, rapid testing gives too many false-negative results to be useful. Rapid testing of nasal specimens is available. Two of these (Quickvue and ZStatFlu) can be conducted in the office in less than 30 minutes, allowing physicians to act on the diagnostic information. Others are restricted to laboratory use. Rapid tests have low sensitivity (65%-86%), especially among adults, but high specificity (>90%). Thus, a positive test confirms the diagnosis, but a negative test does not exclude it, especially when influenza is circulating locally. Decision analyses and cost-effectiveness analyses have demonstrated that rapid testing is reasonable when clinical suspicion is low. In such cases, testing is superior to either empiric antiviral therapy or symptomatic therapy. When clinical suspicion is high, testing is not recommended, because the high false-negative rate can lead to patients with true influenza going untreated. Until recently, clinicians rarely knew the local prevalence of influenza. Reports from state health departments and the Centers for Disease Control and Prevention (CDC) often lagged by several weeks and were not easily obtainable. Now, however, a number of Internet resources provide real-time surveillance. FluWatch.com and Flustar.com offer free twice-weekly reports of local influenza prevalence by zip code. Prevention and Treatment Vaccination and antiviral medication are the two methods of prophylaxis. Antiviral medications are also used for treatment. VACCINE Influenza vaccination is the mainstay of prevention. Annual vaccination prevents influenza illness, complications, hospitalizations, and death in high-risk patients, and it is cost saving in elderly patients. Annual vaccination is required because immunity wanes and because antigenic drift results in new viruses

each year. Patients receiving vaccine 2 or more years in a row have heightened immunity. Current influenza vaccines contain two strains of influenza A, an H3N2 and an H1N1, and a single strain of influenza B. The strains for the coming season are chosen each spring by independent experts to allow time for vaccine production.

CURRENT THERAPY Antiviral therapy is an adjunct to, not a replacement for, influenza vaccination. Antiviral therapy is most beneficial for high-risk patients and must be started within 48 hours of onset of symptoms to be effective. Earlier treatment is more effective. Due to current resistance patterns, only neuraminidase inhibitors should be used for treatment or prophylaxis. Choice of therapy depends on side effect profile, cost, and availability. Efficacy

Vaccine efficacy depends on the degree of similarity between the vaccine strains and those in circulation and on the age and immunocompetence of the vaccine recipient. For healthy adults younger than 65 years, a well-matched vaccine prevents 70% to 90% of influenza illness. The efficacy declines to 58% in community-dwelling elderly and 30% to 40% among nursing home patients. However, efficacy in preventing complications, including hospitalization and death, is much higher in elderly persons and nursing home patients, with vaccination preventing 80% of deaths, even among debilitated patients. Administration

The Centers for Disease Control and Prevention (CDC) recommends intramuscular administration of inactivated influenza vaccine for the following groups: •

•

Persons at high risk for influenza-related complications and severe disease •

Children ages 6 to 59 months

•

Pregnant women

•

Persons older than 50 years

•

Persons of any age with certain chronic medical conditions

Persons who live with or who care for persons at high risk •

Household contacts who have frequent contact with persons at high risk and who can transmit influenza to persons at high risk

•

Health care workers.

Healthy persons wishing to decrease their risk of influenza may also be vaccinated, although such vaccination might not be cost-effective.

For the past several years, there has been a shortage of influenza vaccine in the United States. In an effort to improve the quantity and reliability of available vaccine, the FDA in 2006 approved 5 different vaccine formulations, each with a different indication ( Table 1 ). The live attenuated influenza vaccine (LAIV) (FluMist), administered via the nasal passages, causes a localized influenza infection of the nasopharyngeal epithelium and is not approved for use in high-risk patients. It can be given to healthy children and adults ages 5 to 49 years, although it is more expensive than the inactivated vaccine. After receiving LAIV, vaccinees might shed virus and should avoid contact with immunosuppressed patients for 7 days. Efficacy of LAIV in healthy adults is comparable with that of inactivated vaccine.

TABLE 1 -- Approved Influenza Vaccines for Different Age Groups—United States, 2007-2008 Season Thimerosal Mercury Trade Content (µ g Hg/0.5 mL Age No. of Name Group Doses Manufacturer Dose/Presentation Dose) Route Inactivated (TIV) Fluzone

Fluvirin

Sanofi Pasteur

Novartis Vaccine[‡]

0.25-mL pre-filled syringe

0

6-35 mo

1 or 2[*]

IM [†]

0.5-mL pre-filled syringe

0

=36 mo 1 or 2[*]

IM [†]

0.5-mL vial

0

=36 mo 1 or 2[*]

IM [†]

5.0-mL multidose vial 25

=6 mo

1 or 2[*]

IM [†]

0.5 mL pre-filled syringe

=4 yr

1 or 2[*]

IM [†]

=4 y

1 or 2[*]

IM [†]

=18 y

1

IM [†]

=18 y

1

IM [†]

5-49 y

1 or 2[§]

Intranasal

30)

Multiple, symmetric

Size of lesions

Variable, usually large

Variable

Variable, not very large[†]

Small

Surface

Very dry, scaly, Dry lesions look turgid

Dull, slightly shiny

Shiny

Shiny

Variable, some are large

Observation

TT

BT

BB

BL

LL

Sensations in lesions

Absent

Markedly diminished

Moderately diminished

Slightly diminished

Minimally diminished or not affected

Hair growth in lesions

Absent

Markedly diminished

Moderately diminished

Slightly diminished

Not affected

AFB in lesions

Nil

Nil or scanty

Moderate number

Many

Very many (globi)

Lepromin

Strongly positive (++++)

Weakly positive Negative (+ or ++)

Negative

Negative

Abbreviations: AFB = acid fast bacilli; BB = borderline borderline leprosy; BL = borderline lepromatous leprosy; BT = borderline tuberculoid leprosy; LL = lepromatous leprosy; TT = tuberculoid leprosy.

* Compartmentalization of the features is not very stringent. All these features occur in various combinations as the disease progresses. † Presence of large lesions indicates downgrading of the disease from a higher spectrum.

Inspection of the whole body in good light is important because otherwise lesions with faint erythema or slight hypopigmentation (more often on covered areas in borderline disease) might be missed. Skin lesions should be examined for hypoesthesia to light touch and temperature and for anhidrosis. TYPES OF LEPROSY Indeterminate Leprosy

The classic skin lesion of indeterminate leprosy is most commonly found on the face, the extensors of the limbs, the buttocks, or the trunk. There may be one or more slightly hypopigmented or erythematous macules, a few centimeters in diameter, with poorly defined margins ( Figure 1 ). Hair growth and nerve function are usually not affected. A biopsy might show perineurovascular infiltrate; however, acid-fast bacilli (AFB) are mostly not demonstrable. Many patients do not notice such lesions and present only with characteristic determinant lesions at some point. Perhaps three out of four indeterminate lesions heal spontaneously and the rest become determinate and enter the clinical spectrum.

FIGURE 1 Indeterminate leprosy.

Tuberculoid Leprosy

Tuberculoid leprosy (TT) often has one or few skin lesions, and lesions seldom measure more than 10 cm in diameter. The typical lesion is a well-defined erythematous plaque with a raised and clear-cut edge sloping toward a rather flattened and usually hypopigmented center, acquiring an annular configuration. Erythema might not be apparent on dark skin. The surface is dry, hairless, anesthetic, and sometimes scaly. Sensory impairment may be difficult to demonstrate on the face because of the generous supply of sensory nerve endings. Less commonly, the lesion is a dry, anesthetic macule with sparse hair; the lesion appears erythematous on light skin and hypopigmented (never depigmented) on dark skin. Usually, a solitary peripheral nerve trunk is thickened in the vicinity of a TT lesion—for example, a thickened ulnar nerve if the lesion is on the arm. Borderline Tuberculoid Leprosy

The skin lesions of borderline tuberculoid (BT) leprosy resemble those of tuberculoid leprosy, but there is evidence that the disease is not contained. Individual lesions do not show the well-defined margins, and the edge in part might fade imperceptibly into normal skin ( Figure 2 ). There may be satellite lesions. The number of lesions can vary from three to ten and show variation in size and contour. Loss of sensation is less intense than in the lesions of tuberculoid leprosy. Xerosis, scaling, and erythema or hypopigmentation

are also less conspicuous than in the TL form.

FIGURE 2 Borderline tuberculoid leprosy.

Several of the peripheral nerves are likely to be enlarged irregularly and in an asymmetric pattern. Nerve damage is an important characteristic of BT leprosy, and anesthesia or motor deficit is often found at the time of presentation. Borderline Borderline Leprosy

Borderline borderline (BB) disease is unstable and mostly downgrades toward the lepromatous pole, especially when it is untreated. There are many skin lesions of all shapes and sizes including papules, nodules, plaques, and circinate lesions. Characteristic skin lesions are annular or dimorphic. In annular lesions, the inner edge is abrupt, and the outer edge slopes toward normal skin and has islands of clinically normal-looking skin within the plaque, giving a Swiss cheese appearance. The classic dimorphic lesion is shown in Figure 3 .

FIGURE 3 Borderline borderline leprosy.

The face might show infiltration, with occasional nodules over the ears and chin. Because of immunologic instability, the BB state is short-lived, and such patients are evidently rarely seen; the disease usually changes rapidly to borderline lepromatous (BL) or BT leprosy. Many nerves are involved, although not symmetrically as in lepromatous leprosy. Borderline Lepromatous Leprosy

There are numerous skin lesions in BL, and they are classically distinct but not so well defined. There occur slightly infiltrated macules variable in shapes in not so symmetric distribution, with areas of apparently normal skin in between. With disease progression, papules, nodules, and plaques can develop, although they usually have sloping margins that merge imperceptibly into normal skin ( Figure 4 ). Associated large lesions and of variable morphology indicate downgrading of disease from a higher spectrum. Eyebrows are not completely lost. Peripheral nerve trunks become thickened and develop corresponding anesthesia and paresis but lack symmetry. Nerves are, however, unlikely to be damaged as quickly as in BB and BT leprosy.

FIGURE 4 Borderline lepromatous leprosy.

Lepromatous Leprosy

The early lesions of lepromatous leprosy (LL) are minimally infiltrated macules that are innumerable, widely disseminated, and symmetrically distributed. The edges are indistinct, and their surface is shiny and erythematous rather than hypopigmented. In rapidly progressive cases, they coalesce so that the skin is diffusely involved. The early macules of LL are not anesthetic. If the disease is untreated and allowed to progress, the affected skin takes on a waxy appearance and feels full. Thickness of skin is most marked over the face, especially the forehead, earlobes, eyebrows, nose, and malar surfaces ( Figure 5 ). The eyebrows and, ultimately, the eyelashes are lost. The thickened skin accentuates into folds, producing the classic leonine facies. Nodules and even plaques on the face and other areas of the body can follow. By this time, peripheral anesthesia is extensive and is accompanied by anhidrosis, with compensatory hyperhidrosis of the trunk and axillae.

FIGURE 5 Lepromatous leprosy (diffuse infiltration).

The sensory loss is symmetric and is first detected over the extensors of forearms, legs, hands, and feet, which gradually results in the typical glove-and-stocking distribution. Weakness usually starts in the intrinsic muscles of the hands and feet. EXTENT OF INVOLVEMENT Nerve Involvement

Nerve damage occurs in two settings: peripheral nerve trunks and small dermal nerves. Small dermal sensory and autonomic nerves are affected in the early part of disease establishment, producing hypoesthesia and anhidrosis within skin lesions. The posterior tibial is the most commonly affected nerve trunk, followed by the ulnar, median, lateral popliteal, and facial nerves. Involvement of these nerves produces enlargement, with or without tenderness, and regional sensory and motor loss. Thickening of the greater auricular nerve is better seen than felt ( Figure 6 ). Rarely, nerve abscess is encountered in peripheral nerve trunks, mostly in the ulnar and lateral popliteal nerves.

FIGURE 6 Nerve involvement (greater auricular nerve thickening).

The morbidity and disability associated with leprosy are secondary to nerve damage. About 25% of leprosy patients have some degree of disability, which is greatest in patients with BL and LL disease. Early recognition and treatment are crucial to prevention of deformities. Systemic Involvement

Features of systemic involvement occur usually in longstanding disease and are mainly seen in patients near the lepromatous pole because of bacillary infiltration and the associated granulomatous infiltration that affects various organs, especially the nasal mucosa, eyes, bones, testes, kidneys, lymph nodes, liver, and spleen. Besides the disease, systemic manifestations in the form of such constitutional symptoms as fever, malaise, joint pains, and acute inflammation of eyes, joints, and the reticuloendothelial system (among others) can occur as a part of a type 2 lepra reaction. Diagnosis CLINICAL DIAGNOSIS The diagnosis and classification of leprosy have been based on clinical features and skin smears when facilities are available. Clinical diagnosis of leprosy is based on patients having one or more of the three

cardinal signs. The cardinal signs are hypopigmented or erythematous skin lesion(s), with definite loss of or impairment of sensations; involvement of the peripheral nerves, as demonstrated by definite thickening, with sensory impairment; and skin smear positive for AFB. LABORATORY DIAGNOSIS Laboratory diagnostic tests such as slit skin smears, histologic examination of involved tissues, serology, and polymerase chain reaction (PCR) studies have been confined to areas where such facilities are available and in academic and research centers. Slit Skin Smears

The diagnostic specificity of skin smears is almost 100%; however, the sensitivity is rarely more than 50% because smear-positive patients represent only 10% to 50% of cases. The inherent problems of skin smears are the logistics and the reliability of the technique of taking, staining, and interpreting the smears. Skin smears help identify patients with MB disease and patients who are experiencing clinical relapse. Skin Biopsies

The biopsy helps to confirm the clinical diagnosis and classification of disease, but it cannot be regarded as the diagnostic gold standard because a number of the histologic features can be nondiagnostic or doubtful. In practice, a clinical and histopathologic correlation may be necessary for resolving a diagnostic difficulty. Serology and Polymerase Chain Reaction

Serology and PCR are rarely used in endemic countries because of their limited availability and lack of uniform diagnostic values across the disease spectrum. The basis of serologic tests is to determine the presence of anti–phenolic glycolipid-1 (PGL-1) antibodies by the M. leprae particle agglutination assay (MLPA) and the enzyme-linked immunosorbent assay (ELISA) techniques. The PGL-1 antibody test is specific and more sensitive in patients with MB disease, but unfortunately it is not very helpful in the diagnosis of paucibacillary (PB) disease, and it has low predictive value for diagnosis of early disease. Antibodies to the 35-kD protein of M. leprae have been studied for their role in diagnosis of disease with comparable results. PCR for detection of M. leprae DNA encoding specific genes is highly sensitive and specific, because it detects M. leprae DNA in 95% of MB and 55% of PB patients. Currently, PCR is not used in routine clinical practice. Lepromin Test

The lepromin test is not a diagnostic test, but it is helpful for identifying the level of CMI against M. leprae in a given patient. It is a nonspecific test of some value in classifying a case of leprosy. It is strongly positive in TL; weakly positive in BT; negative in BB, BL, and LL; and unpredictable in indeterminate leprosy. Lepromin (lepromin A, 160 million bacilli/mL) 0.1 mL is injected intradermally, and the reaction is read at 48 hours (Fernandez reaction) and at 3 to 4 weeks (Mitsuda reaction). Neither test is diagnostic, because both may be positive in persons with no evidence of leprosy. However, close contacts of an MB patient who have negative lepromin tests have a greater risk of developing disease. Classification Of Disease

Ridley and Jopling (1966) defined five groups on the basis of clinical, bacteriologic, histologic, and immunologic features. These groups are tuberculoid, borderline tuberculoid, midborderline (borderline borderline), borderline lepromatous, and lepromatous leprosy. This is a very useful classification for research purposes, but it is often not feasible in field conditions and primary health centers. This classification does not include the indeterminate and pure neuritic type of leprosy. In general, PB disease is equivalent to indeterminate, tuberculoid, and BT leprosy, and MB disease is equated with BB, BL, and LL disease. In 1998, the WHO Expert Committee on Leprosy declared skin-slit smears as not essential for institution of MDT. This was necessitated by the unavailability or unreliability of technical expertise for the skin smear in many leprosy-control programs and the potential for transmitting HIV and hepatitis by nonsterile techniques. Recently, for field workers, WHO has classified leprosy based on the number of skin lesions for treatment purposes. PB leprosy is leprosy with one to five skin lesions. MB leprosy includes more than five skin lesions. If facilities are available, any patient with a positive slit-skin smear should be considered to have MB leprosy. Rare Variants LUCIO LEPROSY

Lucio leprosy (LuLp) is a diffuse form of LL. It is common in Mexico and Costa Rica and less common in the Gulf Coast, but it is quite rare in the rest of the world. It manifests as slowly progressive, diffuse, shiny infiltration of skin of the face and most of the body (lepra bonita, “beautiful leprosy”). There is loss of eyebrows, hoarseness of voice, and numbness and edema of hands and feet that mimic myxedema. This form of the disease is liable to the most severe of all reactional states, the Lucio phenomenon, in which destructive vasculitis leads to skin necrosis and ulcers. Pure Neuritic Leprosy

Pure neuritic leprosy is characterized in the absence of any skin patch by an area of sensory loss along the distribution of a thickened nerve trunk with or without motor deficit. This form is seen most often, but not exclusively, in India and Nepal, where it accounts for 5% to 10% of leprosy cases. Histology of a cutaneous nerve might reveal an infiltrate that is characteristic of any type of leprosy.

CURRENT DIAGNOSIS A case of leprosy is diagnosed in a person who has one or more of the following cardinal signs and who has yet to complete a full course of treatment: Hypopigmented or erythematous skin lesion(s) with definite loss or impairment of sensations Involvement of the peripheral nerves, as demonstrated by definite thickening with sensory impairment Skin smear positive for acid-fast bacilli Histoid Leprosy

Histoid leprosy, first described in 1960, is now a well-recognized but rarely reported entity. Controversy still remains whether to consider histoid leprosy as a separate entity. It usually occurs in patients who had received irregular or inadequate treatment or dapsone monotherapy or as a spectrum under lepromatous leprosy. It manifests as superficially or deeply fixed cutaneous nodules, plaques, or pads ( Figure 7 ). In a given patient, the number of lesions can vary from a few to a hundred. Histopathologically, the striking feature is predominance of spindle-shaped cells and unusually large numbers of AFB.

FIGURE 7 Histoid leprosy.

Treatment The concept of chemotherapy for leprosy has undergone a phenomenal change over the last two decades. The WHO MDT has been successful in eliminating leprosy in many countries. However, the search for new drugs and new drug regimens continues. The goals of advanced therapy include improved patient compliance, alternative agents against clofazimine- and rifampin-resistant bacilli, more efficient killing of persistent bacteria, uniform MDT for all types of leprosy, and supervised short regimens for preventing drug resistance. WHO MULTIDRUG THERAPY The MDT introduced in 1982 has proved to be the most effective tool in controlling leprosy. More than 18 million patients have been cured of the disease, with acceptable cumulative relapse rates of 0.77% for MB and 1.07% for PB disease. MDT as recommended by WHO remains the current and most accepted

treatment by all countries with endemic leprosy. A single dose of rifampin (Rifadin)[1] 600 mg plus ofloxacin (Floxin)[1] 400 mg and minocycline (Minocin)[1] 100 mg (ROM therapy) is an acceptable and cost-effective alternative regimen for PB leprosy with one skin lesion, although most still favor the conventional WHO MDT PB regimen.

CURRENT THERAPY Multidrug Therapy Regimen for Paucibacillary Leprosy (6 months) ADULT (50-70 KG)

Dapsone: 100 mg daily Rifampin (Rifadin)[1]: 600 mg once a mo under supervision CHILD (10-14 Y)

Dapsone: 50 mg daily Rifampin: 450 mg once a mo under supervision Adjust dose appropriately for a child younger than 10 y. For example, dapsone 25 mg daily and rifampicin 300 mg given once a mo under supervision. Multidrug Therapy Regimen for Multibacillary Leprosy (12 months) ADULT (50-70 KG)

Dapsone: 100 mg daily Rifampin:[1] 600 mg once a mo under supervision Clofazimine (Lamprene): 50 mg daily and 300 mg once a mo under supervision CHILD (10-14 Y)

Dapsone: 50 mg daily Rifampin[1]: 450 mg once a mo under supervision Clofazimine: 50 mg daily and 150 mg once a mo under supervision Adjust dose appropriately for a child less than 10 y. For example, dapsone 25 mg daily and rifampin 300 mg given once a mo under supervision, clofazimine 50 mg given twice a wk, and clofazimine 100 mg given once a mo under supervision. OTHER REGIMENS FOR SPECIAL SITUATIONS

Drug Substitutions

For adult MB patients who cannot take rifampin, the Seventh WHO Expert Committee on Leprosy recommended daily administration of 50 mg of clofazimine (Lamprene), together with two of the following three drugs: 400 mg ofloxacin,[1] 100 mg minocycline,[1] or 500 mg clarithromycin (Biaxin)[1] once daily for 6 months, followed by daily administration of 50 mg clofazimine plus 100 mg minocycline or 400 mg ofloxacin for at least an additional 18 months. For MB patients who cannot take clofazimine, clofazimine should be replaced with ofloxacin 400 mg daily or minocycline 100 mg daily. Alternatively, the patient may be treated with a monthly administration of a combination consisting of rifampin[1] 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM therapy) for 24 months. MB patients who cannot tolerate dapsone should receive only daily clofazimine with no substitution; in PB cases dapsone should be replaced with clofazimine. Accompanied Multidrug Therapy

Accompanied MDT (A-MDT) recommended by WHO is an essential element of the “flexible and patient friendly MDT delivery system” suitable to migrant populations, patients living in remote areas, and patients living in areas of civil war. In this policy, the patient is provided the entire supply of MDT drugs at the time of diagnosis: 6 months of medication for a PB patient and 12 months for an MB patient, while asking “someone close or important to the patient” to assume the responsibility of helping the patient complete the full course of treatment. However, poor adherence to self-administration of treatment, a common phenomenon in tuberculosis and leprosy patients, and the associated risk of drug resistance and relapses are to be expected. Pregnancy and Lactation

Leprosy is exacerbated during pregnancy, so it is important that the standard multidrug therapy be continued during pregnancy. The standard MDT regimens are safe, both for the mother and the child, and therefore should be continued unchanged during pregnancy and lactation. Concomitant Active Tuberculosis

If the patient has both leprosy and active tuberculosis, it is necessary to treat both infections at the same time. Give appropriate antituberculosis therapy in addition to the MDT appropriate to the type of leprosy. Rifampin is common to both regimens, and it must be given in the doses required for tuberculosis. Concomitant HIV Infection

The management of a leprosy patient infected with HIV is the same as that of any other leprosy patient without infection with HIV. NEWER DRUGS A few new drugs are available to complement or replace the currently used MDT ( Box 1 ). The objective of the new drugs is not to induce quick clinical regression but to minimize relapses or to address special situations like drug resistance or drug intolerance. Promising bactericidal activity of ofloxacin,[1] clarithromycin,[1] and minocycline[1] against M. leprae has been demonstrated in the mouse foot-pad system

and then confirmed in clinical trials. Strong bactericidal effects against M. leprae of moxifloxacin (Avelox)[1], rifapentine (Priftin),[1] and other derivatives have been identified in in vitro studies. However, no precise recommendation of their use is available yet. BOX 1 Newer Drugs and Alternate Drugs Quinolones

•

Clinafloxacin[5]

•

Moxifloxacin (Avelox)[1]

•

Ofloxacin (Floxin)[1]

•

Pefloxacin (Pefocin)[2]

•

Sparfloxacin (Zagam)[2]

•

Temafloxacin (Omniflox)[2]

Macrolides

•

Clarithromycin (Biaxin)[1]

Tetracyclines

•

Minocycline (Minocin) [1]

Ansamycins

•

KRM-1648[5]

•

KRM-1657[5]

•

KRM-1668[5]

•

Rifabutin (Mycobutin)[1]

•

Rifapentine (Priftin)[1]

5 Investigational drug in the United States. 1 Not FDA approved for this indication. 2 Not available in the United States.

Reactions During the course of leprosy, immunologically mediated episodes of acute or subacute inflammation known as reactions can occur. Most reactions belong to one of the two major types; reversal reaction (RR or type 1) or erythema nodosum leprosum (ENL or type 2). Reversal reactions can occur throughout the spectrum of leprosy but are more common in patients with borderline leprosy. On the other hand, ENL occurs exclusively

in patients with MB disease, especially lepromatous and borderline lepromatous leprosy. Reactions can be disastrous; they cause acute nerve damage resulting in deformities. Almost 30% of MB patients develop reactions during the course of their disease. Reactions may be seen at presentation, during treatment, and even after treatment. The principles of treatment of reactions are to control the acute inflammation in skin and nerves, ease the pain, halt eye damage, and prevent spread of the disease. Standard antileprosy chemotherapy should be started or continued along with antireaction treatment. Clinical evidence of ongoing neuritis (nerve tenderness, new anesthesia, motor loss) should be carefully sought and, if neuritis is present, corticosteroid treatment should be started immediately. TYPE 1 REACTIONS The type 1 reaction is a type IV hypersensitivity (delayed-type hypersensitivity) reaction, and it typically occurs in borderline disease. It is characterized by acutely inflamed skin lesions or acute neuritis, or both. Existing skin lesions become erythematous or edematous and can desquamate or, rarely, ulcerate. Often, new small lesions also appear at distant sites ( Figure 8 ). Occasionally, edema of face, hands, or feet is the presenting symptom; however, constitutional symptoms are unusual. Although type 1 reactions can occur spontaneously and at any time during the course of the disease, the usual times are after starting treatment and during the puerperium.

FIGURE 8 Borderline tuberculoid leprosy with type 1 reaction

Because of the high risk of permanent damage to peripheral nerve trunks, RR needs to be diagnosed as soon as possible and managed adequately. The drug of choice is prednisolone (Delta-Cortef). The usual course begins with 40 to 60 mg daily (up to a maximum of 1 mg/kg), gradually reducing the dose weekly or biweekly and eventually stopping in about 12 weeks. Neural impairment of up to 6 months' duration may be helped by systemic corticosteroid therapy tapered over a period of 4 to 6 months. Adverse effects associated with long-term corticosteroid therapy must be kept in mind. TYPE 2 REACTIONS The type 2 reaction, a type III hypersensitivity reaction (immune-complex mediated) occurs in patients with LL and BL disease. Attacks are often acute in onset but can become chronic or recur over several years. ENL typically manifests as painful, red evanescent nodules on the face and extensor surfaces of the limbs. Rarely, they appear as bullous, pustular, necrotic forms. ENL is often accompanied by systemic symptoms producing fever and malaise, and in severe form it may be complicated by uveitis, dactylitis, arthritis, neuritis, lymphadenitis, myositis, and orchitis. Acute or subacute neuritis with or without nerve function impairment is one of the major criteria for distinguishing mild and severe ENL. The treatment of ENL should start with general measures as in type 1 reaction. Mild ENL can be treated with analgesics like aspirin. In moderate and severe ENL, corticosteroids or thalidomide (Thalomid) are more useful and may be life saving. Thalidomide (100 mg q8h) has a dramatic effect in controlling ENL, and it may be useful in preventing recurrent ENL, but its teratogenic effects preclude its use in women of childbearing age. Clofazimine (Lamprene) has a useful anti-inflammatory effect in ENL and can be used at 300 mg daily in divided doses as an adjuvant to prednisolone and tapered over several months. Injectable antimonials are often used by Indian leprologists. LUCIO'S PHENOMENON The Lucio phenomenon occurs only in patients with Lucio leprosy. It results from infarction consequent on deep cutaneous vasculitis, causing the appearance of irregularly shaped erythematous patches. The patches sometimes darken and heal, but sometimes they form bullae that necrose, leaving deep, painful ulcers that are slow to heal. The systemic features are severe and can be fatal. Treatment with glucocorticoids (prednisolone) should be instituted at doses of 60 to 80 mg in two equal daily doses supplemented preferably with an augmented daily dose (200-300 mg) of clofazimine. Prevention Of Disabilities and Rehabilitation The socioeconomic impact resulting from the physical and psychological disabilities of leprosy continues to be a burden in endemic countries. Approximately 25% of leprosy patients have some degree of disability, which is greatest in patients with long-standing BL and LL disease. Preventing patients with nerve damage from progressing to disability and deformity is a challenge that will last for the patient's lifetime. Among the important efforts for prevention are periodic measurement of neural

impairment, early and adequate management of reactions, and advice for care of eyes, hands, and feet. Special footwear needs to be provided for patients with foot deformities to prevent ulceration. Early detection and treatment of reactions significantly reduce and prevent such complications as nerve damage with its resultant impairment, eye involvement, and loss of vision. Socioeconomic rehabilitation is another important component of caring for patients. Prevention Large population-based trials in different countries suggest that bacille Calmette-Guérin (BCG) vaccine[1] gives variable protection against leprosy, ranging from 34% to 80%. Therefore, BCG immunization of children for tuberculosis can contribute to leprosy control. In a recently published large study from India, vaccine containing cultivable mycobacterium, ICRC,[5] provided a protective efficacy of 65% (heat-killed M. leprae BCG provided 64% protective efficacy). The role of chemoprophylaxis with bactericidal drugs in contacts of leprosy patients is still debated. WHO Strategy For 2006 Through 2010 The WHO Technical Advisory Group (TAG) recognizes that new cases will continue to appear in most of the currently endemic countries, and therefore, expertise will have to be maintained at the appropriate level even within an integrated system. The main aim of the strategy is to sustain antileprosy services and the gains made so far. It is expected that by 2010 the disease burden will be further reduced to very low levels through services that would ensure enhancing community awareness, quality diagnosis, adequate management of patients including referral facilities, reduction of stigma, prevention of disabilities, rehabilitation, long-term care of the disabled, and effective partnerships among all stake holders.



REFERENCES Abulafia and Vignale, 1999. Abulafia J, Vignale RIA: Leprosy: Pathogenesis updated. Int J Dermatol 1999; 38:321-334. Bhattacharya and Sehgal, 2002. Bhattacharya SN, Sehgal VN: Reappraisal of the drifting scenario of leprosy multi-drug therapy: New approach proposed for the new millennium. Int J Dermatol 2002; 41:321326. Britton and Lockwood, 2004. Britton WJ, Lockwood DN: Leprosy. Lancet 2004; 363:1209-1219. Grosset, 2001. Grosset JH: Newer drugs in leprosy. Int J Lepr Other Mycobact Dis 2001; 69(2 suppl):S14S18. Gupte, 2000. Gupte MD: South India immunoprophylaxis trial against leprosy: Relevance of the findings in the context of trends in leprosy. Lepr Rev 2000; 71(suppl):S43-S47.discussion S47-S49 Kumar et al., 2004. Kumar B, Dogra S, Kaur I: Epidemiological characteristics of leprosy reactions: 15 years experience from North India. Int J Lepr Other Mycobact Dis 2004; 72:125-133. Kumar et al., 2004. Kumar B, Kaur I, Dogra S, Kumaran MS: Pure neuritic leprosy in India: An appraisal. Int J Lepr Other Mycobact Dis 2004; 72:284-290. Lockwood and Kumar, 2004. Lockwood DN, Kumar B: Treatment of leprosy. BMJ 2004; 328:1447-1448. Naafs, 2000. Naafs B: Current views on reactions in leprosy. Indian J Lepr 2000; 72:97-122. Noordeen, 2004. Noordeen SK: Vision beyond 2005. Indian J Lepr 2004; 76:171-172. Pfaltzgraff and Bryceson, 1989. Pfaltzgraff RE, Bryceson A: Clinical leprosy. In: Hastings RC, ed. Leprosy, New York: Churchill Livingstone; 1989:134-176. WHO Expert Committee on Leprosy, 1998. WHO Expert Committee on Leprosy : Seventh Report. WHO Technical Report Series No. 874, Geneva, World Health Organization, 1998. World Health Organization, 2006. World Health Organization : The Weekly Epidemiological Record 2006; 81:309-316.32:(accessed May 15, 2007).



Chapter 26 – Malaria

Method of: Paul M. Arguin, MD S. Patrick Kachur, MD[*] * The findings and conclusions in this chapter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Malaria is caused by infection with protozoa of the genus Plasmodium; it is transmitted by the bite of a female Anopheles mosquito, which serves as the vector and definitive host for plasmodia. Rarely, malaria can be transmitted through exposure to infected blood and blood products, injection equipment, or organ transplantation (induced malaria) or by vertical transmission (congenital malaria). Malaria remains one of the most prevalent infectious diseases in the world. There are an estimated 350 million to 500 million cases every year, and more than 1 million deaths, mostly in children younger than 5 years of age, attributable to this disease. Precise estimates of the burden of the disease are hampered by both massive underreporting from areas lacking adequate health infrastructure and overestimation when liberal case definitions are employed that are not based on laboratory confirmation. In nonendemic countries, imported malaria (malaria acquired while traveling in an endemic area) is also a significant public health concern. Each year there are about 235 million trips to malaria-endemic countries; about 25 million of these travelers are residents of the United States. As a result, health care providers in nonendemic areas such as the United States must be able to adequately prepare these travelers to help reduce their risk of becoming infected with malaria while traveling and must be alert for the diagnosis in returning ill travelers. In addition, blood banks must also be aware of the travel history of potential donors who may be harboring malaria parasites at the time of donation in order to prevent cases of transfusiontransmitted malaria. The Centers for Disease Control and Prevention (CDC) receives reports of, on average, 1,300 cases of imported malaria and seven malaria deaths in the United States each year. Each year there are about five cases of malaria reported in persons who do not have a travel history, including cases of congenitally acquired infection, transfusion-transmitted infection, cryptic infection, and occasional instances of locally acquired mosquito-borne infection. In areas where malaria is not endemic, such as the United States, locally acquired mosquito-borne transmission of malaria (introduced malaria) can occur when a local mosquito acquires the parasite by biting an infected person and then transmits that infection to another person. There have been 11 outbreaks of locally acquired mosquito-borne malaria transmission in the United States since 1992, with the most recent one involving eight cases of Plasmodium vivax infection in Florida in 2003. Although the United States was officially recognized as malaria-free in 1970, competent malaria vectors continue to exist in the 48 continental states, Puerto Rico, the Virgin Islands, and Guam. Local transmission can occur whenever infectious persons, competent vectors, conducive environmental conditions, and opportunities for exposure

of susceptible persons to mosquitoes come together. Etiology Infection with protozoa of the genus Plasmodium causes malaria. Only four species of Plasmodium typically cause clinical disease in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. The life cycle of malaria starts with inoculation of sporozoites into humans from the salivary glands of a female Anopheles mosquito during a blood meal ( Figure 1 ) and progresses through an exoerythrocytic phase (tissue schizogany) and an erythrocytic phase (blood schizogany). The development of gametocytes that can be ingested by a subsequent female Anopheles mosquito allow the completion of the life cycle.

FIGURE 1 The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and release merozoites (4). (In P. vivax and P. ovale, a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks or even years later.) After this initial replication in the liver (exo-erythrocytic cycle or tissue schizogony A), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic cycle or blood schizogony B). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture, releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood-stage parasites are responsible for the clinical manifestations of the disease.

In P. vivax and P. ovale infections, some sporozoites might not enter exoerythrocytic schizogony but instead develop into latent hepatic forms, or hypnozoites. These forms can reactivate later and cause acute illness. The resulting infection, which is termed relapse, can occur months to years after the initial infection. Persons with P. vivax or P. ovale infection can have several relapses for up to 4 years and occasionally longer after the primary infection. However, if P. vivax or P. ovale infections are acquired congenitally or through exposure to blood or blood products, no liver phase occurs and therefore relapses cannot occur. Neither P. falciparum nor P. malariae has a hypnozoite form. However, if P. malariae infection is not treated, symptomatic recrudescences, often associated with splenectomy or immunosuppression, can occur decades after the primary infection. The incubation period, or the period from infection to the appearance of symptoms, is species dependent. The incubation period is usually 9 to 14 days for P. falciparum, 12 to 17 days for P. vivax, 16 to 18 days for P. ovale, and 18 to 40 days (or longer) for P. malariae. Persons taking chemoprophylaxis and those who have acquired partial immunity from repeated exposure to malaria infection can experience a prolonged incubation period. Epidemiology Malaria is endemic to Africa, South Asia, Southeast Asia, parts of Central Asia and the Caucasus, Oceania, Central America, parts of South America, Haiti and the Dominican Republic, and parts of Turkey and the Middle East. The species-specific geographic distribution is presented in Table 1 . P. falciparum is the most common species in the tropics and subtropics. P. vivax is prevalent in many temperate zones as well as in the tropics and subtropics, making it the species with the widest geographic distribution. Together, P. falciparum and P. vivax account for more than 90% of clinical malaria illnesses worldwide.

TABLE 1 -- Malaria Species Distribution and Drug-Resistance Pattern Species

Known Geographic Distribution

Drug-Resistance Pattern

Plasmodium falciparum

Most malaria-endemic areas except Republic of Korea, China north of Yunnan Province, and some areas of Central Asia and the Caucasus

Chloroquine (Aralen) resistance in nearly all endemic countries with the exception of Haiti, the Dominican Republic, Central America west of the Panama canal, and parts of the Middle East (resistance identified in Oman, Saudi Arabia, and Yemen) Sulfadoxine/pyrimethamine (Fansidar) resistance widespread in South America, Southeast Asia, and Africa Mefloquine (Lariam) resistance in parts of Southeast Asia Reduced susceptibility to quinine in Southeast Asia; longer course of therapy required

Plasmodium malariae

Same as for P. falciparum

Plasmodium ovale

Sub-Saharan Africa

No chloroquine resistance is documented

Species

Plasmodium vivax

Known Geographic Distribution

Drug-Resistance Pattern

Reported sporadically in Southern China, Burma, and Southeast Asia

No chloroquine resistance is documented

Central and South America, South Chloroquine resistance in Papua New Guinea, Indonesia Asia, Southeast Asia, Oceania, parts and East Timor of the Middle East, Mexico, North Rare instances of chloroquine-resistant P. vivax have Africa, and Horn of Africa been reported in Myanmar, India, and Central and South America Not common to absent in subSaharan Africa, Haiti, and the Dominican Republic

The development of resistance to antimalarial drugs has complicated malaria prophylaxis and treatment. Species-specific resistance patterns are presented in Table 1 . Knowledge of species-specific resistance patterns is essential to making appropriate decisions about chemoprophylaxis and treatment. The most upto-date information about this rapidly evolving process can usually be found on the CDC Web site ) and the World Health Organization (WHO) Web site (www.who/int/topics/malaria (www.cdc.gov/malaria ).

Among U.S. travelers, the majority of cases of malaria diagnosed each year are acquired in sub-Saharan Africa. Most of these patients report not taking any or one of the recommended drugs for malaria chemoprophylaxis. Also, the most common subgroup of travelers who become infected with malaria are first- and second-generation immigrants who return to their countries of origin to visit friends and relatives (VFR travelers). Clinical Features The clinical presentation of malaria is nonspecific; therefore, clinicians must maintain a high index of suspicion of malaria and routinely elicit a travel history from febrile patients. The clinical presentation of malaria can vary substantially, depending on the infecting species, the level of parasitemia, and the immune status of the patient. The initial clinical symptoms usually include a flu-like prodrome with headache, malaise, and myalgias that is followed by fever. In travelers with these symptoms, the differential diagnosis should include influenza, meningitis, typhoid fever, dengue fever and other arboviral infections, leptospirosis, typhus, and hepatitis. Malaria paroxysms are produced when infected red blood cells rupture and release merozoites. After a number of cycles of erythrocytic schizogony, the release of merozoites can become synchronized, resulting in classic cyclic fevers. With P. falciparum, P. vivax, and P. ovale infections (tertian malaria), the paroxysms occur in 48-hour cycles, whereas with P. malariae infections (quartan malaria), the cycles are 72 hours. However, patients, particularly those with P. falciparum, might not develop cyclic paroxysms at all, and so a lack of cyclic fevers should not rule out a diagnosis of malaria. Other symptoms include headache, chills, rigors, myalgias and arthralgias, and abdominal pain. Patients

also might complain of diarrhea, vomiting, chest pain, and cough. The presence of gastrointestinal and respiratory symptoms should not lead the physician to exclude malaria as a potential diagnosis. On physical examination, a patient might have jaundice, tachycardia, hypotension (usually secondary to dehydration), and splenomegaly. Laboratory abnormalities in cases of uncomplicated malaria can include mild anemia, an elevated reticulocyte count, thrombocytopenia, lymphopenia, hyperbilirubinemia, and mildly elevated transaminases. An uncomplicated malaria infection can progress to severe disease or death within hours. Risk factors for severe malaria include delays in treatment, inadequate or inappropriate treatment, a high parasite burden, and lack of acquired immunity. P. falciparum, more than any other species of Plasmodium, is responsible for the severe disease and death associated with malaria. This tendency has been linked to several features of this species. The tissue and blood schizonts in P. falciparum release a larger number of merozoites when they rupture, resulting in a more rapid rise in parasitemia. P. falciparum, unlike the other species, can infect both reticulocytes and mature erythrocytes. This destruction of large numbers of red blood cells and suppression of erythropoiesis can produce devastating anemia. In addition, P. falciparum–infected erythrocytes adhere to the vascular endothelium of postcapillary venules. It is believed that cytoadherence and severe anemia contribute to tissue hypoxia and end-organ dysfunction. Even the immune response itself contributes to many of the cellular and humoral processes that manifest in severe malaria illness. Severe malaria caused by P. falciparum is associated with a 15% to 20% mortality rate. Signs and symptoms of severe malaria can include impaired consciousness, coma (cerebral malaria), generalized seizures, severe anemia, acute renal failure, pulmonary edema, acute respiratory distress syndrome, hypotension and circulatory collapse, disseminated intravascular coagulation, spontaneous bleeding, metabolic (lactic) acidosis, hypoglycemia, hemoglobinuria, jaundice, and a parasitemia greater than 5%. Cerebral malaria is characterized by coma that is not attributable to any other cause in a patient infected with P. falciparum. It is a life-threatening complication with an estimated 10% to 40% mortality rate. Coma or impaired mental status caused by malaria has to be distinguished from other causes of neurologic symptoms, including hyperpyrexia, hypoglycemia, and concurrent infections. Signs of cerebral malaria range from disorientation to focal neurologic signs to coma with extensor posturing (including decorticate or decerebrate rigidity) or opisthotonos. Complications with other species are rare. Splenic rupture has been described in patients who, because of long-standing untreated P. vivax infection, have developed massive splenomegaly. With effective chemotherapy, this complication is unusual. Nephritis is a rare complication of persistent P. malariae infection but occurs more commonly in children. Diagnosis To provide appropriate therapy, it is essential to identify the infecting malaria species, determine where the infection was acquired, and determine the parasite density. Health care providers evaluating patients for possible malaria must get the results of their malaria smears immediately. Sending these diagnostic tests to offsite laboratories where results are not available for extended periods of time is an unacceptable practice that can result in increased morbidity and mortality from delayed diagnosis and delayed recognition of hyperparasitemia. Initial evaluation of patients with slide-confirmed malaria ideally also should include glucose, a complete blood count, electrolytes, creatinine, urea, and liver function tests. In patients with

severe disease or respiratory symptoms, lactate level and arterial blood gases to determine acid-base status should also be obtained. Malaria should be considered in any febrile patient with a history of travel to an area of malaria transmission regardless of whether the patient gives a history of taking prophylaxis. Information on the location and duration of the trip, the date of return, the history of prophylaxis, and the date of symptom onset enables the physician to assess the risk of malaria and, if necessary, to choose an appropriate course of treatment. Rapid diagnosis and institution of antimalarial treatment can prevent the development of severe morbidity and mortality. A list of key diagnostic points, including elements of the history, physical examination, and laboratory investigations, is presented in the Current Diagnosis box. A thick and a thin blood smear should be obtained from any patient suspected of having malaria. Blood smears can be used to detect the presence of parasites, identify the species, and determine the parasite density. Initial blood smears may be negative, particularly in symptomatic semi-immune persons and those taking prophylaxis. Consequently, a diagnosis of malaria cannot be dismissed on the basis of a single negative smear. Blood smears should be repeated every 12 to 24 hours for a total of 48 to 72 hours before the diagnosis of malaria is excluded. Nearly all patients with clinical symptoms caused by malaria have detectable parasites on well-stained thick blood smears within 48 hours of symptom onset.


Did the patient travel to a malaria-endemic area? (including duration of journey and date of return) Which medicine (if any) was prescribed for prophylaxis? Was the patient fully compliant with the malaria prophylaxis regimen? Is there a history of blood transfusion, organ transplant, intravenous drug use? Is there a history of previous malaria infection? Has the patient been exposed to mosquitoes? Has the patient been around recent visitors from malaria-endemic areas? Signs and Symptoms

Prodrome with headaches, myalgias, and malaise Fever Chills Abdominal pain, nausea, vomiting, diarrhea Respiratory distress Splenomegaly Tachycardia Hypotension Jaundice Seizures Altered consciousness, coma Initial Laboratory Investigations

Thick and thin blood smears required for diagnosis; results must be available immediately Thick smear used for parasite detection Thin smear used for species identification and determination of parasite density Complete blood count Electrolytes Blood urea nitrogen and creatinine Hepatic transaminases Blood smears should he prepared with Giemsa stain and examined under a light microscope. Thick blood smears are more sensitive in detecting malaria parasites, and thin smears are more reliable for identifying species. Both thick and thin smears should be scanned at low magnification and then examined using the 100 × oil-immersion lens. The easiest way to determine the percent parasitemia using the thin smear is to count the parasitized erythrocytes among 500 to 2000 erythrocytes, divide the number of parasitized erythrocytes by the total number of erythrocytes counted, and multiply by 100. To avoid missing low-density infections, at least 300 high-power fields should be examined before a slide is considered negative. Further details about preparation and interpretation of smears can be found at the CDC ). Division of Parasitic Diseases diagnostic Internet site (www.dpd.cdc.gov/dpdx

The severity of malaria can vary with the percent parasitemia. Persons with parasitemia lower than 1% usually have mild disease. Those with 1% to 5% parasitemia can have manifestations of more moderate disease. Although severe malaria can occur even with apparently low parasitemia, persons with greater than 5% parasitemia are at high risk for severe malaria. Thus, it is essential to determine the parasite burden at the time of diagnosis as an assessment of disease severity.

If malaria parasites are detected, blood smears should he repeated every 12 to 24 hours, depending on the severity of illness, until the smears are negative. Sequential smears are useful for monitoring the response to treatment and detecting potential drug failure. Although gametocytes can persist much longer, blood smears should be negative for asexual parasites within 48 to 72 hours after the completion of therapy. Alternative methods for diagnosis are available. Rapid diagnostic tests (RDTs) detect the presence of parasite antigens by measuring either histidine-rich protein-2 (HRP-2) or parasite enzymes like aldolase and lactate dehydrogenase (pLDH). Determination of parasite density is not possible with these methods. The polymerase chain reaction (PCR) method may be more sensitive for detecting parasites than is microscopy. PCR is particularly valuable for identifying the species of a parasite when species cannot be determined by morphology alone. Currently, PCR is used mostly as a research tool and is available only in reference laboratories. Malaria serology detects antibodies to all four species but cannot be used to diagnose current infections. However, it may be useful for identifying an infective donor in cases of transfusion-related malaria, investigating congenital malaria, assessing the validity of clinical malaria diagnoses in empirically treated nonimmune travelers, and diagnosing tropical splenomegaly syndrome. Treatment GENERAL INFORMATION Ideally, treatment for malaria should not be initiated until the diagnosis has been confirmed by laboratory investigations. However, health care providers should not delay treatment when malaria is strongly suspected but the health care system fails to meet the standard of care and provide smear results in a timely manner. Once the diagnosis is confirmed, appropriate antimalarial therapy must be initiated immediately. The choice of treatment should he guided by the degree of parasitemia and the species of Plasmodium found, the clinical status of the patient, and the likely drug susceptibility of the infecting species as determined by where the infection was acquired. Although all four species require treatment with a rapidly acting blood schizonticide, patients with P. vivax or P. ovale also require treatment with primaquine phosphate to decrease the likelihood of a relapse. Species identification is necessary to distinguish falciparum malaria from nonfalciparum malaria. P. falciparum can cause rapid progression of disease and death. Patients with P. falciparum, mixed infections with P. falciparum, or infections in which the species cannot be identified immediately should he hospitalized and monitored closely to assess for the development of severe malaria and subsequent complications. If the infecting species or probable origin of infection cannot be determined, patients should be treated for multidrug–resistant P. falciparum until another species is identified. All patients should have repeat blood smears 12 to 24 hours after initiating treatment to assess for appropriate response. Using available clinical and laboratory data, physicians must determine whether a patient has uncomplicated or severe malaria. Patients with uncomplicated malaria typically can be treated with oral therapy but might need parenteral therapy if they are unable to take oral medication because of nausea, vomiting, or other reasons. Patients with severe malaria should be immediately started on parenteral malaria therapy. For detailed treatment information, including doses and frequency of therapy, refer to Table 2 .

TABLE 2 -- Malaria Treatment Recommendations Drug Adult Dose

Pediatric Dose

AtovaquoneAdult tab contains 250 mg atovaquone and Pediatric tab contains 62.5 mg atovaquone proguanil (Malarone) 100 mg proguanil and 25 mg proguanil 4 adult tabs PO as a single daily dose for 3 Daily dose taken for 3 consecutive d: consecutive d 5-8 kg: 2 pediatric tabs 9-10 kg: 3 pediatric tabs 11-20 kg: 1 adult tab 21-30 kg: 2 adult tabs 31-40 kg: 3 adult tabs =41 kg: 4 adult tabs Chloroquine phosphate (Aralen and generic)

600 mg base (=1 g salt) PO, then 300 mg base (=500 mg salt) at 6, 24, and 48 h

10 mg base/kg PO, then 5 mg base/kg at 6, 24, and 48 h

Clindamycin oral (Cleocin)[1]

20 mg base/kg/d PO divided tid for 7 d

20 mg base/kg/d PO divided tid for 7 d

Clindamycin parenteral (Cleocin)[1]

10 mg base/kg IV followed by 5 mg base/kg 10 mg base/kg IV followed by 5 mg base/kg IV q8h IV q8h Switch to oral clindamycin as soon as the patient is able, to complete a 7-d course

Switch to oral clindamycin as soon as the patient is able to complete a 7-d course

Doxycycline[*] (Vibramycin and generic) [1]

100 mg PO or IV bid for 7 d

2.2 mg/kg PO or IV bid for 7 d[*]

Mefloquine (Lariam and generic)[†]

750 mg salt (=684 mg base) PO followed by 500 mg salt (=456 mg base) PO 6-12 h after the initial dose

15 mg salt/kg (=13.7 mg base/kg) PO followed by 10 mg salt/kg (=9.1 mg base/kg) PO 6-12 h after the initial dose

Primaquine[‡] Quinidine gluconate

30 mg base PO qd for 14 d[3]

0.6 mg base/kg PO qd for 14 d[3]

6.25 mg base/kg (=10 mg salt/kg) loading dose[§] IV over 1-2 h, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for =24 h

6.25 mg base/kg (=10 mg salt/kg) loading dose[§] IV over 1-2 h, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for =24 h

Alternative regimen: 15 mg base/kg (=24 mg salt/kg) loading dose IV infused over 4 h, followed by 7.5 mg base/kg (=12 mg salt/kg) infused over 4 h q8h, starting 8 h after the loading dose

Alternative regimen: 15 mg base/kg (=24 mg salt/kg) loading dose IV infused over 4 h, followed by 7.5 mg base/kg (=12 mg salt/kg) infused over 4 h q8h, starting 8 h after the loading dose

Drug

Adult Dose

Pediatric Dose

Once parasite density is 2.0 µg/mL) or cephalosporins (MIC >4.0 µg/mL), vancomycin should not be used as a single agent if corticosteroids are used. The addition of rifampin (Rifadin[1]) is often recommended in these situations. 1 Not FDA approved for this indication.

Chemoprophylaxis for Bacterial Meningitis

Prophylactic antibiotics are recommended in case of meningitis caused by Neisseria meningitidis and Haemophilus influenzae type b. Prophylaxis is provided to eliminate the carriage of organisms among contacts and prevent spread to hosts susceptible to invasive disease. In cases of meningococcal meningitis, prophylaxis is indicated only for those with household or close intimate contact with the index case. Administration of prophylaxis to large groups (e.g., college students, schoolchildren, or preschool classes) requires a special assessment and a recommendation of local or regional health departments. Chemoprophylaxis is not necessary for casual contacts or medical personnel unless there is a direct exposure to respiratory secretions. The recommended dose of rifampin (Rifadin) is 10 mg/kg (600 maximal, adults) twice a day for 2 days; ciprofloxacin (Cipro[1]), 500 mg as single dose, is also effective for adults. Third-generation cephalosporins used in treatment of the index case of meningitis are sufficient to eliminate carriage of the organism. Chemoprophylaxis for H. influenzae type b is recommended for all household contacts of an index case if one of the contacts is an unvaccinated child younger than 4 years. If the index case is treated with ceftriaxone (Rocephin) or cefotaxime (Claforan), prophylaxis is not required, but if treated with ampicillin or chloramphenicol (Chloromycetin), prophylaxis is recommended to eliminate carriage. The recommended regimen for prophylaxis is rifampin,[1] 20 mg/kg (or 600 mg in adults) once a day for 4 days. With the near elimination of invasive infections caused by Haemophilus influenzae type b, with the use of routine immunization of children with conjugate haemophilus vaccines, Haemophilus influenzae types A, F, and rarely other serotypes have emerged, and the use of prophylaxis is not recommended in these situations because sufficient data are not available to support its efficacy, nor has spread within contacts been documented with any frequency. Vaccines for Bacterial Meningitis The universal recommendation for the use of protein-polysaccharide conjugate Haemophilus influenzae type b (HIB) vaccines in 1987 reduced the incidence of bacterial meningitis by this organism by greater than 97%. Three HIB vaccines (PedvaxHIB, ActHIB, HibTITER), licensed in the United States, are routinely given to children in dosage schedules employing three to four doses by 12 to 18 months of age (see www.cdc.gov ).

A pneumococcal protein-polysaccharide conjugate vaccine (Prevnar) licensed in 2000 is routinely recommended for children and has markedly reduced the incidence of invasive infections with seven serotypes of pneumococci in children. This vaccine is also recommended for children at high risk of pneumococcal infections (e.g., HIV infection, asplenia, sickle cell disease, and others). A pneumococcal polysaccharide vaccine (Pneumovax 23) is recommended for adults older than 65 years or for those over 50 years with risk factors (e.g., alcoholism, diabetes or other metabolic or renal disease, chronic pulmonary or cardiac disease). Although clear evidence for prevention of bacterial meningitis is lacking, evidence supports its efficacy against invasive pneumococcal diseases, many of which are the preceding infections leading to bacteremia and meningitis. Currently two vaccines remain available for prevention of meningococcal disease caused by four serotypes, A, C, Y, and W-135. The meningococcal polysaccharide vaccine (Menomune) is recommended for persons older than 2 years at high risk for severe meningococcal infections including adolescents and college students (particularly those residing in dormitories), military recruits, and those with complement deficiencies and asplenia. A quadrivalent protein-polysaccharide conjugate vaccines (Menactra) was licensed in 2005.

This vaccine is recommended for routine immunization of all children 11 to 12 years of age and adolescents and college students at high risk as well as those more than 11 to 55 years of age with high-risk factors for meningococcal infection.



REFERENCES Anderson and Yogev, 2005. Anderson EJ, Yogev LR: A rational approach to the management of ventricular shunt infections. Pediatric Infect Dis J 2005; 24:557-558. Andes and Craig, 1999. Andes DR, Craig WA: Pharmacokinetics and pharmacodynamics of antibiotics in meningitis. Infect Dis Clin North Am 1999; 13(2):595-618. De Gans and van de Beek, 2002. De Gans J, van de Beek : Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549-1564. Gray and Fedorko, 1992. Gray LD, Fedorko DP: Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992; 5:130-145. Hussein and Shafran, 2000. Hussein AS, Shafran SD: Acute bacterial meningitis in adults: A 12-year review. Medicine (Baltimore) 2000; 79:360-368. Klinger et al., 2000. Klinger G, Chin C-Y, Beyene J, et al: Predicting the outcome of neonatal bacterial meningitis. Pediatrics 2000; 106:477-482. Klein, 2002. Klein JO: Bacterial sepsis and meningitis. In: Remington JS, Klein JO, ed. Infectious Diseases of the Fetus and Newborn Infant, 5th ed.. New York and Saint Louis: WB Saunders; 2002:943-998. Odio et al., 1991. Odio CM, Faingezicht I, Paris M, et al: The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 1991; 324:1525-1531. Ronan et al., 1995. Ronan A, Hogg GG, Klug CL: Cerebrospinal fluid shunt infections in children. Pediatr Infect Dis J 1995; 14:782-786. Schuchat et al., 1997. Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 1997; 337:970-976. Unhanand et al., 1993. Unhanand M, Mustapha MM, McCracken GH, et al: Gram-negative enteric bacillary meningitis: A twenty-one year experience. J Pediatr 1993; 122:15-17. Van de Beek et al., 2004. Van de Beek D, de Gans J, Spanjaard L, et al: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351:1849-1858.



Chapter 28 – Infectious Mononucleosis

Method of: Leonard R. Krilov, MD Infectious mononucleosis is a clinical illness characterized by fever (typically not higher than 39.5°C [103°F]), sore throat, tender cervical lymphadenopathy, fever, malaise, and anorexia; it occurs most commonly in adolescence and young adulthood. Initially described in the 19th century as glandular fever, the characteristic mononuclear response with atypical-appearing lymphocytes led to the name infectious mononucleosis. Etiology Epstein-Barr virus (EBV) was recognized as the primary cause of infectious mononucleosis in 1968. Other infectious agents such as cytomegalovirus (CMV), toxoplasma, or adenoviruses may cause a minority of cases of mononucleosis (or mononucleosis-like illness). Epstein-Barr virus is an enveloped, double-stranded DNA virus of the Herpesviridae family. After primary EBV infection, as with other herpesviruses, the virus persists in a latent state throughout the patient's lifetime in a few B lymphocytes and is shed in saliva intermittently. The virus has also been associated with African Burkitt's lymphoma, nasopharyngeal carcinoma, lymphoproliferative diseases after organ and bone marrow transplantation, and hairy leukoplakia and lymphocytic interstitial pneumonitis in HIV-infected patients. X-linked proliferative disease (Duncan syndrome) is a rare condition in which affected boys develop fulminant uncontrolled lymphoproliferation after acute infectious mononucleosis. Survivors develop severe chronic hypogammaglobulinemia, chronic EBV and enteroviral infections and B-cell lymphomas. Epidemiology Epstein-Barr virus infections occur at a younger age in lower socioeconomic groups; 70% to 90% of such children developing EBV antibodies by age 5 years compared to only 40% to 50% of those from higher socioeconomic groups. For unknown reasons primary infections occurring in adolescence and young adulthood are more likely to manifest as infectious mononucleosis than when initial infection occurs at a younger age. In younger children acute EBV infection is usually clinically inapparent or manifested by a nonspecific, uncomplicated upper respiratory tract infection or pharyngitis. Thus, infectious mononucleosis occurs most commonly among white high school and college students with an annual incidence of approximately 1 in 2500 among such individuals aged 15 to 25 years. EBV transmission occurs through intimate sharing of saliva (thus, its description as the kissing disease) with an incubation period of 20 to 30 days (range 2 to 6 weeks). The efficiency of transmission is low, and

outbreaks of disease are rare. Epstein-Barr virus' viral load in whole blood in the acute phase correlates with the severity of symptoms; but viral load in oral secretions is independent of symptoms. There is no seasonality or sex predilection to EBV infections. Post-transfusion development of symptoms of mononucleosis is most often associated with CMV infection. Clinical Manifestations The classic manifestations of infectious mononucleosis are fever, painful exudative pharyngitis, and lymphadenopathy. The enlarged nodes may be limited to the cervical regions (including posteriorly) or generalized. Splenomegaly and frequently hepatomegaly are the other hallmark findings of the illness. Elevated liver function tests are common in the acute phase of disease, but symptomatic jaundice is rare. Eyelid edema (Hoagland sign) has been reported in approximately 25% of cases. The acute symptoms typically resolve over 1 to 4 weeks, but lymphadenopathy and fatigue may last for 2 to 3 months. Less common clinical manifestations include autoimmune hemolytic anemia (approximately 3%), severe neutropenia to less than 1000/mm3 (approximately 3%), and neurologic involvement in up to 5% of cases. The reported neurologic manifestations of acute EBV infection include meningoencephalitis, Guillain-Barré syndrome, transverse myelitis, facial paralysis, optic neuritis, and metamorphopsia or Alice in Wonderland syndrome with altered perception of sizes, shapes, and spatial relationships. Most cases of mononucleosis resolve uneventfully. Splenic rupture and the previously cited neurologic complications are the most frequent serious complications of mononucleosis with rare deaths reported. Diagnosis In the presence of the clinical features noted earlier, infectious mononucleosis is diagnosed by the presence of atypical lymphocytosis (>5% to 10% of all leukocytes) frequently in association with a decline in the number of granulocytes and platelets. Additionally, among school-age children and young adults, heterophil or Paul-Bunnell antibodies are detectable in 80% to 90% of cases beginning in the second week of illness and can be detected for up to 6 to 9 months after resolution of symptoms. These IgM antibodies react with horse, sheep, and beef erythrocytes but not guinea pig red cells. They are not EBV-specific and are present in only 50% or fewer of children younger than 4 years of age. Office-based commercial rapid slide kits for detecting heterophil response are 96% to 99% sensitive and give a result in 2 minutes.

CURRENT DIAGNOSIS The clinical triad of fever, exudative pharyngitis, and lymphadenitis in association with atypical lymphocytosis and a positive heterophil response makes the diagnosis of infectious mononucleosis. Epstein-Barr virus serologies should be reserved for uncertain cases or to confirm the diagnosis in younger children who may not mount a heterophil response.

Measurement of specific antibodies to EBV can be used to confirm the diagnosis. In the acute phase of illness, IgM and IgG antibodies to the viral capsid antigen (VCA) of EBV are detectable. The IgM response persists for approximately 4 months, whereas the IgG antibodies remain for life. Although the height of the

VCA-IgG response decreases as the acute infection resolves, serial measurements of antibody titers are not clinically beneficial as a rule. Antibodies to the EBV nuclear antigen (EBNA) appear several weeks to months after a primary infection and are considered a marker for a past or convalescent infection, but 10% to 20% of individuals never develop detectable levels of EBNA antibodies. More than 80% of patients develop transient antibodies to the early antigen (EA) of the virus as the VCA-IgM clears and EBNA responses develop ( Table 1 ).

TABLE 1 -- Infectious Mononucleosis Serological Response Patterns (Typical Patterns) Heterophil Antibody EBV VCA-IgM EBV VCA-IgG EBV EA EBV EBNA No Infection

-

-

-

-

-

Acute Infection

+

+

+/+

+/-

-

Past Infection

-

-

+

+/-

+

Abbreviations: EA = early antigen; EBNA = Epstein-Barr (virus) nuclear antigen; EBV = Epstein-Barr virus; VCA = viral capsid antigen.

Treatment There is no effective antiviral therapy for EBV-associated infectious mononucleosis. Rest and supportive care are mainstays of therapy. Corticosteroids are frequently prescribed for severe cases, but critical evaluation of this modality is lacking. Indications include marked tonsillar hypertrophy with upper airway obstruction, neurologic manifestations, and hemolytic anemia. High-dose, short-term courses of steroids (dexamethasone [Decadron][1] [0.25 mg/kg every 6 hours]; methylprednisolone [Solu-Medrol][1] [1 mg/kg every 6 hours]; oral prednisone[1] [40 mg/day]) have been used with dramatic improvement typically noted over 24 to 72 hours.

CURRENT THERAPY Rest and supportive care with limitation of physical activity during the first 1 to 4 weeks of illness are the mainstays of managing infectious mononucleosis. Corticosteroids are reserved for severe illness, especially with upper airway obstruction because of tonsillar hypertrophy.




REFERENCES Ambinder and Lin, 2005. Ambinder RF, Lin L: Mononucleosis in the laboratory. J Infect Dis 2005; 192:15031504. Balfour et al., 2005. Balfour Jr HH, Holman CJ, Hokanson KM, et al: A prospective clinical study of EpsteinBarr virus and host interactions during acute infectious mononucleosis. J Infect Dis 2005; 192:1505-1512. Barone and Krilov, 2001. Barone SR, Krilov LR: Infectious mononucleosis and other Epstein-Barr virus infections. In: Hoekelman RA, ed. Primary Pediatric Care, 4th ed.. St. Louis: Mosby; 2001:1573-1577. Fafi-Kremer et al., 2005. Fafi-Kremer S, Morand P, Brion J-P, et al: Long-term shedding of infectious Epstein-Barr virus after infectious mononucleosis. J Infect Dis 2005; 191:985-989. Giffen and Xue, 1998. Giffen BE, Xue S: Epstein-Barr virus infections and their association with human malignancies: Some key questions. Ann Med 1998; 30:249-254. Henle et al., 1968. Henle G, Henle W, Diehl V: Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci U S A 1968; 59:94-101. McGowan et al., 1992. McGowan JE, Chesney PJ, Crossley KB, et al: Guidelines for the use of systemic glucococorticosteroids in the management of selected infections. Working group on steroid use, Antimicrobial Agents Committee, Infectious Diseases Society of America. J Infect Dis 1992; 165:1-13. Paul and Bunnell, 1982. Paul JR, Bunnell WW: Classics in infectious diseases. The presence of heterophile antibodies in infectious mononucleosis by John R. Paul and W. W. Bunnell. American Journal of the Medical Sciences, 1932. Rev Infect Dis 1982; 4:1062-1068. Sumaya and Ench, 1985. Sumaya CV, Ench Y: Epstein-Barr virus infectious mononucleosis in children. I. Clinical and general laboratory findings. Pediatrics 1985; 75:1003-1010. Sumaya and Ench, 1985. Sumaya CV, Ench Y: Epstein-Barr virus infectious mononucleosis in children. II. Heterophil antibody and viral-specific responses. Pediatrics 1985; 75:1011-1019.



Chapter 29 – Chronic Fatigue Syndrome

Method of: James F. Jones, MD Definition Chronic fatigue syndrome (CFS) is the name applied to an illness of unknown origin that at face value resembles unresolved infections, depression, endocrinologic and metabolic disorders, sleep disorders, and many other conditions that include fatigue in their diagnostic criteria. In the modern era, interest in this illness began with the question of a relationship with a chronic active Epstein-Barr virus infection. Subsequent studies did not support Epstein-Barr virus as the only cause of this syndrome, but several recent studies have found 10% of patients with acute infectious mononucleosis and other infectious diseases might have a similar illness or postinfection fatigue syndrome. The lack of association with a specific infectious agent led to the generation in 1988 of a definition based on the presence of incapacitating fatigue and varying combinations of signs and symptoms. Any preexisting medical or psychiatric condition was exclusionary. Evaluation of this definition at a number of centers in the United States, Great Britain, and Australia led to the current definition published in 1994 ( Box 1 ). The definition was altered so that preexisting medical conditions that were treated satisfactorily were allowed, as well as certain psychiatric and syndromic diagnoses. Additional changes in the definition included a decrease in the number of symptoms and removal of the signs; signs had been shown to be somewhat arbitrary, and patients could be identified in their absence. The greater number of symptoms in the 1988 version did not allow identification of a specific illness, and they increased the possibility that patients who had primary psychiatric illnesses (e g., somatiform disorders) would be mislabeled with CFS. The 1994 definition still requires more than 6 months of fatigue, but it dropped the 50% level of activity present inthe 1988 definition because the requirement was impossible to apply evenly across all patients. BOX 1

International Consensus Definition of Chronic Fatigue Syndrome •

Clinically evaluated, unexplained, persistent or relapsing chronic fatigue (lasting more than 6 months) that is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

•

Four or more of the following symptoms are concurrently present for more than 6 months:

•

•

Impaired memory or concentration

•

Multijoint pain

•

Muscle pain

•

New headaches

•

Postexertional malaise

•

Sore throat

•

Tender cervical or axillary lymph nodes

•

Unrefreshing sleep

Exclusionary clinical diagnoses: •

Any active medical condition that could explain the chronic fatigue

•

Any previously diagnosed medical condition whose resolution has not been documented beyond reasonable clinical doubt and whose continued activity can explain the chronic fatiguing illness

•

Psychotic major depression, bipolar affective disorder, schizophrenia, delusional disorders, dementias, anorexia nervosa, bulimia nervosa

•

Alcohol or other substance abuse within 2 years prior to the onset of the chronic fatigue and at any time afterward

Adapted from Fukuda K. Straus SE, Hickie I, et al: The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959. The diagnostic criteria, including exclusion of other illnesses, are described in the Current Diagnosis box. The definition was originally designed as a research tool and included suggestions for unifying the measurement of fatigue and evaluation of the mental status of patients. Epidemiology The prevalence of the syndrome using the 1988 definition is approximately 13 per 100,000, whereas the 1994 definition identified approximately 300 per 100,000. Application of an empiric definition (see later) in a population recruited with unwellness, rather than fatigue, identified a higher prevalence of CFS (Reeves et al, 2007). An increase in CFS cases in an unwell population highlights the need to address illness in general and not just fatigue when considering this diagnosis. One demographic variable that has remained stable is the 3:1 ratio of women to men.

Diagnosis Diagnosis of CFS begins with exclusion of other illness processes associated with fatigue and unwellness and subsequent suspicion of the syndrome after taking a history and performing a physical examination and screening laboratory tests ( Box 2 ). It should not be assumed that a patient with fatigue as a presenting complaint has CFS. The history shows whether the illness began acutely or more gradually and whether there are preexisting symptoms. History often provides insight into previously identified factors that influence patient perception of illness. Questioning about typical episodes provides information about cyclic events, possible triggers of symptoms, and possible exposures. BOX 2 Screening Laboratory Tests •

Alanine aminotransferase

•

Albumin

•

Alkaline phosphatase

•

C-reactive protein

•

Complete blood count

•

Creatinine

•

Electrolytes

•

Globulin

•

Glucose

•

Thyroid-stimulating hormone and free T4

•

Total protein

•

Urinalysis

Abbreviation: T 4 = thyroxine. The interviewer gives the patients the opportunity to describe the history of the illness. The interviewer simply guides the patient and tries not to ask leading questions. This process not only gathers information but also serves as an ice breaker between the interviewer and the patient. It allows the interviewer to determine the mental status of the patient, the patient's concentration and memory capabilities, and what may be on the patient's agenda. It usually allows the examiner to determine the kind and scope of prior medical and alternative care evaluations the patients has received. The diagnosis of CFS should not be made on the first visit. Attempts should be made to determine the duration, the mode of onset, the magnitude, and the consequences of each complaint, although these are not included in the working definition. Only with such thorough questioning will an underlying process responsible for the illness be identified or suspected.

A more recent application of the definition uses three validated questionnaires: the Medical Outcomes Survey Short Form-36 (SF-36), the Multidimensional Fatigue Inventory (MFI), and the CDC Symptom Inventory. These questionnaires provide numeric scores that identify persons with CFS and provide a record of their level of impairment. The Symptom Inventory collects information about the presence, frequency, and intensity of 19 fatigue- and illness-related symptoms during the month preceding the interview; these include all eight CFS-defining symptoms (postexertional fatigue, unrefreshing sleep, problems remembering or concentrating, muscle aches and pains, joint pain, sore throat, tender lymph nodes and swollen glands, and headaches). Perceived frequency of each symptom is rated on a four-point scale (1 = a little of the time, 2 = some of the time, 3 = most of time, 4 = all of the time), and severity or intensity of symptoms is measured on a three-point scale (1 = mild, 2 = moderate, 3 = severe). The case definition specifies that CFS causes substantial reduction in occupational, educational, social, or recreational activities. Substantial reduction is defined as scores lower than the 25th percentile on the SF-36 using the following four factors: physical function (=70), or role physical (=50), or social function (=75), or role emotional (=66.67) subscales of the SF-36, related to published norms of the U.S. population according to Ware and Sherbourne. We defined severe fatigue using the Multidimensional Fatigue Inventory as a score of 13 or higher on the general fatigue scale or 10 or higher on the reduced activity scales of the MFI (their respective medians). Finally, because the case definition specifies that characteristic symptoms accompany fatigue, subjects reporting at least 4 symptoms and scoring at least 25 on the Symptom Inventory Case Definition Subscale were considered to have substantial accompanying symptoms.

CURRENT DIAGNOSIS Identify duration of fatigue and its consequences. Identify primary symptoms. Exclude other illnesses/diseases. Reconsider the diagnosis on an ongoing basis. Chronic fatigue syndrome is a working diagnosis. Routine laboratory evaluations are recommended to address contributory illnesses (see Box 2 ). Routine testing does not include specific antibody testing, tests of immune function per se, or single-photon emission computed tomography (SPECT) or magnetic resonance imaging (MRI) of the brain. Negative screening test results do not automatically exclude an alternative diagnosis. Specific testing, for example, for a sleep disorder or chronic sinusitis may be necessary. A mental status examination, either informally or by using a standard instrument when indicated, is equally important. A working diagnosis of CFS may then be made if the evaluation fails to identify an underlying illness. This approach is warranted because the patient's underlying disease might declare itself in the future. Continued adherence to a diagnosis of CFS in the face of an evolving or readily identifiable medical or psychiatric illness is the single most detrimental outcome of a premature or prolonged diagnosis of CFS. Additional laboratory or other diagnostic testing is based on the individual patient's complaints. The interview

techniques listed earlier assist in this process. An additional valuable tool that will lead the interviewer to identify a specific illness or symptoms requiring intervention is simply to ask the patient to list the problems described in decreasing order of magnitude. Which problem causes the most difficulty? Or which problems interfere with the ability to carry out daily functions? Patients often use this exercise to list the consequences of their illness. Therapy Treatment regimens vary with the needs of the individual patient and how he or she perceives the illness. The goals of treatment depend on the person's specific symptoms and eventually the patient's identified needs within a framework of providing reentry into their premorbid condition. Complete return to normal might not be possible immediately, however, nor is this goal appropriate if it is too lofty. In fact, the desire for total immediate recovery can hamper clinical improvement. The patient's adaptation to this new, albeit temporary, state is often a more realistic short-term goal. Therapeutic modalities include education regarding the boundaries and limitations of the diagnosis, development of coping skills, institution of a graduated exercise program when possible, and use of medications to treat symptoms. If the patient is being seen in a multidisciplinary setting, these approaches may be combined into a specific program. If CFS is an infrequent diagnosis in a practice, identifying the problems that cause loss of function becomes critical.

CURRENT THERAPY Education regarding the advantages and disadvantages of CFS as a diagnosis Development of coping skills Cognitive behavior therapy Initiation of a graded exercise program Symptomatic medication EDUCATION All physicians who make the diagnosis must provide information regarding the illness in general and the specific criteria that allowed recognition of the problem. Just as education regarding asthma and diabetes mellitus is a critical component of therapy for those diseases, education regarding the origin, specific components, and outcome of the syndrome is more critical in this situation. The literature supports CFS as a condition that is not life threatening or progressive. Lay representations, which are readily available, are often incorrect in painting a uniformly dismal outcome. Physicians should counsel their patients that all illness symptoms should not be attributed to CFS, and patients should seek medical advice when new problems arise or old problems become more prominent. Patients should also be taught that persistent efforts to find a cure via experiences of their acquaintances or the newest information in magazines or on the Internet are not as productive as their participation in a specifically designed program as outlined here. Paramount in this process is their consideration of acceptance of their current, albeit temporary, status. Wanting their lives back and attempting to regain them with a pill are not effective approaches.

A major part of the education and treatment process is the interview process. Giving the patient the opportunity to describe the illness and its consequences in a nonjudgmental situation is critical to gaining the patient's confidence. A physician who makes the diagnosis of CFS literally establishes a contract for longterm care with the patient, and it must be based on mutual trust. DEVELOPMENT OF COPING SKILLS To recommend coping strategies, the provider must know the needs of the patient, another rationale for the patient-generated problem list. If the patient complains of problems with memory and concentration, simple advice regarding using lists and audiotaping activities or needs is logical. If they cannot perform on the job or their behavioral responses to these complaints aggravate the consequences, formal neuropsychological testing or therapy, or both, is required. Assistance with understanding losses is also very important. Depending on the magnitude of the consequences of their illness, patients can lose self-respect and the appreciation of their families, employees, and coworkers. They need to learn that as individuals they are not responsible for these losses but that they are responsible, at least in part, for their recovery. They need to go through a grieving process and then learn how to adapt to their current state. They need to learn to accept and desire incremental levels of progress. Formal psychological therapy may be required to achieve these goals. The origin of the illness and the character of the fatigue dictate the approach in many cases. If the origin is with an apparent, usually unidentified, flu-like illness that does not resolve, or if the character of the fatigue simulates the malaise of such an illness, the patient needs to know that the symptoms are normal responses. The duration and consequences in the eyes of society and the individual patient are the factors that differentiate a normal resolution of an illness from a prolonged or chronic condition. The patient also needs to know that resumption of normal activity is not the correct approach. Most patients have symptoms on a daily basis, but they also have days when the symptoms are more or less pronounced (bad and good days). A typical patient performs on the good days as if there were no illness. This action is then followed in 1 or 2 days by an exacerbation of symptoms. Learning to compartmentalize activities and to never exceed their personal limits are critical steps in coping with CFS. On the other hand, total acceptance of such a program is not appropriate either. Usually, acute-onset patients notice that they can be more active without exacerbation of symptoms regardless of their therapeutic program. This observation usually heralds resolution of the illness. In some instances, the illness is resolving, but the patient perceives the outcome of increased physical activity (e.g., muscle aches and tiredness) as illness symptoms rather than simply the expected consequences of increased activity. The recurrence of the patient's whole syndrome following activity, however, suggests that resolution has not taken place. EXERCISE It seems contradictory to follow the discussion about listening to one's body and avoiding excessive activity with a section that recommends regular exercise. The studies on muscle function show that patients are tired after performing repetitive acts and that there appears to be no primary problem in muscle function. There may a problem in fitness or conditioning, however. Whether this result is a consequence of the illness

or the inactivity that accompanies the syndrome is not known. Lessons from the rehabilitation of patients with cardiac and pulmonary diseases teach us that anaerobic exercise to regain strength should precede exercises to improve aerobic fitness and overall conditioning. A program that includes active stretching followed by range-of-motion contractions and extensions that eventually includes resistance is usually an effective start. Five minutes per day is a typical starting point for a patient who has been totally inactive. The endpoint of each session should be preset by the clock or number of repetitions and should be reached before the patient becomes tired. This endpoint is based on the fact that either tiredness is a trigger for the production of biological changes that are a part of the host's attempt to limit activity or the perception that tiredness triggers illness behavior. At this stage in the understanding of the illness, prevention of activation of either of these pathways and an increase in overall fitness are appropriate goals. This section may be summarized by the adage that no exercise is bad, some is good, and too much exercise is not helpful. The previous sections on education, coping skills, and exercise provide the kinds of therapy that are offered in cognitive behavior therapy programs. SYMPTOMATIC THERAPY One usually associates symptomatic therapy with medication. Some interventions require alterations in patient habits or changes in biological processes that do not require medication per se. Sleep Therapy

The primary example is treatment of sleep problems. A very large percentage of patients presenting for evaluation of fatigue, many of whom carry the diagnosis of CFS, have sleep disorders or disturbances. Some have problems with sleep hygiene. They may read or watch television for prolonged periods (longer than 15 minutes) before trying to go to sleep. This habit can actually allow arousal of the brain within several hours following sleep onset, thus leading to interrupted sleep. Caffeine ingestion after 6 pm and exercise within 4 hours of bedtime can impede getting to sleep. Patients are often given medication for insomnia that is manifested by going to bed at 11 pm but not being able to get to sleep until 1 or 2 am, with a waking time of 10 am. A hypnotic might be prescribed that allows induction of sleep at an earlier time, but the patient might still not experience restorative sleep. One explanation for this series of events is that the patient has a phase-delay syndrome and needs to alter the sleep cycle with prescribed light therapy before improvement is expected. Appropriate use of hypnotics may be important in allowing initial normalization of sleep cycling, but these agents are not sufficient as the sole mode of therapy, nor should they be used for prolonged periods. Daytime sleepiness is another common problem with multiple origins. Ill-advised symptomatic therapy includes self- or physician-generated use of stimulants. These drugs include caffeine, herbs that contain ephedrine such as Ma huang (Ephedra sinica), and antidepressants that actually serve as stimulants (serotonin and norepinephrine reuptake inhibitors [SNRIs]). These substances might allow short-term improvement in daytime function, but they block identification of the underlying nighttime or daytime origin of the sleep problem.

Pharmacologic Therapy

Premature treatment can prevent adequate diagnosis and treatment of readily remediated problems. However, symptomatic medications have a definite place in the therapy of CFS. Many CFS patients do not tolerate standard doses of any of the medications used for symptomatic relief. Classes of drugs that might have beneficial effects for symptom relief include hypnotics of various types, antidepressants of several types if depression is evident, and non-narcotic analgesics. As used in the treatment of fibromyalgia, tricyclic antidepressants and SNRIs are used for symptomatic therapy in the absence of formal depression. Because these classes of medications are being used as adjuncts to the other modes of therapy, they are not always successful. They might need to be changed during the course of the illness. Often patients come to the physician using a large number of medications. It might not be possible to determine by the history alone whether the patient's symptoms are not at least in part due to the medication regimen. Often the medications need to be tapered and stopped to sort out their influence on the manifesting complaints. Popular remedies for CFS are discussed primarily to familiarize the practitioner with them and to support previous warnings regarding lack of efficacy. The primary problem with their use is that proof is lacking that such intervention has been uniformly beneficial. This statement is particularly true in cases of parenteral (injectable) repetitious therapy with any substance. Alternative Therapies

The effectiveness of diet manipulations and ingestion of herbs, enzymes, amino acids, vitamins, minerals, or hormones, although usually safe, is equally unproven. These agents constitute a large component of the therapeutic armamentarium in use by patients with CFS. Herbs are particularly in vogue. Many of them have medicinal qualities and if taken in excessive amounts may be injurious. Because many of these substances are readily available, they are used by patients who are anxious for improvement in their illness. If the reader has such patients or is such a patient, one must make sure that the remedy in question is safe and that its use is affordable and does not hide illness parameters that require specific identification. If patients are intent on taking these types of remedies, they should be advised to at least seek the advice of a responsible care provider who is knowledgeable in their use and adverse consequences. Alternative care in many forms is also in vogue and may be helpful if provided in a responsible fashion. Some patients with myalgias and other pain complaints find particular benefit from acupuncture and therapeutic massage. Therapeutic Plan

Therapy for CFS patients continues to be directed at relieving symptoms and consequences of the syndrome. It is clear, however, that one approach or one medication is not satisfactory for all patients. Identifying the patient's most problematic symptoms and using a variety of modalities that address those problems in the treatment plan are the most effective ways of assisting the patient. Patients should be

reminded not to expect total return to their premorbid state to occur immediately. Because the use of medications remains arbitrary, failure of one regimen may be followed by successful relief using the more effective modes of therapy, such as cognitive behavior therapy and graduated exercise. Eventually the origins of symptom production will be understood and therapy can be directed with some authority. As it stands now, one must always be careful that whatever the treatment, it must not aggravate the illness.



REFERENCES Bazelmans et al., 2005. Bazelmans E, Prins JB, Lulofs R, The Netherlands Fatigue Research Group Nijmegen , et al: Cognitive behaviour group therapy for chronic fatigue syndrome: A non-randomised waiting list controlled study. Psychother Psychosom 2005; 74(4):218-224. Jones et al., 2007. Jones JF, Maloney EM, Boneva RS, et al: Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States. BMC Complement Altern Med 2007; 7:12. Jones et al., 2003. Jones JF, Nisenbaum R, Reeves WC: Medication use by persons with chronic fatigue syndrome: Results of a randomized telephone survey in Wichita, Kansas. Health Qual Life Outcomes 2003; 1(1):74. Moss-Morris et al., 2005. Moss-Morris R, Sharon C, Tobin R, Baldi JC: A randomized controlled graded exercise trial for chronic fatigue syndrome: Outcomes and mechanisms of change. J Health Psychol 2005; 10(2):245-259. Nater et al., 2006. Nater UM, Wagner D, Solomon L, et al: Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS. J Psychosom Res 2006; 60(6):567-573. Reeves et al., 2007. Reeves WC, Jones JF, Maloney E, et al: Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr 2007; 5:5. Reeves et al., 2005. Reeves WC, Wagner D, Nisenbaum R, et al: Chronic fatigue syndrome: A clinically empirical approach to its definition and study. BMC Med 2005; 3(1):19. Wagner et al., 2005. Wagner D, Nisenbaum R, Heim C, et al: Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome. BioMed Central Popul Health Metr 2005; 3:8. Ware and Sherbourne, 1992. Ware JE, Sherbourne CD: The MOS 36-item short form health survey (SF-36): Conceptual framework and item selection. Med Care 1992; 30:473-483. Whiting et al., 2001. Whiting P, Bagnall AM, Sowden AJ, et al: Interventions for the treatment and management of chronic fatigue syndrome: A systematic review. JAMA 2001; 286:1360-1368.



Chapter 30 – Mumps

Method of: Joel D. Klein, MD, FAAP Mumps is a respiratory viral infection caused by mumps virus, an RNA virus in the family Paramyxoviridae. The virus is spread from human to human through direct contact with airborne droplets. Epidemiology Before the introduction of mumps vaccine, there were large yearly epidemics, usually occurring in the winter and early spring. Infection generally occurred among young children (younger than 15 years), with rare cases in young adults. With the introduction of the mumps vaccine in 1967, there was a dramatic decrease in the number of cases. However, in 1986 and 1987, there was a resurgence of mumps among teenagers and young adults, most of whom were born before routine immunization with the mumps vaccine. Outbreaks were also seen among some children who had received mumps vaccine, because a single dose of the vaccine did not always confer immunity. In 1989, a second dose of mumps vaccine was recommended to address this issue. Mumps vaccine currently is usually administered as part of a combined vaccine such as measles-mumps-rubella (MMR) or most recently measles-mumps-rubella-varicella (MMRV) (Proquad). Despite these changes, outbreaks of mumps occasionally occur, usually among college-aged persons. Recent examples include an epidemic in the United Kingdom in the winter of 2004 to 2005 and in the United States in 2006. Clinical Manifestations The incubation period of mumps is 14 to 25 days and involves nonspecific complaints of malaise, low-grade fever, and anorexia. The single most diagnostic physical finding in mumps is unilateral or bilateral parotitis, which occurs in up to 40% of cases. Mumps parotitis can occur early in the disease and may be associated with swelling and pain in other salivary glands. There often is erythema of the area and tenderness with palpation of the affected parotid. Patients at times also complain of earache and headache. Swelling over the parotid and related glands can occur rapidly and can result in distortion of the contours of the face, pushing the earlobe upward and outward. Edema can extend to the anterior chest wall as well. Examination of the oral cavity can reveal erythema of the orifice of Stensen's duct without purulent discharge. Parotitis generally resolves within 1 week.

CURRENT DIAGNOSIS Painful parotid swelling Edema of the face in the area of the parotid Elevation of serum amylase Headache and occasional meningismus Viral isolation or serology can confirm diagnosis The most commonly reported complications of mumps are aseptic meningitis and encephalitis, which can occur individually or together. Meningitis occurs in 10% to 15% of cases but probably is underreported. There is a typical viral-like pleocytosis in the cerebrospinal fluid (CSF), but the CSF glucose may be low. Encephalitis is rare and is seen in 1 or 2 per 100,000 cases. Orchitis, either unilateral or bilateral, may be seen in as many as 50% of infected men. This complication can have a rapid onset and can be associated with increased fever, abdominal pain, nausea, and testicular swelling. This complication generally resolves within 1 week and can result in testicular atrophy but rarely infertility. Pancreatitis is sometimes seen, is usually mild, and may be associated with transient hyperglycemia. Table 1 lists the incidence of complications of mumps.

TABLE 1 -- Complications of Mumps Infection Mumps Complications Incidence of Complications Central nervous system 40%-50% Orchitis and epididymitis 15%-30% Oophoritis

7%

Pancreatitis

2%-5%

Deafness

1 in 20,000 reported cases

Myocarditis

Rare

Arthritis

Rare

Thyroiditis

Rare

Diagnosis Diagnosis of mumps is usually made by clinical examination and history. It should be considered in any patient with sudden onset of parotid swelling and fever. Mumps virus isolation may be attempted on fluids obtained by nasopharyngeal swab and urine. Virus may be excreted for 1 week before and 1 week after the onset of parotitis. When available, PCR may also be used to detect mumps virus in secretions. Serum amylase determinations, although not specific, may be helpful in situations where mumps is suspected. Serology, which is readily available, may be diagnostic as well. Mumps IgM obtained during the

acute infection is usually elevated and diagnostic. Acute and convalescent-paired sera can also be used to retrospectively confirm the diagnosis. Other commonly ordered laboratory tests, including complete blood count (CBC) are not particularly helpful. The CBC might show mild leukopenia with lymphocytosis. Differential diagnosis of mumps parotitis includes many infections that are listed in Box 1 . BOX 1 Differential Diagnosis of Mumps Parotitis •

Parainfluenza virus infection

•

Enterovirus infection

•

Epstein-Barr virus

•

Cytomegalovirus infection

•

HIV

•

Suppurative bacterial infection (Staphylococcus aureus, Streptococcus pneumoniae)

•

Nontuberculous mycobacterial infection

CURRENT THERAPY Analgesia for pain Warm or cold compresses Droplet isolation in the hospital Patient may return to school 9 days after the onset of parotid swelling Treatment There is no specific therapy for mumps. Adequate analgesia is important, because many patients are quite uncomfortable. Because most patients are febrile, hydration also plays an important role. This is particularly critical because there may be difficulty swallowing and pain with mastication. Children with mumps should be excluded from school for 9 days from onset of parotid swelling. Droplet precautions are recommended for patients with mumps admitted to the hospital for a period of 9 days from onset of parotid swelling. Prevention Mumps vaccine should be administered to children at age 12 to 15 months. A second dose should be given at age 4 to 6 years. Patients with HIV who are not severely immunocompromised may receive a combination mumps vaccine. Adults born in 1957 or later, in whom immunity is not known, should receive one dose of a

mumps combination vaccine (MMR). Persons born before 1957 are usually considered immune, but they might benefit from immunization during a mumps community outbreak.



REFERENCES American Academy of Pediatrics Committee on Infectious Diseases, 2006. American Academy of Pediatrics Committee on Infectious Diseases : Mumps. In: Pickering LK, ed. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village, Ill: American Academy of Pediatrics; 2006:464-468. Cherry, 2004. Cherry JD: Mumps Virus. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL, ed. Textbook of Pediatric Infectious Diseases, 5th ed.. Philadelphia: WB Saunders; 2004:2305-2314. Gupta et al., 2005. Gupta RK, Best J, MacMahon E: Mumps and the UK epidemic 2005. BMJ 2005; 330:1132-1135. Litman and Baum, 2005. Litman N, Baum SG: Mumps virus. In: Mandell GL, Bennett JE, Dolin R, ed. Principles and Practice of Infectious Diseases, 6th ed.. Philadelphia: Churchill Livingstone; 2005:2003-2008. Maldonado, 2004. Maldonado Y: Mumps. In: Behrman RE, ed. Nelson Textbook of Pediatrics, 17th ed.. Philadelphia: WB Saunders; 2004:1035-1036. McQuone, 1999. McQuone SJ: Acute viral and bacterial infections of the salivary glands. Otolaryngol Clin North Am 1999; 32(5):793-811.



Chapter 31 – Plague

Method of: Douglas A. Drevets, MD, DTM&H Plague caused by Yersinia pestis is an ancient disease, and historical descriptions indicate that it probably caused Justinian's Plague (ad 541) that led into the first plague pandemic. The second plague pandemic, also known as the Black Death, began in Central Asia in 1347 and then spread to Europe, Asia, and Africa. It killed an estimated 50 million persons. The third and current plague pandemic began in China and then disseminated throughout the world by shipping routes in 1899-1900. Y. pestis is a gram-negative, nonmotile, facultatively anaerobic, non-spore-forming coccobacillus that is approximately 0.5 to 0.8 µm in diameter and 1 to 3 µm in length. Genomic sequencing shows that Y. pestis is a recently emerged clone of Y. pseudotuberculosis. Epidemiology Plague is a zoonosis that is usually spread between mammalian hosts by the bite of infected fleas. The most important enzootic reservoirs are urban and sylvatic rodents; however, domestic cats and dogs also are linked to human disease. Human plague occurs in North and South America, Asia, and Africa. An average of 2547 cases of human plague were reported yearly to the World Health Organization between 1988 and 1997, 76% of which were from Africa, with an overall case fatality rate of 7.1%. In North America, 82% of 295 indigenous cases were from Arizona, Colorado, and New Mexico. Bubonic plague is the most common form in humans, accounting for 97% of cases in a recent outbreak in Madagascar. Similarly, 84% of U.S. cases reported between 1947 and 1996 were the bubonic form, with septicemic and pneumonic plague accounting for 13% and 2%, respectively. Modes of Transmission Most human infections are transmitted from rodent to humans via the bite of an infected flea. Infection also can be acquired by contact with body fluids from infected animals, such as during field dressing of game or by inhalation of respiratory droplets from animals, particularly cats, or humans with pneumonic plague. Bioterrorism Threat Plague was used as an agent of biowarfare by the Japanese in World War II and was a focus of intensive research and development in the former Soviet Union during the Cold War. Primary pneumonic plague is the most likely form of exposure because of biowarfare or bioterrorism. Pathogenesis and Clinical Syndromes Transdermal inoculation of bacilli from the bite of an infected flea ultimately leads to infection of the regional lymph nodes in which massive replication of bacteria creates the bubo (derived from the Greek “bubon” or

“groin”), a swollen, erythematous, and painful lymph node in the groin, axilla, or cervical region. Bacteremia and septicemia frequently develop and lead to secondary infection of other organs including lungs, spleen, and the central nervous system. Primary pneumonic plague is a rare natural occurrence and results from the inhalation of respiratory droplets containing Y. pestis bacilli from another case of pneumonic plague, usually in humans or in cats. Secondary pneumonic plague results from seeding of the lungs by blood-borne bacteria in the setting of either bubonic or septicemic plague. Septicemic plague also begins with a transdermal exposure but manifests as primary bacteremia/septicemia without the bubo. Less common manifestations include meningitis, pharyngitis, and gastroenteritis. Bubonic plague is an acute febrile lymphadenitis that develops 2 to 8 days after inoculation. Inflamed lymph nodes are usually 1 to 6 cm and painful. Abrupt onset of fever is an almost universal finding and occurs simultaneously with, or up to 24 hours before, the appearance of the bubo. Headache, malaise, and chills are frequent, along with nausea, vomiting, and diarrhea. Most patients are tachycardic, hypotensive, and appear prostrate and lethargic with episodic restlessness. Leukocytosis with a left shift is typical. Complications include pneumonia, shock, disseminated intravascular coagulation, purpuric skin lesions, acral cyanosis, and gangrene. The differential diagnosis of bubonic plague includes tularemia and Group A ß-hemolytic streptococcal adenitis with bacteremia.

CURRENT DIAGNOSIS Travel to a plague endemic area or contact with a case of animal or human plague. Abrupt onset of fever and prostration. Bubo in groin, axillae, or cervical areas. Gram-negative coccobacilli with bipolar staining identified in aspirate from bubo, on blood smear, or from blood-tinged sputum. The symptoms of septicemic plague are not distinct from those caused by other gram-negative bacteria, and they are very similar to those of bubonic plague except that abdominal pain is more common in septicemic plague. Septicemic plague must be differentiated from fulminate septicemia caused by other gram-negative bacteria. Primary pneumonic plague has an abrupt onset of fever and influenza-like symptoms 1 to 5 days after inhalation exposure. Symptoms include shortness of breath, cough, chest pain, and bloody sputum with rapid progression to fulminate pneumonia and respiratory failure. Patients with secondary pneumonic infection show respiratory symptoms in addition to those attributed to the bubo or sepsis. Radiographic findings include patchy bronchopneumonia, multilobar consolidations, cavitations, and alveolar hemorrhage and are not pathognomonic of Y. pestis. Plague pneumonia must be differentiated from severe influenza, inhalation anthrax, and overwhelming community-acquired pneumonia. Diagnosis Plague is diagnosed by demonstrating Y. pestis in blood or body fluids such as a lymph node aspirate, sputum, or cerebrospinal fluid. A tentative diagnosis of bubonic plague can be made rapidly with fluid aspirated from a bubo showing gram-negative coccobacilli with bipolar staining. Serology showing a fourfold rise in antibody titers to F1 antigen or a single titer of more than 1:128 is also diagnostic.

Treatment The aminoglycosides gentamicin (Garamycin) and streptomycin, the fluoroquinolones ciprofloxacin (Cipro), levofloxacin (Levaquin), and ofloxacin (Floxin), and tetracyclines (i.e., doxycycline [Vibramycin]) are the first-, second-, and third-line classes of antibiotics, respectively. Typical minimal inhibitory concentrations for 90% (MIC90) of tested strains for the fluoroquinolones are less than 0.03 to 0.25 µg/mL compared with less than 1.0 µg/mL and less than 1.0 µg/mL to 4.0 µg/mL for gentamicin and streptomycin, respectively, and less than 1.0 µg/mL for doxycycline. Streptomycin (15 mg/kg up to 1 g intermuscularly [IM] every 12 hours) and gentamicin (5 to 7 mg/kg/day intravenously [IV]/IM in one or two doses daily) are the drugs of choice for severe infection. Standard doses for the fluoroquinolones include ciprofloxacin, 400 mg IV/500 mg orally every 12 hours; levofloxacin, 500 mg IV/orally daily; and ofloxacin, 400 mg IV/orally every 12 hours. Doxycycline is administered at 100 mg IV/orally every 12 hours. Chloramphenicol (25 mg/kg IV/orally every 6 hours) can be used in select circumstances. Antibiotic therapy should be continued for a total of 10 days.

CURRENT THERAPY Prompt administration of gentamicin or ciprofloxacin. Aggressive supportive care. Respiratory isolation of hospitalized cases. Postexposure prophylaxis to close contacts. Prevention and Control Standard infection control procedures that should be used when caring for patients with suspected plague include a disposable surgical mask, latex gloves, devices to protect mucous membranes, and good hand washing. Hospitalized patients with known or suspected pneumonic plague should be placed in strict isolation for at least 48 hours after appropriate antibiotics are initiated. Postexposure prophylaxis should be given to individuals with close contact (defined as less than 2 meters) with an infectious case or who have had a potential respiratory exposure. The recommended adult antibiotics for prophylaxis are doxycycline or ciprofloxacin in the same doses used for treatment. Postexposure prophylaxis can be given orally and should be continued for 7 days following exposure. Currently, there is no licensed plague vaccine.



REFERENCES Butler, 1972. Butler T: A clinical study of bubonic plague. Observations of the 1970 Vietnam epidemic with emphasis on coagulation studies, skin histology and electrocardiograms. Am J Med 1972; 53:268-276. Boulanger et al., 2004. Boulanger LL, Ettestad P, Fogarty JD, et al: Gentamicin and tetracyclines for the treatment of human plague: Review of 75 cases in New Mexico, 1985–1999. Clin Infect Dis 2004; 38:663669. Cler et al., 1997. Cler DJ, Vernaleo JR, Lombardi LJ, et al: Plague pneumonia disease caused by Yersinia pestis. Semin Respir Infect 1997; 12:12-23. Gage et al., 2000. Gage KL, Dennis DT, Orloski KA, et al: Cases of cat-associated human plague in the Western US, 1977–1998. Clin Infect Dis 2000; 30:893-900. Hull et al., 1987. Hull HF, Montes JM, Mann JM: Septicemic plague in New Mexico. J Infect Dis 1987; 155:113-118. Inglesby et al., 2000. Inglesby TV, Dennis DT, Henderson DA, et al: Plague as a biological weapon: Medical and public health management. Working Group on Civilian Biodefense. JAMA 2000; 283:2281-2290. Perry and Fetherston, 1997. Perry RD, Fetherston JD: Yersinia pestis—etiologic agent of plague. Clin Microbiol Rev 1997; 10:35-66. Prentice and Rahalison, 2007. Prentice MB, Rahalison L: Plague. Lancet 2007; 369:1196-1207. Ratsitorahina et al., 2000. Ratsitorahina M, Chanteau S, Rahalison L, et al: Epidemiological and diagnostic aspects of the outbreak of pneumonic plague in Madagascar. Lancet 2000; 355:111-113. Wong et al., 2000. Wong JD, Barash JR, Sandfort RF, Janda JM: Susceptibilities of Yersinia pestis strains to 12 antimicrobial agents. Antimicrob Agents Chemother 2000; 44:1995-1996.



Chapter 32 – Anthrax

Method of: Jon B. Woods, MD Anthrax has been a significant disease for both humans and their livestock for millennia. It was the first disease to fulfill Koch's postulates in 1876, as well as the first bacterial disease for which an effective vaccine was developed, for livestock, in 1880. This gram-positive rod-shaped bacillus species differs from the more benign members of its genera in containing two additional plasmids, one encoding for an antiphagocytic poly-D-glutamic acid capsule and the other encoding for two toxins. Three distinct toxin components combine to form two toxins, edema toxin and lethal toxin; the common component, protective antigen (PA), forms a pore through eukaryotic cell walls that allows the other two toxin components, edema factor (EF) and lethal factor (LF), to enter affected host cells. EF is an adenylate cyclase affecting many cell types and is responsible for the edema associated with anthrax infections. LF is a zinc metalloprotease that seems to have its greatest affect on macrophages; within the cells it cleaves mitogen-activated protein kinase and disrupts the cellular response to infection. Background Anthrax is an enzootic, and occasionally epizootic, disease of grazing animals worldwide. The incredibly durable spores of this bacillus can persist in soil for decades. These spores, when inadvertently ingested by herbivores while grazing, can germinate and then replicate in a rapid progression to bacteremia and subsequent death of the animal. At the time of death these animals can have as many as 108 vegetative bacilli per milliliter of blood. Those bacilli, which are exposed to oxygen upon the animal's death, can sporulate and then reenter the soil to begin the cycle anew. Human anthrax can take several forms, most commonly cutaneous, but also intestinal, oropharyngeal, and inhalational disease. Naturally occurring human anthrax disease has typically been the result of exposure to infected animals or contaminated animal products such as hair or wool, bone meal, hides, or meat. Less commonly, human cutaneous anthrax has resulted from the bites of flies that have recently fed on infected animals. Gastrointestinal and oropharyngeal anthrax can result from ingestion of the raw or inadequately cooked flesh of an animal infected with anthrax. Endemic inhalational anthrax, or woolsorter's disease, results from inhalation of anthrax spores aerosolized during the manipulation of contaminated animal products, especially hair or wool; this was an exceedingly rare form of disease even prior to the institution of more stringent control measures and closure of most of the U.S. textile mills processing foreign-acquired goat hair by the 1970s. More recently, inhalational anthrax and cutaneous cases have resulted from exposure to spores intentionally processed and disseminated as biologic weapons. The extreme environmental stability of the spores, their ease of production, and their infectivity via the aerosol route are some features that have made Bacillus anthracis a top candidate for both nations and terrorists seeking biologic weapons. An apparently accidental aerosol release of dried anthrax spores from a biologic weapons facility in the Soviet city of Sverdlovsk in 1979 resulted in as many as 68 deaths because of inhalational anthrax. More recently, anthrax spores intentionally sent through the U.S. postal system resulted in 11 cases of inhalational anthrax and perhaps as many as 11 cases of cutaneous anthrax.

Clinical Features Cutaneous anthrax represents approximately 95% of naturally occurring human anthrax cases. It typically occurs 1 to 7 days after exposure to infected livestock or contaminated livestock products, but rarely it is transmitted to humans by the bites of flies that have recently fed on infected animals. The lesion begins as a painless or mildly pruritic papule at the site of spore inoculation, progressing into an expanding round ulcer by the following day. Over the following several days the ulcer dries to a dark, almost black eschar, which resolves over the ensuing 1 to 2 weeks. The lesion can be surrounded by significant local edema and may be accompanied by regional lymphadenopathy. Treated, cutaneous anthrax is rarely fatal, although without antibiotics, progression to bacteremia and ultimately death can occur in up to 10% to 20% of cases. Both forms of gastrointestinal anthrax are acquired via ingestion of insufficiently cooked meat from infected animals. The infectious dose is unknown. Intestinal anthrax may be initially misdiagnosed as either gastroenteritis or acute abdomen, typically presenting 1 to 6 days following contaminated meat consumption with fever, nausea, vomiting, and focal abdominal pain. Without prompt initiation of antibiotic therapy, disease can progress to hematemesis, hematochezia or melena, massive serosanguineous or hemorrhagic ascites, and sepsis, with mortality rates greater than 50%. Oropharyngeal anthrax typically presents after a 1- to 6-day incubation period with severe pharyngitis and fever, followed by appearance of pharyngeal or tonsillar ulcers. Gray or tan pseudomembranes can form over the ulcers, which are often accompanied by significant cervical lymphadenopathy and unilateral neck edema. Mortality of oropharyngeal anthrax varies from 10% to 50%. Inhalation of aerosolized anthrax spores into the pulmonary alveoli can result in inhalational anthrax. The lethal dose via inhalation for 50% of humans (LD50) is thought to be between 8000 and 55,000 spores. The alveolar spores are ingested by macrophages and carried to regional lymphatics, where they can germinate and replicate, eventually leading to hemorrhagic mediastinitis. The incubation period is presumably dose dependent, and although typically 1 to 6 days was suspected in at least one human case to be 43 days. Early inhalational anthrax presents suddenly as a nonspecific syndrome consisting of fever, malaise, headache, fatigue, and drenching sweats. Other common symptoms include nausea, vomiting, confusion, a nonproductive cough, and mild chest discomfort. Upper respiratory symptoms are notably absent. Physical findings are nonspecific in the early phase of the disease, but tachycardia is common. Auscultatory lung exam is typically normal at this stage, but dullness to percussion can develop over time in the lower lung fields as hemorrhagic pleural effusions accumulate. These early findings generally persist for 2 to 5 days before progressing fulminantly to tachypnea, cyanosis, shock, and multiorgan system failure. These late findings typically herald impending death within 24 to 36 hours. Gastrointestinal hemorrhage and hemorrhagic meningitis are common at autopsy. Prognosis is poor in the absence of intensive supportive care and early initiation of appropriate antibiotic combinations. Mortality ranges from 45% to more than 85% historically. Diagnosis None of the forms of human anthrax disease can be diagnosed on the basis of clinical findings alone ( Table 1 ). For example, diagnosis ofcutaneous anthrax requires the presence of a compatible skin lesion accompanied by confirmatory laboratory studies; an exposure history, or a known risk may also be present. Both forms of gastrointestinal anthrax are typically accompanied by a history of ingestion of the meat of anthrax-infected animals. Early intestinal anthrax can be difficult to differentiate clinically from other causes

of gastrointestinal illness to include acute gastroenteritis, dysentery, or even peritonitis. Later in the course of intestinal disease, surgical or autopsy findings may include ileal or cecal ulceration, and bowel edema and necrosis is associated with hemorrhagic mesenteric adenitis and serosanguineous to hemorrhagic ascites. Oropharyngeal anthrax can clinically resemble diphtheria, with pharyngeal lesions and an edematous socalled bull neck. Early inhalational anthrax is a nonspecific febrile syndrome that may be difficult to distinguish clinically from many other infectious diseases. However, the presence of mental status changes, profuse sweating, and absence of upper respiratory symptoms or pneumonia in inhalational anthrax may aid in differentiating it from influenza-like respiratory illnesses.

TABLE 1 -- Empirical Antibiotic Therapy for Anthrax[*] Cutaneous Anthrax (without Systemic Inhalational, Gastrointestinal, or Cutaneous Disease with Symptoms) Systemic Symptoms Ciprofloxacin (Cipro[1]) •

500 mg PO twice daily (adults)

•

15 mg/kg (up to 500 mg/dose) PO twice daily (children)

or

Ciprofloxacin (Cipro IV[1]) 400 mg IV q12h (adult)

•

15 mg/kg/dose (up to 400 mg/dose) q12h (children)

or Doxycycline (Vibramycin) •

100 mg PO twice daily (adults)

•

2.2 mg/kg (up to 100 mg/dose) PO bid (children 8 y and >45 kg

•

2.2 mg/kg PO bid (up to 200 mg/d) for children 38.3°C), maculopapular rash (= 3 d), and at least one of the symptoms of cough, coryza, or conjunctivitis. Laboratory confirmation is based on measlesspecific IgM by enzyme-linked immunosorbent assay (ELISA), detected from onset of rash until weeks later. When IgM and IgG are negative early after onset of rash, repeat testing is warranted. The diagnosis can also be confirmed by an increase in measles-specific IgG between paired sera, detection of viral RNA by reverse-transcriptase polymerase chain reaction (RT-PCR), or virus isolation. Nasopharyngeal swabs, oral fluid, peripheral blood mononuclear cells (PBMCs), and the cellular fraction of urine are appropriate specimens for measles RT-PCR and virus isolation, as well as for genotyping of the virus in specialized laboratories. In most countries, confirmed or even suspected cases must be reported to the national health authorities.

CURRENT DIAGNOSIS Fever (>38.3°C) and maculopapular rash (=3 d) in association with cough, conjunctivitis, or coryza or some combination of these (CDC clinical case definition) Pathognomonic Koplik's spots on the buccal mucosa Detection of measles-specific IgM or increase in measles-specific IgG in paired sera Detection of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR) in nasopharyngeal swabs, oral fluid, urine, peripheral blood mononuclear cells (PBMCs), (or dried blood spots) with or without virus isolation Treatment There is no specific treatment for acute measles. Supportive therapy includes hydration, antipyretics, bedrest, and protection from light for patients with photophobia. Secondary bacterial infections are treated with antibiotics. Vitamin A supplementation[1] has been shown to improve the clinical outcome in malnourished patients and patients with vitamin A deficiency. Ribavirin (Virazole) [1] and isoprinosin,[2] combined with interferon-a (IFN-a), have been used with limited success in experimental treatments of SSPE.

1 Not FDA approved for this indication. 2 Not available in the United States.

Prevention Measles virus has only one serotype, and current live-attenuated vaccines are effective against all of the 23 known genotypes. Vaccination induces long-lasting protection against the disease even after a single dose. Transplacentally acquired maternal antibodies and immaturity of the infant immune system interfere with seroconversion rates, which, after the first dose, range between 80% and 95% depending on the age of the vaccinee. Improper handling of the vaccine can be another reason for primary vaccine failures. Therefore, two-dose vaccination programs are necessary to achieve a population immunity greater than 95%, which is necessary to interrupt virus circulation.

CURRENT THERAPY Treatment

There is no specific therapy for treating acute measles. Patient care is limited to supportive therapy. Secondary bacterial infections are treated with antibiotics. Vitamin A supplementation [1] might improve the clinical outcome. Supportive Therapy

Hydration Antipyretics Rest Protection from light Vitamin A[1] Treatment for secondary bacterial infections Measles vaccination is recommended in virtually all countries, but immunization schedules depend on the specific epidemiologic situation of each country. Many industrialized countries use measles-mumps-rubella (MMR) combined vaccines, with a first dose given at 12 to 15 months of age and a second dose at 3 to 6 years of age to catch up children with primary or secondary vaccine failure after the first dose. In many developing countries with large birth cohorts and a higher measles incidence, monovalent measles vaccines (Attenuvax) are administered at 6 to 9 months of age to offset the higher risk of early exposure to wild-type virus and the earlier loss of maternal antibodies. A second dose should be provided as a routine revaccination during early childhood or in follow-up campaigns including broader age groups. Transient fever and rash are observed in 5% to 10% of patients vaccinated with live attenuated strains. Much

publicized links to autism or other chronic diseases have never been confirmed by national or international scientific panels. The vaccine is not recommended for children with primary or acquired severe immunodeficiency, except for children with asymptomatic HIV infection. The disease may be prevented in susceptible persons by hypergammaglobulin given within 6 days or by active immunization within 3 days after exposure. Passive immunization is also recommended in persons with some malignant diseases or deficits in cellular immunity.



REFERENCES Bannister et al., 1996. Bannister BA, Begg NT, Gillespie SH: Childhood Infections: Measles. Infectious Disease, Oxford: Blackwell Science; 1996:256-260. Campbell et al., 2005. Campbell C, Levin S, Humphreys P, et al: Subacute sclerosing panencephalitis: Results of the Canadian Paediatric Surveillance Program and review of the literature. BMC Pediatr 2005; 5:47. Gershon, 1995. Gershon AA: Measles virus. In: Mandell GL, Bennett JE, Dolin R, ed. Principles and Practice of Infectious Diseases, New York: Churchill Livingstone; 1995:1519-1525. Griffin, 2001. Griffin DE: Measles virus. In: Knipe DM, Howley PM, ed. Fields Virology, Philadelphia: Lippincott Williams & Wilkins; 2001:1401-1424. World Health Organization, 2006. World Health Organization : Progress in reducing global measles deaths: 1999-2004. Wkly Epidemiol Rec 2006; 81(10):90-94.



Chapter 41 – Tetanus

Method of: Samuel S. Hsu, MD Tetanus is a toxin-mediated infectious disease that is acquired from wounds and that results in muscular hyperexcitability and autonomic instability. It has a high mortality rate despite optimal treatment. It is best managed by prevention, which is accomplished with a highly effective low-cost vaccine. Victims are typically inadequately immunized. Etiology The causative agent of tetanus is Clostridium tetani, a spore-forming, gram-positive bacillus. The vegetative form is an obligate anaerobe, but the spores remain viable at ambient oxygen concentrations. The spores are ubiquitous in soil, are highly resistant to extremes in temperature and humidity, and can survive indefinitely. When spores enter wounds, they might not germinate immediately if tissue conditions are unfavorable. They can activate well after the wound has healed, which might account for cases of tetanus that have no identifiable source. When conditions are favorable, the spores germinate into mature bacilli, which release the toxin tetanospasmin. Tetanospasmin is responsible for the clinical manifestations of tetanus. It enters peripheral nerves and travels via retrograde axonal transport to the central nervous system. Tetanospasmin then enters presynaptic neurons and disrupts the release of -amino butyric acid (GABA) and glycine, which are inhibitory neurotransmitters. This results in a disinhibition of end-organ neurons, such as motor neurons and those of the autonomic nervous system. Recovery depends on synthesis of new presynaptic components, a process that occurs over 2 to 3 weeks. Epidemiology Most cases occur in developing countries. In 2005, the World Health Organization (WHO) received reports of more than 15,000 cases, two thirds of which occurred in neonates. In contrast, tetanus is a disease of older adults in developed countries. According to the latest data from the Centers for Disease Control and Prevention (CDC), there are an average of 43 cases of tetanus per year in the United States, and the incidence is 0.16 per million population. Even with optimal treatment, the mortality of tetanus is very high. The global fatality rate is estimated to be 30% to 50%. In the United States, the fatality rate ranges from 11% to 25%. Older adults have a higher mortality, 40% in those older than 60 years compared with 8% in those ages 20 to 59 years. Lack of immunization is the greatest risk factor for contracting tetanus. The largest groups with the lowest rates of immunization in the United States are older adults and immigrants from Latin America. Serologic

surveys show that although 95% of those 6 to 39 years old are adequately immunized, only 74% of those older than 60 years and 59% of those older than 70 years are adequately immunized. Only 75% of Latin American immigrants are adequately immunized. The result is a higher incidence of tetanus in these groups: 0.35 per million adults older than 60 years and 0.38 per million Latin Americans. Clinical Features An acute injury precedes most cases of tetanus, the most common being puncture wounds and lacerations. Nonacute etiologies include chronic wounds, IV drug use, and complications of diabetes. Cases have occurred without a clear etiology. The median time between an injury and onset of symptoms is 7 days, but there have been delayed presentations of up to 3 months. A more rapid onset correlates to a more severe clinical presentation. There are four clinical forms of tetanus representing the extent and location of neurons involved: generalized, local, cephalic, and neonatal. In the United States and other developed countries, generalized tetanus is the most common form. The initial symptom in 50% to 75% of cases is trismus (“lockjaw”) secondary to masseter muscle spasm. Risus sardonicus, the “ironical smile of tetanus,” can occur due to facial muscle contraction. Nuchal rigidity and dysphagia can also be initial complaints. As the disease spreads, generalized muscle spasms occur, either spontaneously or to minor stimuli such as touch or noise. Opisthotonos, a tonic contraction very similar to decorticate posturing, is classically described with tetanus. Severe spasms can result in bone fractures, tendon detachments, and rhabdomyolysis. Mental status is not affected, and spasms are experienced with severe pain. In the acute phase, death results from acute respiratory failure due to diaphragmatic paralysis or laryngeal spasms. In severe cases, autonomic instability can occur, resulting most importantly in labile hypertension, tachycardia, and pyrexia. Hypotension and bradycardia can also occur. Arrhythmias and myocardial infarction are the most common fatal events. The exact mechanism of this syndrome is unclear but likely involves disinhibition of the sympathetic nervous system. Local tetanus manifests as persistent muscle rigidity close to a site of injury. The rigidity can linger for weeks to months and often resolves without sequelae. Localized tetanus rarely progresses to generalized tetanus.

CURRENT DIAGNOSIS Tetanus is diagnosed on clinical grounds alone. Involuntary muscle spasms are the hallmark of tetanus. Generalized tetanus is the most common form. Characteristic features include trismus (lockjaw), risus sardonicus, and opisthotonos. Sensory function and mental status are preserved. Mimics of tetanus can be excluded by physical findings and select laboratory tests. Cephalic tetanus is an uncommon variant of localized tetanus that involves the cranial nerves. Cephalic tetanus uniquely results in nerve palsies and muscle spasms. The seventh cranial nerve is most often involved, followed by the sixth, third, fourth, and 12th in decreasing order of frequency. With its predilection for the seventh cranial nerve, it commonly mimics Bell's palsy. Cephalic tetanus also manifests with trismus, but cranial nerve deficits precede the onset of trismus about 40% of the time. Head trauma and otitis media are commonly cited etiologies. About two thirds of cases progress to generalized tetanus. Neonatal tetanus is generalized tetanus that occurs in newborns around the first week of life. Symptoms begin with nonspecific irritability and poor feeding, and they rapidly progress to generalized spasms. The portal of entry is the freshly cut umbilical cord. The risk of contracting neonatal tetanus is directly related to maternal immunization status, because passive transfer of maternal immunoglobulins is protective. Mortality is very high, 50% to 100%, due to the high load of toxin per body weight in neonates. In the United States, there were three reports of neonatal tetanus in the 1990s, all involving inadequately immunized mothers. Diagnosis The diagnosis of tetanus must be made on clinical grounds alone. There are no laboratory tests that can diagnose or exclude tetanus. Wound cultures rarely yield C. tetani and are not available quickly enough to aid diagnosis. Fortunately, the presentation of tetanus is so characteristic that a presumptive diagnosis can be made in most cases. When faced with a potential case of tetanus, it is useful to recall that sensory function and mental status remain normal. The differential diagnosis is minimal. Most possibilities can be excluded by history, examination, and select laboratory tests. Exact mimics of tetanus occur with strychnine poisoning, which disables glycine release as tetanospasmin does, and hypocalcemia. These are easily excluded by laboratory tests. The differential for trismus includes peritonsillar/odontogenic abscesses and dystonic reactions. Cephalic tetanus without trismus can be easily mistaken for Bell's palsy, central nervous system tumor, or stroke. Neonatal tetanus initially manifests much like a host of other disorders. Once generalized spasms begin, the diagnosis is obvious. Apte and Karnad describe a bedside test for tetanus in which a spatula is inserted into the pharynx. If the patient gags and tries to expel the spatula, the test is negative for tetanus; if the patient bites the spatula due to reflex masseter spasm, the test is positive for tetanus. The researchers reported 94% sensitivity and 100% specificity.

Treatment Treatment involves neutralizing tetanospasmin, removing the source of the toxin, and providing supportive care for muscle spasms, respiration, and autonomic instability. Human tetanus immunoglobulin (hTIG, BayTet) 500 IU IM neutralizes circulating tetanospasmin. It cannot inactivate toxin already within neurons. Its half-life is 25 days; only a single dose is necessary. Doses of hTIG up to 10,000 IU have been used, but the lower dose is effective and has the advantage of requiring fewer injections to deliver. This feature is not insignificant, because hTIG is supplied in 250-IU doses, and injections are powerful stimuli for spasms. The adult and pediatric doses are the same. The burden of tetanospasmin, not the patient's size, determines the amount of hTIG needed.

CURRENT THERAPY ACUTE TETANUS

Human tetanus immune globulin (hTIG, BayTet) 500 IU IM neutralizes tetanus toxin. Metronidazole (Flagyl) eliminates reservoirs of Clostridium tetani. Wounds and abscess must be débrided and drained. Benzodiazepines are the drugs of choice to control muscle spasms. In severe cases, paralytics and mechanical ventilation may be required. Tetanus immunization must be initiated because surviving tetanus does not confer immunity. PROPHYLAXIS IN ACUTE WOUNDS

Administer tetanus toxoid (Td) if the last booster was more than 10 y ago in non–tetanus-prone or more than 5 y ago in tetanus-prone wounds. Administer hTIG 250 IU IM if the patient never completed a primary immunization series and has a tetanus-prone wound. Pregnancy is not a contraindication to appropriate use of Td or hTIG. To prevent ongoing production of toxin, antibiotics are needed to eliminate reservoirs of C. tetani. Metronidazole (Flagyl) in standard dose is the drug of choice. Penicillin, the historic drug of choice, does not penetrate devascularized wounds and abscesses well. Penicillin also has GABA-antagonist activity, which can potentiate the effects of tetanospasmin. In addition to antibiotics, obviously dirty wounds, abscesses, or devitalized tissue must be cleaned, drained, or excised to decrease the bacterial load. Benzodiazepines are the drug of choice for muscle spasms because of their GABA-agonist and sedative properties. Daily doses of hundreds or thousands of milligrams have been used to control spasms. For severe cases, paralytics and mechanical ventilation may be needed. Vecuronium (Norcuron)[1] is an ideal agent for immediate and long-term control due to its minimal cardiovascular effects.

Treatment of autonomic instability has been problematic and is the subject of ongoing research. No therapeutic regimen has proved to be universally effective. a-Blockers,[1] ß-blockers,[1] clonidine (Catapres),[1] and magnesium[1] have yielded variable success. Fentanyl (Sublimaze)[1] centrally decreases sympathetic outflow and has produced more consistent control of hypertension and tachycardia. Supportive care includes placing the patient in a quiet, dark environment, minimizing patient manipulation, and treating for complications, most significantly rhabdomyolysis. Importantly, survivors must also receive a tetanus immunization series. The amount of tetanospasmin produced in clinical tetanus is small and partially sequestered in neurons; consequently, an immune response does not occur. Unimmunized survivors of tetanus have become victims a second time. 1 Not FDA approved for this indication.

Prevention Tetanus is preventable with proper use of tetanus toxoid and hTIG. Tetanus toxoid is an inactivated form of tetanospasmin. It is available as a single-antigen tetanus toxoid (TT) and combined with diphtheria and pertussis vaccine. The combination vaccines (e.g., Td for adults) are preferable because concurrent immunization is appropriate. The recommended primary immunization schedule is shown in Table 1 . Adults should receive boosters every 10 years to maintain immunity.

TABLE 1 -- Tetanus Primary Immunization Age Vaccine

No. of Doses Schedule

7 y Td

3

First 2 doses more than 4 wk apart Dose 3 at 6 mo after dose 2

From Immunization Practices Advisory Committee: Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-10):1-28. Abbreviations: DT = diphtheria and tetanus (adult); DTaP = diphtheria and tetanus toxoids and acellular pertussis; Td = diphtheria and tetanus (pediatric).

Common adverse reactions to tetanus toxoid include erythema, swelling, and tenderness at the injection site. Nonspecific systemic effects such as fever, malaise, and anorexia can also occur. Reactions tend to occur more often and more severely if boosters are given more frequently than the recommended schedule. Patients who give a history of “allergy” to tetanus vaccine are most likely referring to a local or nonspecific systemic reaction. These are not contraindications to receiving tetanus toxoid. Other false contraindications include mild, acute illness; fever; and family history of an adverse reaction to vaccination. Anaphylactic reactions, neuropathies, and encephalopathies are rare and constitute the only true contraindications for

giving toxoid. Patients who give a history of anaphylaxis should be referred for skin testing because they might no longer be reactive and can receive future vaccinations. hTIG is derived from human plasma. It is available as 250-IU doses and is approved only for intramuscular use. Intradermal injection cause local irritation due to the concentration of the product and does not represent an allergy to hTIG. Because of this reaction, hTIG should not be infiltrated into the wound. Intravenous injection can cause hypotension. Adverse reactions to properly administered hTIG are rare and consist largely of discomfort at the injection site and slight temperature elevation. In the setting of an acute injury, the CDC recommendations for tetanus prophylaxis depend on the wound characteristics and the patient's immunization history ( Table 2 ). Many acute wounds can be considered not tetanus prone: recent wounds, linear wounds with sharp edges, well-vascularized wounds, and wounds not obviously contaminated or infected. All other wounds are considered tetanus prone, particularly those resulting from blunt trauma and bites and those that are grossly contaminated or infected.

TABLE 2 -- Tetanus Prophylaxis in the Acute Wound Primary Immunization Wound Status Completed or Last Booster Not Completed 5 y

>10 y

Yes

No

No

Yes

Td

Yes

No

Yes

Yes

TIG

Yes

No

No

No

Clean Td[*] Tetanus-prone

Adapted from Immunization Practices Advisory Committee: Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-10):1-28. Abbreviations: DT = diphtheria and tetanus (adult); DTaP = diphtheria and tetanus toxoids and acellular pertussis; Td = diphtheria and tetanus (pediatric); TIG = tetanus immune globulin.

* DTaP or DT for children younger than 7 years.

If the patient has completed primary immunization, a booster is given if the last dose was longer than 5 years ago in a tetanus-prone wound or more than 10 years ago in a non–tetanus-prone wound. Patients with a contraindication to tetanus toxoid must be treated with hTIG alone. If the patient has not completed primary immunization and the wound is tetanus prone, hTIG 250 IU IM is indicated. hTIG should be given at a site contralateral to the tetanus toxoid to prevent interaction between

the two. A tetanus booster is also required, and the patient will need follow-up to complete primary immunization. Due to an aging immune system, in elderly patients tetanus antibodies after vaccination do not form as quickly, do not have as high a peak, and do not persist as long as in younger persons. With low rates of baseline immunity, elderly patients who receive only a tetanus booster can not develop protective levels of antibodies quickly enough in the setting of an acute injury. More liberal use of hTIG in these patients, regardless of primary immunization, may be warranted to ensure protection against tetanus if the last booster was significantly longer than 10 years ago. Td is safe in pregnancy. Generally, routine immunizations are avoided in the first trimester; however there is considerable evidence that Td is not teratogenic. In the setting of acute wounds, Td should not be withheld if indicated. hTIG is also safe in pregnancy. The main risk with donated biological products is infection, not teratogenesis. Other immune globulin products, such as Rh immune globulin (RhoGam), are commonly used during pregnancy without adverse effects.



REFERENCES Ahmadsyah and Salim, 1985. Ahmadsyah I, Salim A: Treatment of tetanus: An open study to compare the efficacy of procaine penicillin and metronidazole. Br J Med (Clin Res Ed) 1985; 291:648-650. American College of Obstetrics and Gynecology, 2003. American College of Obstetrics and Gynecology : Immunization during pregnancy. ACOG Committee Opinion No. 282. Obstet Gynecol 2003; 101:207-212. Apte and Karnad, 1995. Apte NM, Karnad DR: Short report: The spatula test: A simple bedside test to diagnose tetanus. Am J Trop Med Hyg 1995; 53(4):386-387. Bleck and Brauner, 1997. Bleck TP, Brauner JS: Tetanus. In: Scheld WM, Whitely RJ, Durack DT, ed. Infections of the Central Nervous System, 2nd ed.. Philadelphia: Lippincott-Raven; 1997:629-653. Centers for Disease Control, 1991. Centers for Disease Control : Prevention: Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40(RR-10):1-28. Centers for Disease Control and Prevention, 2003. Centers for Disease Control and Prevention : Tetanus surveillance—United States, 1998-2000. MMWR Surveill Summ 2003; 52(SS-3):1-8. Dietz et al., 1997. Dietz V, Galazka A, Loon F, et al: Factors affecting the immunogenicity and potency of tetanus toxoid: Implications for the elimination of neonatal and non-neonatal tetanus as public health problems. Bull World Health Org 1997; 75(1):81-93. Sanford, 1995. Sanford JP: Tetanus—forgotten but not gone. N Engl J Med 1995; 332(12):812-813. Silveira et al., 1995. Silveira CM, Caceres VM, Dutra MG, et al: Safety of tetanus toxoid in pregnant women: A hospital-based case-control study of congenital anomalies. Bull World Health Org 1995; 73:605-608. Talan et al., 2004. Talan D, Abrahamian F, Moran G, et al: Tetanus immunity and physician compliance with tetanus prophylaxis practices among emergency department patients presenting with wounds. Ann Emerg Med 2004; 43(3):305-314.



Chapter 42 – Pertussis

Method of: Michael E. Pichichero , MD Pertussis, or whooping cough, is a highly contagious acute respiratory tract infection caused by Bordetella pertussis . It causes prolonged cough illness, without associated fever, characterized by paroxysms of coughing, inspiratory “whoops,” and post-tussive vomiting in severe cases and persistent intermittent staccato cough episodes in teenagers and adults. The incidence of pertussis is rising in the United States despite record-high vaccination coverage. In 2004, more cases occurred in adolescents and in adults than children. Microbiology and Pathophysiology B. pertussis is a gram-negative coccobacillus that is difficult to grow with standard media. B. pertussis does not invade the human host; bacteremia does not occur. The systemic effects of illness are produced by the organism's toxins, especially pertussis toxin. B. pertussis attaches to the nasopharynx and tracheobronchial tree with adhesins such as fimbriae, filamentous hemagglutinin, and pertactin where it produces toxins such as pertussis toxin, adenylate cyclase toxin, and tracheal cytotoxin that paralyze the respiratory cilia, resulting in inflammation of the respiratory tract. Epidemiology B. pertussis is a human pathogen transmitted from person to person via aerosolized droplets. Pertussis is highly contagious, similar to varicella, infecting 80% to 90% of susceptible contacts. Persons with pertussis are most contagious in the 2 weeks before cough onset and during the first 2 weeks of cough, typically a time frame before medical care is sought or clinicians consider the possibility of the diagnosis. In 2004, approximately 20,000 cases of pertussis were reported to the Centers for Disease Control and Prevention (CDC); because substantial underreporting is a recognized problem, current estimates of true pertussis incidence per year in the United States probably is in the range of 1 to 3 million cases. A new development is the recognition that pertussis is a disease of adolescents and adults as well as children. Several studies showed that among teenagers and adults who seek care for cough illness of more than 1 week duration, approximately 20% have pertussis. Immunity It has been known for decades that immunity to tetanus wanes over time and boosters are needed approximately every 10 years to sustain protective antibody levels. The phenomenon of waning immunity to pertussis is a newer observation and one of the explanations of the rising incidence of pertussis in the United States. Apparently boosters of pertussis vaccines are also needed, perhaps, like tetanus, approximately every 10 years. Two new adolescent/adult pertussis vaccine formulations that are combined with tetanus and diphtheria vaccines (Boostrix, Adacel) were licensed and recommended for universal use in

2005 to address this problem. Clinical Symptoms Classic pertussis is a 30- to 90-day illness that presents in three stages: catarrhal, paroxysmal, and convalescent. The stages may be shorter in immunized children, adolescents, and adults. Pertussis is most severe when it occurs during the first 6 months of life. In the catarrhal stage, nonspecific symptoms similar to the common cold predominate. The paroxysmal stage is characterized by a persistent cough, sometimes with bursts of numerous rapid coughs. A long inspiratory effort sometimes causes a high-pitched whoop. Typically, the patient is afebrile and, between coughing attacks, usually appears normal. The paroxysmal stage usually lasts 6 weeks. The cough gradually lessens over 2 to 3 weeks during the convalescent period. Milder paroxysms may recur with subsequent respiratory infections for many months following a pertussis infection. Infants may appear very ill and distressed during the paroxysmal stage and require close observation and supportive care. Older children, adolescents, and adults have a prolonged cough with paroxysms but no whoop. Complications Complications occur most commonly among young infants with pertussis. The most common complication is secondary bacterial pneumonia. Hypoxia or effects of pertussis toxin may contribute to neurologic complications including seizures and encephalopathy. In the United States, 90% of deaths occur in children younger than 6 months. Complications from pertussis in adolescents and adults are not uncommon ( Table 1 ).

TABLE 1 -- Complications From Pertussis in Adolescents and Adults Paroxysmal cough 100% 85% 87% Whooping 26% 30% 35% Post-tussive emesis 56% 45% 41% Apnea — 19% 37% Cyanosis — 6% 9% Hospitalization

0% 1.4% 3.5% Massachusetts Symptoms/Signs Minnesota Adolescents Adults Diagnosis A clinical diagnosis of pertussis is typically made based on the characteristic cough, although patients are often seen several times before the correct diagnosis is considered. absolute lymphocytosis (>10,000 lymphcytes/mm3 ) may be seen during the late catarrhal and paroxysmal stages but is less common among adults and immunized children. Chest radiographs may show peribronchial consolidation, interstitial edema, or variable atelectasis. The presence of fever and consolidation with pertussis suggests a secondary bacterial pneumonia. CURRENT DIAGNOSIS

An illness marked by a staccato cough lasting >7 d in the absence of fever in an adolescent or adult may be pertussis. Isolation of B. pertussis from a culture of nasal secretions remains the gold standard for laboratory diagnosis. A nasopharyngeal specimen is obtained by inserting a small flexible Dacron or calcium alginate swab through the nose to the posterior nasopharynx (attempting to touch the adenoids) where it is held for a few seconds, perhaps inducing a cough. The specimen is transferred to Bordetella -specific transport media and subsequently plated on Regan-Lowe charcoal agar or Stainer-Scholte agar. Cultures are usually positive if obtained in the catarrhal or early paroxysmal stage of disease. Success in isolating B. pertussis diminishes if patients have received pertussis vaccine or recent antimicrobials or if specimens are obtained beyond the first 2 weeks of cough. Polymerase chain reaction (PCR) is more sensitive among persons with mild or atypical symptoms and those who have received prior antimicrobial therapy. The CDC recommends using PCR as a presumptive assay in conjunction with culture. Direct fluorescent antibody (DFA) testing has a low sensitivity and variable specificity, requiring experienced laboratory personnel for consistent results. DFA testing should only be performed as a adjunct to culture or PCR. Serologic testing methods have recently emerged as a very valuable diagnostic tool. Single samples of 100 µL of blood can be used to measure pertussis antibodies that are compared to age-specific standards to confirm a clinical diagnosis. These methods are not widely available in hospitals or private laboratories, but state laboratories often can provide this testing. Treatment Infants and children with severe cough paroxysms associated with cyanosis or apnea require hospitalization and intensive care. Infants younger than 3 months should be admitted routinely for observation of their paroxysmal episodes, their need for supportive interventions, and their ability to feed appropriately. Continuous monitoring of heart rate, respiratory rate, and oxygen saturation is indicated.

CURRENT THERAPY

Early treatment of pertussis not only eliminates contagion, it also shortens the illness.

Macrolides are the treatment of choice; azithromycin (Zithromax) is preferred for ease of dosing, tolerability, and short duration of treatment. All patients should receive antibiotics. Macrolides are the treatment of choice: erythromycin, clarithromycin (Biaxin),[1 ] azithromycin (Zithromax),[1 ] or telithromycin (Ketek).[1 ] Fluoroquinolones are also effective therapy for pertussis. Trimethoprim-sulfamethoxazole (Bactrim)[1 ] is an alternative choice although less effective. 1 Not FDA approved for this indication.

Prevention Pertussis is a preventable disease by vaccination. Vaccines are available and recommended for universal use in infants, children, adolescents, and selected adult populations (health care workers, adults caring for infants younger than 6 months, and those with chronic respiratory conditions, e.g., chronic obstructive pulmonary disease). Table 2 lists the vaccines licensed in the United States.

TABLE 2 Adults Antigens

PT (µg) 23.4 25 10 8 2.5 FHA (µg) 23.4 25 5 8 5 PRN (µg) —

-- Licensed Vaccines for the Prevention of Pertussis in Infants, Children, Adolescents, and

8 3 2.5 3 FIM 2 + 3 (µg) — — 5 — 5 D (Lf) 6.7 25 15 2.5 2 T (Lf) 5 10 5 5 5 Sanofi Pasteur GlaxoSmithKline Sanofi Pasteur Sanofi Pasteur Indicated Tripedia Infanrix [* ] Daptacel GlaxoSmithKline Adacel infants/children[† infants/children[† infants/children[† Boostrix adults/adolescents[‡ Age ] ] ] ] Group adolescents[‡ ] Abbreviations: D = diphtheria toxoid; FHA = filamentous hemagglutinin; FIM 2 + 3 = fimbrial agglutinogen 2 and 3; PRN = pertactin; PT = pertussis toxoid; T = tetanus toxoid.

* PEDIARIX also contains these DTaP components. † 6 wk to 2 weeks) should be avoided because these drugs can cause rebound hyperemia. For frequent attacks of allergic conjunctivitis (>2 days/mo), a combination drug such as olopatadine (Patanol), consisting of an antihistamine and a mast cell stabilizer, can be used safely up to four times daily[3] for acute exacerbations and twice daily prophylactically. If symptoms remain unresolved, one could try oral antihistamines and combinations of antihistamines and decongestants such as fexofenadine (Allegra), fexofenadine plus pseudoephedrine (Allegra D), loratadine (Claritin), loratadine plus pseudoephedrine (Claritin-D), or cetirizine (Zyrtec). These drugs are best used prophylactically and in combination with artificial tears (due to drying of mucosal surfaces). 3 Exceeds dosage recommended by the manufacturer.

Seasonal and Perennial Allergic Conjunctivitis

Seasonal allergic conjunctivitis, also known as hay fever–type conjunctivitis, is a mild form of ocular allergy commonly associated with rhinitis. It occurs in spring and late summer. It occurs in sensitized persons and is caused by exposure to pollen, grasses, and ragweed. Perennial allergic conjunctivitis is a mild, chronic allergic conjunctivitis related to environmental exposure to year-round allergens such as dust mites and mold. Both seasonal and perennial allergic conjunctivitis demand frequent, active treatment. Olopatadine (Patanol) is the first-line drug of choice. It should be commenced 2 weeks before the onset of symptoms is anticipated and taken two to four[3] times daily. Additionally, artificial tears (used at least four times a day) along with oral antihistamines may be helpful. If failed therapy persists for 2 to 3 weeks, a short two-week course of topical steroids such as prednisolone (Pred Mild), fluorometholone (FML), loteprednol (Lotemax), or rimexolone[1] (Vexol) two to four times per day might slow the immune response. If control is still not obtained, the patient should be referred to an allergist for consideration of immunotherapy. 1 Not FDA approved for this indication.

Atopic and Vernal Keratoconjunctivitis

Atopic keratoconjunctivitis a rare, severe, bilateral chronic allergic eye disease. It primarily affects adults older than 40 years and is slightly more prevalent in men than women. Severe itchiness is characteristic and the eyelids are thickened and eczematous. It is commonly associated with blepharitis and occasionally with cataracts and keratoconus. Vernal keratoconjunctivitis is a severe bilateral allergic eye disease that mainly affects young boys 7 to 10 years old. Patients usually outgrow the disease with the onset of puberty. Exacerbations are common in spring and mainly in warm, dry climates. It is characterized by giant papillae on the upper tarsus, thick mucus discharge, and corneal ulcers. Vernal keratoconjunctivitis is more common in the Mediterranean region, Central America, and South America. First-line treatment in both syndromes comprises punctal plugs, frequent use of artificial tears, and olopatadine. In fact, olopatadine should be used as daily long-term prophylactic therapy. During exacerbations, pulse therapy with topical steroids may be necessary, with close follow-up with an ophthalmologist. For severe cases, topical cyclosporine emulsion (Restasis) can provide excellent therapy. Giant Papillary Conjunctivitis

Giant papillary conjunctivitis (GPC), which might or might not have a true allergic origin, can be described as a reaction to lid movements over foreign materials such as a contact lens, other ocular prosthesis, or exposed suture. As the name suggests, giant papillae characteristically form on the upper tarsus, and the patient complains of a foreign-body sensation. GPC typically occurs in young adults, the same age distribution as contact lens wearers. GPC usually resolves in less than a week if the mechanical stimulus is removed. Old lenses should be thrown out. All lens solutions should be preservative free, and daily disinfection with 3% hydrogen peroxide is recommended. Lenses should be reintroduced approximately 2 to 3 weeks after symptoms resolve. Frequent use of preservative-free artificial tears may be helpful, and topical antihistamines can relieve acute itching. Topical corticosteroids should be considered only in severe cases of GPC. TOXIC CONJUNCTIVITIS Toxic conjunctivitis, although not an ocular allergy, is a direct and destructive reaction to an offending agent, usually a medicine or a preservative. Successful treatment of this condition depends imperatively on removing the offending agent. Diagnosis HISTORY The history should include symptoms and signs and their duration. Are the symptoms and signs potentially related to systemic diseases? Are they unilateral or bilateral? What is the character of the discharge? Determine if the patient has had recent exposure to an infected person, trauma, or contact lens wear. Does the patient have any allergy, asthma, or eczema? What is the patient's use of topical and systemic medications? The history should also include details of any previous episodes of conjunctivitis, previous

ophthalmic surgery, and any prior systemic diseases, as well as information about the patient's smoking habits, occupation and hobbies, travel, and sexual activity. EXAMINATION The initial eye examination should incorporate measurement of visual acuity, external examination, and slitlamp biomicroscopy.

CURRENT DIAGNOSIS History Symptoms and signs Duration Potentially related to systemic diseases Unilateral or bilateral presentation Character of discharge Recent exposure to an infected person Trauma Contact lens wear Allergy, asthma, eczema Use of topical and systemic medications Previous episodes of conjunctivitis Previous ophthalmic surgery Prior systemic diseases Smoking habits, occupation and hobbies, travel, and sexual activity Examination

Measurement of visual acuity External examination Skin Abnormalities of the eyelids and adnexa Signs of regional lymphadenopathy Conjunctiva Slit-lamp biomicroscopy Eyelid margins Eyelashes Lacrimal puncta and canaliculi Tarsal and forniceal conjunctiva Bulbar conjunctiva, limbus Cornea Anterior chamber, iris Dye-staining pattern The external examination should include in particular the skin, any abnormalities of the eyelids and adnexa, any signs of regional lymphadenopathy, and the conjunctiva. The slit-lamp biomicroscopy should include careful evaluation of the eyelid margins, eyelashes, lacrimal puncta and canaliculi, tarsal and forniceal conjunctiva, bulbar conjunctiva and limbus, cornea, anterior chamber and iris, and dye-staining pattern. DIAGNOSTIC TESTS Cultures of the conjunctiva are indicated in all cases of suspected infectious neonatal conjunctivitis and in adults with bacterial conjunctivitis. Smears for cytology and special stains (e.g., Gram, Giemsa) should also be considered in cases of suspected infectious neonatal conjunctivitis and gonococcal conjunctivitis in any age group. Conjunctival biopsy is indicated when diseases such as ocular cicatricial pemphigoid or sebaceous gland carcinoma manifest as conjunctivitis. COUNSELING AND REFERRAL When conjunctivitis is associated with a sexually transmitted disease, patients and their sexual partners should be referred to an appropriate medical specialist. In cases of ophthalmia neonatorum caused by gonorrhea, chlamydia, or herpes simplex virus infection, the infant should be referred to a pediatric specialist. If conjunctivitis appears to be a manifestation of a systemic disease, the patient should be referred for evaluation by an appropriate medical specialist.

CURRENT THERAPY Viral and bacterial conjunctivitis are highly contagious, and patients should be warned to avoid contact with family members. Frequent hand washing should be encouraged. Viral conjunctivitis should be treated conservatively with artificial tears and warm compresses. Bacterial conjunctivitis should be treated with fluoroquinolone drops as the first line. Gonococcal infections should be treated as an emergency with both topical and systemic antibiotics. Allergic conjunctivitis is best treated by avoiding the allergen where possible and with antihistamine, mast cell stabilizers, and a short course of steroids. Contact lens wearers who develop red eye should be advised to stop wearing the lens and referred immediately to an ophthalmologist. Any patient with decreasing vision, increasing pain, and purulent discharge should be referred to an ophthalmologist. An evaluation of conjunctivitis warrants prompt referral to an ophthalmologist in the following scenarios: •

Vision loss

•

Moderate or severe pain

•

Severe, purulent discharge

•

Corneal involvement

•

Conjunctival scarring

•

Lack of response to therapy

•

Recurrent episodes

•

History of herpes simplex virus (HSV) eye disease.

Treatment Viral and bacterial conjunctivitis are highly contagious, and patients should be warned to avoid contact with family members. Frequent hand washing should be encouraged. Viral conjunctivitis should be treated conservatively with artificial tears and warm compresses. Bacterial conjunctivitis should be treated with fluoroquinolone drops as the first line. Gonococcal infections should be treated as an emergency with both topical and systemic antibiotics. Allergic conjunctivitis is best treated by avoiding the allergen where possible and with antihistamine, mast cell stabilizers, and a short course of steroids. Contact lens wearers who develop red eye should be advised to stop wearing the lens and referred

immediately to an ophthalmologist. Any patient with decreasing vision, increasing pain, and purulent discharge should be referred to an ophthalmologist.



REFERENCES Frackler, 2005. Frackler CR: Chlamydia trachomatis infections in the newborn, 2005. Available at UpToDate website (subscription with password required). Garcia-Ferrer et al., 2004. Garcia-Ferrer FJ, Schwab IR, Shetler DJ: Conjunctiva. In: RiordanEva P, Whitcher JP, ed. Vaughan & Asbury's General Ophthalmology, 16th ed.. New York: McGrawHill; 2004:100-128. Maw and Reza Dana, 2005. Maw R, Reza Dana M: Allergic eye disease, 2005. Available at UpToDate website (subscription with password required). Schachter and Grossman, 2001. Schachter J, Grossman M: Chlamydia. In: Remington JS, Klein JO, ed. Infectious Diseases of the Fetus and Newborn, 5th ed.. Philadelphia: WB Saunders; 2001:769-778.



Chapter 53 – Optic Neuritis

Method of: Andrew G. Lee, MD Steven L. Galetta, MD Optic neuritis (ON) is the most common cause of acute loss of vision caused by an optic neuropathy in a young adult. In this chapter we use the term ON to refer to cases that are idiopathic or demyelinating. Clinical Features of Demyelinating Optic Neuritis The typical patient with ON is a young adult woman presenting with acute, unilateral visual loss associated with pain worsened by eye movement. ON can occur in patients of any age and in either gender, however. The examination shows variable loss of visual acuity (20/20 to no light perception), visual field, or color vision, and an ipsilateral relative afferent pupillary defect (RAPD). The optic nerve typically appears normal at onset (i.e., retrobulbar optic neuropathy) but may be swollen (i.e., papillitis). Optic atrophy may develop over time in a sector or diffuse pattern. In cases with papillitis, the disc edema is typically mild. The presence of retinal hemorrhages, exudates, or cotton wool patches should suggest an alternative optic neuropathy (e.g., anterior ischemic optic neuropathy, inflammatory or infiltrative optic neuropathy). The Optic Neuritis Treatment Trial (ONTT) was a randomized, controlled clinical trial in the United States that has provided excellent clinical information on ON. Table 1 summarizes the typical features, and Table 2 summarizes the atypical features of ON. Table 3 summarizes the recommendations for ON.

TABLE 1 -- Features of Typical Optic Neuritis in Adults Acute to subacute onset Usually unilateral loss of visual acuity, contrast, color, or visual field An ipsilateral relative afferent pupillary defect (RAPD) Periocular pain (90%), especially with eye movement Normal (65%) or swollen (35%) optic nerve head A young adult patient (usually 50 y Diagnosis or evidence of other systemic conditions other than multiple sclerosis that might cause an optic neuropathy Extremely steroid-sensitive or steroid-dependent optic neuropathy No light perception vision All patients in the Optic Neuritis Treatment Trial (ONTT) underwent brain MR scan, laboratory testing (e.g., antinuclear antibody (ANA) for systemic lupus erythematosus, serologic testing for syphilis), and a chest radiograph for sarcoidosis. A lumbar puncture however was optional. None of the laboratory testing proved to be helpful in the diagnosis of ON in typical cases. The lumbar puncture only showed demyelinating disease in cases where the cerebrospinal fluid was abnormal. The cranial MR scan however is a powerful predictor for the development of demyelinating disease. Treatment of Optic Neuritis In the ONTT, there were three treatment groups: oral prednisone, intravenous (IV) methylprednisolone followed by oral prednisone, and oral placebo. The final visual outcome was the same in all of the treatment groups, although IV steroids sped the rate of visual recovery. Oral steroids alone, however, at least in conventional doses, increased the rate of new attacks and therefore are not currently recommended in conventional doses for ON. The Controlled High-Risk Subject Avonex Multiple Sclerosis Prevention Study The Controlled High-Risk Subject Avonex (i.e., interferon ß-1a) Multiple Sclerosis Prevention Study (CHAMPS) was a randomized, double-blind, placebo-controlled, clinical trial (n = 383). All patients had an acute clinical demyelinating event (e.g., ON) and demyelinating white matter lesions on brain MR scan. All patients received IV methylprednisolone followed by treatment in one of two treatment arms: weekly intramuscular (IM) injections of 30 µ g of IFN ß-1a (n = 193) and placebo (n = 190). The treatment group had a 44% reduction in the rate of clinically definite MS after 3 years compared to placebo (p = 0.002); a relative reduction in the volume of brain lesions (p < 0.001); fewer new or enlarging MR lesions (p < 0.001); and fewer gadolinium-enhancing lesions (p < 0.001). The Early Treatment of Multiple Sclerosis (ETOMS) study was a randomized, placebo-controlled trial (n = 308) of interferon ß-1a (Rebif) 22 g subcutaneously weekly. As in CHAMPS, patients had an initial demyelinating event and demyelinating lesions on MRI. There was a decreased rate of progression to

clinically definite MS and a reduction in MRI abnormalities in the treatment group. Treatment with interferon ß-1b also delays the onset of definite MS in patients with clinically isolated neurologic syndromes.

* Anterior uveitis, pars planitis, and retinal periphlebitis may be seen in optic neuritis associated with multiple sclerosis but should be considered as unusual findings Modified with permission from Lee AG, Brazis PW: Clinical Pathways in Neuro-ophthalmology: An Evidencebased Approach, 2nd ed. New York, Thieme, 2003.

TABLE 3 -- Summary of Recommendations for Optic Neuritis Cranial MRI scan should be strongly considered for all patients with ON. The cranial MR scan is the most powerful predictor for clinically definite MS. Even a single attack of ON is a risk factor for developing clinically definite MS. Neurologic consultation should be considered to discuss the risks of MS and the options for treatment (e.g., interferon ß-1a or 1b). Abbreviations: MRI = magnetic resonance imaging; MS = multiple sclerosis; ON = optic neuritis.

Clinical Course The majority (95%) of cases of ON recover vision (20/40 or better). Recurrence of ON is seen in up to 19% of patients in the affected eye and 17% in the fellow eye over a 10-year period. Patients with ON are at risk for the development of multiple sclerosis (MS), and that risk may be predicted by the findings on brain magnetic resonance imaging (MRI). Those patients with white matter lesions typical of demyelinating disease on a baseline MRI have a 56% chance of developing clinically definite MS, whereas those with a normal scan have a 22% chance over a 10-year period.

CURRENT DIAGNOSIS Young (15 mm Hg while taking steroids; therefore, patients with known glaucoma on long-term steroids (>1 month) need close follow-up with an ophthalmologist. Primary angle-closure glaucoma has an acute onset with pain, haloes, red eye, decreased vision, and nausea and/or vomiting. Emergent ophthalmologic referral is required. Abbreviations: IOP = intraocular pressure; POAG = primary open-angle glaucoma.

Diseases such as diabetes mellitus, systemic hypertension, and vasospastic disorders have been associated with glaucoma but are not clearly linked to the disease. Increasing age is a risk factor, because 8% of the population older than 70 years old and only 0.1% of those younger than 40 years of age are affected. African American patients have a 5 to 15 times greater risk than white patients. Immediate family members of glaucoma patients have a 10- to 15-fold increased risk for developing glaucoma. The prolonged asymptomatic phase of POAG can only be discovered by ocular evaluation. Complete eye examination is recommended every 2 to 4 years for patients older than 40 years of age and every 1 to 2 years for those older than 65 years. Patients with risk factors (age, race, family history) should be evaluated earlier and more frequently. Screening in the primary care setting can include a family and medical history, vision (and possibly IOP) screening, and examination of the optic nerve head by direct ophthalmoscopy. Clinical findings may be subtle. Visual acuity is often normal, and decreased central vision secondary to glaucoma suggests advanced disease. Normal confrontation fields do not exclude glaucoma because this examination technique has a very low yield in identifying glaucomatous visual field loss. Formal visual field testing is preferred. Although not diagnostic, intraocular pressure greater than 21 mm Hg warrants thorough evaluation. Dilated fundus examination shows enlarged cupping of the optic nerve head and/or asymmetry between the optic nerves. Focal loss of neural rim tissue (notching) may occur, and flame hemorrhages may be seen at the disc margin, especially in actively progressing disease. If glaucoma is suspected, a patient should be referred for further ophthalmologic evaluation. Patients with suggestive findings but no definitive glaucomatous damage are classified as glaucoma suspects. The Ocular Hypertension Treatment Study, a recent multicenter randomized, controlled clinical trial, conducted a long-term follow-up of glaucoma suspects with elevated IOP, normal optic nerve appearance, and no visual field defects. This study found that over 5 years, maintaining IOP 20% below baseline reduced the rate of progression to POAG from 9.5% to 4.4%.

SECONDARY OPEN-ANGLE GLAUCOMA Secondary open-angle glaucomas result from increased resistance to outflow through the trabecular meshwork because of a preexisting or underlying condition. Examples include pigmentary, pseudoexfoliative, traumatic, and steroid-induced glaucoma. In pigment dispersion syndrome and pseudoexfoliation syndrome, deposition of iris pigment and fibrillar protein, respectively, in the trabecular meshwork may obstruct aqueous outflow and secondarily elevate IOP, leading to glaucoma. Blunt ocular trauma (often remote) is a common cause of unilateral glaucoma because of structural changes in the trabecular meshwork. Chronic use of glucocorticosteroids can create resistance to trabecular outflow and IOP elevation, resulting in a glaucoma resembling POAG. Steroid-induced pressure elevation generally correlates with the dose and length of administration. Although most often seen with topical and periocular use, it can also result from systemic or inhaled administration. Steroid responses of greater than 15 mm Hg IOP elevation can develop in 95% of patients with POAG and in only 15% of patients without glaucoma. All patients with a known diagnosis of glaucoma should be evaluated by an ophthalmologist within 1 month of initiating a long-term steroid regimen for systemic diseases. PRIMARY ANGLE-CLOSURE GLAUCOMA Primary angle-closure glaucoma can have an acute, subacute, intermittent, or chronic presentation. Attacks of acute angle closure are ocular emergencies, because irreversible vision loss can occur within hours. Those at risk have an anatomic predisposition with narrow anterior chamber angles. If the pupillary margin of the iris contacts the lens for 360 degrees, which may occur in susceptible eyes when the iris is middilated, flow of the aqueous humor from the posterior to the anterior chamber is blocked. The peripheral iris bows anteriorly and apposes the trabecular meshwork, obstructing outflow. The IOP may rise rapidly to greater than 60 mm Hg. In Asian populations primary angle-closure glaucoma is more common than open-angle glaucoma. The risk increases with age, with most cases occurring during the sixth and seventh decades. Women have primary angle-closure glaucoma attacks 2 to 4 times as often as men. Environmental circumstances may trigger an acute attack of angle closure in predisposed eyes; these include movie theaters or dark rooms (physiologic mydriasis), sudden anxiety or pain (sympathetic stimulation causing pupil dilation), or medications causing mild mydriasis (anticholinergics and adrenergic stimulants such as sleep and cold medications). The diagnosis of an acute angle-closure glaucoma attack requires gonioscopic evidence of a closed anterior chamber angle preventing aqueous flow into the trabecular meshwork. Patients may complain of ocular pain, brow ache, rainbow-colored halos around lights, and/or blurred vision. They may experience intense nausea and vomiting, bradycardia, and sweating. Ocular exam reveals elevated IOP, conjunctival vascular injection, a cloudy cornea (if IOP rose acutely and recently), a shallow anterior chamber, a closed angle by gonioscopy, and a globe, which is firm to palpation. SECONDARY ANGLE-CLOSURE GLAUCOMA

Scarring and adhesions between the peripheral iris and the anterior chamber angle may block outflow of aqueous. Diabetes mellitus may result in neovascularization of the retina, which can progress to neovascularization of the anterior segment including the iris and angle, blocking aqueous outflow and/or closing the angle. The resultant neovascular glaucoma can be devastating and refractory to treatment. Central retinal vein occlusion, a vascular accident closely linked to uncontrolled hypertension and diabetes, can also lead to retinal neovascularization and a similar process. Uveitis from systemic diseases such as sarcoidosis or autoimmune arthropathies can produce intraocular scarring and secondary angle closure if not controlled. Sulfonamide-based systemic medications can rarely cause swelling of the ciliary body, which anteriorly displaces the lens and iris. This can produce a secondary acute angle-closure glaucoma, which requires discontinuation of the medication and urgent lowering of the IOP. This phenomenon has also been reported with topiramate (Topamax).

CURRENT THERAPY Although POAG is typically treated first medically, in select circumstances laser and incisional surgery may be appropriate first-line interventions. Glaucoma medications lower IOP by either decreasing production of aqueous humor or increasing its outflow. Topical ß-blockers have been the traditional primary medical therapy for POAG, but prostaglandin analogues are now emerging as the first-line choice. Laser trabeculoplasty increases aqueous outflow through the trabecular meshwork. Incisional filtering surgery creates a new outflow drain, which bypasses the dysfunctional trabecular meshwork. Primary angle closure attacks require emergent treatment both medically and with laser iridotomy. Secondary angle closure glaucoma may be difficult to manage medically and often requires surgery. Abbreviations: IOP = intraocular pressure; POAG = primary open-angle glaucoma. CHILDHOOD GLAUCOMA Congenital or childhood glaucoma develops from aqueous outflow obstruction because of abnormal anatomical development of the angle, ocular inflammation, or trauma. Primary congenital glaucoma often presents in infancy with the classic triad of photophobia, epiphora (tearing), and blepharospasm, but these signs are unnecessary for diagnosis. Buphthalmos (enlarged eye) may occur secondary to increased IOP if the glaucoma develops during the first 3 years of life. Juvenile glaucoma is similar in etiology to POAG and has been linked to several specific genetic loci. Enlargement of the cornea and sclera is not seen in this subtype. Treatment

The Glaucoma Preferred Practice Pattern Committee of the American Academy of Ophthalmology suggests a target of 20% to 30% reduction of IOP from the untreated levels. Medical treatment is usually attempted first. Parameters that factor into selection of medications include efficacy in lowering IOP, systemic and localized side effect profiles, ease of compliance, and cost ( Table 1 ). Noncompliance with treatment regimens may be responsible for 10% of visual loss in glaucoma; and in one study, approximately 60% of patients failed to use eyedrops as prescribed. If medications fail to control IOP, changes in optic nerve structure and visual field function may occur. Surgical treatment may become necessary to slow the progression of glaucomatous damage.

TABLE 1 Topical Medications

Efficacy Local Side Effects Systemic Side Effects Dosing

Cost

Prostaglandin analogues

+++

++

none to +

Once daily + + +

ß-Blockers

+++

+

+++

bid

+ +[*]

a2 Agonists

++

++

++

bid–tid

+ + +[*]

Carbonic anhydrase inhibitors + +

++

+ to + +

bid–tid

+ + +[†]

+++ = high ++ = moderate + = low

* = generic available † = systemic form less costly

PROSTAGLANDIN ANALOGUES This newest class of antiglaucoma agents has become a popular initial medical treatment because of the efficacy and lack of major systemic side effects. These medications reduce IOP by increasing aqueous humor outflow. Latanoprost (Xalatan), bimatoprost (Lumigan), and travoprost (Travatan) require only once daily dosing, whereas unoprostone (Rescula) is administered twice daily. Side effects include conjunctival hyperemia during the first several weeks of therapy, eyelash lengthening and thickening, occasional iris and periocular skin hyperpigmentation, and rarely, exacerbation of ocular inflammation. BETA-ADRENERGIC ANTAGONISTS Beta-adrenergic antagonists lower IOP by decreasing the production of aqueous humor. They are very effective at lowering IOP and include timolol (Timoptic, Betimol, Istalol), carteolol (Ocupress), metipranolol (OptiPranolol), and levobunolol (Betagan). Topical formulations may be absorbed into the bloodstream, and potential side effects are similar to systemic ß-blockers, including exacerbation of chronic obstructive or reactive pulmonary disease, worsening of heart block or heart failure, bradycardia, systemic hypotension,

mood effects/altered mental status, decreased libido, and masking of hypoglycemic symptoms in diabetic patients. Care should be taken in patients already taking systemic ß-blockers, because additive side effects may develop. Betaxolol (Betoptic) is a selective ß1 antagonist, which may minimize the pulmonary side effects, but still must be used cautiously in patients suffering from asthma or COPD. Topical ß-blockers are dosed once or twice daily, depending on the formulation of the eyedrop. a2 AGONISTS a2 Adrenergic agonists such as apraclonidine (Iopidine) and brimonidine (Alphagan) lower IOP by decreasing aqueous humor production. They are dosed 2 to 3 times daily. Major systemic side effects include somnolence and dry mouth. These medications should be used cautiously in infants and young children because of the risk of respiratory depression. a2 Agonists are contraindicated in patients taking monoamine oxidase (MAO) inhibitors because of potential systemic hypertension. Ocular side effects include allergic follicular conjunctivitis, which may necessitate discontinuation. CARBONIC ANHYDRASE INHIBITORS Carbonic anhydrase inhibitors decrease production of aqueous humor. Systemic carbonic anhydrase inhibitors such as acetazolamide (Diamox) and methazolamide (Neptazane) have been used to treat glaucoma for decades, but up to 60% of patients are intolerant of the side effects. These include metallic taste alteration, loss of appetite, fatigue, confusion, nausea and vomiting, paresthesias, polyuria, urolithiasis, and hearing dysfunction or tinnitus. Rare side effects include Stevens-Johnson syndrome (in patients with sulfonamide allergies) and idiosyncratic aplastic anemia. Oral agents may also lower serum potassium levels, and patients on diuretics or digoxin should be monitored closely. Dorzolamide (Trusopt) and brinzolamide (Azopt) are topical preparations of carbonic anhydrase inhibitors dosed 2 to 3 times daily. Systemic side effects are minimized, but ocular stinging, localized allergic responses, and metallic taste alteration may occur. Systemic carbonic anhydrase inhibitors are more efficacious, but the improved tolerability of the topical agents has made them popular. NONSPECIFIC SYMPATHOMIMETICS AND PARASYMPATHOMIMETICS Nonspecific sympathomimetic and parasympathomimetic drugs have historically been used for the treatment of glaucoma, but with the newer agents available these are no longer commonly prescribed. The mechanism for both classes involves increasing aqueous humor outflow. The sympathomimetic agents include epinephrine (Epifrin) and dipivefrin (Propine). Potential adverse effects include systemic hypertension, headache, cardiac arrhythmias including premature ventricular contractions and tachycardia, and anorexia. Parasympathomimetic medications such as pilocarpine (Pilocar) can cause gastrointestinal cramping, diarrhea, vomiting, syncope, hypotension, increased sweating, and pupillary constriction. ACUTE ANGLE CLOSURE Acute angle closure patients require emergent ophthalmologic referral and treatment to prevent severe permanent sequelae. If this is not immediately possible, treatment should be initiated promptly with a topical ß-blocker and a topical a2 agonist every 30 minutes and a single dose of oral acetazolamide (Diamox) (250 mg × 2 tablets). Oral glycerin (Osmoglyn) or intravenous mannitol (Osmitrol) (1.0 to 1.5 g/kg) may be used if necessary. Pilocarpine should be used cautiously because it may worsen underlying inflammation. Once the attack has been broken medically, the corneal edema will clear and a laser peripheral iridotomy can be

made to prevent future attacks. This opening in the peripheral iris allows aqueous flow to bypass any obstruction caused by pupillary block. Prophylactic iridotomy of the other eye is recommended if anatomically at risk. The management of chronic angle-closure glaucoma is generally similar to that for POAG. LASER Laser may also be used to treat open-angle glaucomas. Argon laser trabeculoplasty (ALT) or the newer selective laser trabeculoplasty (SLT) lowers IOP by facilitating aqueous outflow. For pigmentary, pseudoexfoliative, and select POAG patients, this may be an effective adjunct to medical therapy. SURGERY Surgical measures to control glaucoma include filtering procedures such as trabeculectomy or aqueous shunt placement, which increase aqueous outflow by creating alternative filtration pathways. After trabeculectomy, patients are warned of an increased lifetime risk for serious ocular infection and must report to an ophthalmologist immediately for any changes, including redness, pain, and/or decrease in vision. For poor surgical candidates with severely advanced disease, cyclodestructive procedures can be performed in the office to decrease aqueous production by ablating the ciliary body. If glaucomatous damage has left an eye with no vision, the only reason to treat IOP is to control pain. In most cases, topical agents will suffice. If pain becomes frequent and severe, injections of retrobulbar absolute alcohol or even enucleation of the blind, painful eye may be offered.



REFERENCES Allingham, 2005. Allingham RR: Shields' Textbook of Glaucoma, 5th ed.. Philadelphia, Lippincott Williams & Wilkins, 2005. American Academy of Ophthalmology Online, 2003. American Academy of Ophthalmology Online : Preferred practice patterns: Primary angle Closure glaucoma, primary open angle glaucoma, primary open angle glaucoma suspect 2003. Available at http://www.aao.org/ Kass et al., 2002. Kass MA, Heuer DK, Higginbotham EJ, et al: The ocular hypertension treatment study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120:701-713. Morrison and Pollack, 2003. Morrison JC, Pollack IP: Glaucoma: Science and Practice, New York, Thieme, 2003. Tsai and Forbes, 2004. Tsai JC, Forbes M: Medical Management of Glaucoma, 2nd ed.. West Islip, NY, Professional Communications, 2004.



Chapter 55 – Otitis Externa

Method of: Jeffrey T. Vrabec, MD Otitis externa is defined as an acute infection originating in or limited to the external auditory canal. This common affliction may occur in any age group and may be caused by a variety of infectious agents. Anatomy and Physiology Functionally, the ear canal serves two purposes. It is important for sound localization and because of resonance effects it improves sound perception in the frequency range from 2500 to 4000 hertz (Hz). The ear canal is approximately 25 mm in length and has a diameter of approximately 7.5 mm. The medial half is an osseous channel formed by the merger of the tympanic bone with the mastoid posteriorly and the squamous portion of the temporal bone superiorly. The lateral half of the canal wall is cartilaginous with a thick squamous epithelium that contains sebaceous glands, sweat glands, and hair follicles. The medial skin covering the bony canal is quite thin, measuring only 0.2 mm in thickness. The medial skin lacks a subcutaneous layer and is in continuity with the outermost layer of the tympanic membrane. The external canal receives its blood supply from the superficial temporal and posterior auricular branches of the external carotid artery. Venous drainage is to the external jugular vein. The external canal receives sensory innervation via multiple cranial nerves. The trigeminal nerve supplies sensation to the superior and anterior aspect of the canal, the facial nerve supplies the anterior inferior area, and the glossopharyngeal and vagus nerves innervate the inferior and posterior regions. Because of the diverse nerve supply, otalgia may often reflect referred pain from oral cavity, nasal, or pharyngeal sources. Several anatomic features serve to protect the external canal and tympanic membrane (TM) from injury or infection. The gentle curvature of the canal and the narrowing at the bone–cartilage junction (the isthmus) reduce the probability of large objects penetrating the TM. The hair and cerumen also protect the canal, trapping airborne particles that enter the external meatus. Cerumen has the additional benefit of repelling water. The acidic composition of cerumen lowers the ambient pH of the external canal, making it less hospitable to infectious organisms. The phenomenon of epithelial migration is documented in the ear canal. Surface epithelium moves laterally from the umbo to the annulus of the TM and then laterally to the external meatus. Epithelial movement on the TM proceeds at a rate of 0.05 mm per day and is typically slower in the external canal. Lateral migration helps clear the medial canal of surface epithelium and attached debris. This migratory pattern is arrested in chronic infection of the external canal. Diagnosis Infections develop in the external canal when organisms breach the anatomic barriers. Trauma to the canal skin, excessive removal of the cerumen, and excessive moisture in the canal may all facilitate otitis externa. Presenting symptoms of an external ear infection include pain, itching, and hearing loss. Pain develops

rapidly, is typically constant, and may be quite severe. Manipulation of the ear or jaw movement exacerbates the pain. Conductive hearing loss occurs because of accumulation of debris in the external canal and is exacerbated by concurrent edema. Persistent symptoms despite treatment are a matter of great concern and may indicate a developing osteitis. Cranial nerve deficits are ominous symptoms and indicate an advanced osteitis of the temporal bone. Physical examination findings typically include erythema, edema, and drainage. Differences in examination findings can help distinguish bacterial from fungal infections. Bacterial infections usually produce marked edema of the canal skin, especially in the lateral cartilaginous canal. Drainage is usually scant and may have a mucoid or mucopurulent consistency and often has a foul odor. In contrast, fungal infections typically involve the medial canal skin and produce little edema. Drainage is thick and surface spore formation is evident. Focal granulation tissue develops in areas with invasive disease and TM perforations are occasionally present. Bloody drainage can be seen with either bacterial or fungal infections because of maceration of the canal skin or from granulation tissue formation. Regional or systemic symptoms are uncommon in otitis externa. Periaural erythema, mild lymphadenopathy, and low-grade fever are possible. The presence of regional symptoms indicates a more virulent infection. Treatment The initial approach to outer ear infections involves aural toilet and avoidance of further trauma or moisture. Topical antibiotics are prescribed in accordance with the likely infectious organism. Many preparations have a rather broad spectrum of efficacy so routine culture of aural discharge is not performed. It is prudent to obtain culture and sensitivity data in recalcitrant cases. Analgesics are prescribed as necessary to control pain. Narcotics are occasionally required. Patients are instructed to avoid or minimize water exposure. With appropriate treatment, symptoms improve rapidly, and complete healing is seen in 2 weeks or less. The most common organism identified in routine cases of external otitis is Pseudomonas aeruginosa. Staphylococcal species are the next most common. Topical fluoroquinolone or aminoglycoside antibiotics are the most appropriate choice for treatment. Preparations that include a steroid are recommended. Drops are instilled three times daily until resolution of the infection, usually 7 to 10 days. When severe edema of the canal skin is present, a wick is inserted into the canal to facilitate drug delivery. Persistent symptoms indicate inadequate treatment, although this may also be because of inappropriate antibiotic, inefficient drug delivery, noncompliance, or progressive infection. Differential Diagnosis and Treatment There are many other infectious disorders of the external canal, although each can usually be distinguished by characteristic clinical findings. Malignancy may also mimic chronic infection. Biopsy is recommended for abnormal tissue that does not quickly resolve with treatment. ACUTE INFECTIONS Furuncles occur at the external meatus in the hair-bearing skin. Erythema and edema are localized, and skin a few millimeters away from the infection has a healthy appearance. Pain can be severe and is exacerbated

by pressure or manipulation of the auricle. Furuncles are caused by staphylococcal infection. Spontaneous rupture of the lesion leads to resolution of the infection and pain. If fluctuance is present at presentation, the lesion is drained under local anesthesia. Topical antibiotics (bacitracin, neomycin, or mupirocin [Bactroban] ointment or solution) are a useful adjunct.

CURRENT DIAGNOSIS Presenting symptoms include:

Pain: develops rapidly, typically constant; exacerbated by movement of ear or jaw Itching Hearing loss: exacerbated by concurrent edema Exam findings include:

Erythema Edema Drainage: sometimes bloody Bacterial infections: often have edema of the canal skin with minimal drainage that has foul odor Fungal infections: involve the medial canal skin with slight edema, thick drainage, evident surface spore formation The physical findings in otomycosis were outlined earlier. The predominant organisms are Aspergillus and Candida with considerable variation in prevalence according to geographic region. Fungal infections produce more destruction of the canal skin but less edema. Granulation tissue and TM perforations are not uncommon, although most perforations heal spontaneously after eradication of the infection. Treatment requires meticulous cleaning of debris and topical antifungals. Clotrimazole (Lotrimin) solution is effective for Candida species, but eradication of Aspergillus species is most efficient with ketoconazole (Nizoral) cream applied directly to the affected skin. Bullous external otitis is diagnosed based on the characteristic finding of hemorrhagic vesicles in the external canal. Spontaneous rupture of the lesions produces bloody otorrhea. The lesions are quite painful, and lancing the bullae to drain the fluid does not provide relief as is seen in bullous myringitis. Involvement of the medial canal skin is typical. The etiology of this infectious process is unclear. However, the disease responds to a broad spectrum of topical antibiotics. Topical or oral analgesics are a useful adjunctive treatment. Herpes zoster oticus, or Ramsay Hunt syndrome, occurs because of reactivation of latent varicella zoster virus in the geniculate ganglion. Vesicles may develop in the sensory distribution of the facial nerve. The appearance of skin lesions is characteristic of zoster eruptions. Initially, the vesicles are erythematous with a straw-colored fluid. Spontaneous rupture results in a crusted ulcer that may take several weeks to heal. Facial paralysis, dysgeusia, dizziness, and sensorineural hearing loss are typical in herpes zoster oticus but

extremely rare in other infectious diseases of the external ear canal. Treatment of the facial paralysis is the primary objective, necessitating systemic steroids and antivirals. The skin lesions of the ear canal usually heal without incident, but secondary bacterial otitis externa is possible.

CURRENT THERAPY Provide aural toilet and encourage avoidance of further trauma and water exposure. Obtain culture and sensitivity data in recalcitrant cases. Prescribe topical antibiotics that include a steroid and analgesics (for pain) as needed. CHRONIC INFECTIOUS DISORDERS Skull base osteitis occurs when disease extends from soft tissues of the canal into the temporal bone. Elderly patients, diabetics, and immunocompromised individuals are at increased risk of developing osteitis. The diagnosis is suspected when pain, discharge, fever, and/or granulation tissue persist despite treatment. Progressive involvement of the skull base may lead to cranial nerve palsies, vascular thrombosis, and intracranial infection. Laboratory testing reveals a markedly increased sedimentation rate. Technetium-99m bone scan displays increased uptake throughout the course of the disease and is useful for initial diagnosis. Computed tomography (CT) of the temporal bone displays bone erosion in advanced cases. Magnetic resonance imaging (MRI) is useful to detect soft-tissue and dural involvement. Biopsy of infected tissue or bone may be necessary to identify the responsible organism. Systemic antibiotics are selected according to culture and sensitivity data and should be continued until the sedimentation rate returns to normal. This may require months of treatment. Osteoradionecrosis is a late complication of temporal bone irradiation. Contemporary stereotactic techniques should significantly reduce the incidence of this problem. The process is typically limited, and symptoms are much less severe than in skull base osteitis. Exposed necrotic bone with slight granulation and purulent drainage is seen on examination. Local débridement and topical antibiotics are usually sufficient to control the infection. Recurrence is common because the irradiated ear canal is highly susceptible to infection after exposure to water or minor trauma. MISCELLANEOUS With the exception of herpes zoster oticus, none of the entities just described typically involves the pinna. Inflammation of the external canal in conjunction with pinna involvement may signify dermatologic disease. Some common entities include eczema, neomycin allergy, relapsing polychondritis, and erysipelas.



REFERENCES Clark et al., 1997. Clark WB, Brook I, Bianki D, Thompson DH: Microbiology of otitis externa. Otolaryngol Head Neck Surg 1997; 116:23-25. Hawke et al., 1984. Hawke M, Wong J, Krajden S: Clinical and microbiological features of otitis externa. J Otolaryngol 1984; 13:289-295. Hurst, 2001. Hurst WB: Outcome of 22 cases of perforated tympanic membrane caused by otomycosis. J Laryngol Otol 2001; 115:879-880. Litton, 1963. Litton WB: Epithelial migration over tympanic membrane and external canal. Arch Otolaryngol 1963; 77:254-257. Lucente, 1993. Lucente FE: Fungal infections of the external ear. Otolaryngol Clin North Am 1993; 26:9951006. Sreepada and Kwartler, 2003. Sreepada GS, Kwartler JA: Skull base osteomyelitis secondary to malignant otitis externa. Curr Opin Otolaryngol Head Neck Surg 2003; 11:316-323. Sweeney and Gilden, 2001. Sweeney CJ, Gilden DH: Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149-154.



Chapter 56 – Otitis Media

Method of: J. Scott McMurray, MD Ear infections, their complications and sequelae, comprise most patient-clinician interactions. Estimates suggest nearly $3 billion in direct and indirect cost for acute otitis media (AOM) and otitis media with effusion were spent in 1995 alone. In 2000 more than 16 million office visits were made for otitis media and 802 prescriptions per 1000 visits were written for a total of more than 13 million prescriptions. As common as the problem may be, it continues to be a source of confusion and controversy in terms of its diagnosis, treatment, and expectation for outcomes. Recently, there has been a renewed interest in determining the appropriate evaluation and management of these afflicted children, based on evidence-based medicine. Along with new diagnostic protocols and realigned treatment strategies, there is a realization that children may fall into different at-risk groups and will therefore benefit from different treatment options. In his recent editorial in the International Journal of Pediatric Otolaryngology on a practical classification of otitis media subgroups, Richard Rosenfeld quoted Stanley Hoerr saying, “It is difficult to make the asymptomatic patient feel better.” Yet, he added, much of the research on which we base our decisions to treat or not to treat children with otitis media has been formulated on those who would otherwise do well without treatment, the so-called innocent bystander. Children in the at-risk or suffering groups have been excluded from research trials for ethical reasons against withholding treatment. It is possible to group children into four subgroups with otitis media: 1.

Innocent bystander

2.

Susceptible child

3.

At-risk child

4.

Suffering child

These different subgroups imply different treatment limbs. The innocent bystander may do well without any therapy and may tolerate careful observation, whereas the suffering child with a similar disease process deserves rapid and intensive medical or surgical treatment or both. The stratification of children into different subgroups may appear daunting at first glance but after closer reflection answers the problem of conflicting research data and perhaps uses more common sense (confirmed by clinical trials) in determining treatment. Otherwise developmentally and physically healthy children may be closely observed rather than treated medically or surgically for their acute ear infection or middle ear effusion (MEE). Other children who are at risk for developmental delays, physically challenged, or suffering from the effects or side effects of AOM or otitis media with effusion should be treated more aggressively with either the appropriate medical or surgical plan of care. Unfortunately, this increases the number of possible permutations when determining the appropriate treatment for the afflicted child. Fortunately, however, this new paradigm allows more freedom in determining the appropriate treatment option to be followed. Our challenge lies in honing our abilities to make a correct diagnosis and an accurate

assessment of risk so that an appropriate treatment protocol with adequate follow-up can be implemented. In 2004, the American Academy of Pediatrics, the American Academy of Family Practice, and the American Academy of Otolaryngology Head and Neck Surgery combined forces to create two separate clinical guidelines for AOM and otitis media with effusion. These guidelines serve as an excellent frame on which to build a knowledge base and understanding for the treatment of all children with AOM or otitis media with effusion. These references are invaluable and are recommended reading for all who treat children with ear pathology. Definitions Acute otitis media is defined as an abrupt onset of inflammation of the middle ear space. This contrasts with otitis media with effusion, which is fluid in the middle ear without signs and symptoms of inflammation. Otitis media with effusion is much more common than AOM but may be seen as a residual finding of a recently resolved infection. The distinction between the two and the ability of the clinician to distinguish between these disease entities is paramount to decision making and appropriate treatment. The signs and symptoms of AOM are found in an abrupt onset of fluid in the middle ear with redness or distinct pain. Children suffering with AOM may or may not also exhibit systemic signs of infection, such as fever. Fever, pain, and irritability are seen in 90% of children with AOM, but it is also seen in 76% of children with upper aerodigestive tract viral illnesses as well. History alone may lead to an erroneous conclusions and unnecessary treatment. The distinction lies in the physical findings of MEE with inflammation. Fullness or bulging of the tympanic membrane, air fluid levels, opacification of the tympanic membrane, or bullous vesicles on the tympanic membrane are signs suggesting AOM when associated with acute inflammation. Visualization of the tympanic membrane and the use of pneumatic otoscopy should confirm the presence of a MEE and inflammation. Tympanometry can confirm suspicion of a MEE, but the clinician should work to be proficient with pneumatic otoscopy. Otitis media with effusion alone may result from a resolved infection or from eustachian tube dysfunction alone. The physical findings are similar to those described but without the signs of acute inflammation. Although the tympanic membrane may be red in the otherwise healthy child crying at the displeasure of being examined, pain and an effusion are not generally associated with normal health. Treatment Recommendations Children with AOM should have adequate pain management. Acetaminophen, ibuprofen, and occasionally narcotics are useful in treating the pain of AOM. Rarely, myringotomy is required to relieve the discomfort of an acute ear infection. If an acute bacterial infection in the middle ear is recognized, antibacterial therapy may be used in all age groups. If the diagnosis is uncertain, antibacterial therapy is recommended in the very young, younger than age 6 months. Antimicrobials may also be administered if one is uncertain of the diagnosis, if the illness is severe in those from 6 months to 2 years of age. If the child is older than age 2 years and the diagnosis is uncertain, observation and close follow-up is recommended.

If antibacterial treatment is instituted, amoxicillin at 80 to 90 mg/kg/day is used as a first line of therapy. If severe illness is encountered or if coverage for beta-lactamase–positive organisms such as Haemophilus influenzae or Moraxella catarrhalis is required, amoxicillin-clavulanate (Augmentin) is suggested (90 mg/kg/day of the amoxicillin component). Children who are allergic to amoxicillin, but not with urticaria or anaphylaxis, may be given cefdinir (Omnicef), cefpodoxime (Vantin), or cefuroxime (Ceftin). Children with type-1 hypersensitivity to amoxicillin may be given azithromycin (Zithromax), clarithromycin (Biaxin), erythromycin-sulfisoxazole (Pediazole), or sulfamethoxazole-trimethoprim (Bactrim). In AOM where the organism is thought to be penicillin resistant Streptococcus pneumoniae, clindamycin is a reasonable choice. Patients who fail to respond within 48 to 72 hours, whether in the observation or antibacterial therapy group, should be reassessed and treatment changed depending on the findings. Reduction of risk factors for AOM is encouraged for everyone. No recommendations were made regarding the efficacy of complementary and alternative medicine for the treatment of AOM. Otitis media with effusion is common after resolution of acute otitis. Some children also present with asymptomatic otitis media with effusion as well. Treatment of children with persistent middle effusion depends on their at-risk grouping. Children at risk for speech, language, or other learning problems should be treated more promptly than other children not at risk. The at-risk groups include children with a permanent hearing loss independent of the otitis media, suspected or known speech and language delays, autism-spectrum disorder or other pervasive developmental disorder, syndromes or craniofacial disorders, blindness or uncorrectable visual impairment, cleft palate with or without associated syndrome, or developmental delay. The management of the child with otitis media with effusion in these at-risk groups should include hearing tests, speech and language assessment and therapy, hearing aids or other amplification devices for hearing loss independent of the otitis media, tympanostomy tube placement, and assessment of hearing after resolution of the otitis media with effusion to detect underlying hearing loss independent of the middle ear fluid.

CURRENT THERAPY Adequate pain management is key in treating AOM. If a child has an acute bacterial otitis media, antibiotics are indicated. Amoxicillin at 80 to 90 mg/kg/day is the first therapy of choice in nonallergic children. Children older than age 2 years may be observed without antibiotic therapy if the diagnosis is uncertain. Children younger than age 2 years may be treated with antibiotics if the diagnosis is uncertain. Abbreviation: AOM = acute otitis media.

CURRENT DIAGNOSIS The diagnosis of AOM requires acute signs of illness such as fever and pain along with signs of middle ear inflammation such as fluid and erythema. Associated symptoms of AOM include fever, pain, and irritability. Visualization of the tympanic membrane and pneumatic otoscopy are required to confirm the diagnosis of AOM. Fluid behind the tympanic membrane does not necessarily indicate an infection in the middle ear space. Abbreviation: AOM = acute otitis media.

Children who do not fall in the at-risk group may be watched for 3 months before intervention. If the MEE persists for longer than 3 months, audiometric assessment of hearing should be obtained. Intervention is then based on the presence of a hearing loss of generally greater than 20 decibels, suspicion of language development delay, or other impending complications related to the MEE. If the hearing loss is mild (21 to 39 decibels), strategies to optimize the listening and learning environment and/or surgical intervention should be suggested. If the hearing loss is greater than 40 decibels, surgical intervention to correct the MEE is indicated and most efficacious. Initial surgical treatment of a problematic persistent MEE as described earlier is tympanostomy tube placement. Adenoidectomy is reserved for children who have other distinct indications, such as nasal airway obstruction or chronic adenitis, or in whom another set of pressure equalization tubes are necessary. Approximately 20% to 50% of children relapse after their tympanostomy tubes extrude and will require additional tubes. When adenoidectomy is performed with the second set of tubes, the rate of recidivism is decreased by 50%. This advantage is seen in children as young as age 2 years, with the greatest effect seen in children aged 3 years and older, regardless of adenoidal size. Children older than age 4 years may also benefit from adenoidectomy and myringotomy without tube placement. Myringotomy alone without tympanostomy tube insertion and/or tonsillectomy alone solely for the treatment of otitis media with effusion has not been found to be efficacious. Conclusion The key to successful management of a child with AOM or otitis media with effusion, as it is with any medical problem, is based on the clinician's ability to correctly diagnose and stratify at-risk groups. The new recommended clinical pathways developed by the AAP, AAFP, and AAO-HNS for AOM and otitis media with effusion may at first seem to increase complexity of treatment because it increases the number of pathways possible. Closer reflection, however, will reveal an easier paradigm. It is the clinician's responsibility to attain the skills and knowledge set to make the correct initial diagnosis and assessment of risk for the patient. The support from the evidence-based-medicine clinical pathways will then help in the decision making and treatment formulation.



REFERENCES American Academy of Family Physicians et al., 2004. American Academy of Family Physicians , American Academy of Otolaryngology Head and Neck Surgery , American Academy of Pediatrics Subcomittee on Otitis Media with Effusion : Otitis media with effusion. Pediatrics 2004; 113(5):1412-1429. American Academy of Pediatrics Subcomittee on Acute Otitis Media, 2004. American Academy of Pediatrics Subcomittee on Acute Otitis Media : Diagnosis and management of acute otitis media. Pediatrics 2004; 113(5):1451-1465. Bell, 2005. Bell LM: The new clinical practice guidelines for acute otitis media: An editorial. Ann Emerg Med 2005; 45(5):514-516. Bluestone, 1998. Bluestone CD: Epidemiology and pathogenesis of chronic suppurative otitis media: Implications for prevention and treatment. Int J Pediatr Otorhinolaryngol 1998; 42(3):207-223. Ohlms et al., 1999. Ohlms LA, Chen AY, Stewart MG, Franklin DJ: Establishing the etiology of childhood hearing loss. Otolaryngol Head Neck Surg 1999; 120(2):159-163. Paradise et al., 2005. Paradise JL, Campbell TF, Dollaghan CA, et al: Developmental outcomes after early or delayed insertion of tympanostomy tubes. N Engl J Med 2005; 353(6):576-586. Rosenfeld, 2005. Rosenfeld RM: A practical classification of otitis media subgoups. Int J Pediatr Otorhinolaryngol 2005; 69(8):1027-1029. Rosenfeld et al., 2004. Rosenfeld RM, Culpepper L, Doyle KJ, et al: Clinical practice guideline: Otitis media with effusion. Otolaryngol Head Neck Surg 2004; 130(5 Suppl):S95-S118. Rosenfeld et al., 2005. Rosenfeld RM, Lous J, Bluestone CD, et al: Recent advances in otitis media. 8. Treatment. Ann Otol Rhinol Laryngol Suppl 2005; 194:114-139.



Chapter 57 – Episodic Vertigo

Method of: Joseph M. Furman, MD, PhD Vertigo occurs when a patient perceives motion that is not real. Vertigo is caused by erroneous neural signals arising from the labyrinth or from abnormal processing of balance signals in the brain. Strictly speaking, the term vertigo should be reserved for an illusory sensation of motion of self or surroundings. In this context, vertigo usually represents the manifestation of a peripheral vestibular disorder, but not always. However, “vertigo” is used by many people to represent a specific diagnosis. This use of the term vertigo as a diagnosis, rather than as a symptom, can be counterproductive; the clinician may be lulled into a false sense of security and provide suboptimal or delayed treatment. Determining the optimal treatment for a patient with episodic vertigo often requires establishing a definitive diagnosis. Fortunately, in many patients with episodic vertigo, a specific diagnosis can be reached. However in a significant number of patients, no specific diagnosis can be reached. When a definitive diagnosis cannot be reached, a clinical assessment often points to either a peripheral (inner ear) or to a central (brain) vestibular disorder, which can be helpful in selecting a treatment. Obtaining a detailed history, performing a physical examination, and, when appropriate, ordering laboratory testing are the principal diagnostic tools for assessing a patient with episodic vertigo. Obtaining a history from a patient with episodic vertigo is especially important because vertigo is subjective, usually transient, and often unaccompanied by physical findings. It is difficult for many patients to describe their abnormal sensations of motion. Rather than vertigo, they might use the terms dizziness, lightheadedness, giddiness, or dysequilibrium. Regardless of the terminology that the patient uses, it is essential to ask about time course, aggravating factors, and associated symptoms. Some patients with episodic vertigo experience symptoms between as well as during attacks. Physical examination of the patient with episodic vertigo should include a neurologic and otologic examination and a neuro-otologic examination that uses several specialized bedside evaluation methods. Laboratory testing of the patient with episodic vertigo may include vestibular laboratory testing, audiometry, and brain imaging. Some recognized causes of episodic vertigo are relatively common and others are unusual. A few vestibular disorders that cause episodic vertigo are controversial. Some patients suffer from more than one episodic disorder. The Current Diagnosis box lists disorders that cause episodic vertigo. Benign Paroxysmal Positional Vertigo Benign paroxysmal positional vertigo (BPPV) is a well-defined disorder characterized by episodic vertigo

induced by rolling in bed and by tipping one's head backward. The disorder is caused by free-floating debris in the posterior semicircular canal. The preferred treatment is a particle-repositioning maneuver ( Figure 1 ). This treatment is highly successful and provides complete relief for nearly all patients. Some patients cannot undergo a particle repositioning maneuver. For these patients, Brandt-Daroff exercises should be prescribed. Vestibular-suppressant medications may be used early in the disorder, but after several days they should be used sparingly, if at all.

FIGURE 1 Bedside maneuver for treatment of a patient with benign paroxysmal positional vertigo affecting the right ear. The

presumed position of the debris within the labyrinth during the maneuver is shown in each panel. The maneuver is a three-step procedure. A, The Dix-Hallpike test is performed with the patient's head rotated 45 degrees toward the right ear and the neck slightly extended with the chin pointed slightly upward. This position results in the patient's head hanging to the right. B, Once the vertigo and nystagmus provoked by the Dix-Hallpike test cease, the patient's head is rotated about the rostral-caudal body axis until the left ear is down. C, The head and body are further rotated until the head is face down. The vertex of the head is kept tilted downward throughout the rotation. The maneuver usually provokes brief vertigo. The patient should be kept in the final, facedown position for about 10 to 15 seconds. D, With the head kept turned toward the left shoulder, the patient is brought into the seated position. Once the patient is upright, the head is tilted so that the chin is pointed slightly downward. (Adapted from Furman JM, Cass SP: Benign paroxysmal positional vertigo. N Engl J Med 1999;341[21]:1590-1596.)

Approximately 15% of patients with one episode of BPPV have a recurrence within 1 year. Home particle repositioning has been advocated for persons with repeated episodes of BPPV. Rarely, surgical procedures are required for patients whose BPPV is refractory to nonsurgical treatments. Meniere's Disease Treatment for this disorder is discussed in depth elsewhere in this volume. The typical manifestation of Meniere's disease includes fluctuating aural fullness, tinnitus, hearing loss, and recurrent bouts of vertigo. Endolymphatic hydrops (swelling of the endolymphatic space) is thought to be the underlying pathophysiologic process of Meniere's disease. The medical treatment of endolymphatic hydrops includes taking a diuretic and restricting dietary sodium. A combination of hydrochlorothiazide and triamterene (Dyazide) is the diuretic of choice. Dietary sodium should be held below 2 g per day. About 10% to 15% of persons with Meniere's disease eventually fail medical therapy. Surgical treatment options for Meniere's disease, discussed elsewhere in this volume, include chemical labyrinthectomy, endolymphatic sac surgery, labyrinthectomy, and vestibular nerve section. Migraine-Related Dizziness Migraine-related dizziness is a diagnosis of exclusion and should be suspected in patients with nonspecific dizziness or vertigo associated with headache. A past history of migraine headaches or a positive family history of migraine increases the likelihood of this disorder. Patients with migraine-related dizziness almost invariably report exacerbation of symptoms by viewing certain moving visual environments or significant motion sickness sensitivity. Treatment options for patients with migraine-related dizziness are summarized in Box 1 . The patient should be informed about the association between dizziness and an underlying migraine condition and the importance of avoiding dietary triggers such as tyramine-containing foods, alcohol, and caffeine. The underlying migraine condition should be treated with prophylactic antimigraine medications, even if headaches are not currently prominent. If the most prominent vestibular symptom is movement-associated disequilibrium or unsteadiness, vestibular rehabilitation therapy is recommended. If the patient reports severe space and motion discomfort, prescribe low-dose clonazepam[1] (Klonopin) 0.25 mg twice daily. In patients with panic attacks or agoraphobia (migraine-anxiety-related dizziness [MARD]), psychiatric consultation should be obtained, and behavioral therapy and specific medical therapy using antidepressant medications should be considered. Consider triptans to abort episodes of acute migraine-related vertigo. BOX 1

Treatment Options for Migraine-Related Dizziness •

Avoid dietary triggers

•

Treat underlying migraine phenomenon •

Anticonvulsants (e.g., topiramate [Topomax] 25 mg/d to 50 mg bid)

•

Antidepressants (e.g., imipramine [Tofranil][1] 10-100/mg/d or sertraline[1] [Zoloft] 25-75 mg/d)

•

ß-Blockers (e.g., propranolol [Inderal] 80-320 mg/d)

•

Calcium channel blockers (e.g., verapamil [Calan] 80-120 mg/d)

•

Treat movement-associated disequilibrium with vestibular rehabilitation therapy

•

Treat space and motion discomfort with clonazepam (Klonopin)[1] 0.25-0.5 mg bid

•

Treat associated anxiety or panic disorder

•

•

Behavioral therapy

•

Pharmacotherapy

•


Consider abortive treatment with a triptan for acute migrainous vertigo


Anxiety-Related Dizziness Anxiety often accompanies dizziness. The cause-and-effect relationship between anxiety and dizziness is uncertain but may be related to a somatopsychic, a psychosomatic, or a common neurologic mechanism. The term psychogenic dizziness should be avoided in favor of the term psychiatric dizziness. Psychiatric dizziness should be used to describe dizziness that occurs exclusively in combination with other symptoms as part of a recognized psychiatric symptom cluster. Hyperventilation is a maneuver that is commonly used to determine whether dizziness is psychogenic, but the test is actually quite nonspecific, and the results of such testing should be interpreted with great caution. Treatment of patients with a combined anxiety and vestibular disorder should include measures aimed at both conditions simultaneously. The vestibular disorder should be treated in whatever manner is appropriate. The treatment of anxiety disorders includes pharmacotherapy and behavioral therapy. A psychiatric referral is warranted for patients who are suffering from frequent panic attacks or from panic disorder with agoraphobia. Nonspecific Vestibulopathy Vestibulopathy of unknown origin and nonspecific vestibulopathy describe a complex of nonspecific symptoms that suggest some impairment of the balance system but that do not fit any recognized vestibular syndromes.

Nonspecific vestibulopathy is a diagnosis of exclusion. Conditions that should be considered and ruled out include Meniere's disease (endolymphatic hydrops), BPPV, migraine-related dizziness, anxiety and panic disorders, and potential central nervous system abnormalities such as multiple sclerosis, Chiari malformation, or neoplasm. Follow-up is important because a specific diagnosis can become evident over time. Treatment options for nonspecific vestibulopathy include medications and a course of vestibular rehabilitation therapy. The choice of treatment depends on the physician's judgment about the importance and predominance of symptoms of nausea, dizziness, anxiety, depression, or a functional impairment of balance. Medications commonly used to decrease dizziness, vertigo, and nausea are listed in Table 1 . Sertraline (Zoloft)[1] has been suggested for patients with nonspecific dizziness.

TABLE 1 -- Medications Commonly Used to Reduce Dizziness, Vertigo, and Associated Nausea Generic Name (Brand Class Name)

Dosage

Primary Symptom Being Treated

Side Effects

Clonazepam[1] (Klonipin)

Benzodiazepine

0.25 mg bid

Dizziness

Drowsiness

Cyclizine (Marezine)

Piperzine (H1blocking agent)

50 mg PO or IM q4-6h

Dizziness

Drowsiness

Diazepam[1] (Valium)

Benzodiazepine

1-10 mg PO, IM, Dizziness or IV q12h

Lethargy

Dimenhydrinate (Dramamine)

Ethanolamine (H1blocking agent)

50 mg PO q4-6h Dizziness

Drowsiness

Diphenhydramine

Ethanolamine (H1blocking agent)

25-50 mg PO, IM, or IV q6h

Nausea

Drowsiness

Hydroxyzine[1] (Vistaril, Piperazine derivative 25-100 mg PO[1] Nausea Atarax) q8h

Drowsiness

Meclizine (Antivert, Bonine)

Piperazine (H1blocking agent)

25 mg PO q4-6h Dizziness

Drowsiness

Prochlorperazine Compazine)

Phenothiazine

10 mg PO or IM Nausea q6h or 25 mg PR q12h

Extrapyramidal reactions, drowsiness, anticholinergic effects


Phenothiazine

25 mg PO or PR Nausea q6h

Extrapyramidal reactions, drowsiness

Scopolamine (Transderm Scop)

Amine antimuscarinic

0.5-mg adhesive Dizziness skin patches q3d

Dry mouth, blurred vision, drowsiness, disorientation

Trimethobenzamide (Tigan)

Substituted ethanolamine

300 mg PO q6Nausea 8h or 200 mg PR or IM

Extrapyramidal reactions (unusual)


Bilateral Vestibular Loss Bilateral vestibular loss most commonly occurs as a result of aminoglycoside-induced ototoxicity. Other pharmaceutical agents such as cisplatin can also cause bilateral vestibular loss. Bilateral vestibular loss can be caused by bilateral Meniere's disease, autoimmune inner ear disease, otosyphilis, or bilateral acoustic neuromas, and it can be idiopathic. The combination of oscillopsia and ataxia (Dandy's syndrome) is pathognomonic for bilateral vestibular loss. Prevention is the best management for ototoxicity. Treatment for bilateral vestibular loss should include discontinuation of all vestibular suppressant medications and referral for a course of balance rehabilitation therapy. If at all possible, the patient should not receive further ototoxic medications. Patients should be taught how to use sensory input other than that from the vestibular system, such as from vision and proprioception. A properly fitted cane can provide increased proprioceptive input. The patient should also be cautioned to remove all loose rugs from the home, install night-lights, and install hand rails on stairways and in the bathroom. Recently, several prosthetic devices have been developed for patients with bilateral vestibular loss. These devices are currently being evaluated for efficacy. Acoustic Neuroma A cerebellopontine angle lesion should be suspected in the setting of dizziness associated with unilateral or asymmetric hearing loss or tinnitus. Diagnostic considerations should include a large acoustic neuroma or meningioma involving the posterior fossa. Large cerebellopontine angle tumors can produce a combination of peripheral and central vestibular abnormalities. Both vestibular nerve and cerebellar function may be impaired. Management options include observation, microsurgical excision of the tumor, and radiosurgery. Selection of the appropriate treatment option depends on many factors and should be individualized. Patients should be counseled regarding the possible occurrence of vestibular symptoms following treatment. Vertebrobasilar Insufficiency The blood supply of the vestibular system is derived from the basilar artery. The internal auditory artery arises from the anterior inferior cerebellar artery and gives rise to the anterior vestibular artery, which supplies the vestibular apparatus. Thus, ischemia in the vertebrobasilar artery system can cause vestibular symptoms on the basis of either peripheral vestibular dysfunction, central vestibular dysfunction, or both. A diagnosis of vertebrobasilar insufficiency should be reserved for patients who have clearly defined episodes of transient neurologic symptoms and signs that can be localized to the posterior circulation. Isolated vertigo, especially if chronic, is rarely a symptom of vertebrobasilar insufficiency.

Management of vertebrobasilar insufficiency includes a thorough cerebrovascular assessment and often an antiplatelet agent. Recurrent Vestibulopathy, Recurrent Vestibular Neuritis, and Impaired Compensation Recurrent vestibulopathy is a clinical syndrome that consists of multiple episodes of vertigo lasting minutes to hours without auditory or neurologic signs or symptoms. Recurrent vestibulopathy is a diagnosis of exclusion. Several other disorders that can cause recurrent vertigo, such as Meniere's disease (endolymphatic hydrops), BPPV, migraine-related dizziness, vertebrobasilar insufficiency, and panic disorder should be excluded before diagnosing recurrent vestibulopathy, which may be a provisional diagnosis and cannot be distinguished clinically from recurrent vestibular neuritis. Treatment for recurrent vestibulopathy is nonspecific and includes antinausea and antiemetic agents ( Table 1 ), which should be prescribed for the patient to have on hand in the event of an episode of acute vertigo. Most patients who have suffered from a unilateral vestibular loss, such as vestibular neuritis, undergo vestibular compensation, a rebalancing of the neural activity in central vestibular structures that leads to a resolution of the vertigo, nausea, vomiting, blurred vision, and disequilibrium that characterizes an acute unilateral vestibular syndrome. Through compensation, vestibulo-ocular, vestibulospinal, perceptual, and autonomic symptoms and signs of the acute vestibular syndrome largely resolve. Vestibular compensation occurs automatically in persons with a normal central nervous system who have normal vision, normal proprioception, and adequate physical activity. Persistent dizziness that continues following an acute peripheral vestibular ailment may be the result of impaired vestibular compensation. Failure to compensate for a peripheral vestibular lesion can be the result of fluctuating or aberrant peripheral vestibular activity, a central nervous system abnormality, clinical or subclinical involvement of the contralateral ear, other sensory deficits (especially involving vision and somatosensation), or a sedentary lifestyle. Central nervous system abnormalities that impair vestibular compensation include structural abnormalities and dysfunction caused by certain drugs (e.g., benzodiazepines). Treatment of patients with impaired vestibular compensation includes tapering vestibular suppressant medications and performing a course of vestibular rehabilitation therapy. Multiple Sclerosis Vertigo and imbalance in multiple sclerosis can indicate a lesion in central vestibular structures. A peripheral vestibular abnormality independent of multiple sclerosis should also be considered. Both peripheral and central vestibular symptoms and signs can be seen in patients with multiple sclerosis if they have a lesion that includes the root entry zone in addition to other brainstem structures. A prolonged recovery can be seen in patients with root entry zone lesions caused by multiple sclerosis. Treatment of multiple sclerosis is discussed elsewhere in this volume. Mal De Debarquement Syndrome Normally, a return to stable land after prolonged sea or air travel produces sensations of motion that last for hours to days. In mal de debarquement syndrome, the sensation of motion persists for months or even years. The pathophysiology of mal de debarquement syndrome is probably related to the capability of the vestibular system to adapt to various motion environments that include combinations of vestibular and visual

stimuli. Treatments for mal de debarquement syndrome include vestibular suppressants, anxiolytics,[1] antidepressants,[1] and acetazolamide[1] (Diamox). Most cases of mal de debarquement syndrome resolve spontaneously within weeks to months. Autoimmune Inner Ear Disease Autoimmune inner ear disease is a disorder characterized by auditory and vestibular dysfunction that most often is bilateral and is thought to be produced by damage mediated by both cellular and humoral immune mechanisms. Autoimmune inner ear disease is usually bilateral but can begin unilaterally and rapidly progress to involve both sides. A diagnosis of autoimmune inner ear disease is difficult to confirm. A positive rheumatologic battery or elevated sedimentation rate may be suggestive. Autoimmune inner ear disease is often a diagnosis of exclusion and commonly depends on clinical criteria and response to a trial of corticosteroid therapy. Treatment of autoimmune inner ear disease usually includes corticosteroids, such as prednisone [1] 1 mg/kg/day for 1 to 2 weeks, followed by a tapering dose and maintenance dose if a positive response has occurred. Cytotoxic agents such as azathioprine[1] (Imuran) and cyclophosphamide[1] (Cytoxan) have also been advocated as an adjunct if the disease stops responding to steroid therapy. Plasmapheresis and intravenous immunoglobulin may be effective. Horizontal Semicircular Canal Benign Paroxysmal Positional Vertigo Horizontal semicircular canal benign paroxysmal positional vertigo is a variant of typical benign paroxysmal positional vertigo. This entity is thought to result from debris in the endolymph of the horizontal semicircular canal rather than in the posterior semicircular canal, as occurs in typical benign paroxysmal positional vertigo. The diagnosis of horizontal semicircular canal benign paroxysmal positional vertigo can be made by turning a patient's head to the right and to the left while the patient is supine. The patient will become vertiginous for 10 to 30 seconds and a paroxysmal horizontal nystagmus will be observed for as long as the vertigo persists. Treatment for horizontal semicircular canal benign paroxysmal positional vertigo consists of a particlerepositioning maneuver: The patient is rolled 90 degrees from the supine position toward the unaffected ear, then to the prone position and then to the side-down position with the affected ear down, then back to the seated position. Superior Semicircular Canal Dehiscence Syndrome Superior semicircular canal dehiscence syndrome is a recently described disorder characterized by episodic vertigo induced by loud noises or pressure changes in the external auditory canal. This syndrome can be diagnosed by identifying a thinning (dehiscence) of the superior semicircular canal with careful imaging. Once the syndrome is identified, referral to a neuro-otologic surgeon familiar with the disorder is appropriate because a surgical repair can be helpful. Cervicogenic Dizziness

Cervical vertigo is a poorly defined condition that refers to dizziness and disequilibrium thought to be caused by abnormal afferent activity from the neck. Cervical vertigo is a diagnosis of exclusion. A close temporal association of symptoms of dizziness and neck pain following a neck injury should suggest a diagnosis of cervical vertigo. Cervical vertigo can be seen in association with flexion-extension (whiplash) injuries, severe cervical arthritis, herniated cervical disks, and head trauma, especially blunt trauma to the top of the head. Neck muscle spasm and pain are often associated with symptoms of dizziness. Some patients with cervical vertigo experience a vicious cycle of excessive neck muscle activity exacerbating their dizziness, which subsequently exacerbates their neck discomfort. Treatment of cervical vertigo includes muscle relaxants and physical therapy to improve range of motion of the neck and to reduce neck muscle spasm and discomfort. Use of a cervical collar should be limited to no more than 1 to 2 hours per day.

CURRENT DIAGNOSIS Common Peripheral Vestibular

Benign paroxysmal positional vertigo Meniere's disease Mixed

Anxiety-related dizziness Migraine-associated dizziness Unknown

Nonspecific vestibulopathy Unusual Peripheral Vestibular

Autoimmune inner ear disease Bilateral vestibular loss Horizontal semicircular canal benign paroxysmal positional vertigo Recurrent vestibular neuritis Superior semicircular canal dehiscence syndrome Central Vestibular

Mal de debarquement syndrome Multiple sclerosis Vertebrobasilar insufficiency Mixed

Acoustic neuroma Controversial Disorders Peripheral Vestibular

Vascular cross-compression syndrome of the eighth cranial nerve Other

Cervicogenic dizziness

CURRENT THERAPY Acoustic Neuroma

Observation Surgical management Anxiety-Related Dizziness

Antidepressants Psychotherapy Autoimmune Inner Ear Disease

Corticosteroids[1] Cytoxic agents (e.g., azathioprine[1] and cyclophosphamide[1]) Benign Paroxysmal Positional Vertigo

Particle repositioning Bilateral Vestibular Loss

Physical therapy Prevention Cervicogenic Dizziness

Muscle relaxants Physical therapy Mal de Debarquement Syndrome

Acetazolamide (Diamox)[1] Antidepressants[1] Anxiolytics[1] Vestibular suppressants Meniere's Disease

Hydrochlorothiazide-triamterene (Dyazide) Sodium reduction Migraine-Related Dizziness

Decrease triggers Migraine prophylaxis Triptans Multiple Sclerosis

Corticosteroids Nonspecific Vestibulopathy

Physical therapy Sertraline (Zoloft)[1] Vestibular suppressants Recurrent Vestibulopathy

Antiemetics Antinausea agents Superior Canal Dehiscence Syndrome

Observation Surgical repair Vascular Cross-compression Syndrome

Baclofen (Lioresal)[1] Carbamazepine (Tegretol)[1] Gabapentin (Neurontin)[1] Surgical decompression Vertebrobasilar Insufficiency

Antiplatelet agents Vascular Cross-Compression Syndrome of the Eighth Cranial Nerve Vascular cross-compression syndrome of the eighth cranial nerve, which has been called disabling positional vertigo and vestibular paroxysmia, refers to a cochleovestibular syndrome caused by compression of the eighth cranial nerve by blood vessels within the cerebellopontine angle. The clinical description of vascular compression syndrome of the eighth cranial nerve is controversial, with no agreed-upon set of diagnostic criteria. Treatment options for vascular cross-compression syndrome of the eighth cranial nerve include pharmacotherapy with carbamazepine (Tegretol),[1] baclofen (Lioresal),[1] or gabapentin (Neurontin).[1] Surgical treatment consists of microvascular decompression. A trial of medical therapy is appropriate before referring a patient for a surgical opinion.



REFERENCES Furman et al., 2005. Furman JM, Balaban CD, Jacob RG, Marcus DA: Migraine-anxiety related dizziness (MARD): A new disorder?. J Neurol Neurosurg Psychiatry 2005; 76(1):1-8. Furman and Cass, 1999. Furman JM, Cass SP: Benign paroxysmal positional vertigo. N Engl J Med 1999; 341(21):1590-1596. Hain and Yacovino, 2005. Hain TC, Yacovino D: Pharmacologic treatment of persons with dizziness. Neurol Clin 2005; 23(3):831-853.vii Minor, 2005. Minor LB: Clinical manifestations of superior semicircular canal dehiscence. Laryngoscope 2005; 115(10):1717-1727. Radtke et al., 2004. Radtke A, von Brevern M, Tiel-Wilck K, et al: Self-treatment of benign paroxysmal positional vertigo: Semont maneuver vs Epley procedure. Neurology 2004; 63(1):150-152. Staab et al., 2004. Staab JP, Ruckenstein MJ, Amsterdam JD: A prospective trial of sertraline for chronic subjective dizziness. Laryngoscope 2004; 114(9):1637-1641. Tusa, 2005. Tusa RJ: Bedside assessment of the dizzy patient. Neurol Clin 2005; 23(3):655-673.v Wall et al., 2002. Wall 3rd C, Merfeld DM, Rauch SD, Black FO: Vestibular prostheses: The engineering and biomedical issues. J Vestib Res 2002; 12(2-3):95-113.



Chapter 58 – Ménière's Disease

Method of: Ted A. Meyer, MD, PhD Paul R. Lambert, MD Ménière's disease is a disorder of fluid balance of the endolymph of the peripheral auditory and vestibular systems. The inner ear contains an endolymph-filled membranous labyrinth housed inside the perilymphfilled bony labyrinth. The sensory receptor cells of the inner ear are contained in the membranous labyrinth. The composition of perilymph is very similar to cerebrospinal fluid (CSF) (high sodium, low potassium), whereas the composition of endolymph is like intracellular fluid (high potassium, low sodium). The uniqueness of endolymph lies in its high positive resting potential (+80 mV). Disturbances in the fluid dynamics of the endolymph appear to be involved in the hearing loss and peripheral vestibular disorders associated with Ménière's disease. The exact mechanism or mechanisms involved in Ménière's disease are not completely understood, but it appears that an overabundance of endolymph, either through overproduction and/or underabsorption, is the pathologic basis of the disease. Clinical Presentation The symptomatology of Ménière's disease was first described almost 150 years ago by the French physician for whom it is named, Prosper Ménière. Patients with Ménière's disease present with unilateral fluctuating sensorineural hearing loss, aural fullness, tinnitus, and spells of disabling vertigo that typically last between 20 minutes and 24 hours. Many patients with Ménière's disease have nonspecific dizziness and imbalance in between spells of vertigo as well. A small percentage of patients develop or present with drop attacks, or spells of Tumarkin. These attacks occur when a patient's vestibular system goes into a crisis and the patient loses extensor tone. Patients often describe an aura followed by a feeling that they are going to fall. Patients do not lose consciousness unless they hit their head. Patients with Ménière's disease may not present with all symptoms, and the severity and progression of hearing loss, tinnitus, and vertigo are variable. For the majority of patients, Ménière's disease occurs in a single ear; however, if patients are followed for a long enough time, the literature reports bilateral Ménière's disease in a wide percentage of patients. Patients with bilateral Ménière's disease whose hearing loss progresses to profound levels are excellent candidates for a cochlear implant. Office Evaluation The majority of patients with dizziness or vertigo present to their primary care physician (PCP) or to the emergency room. Many of these patients are given 25 mg of meclizine (Antivert) and are instructed to take it up to three times a day as needed. When the vertigo spells continue, they are often then referred to an otolaryngologist or otologist. Patients who are regularly taking meclizine as a prophylactic should stop the medication as quickly as possible. When the patient with dizziness or vertigo presents to the clinic, the diagnosis of Ménière's disease can usually be obtained through the history and physical examination. The patient should give a history of

disabling spells of vertigo, aural fullness or a “stuffy ear,” fluctuating and progressive hearing loss, and tinnitus. The nature of the vertigo and the duration of the spells aids in the diagnosis. The vertigo is usually severe and can last between 20 minutes and 24 hours. Rarely does a Ménière's attack last longer than 24 hours. Longer attacks (days) are more consistent with vestibular neuritis. The attacks are not provoked by specific movements, such as the brief spell of benign paroxysmal positional vertigo (BPPV) that lasts seconds to a few minutes often after rolling over in bed. Aural fullness is variable, but when present it is often more pronounced during the attack. The sensorineural hearing loss associated with Ménière's disease is often a low-frequency loss that is fluctuant and progressive. The hearing loss is often worse during the attack; however, some patients are so vertiginous and nauseated during an attack that characteristics of their hearing loss or aural fullness are not appreciated. Tinnitus with Ménière's disease is variable, but many patients describe a low-pitched roaring sound, “like a refrigerator running.”

CURRENT DIAGNOSIS Severe and often disabling vertigo lasting minutes to hours Fluctuating and progressive sensorineural hearing loss, often low-frequency Tinnitus: often low-pitched with roaring quality Aural fullness Complete neurologic evaluation Complete audiometric evaluation Consider further testing (MRI, FTA-ABS, tests for autoimmune disorders) Abbreviations: FTA-ABS = fluorescent treponemal antibody absorption (test); MRI = magnetic resonance imaging.

A complete and thorough physical examination should be performed on all patients who present with dizziness or vertigo. The background and expertise of the PCP is different from that of the otologist, and the PCP should evaluate the patient for other causes of dizziness or lightheadedness. The physician should then perform a complete head and neck examination. Otoscopy is usually unremarkable unless the patient has a history of eustachian tube disease. Pneumatic otoscopy should be performed and should not be associated with any vertigo or nystagmus suggestive of a perilymphatic fistula. The cranial nerves and cerebellar function should be assessed. At a minimum, the patient should be evaluated for spontaneous and gaze-evoked nystagmus, and the Dix-Hallpike, Romberg, and Fukuda step tests should be performed. Tuning fork tests should be performed to determine the nature of the hearing loss. Assuming that hearing in the ear not in question is relatively normal, the sound from a tuning fork placed on the center of the head (Weber test) should lateralize to the normal ear. The Rinne test should confirm that hearing by air conduction is louder than bone-conduction hearing. AUDIOMETRIC AND VESTIBULAR TESTING Formal pure-tone and speech audiometry should be obtained on all patients with suspected Ménière's disease. Tympanometry and acoustic reflexes should be obtained as well. Patients usually present with a

characteristic asymmetric low-frequency sensorineural loss that may recover to some degree between attacks. Patients with long-standing diagnoses of Ménière's disease rarely demonstrate normal and symmetric hearing. They often present with pure-tone thresholds in the 60-dB range, with diminished word recognition scores. Vestibular testing is often performed on patients with Ménière's disease. Patients may have relatively normal responses to caloric irrigations in the affected ear; however with long-standing Ménière's disease, caloric responses are usually reduced. The patient should not have spontaneous, positional, or gaze-evoked nystagmus, and ocular motor testing should be unremarkable. Electrocochleography is rarely performed for patients with suspected Ménière's disease anymore. LABORATORY AND RADIOLOGI TESTING Some otologists believe that Ménière's disease is a clinical diagnosis and when they are confident in the diagnosis, they perform few other tests. With concerns about the exponential increase in the cost of health care, we as health care providers must have accurate data to justify this approach. Other clinicians feel that a battery of tests is warranted for patients who present with the clinical and audiologic manifestations of Ménière's disease, including a magnetic resonance imaging (MRI) scan to search for an acoustic neuroma or other retrocochlear pathology, fluorescent treponemal antibody absorption (FTA-ABS) test for syphilis, and the anti68-kD protein test for autoimmune inner ear disease. The clinician may take a prudent approach when ordering tests for patients with classic symptoms and signs of Ménière's disease and consider ordering more tests when the diagnosis is less clear. Treatment The therapeutic goal of treating patients with Ménière's disease is to prevent or minimize the disabling spells of vertigo. The mainstay of modern treatment for patients is management of dietary sodium intake and the use of a diuretic. Patients should be instructed to minimize the sodium in their diet. Patients should typically restrict their sodium intake to 1500 mg per day. Many patients consume 5 to 10 g of sodium per day, and a reduction to 1.5 g per day requires a major change in lifestyle. Patients are also asked to decrease their caffeine and alcohol input, and if they smoke, they are told to stop and given information on different options available for smoking cessation. If the patient is not allergic, and there are no medical contraindications, the diuretic of choice is a combination of 25 mg hydrochlorothiazide and 37.5 mg of triamterene (Dyazide, Maxzide-25). Although triamterene is a potassium-sparing diuretic, patients are still encouraged to eat foods containing potassium (bananas, oranges, potatoes) and watch for signs of hypokalemia.

CURRENT THERAPY Medical

Low sodium diet (100.4°F [38°C]) and sore throat are invariably present in GABHS pharyngitis. The presence of rhinitis, laryngitis, diarrhea, conjunctivitis and bronchitis are inconsistent with this diagnosis and are more characteristic of a viral etiology. Examination reveals pharyngeal erythema or exudative pharyngitis, with or without palatal petechiae, that is associated with significant anterior cervical adenopathy. Untreated, 75% of patients defervesce within 3 days unless there is a local suppurative complication. This may include peritonsillar abscess, suppurative adenitis, and otitis media. Over a few more days, the individual's other signs and symptoms resolve. In the absence of antibiotic therapy, most patients carry streptococci for many months. With appropriate treatment, the carrier state is reduced to between 6% and 29% of patients. Diagnosis Although the diagnosis of GABHS pharyngitis cannot be based solely on clinical signs and symptoms, they have been quite useful in establishing the likelihood of streptococcal infection; especially in adults with an extremely low incidence of “strep throat.” Determining the probability of GABHS pharyngitis is essential for

establishing indications for diagnostic testing, as well as for interpreting the results of these tests. Several such scoring systems stratifying the importance of physical findings and symptoms have been developed. All are quite similar and include the presence of (a) fever higher than 99.9°F (37.7°C), (b) tonsillar exudate, and (c) anterior cervical adenopathy, and (d) absence of cough. The presence of all four makes the probability of GABHS 56%. When three conditions exist, the likelihood decreases to 32% and plummets to 15% and 6% when there are two and one positive indicators, respectively. If there are no positive indicators, the probability of a positive culture is less than 2.5%. At this level of risk, diagnostic testing is usually not required. The throat culture remains the diagnostic gold standard. The throat should be swabbed under direct visualization in repeated sweeps extending from each tonsillar fossa and involving the posterior pharynx but avoiding any other area of the mouth. The swabs should be immediately cultured on sheep blood agar incubated in 10% CO2. If there is no growth at 24 hours, the plate is re-incubated for another 24 hours. Sampling errors may cause false negatives in 9% to 12% of patients. Rarely, GABHS will not produce ß hemolysis. False positives may be due to ß hemolysis produced by non-GABHS organisms. The use of the bacitracin disk controls for this by inhibiting GABHS but not other types of ß hemolytic flora. The specificity of the throat culture ranges from 95% to 99% with 88% to 91% sensitivity. When obtained in physicians' offices, the throat cultures are much less sensitive (60 mmol/L) or

Identification of two CF associated mutations or

Characteristic abnormalities in ion transport measured across the nasal epithelium Characteristic Phenotypic Features:

Chronic sinopulmonary disease

Chronic cough and sputum production

Clinical findings consistent with airway obstruction (wheezing, air trapping)

Pansinusitis, nasal polyps

Persistent pulmonary infection with typical CF pathogens (Staphylococcus aureus, Pseudomonas aeruginosa )

Persistent chest radiograph abnormalities (bronchiectasis, atelectasis, infiltrates, hyperinflation)

Digital clubbing

Gastrointestinal and nutritional abnormalities

Intestinal: Meconium ileus, DIOS, rectal prolapse

Pancreatic: Pancreatic insufficiency (frequent stools), recurrent pancreatitis

Hepatic: Focal biliary cirrhosis

Nutritional: Protein-calorie malnutrition; hypoproteinemia and edema; complications secondary to fat-soluble vitamin deficie

Salt loss syndrome

Acute salt depletion

Chronic metabolism alkalosis

Male urogenital abnormalities resulting in obstructive azoospermia.

Abbreviations: CF = cystic fibrosis; DIOS = distal intestinal obstruction syndrome.

CURRENT THERAPY

Care at an accredited cystic fibrosis center

Careful monitoring of pulmonary function, respiratory tract microbiology, and nutritional status

Daily airway clearance therapies

Inhaled therapies to thin or hydrate mucus

Aggressive use of oral, inhaled, and intravenous antibiotics to suppress and treat pathogens and to resolve exacerbations o pulmonary disease

Control of fat and nutrient malabsorption with exogenous pancrelipase enzymes

Achievement of normal serum levels of fat-soluble vitamins

Normal nutritional status (body mass index at 50th percentile), using behavioral feeding therapy, high-calorie diet, oral supplements, night-time gastrostomy feeds, and appetite stimulants as indicated

Screening for and treatment of complications such as diabetes, decreased bone density, and liver disease

Patient and family involvement in care planning Management

All persons with CF should be followed at a CF care center accredited by the Cystic Fibrosis Foundation, because this ha been demonstrated to result in better outcomes and survival. The multidisciplinary team approach incorporates physician nurses, dietitians, respiratory therapists, physical therapists, and social workers trained specifically to care for CF patient These centers also provide the framework for the myriad clinical research trials now opening to test new therapies.

PULMONARY DISEASE

It is the triad of airway obstruction, inflammation, and infection that causes damage to the airway walls and surrounding tissue, resulting in bronchiectasis (the signature pathologic change), plugged airways, microabscesses, patchy atelectasi and areas of chronic pneumonitis. For end stage lung disease, bilateral lung transplantation is an option. With wellmanaged CF, however, disease progression is slow and pulmonary function can remain excellent for a long time. Freque CF visits, respiratory tract cultures, and measurement of pulmonary function are essential.

Beginning at diagnosis, airway clearance is initiated as a critical part of daily therapy ( Table 2 ). For infants, this means chest physiotherapy, whereas older children and adults more often use device-based techniques such as high frequency chest wall oscillation (vest), positive expiratory pressure (PEP) mask, or oscillatory positive expiratory pressure (Acapella Quake, Flutter). Inhaled bronchodilators such as albuterol (Proventil) or levalbuterol (Xopenex) are often used before respiratory therapy. Nebulized dornase alfa (Pulmozyme) provides documented pulmonary benefits and is commonly incorporated into daily therapy early in life; it reduces mucus viscosity by cleaving DNA, which is present in high levels in CF airways from degraded neutrophils. Nebulized hypertonic saline (7%)[1, ] [6 ] recently was found to improve pulmonary status in CF patients, presumably by inducing mucus hydration and improved secretion clearance.

TABLE 2 -- Common Maintenance Therapies Pancreatic Enzymes Pancrelipase (Creon, Ultrase, Pancrease, Pancrecarb) 1000-2500 U lipase/kg/meal Fat-Soluble Vitamins Vitamins A, D, E, K (AquaDEK, ADEK, ABDEK, Vitamax) 1 mL liquid or 1 or 2 tabs qd Nutritional Supplements High-calorie drinks (Scandishake, Boost Plus, Ensure Plus) Once or twice daily if needed Maintenance Respiratory Medications Albuterol (Proventil) or levalbuterol (Xopenex) 1 nebule or 2-4 puffs bid Dornase alfa (Pulmozyme) 1 nebule (2.5 mg) qd Hypertonic saline, 7%[1 ] , [6 ] 4 mL nebulized qd or bid Tobramycin for inhalation (TOBI) 1 nebule (300 mg) twice daily, in cycles of 28 d on, 28 d off (P. aeruginosa –colonized patients) Airway Clearance Techniques Chest PT, high-frequency chest wall oscillation (vest), PEP mask, oscillatory PEP (Acapella, Quake, Flutter) Twice daily with inhaled therapies Anti-inflammatory Medication Azithromycin (Zithromax) [1 ] 250-500 mg three times weekly (P. aeruginosa –colonized patients) Drug or Therapy Usual Dosage or Frequency Abbreviations: PEP = positive expiratory pressure; PT = physical therapy.

1 Not FDA approved for this indication. 6 May be compounded by pharmacists.

Managing airway infections is key to preserving lung function, and antibiotics are used heavily for both treatment and suppression of bacterial infection. Prophylactic antibiotics are generally not favored. Programmed chronic cycling of inha tobramycin (TOBI) in patients colonized with P. aeruginosa has been proved to decrease bacterial load, decrease neutrophilic inflammation, improve pulmonary function, and decrease exacerbations. For acute treatment of airway infection, the choice of oral, inhaled, or intravenous antibiotic therapy depends on the severity of clinical presentation. Signs of pulmonary exacerbation include increased cough and sputum production, dyspnea, decreased energy, weight loss, new findings on chest auscultation or x-ray, and decreased lung function. For mild exacerbations, oral antibiotics along with intensified respiratory therapies may be adequate; if P. aeruginosa is known or strongly suspected, ciprofloxac (Cipro, 15 mg/kg bid for children[1 ] ; 500-750 mg bid for adults) or levofloxacin (Levaquin, 500-750 mg daily) may be selected. When intravenous therapy is needed, typically a combination of a ß-lactam and an aminoglycoside is appropria ( Table 3 ), and prior culture and sensitivity information may guide specific choices.

TABLE 3 -- Intravenous Antibiotics for Cystic Fibrosis Exacerbations Aminoglycosides Amikacin (Amikin) 5-7.5 mg/kg q8h Peak 25-30 µg/mL, trough 5-10 µg/mL Gentamicin (Garamycin) 3 mg/kg q8h Peak 8-12 µg/mL, trough 5/hour) among adults between 30 and 60 years of age has been estimated at 9% for women and 24% for men. The prevalence of the OSA syndrome, which includes symptoms of excessive sleepiness, is estimated at 2% for women and 4% for men. Clearly, male gender represents an independent risk factor for OSA when compared with premenopausal women. The prevalence among women increases with menopause. In regard to ethnicity, African American, Pacific Islander, and Mexican American patients might be at increased risk for OSA. Clinical Features Snoring represents the most common feature of OSA and is usually reported by a bed partner. Many patients are prompted by their spouses to pursue consultation after many years of enduring the disruptive effects of snoring during sleep. The description of periods of snoring followed by periods of silence, which are terminated by breakthrough snoring make the diagnosis of OSA very likely. In many instances, the patients are described as experiencing stop-breathing episodes during their sleep. Affected patients might not be aware of any difficulties during their sleep, but some report persistent

nocturnal awakenings; some of the awakenings might be associated with a sensation of choking, smothering, or gasping. Nocturnal perspiration, nocturia, and symptoms of nocturnal gastroesophageal reflux are commonly associated with severe OSA. Patients might report awakening unrefreshed, with a dry mouth, and with a headache. Daytime symptoms are commonly encountered; the most frequent complaint is excessive sleepiness, which is a consequence of disrupted sleep. Increased risk of motor vehicle accidents has been reported among OSA patients, and assessment of the patient's level of sleepiness in the context of their employment and their exposure to driving or operating machinery needs to be established during the clinical assessment. Associated features of excessive sleepiness may be manifested as fatigue, impaired memory and concentration, depression, and changes in personality. Among male patients, impotence due to low testosterone levels has been established in some severe cases of OSA. Obesity is common in OSA, and a graded increase in OSA prevalence has been documented with increasing body mass index (BMI), neck circumference, and waist-to-hip ratio. However, a potential diagnosis of OSA should not be dismissed in a nonobese patient presenting with symptoms or having risk factors associated with a potential diagnosis of OSA. Physical findings such as a crowded oropharynx with evidence of a redundant soft palate, redundant soft tissue in the oropharyngeal examination, relative macroglossia, and tonsillar hypertrophy are often encountered among patients with OSA. A narrow oropharynx with a high arched palate and short intermolar distance has also been described among some patients with OSA. Retrognathia or micrognathia might also result in narrowing of the retroglossal area, which might increase the risk of OSA when sleeping in the supine position. OSA has been shown to represent an independent risk factor for systemic arterial hypertension. Thus, difficult to control hypertension should raise the possibility of a diagnosis of OSA. Untreated OSA might also represent a risk factor for stroke; new-onset atrial fibrillation (in particular if triggered during sleep) should raise the clinical suspicion of OSA. Other medical conditions that appear to predispose to OSA include nasal obstruction, nasal septal deviation, hypothyroidism, acromegaly, and congestive heart failure. Evidence of a potential link between OSA and insulin resistance (and diabetes mellitus) has been reported. Ongoing research is actively pursuing this pathophysiologic pathway, and the increased prevalence of the metabolic syndrome in the general population makes the clinical suspicion of OSA very relevant in these patients because both conditions share a number of clinical characteristics. In fact, it is conceivable that the increased cardiovascular risk conferred by OSA is, at least in part, mediated through the metabolic syndrome. Screening and Testing LABORATORY SLEEP TEST The definitive diagnosis of OSA requires an in-laboratory attended sleep test (nocturnal polysomnography), which enables the characterization of multiple physiologic variables. Recording of a limited number of channels in the patient's home can be used for screening purposes (ambulatory oximetry or cardiorespiratory studies, which yield estimates of respiratory disturbance). Although in some cases ambulatory studies might render confirmation of the diagnosis, there is no consensus at present as to the ideal algorithm to be followed to allow the diagnosis of OSA without a sleep laboratory assessment. Ongoing research

efforts will likely result in the diagnosis and treatment of some OSA populations without the need for inlaboratory testing. The in-laboratory sleep test allows characterization of ventilation during sleep. Ventilation includes number of central and obstructive apneas, hypopneas, and RERAs and detailed information on oxygen saturation as well as the depiction of the potentially relevant positional effects on the frequency of respiratory events. Laboratory testing also includes a complete accounting of sleep variables, monitoring of cardiac rhythm, and assessment of possible restless legs syndrome (RLS) or periodic limb movements (PLMs) during sleep. This information enables the clinician to determine the severity of the condition and identifies potentially relevant comorbidities (RLS, PLMs, cardiac arrhythmias). The split-night protocol during the laboratory assessment allows the clinician to derive the diagnosis of the condition during the first half of the night (ideally 4 hours of diagnostic testing with a minimum of 2 hours if an AHI >40 is confirmed). During the second half of the night, the clinician can titrate continuous positive airway pressure (CPAP), which requires a minimum of 3 hours of sleep. This protocol is a cost-effective use of laboratory resources that allows the clinician to identify therapeutic CPAP settings to help implement therapy at home, and in most instances there is no need for a second sleep study. This protocol is particularly well suited for patients with severe OSA. The possible implementation of CPAP titration should be discussed with the patient in advance, because the initial experience with CPAP is a major determinant of long-term use. Several algorithms are available to make clinical predictions about the likelihood of a positive diagnosis of OSA. In general, an obese patient with a large neck size (=17 in for male patients; =16.5 in for female patients) and symptoms of excessive sleepiness is likely to be a good candidate for split-night studies. In cases were a diagnostic polysomnography identified a diagnosis of OSA and CPAP is the therapy of choice, a second night in the laboratory for CPAP titration is indicated. WHOM TO TEST AND THERAPEUTIC OPTIONS Clinical signs and symptoms are not necessarily sensitive or specific enough to establish a definitive diagnosis of OSA. Therefore, sleep studies are required for patients who are symptomatic and for others who are asymptomatic but have clinical signs that suggest the diagnosis. Testing allows the examiner to define the severity of the condition, and the results (with adequate clinical correlation) should guide therapeutic intervention. Epidemiologic data have helped define the index of severity. An AHI of 5 or higher has been shown to represent the minimum threshold value for increased risk of hypertension and an AHI greater than 30 has been associated with a substantial increase in the risk of hypertension. Thus, mild OSA is defined as an AHI of 5 to 15 per hour, moderate OSA is an AHI of 15 to 30 per hour, and severe OSH is an AHI greater than 30 per hour. In addition, a clinically derived index of severity of excessive sleepiness should be determined based on the presence of unwanted sleepiness or involuntary sleep episodes (mild if the episodes occur during activities that require little attention, moderate if the manifestations are associated with activities that require some attention, and severe if sleepiness is present in activities that require active attention).

CURRENT DIAGNOSIS Symptoms and Signs Excessive sleepiness Resuscitative snoring or loud snoring Witnessed stop-breathing episodes Nocturia Risk Factors Obesity; large neck circumference (central obesity) Sex: men, postmenopausal women Age: 30 to 65 years Abnormal upper airway (e.g., nasal obstruction, large tongue, redundant soft tissue, large tonsils, retrognathia) Family history of obstructive sleep apnea Many patients are motivated to pursue treatment because of their desire to eliminate snoring, and others want relief of symptoms of excessive sleepiness. An increasing number of patients understand the potentially negative cardiovascular consequences of untreated OSA and expect therapy if the diagnosis is confirmed. Therapy is justified if the AHI is greater than 5 per hour, and it should not be delayed if the AHI is greater than 30 per hour. Regardless of the severity of the condition, patients who are overweight should be encouraged to lose weight. In some patients with morbid obesity, bariatric surgery might be a means to enable effective weight loss and likely improvement of ventilation during sleep. Patients should be counseled to avoid practices that can potentially worsen the severity of OSA. The use of CNS depressants before sleep (alcohol, sleep medications, pain medications) might worsen ventilation during sleep and should be discouraged. In some patients with positional OSA, avoiding the supine position during sleep might suffice in helping normalize ventilation during sleep. However, one needs to question how this can be done effectively over a long time. If upper airway pathology is identified (nasal septum deviation, enlarged tonsils, craniofacial abnormalities), surgical consultation should be pursued. If patients have symptoms of excessive sleepiness, they should be counseled to avoid driving or operating machinery, and the appropriate local laws should be followed regarding the need to notify the relevant administrative authorities. Treatment CPAP THERAPY The proper positive airway pressure delivered by a flow generator through an interface of the patient's choice represents the gold standard in the therapy of OSA, because it is almost always successful in

maintaining upper airway patency and oxygen saturation, and it improves sleep continuity and architecture. The main barrier to successful therapy is nonacceptance of the therapy or low therapeutic adherence. Treatment is effective as long as the patient uses the device for the entire night, every night. The use of integrated heated humidifiers has minimized issues of upper airway dryness and has helped improve adherence to therapy. There are many manufacturers of CPAP devices and many interfaces that help maximize comfort with treatment. The clinician should be aware of the characteristics of the specific CPAP unit that is being prescribed to the patient and should monitor the level of comfort of the interface that the patient has selected. Expiratory pressure release (EPR) is available through a couple of CPAP manufacturers. EPR does not seem to compromise the effectiveness of CPAP therapy and improves the patient's sense of comfort with therapy, but it does not seem to systematically improve the level of adherence.

CURRENT THERAPY Continuous positive airway pressure (CPAP) represents the gold standard of therapy. Patient education, adequate CPAP settings, and a comfortable interface are critical to achieve a desirable level of treatment adherence. Integrated heated humidification minimizes nasal dryness and improves CPAP adherence. Clinical follow-up to assess tolerance to CPAP and resolution of symptoms is critical to achieve desired outcomes. Improved sleep schedule practices should be encouraged and comorbid conditions should be treated. •

Oral appliance therapy and surgical procedures represent alternative therapeutic options.

Autotitrating CPAP units are available, and their software has been greatly improved. They have been proved effective in improving ventilation during sleep, but no additional clinical benefits over standard CPAP therapy have been demonstrated. Bilevel respiratory assist devices deliver alternating levels of positive airway pressure and might be considered as an alternative therapeutic option when standard CPAP is not tolerated or when oxygen saturation is not raised sufficiently with standard CPAP. In some cases of severe OSA (in particular among patients with underlying pulmonary conditions) supplemental oxygen can be used in conjunction with CPAP therapy. ORAL APPLIANCE THERAPY Prostheses worn in the mouth during sleep can help maintain a patent airway. In general, there are two types of appliances, mandibular advancement appliances and tongue-retaining devices. The mandibular advancement appliances are currently used more often and have been more widely studied. They require viable dentition for retention. They are fitted to the maxillary and mandibular dentition to enable the protrusion of the mandible and therefore increase oropharyngeal patency. The most common side effect is

excessive salivation, but temporomandibular joint pain might limit the viability of this therapy. Chronic use of the appliance can result in a change of the dental occlusion and lead to discontinuation of therapy. A dentist with expertise in sleep medicine should ideally implement and monitor this type of treatment. SURGICAL PROCEDURES Patients with an identifiable anatomic upper airway (soft tissue) abnormality or craniofacial abnormality might benefit from surgery. There are a variety of soft-tissue procedures that might help stabilize the retropalatal region (the uvulopalatopharyngoplasty), and others are intended to stabilize the retrolingual airway (genioglossal advancement and hyoid myotomy). Office-based procedures have also become available, such as the injection snoreplasty and the pillar procedure, which are intended to stiffen the soft palate and thereby decrease snoring and respiratory events. A substantially more invasive procedure, the maxillomandibular advancement, has been shown very effective in a number of case series. However, it is not possible to predict which patients are likely to have a successful surgical outcome. As a result, many patients undergo a surgical procedure that fails to improve their condition and then require additional surgery or medical treatment of OSA. Surgical consultation with an otorhinolaryngologist or oral surgeon should be pursued for patients who might benefit from this therapeutic approach. RESPONSE TO THERAPY The patient's response to therapy needs to be monitored. In the case of CPAP therapy, monitoring of CPAP adherence is critical, because subjective reports are inaccurate. Resolution of excessive sleepiness is the desired outcome for patients who are symptomatic at baseline. If excessive sleepiness remains problematic despite documentation of desirable CPAP adherence, treatment with modafinil (Provigil) 100 to 400 mg in the morning might be considered. Other potential conditions affecting sleep need to be monitored and, if needed, treated. Often, other conditions such as poor sleep hygiene, RLS, PLMs, or psychophysiologic insomnia interfere with adequate response to therapy. For patients who undergo surgery, retesting is indicated. The interval at which retesting should be done depends on the type of surgery that was performed. Retesting 3 months following the surgical intervention is adequate in most cases.



REFERENCES Dinges and Weaver, 2003. Dinges DF, Weaver TE: Effects of modafinil on sustained attention and quality of life in OSA patients with residual sleepiness while being treated with NCPAP. Sleep Med 2003; 4:393-402. Gay et al., 2006. Gay P, Weaver T, Loube D, et al: Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults: A review by the positive airway pressure task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep 2006; 29:381-401. Lindberg and Gislason, 2000. Lindberg E, Gislason T: Epidemiology of sleep-related obstructive breathing. Sleep Med Rev 2000; 4:411-433. Mulgrew et al., 2007. Mulgrew AT, Fox N, Ayas NT, et al: Diagnosis and initial management of obstructive sleep apnea without polysomnography: A randomized validation study. Ann Intern Med 2007; 146:157-166. Rosenthal et al., 1997. Rosenthal L, Bishop C, Guido P, et al: The sleep/wake habits of patients diagnosed as having obstructive sleep apnea. Chest 1997; 111:1494-1499. Rosenthal et al., 2000. Rosenthal L, Gerhardstein R, Lumley A, et al: CPAP therapy in patients with mild OSA: Implementation and treatment outcome. Sleep Med 2000; 3:215-220. Sanders and Givelber, 2006. Sanders M, Givelber R: Overview of obstructive sleep apnea in adults. In: Lee-Chiong TF, ed. Sleep: A Comprehensive Handbook, Hoboken, NJ: John Wiley and Sons; 2006:231240. Senior et al., 2000. Senior B, Rosenthal L, Lumley A, Gerhardstein R, Day R: Efficacy of uvulopalatopharyngoplasty in unselected patients with mild obstructive sleep apnea. Otolaryngol Head Neck Surg 2000; 123(3):179-182. Sleep-related breathing disorders in adults, 1999. Sleep-related breathing disorders in adults : Recommendations for syndrome definition and measurement techniques in clinical research: The report of an American Academy of Sleep Medicine task force. Sleep 1999; 22:667-689.



Chapter 68 – Primary Lung Cancer

Method of: Christopher S. George, MD Teresa M. George, MD Lung cancer is a significant health problem in the United States. It is the second most commonly diagnosed cancer in both men and women. Despite not being the most common form of cancer, it has the highest mortality rate of all malignancies, and tumors of the lung and bronchus account for 32% of all cancer deaths in males and for 25% of all cancer deaths in females. In 2007, it was estimated that 213,380 patients would develop lung cancer and that 160,390 deaths would occur. Both men and women have seen increases in mortality over the last 100 years. The mortality in males is finally starting to decrease; in females, there has been a steady rise in mortality over the last 40 years. Only in recent years has this started to level off. Despite advances in diagnosis and treatment, the overall 5-year survival rate is low at 15%. Risk Factors Cigarette smoking remains the major risk factor for the development of lung cancer. It is associated with pulmonary malignancies in more than 80% of cases. The incidence and mortality trends of lung cancer are reflective of the trends of tobacco use of males and females over the last several decades. Both active and passive tobacco exposure have been implicated in the development of lung cancer. Exposure to tobacco other than in cigarettes (e.g., cigar and pipe smoking) has also caused an increase in the incidence of pulmonary cancers, although to a lesser degree than cigarettes. The smoking of marijuana and cocaine has not been studied as much as cigarette use, but it is believed that use of these substances probably increases the risk of lung cancer. In addition to tobacco, many other environmental and occupational toxins are associated with the development of respiratory cancers. High levels of prolonged exposure to radon, asbestos, haloethers, polycyclic aromatic hydrocarbons, arsenic, and nickel cause lung cancer. Although these increase lung cancer in nonsmokers, the risk appears to be magnified in smokers, demonstrating a synergy between these carcinogens. Other risk factors for the development of pulmonary malignancies include genetic or familial risk factors. First-degree relatives of patients with lung cancer have a 1.5- to 5-fold increased risk themselves. It should be noted that the exact molecular basis accounting for the increased risk is not well understood. Patients with certain benign underlying lung diseases may also be at increased risk for the development of lung cancer. In particular, there is an increased risk in patients with pulmonary fibrosis, asbestosis, and possibly even chronic obstructive pulmonary disease (COPD). Increasing numbers of nonsmokers are developing non–small cell lung cancer in this country. Clinical Manifestations

Occasionally lung cancer is discovered incidentally with bronchoscopy or chest x-ray; in the majority of cases, patients present with signs and symptoms. The exact clinical presentation depends on the site and spread of the primary tumor ( Table 1 ). Many of the symptoms are nonspecific and may be seen more often in other disease entities. Most commonly, patients present with cough, dyspnea, chest pain, or hemoptysis. Fatigue, weight loss, and bone pain are also seen in patients, especially those with metastatic disease.

TABLE 1 -- Clinical Manifestations Associated with Primary Associated with Intrathoracic Secondary to Lesion Spread Metastases

Paraneoplastic Syndromes

Cough

Pleural effusion

Bone pain

Hypercalcemia

Dyspnea

Pericardial effusion

Generalized weakness

Hypertrophic osteoarthropathy

Hemoptysis

Hoarseness

Weight loss

SIADH

Chest pain

Superior vena cava syndrome

Headache

Cushing's syndrome

Weight loss

Pancoast syndrome

Nausea

Eaton-Lambert syndrome

Unilateral wheezing

Horner syndrome

Vomiting

Cerebellar ataxia

Fever secondary to pneumonia

Neurologic symptoms Dementia Abdominal pain

Sensorimotor neuropathies

Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

There are several distinct syndromes that can be seen with pulmonary malignancies. Some of these are caused by the tumor's spread into the mediastinum or surrounding structures. In the superior vena cava syndrome, patients may exhibit periorbital and facial edema and headaches. In later stages, this may be accompanied by a bluish discoloration and new vessel formation on the anterior chest. Pancoast syndrome results from involvement of the brachial plexus by superior sulcus tumors. Patients may present with shoulder and arm pain with associated sensorimotor changes. If the sympathetic trunk is involved, patients may have Horner syndrome, which is characterized by ptosis, miosis, facial flushing, and anhidrosis on the side affected by the tumor.

CURRENT DIAGNOSIS Lung cancer is the second most common cancer in the United States, but has the highest mortality Cigarette smoking is the major risk factor Most common symptoms are cough, dyspnea, chest pain, and hemoptysis Diagnosis is made by cytologic specimen or histologic biopsy Staging must be done on all patients and should consist of history, physical examination, laboratory studies, and radiographic examinations Preoperative evaluation must be done in patients who are considered for surgery In addition to syndromes caused by direct extension of the tumor, patients may also present with syndromes caused by the production of biologically active substances. Some of these are better understood than others. These are collectively referred to as the paraneoplastic syndromes. Examples of paraneoplastic syndromes observed in lung cancer include hypercalcemia from the production of parathyroid hormonerelated peptide, hypertrophic osteoarthropathy, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), Cushing's syndrome, and Eaton-Lambert syndrome. Diagnosis Once lung cancer is suspected, pathologic diagnosis must be made ( Table 2 ). The diagnosis can be established based on cytologic specimens or histologic biopsy. Cytologic specimens may consist of sputum, bronchial washings or brushings, transbronchial or transthoracic needle aspirates, or bronchoalveolar lavage. Histologic biopsy can be from endobronchial, transbronchial, transthoracic, or open biopsy procedures. Generally, if the lesion is central, bronchoscopy is recommended for evaluation. If the abnormality is peripheral, use of computed tomography (CT)-guided transthoracic needle aspiration or biopsy is recommended. If the diagnosis is still equivocal, a more definitive open procedure may be needed.

TABLE 2 -- World Health Organization Histologic Classification of Epithelial Bronchogenic Carcinoma Malignant Squamous cell (epidermal) and spindle cell carcinoma Small cell

Oat cell carcinoma (lymphocytic-like) Intermediate cell type Combined oat cell carcinoma (mixed histologic types, small with squamous cell carcinoma or adenocarcinoma)

Adenocarcinoma

Acinar Papillary Bronchoalveolar Mucinous secreting

Malignant Large cell

Giant cell Clear cell

Adenosquamous carcinoma

Carcinoid Bronchial gland carcinoma Adenoid cystic Mucoepidermoid

Others Adapted from World Health Organization: Histologic Typing of Lung Tumors, 2nd ed. Geneva, WHO, 1981.

Pretreatment Evaluation After a pathologic diagnosis is established, the pretreatment evaluation must be done. This consists of two main parts: complete staging of the tumor so that treatment recommendations can be made ( Table 3 ), and if surgery is a consideration, a preoperative assessment. The primary care physician can take the initial role in both of these evaluations.

TABLE 3 -- International Staging System for Lung Cancer Distant Metastasis (M)

Stage Groupings of TNM Subsets

Primary Tumor (T)

Nodal Involvement (N)

Tx—Primary tumor cannot be assessed or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

Nx—Regional lymph nodes M0—No distant cannot be assessed metastasis

Occult carcinoma Tx, N0, M0

T0—No evidence of primary tumor

N0—No regional lymph node involvement

Stage 0

M1—distant metastasis present or separate tumor odules in a different lobe

Tis, N0, M0 Tis—Carcinoma in situ

N1—Ipsilateral peribronchial or hilar nodes involved

Stage IA

T1, N0, M0 T1—Tumor = 3 cm in greatest dimension, surrounded by lung tissue and no proximal to the lobar bronchus

N2—Ipsilateral mediastinal or subcarinal nodes involved

Stage IB

Primary Tumor (T)

Nodal Involvement (N)

Distant Metastasis (M)

Stage Groupings of TNM Subsets T2, N0, M0

T2—Tumor >3 cm in greatest dimension, or tumor of any size that involves the visceral pleura or is associated with atelectasis extending to the hilum (but not involving the entire lung) and must be =2 cm from the carina

N3—Contralateral mediastinal or hilar nodes or scalene or supraclavicular nodes involved

Stage IIA

T2, N1, M0 T3—Tumor involves the chest wall, diaphragm, mediastinal pleura or pericardium, or is 4 weeks

Itraconazole (Sporanox) 200 mg, once to twice daily for 6–12 weeks[*]

Severe

Amphotericin B (Fungizone) 0.7 mg/kg/d,[†] then itraconazole 200 mg once to twice daily for 12 weeks Consider corticosteroids (effectiveness not proven)

Chronic Pulmonary Disease Mild to moderate

Itraconazole 200 mg once to twice daily for 12–24 months

Severe

Amphotericin B 0.7 mg/kg/d,[†] then itraconazole 200 mg once to twice daily for 12–24 months

Granulomatous Mediastinitis Mild to moderate

Itraconazole 200 mg once to twice daily for 6–12 months

Severe

Amphotericin B 0.7 mg/kg/d,[†] then itraconazole 200 mg once to twice daily for 6–12 months

Disseminated Disease (without AIDS) Mild to moderate

Itraconazole 200 mg once to twice daily for 6-18 months

Severe

Amphotericin B 0.7 mg/kg/d,[†] then itraconazole 200 mg once to twice daily for 6–18 months[‡]

Type of Histoplasmosis

Treatment Regimen

Disseminated Disease (with AIDS) Mild to moderate

Itraconazole 200 mg once to twice daily for life

Severe

Amphotericin B 0.7 mg/kg/d,[†] then itraconazole 200 mg once to twice daily for life

Meningitis

Amphotericin B 0.7 mg/kg/d[†] to total 35 mg/kg over 3–4 months, then fluconazole (Diflucan)[1] 800 mg daily[3] for 9–12 months

* Blood levels may be checked if poor absorption or increased metabolism is suspected. † If amphotericin B is used exclusively, a total course dose of =35 mg/kg is recommended. Lipid preparation of amphotericin may be given at 3 mg/kg/d; recent studies in AIDS patients suggest better outcomes compared to deoxycholate amphotericin B (see text). ‡ Continue treatment until Histoplasma urine and serum antigen concentrations 1:32 Or

Macrolides Doxycycline (Vibramycin)

Fourfold increase in titer

Fluoroquinolones

Gram stain and culture of sputum

ß-Lactam antibiotics

Extrapulmonary manifestations: bullous myringitis, pericarditis, aseptic meningitis, neuropathy, hemolytic anemia Streptococcus pneumoniae

Acute onset with fever, chills, rigors, and rusty sputum Lobar infiltrate

Person to person

Urinary pneumococcal antigen

Macrolides Vancomycin (Vancocin)

Abbreviations: CF = complement fixation; DFA = direct immunofluorescence; EIA = enzyme immunoassay; Ig = immunoglobulin; URI = upper respiratory infection; PCR = polymerase chain reaction; WBC = white blood cell count.

* Available only to military personnel.

DIAGNOSIS Clinical diagnosis of pneumonia can be problematic. There is no single sign or symptom or a constellation of clinical findings that would clinch the diagnosis of pneumonia. Most patients complain of cough productive of sputum, chest pain (pleurisy), and shortness of breath. The fever, rigors, and chills are common signs as

well. Extrapulmonary symptoms include nausea, vomiting, diarrhea, and mental status change. On physical examination, crackles are often heard during auscultation of the lungs. The signs of consolidation, such as bronchial breath sounds, increased vocal fremitus on palpation, whispering pectoriloquy, and dullness to percussion, may be evident. Chest x-ray finding of consolidation, cavitation, or interstitial infiltration is considered necessary for the diagnosis of pneumonia. However, chest x-ray findings can lag behind clinical findings, particularly in neutropenic or volume-depleted patients. In these cases, we recommend obtaining a follow-up chest x-ray within 24 to 48 hours when clinical suspicion of pneumonia is high. Although CT scan of the chest has higher sensitivity in finding pulmonary infiltration, this costly procedure is warranted only if another underlying pathology is suspected such as an underlying tumor. In classic texts, pneumonia syndrome is discussed under atypical and typical pneumonia headings. Typical pneumonia has an abrupt onset of hours or days. Affected patients are febrile and produce mucopurulent sputum. Chills and rigors are usually present. The chest x-ray shows lobar consolidation, sometimes accompanied by a pleural effusion. Leukocytosis or leukopenia may be present. Leukopenia can indicate more severe disease. The organisms that cause typical pneumonia syndrome include S. pneumoniae, Moraxella catarrhalis, H. influenzae, S. aureus, S. pyogenes, gram-negative enterobacteria, and anaerobes. Atypical pneumonia, on the other hand, has a more insidious onset. Cough is not productive. Fever may be low-grade, and malaise is present. Sore throat and earache can be present. Chest x-ray shows patchy or diffuse ground-glass opacities or alveolar interstitial infiltration. Extrapulmonary signs and symptoms such as headache, myalgias, confusion, and electrolyte abnormalities may be more prevalent. Etiologic agents implicated include M. pneumoniae, C. pneumoniae, Legionella pneumophila, and viral infections. Despite these well-defined clinical syndromes, often there is overlap between the two types and also in the etiologic agents that cause them. Therefore, type of clinical presentation might offer a clue to the etiology; however, it should not interfere with empiric coverage of both atypical and typical agents. Recently, the Centers for Disease Control and Prevention (CDC) reported 15 cases of methicillin-resistant S. aureus (MRSA) community-acquired pneumonia. Disease manifestation was with severe pneumonia, and four of these patients died. Importantly, there was a strong association with previous influenza infection in most cases. Community-acquired MRSA pneumonia should be suspected in severely ill patients during the influenza season. LABORATORY TESTING Usefulness of diagnostic testing to identify specific pathogens has been debated. In only 30% of cases of the community-acquired pneumonia, a specific pathogen is identified via cultures or serologic testing. Empiric treatment of pneumonia, particularly in outpatients, is safe and efficacious. However, there is good, although not proved, evidence supporting diagnostic testing in patients who are hospitalized for communityacquired bacterial pneumonia. These include better tailoring of antibiotic therapy based on pathogen identification, preventing increasing antibiotic resistance, cost saving, and identify-ing reportable causes of community-acquired pneumonia such as L. pneumophila and Mycobacterium tuberculosis or MRSA, which would require in-hospital measures for containment.

CURRENT DIAGNOSIS Clinical diagnosis Fever, cough, purulent sputum Crackles or bronchial breath sounds on auscultation Chest x-ray infiltrate might not be present if the patient is dehydrated or neutropenic: Elicit history for drug-resistant pathogens and nosocomial pneumonia Assess severity of pneumonia using pneumonia severity index calculation Gram stain and culture of expectorated sputum might prove useful if an adequate sample for interpretation (25 white blood cells per high-power field) is obtained and processed by an experienced microbiology technician. Under optimal circumstances, sensitivity of Gram stain for pneumococcal pneumonia can reach 90%. Gram stain and culture of expectorated sputum are particularly valuable in cases of community-acquired pneumonia that do not seem to respond to therapy. This constitutes approximately 10% to 15% of all patients with pneumonia. Because patients are already exposed to antibiotics, microbiological testing at the time of failure to respond to therapy is less likely to yield a specific pathogen. Even with invasive modalities such as bronchoscopy, useful information is available only 40% of the time. We advocate processing of good-quality expectorated sputum for Gram stain and culture on admission to the hospital for this reason. Difficulties in obtaining expectorated sputum should not interfere with administration of empiric therapy. The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) recommend obtaining two sets of routine blood cultures in patients with community-acquired pneumonia. However, this modality has a notoriously low yield when applied to the general population of patients with communityacquired pneumonia. Instead, targeted blood cultures for high-risk patients have been recommended. Patients with recent antibiotic therapy, liver disease, low systolic blood pressure, elevated pulse and temperature, elevated blood urea nitrogen (BUN), elevated sodium, and elevated white blood cell count might have higher yields from blood cultures. Our practice is to obtain blood cultures in sicker patients, such as those with Pneumonia Severity Index (PSI) classes IV and V disease. This assessment, however, often meets resistance, because obtaining blood cultures has become a national quality indicator based on association with improved mortality in elderly patients. Urinary antigen testing for L. pneumophila and S. pneumoniae are now widely available. Because culturing L. pneumophila is difficult and sputum direct fluorescent antibody testing is technically challenging and associated with comparatively low sensitivity, urine testing may be the most practical tool for diagnosis. The test currently detects only L. pneumophila group 1 infection. In North America and Europe, this serotype is responsible for more than 80% of cases. The sensitivity and specificity are particularly good if there is bacteremia. L. pneumophila has higher incidence in sicker patients, such as those admitted to the intensive care unit (ICU). Therefore, the usefulness of the test may be better in this group. Testing for pneumococcal antigen in urine has high sensitivity and specificity. It has been recommended to augment diagnostic testing in community-acquired pneumonia.

When the clinical syndrome of pneumonia is suspected, we order a chest x-ray, complete blood count, sputum Gram stain and culture, and routine chemistry. If patients are febrile (38.4°C), in PSI class IV or V, or received antibiotics recently, urine and blood cultures should be sent for Legionella testing. When widely available and affordable, nucleic acid amplification tests such as polymerase chain reaction (PCR) are likely to have significant impact on diagnostic testing. High accuracy, rapid turnaround time, and applicability to nonbacterial infectious agents are particularly attractive features of PCR. RISK STRATIFICATION AND DECISION TO ADMIT The first questions that face the clinician after establishing the diagnosis of pneumonia are how ill the patient is and whether the patient needs admission to the hospital or ICU. Assessment of the severity of illness determines not only the need for hospitalization but also the choice of antibiotic therapy. A number of prognostic scoring rules have been published to aid the clinician in making this assessment. However, these are not meant to replace good clinical sense. The patient's social setting, likelihood of compliance with therapy, and ability to take oral medicine are other factors that need to be taken into account. ATS and IDSA endorse the calculation of the PSI, which was devised by the Pneumonia Patient Outcomes Research Team (PORT). The goal of this prediction rule was to identify patients with community-acquired pneumonia who had a low risk of mortality and adverse outcome. Accordingly, a two-step tool was devised after identifying variables that were associated with increased mortality from a derivation cohort of more than 38,000 adult patients with community-acquired pneumonia. In the first step, the following variables were queried: age older than 50 years, history of neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease and liver disease, physical findings of altered mental status, pulse 125 beats per minute, respiratory rate 30 per minute, systolic blood pressure less than 90 mm Hg, and temperature less than 35°C or 40°C. If none of these features was present, the patients were assigned to class I and outpatient therapy was recommended. Mortality of patients in class I was 0.1%, and only 5.1% required subsequent hospitalization. If any of these variables was identified, then step 2 of the prediction rule was applied. In step 2, points were assigned for age, whether the patient was a nursing home resident, above-mentioned coexisting illnesses and physical examination findings, and the additional laboratory and radiographic findings of an arterial pH less than 7.35, BUN 30 mg/dL, sodium less than 130 mmol/L, glucose 250 mg/dL, hematocrit less than 30%, PaO2 less than 60 mm Hg, and the presence of a pleural effusion. Based on point score, four more classes (II-V) are formed, each representing a group with greater morbidity and mortality. Low-risk patients in classes I to III with mortality ranging from 0.1 to 0.9% can be managed as outpatients or with brief in-house observation (class III). Higher-risk patients in classes IV and V, with a mortality risk of 9.3% and 27%, respectively, should be admitted to the hospital. The PSI has been validated in a number of prospective trials and shown to reduce hospitalization of low-risk patients, resulting in major cost savings without increases in mortality and morbidity. Nevertheless, its calculation (based on 19 variables) has been found to be cumbersome and impractical for busy outpatient settings. Today, simple software programs that can be downloaded from the Internet can help the clinician calculate this index on hand-held computing devices. One such resource is the Agency for Healthcare

Research and Quality (http://pda.ahrq.gov/clinic/psi/psicalc.asp ), which provides a PSI calculator program that can be downloaded for pocket PC and Palm desktop applications. Simpler indices have also been proposed such as the CURB (confusion, urea, respiration, blood pressure) and CURB-65. CURB includes coexisting disease, and CURB-65 adds the variable of age older than 65 years. Patients who display two or more of these variables should be considered for admission to the hospital. This scheme is endorsed by the British Thoracic Society as a simple and effective means of stratifying patients into risk groups. In a prospective study, PSI had higher discriminatory power, allowing definition of a greater fraction of patients at low risk compared with the CURB indices. Studies suggest that incorporation of severity indices into clinical practice would aid in identifying low-risk patients who can be treated as outpatients and translates into major cost savings. Admission to the ICU of patients with community-acquired pneumonia remains a clinical decision. The American Thoracic Society defined severe community-acquired pneumonia as the presence of one of the two major criteria or the presence of two or three minor criteria. The major criteria are the need for mechanical ventilation and septic shock, and the minor criteria include systolic blood pressure 90 mm Hg or less, multilobar disease, and PaO2/Fi O2 ratio less than 250. TREATMENT Early institution of appropriate treatment for community-acquired pneumonia has been associated with improved outcomes. A number of professional societies have issued guidelines concerning empiric antibiotic treatment. These guidelines emphasize the severity stratification of patients and assessment of the risk of drug-resistant bacteria strains. We will discuss the ATS guidelines that were revised in 2001 and point out some principles that are not covered in the ATS document but covered in IDSA and CDC guidelines. The ATS guidelines approach antibiotic therapy after stratifying patients into outpatients with and without cardiopulmonary disease or modifying factors (groups 1 and 2), inpatients who are not in the ICU with or without cardiopulmonary disease and modifying factors (groups 3a and 3b), and patients who are admitted to the ICU with or without risk for Pseudomonas aeruginosa (groups 4a and 4b). A list of modifying factors, including risk factors for P. aeruginosa are given in Box 1 . BOX 1

Modifying Factors that Increase Risk of Infection Drug-Resistant Streptococcus pneumoniae

•

Age >65 y

•

Alcoholism

•

ß-Lactam therapy in the past 3 mo

•

Exposure to a child in daycare

•

Immunosuppression (including corticosteroids)

•

Multiple medical comorbidities

Enteric Gram-Negative Organisms

•

Broad-spectrum antibiotic therapy >7 d in the past month

•

Cardiopulmonary disease

•

Corticosteroid therapy (>10 mg prednisone daily)

•

Malnutrition

•

Multiple medical comorbidities

•

Nursing home residence

•

Pseudomonas aeruginosa infection

•

Recent antibiotic therapy

•

Structural lung disease (e.g., bronchiectasis)

Multidrug-Resistant Organisms

•

Antibiotic therapy in preceding 90 d

•

Chronic dialysis

•

Current hospitalization of 5 d or more

•

Family member with multidrug-resistant pathogen

•

High frequency of antibiotic resistance in the community or in the specific hospital unit

•

Home infusion therapy or wound care

•

Hospitalization for 2 d or more in the preceding 90 d

•

Immunosuppressive disease or therapy

•

Nursing home residence

•

Presence of risk factors for nosocomial pneumonia

CURRENT THERAPY Community-Acquired Pneumonia Group 1 Outpatients

Newer macrolides or Doxycycline (Vibramycin) Group 2 Outpatients with CPD or MF

Oral ß-lactam plus Oral macrolide or doxycycline or Antipneumococcal fluoroquinolone Group 3 Inpatients

CPD or MF Intravenous ß-lactam plus Macrolide or doxycycline or Intravenous antipneumococcal fluoroquinolone No CPD or MF Intravenous azithromycin (If intolerant, doxycycline plus ß-lactam) or Intravenous antipneumococcal fluoroquinolone Group 4 ICU Patients

No pseudomonal risk Intravenous ß-lactam plus Intravenous macrolide or intravenous fluoroquinolone Pseudomonal risk Intravenous antipseudomonal ß-lactam plus Intravenous antipseudomonal quinolone or Intravenous antipseudomonal ß-lactam plus Intravenous aminoglycoside plus Intravenous macrolide or Intravenous nonpseudomonal fluoroquinolone Hospital-Acquired Pneumonia Early Onset

Ceftriaxone (Rocephin) or Levofloxacin (Leaquin), moxifloxacin (Avelox)[1] or ciprofloxacin (Cipro) or Ampicillin-sulbactam (Unasyn)[1] or Ertapenem (Invanz)[1] Late Onset or MDR Risk

Antipseudomonal cephalosporin or Antipseudomonal carbapenem or ß-Lactam—ß-lactamase inhibitor plus Antipseudomonal fluoroquinolone or Aminoglycoside plus Linezolid (Zyvox) or Vancomycin (Vancocin) Abbreviations: CPD = cardiopulmonary disease; ICU = intensive care unit; MDR = multidrug resistant; MF = modifiable factors (see Box 1 ). 1 Not FDA approved for this indication.

This classification is largely based on the different microbiology observed in each group, and antibiotic coverage is determined accordingly. Patients in group 1 are treated with newer macrolides such as azithromycin (Zithromax) or clarithromycin (Biaxin) or doxycycline (Vibramycin) (patients with allergy or intolerance to macrolides). Patients in group 2 are treated with ß-lactam, such as oral cefpodoxime (Vantin), cefuroxime (Ceftin), amoxicillin with or without clavulanate (Augmentin, Amoxil), or parenteral ceftriaxone (Rocephin) followed by oral cefpodoxime, plus a macrolide or doxycycline. An antipneumococcal fluoroquinolone such as levofloxacin (Levaquin), gatifloxacin (Tequin), or moxifloxacin (Avelox) is also considered adequate coverage for patients in group 2. For patients in group 3a, intravenous azithromycin alone is sufficient. Doxycycline or an antipneumococcal fluoroquinolone can be substituted in patients with macrolide intolerance. For patients in group 3b (cardiopulmonary disease or modifying factors), an intravenous ß-lactam antibiotic and intravenous or oral macrolide or doxycycline therapy is recommended. An intravenous antipneumococcal fluoroquinolone alone is also considered sufficient. For patients in group 4a, combination therapy with an intravenous ß-lactam plus either intravenous azithromycin or a fluoroquinolone should be administered. When pseudomonal risk is present (group 4b), an intravenous antipseudomonal ß-lactam plus intravenous ciprofloxacin (Cipro) or intravenous antipseudomonal ß-lactam plus IV aminoglycoside plus either IV azithromycin or nonpseudomonal fluoroquinolone are appropriate choices. ATS guidelines for empiric treatment of community-acquired pneumonia are summarized in the Current Therapy box, and dosing information for select antibiotics for bacterial pneumonia is given in Table 2 .

TABLE 2 -- Antibiotics Used to Treat Community-Acquired and Hospital-Acquired Pneumonia Drug

Dose

Drug

Dose

Aminoglycosides Amikacin (Amikin)

20 mg/kg/d (trough 35). Profound hypoxemia may be accompanied by cyanosis. Hypotension caused by hypoxemia and vascular collapse may follow. The course of severe viral influenza A is fulminant and of short duration. Physical findings are few in viral influenza (i.e., conjunctival suffusion). Auscultation reveals absolutely quiet lungs because the infectious process is interstitial and not alveolar. Routine blood tests are usually unremarkable except for leukopenia/lymphopenia and, less commonly, thrombocytopenia. Few atypical lymphocytes may be noted, and low titers of cold agglutinins may be present. Cold agglutinins (if present) have low titers less than or equal to 1:16. In severe cases, a pale bluelike hue of the skin may be noted, and there may be bleeding from diffuse intravascular coagulation (DIC) from multiple orifices preterminally. The chest radiograph in uncomplicated viral influenza A is unremarkable or may have minimal perihilar bilateral increased prominence of interstitial markings. In severe influenza A pneumonia, the chest radiograph shows bilateral symmetrical perihilar infiltrates without pleural effusions. Patients may die from severe influenza A without superimposed bacterial pneumonia. Most deaths during the 1918 pandemic were young military recruits who died of influenza A pneumonia without bacterial superinfection. Viral influenza may be complicated by bacterial pneumonia. Bacterial pneumonias complicating viral influenza may occur concurrently at presentation or may present 1 to 2 weeks after the presentation of viral influenza. Viral influenza A presenting concurrently with a bacterial pneumonia is usually caused by Staphylococcus aureus. In contrast to uncomplicated viral influenza, bacterial superinfection is manifested by an increase in fever, shaking chills, leukocytosis, purulent sputum, localized rales on auscultation, bacteremia, and focal/segmental infiltrates on chest radiograph. Alternately, patients with viral influenza A may develop a secondary bacterial infection (same manifestations as noted previously) 1 to 2 weeks later. Secondary bacterial pneumonia is less severe than with concurrent S. aureus and is

usually caused by Streptococcus pneumoniae or Haemophilus influenzae. ANTI-INFLUENZA THERAPY Therapy of viral influenza is directed at inhibiting viral replication and preventing further infection of respiratory epithelial cells. The neuramidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu) have anti-influenza A and B activity. Neuramidase inhibitors decrease the severity and duration of influenza symptoms by 1 to 2 days. Amantadine (Symmetrel) and rimantadine (Flumadine) are useful prophylactically and therapeutically in influenza. Amantadine and rimantadine have anti-influenza A activity, but no influenza B activity. Amantadine and rimantadine inhibit early M2 protein-dependent replication and prevent adherence of the influenza virus to respiratory epithelial cells, thus preventing progression of infection and minimizing further cell to cell spread. Amantadine and rimantadine also affect peripheral airway dilatation and oxygenation is improved, which is of critical importance because patients with severe influenza A uncomplicated by bacterial superinfection die of severe hypoxemia. Mild influenza A/B may be treated with neuramidase inhibitors. Mild cases of influenza A should be treated at the onset of the illness. For severe influenza A, amantadine or rimantadine in combination[1] with neuramidase inhibitors provide optimal antiinfluenza therapy ( Table 1 ). For avian influenza (H5N1), these antiviral drugs may be ineffective. TABLE 1 -- Adult Anti-Influenza Antivirals Antiviral Treatment Dose

Prophylactic Dose

Mild Influenza A/B Zanamivir (Relenza)[†]

2 inhalations (5 mg per inhalation) q12h × 5d

No FDA indication

200 mg (PO) q24h

200 mg (PO) q24h

Persons age 65: 100 mg

Persons age 65: 100 mg

Severe Influenza A Amantadine (Symmetrel)[†]

or Rimantadine (Flumadine)

100 mg (PO) q12h

100 mg (PO) q12h

Persons with hepatic/renal failure (CrCl 35), which suggests an interstitial oxygen diffusing defect typical of severe viral influenza pneumonia. Severe tracheobronchitis is common and is manifested by hemoptysis. Leukopenia/lymphopenia is typical; thrombocytopenia may occur. Low titer elevations of cold agglutinins are not infrequent (=1:16).

Patients may have chest pain exacerbated by breathing mimicking pleuritic chest pain. This is the result of direct intracostal muscle involvement with the influenza virus, which results in myositis and pain on inspiration. The chest radiograph in early viral influenza, in mild to moderate cases, is normal or near normal, with minimal, if any, increase in perihilar interstitial markings. The chest radiograph in fulminant cases shows symmetrical bilateral patchy infiltrates without pleural effusion in 24 to 48 hours. Severe viral influenza A is accompanied by severe hypoxemia or cyanosis, which may be followed by a fatal outcome. Influenza pneumonia may present alone without bacterial superinfection. Bacterial infection may accompany or follow. Purulent sputum with viral influenza indicates concurrent bacterial pneumonia usually caused by S. aureus. Bacterial pneumonia following influenza (after 1 to 2 weeks), is suggested by leukocytosis, focal or segmental pulmonary infiltrates, and purulent sputum; the pathogens are not S. aureus, but most commonly are S. pneumoniae or H. influenzae. A laboratory diagnosis may be made by DFA staining of respiratory secretions, viral influenza titers, or viral cultures. Mycoplasma pneumoniae In a patient with CAP and a dry nonproductive cough, without severe headache or myalgias, the most likely diagnosis is M. pneumoniae. M. pneumoniae CAP is commonly accompanied by nonexudative pharyngitis and/or loose stools or watery diarrhea. The temperature is usually less than 102°F (38.9°C) and is not accompanied by frank rigors or pleuritic chest pain. Relative bradycardia and elevations in the serum transaminases are not features of M. pneumoniae CAP. Respiratory viruses are often associated with mild elevations of cold agglutinins (=1:16) but M. pneumoniae is the only pathogen causing CAP associated with highly elevated cold agglutinin titers (=1:64). Elevated cold agglutinin titers occur in up to 75% of patients with M. pneumoniae, and occur early and transiently. In a patient with CAP, elevated cold agglutinin titers (>1:8) effectively rule out the typical pathogens, as well as Legionella species and C. pneumoniae. Elevated M. pneumoniae ELISA IgG titers indicate past exposure/infection and not current infection or co-infection with another pathogen. In the absence of an antecedent respiratory tract infection (e.g., nonexudative pharyngitis, otitis, etc., in the preceding 3 months), the presence of an increased M. pneumoniae ELISA IgM titer is diagnostic of acute infection. THERAPY M. pneumoniae has a predilection for the respiratory epithelial cells and resides literally on their surface. Mycoplasmas have no definite cell wall like the typical pathogens causing CAP. Their position on the surface of the respiratory epithelium and their absence of a cell wall necessitates the therapeutic approach, which

includes non–ß-lactam antibiotics with the capacity to penetrate into the Mycoplasma organisms. Traditionally, macrolides and tetracyclines have been used successfully to treat M. pneumoniae. Both CAP tetracyclines and macrolides are effective against Mycoplasma because they interfere with intracellular protein synthesis at the ribosomal level. Tetracyclines penetrate intracellularly better than macrolides, with the exception of penetration into the alveolar macrophage, which is relevant in Legionella, but not M. pneumoniae, infections. Macrolides and tetracyclines are both active against Mycoplasma; the relative lack of penetration by macrolides into respiratory epithelial cells accounts for differences in therapeutic response. Patients treated with macrolides or tetracyclines defervesce rapidly over 24 to 48 hours. Clinical defervescence manifests by an increased feeling of well-being and a decrease in fever. The dry cough persists during and after therapy regardless of the anti-Mycoplasma antimicrobial used. There are important differences in the shedding rates of Mycoplasma from respiratory epithelial cells posttherapy when using tetracyclines instead of macrolides. Tetracycline therapy is associated with a more rapid decrease in shedding. Tetracyclines with better ability to penetrate intracellularly, such as doxycycline (Vibramycin), are the most rapid at decreasing Mycoplasma shedding, which is an important public health consideration. Mycoplasmas are transmitted by aerosolized droplet infection. Because patients with Mycoplasma have a prolonged cough, organisms not eliminated from respiratory epithelial cells may be aerosolized during coughing for weeks following the acute infection, spreading the infection to susceptible individuals via aerosolized droplets. The aim of therapy is to rapidly treat the patient's pneumonia and extrapulmonary sites of involvement. The secondary goal is to rapidly decrease shedding and aerosolization to prevent the spread of Mycoplasma to other individuals. An additional therapeutic goal is to decrease the incidence of post-Mycoplasma asthma seen in some patients. M. pneumoniae CAP may exacerbate preexisting asthma, but may also cause permanent post-CAP asthma in some individuals. Until recently, doxycycline was the most active antimicrobial to use against M. pneumoniae. Currently, the “respiratory quinolones,” levofloxacin (Levaquin), gatifloxacin (Tequin), moxifloxacin (Avelox), and gemifloxacin (Factive), are all highly active anti-M. pneumoniae antimicrobials. Telithromycin (Ketek), a ketolide antibiotic, also has a high degree of anti-M. pneumoniae activity. The respiratory quinolones and telithromycin all penetrate cells efficiently and interfere with intracellular enzymes or protein synthesis of intracellular organisms. Respiratory quinolones and telithromycin are highly effective anti-Mycoplasma agents and rapidly decrease shedding of M. pneumoniae in respiratory secretions. Therapy for M. pneumoniae is ordinarily 1 to 2 weeks. Patients who have impaired cardiopulmonary disease or compromised host may require 2 full weeks of therapy. In patients with borderline cardiopulmonary function, M. pneumoniae as with other relatively low virulence pathogens may present as severe CAP. Antimicrobial therapy for typical or atypical CAP should be directed against the presumed pathogen and not based on co-morbidities. Normal healthy hosts are treated with the same antimicrobial as patients hospitalized with severe CAP. Patients hospitalized with compromised cardiopulmonary function severe Mycoplasma CAP are most often initially treated intravenously with doxycycline (Vibramycin), a macrolide, or a respiratory quinolone. Most patients with M. pneumoniae CAP present in the ambulatory setting, which permits therapy with oral doxycycline, macrolide, a respiratory quinolone, or telithromycin (Ketek) ( Table 2 ).

TABLE 2 -- Antibiotics Effective Against M. pneumoniae Antibiotic Dose (Adult) Mild/Moderate CAP

Antibiotic

Dose (Adult)

Erythromycin

500 mg (base, estolate, stearate) (PO) q6h

Erythromycin lactobionate

1 g (IV) q6h

Clarithromycin (Biaxin)

500 mg (PO) q12h

Azithromycin (Zithromax) 500 mg (IV) q24h × 2 doses, followed by 500 mg (PO) q24h Gemifloxacin (Factive)

320 mg (PO) q24h

Telithromycin (Ketek)

800 mg (PO) q24h

Doxycycline

100 mg (IV/PO) q12h Severe CAP

Doxycycline

100 mg (IV/PO) q12h

Levofloxacin (Levaquin)

500 mg (IV/PO) q24h, or 750 mg IV/PO q24h (may allow for shorter duration of therapy)

Gatifloxacin (Tequin)

400 mg (IV/PO) q24h

Moxifloxacin (Avelox)

400 mg (IV/PO) q24h

CURRENT THERAPY Viral Influenza The aim of therapy is to inhibit the influenza virus and prevent its attachment/spread to uninfected respiratory epithelial cells. The neuramidase inhibitors shorten the course of influenza by 1 to 2 days and have antiviral activity. These agents are active against both influenza A and B. Amantadine (Symmetrel) or rimantadine (Flumadine) do not have antiviral properties but are important in prevention/therapy. Amantadine and rimantadine prevent the adherence of influenza virus to uninfected upper respiratory epithelial cells, thereby limiting the extent of the infection. Amantadine and rimantadine also have an important therapeutic effect in influenza A by increasing distal airway dilation and increasing oxygen action; their effect on peripheral airways is important in severe influenza A. Amantadine and rimantadine are not active against influenza B. Amantadine and rimantadine should be given for the duration of viral influenza. Used prophylactically, amantadine and rimantadine should be given before, during, and following an outbreak of influenza A. Mycoplasma pneumoniae

The agents active against M. pneumoniae are macrolides, tetracyclines, quinolones, and ketolides. ß-Lactam antibiotics are not active against M. pneumoniae because the organisms do not contain a bacterial cell wall. Goals of therapy of M. pneumoniae CAP are to eradicate the infection, decrease the shedding of Mycoplasma in respiratory secretions posttherapy, and to prevent posttreatment asthma. Therapy is equally efficacious with macrolides, doxycycline (Vibramycin), respiratory quinolones, or telithromycin (Ketek) intravenously, orally, or in combination for 1 to 2 weeks. The mode of administration is determined by the severity of the CAP and the setting. Outpatients are usually treated orally. Patients hospitalized with severe CAP are initially treated intravenously and then changed to an oral agent. Resistance to M. pneumoniae with antimicrobials has not been described and is not a clinical consideration.



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Waites and Talkington, 2004. Waites KB, Talkington DF: Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004; 17:697-728.



Chapter 78 – Legionellosis

Method of: Julio A. Ramirez, MD In the summer of 1976, an outbreak of approximately 182 cases of pneumonia occurred in persons attending the American Legion convention in Philadelphia. One year later, Dr. McDade reported the identification of Legionella pneumophila, the bacterium responsible for the infection. Today, the family of Legionellaceae is composed of more than 40 species, with some species having different serogroups. L pneumophila causes approximately 85% of all Legionella infections. L. pneumophila serogroup 1 is the single most common member of the family causing clinical infections. Epidemiology Legionella is an intracellular organism that lives in natural water. In the aquatic environment, the bacteria live and multiply within freshwater amebae. The number of Legionella organisms in the water can increase significantly with appropriate local conditions such as warm temperature, lack of biocides, stagnant water, and presence of amebae and other nutrients. These special conditions can be present in artificial water systems such as cooling towers, whirlpools, decorative fountains, and respiratory therapy devices. The susceptible host acquires the bacteria from water containing the organism. Infection can be acquired by inhaling aerosols containing Legionella organisms or by microaspiration of water contaminated with Legionella. The hospitalized patient with Legionella pneumonia does not require respiratory isolation because legionellosis is not transmitted from person to person. Clinical Features Once Legionella organisms reach the respiratory tract, based on the interactions of the organism with the host immune system, the patient can have four possible clinical outcomes: asymptomatic infection, Pontiac fever, legionnaires' disease, or extrapulmonary disease involving the liver, heart, brain, or other organs. Pontiac fever is a nonpneumonic form of disease characterized by fever, headaches, myalgias, and malaise. The patient has an influenza-like illness, with resolution of disease in a few days without specific antimicrobial therapy. Patients with legionnaires' disease present with community-acquired pneumonia associated with high fever, gastrointestinal complaints such as diarrhea, and central nervous system complaints such as headaches or mental status changes. Hospital-acquired pneumonia can occur if Legionella is present in the hospital water supply. Diagnosis The currently available laboratory tests for diagnosis of Legionella infections include the direct fluorescent antibody stain (DFA), culture, antigen detection in the urine, antibody detection in serum by indirect fluorescent antibody testing (IFA), and DNA amplification using the polymerase chain reaction (PCR). The

DFA stain can detect all L. pneumophila serogroups, but a large number of bacteria need to be present in sputum for a positive result. Legionella can be cultured from respiratory specimens on selective media composed of buffered charcoal–yeast extract agar. The urinary antigen detection has a specificity greater than 95%; the disadvantage is that the test detects only the antigen of L. pneumophila serogroup 1. Clinical specimens that have been used to detect Legionella by PCR include throat swabs, sputum, tracheal suction, bronchoalveolar lavage fluid, pleural fluid, and lung tissue. Treatment In the pulmonary parenchyma, Legionella can infect and multiply inside alveolar macrophages, alveolar epithelial cells, and capillary endothelial cells. The poor clinical outcome with ß-lactam antibiotics is due to their lack of penetration into cells. Antibiotics with good intracellular penetration that can be used as monotherapy for Legionella infections include macrolides, ketolides, tetracyclines, and quinolones ( Table 1 ). Rifampin (Rifadin)[1] is not used as monotherapy because resistance can rapidly emerge when it is used alone.

TABLE 1 -- Antibiotic Therapy for Legionella Infections Antibiotic Oral Dose Intravenous Dose Ketolides Telithromycin (Ketek)[1]

800 mg qd

—

Macrolides Azithromycin (Zithromax) [1] 500 mg qd

500 mg qd

Clarithromycin (Biaxin)[1]

500 mg bid —

Erythromycin (Ery-Tab)

500 mg q6h 1 g q6h

Quinolones Ciprofloxacin (Cipro) [1]

750 mg bid 400 mg bid

Levofloxacin (Levaquin)

750 mg qd

750 mg qd

Moxifloxacin (Avelox)[1]

400 mg qd

400 mg qd

Rifamycins Rifampin (Rifadin)[1]

300 mg bid 300 mg bid

Tetracyclines Doxycycline (Vibramycin)[1] 100 mg bid 100 mg bid 1 Not FDA approved for this indication.

Therapy of the patient with severe disease is initiated with intravenous antibiotics. Once the patient reaches clinical stability, the intravenous therapy can be switched to oral therapy. Doses for the most common antibiotics for intravenous and oral therapy are depicted in Table 1 . In the nonimmunocompromised patient, the recommended duration of therapy is 7 to 10 days. In immunocompromised patients, because they are at risk for relapsing infection, the recommended duration of therapy is 14 to 21 days.

Several antibiotics have demonstrated clinical efficacy in legionnaires' disease. Data with several in vitro and animal studies comparing different anti-Legionella antibiotics indicate that erythromycin (Ery-Tab) is a weak anti-Legionella agent. If erythromycin is selected for therapy, it is important to add rifampin to the regimen to increase intracellular killing. From the family of macrolides, azithromycin (Zithromax)[1] is the most active. The best bactericidal activity in the laboratory is achieved with quinolones. Retrospective observational studies indicate that patients treated with levofloxacin (Levaquin) have a shorter time to reach clinical stability and shorter duration of hospital stay. These antibiotics are considered primary anti-Legionella agents. In clinical practice, I treat immunocompromised patients who have severe legionnaires' disease with a combination of an intravenous quinolone plus an intravenous macrolide (e.g., levofloxacin plus azithromycin). This regimen is based only on the theoretical consideration that synergistic killing may be obtained using a quinolone to alter DNA synthesis and a macrolide to alter protein synthesis.



Chapter 79 – Pulmonary Embolism

Method of: Victor J. Test, MD, FCCP There are estimated to be at least 600,000 episodes of pulmonary embolism (PE) in the United States annually, resulting in between 100,000 and 200,000 deaths. The overwhelming majority of deaths occur when the disease is not suspected or is misdiagnosed. Once the diagnosis is made and effective treatment is initiated, the risk of death diminishes dramatically. The patient who presents with shock has a dramatically higher risk of death from pulmonary embolism. Pulmonary embolism is closely liked to deep venous thrombosis (DVT). Classically, proximal lower extremity venous thrombosis has been reported to be the source of 90% of emboli, but upper extremity thrombosis and catheter-associated thrombosis are often associated with PE as well. The possibility of thromboembolic disease should be considered in patients who present with chest pain, dyspnea, hemoptysis, syncope, or palpitations. The clinical signs of PE are often quite subtle and can include tachycardia, tachypnea, pleural effusion, jugular venous distention, fever, tricuspid regurgitation, and an increased pulmonic heart tone. Lower extremity findings such as asymmetric edema, leg and calf tenderness, erythema, venous cords, and Homan's signs can indicate a lower extremity DVT. Diagnosis CLINICAL RISK The diagnosis of PE and DVT depends on suspicion of the disease. A number of methods can determine the probability that a patient will have a PE. The traditional risk factors have included age greater than 40 years, previous DVT/PE, surgery requiring anesthesia for more than 30 minutes, prolonged immobilization, stroke, heart failure, malignancy (adenocarcinoma and pancreatic carcinoma), fractures of the long bones or pelvis, spinal cord injury, obesity, smoking, pregnancy, estrogen therapy, inflammatory bowel disease, and genetic or acquired thrombophilia. Renal failure, the nephrotic syndrome, central venous catheterization, chronic obstructive pulmonary disease (COPD), and long-distance travel have been identified as risk factors. CLINICAL DIAGNOSIS Traditional tests include arterial blood gas, electrocardiogram, and chest x-ray. Unfortunately, these tests are neither specific nor sensitive. Over the past decade, a bewildering array of diagnostic studies, used alone or in combination, have been evaluated as a means of excluding or confirming the diagnosis of embolism. Patients can be stratified into high-risk, moderate-risk, or low-risk categories by empiric assessment or by using structured clinical prediction rules such as those devised by Wells, which use a point system based on historical factors such as malignancy, hemoptysis, previous DVT/PE, immobilization, recent surgery, tachycardia, clinical evidence of DVT, and absence of an equally likely alternative diagnosis. Clinical prediction rules seem to be less influenced by experience and allow a more standardized approach to the diagnostic process.

CURRENT DIAGNOSIS The diagnosis of pulmonary embolism is guided by suspicion for the disease. Interpretation of the diagnostic testing should be guided by the clinical probability for the presence of pulmonary embolism. Multiple diagnostic tests and evaluations may be required for assessment of pulmonary embolic disease. In the absence of a contraindication to anticoagulant therapy, therapy should be begun while awaiting confirmatory testing in patients at intermediate or high risk. Table 1 shows studies that can exclude the diagnosis of embolism at different levels of clinical probability. Table 2 shows studies that can confirm the diagnosis of embolism at different levels of clinical probability.

TABLE 1 -- Studies that Exclude the Diagnosis of Embolism Clinical Probability Test

Low

Intermediate High

Computed tomography Normal

Normal

—

Contrast angiography

Normal

Normal

Normal

ELISA D-dimer.

Negative

Negative

—

/

Normal or low Normal

Scan

Normal

Abbreviations: ELISA = enzyme-linked immunosorbent assay;

TABLE 2 -- Studies that Confirm the Diagnosis of Embolism Clinical Probability Test

Low

Intermediate High

Computed tomography Positive Positive

Positive

Contrast angiography

Positive Positive

Positive

Duplex ultrasound

Positive Positive

Positive

—

High

/

Scan

Abbreviations:

= perfusion;

High

= ventilation.

= perfusion;

= ventilation.

Often I use a combination of tests to help me rule out the diagnosis of pulmonary embolism. The enzymelinked immunosorbent assay (ELISA) D-dimer is most useful in ruling out the diagnosis in outpatients at low risk or who have a low pretest probability of pulmonary embolism. In patients who are low risk based on the scoring systems, the incidence of pulmonary embolism at 3 months in the setting of a negative highly sensitive D-dimer assay is extremely low. The sensitivities of the different assays result in a wide variability of sensitivities. In general, intermediate-risk and high-risk patients should receive diagnostic imaging. As documented in the PIOPED 1 study, a normal ventilation-perfusion ( / ) scan virtually rules out a pulmonary embolism. A high-probability scan in someone with a moderate or high risk of pulmonary embolism strongly suggests a pulmonary embolism. Unfortunately, the underlying chest x-rays strongly affect the effectiveness of this test. It is still quite useful but is less available because computed tomography (CT) scanning is now the preferred choice in many centers. The advent of the multislice, multidetector CT scanner has had a substantial impact on the diagnosis of pulmonary embolism. The technology associated with CT scanning has been evolving, whereas the technology associated with / scanning has been more or less static. The PIOPED 2 study compared CT angiogram (CTA) with CT angiogram with venography (CTA/CTV). The sensitivity of CTA was 83% and the specificity was 96% for PE. The sensitivity of CTA/CTV was 90% and the specificity was 95%. It is clear from this study that clinicians must still use the concept of pretest probability in assessing for PE. Unfortunately, most centers do not use this technology, and I am often forced to use duplex ultrasonography to augment the negative CT to rule out a significant pulmonary embolism. The CT angiogram also has the benefit of evaluating for lymphadenopathy and for parenchymal lung disease. The crucial disadvantages are the need to obtain a high-quality and well-timed bolus of contrast to obtain an optimal scan as well as the use of intravenous contrast. CTA typically uses more contrast than standard pulmonary angiography. Pulmonary angiography is the standard imaging procedure but in general has fallen out of use in most centers due to its perceived risk and the increased use of CT scanning. Duplex ultrasonography of the venous system may be used to rule out proximal deep venous thrombosis of the lower extremity. A radiographic or anatomically massive pulmonary embolism does not always cause hemodynamic instability. Transthoracic echocardiogram is often used to assess chest pain. In acute pulmonary embolism, the echocardiogram is useful to stratify hemodynamically stable patients to determine which patient is at risk for a poor outcome. The findings of right ventricular dilatation and pulmonary hypertension are poor markers for increased mortality. The echocardiogram may show evidence of right ventricular strain or overload. In addition, the echocardiogram is often used to identify patients at risk for developing hemodynamic decompensation. Therapy Therapy for DVT/PE should be initiated empirically when there is a significant clinical suspicion for the

disease and if the risk of systemic anticoagulation is low, because PE is associated with significant mortality. Tests to confirm or exclude pulmonary embolism should be arranged as soon as possible. Supplemental therapies such as oxygen should be employed as indicated by the clinical situation.

CURRENT THERAPY If the clinical suspicion is high and there are no contraindications, therapy should begin while confirmatory testing is being arranged For hemodynamically stable patients, therapy with dose-adjusted unfractionated heparin or lowmolecular-weight heparin is indicated in the absence of complications. Unfractionated heparin: 80 IU/kg ideal body weight bolus; 18 IU/kg/h infusion with monitoring of the aPTT every 4-6 h. Adjust to an aPTT 1.5-3 times control. Low-molecular-weight heparin: Enoxaparin (Lovenox)[1] 1 mg/kg SC twice a d or tinzaparin (Innohep)[1] 175 anti-Xa IU/kg SC once daily Warfarin therapy (5 mg/d) should be started on d 1 of therapy with heparin in the absence of contraindications. 1 Not FDA approved for this indication.

UNFRACTIONATED HEPARIN Unfractionated heparin (UFH) has been the mainstay of therapy for DVT/PE since the 1970s. Heparin acts by accelerating the activity of antithrombin III. Heparin does not directly dissolve the thrombus, but it prevents the formation of new thrombi. Heparin can be administered subcutaneously or by intermittent intravenous bolus, but is usually given as a constant intravenous infusion to ensure that an adequate therapeutic level has been achieved. Unfractionated heparin requires monitoring of the activated partial thromboplastin time (aPTT). The typical goal for the aPTT is 1.5 to 3.0 times the control value, which corresponds to a plasma heparin level from 0.3 to 0.7 IU/mL anti-Xa activity. In certain circumstances, such as the presence of a lupus anticoagulant, antiXa levels might have to be monitored. It is crucial to achieve a therapeutic level of anticoagulation within 12 to 24 hours of starting therapy or the morbidity and mortality will increase. The therapy should begin with a heparin bolus of 80 U/kg followed by a continuous infusion of 18 U/kg/hour. The aPTT should be monitored every 6 hours and adjusted according to a weight-based nomogram until a therapeutic range has been reached; aPTT can then be monitored daily. The chief complications of unfractionated heparin are bleeding and heparin-induced thrombocytopenia. It is necessary to monitor the platelet count every other day in patients treated with heparin. LOW-MOLECULAR-WEIGHT HEPARIN

Low-molecular-weight heparins (LMWHs) are single-molecular-weight heparin molecules that act on factor Xa. They have the advantage of being more predictable in their dose effect. For most patients, the LMWH preparations do not require monitoring of their effect for short-term therapy. Monitoring of the anti-Xa levels should be undertaken with long-term therapy, in obese patients (>150 kg), in very small patients (5 mm of induration

•

HIV-positive patients

•

Recent contacts of patients with TB

•

Patients with fibrotic changes on chest radiograph consistent with past TB

•

Organ transplant recipients and other immunosuppressed patients (receiving =15 mg/day of prednisone for =1 month[*])

•

Patients receiving tumor necrosis factor-a inhibitors such as infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira)

Reaction >10 mm of Induration

•

Recent immigrants from high-prevalence countries

•

Injection drug users

•

Residents and employees[†] of prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health care facilities, residential facilities for patients with AIDS, and homeless shelters

•

Personnel working in a mycobacteriology laboratory

•

Persons with silicosis, diabetes mellitus, chronic renal failure, certain hematologic disorders, some malignancies (e.g., carcinomas of the head or neck and lung), weight loss of >10% of ideal body weight, gastrectomy, and jejunoileal bypass patients who are at a high risk for developing TB

•

Children younger than 4 years or infants, children, and adolescents exposed to adults at high risk

Reaction >15 mm of Induration

•

Any person with no risk factors for TB

Abbreviation: TB = tuberculosis. Adapted from the American Thoracic Society and the Centers for Disease Control and Prevention: Targeted tuberculin testing and treatment of latent tuberculosis infection. This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999. Am J Respir Crit Care Med 2000;161(4 Pt 2):S221-S247. * In patients treated with corticosteroids, risk of TB increases with increasing dosage and duration. † For persons who are otherwise at low risk and are tested at the start of employment, a reaction of >15 mm induration is considered positive.

CURRENT DIAGNOSIS It is important to distinguish infection with M. tuberculosis from active TB disease. Diagnosing latent TB infection by targeted tuberculin skin testing and use of interferon- –based assays can facilitate institution of treatment for this condition. Patients with active TB disease present with constitutional symptoms such as fever, malaise, anorexia, weight loss, night sweats, and fatigue. They might also present with symptoms related to the organ system(s) involved. The symptoms classically evolve over 4 to 6 weeks. Atypical presentation is common in immunosuppressed persons, such as those with late HIVinfection, miliary TB, or occult extrapulmonary TB, resulting in a delay in the diagnosis. In patients suspected to have active TB disease, appropriate specimens must be collected for microscopic examination and mycobacterial culture and sensitivity testing and histopathologic examination. Diagnosis is established when clinical and radiologic findings are supported by microbiological or histologic evidence of TB. Abbreviation: TB = tuberculosis.

For patients with a negative TST reaction who are subject to repeat TST testing, an increase in reaction size of greater than 10 mm within a period of 2 years should be considered a skin-test conversion suggesting recent infection with M. tuberculosis. TST is not contraindicated for persons who have been vaccinated with bacille Calmette-Guérin (BCG), and a positive reaction to tuberculin in BCG-vaccinated persons indicates infection with M. tuberculosis when the person tested is at increased risk for recent infection or has medical conditions that increase the risk of disease. Use of TST for detecting LTBI is hampered by poor specificity in BCG-vaccinated populations and by its low sensitivity in immunosuppressed persons, who are at highest risk for progression. Recently, blood tests based on detection of interferon- (IFN- ) released by T lymphocytes in response to M. tuberculosis–specific antigens have become available, and these tests seem to offer an improvement over the TST. Compared with the TST, the IFN- –based assays that use M. tuberculosis–specific region of difference 1 (RD1) antigens such as early secretory antigenic target 6 (ESAT6) and culture filtrate protein 10 (CFP10) might have advantages over the TST. The IFN- assays are available in enzyme-linked immunosorbent assay (ELISA) (e.g., QuantiFERON-TB and the enhanced QuantiFERON-TB Gold assay) and enzyme-linked immunospot (ELISPOT) (e.g., T SPOT-TB assay) formats. The QuantiFERON-TB Gold assay is available in two formats, a 24-well culture plate format (approved by the FDA) and a newer, simplified in-tube format. [1,][2] T SPOT-TB is marketed for use in Europe and is likely to receive FDA approval in the future. Recently, QuantiFERON-TB Gold assay received final approval from the FDA as an aid for diagnosing M. tuberculosis infection. These tests are more specific than TST in the BCG-vaccinated population, require no return visit, give results by the next day, and do not have boosting with repeated testing. However, like the TST, IFN- assays cannot reliably differentiate infection associated with TB disease from LTBI. The performance of QuantiFERON-TB Gold assay is being evaluated in the United States in certain populations targeted by TB control programs for detecting LTBI.

A chest radiograph (posteroanterior view for adults, with appropriate shielding if the subject is pregnant; posteroanterior and lateral views for children) is indicated for all patients being considered for treatment of LTBI to exclude active pulmonary TB. If the subject does not present with symptoms of active TB disease and the chest radiograph is normal, sputum smear examination for acid-fast bacilli (AFB) is not considered necessary, and the patient should be considered for treatment for LTBI. 1 Not FDA approved for this indication. 2 Not available in the United States.

ACTIVE DISEASE In immunocompetent persons with TB disease, pulmonary involvement occurs in 80% of patients, 15% have isolated extrapulmonary TB, and 5% can have pulmonary and extrapulmonary involvement. In contrast, in immunosuppressed persons such as those with late HIV infection, pulmonary involvement occurs in 30% of patients, 20% have isolated extrapulmonary TB, and 50% can have pulmonary and extrapulmonary involvement. Patients with active TB disease present with constitutional symptoms such as fever, malaise, anorexia, weight loss, night sweats, and fatigue. They also present with symptoms related to the organ system(s) involved. For example, those with pulmonary TB complain of cough, sputum, and hemoptysis. The symptoms classically evolve over 4 to 6 weeks. However, atypical presentation is common in immunosuppressed patients such as those with late HIV infection, miliary TB, or occult extrapulmonary TB. This results in a delay in the diagnosis and therefore in the institution of specific antituberculosis treatment. Treatment PRETREATMENT EVALUATION In many countries, the WHO guidelines that target resource-poor nations that have a high burden of TB are followed in national programs for control of TB. For operational, logistic, and economic reasons, these guidelines differ from those advocated by the guidelines of the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America (ATS/CDC/IDSA guidelines), which are followed in the United States. In patients suspected to have active TB disease, the ATS/CDC/IDSA guidelines state that appropriate specimens must be collected for microscopic examination and mycobacterial culture and sensitivity testing. In patients with suspected pulmonary TB, three sputum specimens must be obtained. If the patient is unable to produce adequate sputum, induction of sputum using hypertonic saline and bronchoscopy may be performed under appropriate infection-control measures. All patients with TB should have counseling and testing for HIV infection. A CD4+ T-lymphocyte count should be obtained for HIV-seropositive patients. These guidelines also suggest serologic testing for hepatitis B and C viruses (in patients with risk factors); baseline measurement of serum aminotransferases, bilirubin, alkaline phosphates, creatinine, and platelet count; and testing of visual acuity and red-green color discrimination if ethambutol (Myambutol) will be used.

CURRENT THERAPY Treatment of TB has been considered the most cost-effective health intervention ever conceived. Antituberculosis treatment aims to kill the tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the host's tissues to prevent relapse. To accomplish these goals, several antituberculosis drugs must be taken together for a sufficiently long time. The decision to initiate antituberculosis treatment should be based on clinical, radiographic, microbiological, and histopathologic information. When the patient is seriously ill with a life-threatening condition (such as miliary disease, meningitis) that is believed to be possibly due to TB, treatment using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. DOTS is considered an effective way to control TB. Efficiently run TB-control programs based on a policy of DOTS are essential for preventing the emergence of MDR-TB. Treatment of patients coinfected with HIV and TB is essentially similar to the treatment of TB in HIVnegative patients. Differences include potential for drug interactions between the rifamycins and antiretroviral agents and immune reconstitution inflammatory syndrome (IRIS) (paradoxical reactions). Management of MDR-TB is a challenge that should be undertaken by experienced clinicians at centers equipped with reliable laboratory services for mycobacterial cultures and in vitro sensitivity testing because it requires prolonged use of costly second-line drugs with a significant potential for toxicity. Abbreviations: DOTS = directly observed therapy, short course; MDR = multidrug resistant; TB = tuberculosis. PRINCIPLES OF TREATMENT Treatment of TB has been considered the most cost-effective health intervention ever conceived. Antituberculosis treatment aims to kill the tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the host's tissues to prevent relapse. To accomplish these goals, several antituberculosis drugs must be taken together for a sufficiently long period. WHO recommends the directly observed treatment short-course (DOTS) approach as the only way to control TB globally, and DOTS is the key principle on which many of the TB control programs are run globally. The WHO categorization of patients with TB and the appropriate treatment regimens for each category that is followed in many of the national TB control programs is shown in Table 1 . Drugs currently used for treating TB, preparations available currently, the recommend dosage schedule, and regimens described in the ATS/CDC/IDSA guidelines for patients with drug-susceptible TB are listed in Tables 2, 3, and 4 [2] [3] [4] and Box 2 .

TABLE 1 -- World Health Organization Standard Regimens for Treating Tuberculosis

TB Treatment Regimens[*] Initial Phase

Continuation Phase

New sputum smear–positive PTB

2 H3R3Z 3E3

4 H3R3

New smear–negative PTB[†] with extensive parenchymal involvement

2 HRZE

4 HR

Severe concomitant HIV disease or severe forms of EPTB[‡][§]

2 HRZS

4 HR

Sputum smear–positive relapse

2 S3H3R3Z 3E3

5 H3R3E3

Sputum smear–positive treatment failure

1 H3R3Z 3E3

5 HRE

Sputum smear–positive after treatment interruption

2 HRZES/1HRZE

TB Patients Diagnostic Category I

Diagnostic Category II

Diagnostic Category III Sputum smear–negative PTB and EPTB, not severe[¶]

2 H3R3Z 3

4 H3R3

2 HRZE

4 HR

2 HRZS

4 HR

Diagnostic Category IV Chronic and MDR-TB cases

Specially designed standardized and individualized regimens will be required

Adapted from World Health Organization: Treatment of Tuberculosis: Guidelines for National Programmes. 3rd ed. Geneva: World Health Organization, 2003. Abbreviations: E = ethambutol (Myambutol); EPTB = extrapulmonary tuberculosis; H = isoniazid (INH); PTB = pulmonary tuberculosis; R = rifampin (Rifadin); S = streptomycin; TB = tuberculosis.; TBM = tuberculosis meningitis; Z = pyrazinamide.

* Either daily or three times per week. The number before the letters refers to the number of months of treatment. The subscript number after the letter refers to the number of doses per week. † New sputum smear–negative PTB includes all forms of PTB other than primary complex. ‡ Severe forms of EPTB include TBM, disseminated/miliary TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral or extensive pleurisy, spinal TB with or without neurologic complications, genitourinary tract TB, and bone and joint TB. § In patients with TBM on Category I treatment, the four drugs used during the intensive phase should be HRZS (instead of HRZE). Continuation phase of treatment in TBM and spinal TB with neurologic complications should be given for 6-7 months, extending the total duration of treatment to 8-9 months. ¶ Not severe EPTB includes lymph node TB and unilateral pleural effusion.

TABLE 2 -- Drugs Used to Treat Tuberculosis Drug

Preparations

First-Line Drugs Isoniazid (INH, Nydrazid)

Tab: 50 mg,2 100 mg, 300 mg Elixir: 50 mg/5 mL Aqueous sol'n for IM or IV injection: 100 mg/mL

Ethambutol (Myambutol)

Tab: 100 mg, 400 mg, 800 mg,2 1000 mg2

Pyrazinamide

Tab: 500 mg (scored), 750 mg,2 1000 mg2

Rifabutin (Mycobutin)[1]

Cap: 150 mg

Rifampin (Rifadin)

Cap: 150 mg, 300 mg, 450 mg,2 600 mg2 (powder may be suspended for PO dosing) Aqueous sol'n for IV injection[2] Powder for injection: 600 mg

Rifpentine (Priftin)

Tab: 150 mg (film coated)

Second-Line Drugs Amikacin[1] (Amikin)

Aqueous sol'n for IM or IV injection: 0.5-g and 1-g vials

p-Aminosalicylic acid (PAS) (Paser)

Granules: 4-g packets (can be mixed with food) Tab: 0.5 g, 1 g (film coated)[2] Sol'n for IV injection[2]

Capreomycin (Capastat)

Aqueous sol'n [2] for IM or IV injection Powder: 1-g vials for IM or IV injection

Cycloserine (Seromycin)

Cap: 250 mg

Ethionamide (Trecator-SC)

Tab: 250 mg

Gatifloxacin (Tequin)[1]

Tab: 200 mg, 400 mg Aqueous sol'n for IV injection: 200 mg/20 mL

Kanamycin[1] (Kantrex)

Aqueous sol'n for IM or IV injection: 0.5-g and 1-g vials

Levofloxacin (Levaquin)) [1]

Tab: 250 mg, 500 mg, 750 mg Aqueous sol'n for IV injection: 0.5-g, 0.75-g vials

Moxifloxacin (Avelox))[1]

Tab: 400 mg Aqueous sol'n for IM or IV injection: 400 mg/250 mL

Streptomycin

Aqueous sol'n for IM or IV injection: 0.5-g and 1-g vials[2]

Drug

Preparations Powder: 1-g vials for injection

Abbreviations: cap = capsule; sol'n = solution; tab = tablet.

1 Not FDA approved for this indication. 2 Not available in the United States.

TABLE 3 -- Dosage Schedule of First-Line Drugs Used in the Treatment of Tuberculosis Dosage Interval Drug[*]

Daily

2 Days/Week

3 Days/Week

Important Adverse Effects

Ethambutol (Myambutol)[†] Adults 40- 14.5-20.0 55 kg[‡] mg/kg (800 mg)

36.4-50.0 mg/kg 21.8-30.0 mg/kg Ocular toxicity, retrobulbar neuritis (2000 mg) (1200 mg)

Adults 56- 16.0-21.4 37.3-50.0 mg/kg 26.7-35.7 mg/kg 75 kg[‡] mg/kg (1200 (2800 mg) (2000 mg) mg) Adults 76- 17.8-21.1 44.4-52.6 mg/kg 26.7-31.6 mg/kg 90 kg[‡] mg/kg (1600 (4000 mg)[§] (2400 mg)[§] mg)[§] Children

15-20 mg/kg 50 mg/kg (2500 NA (1000 mg) mg)

Isoniazid (INH) Adults

5 mg/kg (300 mg)

15 mg/kg (900 mg)

Children

10-15 mg/kg 20-30 mg/kg (300 mg)[¶] (900 mg)

15 mg/kg (900 mg)[¶] NA

Pyrazinamide Adults 40- 18.2-25.0 36.4-50.0 mg/kg 27.3-37.5 mg/kg 55 kg[‡] mg/kg (1000 (2000 mg) (1500 mg) mg) Adults 56- 20.0-26.8 40.0-53.6 mg/kg 33.3-44.6 mg/kg 75 kg[‡] mg/kg (1500 (3000 mg) (2500 mg) mg)

Hepatotoxicity, CNS effects, lupus-like syndrome, hypersensitivity reactions

Dosage Interval Drug[*]

Daily

2 Days/Week

3 Days/Week

Important Adverse Effects

Adults 76- 22.2-26.3 44.4-52.6 mg/kg 33.3-39.5 mg/kg Hepatotoxicity, hyperuricemia, arthralgias, GI 90 kg[‡] mg/kg (2000 (4000 mg)[§] (3000 mg)[§] tract upset mg)[§] Children

15-30 mg/kg 50 mg/kg (2000 NA (2000 mg) mg)

Rifabutin (Mycobutin)[1] Adults

5 mg/kg (300 mg)

5 mg/kg (300 mg)

5 mg/kg (300 mg)

Children

NA

NA

NA

10 mg/kg (600 mg)

10 mg/kg (600 mg)

Hepatotoxicity, cutaneous reactions; GI reactions, flu-like syndrome, orange discoloration of bodily fluids, drug interactions, uveitis

Rifampin (Rifadin) Adults

10 mg/kg (600 mg)

Children

10-20 mg/kg NA (600 mg)

Hepatotoxicity, cutaneous reactions; GI reactions, flu-like syndrome, orange discoloration of bodily fluids, drug interactions, uveitis

10-20 mg/kg (600 mg)

Adapted from Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-662; and World Health Organization: Treatment of Tuberculosis: Guidelines for National Programmes, 3rd ed. Geneva: World Health Organization; 2003. Abbreviations: CNS = central nervous system; GI = gastrointestinal; max = maximum; NA = no recommendation.

1 Not FDA approved for this indication. * Maximum dosages are given in parentheses. † Ethambutol can be used safely in older children, but it should be used with caution in children younger than 5 years, in whom visual acuity cannot be monitored. In younger children, ethambutol may be used at 15 mg/kg/d if there is suspected or proven resistance to isoniazid or rifampin. ‡ Based on estimated lean body weight. Children weighing more than 40 kg should receive adult doses. § Maximum dose regardless of weight. ¶ The WHO recommends 10 mg/kg as the dose of isoniazid for adults for the thrice-weekly regimen. The WHO recommends 5 mg/kg as the dose of isoniazid for children for the daily regimen.

TABLE 4 -- Treatment Regimens for Patients with Drug-Susceptible Tuberculosis Intensive Phase Maintenance Phase Interval and Doses[*] (Minimum Regimen Duration)

Interval and Doses[*][†] Regimen (Minimum Duration)

Range of Total Doses (Minimum Duration)

RH

130-182 (26 wk)

Regimen 1 RHZE

7 d/wk for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)[‡]

7 d/wk for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk)[‡]

RH

Twice weekly for 36 doses (18 wk)[§]

76-92 (26 wk)

RpH

Once weekly for 18 doses (18 wk)[¶]

58-74 (26 wk)

7 d/wk for 14 doses (2 wk), then RH twice weekly for 12 doses (6 wk) or

Twice weekly for 36 doses (18 wk)[§]

62-58 (26 wk)

5 d/wk for 10 doses (2 wk),[‡] then twice weekly for 12 doses (6 wk)

Once weekly for 18 doses (18 wk)[¶]

44-40 (26 wk)

Regimen 2 RHZE

RpH

Regimen 3 RHZE

Three times weekly for 24 doses (8 RH wk)

Three times weekly for 54 78 (26 wk) doses (18 wk)

7 d/wk for 56 doses (8 wk) or

7 d/wk for 217 doses (31 wk) or

Regimen 4 RHE

RH

5 d/wk for 40 doses (8 wk)[‡]

273-195 (39 wk)

5 d/wk for 155 doses (31 wk)[‡] RH

Twice weekly for 62 doses (31 wk)

118-102 (39 wk)

Adapted from Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-662 Abbreviations: DOT = directly observed therapy; E = ethambutol; H = isoniazid; R = rifampin; Rp = rifapentine; Z = pyrazinamide.

* When DOT is used, drugs may be given 5 d/wk and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. † Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month maintenance phase. The 7-month maintenance phase is 31 weeks, either 217 doses (daily) or 62 doses (twice weekly). ‡ 5 d/wk administration is always given by DOT. § Not recommended for HIV-infected patients with CD4+ T lymphocyte count 20%

300 bpm, grossly irregular ventricular rhythm with marked variability in QRS, morphology, and amplitude

Torsades de pointes

VT associated with a long QT or QTc interval Congenital, acquired (heart block, medications)

Brugada's syndrome

RBBB with ST segment elevation in leads V1 through V3

Ventricular arrhythmias associated with short QT syndrome

QTc = 300 ms

Fascicular tachycardia

Originates from or requires participation of the distal fascicles (right or left bundle branches)

Bundle branch reentrant tachycardia

Reentry involving the His-Purkinje system, usually with LBBB morphology

Idiopathic RBBB VT

Absence of structural heart disease with RBBB morphology, typically responsive to verapamil

Outflow tract VT

Right or left ventricular outflow tract without structural heart disease

Abbreviations: LBBB = left bundle branch block; RBBB = right bundle branch block; VT = ventricular tachycardia.

Supraventricular or Ventricular? The QRS morphology, the QRS width, presence of P waves, relationship of P waves to QRS complexes, and tachycardia regularity help clarify the tachycardia type. The electrocardiogram (ECG) is the most useful noninvasive tool to diagnose tachycardias. When a tachycardia is present, if possible and if time permits, it is best to obtain a 12-lead ECG. Sometimes an intervention such as a carotid sinus massage or adenosine administration during electrocardiographic recording aids in the diagnosis.

Regular supraventricular tachycardias can have P waves preceding, within, or following the QRS complex. Sinus tachycardias have a P-wave morphology similar to that in sinus rhythm on the 12-lead ECG. The P wave generally precedes the QRS complex. Typical AV nodal reentry supraventricular tachycardia has the P-wave immediately following, or in, the QRS complex. On the ECG, a pseudo-r' in lead V1 may be present ( Figure 4 ). In AV reentry supraventricular tachycardia, due to retrograde conduction through an accessory pathway and due to a macro reentry circuit, the P wave follows the QRS complex and is in the ST segment ( Figure 5 ). In sinoatrial reentry tachycardia, the P wave looks the same as in sinus rhythm, but the tachycardia begins and stops abruptly, similar to other supraventricular tachycardias ( Figure 6 ). Atrial tachycardias have P waves that differ from sinus rhythm. The AV interval can be long, short, or variable, and AV block may be present.

FIGURE 4 AV nodal reentry tachycardia started with a premature atrial beat and an associated long PR interval. The arrows point to the pseudo-r' wave in V1. This wave is characteristic of this tachycardia.

FIGURE 5 AV reentry tachycardia caused by retrograde conduction via an accessory pathway. The P wave is buried in the ST segment.

FIGURE 6 Sinoatrial reentry tachycardia. The P wave during tachycardia is similar to the sinus P wave. Tachycardia starts and stops abruptly.

If the P-wave morphology is similar beat to beat, but there is irregular AV conduction, the type of supraventricular tachycardia is an atrial tachycardia or atrial flutter. During atrial flutter, there generally is not a flat baseline but evidence of continuous electrical activity, often in a saw-tooth pattern ( Figure 7 ). Atrial flutter tends to have a rate greater than 250 bpm. Atrial tachycardia can be associated with regular P waves but there is generally an isoelectric baseline and the rate tends to be slower than 200 bpm in most cases.

FIGURE 7 Atrial flutter with 2:1 conduction. The characteristic saw-tooth pattern is notable in leads II, III, and aVF. Sometimes flutter waves can be missed. Atrial flutter can masquerade as other arrhythmias.

An irregular narrow complex tachycardia associated with variable P-wave morphologies is multifocal atrial

tachycardia. If there are no clear-cut P waves and the rhythm is irregularly irregular, the diagnosis is atrial fibrillation. Another example of an irregular narrow complex tachycardia is sinus tachycardia with multiple premature atrial contractions. Most regular wide QRS complex tachycardias are ventricular tachycardias. Other possibilities include supraventricular (or sinus) tachycardia with rate-dependent (phase III) aberrancy or preexisting bundle branch block. Pacemaker-mediated tachycardia is yet another type of a wide QRS tachycardia. Several criteria help distinguish supraventricular from ventricular tachycardia when the QRS is wide. The tachycardia is likely to be ventricular tachycardia if the tachycardia is initiated by a premature ventricular beat with a morphology similar to the QRS during tachycardia ( Figure 8 ). Ventricular tachycardia is more likely if the morphology of the QRS is different from the baseline conducted QRS complexes (but a similar morphology does not rule out ventricular tachycardia).

FIGURE 8 This rhythm strip is ventricular tachycardia initiated by a premature ventricular beat (arrow). This initial beat helps with the diagnosis.

Capture or fusion beats indicate ventricular tachycardia. A capture beat occurs when an atrial beat conducts through the AV node to activate the ventricle before a tachycardia beat. A fusion beat is similar, but it collides and fuses with the ventricular tachycardia, resulting in a beat different from the conducted beat and from the tachycardia. Pseudofusion beats can occur when ventricular tachycardia fuses with a ventricular ectopic beat. Complete or incomplete dissociation of the atria from the ventricles during tachycardia is a key diagnostic

feature of ventricular tachycardia. If the wide complex tachycardia has an unusual morphology atypical for a right or a left bundle branch block, an unusual QRS axis (markedly rightward or superior), and very wide QRS complex (>160 ms with a baseline conducted QRS complex 75 years) patients, diabetics, and female patients are more likely to present with dyspnea as their primary symptom. Patients with AMI usually do not have pleuritic chest pain, which suggests an alternative diagnosis such as pericarditis, pulmonary embolism, pneumothorax, or pneumonia. Patients with tearing pain may have aortic dissection.

FIGURE 1 Algorithm for evaluation and treatment of patients with suspected acute coronary syndromes. ACS = acute coronary syndrome; ALT = alanine amino transferase; ASA = aspirin; CBC = complete blood count; CXR = chest radiograph; ECG = electrocardiogram; H&P = history and physical; IV = intravenous; MI = myocardial infarction; NSTEMI = non-ST-segment-elevation myocardial infarction; NTG = nitroglycerin; PCI = percutaneous coronary intervention; SL = sublingual.

1

Troponin, CBC, electrolytes, creatinine, ALT, CXR.

2

Reserve IV beta-blocker therapy for those patients with other indications for IV beta-blocker therapy.

3

Low-molecular-weight heparin appears superior to IV unfractionated heparin in patients with unstable angina with high risk features and those with NSTEMI. Some interventionists prefer IV unfractionated heparin in patients undergoing coronary angiography/PCI.

4

See Table 1 for risk assessment.

5

For intermediate-risk patients, consider risk stratification if the chest pain unit is available.

6

Consider addition of glycoprotein (GP) IIb/IIIa inhibitor. GP IIa/IIIb inhibitor can be initiated upon admission or just prior to PCI in the cardiac catheterization laboratory.

7

Exercise electrocardiogram preferred; exercise imaging study if baseline ST changes present or if patient is on digoxin; pharmacologic imaging study if unable to walk on treadmill to acceptable workload.

8

Administer reperfusion therapy if symptom onset within 12 hours. Refer for coronary angiography if symptom onset more than 12 hours and persistent chest symptoms or hemodynamic instability.

9

Can consider transport to primary PCI facility if door-to-balloon time still less than 90 minutes.

10

See Table 2 for absolute and relative contraindications to thrombolytic therapy.

11

Door-to-needle time should be less than 30 minutes.

12

Door-to-balloon time should be less than 90 minutes; goal is less than 60 minutes.

PHYSICAL EXAMINATION The physical examination usually does not help significantly in the diagnosis of AMI, but it does it aid in the risk stratification of patients with suspected AMI and in an evaluation for non-AMI etiologies responsible for patient symptoms. Hemodynamic stability should be assessed. Evaluation of jugular venous pressure and wave form can give clues to right ventricular infarction and right atrial pressure as well as indirect information about left heart function and intravascular volume status. Lung evaluation should note the presence of rales, indicating left heart failure. Cardiac palpation can give clues to underlying cardiomyopathy. A soft S1 suggests reduced left ventricle (LV) systolic function or first-degree atrioventricular (AV) block. A holosystolic murmur could indicate mitral regurgitation resulting from ischemic papillary muscle dysfunction or ventricular septal defect. An S 4 gallop is often present, indicating abnormal left ventricular relaxation, whereas an S3 gallop suggests elevated left ventricular end-diastolic pressure. Hypotension at the time of presentation is usually caused by large areas of ischemic myocardium. Hypotension and rales greater than one third of the lung field are indicators of increased morbidity and mortality during hospitalization. Unstable patients should also be assessed for mechanical complications of AMI such as papillary muscle rupture, ventricular septal defect, and left ventricular free-wall rupture. Alternative etiologies responsible for the patient's presentation should also be sought during the physical examination. Symmetry of pulses in all extremities and symmetry of blood pressure in both arms should be assessed in evaluating for aortic dissection. A pericardial rub suggests pericarditis, whereas a pleural rub suggests pulmonary embolism or pneumonia. Palpation of the chest wall may be helpful in identifying musculoskeletal etiologies. However, for unclear reasons, patients with documented AMI may have increased pain with chest wall palpation. ELECTROCARDIOGRAM The initial ECG plays an important role in the diagnosis, risk stratification, and management of patients with AMI and should be performed on all patients with chest pain and/or dyspnea immediately upon presentation. Patients presenting with AMI should be classified as non-ST-elevation ACS or ST-segment-elevation ACS.

This nomenclature is preferred because ST-segment elevation at the time of presentation indicates ongoing myocardial injury and identifies patients who can benefit from prompt reperfusion therapy. The ECG is normal at the time of presentation in 10% of patients with AMI and therefore should be used as a supportive tool in addition to the clinical history, physical examination, and laboratory evaluation. ST-Segment-Elevation Myocardial Infarction

STEMI is characterized by at least 1 mm of ST-segment elevation in two or more contiguous ECG leads. Reciprocal ST-segment depression may be present in leads remote from those with ST elevation and is associated with higher risk. The distribution of ST-segment elevation on the ECG can give clues to the coronary artery responsible for the ischemia ( Table 1 ). A right-sided ECG should be obtained in all patients with inferior STEMI to evaluate for evidence of right ventricular infarction manifest by ST-segment elevation in lead V3R and/or V4R. Marked ST depression in leads V1 to V3 is the hallmark of acute posterior infarction, which can be confirmed by ST-segment elevation in posteriorly placed leads (V7R to V9R), and should be treated as an STEMI. Patients presenting with symptoms consistent with AMI and a new left bundle branch block should be triaged and managed as an STEMI.

TABLE 1 -- Infarct-Related Artery and Associated Distribution of Electrocardiographic ST-Segment Elevation Distribution of ST-Segment 30-Day Mortality with Location of Coronary Occlusion Elevation Successful Reperfusion[*] Proximal LAD (proximal to first septal perforator)

V1-V6, aVL, I, new LBBB common

19.6%

Mid-LAD (distal to first septal perforator and proximal to first large diagonal branch)

V1-V6, aVL, I,

9.2%

Distal LAD (distal to first large diagonal branch) or diagonal branch

V1-V4, or aVL, I, V5-6

6.8%

Right coronary artery

II, III, aVF, V5-6 (V3R, V4R with RV infarction)

6.4%

Left circumflex

V5-6, III, II, aVF (can have minimal ECG changes)

4.5%

Abbreviations: ECG = electrocardiogram; LAD = left anterior descending; LBBB = left bundle branch block; RV = right ventricle.

* Derived from Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I (GUSTO-I) cohort population of patients receiving successful reperfusion therapy.

Other disease entities with associated ST-segment elevation should be kept in mind when assessing a patient with suspected STEMI. These include pericarditis, myocarditis, left ventricular aneurysm, early repolarization, coronary artery spasm, intracranial bleeding, head trauma, and transient left ventricular apical ballooning syndrome.

Non-ST-Segment-Elevation Myocardial Infarction

Patients with NSTEMI can present with marked or minimal ST-segment depression, isolated T wave changes, or with no ST-segment or T wave changes at all. ST-segment depression identifies patients at higher risk who subsequently benefit most from an aggressive management strategy. BIOMARKERS OF CARDIAC INJURY Because of their high sensitivity and specificity for myocardial necrosis, cardiac troponin T and troponin I assays are preferred in the initial evaluation of patients with suspected AMI. Detectable troponin elevations usually occur 3 to 6 hours following onset of myocardial necrosis and thus may not be abnormal at the time of initial presentation. As a result, troponin may not be useful in the early diagnosis of STEMI and is most helpful in discerning UA and NSTEMI. Troponin remains elevated for 7 to 14 days following AMI. Creatine kinase (CK) and CK-MB are less sensitive and less specific for myocardial necrosis. Elevated CK levels are detectable 4 to 6 hours following AMI and peak around 24 hours following the onset of necrosis. CK concentrations return to normal by 72 hours and thus may be useful in the diagnosis of reinfarction. CKMB is not entirely specific for myocardial muscle and can be elevated in situations of skeletal muscle, bowel, and prostate injury. Risk Stratification Several characteristics are associated with a worse prognosis in patients with unstable angina ( Table 2 ), NSTEMI, and STEMI, including advanced age, female gender, hemodynamic alterations (hypotension, tachycardia), left heart failure (pulmonary rales, S3 gallop, elevated BNP [brain natriuretic peptide]), cumulative extent of ST-segment deviation, new bundle branch block, proximal or mid-LAD (left anterior descending coronary artery) occlusion, aspirin use at the time of AMI, elevated C-reactive protein, diabetes mellitus, prior myocardial infarction or prior coronary artery bypass grafting, concomitant peripheral vascular disease, and underlying renal insufficiency. The thrombolysis in myocardial infarction (TIMI) risk scores for STEMI and NSTEMI are prognostically useful (Table 3 and 4 [3] [4]). Intermediate-risk UA patients may be risk stratified over 6to 9 hours with serial biomarkers and an exercise ECG. Ifbiomarkers become positive or the stress test is positive, the patient should be admitted. If negative, the patient should be dismissed with follow-up in 72 hours for re-evaluation and coronary artery disease (CAD) risk factor modification.

TABLE 2 -- Risk Stratification in Patients With Unstable Angina High Risk (20% Event Rate[*])

Intermediate Risk (~6% Event Rate[*])

Presence of at least one of the following:

No high-risk features but at least one of the following:

Low Risk (~ 20 min

-

Age >75 y

-

New or worsening MR murmur

-

Pulmonary edema or evidence of worsening heart failure.

Intermediate Risk (~6% Event Rate[*]) -

Known atherosclerotic vascular disease (prior MI/PCI/CABG, peripheral, cerebrovascular)

-

Rest pain (>20 min) now resolved with moderate or high likelihood of CAD

-

Rest angina 70 y

-

Prior aspirin usage

-

Hemodynamic instability

-

T wave inversions > 0.2 mV

-

Rest angina associated with dynamic ST-segment deviation >0.05 mV

-

Q waves

-

New bundle branch block

-

Ventricular tachycardia

Low Risk (~8

35.9

Abbreviations: BP = blood pressure; HTN =hypertension; LBBB = left bundle branch block; MI = myocardial infarction.

Treatment The goals of initial treatment of patients presenting with AMI are: •

Obtain intravenous (IV) access and stabilize hemodynamics if unstable.

•

Relieve ischemic discomfort using IV morphine and sublingual or IV nitroglycerin.

•

Minimize myocardial oxygen supply-and-demand mismatch with IV ß-blockers (goal: heart rate less than 70 beats per minute as blood pressure tolerates) and supplemental oxygen.

•

Maintain or restore myocardial perfusion using aspirin and heparin (either IV unfractionated or subcutaneous low molecular weight).

Patients with STEMI should receive prompt reperfusion therapy (thrombolysis or primary percutaneous intervention). Table 5 outlines the recommended dosing regimens of medications commonly used in ACS.

TABLE 5 -- Dosage of Medications Commonly Used in the Treatment of Myocardial Infarction

Medication Aspirin

Clopidogrel (Plavix)

Dosing and Administration •

324 mg chewed and swallowed (81 mg × 4) upon presentation, then 81 to 325 mg daily.

•

If unable to take PO, crush and administer via NG tube or as 325-mg rectal suppository.

•

300-mg oral loading dose, then 75 mg PO daily for 9 to 12 mo or indefinitely in high-risk patients.

Heparin •

IV unfractionated

•

•

Low-molecular-weight Enoxaparin (Lovenox) (Dalteparin (Fragmin)

60 U/kg IV bolus (max: 5000 U), then 12 U/kg/h (max: 1000 U/h) for 48 h or PCI (goal aPTT 1.5 = 2.5 × control).

•

1 mg/kg SC Q12 h for 48 to 72 h or until PCI. Initial 30mg IV bolus can be given.

•

120 IU/kg SC (max 10,000 IU) Q12 h.

•

5 mg IV Q5 min × 3 to goal heart rate 60-65/min or hypotension, then 50 mg PO Q12 h.

•

5 mg IV Q5 min × 3 to goal heart rate 60-65/min or hypotension, then 50-100 mg PO daily.

•

500 µg/kg IV bolus, then 50 µg/kg/min titrating to HR.

ß-Blockers •

Metoprolol (Lopressor)

•

Atenolol (Tenormin)

•

Esmolol (Brevibloc)

0.4 mg sublingual Q5 min × 3 for persistent ischemic pain or IV infusion starting at 5-10 µg/min with up titration for persistent ischemic pain. 4 to 6 mg IV; repeat as needed. Nitroglycerin Morphine sulfate GP IIb/IIIa inhibitors •

Eptifibatide (Integrelin)

•

Tirofiban (Aggrastat)

•

Abciximab (ReoPro)

•

180 µg/kg IV bolus, then infuse at 2.0 µg/kg/min × 72 h to 96 h

•

0.4 µg/kg/min IV for 30 min, then 0.1 µg/kg/min × 48 to 96 h

•

Use ony if PCI planned or likely; 0.25 mg/kg bolus followed by infusion at 0.125 µg/kg/min (max 10 µg/min) for 12 to 24 h.

Abbreviations: IV = intravenous; HR = heart rate; NG = nasogastric; PCI = percutaneous coronary intervention; PO = by mouth; SC = subcutaneous.

Aspirin

All patients presenting with a proved or suspected AMI should receive 324 mg of aspirin (four 81 mg tablets chewed and swallowed or as a rectal suppository if unable to take orally) and continue at 81 mg daily thereafter. Aspirin significantly reduces mortality in AMI. In patients with STEMI, aspirin reduces mortality to a similar extent as thrombolytic therapy, with additive benefits of both. Aspirin-allergic patients should receive 300 mg of clopidogrel (Plavix). Clopidogrel

Clopidogrel (Plavix) blocks the platelet ADP receptor and can be given in place of aspirin in aspirin-allergic patients. A 300-mg loading dose is administered with 75 mg daily administered thereafter. We prefer to administer 600 mg clopidogrel in ACS patients who are expected to have PCI within 6 hours of initial medical contact; otherwise, we give 300 mg on admission. The 600-mg dose of clopidogrel has been shown to shorten the time to attainment of maximal platelet inhibition. Clopidogrel is as efficacious as aspirin in AMI. Clopidogrel is beneficial in those undergoing primary percutaneous intervention for STEMI. Clopidogrel in addition to aspirin, compared with aspirin alone, reduces the risk of cardiovascular death, myocardialinfarction, or stroke in patients with NSTEMI who donot undergo percutaneous revascularization (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events] trial) and in those who do undergo percutaneous revascularization (PCI-CURE [Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events] and CREDO [Clopidogrel forthe Reduction of Events During Observation] trials). The decision to give clopidogrel prior to coronary angiography in patients with AMI should take into account the ultimate requirement of coronary artery bypass graft (CABG) in some patients, which would delay CABG for 5to 7 days following the administration of clopidogrel. Clopidogrel, 75 mg daily, should be continued for at least9, and preferably, 12 months following percutaneous coronary revascularization in the setting of AMI. If coronary angiography is not anticipated, clopidogrel should be initiated and also continued for 9 to 12 months. A recent study suggests that clopidogrel imparts incremental benefit when given in combination with thrombolytic therapy in the setting of STEMI. Heparin

Patients presenting with AMI should be treated with either IV unfractionated heparin (IVUFH) (60 IU/kg bolus, then 12 IU/kg per hour infusion) or subcutaneous low-molecular-weight heparin (LMWH), except for STEMI patients receiving streptokinase. In STEMI, IVUFH is required to maintain vessel patency in those receiving a fibrin-specific thrombolytic agent (alteplase, reteplase, andtenecteplase). The use of LMWH in combination with thrombolytic therapy is still being evaluated in clinical trialsand is not currently recommended. Administration ofLMWH reduces the risk of death and ischemic events compared with IVUFH in patients with NSTEMI and inunstable angina when high-risk features are present (seeTable 2). LMWH appears safe when continued up until the time of coronary angiography and percutaneous intervention; however, individual PCI operator preference should be taken into account. LMWH should not be givento patients with significant renal insufficiency (creatinine clearance less than 30 mL per minute) or morbid obesity. ß-Blockers

All patients with suspected or confirmed AMI should receive prompt oral ß-blocker therapy, which should be continued indefinitely in the absence of contraindications. We prefer metoprolol in the acute setting given its relatively short half-life compared with atenolol. Intravenous ß-blockers should be reserved for patients with an urgent indication for intravenous ß-blockade such as those with a concomitant supraventicular tachyarrhythmia. Routine intravenous ß-blocker administration in those with AMI has been associated with worse outcomes, including higher rates of heart failure. ß-blockers are beneficial in AMI due to their ability to reduce oxygen supply-and-demand mismatch by lowering heart rate, reducing myocardial contractility, and reducing afterload through systemic blood pressure reduction. In addition to reducing mortality in AMI, oral ß-blockers also reduce the risk of atrial and ventricular tachyarrythmias and reduce the risk of mechanical complications such as free wall rupture. Nitroglycerin

Nitroglycerin can be administered as a sublingual formulation or as an IV infusion and is given if symptoms of ongoing myocardial ischemia persist. Nitroglycerin does not improve prognosis in AMI and should be used with caution in patients with right ventricular infarction that could result in hypotension. Nitroglycerin should not be administered to patients who have taken Viagra or other phosphodiesterase inhibitor within 24 hours. Glycoprotein IIb/IIIa Inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors block the GP IIb/IIIa platelet receptor, which functions as the receptor for fibrinogen adherence. GP IIb/IIIa inhibitors reduce ischemic complications associated with PCI and should be administered in patients for whom an early invasive strategy is planned. It is not clear if upstream GP IIb/IIIa administration upon admission is superior to initiation in the catheterization laboratory just prior to PCI. Benefit isshown with eptifibatide (Integrilin) and tirofiban (Aggrastat) in patients with non-ST-elevation ACS who do not undergo early PCI. This benefit appears isolated to high-risk patients including those with troponin elevation, ST-segment depression more than 0.5 mV, diabetes mellitus, and LV ejection fraction less than 40%. Post hoc analyses suggest a potential differential benefit of GP IIb/IIIa therapy in men versus women, and it is an area of continued investigation. HMG-CoA Reductase Inhibitors (Statins)

Early, aggressive statin therapy in patients with AMI has been shown to improve early clinical outcomes. Two large randomized trials have demonstrated a clinical benefit in patients randomized to atorvastain 80 mg soon after presentation with AMI. The PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial showed that intensive atorvastatin therapy with 80 mg daily (mean LDL [low-density lipoprotein]: 62 mg/dl) initiated following ACS significantly reduces adverse cardiac events compared with less intensive statin therapy using pravastatin 40 mg daily (mean Ldl:95 mg/dl). A recently published randomized trail (ARMYDA-ACS) demonstrated that pretreatment of ACS patients with atorvastatin 80 mg 12 hours prior to PCI conferred an 88% reduction in 30-day major adverse cardiac events and significantly reduced peri-procedural MI rates. We administer immediate aggressive statin therapy to all patients presenting with suspected ACS/AMI. REPERFUSION THERAPY IN ST-SEGMENT-ELEVATION MYOCARDIAL INFARCTION Patients presenting with STEMI represent a true medical emergency and require accurate, yet expeditious

evaluation and treatment directed at reperfusion of ischemic myocardium. Regardless of the modality of reperfusion used, the time from symptom onset to establishment of myocardial reperfusion is the strongest predictor of myocardial salvage, recovery of myocardial function, and reperfusion-mediated improvements in mortality. Patients receiving successful reperfusion within 2 hours of symptom onset derive the greatest benefit from reperfusion therapy. Thrombolysis

Thrombolytic therapy is the most commonly utilized methodof reperfusion worldwide. The fibrin-specific t-PA derived thrombolytic agents (alteplase [Activase], reteplase [Retavase], and tenecteplase [TNKase]) have proved superior but significantly more expensive than the fibrin-nonspecific agents such as streptokinase. The fibrin-specific agents reduce 30-day mortality rates by 15% compared withstreptokinase and appear to provide similar rates of successful reperfusion and mortality reduction. They differ primarily in the manner in which they are given and subsequently the ease of administration ( Table 6 ). Clinically, successful thrombolysis is associated with resolution of chest symptoms and reduction of ST-segment elevation by at least50%. Patients with persistent symptoms, persistence of ST-segment elevation, and/or hemodynamic instability following thrombolysis should be referred for emergent coronary angiography. The absence of contraindications to thrombolytic therapy should be assured prior to administration ( Box 1 ).

TABLE 6 -- Thrombolytic Agents Fibrin Specific

Thrombolytic

Dosing/Administration

Alteplase (t-PA) (Activase)

15 mg IV bolus, then 0.75 mg/kg over 30 min (max 50 mg), then 0.5 mg/kg Yes over 60 min (max 35 mg)

Reteplase (rPA) (Retevase)

10 U IV bolus over 2 min, then second 10-U IV bolus 30 min later

Tenecteplase (TNK) (TNKase)

0.5 mg/kg single IV bolus (max 50 mg), or weight 10 min) CPR

•

Pregnancy

•

Current use of warfarin (Coumadin) with INR >2.0

•

Noncompressible vascular puncture

•

Significant hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)

•

History of chronic, severe, poorly controlled hypertension

•

Active peptic ulcer disease

•

Prior streptokinase exposure (for repeat streptokinase administration)

Abbreviations: CPR = cardiopulmonary resuscitation; DBP = diastolic blood pressure; INR = international normalized ratio; SBP = systolic blood pressure.

The benefit of routine predischarge coronary angiography in patients with apparent successful thrombolysis has been shown to be beneficial in a recent randomized trial. Patients who successfully reperfuse following thrombolysis and do not undergo in-hospital coronary angiography should undergo a submaximal exercise stress test or pharmacologic stress test prior to hospital discharge. Patients with an abnormal predischarge stress test, recurrent symptoms, or ECG changes, and those with an LV ejection fraction less than 40%, should undergo coronary angiography with PCI as warranted prior to discharge. Early Invasive Versus Conservative Therapy in Unstable Angina/Non-ST-Segment-Elevation Myocardial Infarction

Patients with NSTEMI usually do not have complete occlusion of the culprit coronary artery. Thus emergent

revascularization is generally not indicated except in patients with hemodynamic instability or persistent symptoms despite initial medical therapy. Whether or not patients with UA/NSTEMI benefit from an early invasive approach (i.e., routine coronary angiography and PCI as indicated during hospitalization) was evaluated in three studies using modern antithrombotic/antiplatelet therapy and current PCI technology. The FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), TACTICS-TIMI 18 (Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive orConservative StrategyThrombolysis in Myocardial Infarction), and RITA 3 (Randomized Intervention Trial of Unstable Angina 3) trials demonstrate improved outcomes with an early invasive strategy in intermediate- and high-risk patients with unstable angina and in patients with NSTEMI. In response to the accumulating data demonstrating a benefit from an early invasive approach using contemporary medical management and modern interventional techniques, the ACC/AHA guidelines now recommend an early invasive approach in patients with NSTEMI. ELECTRICAL COMPLICATIONS ASSOCIATED WITH ACUTE MYOCARDIAL INFARCTION Conduction abnormalities are common in patients with AMI and should be assessed in all patients. Ischemia-mediated alterations in cardiac conduction can manifest as AV block (first, second, and third degree), bundle branch block, and fascicular block. Conduction abnormalities at the AV node level in the setting of inferior AMI are usually transient and usually do not require transvenous pacing, even in the setting of high-grade AV block. AV block as well as new bundle branch block in patients with anterior STEMI portends a worse prognosis and is associated with a high risk of progression to complete heart block. Temporary transvenous pacing should be considered in those with anterior myocardial infarction (MI) and Mobitz 2 AV block, third-degree AV block, or new left bundle-branch block (LBBB). Ventricular fibrillation can complicate myocardial infarction and should be treated promptly with unsynchronized electrical shock as per current ACLS guidelines. Table 7 lists recommendations for the approach andtreatment of ventricular tachycardia in the setting ofAMI.

TABLE 7 -- Treatment of Ventricular Arrhythmias Associated With Acute Myocardial Infarction Electrical Arrhythmia Other Therapeutic Measures Shock[*] Sustained polymorphic VT

Yes, 200 J, 300 J, 360 J

As per current ACLS recommendations Normalize electrolyte abnormalities

Sustained monomorphic VT: with symptoms or hemodynamic compromise

Yes, 100, As per current ACLS recommendations 200, 300, 360

Sustained monomorphic VT: without symptoms or hemodynamic compromise

No

Amiodarone (Cordarone), 150 mg IV infused over 10 min, then 360 mg over 6 h (1 mg/min), then 540 mg over 18 h (0.5 mg/min) (max 2.2 g over 24 h)

Nonsustained VT (within 48 h of MI)

No

No treatment recommended unless symptomatic or associated with hemodynamic compromise

Arrhythmia

Electrical Shock[*]

Other Therapeutic Measures

Nonsustained VT (>48 h following No MI)

Electrophysiology study with programmed stimulation. If sustained VT inducible, then insertion of AICD.

Accelerated idioventricular rhythm No

None

Abbreviations: ACLS = Advanced Cardiac Life Support; AICD = Automatic Implantable Cardioverter Defribrillator; MI = myocardial infarction; VT = ventricular tachycardia.

* Energy is for monophasic defibrillators.

ADJUNCTIVE THERAPY/HOSPITAL DISCHARGE MEDICATIONS Aspirin, 81 mg to 325 mg, should be continued indefinitelyin all ACS patients. An angiotensin-converting enzyme inhibitor (ACEI) should be started within 24hours in all hemodynamically stable patients with large anterior infarctions and in patients with LV ejection fraction less than 40%. We prefer starting with a shortacting ACEI such as captopril (Capoten), 3.125 mg by mouth every 8 hours, with titration upward as tolerated. Upon discharge, a longer acting ACEI can be substituted. Statin therapy in the setting of ACS improves short- and long-term outcomes and should be initiated before discharge in all ACS patients regardless of cholesterol levels. Patients should be continued on aggressive statin lipid-lowering therapy with a goal LDL =70 mg/dl. All patients with ACS should be discharged on a ß-blocker unless a contraindication exists. One randomized trial (COMET [Carvedilol Or Metoprolol European Trial]) suggests that carvedilol (Coreg) at optimal doses is superior to short-acting metoprolol tartrate (Lopressor) in patients with symptomatic chronic heart failure and LV ejection fraction of less than 35%. Patients receiving a drug eluting stent as a part of their AMI treatment need to continue clopidogrel therapy uninterrupted for at least 9 and preferably 12 months due to the risk of acute stent thrombosis. Patients receiving a bare metal stent need to continue clopidogrel for at least 1 month uninterrupted following stent placement. This should be reinforced to the patient as a part of their discharge instructions. CARDIAC REHABILITATION/SECONDARY PREVENTION/RISK FACTOR MODIFICATION All patients should undergo cardiovascular risk factor assessment and modification during and following hospitalization. Blood pressure readings should ideally be lower than 120/80 mm Hg. Smoking cessation should be addressed and glycemic control optimized in diabetic patients. Patients should be instructed on an AHA step II low-fat diet, and statin therapy should be initiated and/or modified to achieve an LDL lower than 70 mg/dL. The goal of cardiac rehabilitation is to help the patient safely return to and maintain normal daily activities and promote secondary prevention measures. This generally includes a staged approach with patients attending monitored exercise sessions for the first 6 to 8 weeks following MI during which levels of exercise are gradually increased. Following an uncomplicated MI, patients are instructed to return to work in 14 to 28 days, with driving allowed within 7 to 14 days. Patients with complicated MI, including those with significant ventricular arrhythmias, require a more gradual return to normal daily activities. HOSPITAL FOLLOW-UP VISIT

Patients should generally be seen in follow-up between 3and 6 weeks following hospital discharge. They should beevaluated for recurrence of symptoms, evidence of heart failure, and medication intolerance or noncompliance. Medications should be reviewed individually and therationale for each discussed. Modification of cardiovascular risk factors should continue. A transthoracic echocardiogram should be obtained to assess LV function 4 to 6 weeks following discharge. Patients with an LVEF of less than 30% should be considered for prophylactic internal defibrillator insertion. Patients with an LVEF between 31% and 40% should undergo 48-hour Holter monitoring with subsequent referral to an electrophysiologist if nonsustained ventricular tachycardia (VT) is present.

CURRENT DIAGNOSIS Acute myocardial infarction is defined as the typical rise and fall of cardiac troponin or creatine kinase myocardial band in addition to one of the following: Symptoms consistent with myocardial ischemia Electrocardiogram changes indicating myocardial ischemia (ST-segment depression or elevation) New pathologic Q waves Percutaneous coronary intervention

CURRENT THERAPY All patients with suspected AMI should immediately receive aspirin, 324 mg chewed and swallowed, with subsequent administration of ß-blockers, heparin, and nitrates as indicated. Administration of adjuvant antithrombotic therapy using low molecular weight heparin, clopidogrel, and GP IIb/IIIa inhibitors should be used in high-risk patients including those with NSTEMI. Those with STEMI should receive either thrombolysis (if within 12 hours of symptom onset) or undergo emergent primary percutaneous intervention (if within 24 hours of symptom onset). Patients with NSTEMI and those with unstable angina with high-risk features benefit from an early invasive treatment strategy that includes coronary angiography and percutaneous coronary intervention as warranted. Patients younger than age 75 years presenting with AMI and cardiogenic shock should preferentially undergo emergent coronary angiography with percutaneous coronary intervention. Abbreviations: AMI = acute myocardial infarction; GP = glycoprotein; MI = myocardial infarction; NSTEMI = non-ST-segment-elevation myo-cardial infarction; STEMI = ST-segment-elevation myocardial infarction.



REFERENCES Antman et al., 2004. Antman EM, Anbe DT, Armstrong PW, Bates ER, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2004. Available at www.acc.org/clinical/guidelines/stemi/index.pdf Boersma et al., 2002. Boersma E, Harrington RA, Moliterno DJ, et al: Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomized clinical trials. Lancet 2002; 359:189198. Braunwald et al., 2002. Braunwald E, Antman EM, Beasley JW, Califf RM, et al: ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002; 40:1366-1374. Cannon et al., 2001. Cannon CP, Weintraub WS, Demopoulos LA, et al: Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344:1879-1887. Cohen et al., 1997. Cohen M, Demers C, Gurfinkel EP, et al: A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337:447-452. Fox et al., 2002. Fox KA, Poole-Wilson PA, Henderson RA, et al: Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: The British Heart Foundation RITA 3 randomised trial. Randomized intervention trial of unstable angina. Lancet 2002; 360:743-751. Hochman et al., 1999. Hochman JS, Sleeper LA, Webb JG, et al: Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625-634. Schwartz et al., 2001. Schwartz GG, Olsson AG, Ezekowitz MD, et al: Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001; 285:1711-1718. Yusuf et al., 2001. Yusuf S, Zhao F, Mehta SR, et al: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494-502.



Chapter 98 – Pericarditis

Method of: Brian D. Hoit, MD Although the diagnosis and treatment of pericardial disease is often simple and rewarding, it may offer unexpected challenges and frustrations to both clinician and patient for several reasons. First, the presence of pericardial heart disease may escape detection, often remaining clinically silent, being apparent only during the evaluation of unrelated complaints. In addition, pericardial disease may complicate, and be overshadowed by, extracardiac manifestations from a number of systemic disorders. Second, although guidelines for the diagnosis and management of pericardial diseases are now available, there are few randomized, placebo-controlled trials from which appropriate therapy may be selected and important clinical decisions supported. The physician thus often must rely heavily on clinical judgment because most data originate from small uncontrolled trials and anecdotal experience. Finally, therapeutic options in most cases are limited to nonspecific anti-inflammatory agents, drainage of pericardial fluid, and pericardiectomy. Although there is general agreement on how these measures should be applied in the patient with either very mild or severe disease, there is little consensus on how the large number of cases encountered with clinical manifestations between these two extremes should be managed. With these important caveats in mind, the options available for treating pericardial heart disease are reviewed here. Acute Pericarditis Hospitalization is warranted for most, if not all, patients who present with an initial episode of acute pericarditis to determine an etiology and to observe for the development of cardiac tamponade; close, early follow-up is critically important in the remainder. Table 1 lists the major definable causes of pericardial heart disease; however, in many cases, the etiology of pericardial heart disease is never identified. Features indicative of high-risk pericarditis that warrants hospitalization include fever higher than 38°C (100°F), subacute onset, an immune depressed state, trauma, oral anticoagulant therapy, myopericarditis, large pericardial effusion, cardiac tamponade, and aspirin failure. Establishing the exact cause of acute pericarditis is an important part of management in the high-risk case, but considerable judgment must be exercised when deciding whether and how to investigate suspected acute viral and idiopathic pericarditis.

TABLE 1 -- Etiology of Pericardial Heart Disease

Idiopathic Infectious (viral, bacterial, mycobacterial, fungal, protozoal, AIDS) Neoplastic (breast, lung, melanoma, lymphoma, leukemia; mesothelioma) Post myocardial infarction Radiation induced Nephrogenic (dialytic and uremic) Traumatic (blunt and penetrating, chylopericardium) Connective tissue diseases and arteritides (rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polyarteritis nodosa, Takayasu's arteritis, Wegener's granulomatosis) Myxedema Iatrogenic (diagnostic and therapeutic procedures, drugs) Miscellaneous (sarcoidosis, amyloidosis, Whipple's disease, dissecting aortic aneurysm) Reproduced with permission from Hoit BD: Pericarditis. In Rakel RE, Bope ET (eds): Conn's Current Therapy 2002. Philadelphia, Elsevier, 2002.

Acute pericarditis usually responds to oral nonsteroidal anti-inflammatory drugs (NSAIDs), such as ASA, 650 mg every 4 to 6 hours, or ibuprofen, 300 to 800 mg every 6 to 8 hours. Gastrointestinal (GI) prophylaxis with H2 blockers or proton pump inhibitors is often warranted, particularly in those at high risk or who require longer durations of treatment. Selective COX-2 inhibitors are NSAIDs withfew adverse GI effects, but they are implicated in adverse cardiovascular events; moreover, they have not been tested in acute pericarditis. Cumulative anecdotal data suggest that colchicine[1] (1 mg/day, with or without a 2 mg loading dose), either as a supplement to the use of NSAIDs or as monotherapy, is effective for the acute episode, well tolerated, and may prevent recurrences. Arecent prospective randomized, open-label trial found that colchicine[1] (1 to 2 mg for the first day, followed by 0.5 to 1 mg/day for 3 months) in addition to aspirin was more effective than aspirin alone in reducing symptoms and recurrences. Side effects (diarrhea and nausea) are usually mild and most often do not necessitate withdrawal of thedrug. Chest pain is often alleviated in 1 to 2 days, and the friction rub and ST segment elevation resolve shortly thereafter. The duration of therapy is controversial; a month of NSAIDs (e.g., high-dose aspirin for 7 to 10 days followed by a taper over 3 to 4 weeks) and 3 months of colchicine[1] is a regimen based on evidence. The intensity of therapy is dictated by the distress of the patient, and intravenous (IV) ketorolac (Toradol), 30 mg every 6 hours, or narcotics may be required for severe pain. Although some cases necessitate steroid therapy (prednisone, 60 to 80 mg/day) for a week to control pain (with the dosage tapered carefully on an individual basis thereafter), corticosteroids should be avoided unless there are specific indications (such as connective tissue disease, autoreactive, or uremic pericarditis) because they enhance viral multiplication and may result in recurrences when the dosage is tapered; colchicine[1] may be particularly useful in this situation. Importantly, tuberculous and pyogenic pericarditis should be excluded before steroid therapy is initiated. Intrapericardial instillation of triamcinolone (Kenalog), 300 mg/m2, avoids systemic side effects and is highly effective. Patients in whom pericarditis represents one manifestation of systemic illness (such as sepsis, uremia, connective tissue disease, or neoplasia) should receive therapy directed toward the primary disorder in addition to palliative and supportive treatment.

CURRENT DIAGNOSIS

Acute Pericarditis

Acute Myocardial Infarction

History

Sharp, retrosternal pain, pleuritic, radiates to trapezius ridge

Dull, precordial chest pain, radiates to neck/arm

Physical

Friction rub; may be fever, signs of inflammation, signs of underlying associated diseases

May be murmurs, ventricular gallops; signs of pulmonary congestion

EKG

Diffuse; characteristic evolutionary pattern;

Indicative ST and Q waves; characteristic evolutionary pattern

PR depression; absent Q waves pattern CXR

Echo

May be normal in uncomplicated cases

May be normal in uncomplicated cases

May be signs of effusion, associated diseases

May be large heart, signs of pulmonary congestion

Pericardial effusion confirms clinical suspicion

Regional wall motion abnormalities

May be normal

May identify mechanical complications

Laboratory Nonspecific markers of inflammation;

Characteristic CK and troponin isoenzymes

With extensive pericarditis may see isoenzyme changes characteristic of acute MI Abbreviations: CK = creatine kinase; CXR = chest radiograph; EKG = electrocardiogram; MI = myocardial infarction.


Recurrent Pericarditis Recurrent or relapsing acute pericarditis is one of the most distressing disorders of the pericardium for both patient and physician. Atypical features, such as the absence of physical findings, offer challenges for diagnosis and management and often necessitate close follow-up and rigorous emotional support. Recurrences occur with highly variable frequency over a course of many years; although they may be spontaneous, occurring at varying intervals after discontinuation of drug (i.e., “recurrent”), they are more commonly associated with either discontinuation or tapering of anti-inflammatory drugs (i.e., “incessant”). Painful recurrences of pericarditis may respond to NSAIDs but commonly require additional therapy. A recent prospective, randomized open-label trial compared aspirin (or steroids when necessary) and colchicine[1] (0.5 to 1 mg/day after a 1- to 2-mg load for 6 months) with aspirin alone. This study suggests

that colchicine[1] is both efficacious and safe for the prevention of recurrences; moreover, corticosteroid use was an independent risk factor for further recurrences. When necessary, prednisone is begun at a high dose (1 to 1.5 mg/kg/day) for at least 4 weeks and tapered slowly (approximately 5 mg every 3 days) over the next 2 to 3 months. Azathioprine[1] (Imuran) and cyclophosphamide[1] (Cytoxan) are used to prevent recurrent episodes in patients who fail to respond to high-dose corticosteroids or who experience severe corticosteroid side effects; pericardiectomy should be considered only when repeated attempts at medical treatment have clearly failed, especially when there is evidence (e.g., from serial bone density scans) of steroid-induced complications. Treatment of Specific Causes ofPericarditis PURULENT PERICARDITIS The incidence and bacterial spectrum of purulent pericarditis have changed because of the increasing frequency of cardiac surgery and instrumentation, selection-induced changes in the flora responsible for hospital-acquired infections, and the prolonged survival of immunocompromised hosts. Bacterial pericarditis is treated with surgical exploration and drainage (pericardiectomy is preferable) and appropriate systemic antibiotics. A high index of suspicion is critical because in the appropriate setting, pericardial involvement is often unrecognized when it complicates systemic infection, and the characteristic features of acute pericarditis are frequently absent. The threshold for echocardiography in the septic patient should be low, and whenever purulent pericarditis is suspected, the pericardial space should be explored. Fibrinolytics may be used to lyse fibrous adhesions, liquefy purulent exudates, and prevent constrictive pericarditis. MYCOBACTERIAL AND FUNGAL PERICARDITIS Tuberculosis is a major cause of pericarditis in nonindustrialized countries but is an uncommon cause of pericarditis in the United States. Nevertheless, its incidence is increasing because of HIV infection. Pericardial fluid should be removed, cultured, and antituberculous therapy begun. Depending on the echocardiographic appearance, subxiphoid drainage may be necessary. Some recommend early pericardiectomy in all cases of tuberculosis pericarditis, but the long-term (16 years) prognosis of patients without cardiac compression during the acute illness who are treated with medical therapy alone is excellent. Multiple drug therapy and corticosteroids are effective in tuberculous pericarditis, whereas atypical mycobacterial infections (especially Myobacterium avium intracellulare) may be resistant to treatment. Patients with tuberculous pericarditis should receive triple drug therapy (isoniazid, 5 mg/kg to a maximum of 300 mg; rifampin [Rifadin], 10 mg/kg to a maximum of 600 mg; and either streptomycin, 15 mg/kg toa maximum of 1 g, or ethambutol [Myambutol], 5 to 25 mg/kg to a maximum of 2.5 g) for a minimum of 9 months. Corticosteroids (prednisone, 1 to 2 mg/kg/day) may be useful if pericardial effusion persists or recurs during therapy, and they appear beneficial acutely in reducing morbidity and mortality. Pericardiectomy may be necessary for recurrent cardiac tamponade. Patients should be observed for constriction because upto half of patients require pericardiectomy; failure toimprove or worsening over 1 to 2 months, pericardial thickening, or evidence of constriction requires urgent pericardiectomy. In patients with hemodynamics consistent with effusive-constrictive pericarditis, plans for visceral and parietal pericardiectomy after a few weeks of chemotherapy are advisable. Persistent hypotension may signify tuberculous adrenal insufficiency. Pericarditis complicating deep fungal infection with histoplasma or coccidiomycosis may be immunologic,

resolve spontaneously, and not require specific therapy. Amphotericin B (up to 2.5 g total), itraconazole (Sporanox), 200 to 400 mg/day, ketoconazole (Nizoral), 200 to 400 mg/day, and fluconazole (Diflucan), 200 to 400 mg/day, are rarely required. Tamponading effusion and constriction require decompression. Surgical decompression and specific antifungal or antimicrobial therapy may be necessary for disseminated infection with Candida, Aspergillus, Actinomycetes, and Nocardia.

CURRENT THERAPY

Type

Therapy

Acute viral/nonspecific pericarditis

ASA, NSAIDS, colchicine

Recurrent pericarditis

Colchicines in addition to ASA/NSAIDs; prednisone[*]

Purulent pericarditis

Specific systemic antibiotics; drainage; fibrinolytics

TB pericarditis

Antituberculous therapy; steroids; May require pericardiectomy

Neoplastic pericarditis

May require drainage; recurrences reduced by sclerosis, pericardiectomy

Postinfarction pericarditis

ASA

Nephrogenic pericarditis

Intensification of dialysis; drainage for tamponade and large resistant chronic effusions; instillation of steroids

See text for details, specific indications, and doses. Abbreviations: ASA = aspirin; NSAIDS = nonsteroidal anti-inflammatory drugs; TB = tuberculosis.

* Prednisone should be avoided if possible.

NEOPLASTIC PERICARDITIS Metastatic neoplasia remains the leading cause of pericardial disease in hospitalized patients, most often in patients with lung or breast cancer, melanoma, lymphoma, and acute leukemia. Many cases are asymptomatic and found only incidentally at autopsy, but others cause symptoms and may progress to cardiac tamponade. The pericardium may be thickened and cause constriction; less commonly, effusiveconstrictive pericarditis occurs. In almost every case, fluid should be removed if large effusions are refractory or if tamponade ensues. The specific approach depends on the patient's expected longevity and medical condition. Pericardiocentesis is associated with a high recurrence rate and does not provide tissue for biopsy. Sclerosing agents, such as tetracycline (500 to 1000 mg in 20 mL of sterile saline), reduce recurrences and can be considered for patients with a poor prognosis. However, sclerosis is painful, does not improve prognosis, and may not be superior to an indwelling catheter alone. Subtotal pericardiectomy is most effective but should only be

performed in carefully selected patients. Balloon pericardiotomy avoids the discomfort and risk of surgery in critically ill patients with predictably limited survival. PERICARDITIS COMPLICATING MYOCARDIAL INFARCTION Pericarditis is common in the first few days after myocardial infarction, occurring in as many as 28% to 43% of fatal infarctions, but it is clinically apparent in as few as 7% of cases. Pericardial involvement is related to infarct size and associated with a poor prognosis. An important clinical issue is the extent to which acute pericarditis in myocardial infarction influences management with anticoagulants. A pericardial friction rub occurring in the first 2 or 3 days without an associated pericardial effusion should not influence clinical decisions, but pericarditis occurring later in the course or accompanied by pericardial effusion or tamponade is a contraindication to anticoagulant therapy. Cardiac tamponade seldom occurs, except in patients who receive systemic anticoagulants or have cardiac rupture. Treatment of infarct pericarditis is seldom indicated, but when symptomatic it responds to ASA; corticosteroids should be avoided because of concerns of impaired infarct healing, steroid dependency, and toxic side effects. RADIATION-INDUCED PERICARDIAL DISEASE Acute pericarditis occurring early during radiation therapy is uncommon and most likely the result of the radiation-induced effects on the tumor rather than a direct toxic effect of the radiation on the pericardium. In this instance, therapy should not be disrupted, although a reduction in dose may be necessary. A delayed (usually less than 1 year, but highly variable) form of pericardial injury may present as acute pericarditis or effusion (often with some degree of cardiac compression); constrictive and effusive-constrictive pericarditis may become manifest only after many years. Acute radiation-induced pericarditis can be managed symptomatically as acute idiopathic pericarditis. Hemodynamically insignificant pericardial effusion can also be managed conservatively because spontaneous resolution is the rule; however, pericardiectomy should be offered to symptomatic patients with large recurrent pericardial effusions. Constrictive pericarditis requires pericardiectomy unless otherwise contraindicated. PERICARDIAL DISEASE IN PATIENTS WITH RENAL FAILURE Pericarditis complicates both uremia and dialytic therapy (hemo- and peritoneal), and may be clinically silent. The clinical manifestation of nephrogenic pericardial disease may be acute fibrinous pericarditis, pericardial effusion, or cardiac tamponade; classic constrictive pericarditis is rare. Although intensification of dialysis is an accepted treatment modality for hemodynamically insignificant disease, considerable controversy exists regarding the optimal management of large, persistent, or recurrent pericardial effusion. Tamponade is an indication for pericardial drainage, and large resistant, chronic effusion warrant pericardiocentesis, but a conservative approach—that is, intensification of dialysis and NSAIDs—may suffice in less severe cases. The instillation of nonabsorbable steroids (triamcinolone, 50 mg every 6 hours3 for 2 to 3 days) directly into the pericardial space is advocated, but randomized controlled

data are absent. If needle drainage is necessary, an indwelling catheter should be left in the pericardial space for at least 2 to 3 days. Dialysis-associated effusive pericarditis usually responds to intensification of dialysis and regional heparinization or by changing to peritoneal dialysis. Pericardiectomy may be necessary for intractable effusions. Other Causes of Pericardial Disease Pericarditis may accompany virtually any connective tissue disease and may present as either acute or chronic pericarditis with or without an effusion. However, most cases are subclinical and in many instances are recognized only at autopsy. In the absence of tamponading or secondarily infected effusions, NSAIDs and corticosteroids are useful. Myxedema-associated effusions develop slowly and may grow very large; slow resolution usually follows institution of thyroid replacement therapy. Iatrogenic pericardial disease results from both the calculated complications and the unanticipated misadventures of diagnostic and therapeutic procedures. Importantly, a wide variety of drugs and toxins may cause pericardial heart disease by producing drug-induced lupus (e.g., procainamide, hydralazine, isoniazid), a hypersensitivity or idiosyncratic reaction (e.g., penicillins, thiazides, anthracyclines), pericardial irritation, or hemorrhage (e.g., anticoagulants). Chylous pericardial effusions generally follow traumatic or surgical injury to the thoracic ductbut may result from neoplastic obstruction of the thoracic duct, or they may be idiopathic. Failure to respond to either ligation of the thoracic duct and partial pericardiectomy or to a diet rich in medium chain triglycerides warrants implantation of a valved pericardioperitoneal conduit. Pericardial Effusion andTamponade In the absence of tamponade or suspected purulent pericarditis, there are few indications for pericardial drainage. Persistent large and unexplained effusions (especially when tuberculosis is suspect or when present for more than 3 months) may warrant pericardiocentesis. Occasionally, suspected malignancy or systemic disease may necessitate pericardial drainage and biopsy. However, routine drainage of large effusions (20 mm echo-free spacein diastole) has a very low diagnostic yield (7%) and no therapeutic benefit. Figure 1 presents an approach tothe management of moderate and large pericardial effusions.

FIGURE 1 Algorithm for the management of moderate to large pericardial effusions. *Right heart catheterization may be required. †Anti-inflammatory treatment if there are signs of pericarditis. (Reprinted with permission from Hoit BD: Management of effusive and constrictive pericardial heart disease. Circulation 2002;105: 2939-2942.)

It is important to remember that tamponade is a clinical diagnosis and “echocardiographic signs of tamponade” is not by itself an indication for pericardiocentesis. Although the absence of any cardiac chamber collapse has a high negative predictive value (92%), the positive predictive value is substantially reduced (58%).

Removal of small amounts of tamponading pericardial fluid (approximately 50 mL) produces considerable symptomatic and hemodynamic improvement because of the steep pericardial pressure–volume relation. Unless there is concomitant cardiac disease or coexisting constriction (i.e., effusive-constrictive pericarditis), removal of all of the pericardial fluid normalizes pericardial, atrial, ventricular diastolic and arterial pressures, and cardiac output. Mild or low-pressure tamponade (i.e., when the venous pressure is less than 10 cm of water, arterial blood pressure is normal and pulsus paradoxus is absent), particularly when the etiology is idiopathic, viral, or when responsive to specific therapy (e.g., thyroid hormone), does not require pericardiocentesis. At the other extreme, hyperacute tamponade (usually resulting from cardiac trauma) necessitates immediate pericardiocentesis as an initial triage measure. However, the majority of patients fall between these two extremes and require pericardial drainage. Either surgical means (via subxiphoid incision, video-assisted thoracoscopy, or thoracotomy) or percutaneously (with a needle or balloon catheter) accomplishes pericardial drainage. The choice between needle pericardiocentesis and surgical drainage depends on institutional resources and physician experience, the etiology of the effusion, the need for diagnostic tissue samples, and theprognosis of the patient. Unless the situation is immediately life threatening, experienced staff should perform pericardiocentesis in a facility equipped with radiographic, echocardiographic, and hemodynamic monitoring to optimize the success and safety of the procedure. The safety of the procedure is increased by using 2D echo guidance. Pericardiocentesis is ill advised when there is less than 1 cm of effusion, loculation, or evidence of fibrin and adhesion. Recurrent effusions may be treated by either repeat pericardiocentesis, sclerotherapy with tetracycline, surgical creation of a pericardial window, or pericardiectomy. Subtotal pericardiectomy is preferred when the patient is expected to survive greater than 1 year. A pleuropericardial window provides a large area for fluid to be reabsorbed and is often performed in patients with malignant effusions. Pericardiectomy may be required for recurrent effusions in dialysis patients. In critically ill patients, a pericardial window may be created percutaneously with a balloon catheter. Constrictive Pericarditis Constrictive pericarditis is a condition in which a thickened, scarred, and often calcified pericardium limits diastolic filling of the ventricles. Although acute pericarditis from most causes may eventuate in constrictive pericarditis, the most common antecedents are idiopathic, cardiac trauma and surgery, mediastinal irradiation, tuberculosis and other infectious diseases, neoplasms (particularly lung and breast), renal failure, and connective tissue diseases. Although it is commonly thought that a normal pericardial thickness excludes the diagnosis of constrictive pericarditis, 28% of 143 surgically confirmed cases had normal pericardial thickness on CT scan, and 18% had normal thickness on histopathologic examination. Classic chronic constrictive pericarditis is less frequently encountered than in the past, whereas subacute constrictive pericarditis (weeks to months after the inciting injury, e.g., after cardiac surgery) is becoming more common. In this latter group of patients, constriction may be transitory, with a course that may span a matter of weeks to a few months; not surprisingly, pericardial calcification is uncommon. Doppler-detected constrictive physiology resolved without pericardiectomy in 36 of 212patients studied retrospectively at Mayo Clinic after an average of approximately 8 weeks. Pericardiectomy is the definitive treatment for constrictive pericarditis but is unwarranted either in very early constriction (occult and functional class I) or in severe, advanced disease (functional Class IV) when the risk of surgery is excessive (operative mortality 30% to 40% vs. 6% to 19%) and the benefits are diminished. It is

prudent to give hemodynamically stable patients with subacute constrictive pericarditis a trial of conservative management for 2 to 3 months until it is clear that the constrictive process is permanent before recommending pericardiectomy. Complete or extensive pericardial resection is desirable. Medical therapy of constrictive pericarditis has a small but important role. In some patients, constrictive pericarditis resolves either spontaneously or in response to various combinations of NSAIDs, steroids, and antibiotics; in the remaining patients, medical therapy is adjunctive.



REFERENCES Haley et al., 2004. Haley JH, Tajik AJ, Danielson GK, et al: Transient constrictive pericarditis: Causes and natural history. J Am Coll Cardiol 2004; 43:271-275. Imazio et al., 2005. Imazio M, Bobbio M, Cecchi E, et al: Colchicine as first-choice therapy for recurrent pericarditis: Results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med 2005; 165:1987-1991. Imazio et al., 2005. Imazio M, Bobbio M, Cecchi E, et al: Colchicine in addition to conventional therapy for acute pericarditis: Results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112:20122016. Imazio et al., 2004. Imazio M, Demichelis B, Parrini I, et al: Day-hospital treatment of acute pericarditis: A management program for outpatient therapy. J Am Coll Cardiol 2004; 43:1042-1046. Maisch et al., 2002. Maisch B, Ristic AD, Pankuweit S: Intrapericardial treatment of autoreactive pericardial effusion with triamcinolone; the way to avoid side effects of systemic corticosteroid therapy. Eur Heart J 2002; 23:1503-1508. Maisch et al., 2004. Maisch B, Seferovic PM, Ristic AD, et al: Guidelines on the diagnosis and management of pericardial diseases executive summary: The task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J 2004; 25:587-610. Merce et al., 1998. Merce J, Sagrista-Sauleda J, Permanyer-Miralda G, Soler-Soler J: Should pericardial drainage be performed routinely in patients who have a large pericardial effusion without tamponade?. Am J Med 1998; 105:106-109. Talreja et al., 2003. Talreja DR, Edwards WD, Danielson GK, et al: Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation 2003; 108:1852-1857.



Chapter 99 – Peripheral Arterial Disease

Method of: Jason T. Lee, MD Maisie M. Fung, MD E. John Harris Jr., MD Peripheral arterial disease (PAD) encompasses a wide spectrum of disease entities involving blood vessels outside of the heart and the brain. This includes blood vessels of the upper and lower extremities, the carotid artery, and the aorta. The majority of the clinical manifestations of PAD occur as a consequence of progressive atherosclerotic narrowing of these vessels. Other acquired diseases of arteries are related to aneurysm formation, inflammation, or degenerative disorders. Significant morbidity and mortality results from PAD, and patients can present in very acute or chronic settings. Recognizing the signs and symptoms of these diseases is paramount for the primary care physician to formulate an accurate differential diagnosis. Prompt diagnostic testing and appropriate referral to a vascular surgeon are necessary to provide definitive management and optimize patient outcomes. In the past decade, there have been numerous advances in the diagnosis, management, and treatment of PAD. Less invasive screening tests are supplementing and even replacing traditional angiography, and treatment options with endovascular approaches such as angioplasty and stenting are increasingly available and being shown to be feasible. In this chapter we focus on the most commonly encountered PADs including carotid artery stenosis and lower extremity occlusive disease. Carotid Artery Disease Carotid artery disease most commonly involves atherosclerotic changes in the carotid arteries resulting in stenosis of the vessels around the carotid bifurcation. Diminished flow and irregular plaque formation of the common and internal carotid arteries can lead to embolic or thrombotic events that may cause transient ischemic attacks (TIAs), amaurosis fugax, or stroke. Carotid occlusive disease accounts for 30% to 40% of all reported strokes. Stroke remains the third leading cause of death inthe United States (only behind heart disease and cancer). According to the American Heart Association (AHA), 700,000 people in the United States experienced astroke in 2001, with nearly a third being recurrent. Onein15 deaths in the United States in 2001 was from a cerebrovascular accident. On a positive note, there was a 63% decrease in stroke/death rates from 1970 to 2002. There remains, however, high cost associated with the care of stroke survivors in terms of long-term rehabilitation, diminished productivity, chronic medications, and other co-morbid medical conditions. Risk factors for carotid artery disease include smoking, diabetes, hypertension, high cholesterol, and family history of disease. Prevention strategies focus on the use of antiplatelet agents, smokingcessation, hypertension control, lipid-lowering medications, diabetes control, and screening for carotid artery disease.

CURRENT DIAGNOSIS Routine examination including palpation of extremity pulses and auscultation for bruits of the carotid artery and abdominal aorta should be performed during all health maintenance examinations. Duplex ultrasound by an accredited vascular laboratory can accurately measure the degree of carotid disease and determine which patients will benefit from carotid intervention. Vascular claudication is described as reproducible pain in the lower extremities brought on by exertion that is relieved by rest and should be evaluated by lower extremity duplex ultrasound evaluation of arterial waveforms with ankle-brachial indexes.

CURRENT THERAPY Carotid endarterectomy is a durable and safe procedure that is indicated for symptomatic carotid stenosis >70% and asymptomatic carotid stenosis >80% to reduce future stroke risk. Symptomatic patients who are deemed high risk can be considered for carotid stenting at a highvolume vascular center. Aggressive medical management and risk factor modification with a supervised exercise regimen should be instituted for all patients with claudication. Critical limb ischemia is a progressive process that requires urgent referral to a vascular surgeon for revascularization by open surgical or endovascular techniques. Carotid artery disease can be symptomatic or asymptomatic. Asymptomatic patients may be diagnosed by the primary care physician after a carotid bruit is detected on physical examination, but more commonly no bruit is auscultated and risk factors and/or family history lead to a screening duplex ultrasound. Recently, patients are seeking consultation for confirmation of a carotid duplex examination done as part of a vascular screening series ortotal body scan outside of the physician's office. Symptomatic patients present with symptoms of stroke or TIAs. TIAs differ from strokes in that they are acute, focal neurologic deficits that resolve completely within 24 hours, whereas strokes involve incomplete recovery. A classic type of ocular TIA is amaurosis fugax, where there is a painless monocular loss of vision caused by retinal artery embolus or thrombus. Patients classically describe a curtain being drawn over the eye that appears and resolves suddenly and completely. Other symptoms associated with TIAs or strokes include motor, sensory, or speech defects. Global symptoms such as dizziness, syncope, or altered mentation are less clearly associated with carotid occlusive disease. Patients with suspected carotid artery disease should undergo a thorough physical examination including pulse examination, listening for bruits, and neurologic examination. Diagnosis can be confirmed via duplex ultrasound scan of both carotid arteries ( Figure 1 ). This can quantify the degree and location of the stenosis. The degree of stenosis is typically reported as a percentage of narrowing and is based on velocity criteria standardized and validated for each vascular laboratory. Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain is necessary when stroke or TIA is suspected. Positive imaging findings within brain parenchyma indicate that an acute event has occurred. The advantage of MRI is that imaging of the neck and brain with magnetic resonance angiography (MRA) can be performed

simultaneously to give details regarding carotid and vertebral artery anatomy as well as the intracranial circulation. The degree of stenosis seen on MRA is often overestimated and should be corroborated by a duplex ultrasound. Cerebral arteriography is currently used infrequently in the preoperative phase and reserved for cases in which questions remain unresolved with the other imaging modalities. Improvements in imaging technology also are allowing CT angiography to become more widely available.

FIGURE 1 Duplex ultrasound scan of 51-year-old man with hypercholesterolemia and hypertension found to have a right carotid bruit on examination. Note the severe narrowing of the right internal carotid artery orifice (evidenced by a peak systolic velocity of 4.64 m/s, which corresponds to a stenosis of 80%–89% by velocity criteria). He underwent successful right carotid endarterectomy.

Management of carotid artery disease is based on the degree of carotid stenosis measured by the various imaging modalities. Carotid endarterectomy (CEA) remains the most common procedure performed by vascular surgeons in the United States and is one of the most extensively studied operative procedures in the medical literature. Randomized, prospective trials including the North American Symptomatic Carotid Endarterectomy Trial (NASCET), European Carotid Surgery Trial (ECST), andthe Veterans Affairs (VA) trial showed an approximately 50% relative risk reduction in symptomatic patients with more than a 70% stenosis who underwent surgery compared with medical treatment with aspirin. In the NASCET trial, the ipsilateral stroke rate at 2-year follow-up was reduced to 9% in the surgically treated patients as opposed to 26% in the medically treated patients, and the study was halted with all patients in the medical arm then offered CEA. The VA trial and ECST provide similar data documenting the benefit of surgical intervention in symptomatic

patients with greater than 70% stenosis. For asymptomatic patients, the Asymptomatic Carotid Atherosclerosis Study (ACAS) showed a 53% relative risk reduction of ipsilateral stroke at 5 years from 11.0% to5.1% in surgically treated patients with greater than 60% stenosis. This represents, however, only a 1% absolute risk reduction per year, which is certainly less dramatic than the protective effects of intervention on a symptomatic patient. For this reason and with the development of newer antiplatelet agents like clopidogrel (Plavix), surgery at our institution is offered to asymptomatic patients only when they have reached 80% stenosis. Potential complications of surgery for either symptomatic or asymptomatic patients include myocardial infarction, stroke, bleeding, infection, cranial nerve injury, and recurrent stenosis. The possibility of recurrent disease highlights the importance of long-term follow-up after CEA that should include yearly duplex examination. With the advent of endovascular techniques being driven by industry and patient desires for more minimally invasive interventions, it is no surprise that carotid angioplasty and stenting (CAS) has emerged as an alternative therapy. Recently published data, although sparse, suggests that in high-risk patients, CAS is not worse than traditional open surgery in terms of stroke and death rates. However, the best candidates for these procedures and long-term durability of these approaches are yet to be delineated. High-risk patients are defined differently at various institutions, but typically include those with severe uncontrolled co-morbid coronary symptoms, recurrent disease after previous endarterectomy, or irradiated necks. Currently there are only two FDA-approved devices for use (RX ACCULINK, manufactured by the Guidant Corporation, Indianapolis, Indiana; and Xact, manufactured by Abbott Laboratories, Abbott Park, Illinois). We believe carotid angioplasty and stenting should only be performed in high-volume centers with multidisciplinary expertise and the desire to track patients long term. For patients who do not yet meet the criteria for surgery as determined by percentage of carotid stenosis, daily aspirin and aggressive risk factor reduction are indicated. These patients should be followed by duplex ultrasounds every 6 months and seen regularly by the vascular surgeon. Any new symptoms or progression of disease to a criticalstenosis warrants a more aggressive approach to intervention. Lower Extremity Arterial Occlusive Disease Lower extremity peripheral arterial disease is a broad category of clinical entities that includes aortoiliac occlusive disease and femoropopliteotibial occlusive disease. The most common etiology of these diseases is atherosclerosis causing narrowing within these blood vessels. Risk factors again include smoking, hypertension, diabetes, elevated cholesterol, and family history. Up to 40% of patients also have coexisting coronary artery disease (CAD). Patients typically present with claudication, defined as pain in the lower extremities brought on by a reproducible amount of exercise and relieved only by a short period of rest. Depending on the location of the occlusion, symptoms may involve the buttocks, hip, thigh, or calf, and they can include impotence in men. Lower extremity claudication is a significant health careissue, with studies documenting that 12% of the population experience claudication. Patients typically describe the pain as a sensation of muscle cramps or fatigue. This leads to chronic pain and health care provider visits, decreased productivity at work, and the possible progression toward a more sedentary lifestyle. The presence of claudication doubles age-specific mortality and decreases life expectancy on average by 10 years, and for this reason, patients should be aggressively managed medically with selective surgical intervention. It is important to note that the rate of

limb loss in patients with claudication is approximately 3% to 6% over 10 years, so preventive care measures instituted by the primary care physician are a vital adjunct to vascular consultation. Approximately 15% of mild cases of claudication progress to more significant lower extremity ischemia manifested by rest pain and tissue loss; typically seen in diabetic patients who continue to smoke. This indicates more severe atherosclerotic narrowing and the need for more aggressive and urgent management. Patients typically describe pain in the front of the foot occurring at night that is relieved by hanging the foot over the edge of bed or getting out of bed. Careful physical inspection looking for tissue changes is also important to document the severity of lower extremity occlusive disease. Skin atrophy with thickened nails, loss of hair on dorsum of the foot, shiny skin, and toe or heel ulcerations are all signs of significant atherosclerotic disease. Documentation of pulses is important and can be graded as diminished or absent. Pulse palpation, however, is quite subjective and predisposed to error. When pulses are not easily palpable, a handheld Doppler in the clinic can be used objectively to assess blood flow, especially when ankle blood pressures are obtained. The ankle-brachial index (ABI) is obtained by dividing the systolic pressure at the ankle into that of the arm. Normal ABIs range from 1.0 to 1.2. Patients with claudication usually have an ABI less than 0.7, and patients with tissue loss have an ABI less than 0.5. An ABI less than 0.3 suggests critical ischemia and warrants urgent evaluation and intervention. Caution must be used in interpreting ABIs from diabetic patients because their arteries may be calcified, which leads to falsely elevated ABIs. The vascular laboratory can provide useful diagnostic information regarding lower extremity blood flow. Referral for formal duplex ultrasound with arterial waveform analysis is extremely helpful in determining the degree and location of stenosis. It is appropriate to obtain vascular consultation for patients with diminished ABIs and symptoms of lower extremity arterial occlusive disease. The decision to obtain more invasive and expensive studies should be made in consultation with the vascular surgeon. Recent advances in imaging technology have allowed CT angiography ( Figure 2 ) and MRA to be a less invasive method of determining the extent of aortic, iliac, and distal occlusive changes. Traditional diagnostic angiography can be performed to delineate further the extent of disease, and it has the advantage of allowing access for percutaneous endovascular treatment of focal occlusive disease in the same setting.

FIGURE 2 Computed tomographic (CT) angiography of an 81-year-old woman with severe thigh, buttock, and leg claudication and rest pain and a nonhealing left foot wound demonstrating severe calcified disease of her abdominal aorta and occluded iliac vessels and superficial femoral vessels. She underwent open aortofemoral bypass, which resulted in significant improvement in her walking and healing of her wound.

Patients with mild claudication should be treated medically with aggressive risk factor reduction. Emphasis should be placed on smoking cessation, increasing exercise, weight loss, and controlling diabetes, hypertension, and high cholesterol. A strictly supervised exercise regimen is the only consistent therapy that increases pain-free walking distance and maximal walking distance. Numerous studies have looked at various medications for the treatment of claudication, all with conflicting and often short-term success. FDA-

approved medications include pentoxifylline (Trental) and cilostazol (Pletal), yet only a 30% response rate is observed in typical claudicants. These agents help lower blood viscosity and inhibit platelet aggregation. Although results with these medications are variable, a trial of 6 to 8 weeks of therapy should be attempted along with the exercise regimen. Long-term population studies have found that approximately 75% of patients experience improvement in symptoms with medical management alone. Sustained symptom relief requires a regular walking regimen. Patients who do not respond to medical management alone may be candidates for revascularization. Indications for revascularization include claudication that significantly interferes with lifestyle, rest pain, nonhealing wounds, andtissue loss or necrosis. Open surgical options include aortofemoral reconstruction for aortoiliac occlusive disease and femoral-tibial bypasses for more distal disease. Long-term results from these operations are excellent in terms of relief of symptoms and wound healing. Morbidity rates from open surgery are in the range of 2% to 6% with possible complications including myocardial infarction, bleeding, wound infections, graft infection or thrombosis, and limb loss. Careful graft surveillance after bypass with duplex ultrasound is an important adjunct to maintain long-term patency of grafts. Endovascular interventions of the lower extremities typically include angioplasty, stenting, and atherectomy. These procedures are most successful in cases involving short stenoses of the iliac arteries. As the disease enters the more distal vessels, there is a significant decrease in the durability of traditional angioplasty and stenting. Future improvements in the technology and developments such as drug-eluting stents may improve future use of endovascular interventions in the lower extremities. As with open surgical revascularization, the importance of long-term surveillance with duplex ultrasound allows reintervention when restenosis occurs. In contrast to failed surgical revascularization, failed endovascular revascularizations can lead to worsened and more acute limb ischemia. Although percutaneous methods appear to be less invasive, they are clearly not less risky, and ideally should be performed by vascular specialists dedicated to caring for all aspects of patients with lower extremity occlusive disease.



REFERENCES Jemal et al., 2005. Jemal A, Ward E, Hao Y, Thun M: Trends in the leading causes of death in the United States, 1970–2002. JAMA 2005; 294:1255-1259. Moore et al., 1995. Moore WS, Barnett MJ, Beebe HE, et al: Guidelines for carotid endarterectomy: A multidisciplinary consensus statement from the Ad Hoc Committee, American Heart Association. Stroke 1995; 26:188-201. The Executive Committee for the Asymptomatic Carotid Atherosclerosis Study, 1995. The Executive Committee for the Asymptomatic Carotid Atherosclerosis Study : Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421. Norgren et al., 2007. Norgren L, Hiatt WR, Dormandy JA, et al: Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45:S5-S67.



Chapter 100 – Venous Thrombosis

Method of: Paul L.F. Giangrande, MD Air Travel And Thrombosis The subject of air travel and thrombosis has been the subject of much debate in both the lay and medical press in recent years, although a possible link has been recognized for many years, and the very first report concerned a physician who traveled from Boston to Venezuela in 1946. However, venous thromboembolism is not exclusively associated with air travel, and it has also been documented following long car, bus, and train journeys. A case-control study of 160 consecutive patients with deep venous thrombosis (DVT) showed that 39 of 160 (24.5%) had recently completed a journey by car, train, or plane of longer than 4 hours; nine of these patients had traveled by air. When the patients with DVT were compared with the control group, a history of recent travel was reported four times more often in the subjects with venous thromboembolism (odds ratio [OR] = 4). This correlation has been confirmed by a recent and much larger case-control study, the Multiple Environment and Genetic Assessment (MEGA) study, from the Netherlands, which confirmed that travel by car, bus, train, or plane is associated with an increased risk of venous thrombosis. Thrombosis associated with flight is also by no means restricted to those in the relatively confined conditions of economy class, and thus the alternative term of “travelers' thrombosis” has been suggested. It is possible to derive some general conclusions from published cases of venous thromboembolism associated with travel. Thromboembolism is rarely observed after flights of less than 5 hours, and typically, the flights are 12 hours or longer. The risk rises with age, and persons older than 50 years are more at risk, whereas those younger than 40 years are less vulnerable. Symptoms of thromboembolism do not usually develop during or immediately after the flight but tend to appear within 3 days of arrival, when the patient may present far away from the airport, and thus the causal link might not be immediately apparent. Symptoms of thrombosis or pulmonary embolism have been reported up to 2 weeks after a long flight. Pulmonary embolism may also be the first manifestation, without any symptoms in the lower limbs. Although most case reports and studies involve DVT in the lower limbs, there are also reports of cerebral venous thrombosis and arterial thrombosis associated with long flights. The consequences of venous thromboembolism are not insignificant. Quite apart from the pain and discomfort, which can ruin a holiday or business trip, pulmonary embolism is estimated to develop in approximately 10% of cases. The mortality associated with pulmonary embolism rises with increasing age, but it is in the range of 2% to 15% of cases. The inconvenience and side effects of warfarin treatment should also not be overlooked. Approximately 60% of patients develop postphlebitis syndrome (persistent swelling and discomfort of the leg, often associated with ulceration) within 2 years despite appropriate anticoagulant therapy. A history of

thrombosis precludes future prescription of hormone replacement therapy (HRT) or oral contraceptive pills (OCPs) for women, and it can make it difficult to secure travel insurance in the future because of the increased risk of recurrence. Epidemiology The precise incidence of thromboembolism in relation to air travel is uncertain, though it has been estimated that at least 5% of all cases of DVT may be linked to air travel. A study based on 56 confirmed cases of pulmonary embolism among 135.3 million passengers passing through one airport in the period between 1993 and 2000 clearly demonstrated an association between duration of travel and risk of pulmonary was significantly higher (1.5 cases per million) for passengers traveling more than 5000 km when compared with a risk of only 0.01 cases per million among passengers traveling less than 5000 km. Cases of pulmonary embolism clearly only represent the tip of the iceberg of cases of DVT. A recent observational study from New Zealand, based on the study of 878 passengers who traveled extensively (at least 10 hours; mean, 39 hours) reported an incidence of venous thromboembolism of 1%, including four cases of pulmonary embolism and five of DVT. However, the incidence of latent, asymptomatic thrombosis is likely to be even higher. A prospective study of long-haul air passengers older than 50 years reported that 12 of 116 passengers (10%) were found by duplex scanning to have asymptomatic DVT confined to the calf. Etiology The etiology of venous thrombosis is usually multifactorial, with a combination of both constitutional and environmental factors responsible for causing a thrombosis in a patient at a given time. The three underlying causes of thrombosis are classically defined as Virchow's triad: stasis, hypercoagulability of the blood, and vessel wall disease. Stasis in the venous circulation of the lower limbs is undoubtedly the major factor in promoting the development of venous thromboembolism associated with travel. The potential danger of confinement in cramped conditions has been recognized for some years. An increase in the incidence of fatal pulmonary embolism was reported during the Blitz in London during the Second World War. Simpson recognized that the primary cause was mechanical impairment of venous circulation due to squatting for a prolonged period in air raid shelters, and he recommended that bunks should be installed. The term economy class syndrome was coined to describe the phenomenon, and this also emphasizes the role of impaired venous circulation due to prolonged immobility in a cramped position. Ingestion of alcohol also encourages immobility during a flight, and the use of strong sedative medication may also be associated with an increased risk of venous thrombosis. A number of other risk factors are now also recognized, primarily through clinical experience in the setting of surgery, which predispose to venous thromboembolism. These are listed in Box 1 . BOX 1

Risk Factors for Venous Thromboembolism •

Age greater than 40 years (but especially the elderly)

•

Previous thrombotic episode (especially pulmonary embolism)

•

Documented thrombophilic abnormality (e.g., antithrombin deficiency)

•

Other hematologic disorders (polycythemia and thrombocythemia)

•

Pregnancy and puerperium

•

Malignancy

•

Congestive heart failure or recent myocardial infarction

•

Recent surgery (especially lower limb)

•

Chronic venous insufficiency

•

Estrogen therapy (e.g., OCP, HRT)

•

Obesity

•

Prolonged recent immobility (e.g., after recent stroke)

•

Dehydration (diarrhea)

Abbreviations: HRT = hormone-replacement therapy; OCP = oral contraceptive pill.

The effect of age was highlighted in a recent study from Australia, which concluded that the annual risk of venous thromboembolism is increased by 12% if one long-haul flight is undertaken annually. However, the incidence of thromboembolism was less than 1 per 100,000 arriving passengers younger than 40 years, but it rose steadily to exceed 14 per 100,000 in those aged 75 years or older. A hematologic abnormality might predispose a person to development of venous thromboembolism. Such disorders include the relatively rare congenital (inherited) deficiencies of natural anti-coagulants, such as antithrombin, protein C, or protein S. A recent study demonstrated that an inherited thrombophilic defect or use of an OCP increased the risk of thrombosis associated with air travel 16-fold and 14-fold, respectively. The MEGA study has also demonstrated that positivity for the factor V Leiden thrombophilic mutation, body mass index greater than 30, height greater than 1.9 or less than 1.6 meters, and use of OCPs are strong susceptibility factors. In one small uncontrolled, retrospective study of patients with flight-related DVT, 6 of 20 (30%) subjects had a thrombophilic defect (factor V Leiden in 5). Four subjects had a history of a previous episode of thrombosis, and other potential risk factors were identified in 10 subjects (including malignancy, leg in plaster cast, use of OCP or HRT). Five of the 20 patients had a negative thrombophilia screen and no other identifiable risk factor. The value of screening passengers for thrombophilic defects before long-haul flights has been raised. It is generally accepted that routine screening of passengers or screening of pilots as part of their medical screening is not justified or cost-effective. Such screening is not, of course, routinely offered in other circumstances associated with an increased risk of thrombosis (e.g., before starting an OCP, pregnancy, before orthopedic surgery), and no case has yet been established for air travel to be treated differently from

current practice for thrombophilia screening in other fields. Some evidence now suggests that exposure to the mild hypobaric hypoxia encountered in pressurized aircraft might also result in activation of the coagulation and thus encourage thrombosis. Aircraft typically fly at altitudes of between 35,000 and 40,000 feet to avoid turbulence and drag, thus benefiting fuel consumption. The cabin air is derived from the outside atmospheric air, which is drawn in and compressed. The maximum pressure in the cabin at cruising altitude is influenced by the allowable differential pressure across the wall of the cabin. This varies with aircraft design, but the lowest pressure permitted by the regulatory authorities for civil aircraft is equivalent to atmospheric pressure at an altitude of 8000 feet. Although the percentage of oxygen in the cabin remains unchanged at around 21%, the partial pressure of oxygen is reduced to around 74% of the sea level value. The very cold air at this altitude (typically around 50°C) contains only negligible water vapor, and the humidity in the cabin is thus typically very low. Markers of activation of coagulation were transiently elevated in an uncontrolled study of 20 healthy male volunteers who were exposed to a hypobaric environment designed to simulate the conditions of an airplane cabin. The plasma levels of prothrombin fragments 1 and 2, thrombin-antithrombin (TAT) complex, and activated coagulation factor VII increased significantly, although the D-dimer level remained unchanged. Treatment with heparin inhibited the development of this apparent activation of the coagulation cascade. Another study of eight subjects who ascended rapidly to high altitudes by helicopter in Nepal documented increases in the levels of prothrombin fragments 1 and 2 and PAI-1 (plasminogen activator inhibitor, a key inhibitor of fibrinolysis). Activation of coagulation associated with flight, reflected by an increase in plasma levels of TAT complex, was also demonstrated in a crossover study in which 71 healthy volunteers were studied in the setting of an 8-hour flight, with the same volunteers monitored in two controlled-exposure situations. Contrary to the widespread belief that passengers on long-haul flights can develop dehydration through increased insensible loss of water across the skin and mucous surfaces, it has been calculated that the maximum possible increase in insensible loss of water over an 8-hour period in such conditions is only around 100 mL. Although systemic dehydration is not a significant factor in healthy persons, the low humidity in an aircraft cabin can certainly lead to dryness of the mucous membranes and a sensation of thirst. Excessive consumption of alcohol or gastrointestinal infections associated with vomiting and diarrhea can also exacerbate dehydration. Prevention A number of general measures may be taken to minimize the risk of thrombosis associated with long flights. Perhaps the most important step is to consider at the outset whether the passenger is actually fit to fly in the first place. For example, it is probably wise to defer long-haul travel after recent major orthopedic surgery. Passengers should be encouraged to carry out leg exercises from time to time while seated (e.g., flexion, extension, and rotation of the ankles help to promote circulation in the lower limbs). However, many airlines discourage unnecessary walking about in the cabin because there is always the possibility of encountering unexpected air turbulence. Hand luggage stowed under seats also restricts movement. Passengers should take advantage of refueling stops on long-haul flights to get off the plane and walk around for awhile. Adequate hydration should be ensured during the flight. It is not necessary to abstain from alcohol, but excessive consumption should be avoided because it promotes diuresis and discourages mobility. Similarly, sedatives are best avoided. Although estrogen-containing OCPs and HRT are recognized risk factors for

venous thrombosis, I do not advocate interrupting such hormonal medication for the period of travel. A recent review of 10 randomized studies for the Cochrane database has confirmed the value of compression hosiery (flight socks). In the very first study performed, 231 passengers were recruited before long-haul flights and randomized into two groups. Of those who did not wear compression hosiery, 12 of 116 (10%) were found after the flight to have asymptomatic calf DVT with duplex ultrasonography, but none of the 115 who wore compression hosiery was affected. In the LONFLIT-4 study of 372 passengers considered to be at medium to high risk of thromboembolism, none of the 179 subjects wearing compression hosiery developed DVT, but six of 179 (3.35%) controls developed asymptomatic DVT (four DVT, two superficial) (P 125,000/L of blood[*] Indirect bilirubin concentration between 1 and 5 mg/dL[†] Haptoglobin concentration 30% unless there are attendant problems). Furthermore, although the titer of the direct antiglobulin (Coombs) test may decrease in response to therapy, it is unusual for the test to become negative. Thus, a goal of therapy should not be normalization of the Coombs test. It is important to keep in mind that idiopathic warm AIHA is a chronic disease and that relapses are common. Steroids should be tapered very slowly (over several months); however, disease exacerbations during the taper are frequently observed and are frustrating for both patient and physician. Patients requiring more than 10 mg of prednisone every day or more than 15 mg of prednisone every other day for more than a few months are candidates for splenectomy. Patients undergoing splenectomy should receive preoperative

vaccinations against pneumococcal and meningococcal disease and against Haemophilus influenzae type B. Management of chronic AIHA is challenging, and not unusually patients require a combination of steroids, splenectomy, and immunosuppressive therapy. Patients should be informed that the disease is usually chronic and that relapses are common. Physicians should be prepared to monitor the patient frequently so that relapses can be treated promptly and therapy-related problems prevented. Prolonged use of steroids at unacceptably high levels is the most frequent cause of iatrogenic problems associated with treatment of chronic warm-antibody AIHA. If the dose of prednisone required to maintain an appropriate hematocrit is unacceptably high after splenectomy, then immunosuppressive therapy should be initiated. In patients younger than 70 years, azathioprine (Imuran) is preferred over cyclophosphamide (Cytoxan) because the former is less leukemogenic than the latter. During the course of treatment, the hematocrit level, reticulocyte count, and lactate dehydrogenase (LDH) should be monitored regularly. A rising hematocrit in association with a falling reticulocyte count and LDH is consistent with a response to therapy. On the other hand, a falling hematocrit in association with a falling reticulocyte count suggests a superimposed bone marrow problem (e.g., parvovirus infection or megaloblastic crisis associated with folate deficiency) that requires further evaluation. TRANSFUSION Transfusion of patients with warm-antibody AIHA should be undertaken with caution. It is important to remember that response to steroid therapy is usually rapid (within a few days). Therefore, in most instances, transfusion can be avoided by reducing oxygen demand, which is accomplished by placing the patient at rest. Nonetheless, in cases of fulminant hemolysis or when a patient at rest becomes symptomatic while awaiting a response to therapy, transfusion can be lifesaving. Careful consideration should be given to the volume of blood infused because overtransfusion can be dangerous for two reasons. First, patients may become volume overloaded, causing further cardiopulmonary embarrassment. Second, the rate of hemolysis of donor red cells is exponentially related to the amount of blood infused. Consequently, problems associated with acute hemolysis are more likely to occur in patients who have received relatively large amounts of blood. Accordingly, the minimum amount of blood required to control the patient's symptoms should be transfused (e.g., 100 mL of packed cells twice per day may be effective in preventing high-output heart failure). Because the autoantibody is almost always a panagglutinin, it is virtually impossible to find donor cells that are not recognized by the patient's antibody. Therefore, the goal of the blood bank staff is not to find donor cells that are unreactive in the cross-matching studies but rather to ensure that the patient's ABO and Rh phenotypes are properly determined and that the patient does not have an alloantibody in addition to an autoantibody. A detailed history of previous pregnancies and transfusions is important because patients with warm-antibody AIHA who have never been pregnant or been transfused likely would not have become alloimmunized. A number of assays are available that allow identification of a concurrent alloantibody, but these types of studies are not performed routinely. Accordingly, it is important that the blood bank have a level of sophistication and experience that ensures competence in the performance and interpretation of these critical studies. Some immunohematologists advocate that studies be undertaken to determine the relative specificity of the autoantibody so that donor cells lacking the antigen can be transfused. For example, the antibody may react more strongly with cells that have the “little e” antigen than with those that have the “big E” antigen (E and e

are part of the Rh antigen system). In this case, the antibody is said to have relative specificity for “little e.” However, data from limited studies suggesting a clinical benefit from transfusing cells that lack the antigen of relative specificity are not compelling. Nonetheless, it seems prudent to determine the relative specificity of the antibody and to avoid transfusing cells that express the antigen, especially if in vitro studies indicate a strong degree of specificity (e.g., if the antibody induces hemolysis of antigen-positive but not antigennegative cells). Patients with AIHA who are being transfused should be monitored closely both during and after the infusion. Laboratory studies to document the extent of hemolysis (e.g., LDH, haptoglobin, plasma free hemoglobin, and hemoglobinuria) and the development of renal compromise should be obtained. Drug-Induced Immune Hemolytic Anemia In reviews of drug-induced hemolytic anemia from 30 years ago, methyldopa (Aldomet) was reported to be the responsible agent in the majority of cases. Because the use of methyldopa (Aldomet) as an antihypertensive has markedly declined over the last 20 years, the incidence of drug-induced hemolytic anemia has probably fallen. Nonetheless, drug-induced hemolytic anemia continues to account for a significant proportion of all cases of acquired immune hemolytic anemia, with cefotetan (Cefotan) and ceftriaxone (Rocephin) currently the drugs most commonly involved. At least 12 cyclosporins have been reported to cause drug-induced immune hemolytic anemia. When evaluating patients with evidence of immune hemolysis, eliciting a detailed drug history is essential. In addition, a temporal relationship between drug administration and the development of hemolysis should be sought. Unfortunately, such relationships are often rendered inconclusive because patients are taking multiple drugs. Although some drugs induce immune hemolytic anemia more frequently than do others, in any one patient, any drug must be considered potentially culpable. There are three basic mechanisms by which drugs can induce immune hemolytic anemia ( Table 5 ). Prototypic drugs are included for each mechanism, but it is important to keep in mind that these drugs represent the best-characterized examples and that other drugs may induce hemolysis by the same mechanisms. For example, levodopa (Larodopa) and procainamide (Procan) have been reported to induce immune hemolytic anemia in a manner analogous to that of methyldopa (Aldomet). A detailed review of all of the drugs that have been implicated in the production of AIHA is beyond the purview of this article.

TABLE 5 -- Characteristics of Drug-Induced Hemolytic Anemias Quinidine/Quinine Prototype Proposed mechanism The drug acts as a hapten after binding to a cell membrane protein. Consequently, antibodies against constituents of the drug–membrane protein complex arise. Clinical characteristics Small doses of drug induce the process. Intravascular hemolysis is common; hemolysis may be severe and life-threatening. Can produce HUS. Laboratory findings

Direct Coombs test positive for complement but not IgG. Antibody may be IgG or IgM. Positivity of the indirect Coombs test depends on the presence of the drug in the reaction mixture, thus demonstrating the drug-dependent nature of the antibody. Therapy Discontinue drug. Supportive care (maintain renal blood flow, transfuse as needed). In patients with severe hemolysis, an empirical trial of steroids is warranted. Patients with HUS appear to benefit from plasma exchange. Dialysis is often required. Penicillin Prototype Proposed mechanism Drug binds tightly to red cell. Antidrug antibody binds to drug on red cell surface. Clinical characteristics Large doses of drug required (10 million units or more per day). Hemolysis is usually subacute, developing over 1–2 weeks. Patients may have positive Coombs test without clinical evidence of hemolysis. In rare instances, the process may be life-threatening. Laboratory findings Direct Coombs test positive for IgG, rarely positive for complement. Patient's serum will react in indirect Coombs test with red cells coated with drug. Therapy Discontinue drug in cases of overt hemolysis. If hemolysis is clinically insignificant, the drug can be continued while the patient is monitored closely. Methyldopa (Aldomet) Prototype[*] Proposed mechanism Speculative but may alter the immune system, resulting in a pathophysiologic process similar to that observed in idiopathic autoimmune hemolytic anemia. Clinical characteristics Dose and time dependent (patient will have taken drug for at least 3 months). Hemolysis is usually mild and resolves gradually over several weeks after cessation of the drug. Patients may have positive Coombs test without clinical evidence of hemolysis. Laboratory findings Direct Coombs test positive for IgG, rarely for complement. When hemolysis is present, indirect Coombs test is invariably positive. Positivity of Coombs test is not dependent on having the drug in the reaction mixture. Coombs test may be positive for months after cessation of drug. Therapy

Discontinue drug in cases of overt hemolysis. If hemolysis is clinically insignificant, the drug can be continued while the patient is monitored closely. However, the availability of other effective agents makes prudent the switch to a structurally unrelated alternative antihypertensive agent. Abbreviations: HUS = hemolytic uremic syndrome; IgG = immunoglobulin G; IgM = immunoglobulin M.

* Methyldopa (Aldomet) is rarely used in current practice, but the mechanism of drug-induced hemolytic anemia may be applicable to other currently used agents, including levodopa (Larodopa) and procainamide (Procan)

Recent reports strongly suggest that quinine can induce the hemolytic uremic syndrome (HUS). Patients present with chills, sweats, nausea and vomiting, abdominal pain, oliguria, and petechiae following exposure to quinine in the form of medications or beverages. Laboratory studies show anemia, severe thrombocytopenia, markedly elevated serum LDH level, and azotemia. Drug-dependent antibodies reactive with platelets, erythrocytes, and granulocytes have been identified. These patients have a favorable outcome when treated with plasmapheresis with plasma exchange and dialysis as indicated. Thus, prompt recognition and appropriate treatment of this clinical entity are imperative. In an individual patient, almost any drug can produce an idiosyncratic reaction resulting in immune hemolytic anemia. Therefore, for patients with newly diagnosed acquired immune hemolytic anemia, all drugs that are not absolutely essential should be discontinued. Furthermore, any drug implicated by temporal events (and particularly any drug that has been reported to induce immune hemolysis) should be stopped and alternative therapy using a structurally unrelated compound initiated. A causal role for a particular drug can be established by using an in vitro assay. The basis of these types of assays is the indirect Coombs test modified to determine if antibody binding to the red cell is drug dependent. The technical aspects of the test (particularly the concentration of drug to use) can be obtained from published reports if studies of a particular drug have been performed. If a drug that has not been shown to induce immune hemolysis is suspected, experiments to establish the optimal conditions for testing are required. Unfortunately, drug-related antibodies cannot be conclusively demonstrated in many cases in which the clinical suspicion is strong. Adding to the problem is the fact that antibodies may be directed against metabolites rather than to the whole drug. In these cases, ex vivo antigens (present in the serum or urine of the patient) may be required to demonstrate the drug-dependent nature of the antibody. Cold Agglutinin Syndrome Whereas the presence of cold agglutinins in the plasma is relatively common, cold agglutinins that produce clinically significant hemolysis are relatively uncommon. A cold agglutinin titer of less than 1:64 is normal. Patients with cold agglutinin syndrome may complain of Raynaud's phenomenon or of acrocyanosis of the ears, nose tip, fingers, and toes that occurs at cold temperatures and vanishes quickly upon warming. These symptoms arise because as the blood flows through skin capillaries, the intravascular temperature drops to levels at which the cold agglutinin is functional. As a consequence of the agglutination, blood flow through the small vessels is restricted. Hemoglobinuria following exposure to cold may be part of the history, but, in general, this symptom is unusual. Hepatosplenomegaly is not usually prominent, and lymphadenopathy is uncommon. Agglutination of the red cells at room temperature is an obvious consequence of the disease.

The criteria for diagnosis of cold agglutinin syndrome are given in Table 3 . It should be emphasized that mere observance of cold agglutination is not diagnostic of cold agglutinin disease. The antibodies of cold agglutinin disease are almost invariably immunoglobulin M (IgM), and, in the vast majority of cases, they are directed against determinants of the I antigen system. In most instances, the cold agglutinin titer in cold agglutinin syndrome is greater than 1:1000, but the titer at 4°C does not correlate well with the hemolytic potential of the antibody. A more useful characterization is determination of the thermal amplitude of the antibody (defined as the highest temperature at which the antibody causes agglutination). The majority of cold agglutinins that produce clinically significant hemolysis have a thermal amplitude of at least 30°C (if the thermal amplitude is 96 fL) associated with macro-ovalocytes and anisocytosis. Because macrocytosis can be seen in many clinical circumstances in the absence of a megaloblastic state ( Box 1 ), the true diagnosis defines defective erythroid maturation in the bone marrow, wherein the red cell precursors have enlarged reticulated nuclear chromatin characteristic of defective DNA synthesis with normal permissive RNA synthesis, resulting in a large cytoplasmic mass. Because the defective DNA synthesis is not exclusive to the red cells, giant metamyelocytes reflect the defect in white cells, and macromegakaryocytes also occur. Indeed, defective DNA synthesis is seen not only in the bone marrow but also in all proliferating cells (e.g., buccal mucosa, gastrointestinal tract, etc.) BOX 1 Etiologic and Pathophysiologic Mechanisms for Macrocytosis and Megaloblastosis Nonmegaloblastic Macrocytosis[*] These are nonprogressive over time, usually associated with a normal RDW, and banal macrocytes (nonovalocytic macrocytes seen in true megaloblastic states) •

Aplastic anemia

•

Chronic alcohol use

•

Chronic liver disease

•

Myelodysplastic syndromes

•

Postsplenectomy states

Megaloblastic Anemia

•

Deficiency or defects in vitamin B12 (cobalamin) metabolism •

Inadequate diet: Strict vegan patients

•

Inadequate absorption: Lack of intrinsic factor

•

Classic pernicious anemia

•

Aging stomach

•

Intrinsic factor inhibition

•

Small intestinal disease/resection

•

Abnormal utilization (e.g., nitrous oxide anesthesia, etc.)

•

Deficiency or defects in folate metabolism •

Inadequate intake

•

Altered absorption

•

Abnormal utilization—especially chemotherapeutic drugs, anticonvulsants, alcoholism

•

Increased excretion, renal dialysis

* Mean corpuscular volume is usually 96 to 100 µm3.

Etiology Almost one century after Addison's (1855) annotation of an unusual anemia, termed pernicious anemia, Minot and Murphy (1926) showed that the anemia could be “abolished” by (almost) raw liver, and in 1929 Dr. William Castle described an “intrinsic factor” in the stomach, which was required for liver extract to correct the anemia. Then in 1938, Lucy Wills and Barbara Evans described a nutritional anemia in pregnant women that failed to respond to liver extract, thereby posing the conundrum that a second form of megaloblastic anemia existed. Important resolution of this dilemma came when Pfiffner and Stokstad found a relevant growth factor in yeast and green plants, which they named folic acid. In 1948, Karl Folkers identified and crystallized vitamin B12, which was subsequently shown to require intrinsic factor for facilitated absorption in the terminal ileum. Absorption was defined in the upper small intestine. Subsequently, the finding of circulating autoantibodies to intrinsic factor in patients with (genetic) pernicious anemia appeared to complete the pathogenesis and clinical picture related to these two moieties. Almost immediately this simplistic clinical construct began to unravel. As shown in Box 1 , vitamin B 12 (cobalamin) absorption was related to the increasing incidence of megaloblastic anemia with age. The concept of the aging stomach changed the clinical expression of megaloblastic anemia. As we age (after 50 years), the release of vitamin B12 from food proteins declines due to reduced pepsin activity at a low pH. The known decrease in gastric acidity with aging may be the most important factor of such decreased extraction of vitamin B12 from food, but it is clearly not the only factor. However, such patients have normal absorption of crystalline vitamin B12, so that treatment with nonfood vitamin B 12 results in a physiologic response. Clearly a very common addition to the effects with aging is the new ubiquitous use of proton pump inhibitors for the treatment of gastric reflux and heartburn. These agents reduce secretion of intrinsic factor as well as pepsin and gastric acid, and they are now recognized as an important factor in decreased vitamin B 12 absorption.

Clinical Features A very important aspect of vitamin B12 deficiency is that in addition to the anemia, neurologic deficits are a significant part of the clinical expression. Neurologic deficits are being seen with remarkable frequency, and in the past two decades they are actually the common presenting complaint, often occurring in the absence of anemia. These include posterolateral spinal column dysmyelinization with resultant peripheral paresthesias, loss of vibratory and positional sense, decreased deep tendon reflexes, and even ataxia. In addition, classic peripheral neuropathy or even cerebral dysfunction with depression, irritability, and memory loss can occur. Because these signs and symptoms are often present in the absence of anemia, the clinician needs special vigilance to evaluate the neurologic findings and relate them to vitamin B12 deficiency. The explanation for the dichotomy of progressive neurologic deficits in the absence of anemia appears to be the increased availability of folate in fortified food, because folate can replace vitamin B12 in blood cell production but not in neural function. Another correlative clinical event has been the recognition of severe and rapid progressive neurologic lesions in patients undergoing nitrous oxide exposure. This has been seen after its use in open heart surgery and even when used for 2 to 3 hours for oral surgery. We now know that nitrous oxide interferes with the two known enzymatic pathways in vitamin B12 metabolism. As noted earlier, the methylcobalamin methyltransferase biochemical pathway can be bypassed by folate. However, functional inactivation and interference of the second pathway (methylmalonyl coenzyme–mutase reaction) occur. This alteration cannot be bypassed by folate and has been demonstrated to result in nerve dysmyelinization.

CURRENT DIAGNOSIS Pernicious anemia is the result of autoantibody loss of gastric intrinsic factor, resulting in failure of facilitated absorption of vitamin B12 in the terminal ileum. Megaloblastic anemia is almost entirely related to deficiency or defective (altered) utilization of vitamin B 12 or folate. Megaloblastic anemia in association with neurologic deficit is due to vitamin B12. Determination of serum methylmalonic acid and homocysteine are the best, most sensitive, and most specific tests for the etiologic basis of megaloblastic anemia and demonstrate presence of the metabolic defect. Repletement of vitamin B12 or folate is best defined by identifying the pathophysiologic mechanism for the defect. With age, the effective extraction of vitamin B12 from food declines, with resultant vitamin B12 deficiency. Folate supplementation is very important in the first trimester of pregnancy to protect from neural tube abnormalities in the fetus. The changing pattern of the causes of megaloblastic anemia is also related to folate metabolism. The FDAmandated addition of folate to whole grain products beginning in 1998 has remarkably changed the occurrence of folate deficiency in the United States and the development of megaloblastic anemia. It, of

course, may be the basis for the prominent increase in the neurologic presentation in vitamin B12 deficiency. A very important observation relative to folate metabolism is the clear requirement for supplemental folate during pregnancy. The most important reason is that folate is critical for normal neural tube formation in the first weeks of pregnancy. Diagnosis LABORATORY DIAGNOSIS OF VITAMIN B12 AND FOLATE METABOLIC DEFICIENCIES Diagnostic value of a low serum vitamin B12 value in patients with megaloblastic anemia is well confirmed. However, evaluation of patients with little or no hematologic abnormalities, but with a variety of neurologic or psychiatric changes, particularly in the older age group, has defined a significantly decreased sensitivity and specificity for the serum vitamin B 12 assay. Characterization of the only two metabolic pathways for vitamin B12 metabolism had long ago provided assays of the intermediates of the two functional coenzymes: methylcobalamin active in the homocysteineto-methonine pathway and adenosylcobalamine in the salvage pathway. Vitamin B12 deficiency results in an increase in serum methylmalonic acid and serum (or plasma) total homocysteine. Normally, serum methylmalonic acid (MMA) is undetectable (commonly defined as 38.5°C (101.3°F) with an ANC < 500/µL is a medical emergency and requires immediate blood and urine cultures and stat IV antibiotics based on the following considerations (see text): Start an IV line; give standard fluids at 1.5 times maintenance. If taking medications, stop them. Consider past history of antibiotic resistance of previously cultured organisms. Consider patient's clinical stability or instability or shock. Determine if a significant ß-lactam allergy exists or not. Choose appropriate antibiotic combinations based on above. Give IV G-CSF, 5-10 µg/kg (maximum dose, 300 µg) [3] once daily. Abbreviations: ANC, absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor; IV = intravenous. 3 Exceeds dosage recommended by the manufacturer.

Therapy GENERAL MEASURES Management depends on the degree of the neutropenia, its etiology, and the patient's previous history of infections. In healthy-appearing asymptomatic adults and older children with isolated neutropenia and cell counts greater than 750/µL, clinical observation only without further diagnostic study may be warranted. Medications that may account for the neutropenia should be stopped, if possible. Serial blood cell counts

can determine if the neutropenia is transient or persistent. If it persists longer than 4 to 8 weeks, additional workup is needed. If anemia or thrombocytopenia is present at any time, however, bone marrow aspiration or biopsy is the next diagnostic test. Infants, younger children, and patients of all ages with a history of chronic, recurrent, or severe infection with neutrophil counts less than 750/µL, especially less than 500/µL, require further diagnostic testing and a decision about medical intervention. General preventive measures should include good hand washing, meticulous skin care, and good oral hygiene with regular dental checkups and professional cleaning. For neutropenic mouth ulcers, a “magic mouthwash” can be prepared by a pharmacist containing equal parts of 2% viscous lidocaine (Xylocaine) and diphenhydramine (Benadryl) in normal saline. A peroxide-based mouthwash can also be used for oral hygiene. Rectal examinations and rectal temperature taking, as well as suppositories and enemas, should be avoided if possible. Patients who are neutropenic but with ANCs greater than 1000/µL generally exhibit normal defense against infection and can be regarded in the same manner as non-neutropenic patients. For patients with ANCs greater than 500/µL but less than 1000/µL who have recurrent infections, preventive medical therapy is an option. Before the cytokine era, prophylactic antibiotics were sometimes used. The most popular agents were the penicillins and trimethoprim-sulfamethoxazole (Bactrim, Septra). These antibiotics may be effective in diminishing the frequency of infections and can be tried, but there may be significant problems associated with their continuous use. These include gastrointestinal complaints, “selection,” and then overgrowth of antibiotic-resistant organisms and allergic reactions. Patients whose ANC is less than 500/µL are at serious risk of bacterial infection, particularly from pathogens such as Staphylococcus aureus and gram-negative organisms. These are often of endogenous origin in the neutropenic host. The onset of fever of greater than 38.5°C (101.3°F) in these patients should be regarded as a medical emergency. By virtue of the low neutrophil counts, they may have few signs of inflammation but they must be hospitalized and empirically treated with antibiotics while awaiting culture results. In my clinic and emergency department, we immediately activate a treatment protocol before admission to avoid any delay in antibiotic therapy. The protocol was developed in our institution for management of patients on chemotherapy who develop fever-neutropenia, but it is equally suitable for any patient with a neutrophil count of less than 500/µL. EMERGENCY DEPARTMENT MANAGEMENT Stop all medications. Start an intravenous (IV) line and give standard fluids at 1.5 times maintenance. Order a chest film, a serum creatinine study, a urinalysis, and obtain cultures of blood and urine and from any apparent focus of infection. When selecting antibiotics, always consider the patient's past history regarding antibiotic resistance of previously cultured organisms as well as the patient's clinical stability. Standard initial antibiotics for the stable patient as described later may not be appropriate for a patient who has had previous serious infection from an antibiotic-resistant organism. Administer the following antibiotics stat (i.e., they should be given before patient transfer from a clinic or emergency department to a hospital ward and before administration of any blood product): For stable patients with no significant beta-lactam allergy, give:

•

Piperacillin-tazobactam (Tazocin): children: 80 mg piperacillin/kg IV every 8 hours; adolescents and adults: maximum dose, 4 g IV every 8 hours

•

Gentamicin: children younger than 9 years, 10 mg/kg IV every 24 hours; from 9 to younger than 12 years, 8 mg/kg IV every 24 hours; 12 years or older, 6 mg/kg IV every 24 hours; adults, 1 to 2 mg/kg IV every 8 hours or 4 to 6 mg/kg IV every 24 hours

If a significant ß-lactam allergy exists, give: •

Ciprofloxacin (Cipro): children, 10 mg/kg IV every 12 hours; adults, 400 mg IV every 12 hours

•

Clindamycin (Cleocin): children, 10 mg/kg IV every 8 hours; adults, 600 mg IV every 8 hours

•

Gentamicin: dose as above

If the patient is unstable or in septic shock with no significant beta-lactam allergy, give: •

Meropenem (Merrem IV): children, 20 mg/kg IV every 8 hours; adults, 1 g IV every 8 hours

•

Vancomycin (Vancocin): children, 15 mg/kg IV every 6 hours; adults, 1 g IV every 6 hours

•

Gentamicin, dose as above

If a significant ß-lactam allergy exists, give •

Ciprofloxacin: dose as above

•

Vancomycin: dose as above

•

Amikacin (Amikin): children, 20 mg/kg[3] IV every 24 hours; adults, 500 mg IV every 12 hours.

MANAGEMENT AFTER ADMISSION Vital signs are measured hourly until the patient's condition stabilizes and then every 4 hours or as indicated. If blood cultures are subsequently positive, repeat cultures should be drawn when this result becomes known. Antibiotics specifically directed toward the identified organism should be added to the broadspectrum therapy if the initial antibiotics do not provide adequate coverage. Broad-spectrum coverage must not be replaced by specific, narrow-coverage antibiotics alone in the neutropenic patient. For patients who become afebrile, with an ANC of greater than 500/µL and with negative cultures, antibiotics can be stopped. For patients who become afebrile and with negative cultures but with neutrophils less than 500/µL, antibiotics can usually be stopped after 48 hours of therapy. Patients who are persistently febrile but stable should continue to receive the initial empirical antibiotic regimen as described. If the patient's condition indicates an evolving infection at a particular site (e.g., abdominal pain, severe mucositis, pneumonia), antibiotics directed toward possible causative organisms should be added to the broad-spectrum coverage. After 5 to 7 days of persistent fever, consider the addition of amphotericin (Amphocin): for children, 1 mg/kg once a day IV, or, if older than 2 years, caspofungin (Cancidas), 50 mg/m2 once a day IV. For adults, give amphotericin, 3 to 4 mg/kg once a day IV, or caspofungin, 70 mg IV once on day 1 followed by 50 mg IV once a day thereafter. SPECIFIC AND GROWTH FACTOR TREATMENT

Referring to Table 1 , there are several diagnoses of acquired neutropenia that respond to specific treatment. Excluding chemotherapy-induced neutropenia, when a drug is suspected as causing the problem, the product should be stopped and general supportive measures instituted. If neutropenia is severe, administration of growth factor (cytokine therapy) should be started (see later). Autoimmune neutropenia of infancy occurring in the first 3 years of life is clinically benign and self-limited, but the spontaneous resolution may take months to years. No therapy is needed unless a bacterial infection ensues, at which point cytokine therapy is initiated in combination with antibiotics. Treatment of chronic autoimmune neutropenia in older children and adults is usually supportive if the neutropenia is an isolated manifestation. Cytokine therapy and antibiotics should be used, however, if infection is a problem. A more generalized multisystem autoimmune disorder usually requires specialized management, conventionally starting with corticosteroids. One of these disorders, Felty's syndrome (rheumatoid arthritis, splenomegaly, and neutropenia), is managed with options ranging from splenectomy, antirheumatic therapy, immunosuppression, plasmapheresis, IV immunoglobulin (IVIG), and cytokine therapy. Isoimmune neonatal neutropenia is the neutrophil equivalent of Rh hemolytic disease of the newborn and lasts an average of 7 weeks postnatally. Therapy is supportive with antibiotics as necessary, but in lifethreatening infections, plasma exchange to remove antineutrophil antibodies, transfusion of maternal neutrophils that lack the immunogenetic antigen, IV immunoglobulin, and cytokine therapy can be used individually or in combination. In neutropenic neonates born to mothers with pregnancy-induced hypertension, the condition is characteristically limited to the first 72 hours of life and seldom requires treatment. “Hypersplenic” neutropenia is seldom severe enough to cause serious infection. Therapy should be directed at correcting the underlying cause of splenomegaly if possible. Splenectomy is a last resort. Replacement therapy for nutritional deficiencies of vitamin B 12 and folic acid specifically and promptly correct the associated neutropenia. Pure white cell aplasia, in which the bone marrow morphology shows absence of myeloid precursors, occurs in most cases with a thymoma and occasionally with ibuprofen therapy. Thymectomy may be effective in the former situation but usually also requires immunosuppression and/or IV immunoglobulins. With ibuprofen-induced neutropenia, stopping the drug corrects the problem. For many of the congenital or inherited neutropenias, cytokine therapy is extremely effective in reversing the abnormal hematology. Severe chronic neutropenia was targeted in 1987 for clinical trials with G-CSF (filgrastim [Neupogen]), and more than 95% of patients with congenital, cyclic, and idiopathic forms of neutropenia responded completely. Based on data compiled by the Severe Chronic Neutropenia International Registry (University of Washington, Seattle), G-CSF is now considered the standard first-line treatment for these conditions. A second product, granulocyte-macrophage colony-stimulating factor (GMCSF, sargramostim [Leukine]), is second-line therapy for severe chronic neutropenia in North America because of less predictable neutrophilic responses. For adults on chemotherapy for nonmyeloid malignancies, pegfilgrastim (Neulasta) can be used to offset severe neutropenia. The product is a longlasting form of G-CSF that is indicated to decrease the incidence of infection in patients receiving marrowsuppressive antineoplastic agents (see later). For patients with a neutrophil count of less than 500/µL with congenital neutropenia (encompassing

Kostmann's syndrome, Shwachman-Diamond syndrome, glycogen storage disease type 1b, and Fanconi anemia), and for the cyclic and idiopathic forms, G-CSF is started at 5 µg/kg/day subcutaneously. If the ANC rises to 1000 to 5000/µL and plateaus, the same G-CSF dosage is maintained. If the ANC exceeds 5000/µL, the dose is reduced to 3 µg/kg to bring the count to 1000 to 5000/µL. If the ANC still exceeds 5000/µL, the dose is lowered further to 1 µg/kg or to alternate-day dosing, for example, 1 to 2 µg/kg every second day. If there is no response to the starting dose, the G-CSF is increased to 10 µg/kg/day. If there is still no effect, increments are continued every 2 to 4 weeks to 20 µg/kg/day,[3] then 30 µg/kg/day,[3] and so on, up to a maximum of 120 µg/kg/day[3] (which would require a twice-daily administration or multiple subcutaneous injections at the same time). A patient who fails to respond to 120 µg/kg/day is defined as being refractory to G-CSF treatment. A trial of GM-CSF would then be warranted using a starting dose of 3 to 15 µg/kg/day (250 µg/m2/day) subcutaneously. Another option is a hematopoietic stem cell transplantation if there is an HLA-matched donor. G-CSF, 5 to 10 µg/kg/day, either IV or subcutaneously, is also indicated for other forms of severe neutropenia, especially those associated with chemotherapy, using the following guidelines that we developed at the Hospital for Sick Children, Toronto: •

For febrile neutropenic patients who have positive blood cultures, have an identified focus of infection, and/or whose vital signs are unstable

•

For patients receiving chemotherapy protocols that predictably induce severe neutropenia to increase safety and to ensure that the full course of chemotherapy is administered and given on time. G-CSF should be administered after the first and subsequent cycles of the chemotherapy in these patients

•

With antineoplastic dose-escalation protocols that predictably induce severe neutropenia

•

For patients enrolled in multicenter chemotherapy protocols that specify the use of G-CSF

•

For patients receiving antineoplastic agents in conjunction with large-volume irradiation involving bone marrow

In this setting as a preventive agent, G-CSF can be stopped when neutrophils are more than 1500 µL for 2 consecutive days. When G-CSF is given for fever-neutropenia, or to patients whose condition is unstable or who have a focus of infection or a positive culture, it can be stopped when neutrophils are greater than 1000/µL for 2 days if the patient is clinically improved, the focus has resolved, and the cultures are negative. For adults receiving Neulasta, the recommended dosage is a single subcutaneous injection of 6 mg administered once per cycle of chemotherapy. It should not be given in the interval between 14 days before and 24 hours after chemotherapy because of the potential for an increase in sensitivity of rapidly dividing myeloid to cytotoxicity.



REFERENCES Dinauer, 2003. Dinauer MC: The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, ed. Hematology of Infancy and Childhood, 6th ed.. Philadelphia: WB Saunders; 2003:923-1010. Kowalczyk. Kowalczyk A (ed): 2005–2006 Drug Handbook and Formulary, Hospital for Sick Children, 24th ed. pp 178-185. To order or for drug information: Telephone: 416-813-6703; e-mail: druginfo Watts, 2004. Watts RG: Neutropenia. In: Greer JP, Foerster J, Lukens JN, et al ed. Wintrobe's Clinical Hematology, 11th ed.. Philadelphia: Lippincott, Williams & Wilkins; 2004:1777-1800.



Chapter 109 – Hemolytic Disease of the Newborn

Method of: James W. Kendig, MD Hemolytic disease of the fetus and newborn refers to a spectrum of problems that were formerly classified as four separate entities: erythroblastosis fetalis, congenital anemia, icterus gravis neonatorum, and hydrops fetalis. Further studies demonstrated that these entities are all manifestations of a single disease caused by red blood cell isoimmunization (alloimmunization). The major red blood cell surface antigen responsible for this process is the Rho(D) antigen. Because there is no corresponding “d” antigen, the term “d” refers only to the absence of the Rho(D) antigen. Rho(D)-negative individuals (dd) have no Rho(D) antigens on their red blood cells. Rho(D)-positive individuals may be homozygous (DD) or heterozygous (Dd) for the Rh o(D) gene, which is located on the short arm of chromosome 1. In addition to the Rho(D) gene, the Rh blood group system includes the related Cc Ee structural gene, which encodes four specific antigens (C, c, E, and e) on the red blood cell surface. Zygosity for Rho(D) may be predicted on the basis of classic serologic tests for the antigens C, c, D, E, e, and the known incidence of various phenotypes in different racial and ethnic groups. Rho(D) alloimmunization occurs when fetal Rho(D)-positive red blood cells (inherited from the father) cross the placenta and enter the circulation of an Rho(D)-negative (dd) mother. The maternal immune system is stimulated to produce Rho(D) antibodies (IgG). ABO incompatibility (mother 0 and fetus A or B) helps to protect against the Rho(D) sensitization of the Rho(D)-negative mother. The maternal Rho(D) antibodies cross the placenta of the current or a subsequent pregnancy and cause the destruction of the Rho(D)-positive fetal red blood cells. The fetus responds to this hemolytic anemia with extramedullary hematopoiesis involving the liver and spleen. The hepatic production of fetal albumin is compromised, leading to hydrops with edema, ascites, and pericardial and pleural effusions. Bilirubin, produced by the hemolysis of fetal red blood cells, readily crosses the placenta and is excreted by the maternal liver. After delivery, however, neonatal hyperbilirubinemia develops, which may lead to an acute encephalopathy (kernicterus). Other red blood cell antigen–antibody systems (Kidd, Kell, Duffy, the C/c and E/e alleles of the Rh system, and, rarely, the ABO system) may occasionally result in hemolytic disease of the fetus and newborn. In the case of anti-Kell isoimmunization, fetal anemia is caused by a suppression of erythropoiesis in addition to hemolysis. Prevention of Rho(D) Alloimmunization The development, commercial production, and widespread use of commercially prepared Rho(D) immunoglobulin (RhoGAM) for the prevention of Rho(D) alloimmunization are among the greatest scientific and medical achievements of the 20th century. This is an example of passive immunization preventing active immunization, but the precise mechanism by which the administration of the Rho(D) antibody blocks the mother's production of the same antibody is still not fully understood. RhoGAM is not beneficial to the

Rho(D)-negative woman after alloimmunization has taken place, and it does not prevent sensitization because of the C/c and E/e antigens of the Rh blood group system. Box 1 gives a list of events and procedures that may lead to the Rho(D) alloimmunization of the Rho(D)-negative woman. An intramuscular dose of RhoGAM (300 µg) should be administered after these events and procedures. In the event of a severe fetal-to-maternal hemorrhage at delivery, more than 300 µg of RhoGAM may be required. BOX 1 Reproductive Events and Procedures That Can Lead to Alloimmunization of the Rh o(D)-Negative Woman Events

•

Threatened abortion and antepartum hemorrhage

•

Spontaneous abortion

•

Delivery at any gestational age

•

Ectopic pregnancy

•

Hydatidiform molar pregnancy

•

Abdominal trauma and motor vehicle accidents during pregnancy

•

Inadvertent transfusion with Rh-positive blood

Procedures

•

Cordocentesis

•

Chorionic villous sampling

•

Induced abortion

•

Amniocentesis any time during pregnancy

•

External cephalic version

•

Delivery at any time

Blood type (ABO and Rho(D)) and an antibody screen (the indirect Coombs test) should be obtained on the first prenatal visit. The antibody screen detects Rho(D) antibodies as well as antibodies directed against the other red blood cell antigens, such as Kell, Duffy, C/c, and E/e. If the antibody screen is positive, alloimmunization has already occurred, and serial titers should be obtained. If the antibody titer is 1:16 or greater by 20 weeks' gestation, further testing is necessary. ANTEPARTUM PREVENTION At 28 weeks' gestation, all Rho(D)-negative mothers should have an antibody screen (indirect Coombs test). If the test is negative, a prophylactic intramuscular dose of RhoGAM (300 µg) should be administered, unless the father of the infant is definitely known to be Rho(D)-negative (dd). The purpose of this prophylactic antepartum dose is to prevent alloimmunization during the pregnancy. The half-life of this dose

is 12 weeks. This antepartum dose may lead to a weakly positive indirect Coombs test in the mother at the time of delivery and a weekly positive direct Coombs test in the infant. POSTPARTUM PREVENTION Every Rh o(D)-negative mother who has not undergone Rho(D) alloimmunization should receive an intramuscular dose of at least 300 µg of RhoGAM after the delivery of an Rho(D)-positive newborn. This critical step in the prevention of Rho(D) disease requires careful communication among the labor and delivery area, the hospital blood bank, and the postpartum floor. These communication issues are particularly important when early discharge from the hospital is being considered and when the birth has occurred outside the hospital. A single dose of RhoGAM (300 µg) neutralizes approximately 30 mL of Rho(D)-positive fetal whole blood or 15 mL of packed fetal red blood cells. If a large fetal-to-maternal transfusion should occur at the time of delivery, a single dose of RhoGAM may be inadequate to prevent alloimmunization. Because of this possibility, the hospital blood bank should check the mother's blood after delivery to determine the presence and the magnitude of a fetal-to-maternal bleed. The rosette test is used to screen maternal blood for the presence of fetal red blood cells, and the Kleihauer-Betke stain is used to evaluate the magnitude of a fetalto-maternal bleed. This information is used to determine the need for a larger (more than 300 µg) dose of intramuscular RhoGAM. RhoGAM should be administered within 72 hours of delivery. If administration has been inadvertently omitted, it may still be given up to 4 weeks after delivery. The Rho(D)-negative mother who is already Rho(D) alloimmunized at the time of delivery will not benefit from the administration of RhoGAM. Obstetric Management of the Mother With a Positive Initial Antibody Screen All pregnant women should have an antibody screen (indirect Coombs test) at the first prenatal visit. If the result is positive, the blood bank identifies the antibody and determines its titer. The blood bank examines the father's red blood cells for the corresponding antigen. If the father's result is negative for the antigen, and if the mother has absolutely no doubts regarding paternity, no further studies are required. If the father's result is positive for the involved antigen, the mother should have serial antibody titers at 1-month intervals. Early ultrasonography should also be done for gestational age assessment. If a critical antibody titer of 1:16 is reached, there is a risk of the development of erythroblastosis fetalis and hydrops, and further investigation and interventions are required ( Figure 1 ).

FIGURE 1 Algorithm used at Baylor College of Medicine, Houston, for the management of newly diagnosed, red blood cell Rho(D) alloimmunization in pregnancy. (From Moise KJ: Changing trends in the management of red blood cell alloimmunization in pregnancy. Arch Pathol Lab Med 1994;118:421-428. Copyright 1994, American Medical Association. Used with permission.)

The Rho(D)-alloimmunized mother with a history of a previous pregnancy requiring an intrauterine transfusion or a neonatal exchange transfusion is at a high risk for hydrops. With this history, serial OD450 (optical density at 450 nm) evaluations of amniotic fluid are recommended, starting at 20 to 22 weeks' gestation, even if the antibody titer has not reached the critical level of 1:16.

PATERNAL ZYGOSITY If the maternal antibody is Rho(D), and the father has the corresponding Rho(D) antigen, the blood bank determines whether he is homozygous (DD) or heterozygous (Dd). This prediction is based on the classic serologic tests for the C, c, E, and e antigens and the known incidence of various phenotypes in different racial and ethnic groups. If the father is heterozygous, there is a 50% chance that the fetal red blood cells are Rho(D)-negative (dd) and that the fetus is not at risk for the development of erythroblastosis fetalis. If the father is heterozygous, it is useful to determine the fetal blood type. DETERMINATION OF FETAL BLOOD TYPE Techniques for obtaining samples of fetal blood from the umbilical vessels, using ultrasound guidance, have been perfected and are available at large regional perinatal centers. This procedure, known as cordocentesis, involves obvious risks and should be performed only by specialists experienced in fetal and maternal medicine. Several centers have used the polymerase chain reaction (PCR) to identify the fetal Rho(D) genotype. This new technique is based on the amplification of the DNA from a few fetal red blood cells found in a centrifuged sample of amniotic fluid. If the mother has Rho(D) antibodies and the fetus is Rho(D)-negative (by cordocentesis of a fetal blood sample or by PCR of fetal red blood cells from amniotic fluid), no further studies are indicated. AMNIOTIC FLUID OD 450 MEASUREMENTS If the maternal antibody titer reaches a critical titer of 1:16 and if there is a possibility that the fetal red blood cells are positive for the corresponding antigen, serial measurements of amniotic fluid OD450 should be done every 10 to 14 days to evaluate the level of bilirubin in the amniotic fluid. These values are plotted on the modified Liley curve ( Figure 2 ).

FIGURE 2 Amniotic fluid optical density ( OD450) zones for management of pregnancy complicated by Rho(D) alloimmunization. (From Queenan JT, Tomai TP, Ural SH, King JC: Deviation in amniotic fluid optical density at a wavelength of 450 nm in Rhimmunized pregnancies from 14 to 40 weeks' gestation: A proposal for clinical management. Am J Obstet Gynecol 1993;168:13701376. Used with permission.)

INTRAUTERINE FETAL TRANSFUSION When OD450 values climb to the upper indeterminate zone or anywhere in the Rho(D)-positive (affected) zone on the modified Liley curve, cordocentesis should be done to measure the fetal hematocrit. If this value is less than 30%, an intravascular fetal transfusion (via cordocentesis) of packed red blood cells should be carried out at a regional perinatal center by specialists experienced in maternal and fetal medicine. For severe hydrops, more than one intrauterine transfusion may be required. The timing of delivery should be based on gestational age estimates and the determination of fetal lung maturity. Management of the Newborn With Erythroblastosis Fetalis DELIVERY ROOM MANAGEMENT With advances in the field of maternal–fetal medicine and the use of intravascular fetal transfusions, it is

unusual for an infant to be delivered with severe erythroblastosis and hydrops secondary to Rho(D). When this does occur, however, three teams of neonatologists, pediatricians, and nurse practitioners must be immediately available to initiate multiple interventions. One team is responsible for airway management, including intubation, and the initiation of positive-pressure ventilation. This team also monitors the heart rate and initiates chest compressions, if needed. A second team is responsible for securing immediate intravascular access, usually via the umbilical vein. A hematocrit value is obtained immediately, and if it is less than 30%, a partial exchange transfusion using 25 to 80 mL per kg of packed red blood cells is carried out within 30 minutes of birth to raise the hematocrit to 40% or higher. A third team should be available to perform paracentesis and thoracentesis, if needed. With severe hydrops, effective pulmonary ventilation frequently cannot be achieved until large collections of pleural and ascitic fluid have been removed. Immediately after umbilical cord clamping, the obstetric team should obtain a sample of cord blood, which is sent to the laboratory for a direct Coombs test and determination of hematocrit, reticulocyte count, total and direct bilirubin levels, cord pH, and blood gas tension values. INTENSIVE PHOTOTHERAPY Upon admission to the neonatal intensive care nursery, the infant with erythroblastosis fetalis should be placed immediately under intensive phototherapy. This can be achieved by using multiple banks of special blue fluorescent tubes (e.g., F20T12/BB manufactured by General Electric, Westinghouse, and Sylvania). Place the full-term infant in a bassinet rather than an incubator, and line the sides of the bassinet with white linens or aluminum foil to maximize surface area exposure. Obtain serial serum bilirubin values (total and direct) at 2- to 3-hour intervals to establish the rate of rise under intensive phototherapy, and plot the levels, as shown in Figure 3 .

FIGURE 3 Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with birth weight of 2000 g or more, or 35 or more weeks' gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values. The serum bilirubin level was obtained before discharge, and the zone in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile (high-risk zone). (From Pediatrics 2004;114(1):297-316, American Academy of Pediatrics. Used with permission.)

INTRAVENOUS GAMMA GLOBULIN The administration of intravenous immune globulin (IVIG) (0.5 g/kg over 2 hours) is recommended if the total serum bilirubin is rising in spite of intensive phototherapy or if the total serum bilirubin is within 2 to 3 mg/dL of the exchange level shown in Figure 3 . NEONATAL DOUBLE-VOLUME EXCHANGE TRANSFUSION With the widespread use of RhoGAM to prevent the alloimmunization of Rho(D)-negative women, coupled with advances in fetal intravascular transfusion therapy, neonatal double-volume exchange transfusions are becoming rare procedures. When neonatal exchange transfusions are required, they should be done by experienced neonatologists and pediatricians working in neonatal centers that are prepared to deal with the various complications of the procedure, which include hypoglycemia, thrombocytopenia, necrotizing enterocolitis, and infection.

CURRENT DIAGNOSIS •

Blood type—ABO and Rho(D)—and an antibody screen (the indirect Coombs test) should be obtained on the first prenatal visit. If the antibody screen is positive, alloimmunization has already occurred, and serial titers should be obtained. If the titer reaches a critical level of 1:16 or greater, additional testing such as determination of paternal zygosity, amniocentesis, and cordocentesis will need to be done by a specialist in maternal–fetal medicine.

•

All Rho(D)-negative mothers who deliver an Rho(D)-positive infant should be screened with a rosette test or a Kleihauer-Betke test to detect an excessive fetal–maternal hemorrhage. Those mothers with evidence of an excessive fetal–maternal hemorrhage may need more than the standard 1 vial of Rho(D)-immunoglobulin (RhoGAM).

•

There is no single simple test to tell what level of bilirubin is dangerous to any given infant at any given time.

•

Following intensive phototherapy and/or exchange transfusion for moderate to severe erythroblastosis fetalis, serial hematocrit values must be followed carefully for 4 to 8 weeks to determine the need for a top-up transfusion of packed red blood cells.

After the delivery of an infant with erythroblastosis fetalis, serial serum bilirubin values (total and direct) should be obtained at 2- to 3-hour intervals to establish the rate of rise. A serum indirect bilirubin level that is climbing by more than 0.5 mg per dL per hour indicates that there is a relatively brisk hemolytic process that may require a double-volume exchange transfusion within the first 12 hours after birth. Recently published guidelines for exchange transfusions are shown in Figure 3 . In addition to lowering the serum bilirubin level, an early double-volume exchange transfusion helps to correct the fetal anemia and removes a significant portion of the antibody-coated red blood cells before they hemolyze. The blood sample for routine metabolic screens for hypothyroidism, inborn errors of metabolism, and hemoglobinopathies should be drawn before the exchange transfusion is performed.

CURRENT THERAPY •

The unsensitized, Rh o(D)-negative patient should receive prophylactic anti-D immunoglobulin (RhoGAM) at 28 weeks' gestation and again post-delivery at any gestational age if newborn infant is Rho(D) positive.

•

The unsensitized, Rh o(D)-negative patient should receive prophylactic RhoGAM after any of the following events and procedures: Ectopic gestation, abruption of placenta, abortion, abdominal trauma, amniocentesis, cordocentesis, chorionic villous sampling, and external cephalic version.

•

The combined use of intensive phototherapy and intravenous immunoglobulin may reduce the need for an exchange transfusion.

Serial serum bilirubin levels should be continued even if an early double-volume exchange transfusion is not mandated by the rate of rise. It is impossible to determine exactly what level of indirect bilirubin constitutes a risk for encephalopathy (kernicterus on neuropathology) in any given infant at any given time. Prematurity, hypoxia, asphyxia, acidosis, sepsis, and hypoalbuminemia may increase the risk of bilirubin encephalopathy. Various drugs, such as the sulfa preparations and ceftriaxone, displace bilirubin from

albumin-binding sites and increase the risk for encephalopathy. In the otherwise healthy, full-term newborn with hemolytic disease, the indirect bilirubin level should not be permitted to climb above 20 mg per dL. With prematurity and hemolytic disease, lower threshold levels for exchange transfusion, based on gestational age, birth weight, chronologic age in days, and the presence or absence of other risk factors for bilirubin encephalopathy are recommended. Premature newborns with hemolytic disease should be managed by experienced neonatologists working in regional perinatal centers. Phototherapy is used as an adjunct to exchange transfusion, and in the case of mild hemolytic disease, phototherapy alone may be sufficient to control the bilirubin level. DELAYED NEONATAL RED BLOOD CELL TRANSFUSIONS A slow hemolysis frequently continues for up to 6 to 8 weeks after delivery in those infants who received a fetal intravascular transfusion or an exchange transfusion after delivery and in those infants with a mild hemolysis requiring only phototherapy. These infants should be followed up with serial hematocrit determinations at 1- to 2-week intervals during the first 6 to 8 weeks after birth. A transfusion of packed red blood cells (10 to 15 mL per kg) may be necessary to correct severe anemia. With severe hemolytic anemia, particularly in infants who received intrauterine transfusions, fetal and neonatal iron stores are elevated. Neonatal iron therapy should be withheld until the serum ferritin level returns to normal.



REFERENCES American Academy of Pediatrics, 2004. American Academy of Pediatrics : Clinical practice guidelines for manage-ment of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114(1):297-316. American College of Obstetricians and Gynecologists, 1999. American College of Obstetricians and Gynecologists : Prevention of RhD Alloimmunization. ACOG Practice Bulletin 4, Washington, DC, ACOG, 1999. Gottstein and Cooke, 2003. Gottstein R, Cooke RWI: Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88:F6-F10. Harkness and Spinnato, 2004. Harkness UF, Spinnato JA: Prevention and management of RhD isoimmunization. Clin Perinatol 2004; 31(4):721-742. Maisels, 1996. Maisels MJ: Why use homeopathic doses of phototherapy?. Pediatrics 1996; 98:283-287. McKenna et al., 1999. McKenna DS, Nagaraja HN, O'Shaughnessy R: Management of pregnancies complicated by anti-Kell isoimmunization. Obstet Gynecol 1999; 93:667-673.



Chapter 110 – Hemophilia and Related Disorders

Method of: Wing-Yen Wong, MD Hemophilia A and B and von Willebrand's disease (vWd) are the most common causes of bleeding. Less common bleeding disorders also need to be considered in the orderly workup of any coagulopathy. The newborn with prolonged bleeding after circumcision, the toddler with bruises not only on the shins and arms but also in areas not usually subject to direct trauma such as the torso and neck, and the teenager with more than 5 to 7 days of heavy menstrual bleeding all deserve attention. Moderately affected children may not present until toddler age when they are more active. The axiom of joint bleeding as the usual site for the hemophilias and mucosal bleeds for vWd tends to hold true. However, severe vWd can have joint bleeds, and extreme lyonization can result in female carriers of hemophilia presenting with menorrhagia. The important criteria for diagnosis are the patient's medical and family history augmented by age-appropriate interpretation of laboratory tests. This chapter focuses on a practical approach to diagnosis and treatment choices for hemophilia A and B, and vWd. Epidemiology and Genetic Transmission Inheritance patterns are divided into three main groups: hemophilia A and B are X-linked recessive, vWd is usually autosomal dominant, and some vWd and other factor deficiencies are autosomal recessive. Approximately 30% of hemophilia in boys presents with new mutations and negative family histories. Incidence of hemophilia A is estimated at 1 in 5000 male births and 1 in 30,000 for hemophilia B. There are no geographic or racial differences. Mild hemophilia is often misdiagnosed and therefore may be underrepresented. Carrier and prenatal testing from blood and amniotic samples has more than 90% accuracy if performed at established laboratories, particularly if blood samples from various affected family members are available for DNA linkage studies. Inversion within intron 22 of the FVIII gene is found in more than 45% of severely affected hemophilia A patients. DNA analysis for this and other mutations is available at certain research laboratories. Testing from chorionic villus sampling can be done at 10 to 12 weeks' gestation if the specific genetic mutation is known, but sampling of fetal blood for FVIII activity cannot be done prior to 16 weeks' gestation. The incidence of vWd is unknown, and estimates vary from 0.2% to 2.0%. There are no gender or racial differences. The complexity of the various vWd subtypes and the generally mild nature of vWd has not lent itself to easy prenatal testing and hence is not usually performed. A large number of vWd molecular gene defects are identified. The information can be obtained from online databank sites. DNA testing can be helpful for vWd subtypes such as type 2N, which can be misdiagnosed as hemophilia A because both disorders have low levels of FVIII. In vWd type 2A, both vWf (von Willebrand's factor) and ristocetin cofactor (RCoF) are decreased, whereas hemophilia A has normal vWf and RCoF levels. People with blood type O have slightly lower baseline levels of vWd than type AB.

CURRENT THERAPY

Bleeds/Procedures Hemophilia A

Hemophilia B

Type 1 vWd

Minor

20–30 U/kg/12–24 h × 1–3 doses

30–50 U/kg/24-48 h × 1–3 doses

Stimate, 1–2 s/d × 1–2 d

Major*

40–50 U/kg/8–12 h

60–100 U/kg/12–24 h

Humate-P, 30–60 RCoF U/kg/12–24 h

Continuous infusion Load with bolus as above; then 2–5 U/kg/h

Load with bolus as above; then 5–10 U/kg/h

Abbreviations: RCoF = ristocetin cofactor; vWd = von Willebrand's disease.

FXI deficiency is the most common hereditary coagulopathy in patients of Jewish descent. The degree of bleeding is highly variable. Disease Classification and Laboratory Testing The activated partial prothrombin time (APTT) measures most common clotting factor abnormalities associated with bleeding diatheses except for FVII and FXIII. Hemophilia A and B patients with inhibitors have prolonged APTT uncorrected by a 1:1 mixing ratio with normal plasma. FVII deficiency is associated with a prolonged PT, whereas FXIII deficiency has normal prothrombin time (PT), APTT, and thrombin time (TT). Some causes of a prolonged APTT not associated with significant bleeding even with major trauma or surgery include deficiencies of high molecular weight kininogen (HMWK), prekallikrein, and FXII. Exclusion of an inhibitor such as antiphospholipid antibody should also be considered in the face of a prolonged APTT and a benign bleeding history. Excessive fibrinolysis such as a-2-antiplasmin deficiency also causes increased bleeding, but these disorders are rare. The mechanism of disease in the coagulopathies may involve failure of synthesis of the necessary coagulation factor or synthesis of abnormal proteins with impaired activity. Hence, the functional protein activity may differ from the amount of protein measured. Hemophilia A and B result in inadequate generation of thrombin for clot formation. The degree of disease severity and onset of symptoms vary with plasma FVIII or FIX activity levels. Boys with less than 1% factor activity have severe disease with early onset of joint and muscle bleeds. Those with hemophilia A have bleeding symptoms earlier in life, usually within the first year, compared to hemophilia B. Moderate and mild disease correlate to factor activity levels of 1% to 5% and more than 5%, respectively. Carrier females have factor levels ranging from 30% to 70%.

In vWd, the mechanism of disease is associated with failure to form an effective primary platelet plug. There are three main types of vWd and numerous subtypes. Type 1 vWd is caused by a partial quantitative deficiency of vWf, type 2 has qualitative variants, and type 3 has marked, sometimes complete, deficiency of vWf. Overall, types 1 and 2 tend to have mild to moderate severity of bleeding, whereas the rarer type 3 tends to have severe disease. Type 2N has a defective affinity for FVIII, and both FVIII and vWf are markedly decreased. It is critical that physicians, especially gynecologists and obstetricians, consider the workup and diagnosis for vWd in any female with menorrhagia. Diagnosis of vWd can be difficult to ascertain with some affected individuals having near normal or fluctuating von Willebrand's factor antigen (vWf:Ag) and RCoF levels and significant clinical bleeding. Table 1 outlines the main characteristics of hemophilia A and vWd.

TABLE 1 -- Key Diagnostic Comparison of Hemophilia A and von Willebrand's Disease Inheritance

Hemophilia A

vWd [*]

X-linked

Autosomal

Bleeding pattern Mainly joint, muscle bleeds Mainly mucous membrane bleeds (e.g., epistaxis, menorrhagia) PTT

Nl or

FVIIIa

Nl or

vWf:Ag

Nl

or Nl

RcoF

Nl

or Nl

Ivy bleeding time Nl Abbreviations: PTT = partial thromboplastin time; RCoF = ristocetin cofactor; vWd = von Willebrand's disease; vWf = von Willebrand's factor; vWf:Ag = von Willebrand's factor antigen.

* Modifying factors include blood type (type O has decreased vWf), stress, physical activity, estrogen use, and pregnancy. Normal values do not definitively exclude diagnosis of vWd and can vary from time to time within the same individual.

Treatment Options HEMOPHILIA A AND B The hallmark to effective treatment remains replacement of the deficient or abnormal factor as early as possible, at the appropriate dosage and frequency. The ability to self-infuse or have a caregiver administer the factor at home at the first sign of any bleeding has a positive impact on disease outcome. For this approach to be effective, early recognition of bleeding is required. Early symptoms for joint or muscle bleeds include increased warmth, tingling sensations, or a vague feeling at the affected or target joint. Increased irritability in the infant or young child often heralds the onset of a bleed. Patients should not wait for swelling or discoloration to infuse. Care at a specialty hemophilia treatment center (HTC) significantly improves disease outcome. These

facilities have the necessary expertise to coordinate all aspects of diagnosis and care, acute and chronic, as well as a multifaceted team approach. Close telephone contact should be maintained between the family and HTC personnel in the event of any bleeding episode, even when home therapy has been initiated successfully. For mild hemophilia A, desmopressin (Stimate), a concentrated form of desmopressin acetate (DDAVP), can be used without exposure to blood products. This is particularly helpful in persons avoiding blood products for religious reasons and in decreasing the risk of infectious transmissions. Details of this treatment option are covered later in the section on the treatment of vWd. Stimate should not be used for FIX-deficient patients. The current treatment of choice for newly diagnosed severely affected individuals with hemophilia A or B is recombinant FVIII or FIX. New products within this category are being added to our armamentarium. Choice of treatment product for previously treated patients largely depends on patient preference and prior rating of clinical efficacy. Studies showed that infusion of ultra-high-purity products is associated with preservation of CD4 counts in HIV-infected individuals. Table 2 lists the replacement factor choices for hemophilia A and B in categories of purity. With established efficacy, random changes are not advisable unless otherwise clinically indicated. However, because of intermittent product shortages, physicians and patients are sometimes required to substitute proprietary factor concentrates. I attempt to keep within a similar category if at all possible. A product may have two different brand names but can be interchangeable (e.g., Helixate and Kogenate). ReFacto is a recombinant FVIII product that has the B domain deleted and is a slightly smaller molecule. A new longer-acting liposomal-pegylated rFVIII is currently undergoing clinical trials.

TABLE 2 -- FVIII and FIX Concentrates Factor Type FVIII Recombinant

FIX

Helixate FS/Kogenate-FS BeneFix ReFacto Recombinate Advate

Ultra high purity

Hemofil M

AlphaNine SD

Plasma derived

Monarc M

Mononine

Monoclate-P Other plasma derived Alphanate[*] SD

Bebulin VH

Humate-P[*][†] Koate-DVI[*]

Profilnine SD Proplex-T

* Contains varying amounts of von Willebrand's factor. † FDA approved for von Willebrand's disease.

TREATMENT DOSAGE AND FREQUENCY Dosing regimens are targeted to maintain replacement plasma factor at certain levels based on the severity and site of bleed. FVIII has a shorter half-life than FIX and should be infused every 8 to 12 hours for an acute bleed compared to every 12 to 24 hours for FIX. FXIII has the longest half-life T12 and can be replaced monthly for most patients. Mild muscle and soft-tissue bleeds require 30% factor plasma level for 1 to 2 days. Major hemorrhage, surgeries, and gastrointestinal (GI) or central nervous system (CNS) bleeds require more than 90% to 100% levels for at least 72 hours. Continuous infusions are often employed for major surgeries or severe bleeds to achieve consistent plasma factor levels. Here are the calculations to achieve these targeted levels: FVIII infusions: number of units required per dose = weight (kg) × % factor level desired × 0.5 (e.g., to achieve 100% in a 50-kg person, number of units required per dose = 50 × 100 × 0.5 = 2500 U) However, wastage of extra factor above the calculated range is discouraged. Hence, the amount actually given is often rounded up to the closest vial size: FIX infusions: number of units required per dose = weight (kg) × % factor level desired × 1 BeneFix infusion: number of units required per dose = weight (kg) × % factor level desired × 1.2 Monitoring of plasma levels (at 1 hour pre- and postinfusion) with initial infusions and at times of dosage change would guide dosage adjustment needs. TREATMENT IN THE PRESENCE OF INHIBITORS Inhibitory antibodies to FVIII arise in 30% of those with severely affected hemophilia A and 3% to 5% of children with hemophilia B during the first 15 to 30 infusion exposures. These antibodies develop after exposure to the exogenous protein and therefore tend to occur in those with large gene deletions and severe disease. The presence of inhibitors should be suspected when failure to achieve adequate hemostasis with routine replacement therapy is observed. Inhibitors are measured by the Bethesda assay in Bethesda units (BUs). High-titer or high-responding inhibitors are more than 5 BU. The level of inhibitor activity determines the choice of appropriate management options. Low-titer or low-responding FVIII inhibitors can be managed by using higher doses of factor concentrate. For mild to moderate bleeds, a dose of twice the routine amount usually suffices. For major bleeds, a bolus of 100 to 150 U/kg[3] followed by continuous infusion at 15 to 20 U/kg/hour for 3 to 4 days may be required. Inhibitor titers may rise sharply because of an anamnestic response and need to be monitored for optimum care.

High-responding inhibitors pose a difficult therapeutic challenge. Often continuous infusions fail to achieve and maintain hemostasis, particularly in major bleeds or surgery. Porcine FVIII at a 100 to 150 U/kg starting dose is successful in hemophilia A inhibitor patients. Monitoring antiporcine FVIII antibodies should be performed. Prothrombin complex concentrates (PCCs), a pool of FII, FIX, X, and FVII, can be used at 75 to 100 U/kg of FIX for minor bleeds. The dose can be repeated once or twice every 12 hours. If bleeding is not controlled within two to three doses, alternate treatment should be used. Heparin should be added at 5 to 10 U/mL of the reconstituted PCC. The mechanism of action is unclear. Activated prothrombin complex concentrates (APCCs) can be similarly applied at 50 to 75 U/kg FIX. Both PCCs and APCCs have increased thrombogenic potential, and myocardial infarcts are reported with their use. However, frequent monitoring of fibrin-split products or d-dimers as signals of thrombosis is of questionable value. The PCCs (Konyne, Proplex-T) and APCCs (FEIBA) are plasma-derived pooled concentrates. They have been the mainstay of inhibitor therapy and demonstrate good efficacy. Recombinant FVIIa (NovoSeven) is available with less thrombogenic effects. Dosage for rFVIIa is recommended at 90 µg/kg for 2 to 4 hours, but optimum dosing is not known. rFVIIa can be used either in the home or hospital setting. PCCs or APCCs should not be administered in close temporal proximity to rFVIIa because that would potentiate the danger of thrombosis, although there are instances of life-threatening bleeds or surgeries in high-titer inhibitor patients where combination of both were used under close monitoring at a HTC setting. A specific group of FIX inhibitor patients develop anaphylactoid reactions upon infusion of concentrates containing any amount of FIX. The reactions vary from feeling flushed with chest discomfort to coughing, wheezing, and frank hypotension and shock requiring intubation and resuscitative efforts. Vigilance to possible anaphylactoid reactions in hemophilia B patients should be exercised. PCCs and APCCs should be avoided when detected. The use of rFVIIa is a proven safe and effective recourse for these patients. Long-term management of hemophilia A and B inhibitor patients includes immune tolerance induction (ITI) to eradicate the antibody completely. There are numerous approaches involving the use of an immunosuppressant and daily FVIII. These methods vary with the dose of FVIII, use of intravenous immunoglobulin (IVIg) and/or cyclophosphamide, antibody adsorption column, or steroids. The decision to initiate such therapy should only be taken after serious consideration of the risks of failure (10% to 30%), intercurrent bleeding, and the enormous commitment required. Low pre-ITI inhibitor titer and early intervention is associated with a higher success rate. ITI should be performed under the care of an experienced HTC. As such, specific protocols are not outlined in this chapter. 3 Exceeds dosage recommended by the manufacturer.

Acquired Hemophilia Acquired inhibitors occur later in life and are autoantibodies, predominantly to FVIII. Risk factors include diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, malignancies, inflammatory bowel disease, and peripartum. More than 50% of cases have no identifiable cause. An estimated 30% to 40% remit spontaneously, and heroic interventions may not be necessary. When needed, the management of such patients can be difficult, with mortality rates exceeding 20%. A similar approach as outlined earlier for congenital hemophilia patients can be used, including ITI. rFVIIa has had more than 90% efficacy in the surgery setting for this high-risk group. Preventive Measures

The primary focus of early intervention is to prevent the onset of chronic sequelae associated with bleeds. To that aim, primary and secondary prophylaxis are advocated. The success of prophylaxis is evidenced by the marked decline in arthropathies and hospitalizations in the past 5 years. Factor infusion at 20 to 40 U/kg two to three times a week, particularly prior to organized sports or physical activity, reduces bleeds. Plasma factor level should be kept within the 1% to 2% range for effective prophylaxis, although beneficial effects are seen even when these levels are not strictly enforced. In the infant and young child, primary prophylaxis is started prior to chronic arthropathy or co-morbidities. This often requires placement of a central venous access with associated risks of infection and thrombosis. Secondary prophylaxis should be encouraged in the older child or teenager and adult. The benefits of decreased bleeds, increased school or work attendance, and general quality of life is well documented. Routine well child immunizations including hepatitis A and B vaccines should be given. Regular exercise and development of good muscle tone and strength decreases joint and muscle bleeds, not to mention optimizing the development of self-esteem and social interaction. Affected children are encouraged to participate in activities such as swimming and group sports with the proviso of consistent use of protective gear such as helmets and knee/elbow pads. Adjunctive Therapy Antifibrinolytics such as e-aminocaproic acid (eACA) (Amicar) or tranexamic acid (Cyklokapron) decrease clot lysis. eACA is available in liquid, tablet, and IV forms. The liquid preparation comes in 250 mg/mL, and 50 mg/kg can be used four times daily[1] for 5 to 7 days. It should be used with extreme caution, if at all, in GI or renal bleeds. Antifibrinolytics are used with rFVIIa. Other agents include fibrin sealants, topical thrombin, and microfibrillar collagen, especially in the presence of mucosal bleeds. Adequate analgesia, for example, acetaminophen (Tylenol) with codeine or morphine, may be necessary for pain relief. Anti-inflammatory medications such as steroids are used in some cases to reduce edema in acute hemorrhage or synovitis. However, medications affecting platelet function such as aspirin or ibuprofen should be avoided. The mnemonic RICE—Rest, Ice, Compression, Elevation—should be applied to joint bleeds, although ice is often difficult to maintain on an irritable child. Oral contraceptives may reduce menorrhagia and also increase plasma FVIII and FIX levels. 1 Not FDA approved for this indication.

GENE TRANSFER Preliminary clinical trials of various FVIII and FIX gene transfer modalities can produce the target factor but are unable to maintain a sustained factor level. More studies are ongoing, but a detailed discussion is beyond the scope of this article. VON WILLEBRAND'S DISEASE DDAVP (Stimate) is effective in raising FVIII and vWf levels three to four times that of baseline levels in most individuals with mild to moderate hemophilia and vWd. It can be used for dental extractions and minor procedures. Stimate does not raise the level in severely affected individuals adequately to achieve hemostasis (e.g., a 1% baseline vWf level would only increase to 3% to 4% postadministration). Stimate can

be administered IV or intranasally. IV dosage is 0.3 µg/kg. Intranasal dosage is 1 squirt (approximately 150 µg) for those less than 50 kg and 2 squirts for patients more than 50 kg. Intranasal administration is more convenient for most patients with faster access to treatment because they can carry the dispenser with them at all times. Side effects include facial flushing, transient blood pressure increases, and fluid retention. Fluid restriction is required to decrease the risk of hypertension, hyponatremia, and seizures. Stimate is contraindicated in neonates and the elderly (older than 75 years). Average time to peak level of FVIII and vWf is 45 minutes after IV and 90 minutes after intranasal administration. With its rapid response, it is most likely that the mechanism of action of Stimate is release of the premanufactured FVIII and vWf from storage sites. Because of depletion of stores from frequent use, Stimate should only be given one to two times a day for a maximum of 3 days consecutively. A trial dose is given at the HTC, and pre- and postdose levels are measured to document an adequate response prior to prescription of the drug for use. Educational sessions on its appropriate use and possible side effects have to be given prior to dispensing Stimate. A few patients may respond to the IV route of administration after failing the intranasal trial. Key points in the use of DDAVP for mild hemophilia A and type 1 vWd are as follows: •

Only the concentrated form (1.5 mg/mL) of DDAVP should be used. The trade name is Stimate. Reference should be made only to Stimate as the appropriate medication to avoid prescription and dispensing errors. DDAVP used for enuresis is ineffective in achieving hemostatic control.

•

Fluid should be restricted just prior to and for 12 to 24 hours postadministration.

•

The treating physician should be notified if hemostasis is not achieved after the first two doses. Tachyphylaxis and concomitant side effects should be considered.

Treatment for patients with type 2s and 3 vWd require IV factor concentrate replacements containing adequate amounts of vWf. Table 2 lists these preparations that include Humate-P and Alphanate. Dosage for Humate-P can be calculated based on the vWf activity expressed as ristocetin cofactor (vWf:RCoF) units. For minor procedures and bleeding, 40 to 50 IU/kg every 8 to 12 hours for one to two doses is usually sufficient. However, major surgeries and bleeds including suspected intracranial hemorrhage (ICH) would require a loading dose of 60 to 80 IU/kg, then 40 to 60 IU/kg every 8 to 12 hours for a minimum of 5 to 10 days, keeping the vWf:RCoF activity more than 50%. Stimate is used as adjunctive therapy in type 3 vWd but should be avoided in most type 2 and platelet-type vWd patients. Recombinant and high-purity FVIII and FIX concentrates should not be used for vWd. Recombinant vWF is available only at a research level and is being developed for future clinical trials. Adjunctive therapy as listed for hemophilia applies generally to vWd as well, including oral progesteronecontaining contraceptives. Other Related Disorders Deficiencies of the other factors are often diagnosed by the APTT, PT, and TT. There are rare cases of familial combined factor deficiencies (e.g., FV + FVIII, FVIII + FIX, FII + VII + IX + X). In the latter case, high doses of vitamin K may be helpful. Severe FVII deficiency (prolonged PT, less than 1% FVII) can vary in presentation, although most neonates succumb to intracranial hemorrhage (ICH). It would seem rational that the principle of replacing the deficient factor applies in this disease as in hemophilia A and B. rFVII is efficacious in maintaining hemostasis at 20

to 30 µg/kg every 6 to 12 hours. For the rest of the factor deficiencies that present with bleeding, freshfrozen plasma (FFP) is often effective. Specific factor replacement is usually not available in the United States (e.g., FXI). Fibrinogen (Factor I) abnormalities require cryoprecipitate for effective hemostasis. FXIII deficiency can be treated with FFP or cryoprecipitate. Prophylactic treatment with FFP uses 10 mL/kg, or 1 to 2 U in adults every 4 to 6 weeks, or cryoprecipitate, 1 bag/10 kg body weight. The amount of each factor in FFP and cryoprecipitate varies according to the donor pool. Dosage varies according to the severity of bleeds and the half-life of the plasma factor involved. It is advisable for the overall treatment of any patient with a bleeding diathesis to be carried out at or under the guidance of a HTC.



REFERENCES Ewing et al., 1988. Ewing NP, Sanders NL, Dietrich SL, et al: Induction of immune tolerance of factor VIII in hemophiliacs with inhibitors. JAMA 1988; 259:65-68. Fuente et al., 1985. Fuente B, Kasper CK, Rickles FR, et al: Response of patients with mild and moderate hemophilia A and von Willebrand disease to treatment with desmopressin. Ann Intern Med 1985; 103:6-15. Lusher et al., 1993. Lusher JM, Arkin S, Abildgaard CF, et al: Recombinant factor VIII for the treatment of previously untreated patients with hemophilia. N Engl J Med 1993; 328:453-459. Manco-Johnson et al., 1994. Manco-Johnson MJ, Nuss R, Geraghty S, et al: Results of secondary prophylaxis in children with severe hemophilia. Am J Hematol 1994; 47:113-117. Roth et al., 2000. Roth DA, Tawa NE, O'Brien J, et al: Non-viral gene transfer of blood coagulation factor VIII in patients with severe hemophilia A. Blood 2000; 96:2532.[abstract]. Souci et al., 2000. Souci JM, Nuss R, Evatt B, et al: Mortality among males with hemophilia: Relations with source of medical care. Blood 2000; 96:437-442. Tuddenheam et al., 1994. Tuddenheam EGD, Schwabb R, Seehafer J, et al: Haemophilia A: Database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acid Res 1994; 22:3511-3533. Warrier et al., 1997. Warrier I, Koerper MA, DiMichele D, et al: Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol 1997; 19:23-27.



Chapter 111 – Platelet-Mediated Bleeding Disorders

Method of: Suman Sood, MD Charles S. Abrams, MD Quantitative and qualitative platelet defects are commonly encountered in clinical practice and can result in bleeding diatheses. Elements of Platelet Function The vascular endothelium separates platelets from adhesive substrates in the subendothelial connective tissue. Platelet-mediated hemostasis is initiated by adherence to exposed collagen, fibronectin, and laminin following a breach to the vessel wall. Intracellular signaling cascades lead to secretion of platelet granules, synthesis, and release of thromboxane A2, and a conformational change in platelet surface glycoprotein IIb/IIIa (GPIIb/IIIa) that enables it to bind soluble fibrinogen or von Willebrand's factor (vWF). Release of thromboxane A2 and agonists within the secretion granules, such as adenosine diphosphate (ADP) and serotonin, activate neighboring platelets to perpetuate the process. Fibrinogen binding to GPIIb/IIIa cross-links the platelets into a hemostatic plug, resulting in platelet aggregation and accumulation at the site of injury. Other signaling pathways initiated by agonists such as thrombin, thromboxane A2, and collagen help promote the process of aggregation. Activated platelet plasma membrane interacts with circulating coagulation factors and provides a surface for assembly and generation of active factor X and thrombin. Secondary hemostasis occurs when the platelet plug is stabilized further by a thrombin-mediated fibrin mesh. The arrest of bleeding in a superficial wound almost exclusively results from the primary hemostatic plug. Platelet-mediated bleeding disorders are characterized by a prolonged bleeding time, mucocutaneous bleeding, petechiae, and purpura. In contrast, deficiencies in secondary hemostasis result in delayed deep bleeding, such as bleeding into muscles and joints. Quantitative Bleeding Disorders Adequate numbers of platelets are required to achieve primary hemostasis. Thrombocytopenia can result from decreased platelet production by bone marrow megakaryocytes, accelerated platelet removal, or platelet sequestration in an enlarged spleen. The clinical context is essential because there is no easy test to differentiate among these possibilities. Most commonly, thrombocytopenia is caused by accelerated platelet removal. Hemorrhage following trauma or surgery generally does not occur if the platelet count is more than 50,000/µL. In an otherwise hemostatically normal patient, significant spontaneous bleeding usually does not

occur with a platelet count greater than 5000 to 10,000/µL. However, there is no absolute threshold for spontaneous bleeding due to thrombocytopenia, and spontaneous bleeding can occur at higher counts when fever, sepsis, severe anemia, and other hemostatic defects are present or when platelet function is impaired by medication. Notably, a prolonged cutaneous bleeding time does not accurately predict clinical bleeding. THROMBOCYTOPENIA DUE TO DECREASED PLATELET PRODUCTION Decreased platelet production occurs in primary diseases of the bone marrow such as acute leukemia and aplastic anemia; myelophthisic processes in which marrow is replaced by metastatic carcinoma, fibrosis, or multiple myeloma; following chemotherapy or radiation therapy; with ethanol toxicity; and during infections with viruses such as HIV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella. Thrombocytopenia also occurs when megakaryocyte proliferation is impaired by myelodysplasia. Overt bleeding in these disorders, when clearly a result of thrombocytopenia, is treated by platelet transfusion. Prophylactic platelet transfusion, however, is an area of controversy and is complicated by the short life span of platelets (10 days), the 5-day shelf life of stored platelets, and platelet immunogenicity. In patients undergoing treatment for acute leukemia, outcome is unchanged when platelet counts of 5,000 to 10,000/µL are used as the threshold for prophylactic transfusion. Single-donor apheresis platelets or platelet donors who are HLA identical to the recipient should be considered to prevent alloimmunization. The multicenter Platelet Dose trial in patients with malignancy is currently accruing and should help clarify these issues. THROMBOCYTOPENIA DUE TO INCREASED PLATELET DESTRUCTION Nonimmune and immune processes can lead to a shortened platelet life span. Nonimmune causes include sepsis, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), preeclampsia and eclampsia, cardiopulmonary bypass, and giant cavernous hemangiomas. The thrombocytopenia resolves with treatment of the underlying disorder, and platelet transfusion is rarely necessary. In TTP/HUS, thrombocytopenia is associated with thrombosis rather than bleeding, and controversial reports exist of clinical deterioration following platelet transfusion. Immune-mediated platelet destruction can occur due to medication, alloimmune sensitization, or autoimmunity. Medications should always be considered a possible cause of thrombocytopenia. The potential list is long, but drugs with strong evidence of antibody-mediated platelet destruction include quinine (Qualaquin), quinidine, sulfonamides, and gold salts. Besides stopping the offending medication, emergent treatment for severe thrombocytopenia with bleeding includes platelet transfusion, and corticosteroids with or without intravenous immunoglobulin (IVIg). Heparin-induced thrombocytopenia (HIT) is a special case of drug-induced thrombocytopenia associated with arterial and venous thrombosis rather than bleeding. HIT occurs in 2% to 5% of patients given unfractionated heparin by any route for 5 to 10 days. Antibodies develop to a heparin–platelet factor 4 (PF4) complex. HIT must always be considered when thrombocytopenia is detected in a hospitalized patient. If a patient has HIT, all heparin administration should be stopped, and alternative anticoagulation such as the direct thrombin inhibitors recombinant hirudin and argatroban should be instituted, at least until the platelet count normalizes. Warfarin (Coumadin) should not be used in acute HIT because of its delayed therapeutic

effect and association with a syndrome of venous limb gangrene. Platelet transfusions in this disease are controversial, because some reports suggest that they can precipitate thrombotic complications. Alloimmune thrombocytopenia due to sensitization to alloantigens such as PlA1 can result from transfusion (post-transfusion purpura, PTP) or maternal sensitization during pregnancy (neonatal alloimmune thrombocytopenia, NAIT). PTP causes profound thrombocytopenia 7 to 10 days after transfusion and can be treated with IVIg or plasma exchange. NAIT can cause severe thrombocytopenia and bleeding in neonates and is treated with platelet transfusion, corticosteroids, and IVIg. Autoimmune thrombocytopenia, also known as idiopathic thrombocytopenic purpura (ITP), is caused by circulating antiplatelet autoantibodies. An ITP-like picture can also occur in autoimmune diseases such as systemic lupus erythematosus, in patients with low-grade lymphoproliferative disorders such as chronic lymphocytic leukemia, and in patients with HIV infections. ITP can occur at any age in both sexes and manifests with either mucocutaneous bleeding or unexplained asymptomatic thrombocytopenia. The complete blood count (CBC) is otherwise normal, splenomegaly is absent, and peripheral blood smears are only remarkable for a decreased number of platelets, some of which may be larger than normal. Bone marrow examination is usually not necessary in the absence of other findings suggesting myelodysplasia, but it typically shows normal or increased numbers of megakaryocytes.

CURRENT DIAGNOSIS Platelet-mediated bleeding disorders are characterized by a prolonged bleeding time, mucocutaneous bleeding, petechiae, and purpura. Thrombocytopenia can result from decreased platelet production, accelerated platelet removal, or platelet sequestration in an enlarged spleen. In an otherwise hemostatically normal patient, significant spontaneous bleeding generally does not occur until the platelet count declines to 38.0°C). Various combinations of antibiotics can be used but most commonly includes an antipseudomonal cephalosporin such as ceftazidime or cefipime. For patients with clinical signs of sepsis such as hypotension or specific symptoms (severe mucositis or abdominal pain), antibiotic coverage should be broadened to include additional gram-negative coverage with an aminoglycoside, gram-positive coverage with vancomycin, and anaerobic coverage with metronidazole or clindamycin. Carbapenems (i.e., meropenem) are indicated in children with penicillin or cephalosporin allergy. Children receiving high-dose cytarabine therapy (AML and relapsed ALL patients) have a high incidence of life-threatening streptococcus viridans bacteremia. Any child who has received this therapy and presents with fever and neutropenia should receive intravenous vancomycin as well as ceftazidime regardless of presence of specific symptoms. All patients should receive P. jiroveci prophylaxis with TMP-SMX at a dose of 5 mg/kg/day divided into three doses on three sequential days per week throughout therapy and continue for 6 months from the completion of treatment. For patients with sulfa allergy or who cannot tolerate TMP-SMX, second-line options include inhaled pentamidine (Pentam), oral dapsone (Aczone),[1] or oral atovaquone (Mepron). Viral

Leukemia patients presenting with a rash suggesting primary varicella or shingles reactivation should be admitted to the hospital for intravenous acyclovir (Zovirax) treatment until the lesions are crusted, due to risk of dissemination. Asymptomatic children exposed to a sick contact with primary varicella should receive prophylactic intravenous immunoglobulin (IVIg) or, if available, VZIg (varicella zoster immune globulin). Other viral infections do not require hospitalization or specific therapy unless complications occur (e.g., respiratory distress with RSV infection). Patients should receive annual influenza vaccination, but in general,

children with leukemia can tolerate routine viral respiratory and gastrointestinal illnesses and do not require specific isolation precautions outside of the hospital. Fungal

Fungal infections represent an area of additional concern for patients being treated for leukemia, mainly during periods of prolonged neutropenia such as ALL induction or any intensive block of AML therapy. The most common pathogens include Candida and Aspergillus species. In neutropenic patients, fever longer than 5 to 7 days despite adequate antibiotic therapy is an indication for the empiric initiation of broad antifungal therapy, usually with liposomal amphotericin B (Ambisome), as well as imaging for occult fungal infection in the sinuses, lungs, liver, or spleen. Treatment of a probable or confirmed invasive fungal infection often requires long-term multiagent antifungal therapy. Current AML protocols include fungal prophylaxis with either fluconazole or voriconazole due to the high risk of infection in this population and the high rate of morbidity from these infections. Similar prophylaxis should be considered for any child undergoing intensive therapy for relapsed ALL. HEMORRHAGE Prior to the introduction of ATRA, APML induction therapy was associated with significant treatment related mortality due to hemorrhagic complications. Today the use of ATRA[*] with chemotherapy is usually not complicated by a bleeding diathesis. However, the use of ATRA is associated with the retinoic acid syndrome. This is a syndrome characterized by severe respiratory distress, capillary leak syndrome, and pseudotumor cerebri. This complication is successfully managed with temporary cessation of ATRA and administration of decadron. ATRA is usually restarted at a lower dose once the side effects have resolved. * FDA approved for APL but not ALL, AML, or CML.

TRANSFUSION Other important aspects of supportive care for children with leukemia include the judicious use of blood component transfusions. In general, packed red blood cell transfusions are recommended for hemoglobin levels less than 8 g/dL or at higher hemoglobin levels if the child is symptomatic (fatigue, headache, shortness of breath, tachycardia). At the time of diagnosis, children are often severely anemic but minimally symptomatic because the anemia has evolved slowly over time. In this setting, blood transfusion should be administered slowly over hours to avoid volume overload. All transfusions should be irradiated to prevent transfusion-related graft-versus-host disease (GVHD) and to prevent cytomegalovirus (CMV) exposure. Platelet transfusions are indicated for platelet counts less than 10,000/µL or for bleeding. Platelets should be administered to a platelet count greater than 50,000/µL before diagnostic lumbar puncture to prevent a traumatic tap, which can be difficult to interpret and can introduce peripheral blasts into the spinal fluid. In general, growth factors such as G-CSF (granulocyte colony-stimulating factor, Neupogen) and

erythropoietin (Epogen, Procrit) are rarely administered to children being treated for leukemia due to the theoretical risk of stimulating a malignant clone, although G-CSF is becoming an integral part of some highly intensive relapsed ALL protocols. Late Effects of Therapy The success of leukemia therapy comes at a price. Although treatment-related mortality continues to decrease as we implement better supportive care strategies, an increasing number of survivors suffer from late effects of therapy. The Children's Oncology Group has recently published detailed long-term follow-up ). These guidelines for pediatric oncologists and other physicians (http://www.survivorshipguidelines.org/ guidelines do not supplant disease-specific follow-up care, but they seek to complement and standardize the care of childhood, adolescent, and young adult cancer survivors. All pediatric oncology centers should establish late effects clinics to provide care for the increasing population of survivors. As the number of longterm effects investigators grows, their experience and expertise are integral parts of clinical trial development. The ultimate objective is to modulate the intensity of therapy to maximize its efficacy and to minimize the short-term and long-term sequelae. It is necessary for all cancer survivors to have a record of a summary of their cancer therapy. Most leukemia cancer survivors graduate to long-term follow-up within 4 or 5 years after completing therapy. After this, they need follow-up visits once a year. The most concerning toxicity occurs in the CNS from high-dose methotrexate or cytarabine arabinoside and from intrathecal methotrexate with or without craniospinal irradiation. These patients can experience a lower educational attainment due to diminished cognitive functioning and usually experience a greater need for special education services. Many studies document increased weight and body mass index in survivors of childhood leukemia. There is also now increased awareness of adverse cardiovascular and diabetes risk profiles (the metabolic syndrome) due to leukemia therapy. Patients who receive high cumulative doses of anthracyclines also need yearly follow-up of cardiac function. Fertility is another issue of concern; this is now more commonly addressed with adolescents and young adults at diagnosis if the planned therapy could result in sterility. Psychosocial evaluation continues to be an important part of long-term follow-up because many patients deal with issues of assistance to procure educational resources, job placement, and health insurance.



REFERENCES Armstrong and Look, 2005. Armstrong SA, Look AT: Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005; 23:6306-6315. Bonnet and Dick, 1997. Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730-737. Carroll et al., 2006. Carroll WL, Bhojwani D, Min D-J, et al: Childhood acute lymphoblastic leukemia in the age of genomics. Pediatr Blood Cancer 2006; 46:570-578. Chessells et al., 2003. Chessells JM, Veys P, Kempski H, et al: Long-term follow-up of relapsed childhood acute lymphoblastic leukemia. Br J Haematol 2003; 123:396-405. Creutzig et al., 2005. Creutzig U, Renhardt D, Diekamp S, et al: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005; 19:1355-1360. Gaynon, 2005. Gaynon PS: Childhood acute lymphoblastic leukemia and relapse. Br J Haematol 2005; 131:579-587. Jones and Saha, 2005. Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukemia of childhood. Br J Haematol 2005; 130:489-500. Kaspers and Creutzig, 2005. Kaspers GJ, Creutzig U: Pediatric acute myeloid leukemia: International progress and future directions. Leukemia 2005; 19:2025-2029. Meshinchi et al., 2006. Meshinchi S, Alonzo TA, Stirewalt DL, et al: Clinical implications of FLT3 mutations in pediatric AML. Blood 2006; 108:3654-3661. Pui et al., 2004. Pui C-H, Relling M, Downing JR: Mechanisms of disease: Acute lymphoblastic leukemia. N Engl J Med 2004; 350:1535-1548. Pui et al., 2003. Pui C-H, Cheng C, Leung W, et al: Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003; 349:640-649. Pui and Evans, 2006. Pui C-H, Evans W: Drug therapy: Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354:166-178. Ravindranath et al., 1996. Ravindranath Y, Yeager AM, Chang MN, et al: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 1996; 334:1428-1434. Rubnitz et al., 2007. Rubnitz JE, Razzouk BI, Lensing S, et al: Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer 2007; 109:157-163. Sievers et al., 2003. Sievers EL, Lange BJ, Alonzo TA, et al: Immunophenotypic evidence of leukemia after induction therapy predicts relapse: Results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood 2003; 101:3398-3406.

Tallman et al., 2002. Tallman MS, Andersen JW, Schiffer CA, et al: All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100:4298-4302. Webb et al., 2001. Webb DK, Harrison G, Stevens RF, et al: Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 2001; 98:1714-1720. Woods et al., 2001. Woods WG, Neudorf S, Gold S, et al: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 2001; 97:56-62.



Chapter 119 – Chronic Leukemias

Method of: Helen Enright, MD Jonathan Bond, MB, MRCPI Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an incidence of thirty per million per year. Two thirds of patients are male. The median age at presentation is 65 to 70 years of age. Nearly 50% of patients are asymptomatic at presentation with the diagnosis made incidentally following a routine blood count. Symptomatic presentation relates to consequences of bone marrow failure, lymphadenopathy and/or hepatosplenomegaly, constitutional symptoms, or autoimmune complications such as hemolytic anemia. DIAGNOSIS The presence of peripheral blood lymphocytosis of greater than 5 × 109/L is required for the diagnosis of CLL. The blood film typically shows small mature lymphocytes in addition to fragile cells damaged in the film-spreading process called smudge cells. Immunophenotyping shows a clonal population of mature B lymphocytes that aberrantly express CD5. Diagnostic evaluation should include direct Coombs test (DCT) (positive in 35%) and serum immunoglobulin estimation. Bone marrow aspiration and biopsy is important in delineating the extent and pattern of marrow involvement (nodular, diffuse, or interstitial) and to evaluate response to treatment. Cytogenetic analysis may reveal important prognostic information. Two main staging systems exist ( Box 1 ). These are based on the extent of disease and degree of bone marrow failure. BOX 1

The Rai and Binet Staging Systems for Chronic Lymphocytic Leukemia (CLL) Rai System

•

0: No anemia, thrombocytopenia, or physical signs

•

I: Lymphadenopathy only

•

II: Splenomegaly and/or hepatomegaly but no anemia or thrombocytopenia

•

III: Anemia (Hb < 11.0 g/dL)

•

IV: Thrombocytopenia (platelet count 173 mmol/L or >1.96 mg/dL), anemia (hemoglobin 2 g/dL below normal limits), or bone lesions (lytic lesions or osteopenia with compression fracture), abbreviated to the acronym CRAB. Based on the International Working Group criteria for multiple myeloma (MM), smoldering myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS).

INVESTIGATIONS Laboratory

Patients suspected of having myeloma require careful investigation ( Box 1 ). Most patients (98%) with myeloma have an M protein detectable either by serum or urine protein electrophoresis. Serum electrophoresis alone shows a monoclonal band in 80% of cases. The components of the monoclonal immunoglobulin are identified by immunoelectrophoresis and immunofixation. Sixty percent of myeloma patients have a monoclonal immunoglobulin (Ig)G paraprotein, and 20% have a monoclonal IgA. Isolated monoclonal light chain without identifiable heavy chain is detected in another 15% of myeloma patients (commonly known as light-chain myeloma or Bence Jones myeloma). Monoclonal IgD and biclonal gammopathies are rarer; each accounts for 1% to 2% of myeloma cases. In 1% of cases, malignant plasma cells synthesize but do not secrete immunoglobulin, and an M protein cannot be detected (nonsecretory myeloma). BOX 1

Investigations in Multiple Myeloma •

Serum protein electrophoresis

•

24-Hour urine collection for total and Bence Jones protein quantitation

•

Immunoelectrophoresis or immunofixation of serum and urine

•

CBC with differential and reticulocyte count

•

Serum creatinine, calcium, uric acid, electrolytes, lactic acid dehydrogenase, alkaline phosphatase

•

Bone marrow aspirate and biopsy

•

Cytogenetics and/or FISH [e.g., for del(13) and t(4;14)] recommended

•

Skeletal survey

•

ß2-microglobulin, C-reactive protein, plasma cell labeling index if available

•

If indicated: Biopsy of soft tissue masses

•

If hyperviscosity is suspected: Serum viscosity

•

If indicated: Cryoglobulins, MRI or CT of affected areas, biopsy for amyloidosis

Abbreviations: CBC = complete blood count; CT = computed tomography; MRI = magnetic resonance imaging; FISH = fluorescence in situ hybridization.

Bone marrow aspiration and biopsy are essential in the diagnostic process and typically show increased numbers of plasma cells (>10%). Aspiration and biopsy might also reveal abnormal plasma cell morphology or amyloid deposition in the marrow space or within blood vessel walls. Radiology

Plain x-rays of the axial skeleton and long bones are used to survey for skeletal evidence of myeloma and to assess for impending pathologic fracture. Magnetic resonance imaging (MRI) (using T1/T2 settings plus STIR [short T1 inversion recovery] sequences) can also be used and is particularly sensitive in detecting less overt patchy plasma cell involvement of the bone marrow. MRI may be especially useful when plain xray films are negative but the index of suspicion for myeloma remains high. In patients with confirmed multiple myeloma, the size and number of lesions on MRI correlate with prognosis. Computed tomography (CT) is less sensitive than MRI but is useful in defining lesions when cord compression is suspected and urgent treatment may be required. Because myeloma lesions are osteolytic, a nuclear bone scan, which best detects osteoblastic lesions, is not generally useful. DIAGNOSTIC CRITERIA Various minimal criteria for the diagnosis of myeloma have been published, most recently those of the International Myeloma Working Group (see the Current Diagnosis box), which has sought to provide standardization.

The presence or absence of myeloma-related end-organ damage and the levels of monoclonal protein and bone marrow involvement by clonal plasmacytosis are keys to distinguishing symptomatic multiple myeloma (MM) from smoldering myeloma (SMM) and MGUS. Myeloma-related end-organ damage can consist of hyper calcemia, renal impairment, anemia, or bone lesions (CRAB). Other less common criteria for endorgan damage due to myeloma include symptomatic hyperviscosity or recurrent bacterial infections (=2 in 12 months). In most MM patients, plasma cells account for more than 10% of nucleated marrow cells; however, rare symptomatic MM patients can present with plasma cells less than 10%, and a lower limit is not specified in the Working Group criteria. Approximately 1% of patients with symptomatic multiple myeloma do not have a detectable monoclonal protein when highly sensitive techniques are employed. MGUS may be difficult to distinguish from SMM or early stage MM. Features that help to support a diagnosis of myeloma include depression of the normal immunoglobulin levels and high paraprotein concentration (>30 g/L in serum or >1 g/24 h in urine). Although MGUS and SMM do not usually require immediate therapy, it is nevertheless important to distinguish between the two because the prognoses differ. Primary or immunoglobulin light chain (AL) amyloidosis is a plasma cell neoplasm related to myeloma that secretes an abnormal immunoglobulin that deposits in tissues in a ß-pleated sheet conformation. Notably, 20% of AL amyloid patients have overt myeloma, whereas among myeloma patients nearly 15% develop primary amyloidosis. Amyloidosis should be suspected in myeloma patients who develop progressive neuropathy, cardiac dysfunction with hypotension, enlarged tongue, swollen joints, hepatomegaly, or nephrotic syndrome. A needle biopsy of the involved tissue is the most reliable method to yield a diagnosis, but if involved tissue is inaccessible, blind abdominal fat pad needle aspiration may be helpful. Samples are assessed by Congo red staining for birefringence. Staging and Prognosis Several staging systems are in existence. The Salmon/Durie system, developed in 1975, remains widely used and integrates the results of CBC, serum creatinine, calcium, serum and urine M protein levels, and radiology to correlate approximate tumor mass with survival. More recently, the new International Staging System (ISS) has been derived and validated by the International Myeloma Working Group from a cohort of 11,000 patients with newly diagnosed untreated myeloma. The ISS ( Table 1 ) uses a simple combination of serum ß2 microglobulin and serum albumin to provide a reproducible and powerful three-stage classification that stratifies patients to groups with median overall survivals of 62, 44, or 29 months.

TABLE 1 -- International Staging System for Myeloma Stage Criteria

Median Survival[*]

1

Serum ß2 microglobulin 18.5 g/dL for men and >16.5 g/dL for women). This is the reason for using several additional diagnostic elements when making the diagnosis of PV. These diagnostic elements are broadly described as the clinicopathologic features that are associated with erythrocytosis in PV patients (rule-in criteria) and those that are associated with secondary erythrocytosis (rule-out criteria). A medical history should identify most causes of secondary erythrocytosis. A history of cyanotic congenital heart disease, chronic lung disease, kidney transplantation, or medications such as androgens or exogenous erythropoietin excludes PV as the cause of erythrocytosis. Smoking elevates hematocrit not only by inducing lung injury and hypoxemia but also by increasing carboxyhemoglobin concentrations and decreasing plasma volume. One must also be aware of rare inherited polycythemias, and a lifetime personal or family history of erythrocytosis should prompt an evaluation for high oxygen affinity hemoglobin or some other syndrome of hereditary erythrocytosis.

CURRENT DIAGNOSIS Diagnosis requires both absolute criteria plus one major criterion or two minor criteria. Absolute Criteria

Elevated red cell mass >25% predicted or Hb >18.5 or Hct >60 in male patients or Hb >16.5 or Hct >56 in female patients No secondary erythrocytosis No elevation of erythropoietin Normal arterial oxygen saturation Carboxyhemoglobin levels normal Major Criteria

Splenomegaly on examination JAK2 V617F mutation or other evidence of clonality (excluding bcr/abl) Minor Criteria

Thrombocytosis Leukocytosis Low serum erythropoietin Spontaneous erythroid colony growth Adapted from Campbell PJ, Green AR: Management of polycythemia vera and essential thrombocythemia. Hematol Am Soc Hematol Educ Program 2005;201-208; McMullin MF, Bareford D, Campbell P, et al: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haem 2005;130:174-195; and Michiels JJ, De Raeve H, Berneman Z, et al: The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders. Semin Thromb Hemost 2006;32(4):307-340. Hypoxemia-induced erythrocytosis is evaluated by measuring arterial oxygen saturation. Oxygen saturation is unaffected by carboxyhemoglobin, however, and normal O2 saturation does not eliminate a diagnosis of smoker's polycythemia. Patients with obstructive sleep apnea can have normal saturations during the day and yet suffer a secondary erythrocytosis because of nighttime hypoxemia. Renal cell carcinoma and benign renal disease (such as hydronephrosis and polycystic kidneys) can stimulate erythropoietin production and cause erythrocytosis. Nonrenal neoplasms, such as hepatocellular carcinoma and uterine leiomyoma, also lead to pathologic elevations of serum erythropoietin levels directing elevated red cell counts. Elevated

levels of erythropoietin rule out PV and point to a diagnosis of secondary erythrocytosis. A low serum erythropoietin level is consistent with a diagnosis of PV. Normal levels are not helpful because they are seen in PV, secondary erythrocytoses, and apparent erythrocytoses. Other laboratory abnormalities observed in PV include elevated serum vitamin B12 and leukocyte alkaline phosphatase. Iron deficiency may be present because iron is being consumed by the hyperproliferative erythron or because of GI bleeding or therapeutic phlebotomy. Neutrophilia and thrombocytosis often occur and are useful diagnostic adjuncts. The bone marrow typically shows trilineage hyperplasia, varying amounts of reticulin, and absent or low iron, and it is the best test for excluding a diagnosis of myelofibrosis. Erythroid colonies can be cultured from PV blood or bone marrow without adding erythropoietin, and erythropoietin-independent erythroid colony formation is sometimes used as a diagnostic test. An activating mutation has been identified in the JAK2 protein that associates with the cytoplasmic tail of the erythropoietin receptor. This mutation—V617F—is found in patients with all myeloproliferative disorders, but it is most commonly associated with PV. The mutation leads to continual activation of genes usually signaled when erythropoietin binds to its receptor. These genes drive erythropoiesis totally independent of the influence of erythropoietin. The JAK2 mutation has been identified in 65% to 97% of patients with PV. Detection of the JAK2 V617F mutation requires only a simple polymerase chain reaction–based test. A positive test is a major criterion for making the diagnosis of PV. Treatment Morbidity and mortality associated with PV are reduced by lowering the risk of thrombosis and by controlling bleeding and other symptoms. THROMBOSIS The hematocrit (Hct) correlates with the risk of thrombosis, and higher rates of thrombosis are seen at Hct levels greater than 0.45. The cornerstone of treatment is to maintain the Hct below this level using phlebotomy. Moderate iron deficiency should emerge, if it is not present initially, but it does not pose any threat. Patients should be cautioned against taking iron supplements. If iron is required, the hemoglobin (Hb) or Hct should be monitored closely.

CURRENT THERAPY Hematocrit 1.5 times the mean normal value)

•

Congenital coagulation factor deficiencies (antithrombin III; factors II, V, VII, IX, X, and XI; plasminogen; antiplasmin)

•

Acquired coagulation factor deficiencies related to warfarin (Coumadin) therapy, vitamin K deficiency, liver disease, massive transfusion (>1 blood volume in 24 h), and disseminated intravascular coagulation

•

Patients with a suspected coagulation deficiency (PT/PTT pending) who are bleeding, or at risk of bleeding, from an invasive procedure

Unacceptable criteria are empiric use during massive transfusion in which the patient does not exhibit clinical coagulopathy, nutritional supplementation, or volume replacement. There is little evidence to support prophylactic plasma infusion in patients with mild prolongation of the prothrombin time (1.5 times normal) after a loss of less than one blood volume. Fibrinogen is next, dropping below 0.8 g/L, in a little over one blood volume. Platelets stay above 50,000 × 109/L until after losses of more than two blood volumes. Various massive transfusion protocols have been reviewed extensively in the literature. Early plasma replacement at higher plasma–to–red cells ratios (~1:1) is gaining popularity in this clinical setting despite the fear that some patients may be overtransfused. However, there are few studies comparing conservative with liberal plasma and platelet transfusion with regard to outcome. Hypothermia due to massive transfusion of refrigerated and recently thawed products contributes to the coagulopathy associated with massive transfusion. For this reason, many products are transfused through blood warmers. The use of cryoprecipitate for fibrinogen replacement is often necessary and more efficient than use of plasma. OTHER ADVERSE EVENTS Less frequent adverse events of transfusion include hypocalcemia due to large infusions of citrate anticoagulant, hyperkalemia due to RBC leakage during storage, mechanical hemolysis, and iron overload. These events are rare and typically affect infants receiving large amounts of old blood or patients receiving chronic transfusions; thus they are outside of the scope of this article. However, it is important to be aware of their existence and to monitor patients accordingly for signs of their development.



REFERENCES Allain et al., 2005. Allain JP, Bianco C, Blajchman MA, et al: Protecting the blood supply from emerging pathogens: The role of pathogen inactivation. Transfus Med Rev 2005; 19(2):110-126. Blumberg, 2005. Blumberg N: Deleterious clinical effects of transfusion immunomodulation proven beyond a reasonable doubt. Transfusion 2005; 45(suppl):33S-39S. Blumberg et al., 2003. Blumberg N, Heal JM, Gettings KEJ: WBC reduction of RBC transfusions is associated with decreased incidence of RBC alloimmunization. Transfusion 2003; 43:945-952. Dodd et al., 2002. Dodd RY, Notari IV, Stramer SL: Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor population. Transfusion 2002; 42(8):975-979. Goldman et al., 2005. Goldman M, Webert KE, Arnold DM, TRALI Consensus Panel , et al: Proceedings of a consensus conference: Towards an understanding of TRALI. Transfus Med Rev 2005; 19(1):2-31. Hillyer et al., 2007. In: Hillyer CD, Silberstein LE, Ness PM, et al ed. Blood Banking and Transfusion Medicine, 2nd ed.. Philadelphia: Churchill Livingstone; 2007. Hirschberg et al., 2003. Hirschberg A, Dugas M, Banez EI, et al: Minimizing dilutional coagulopathy in exsanguinating hemorrhage: A computer simulation. J Trauma 2003; 54:454-463. Kleinman et al., 2004. Kleinman S, Caulfield T, Chan P, et al: Toward an understanding of transfusionrelated acute lung injury: Statement of a consensus panel. Transfusion 2004; 44(12):1774-1789. Lee, 2006. Lee D: Perception of blood transfusion risk. Transfus Med Rev 2006; 20(2):141-148. Linden et al., 2000. Linden JV, Wagner K, Voytovich AE, Sheehan J: Transfusion errors in New York State: An analysis of 10 years' experience. Transfusion 2000; 40:1207-1213. Luban, 2005. Luban NC: Transfusion safety: Where are we today?. Ann N Y Acad Sci 2005; 1054:325-341. Schroeder, 2002. Schroeder ML: Transfusion-associated graft-versus-host disease. Br J Haematol 2002; 117:275-287. Sheppard et al., 2005. Sheppard CA, Roback JD, Hillyer CD: Transfusion-transmitted cytomegalovirus infection: Consideration toward an optimal plan for its mitigation. Blood Ther Med 2005; 5(1):6-14. Zhou et al., 2005. Zhou L, Giacherio D, Cooling L, Davenport RD: Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Transfusion 2005; 45:1056-1063. Zou et al., 2004. Zou S, Dodd RY, Stramer SL, Strong DM, for the Tissue Safety Group : Probability of Viremia with HBV, HCV, HIV and HTLV among tissue donors in the United States. N Engl J Med 2004; 351(8):751-759.



SECTION 7 – The Digestive System

Chapter 126 – Cholelithiasis and Cholecystitis

Method of: Grant R. Caddy, MD Cholelithiasis Gallstones affect 10% to 12% of people in Western populations, and the prevalence increases with age. The majority of patients with gallstones (approximately 80%) remain asymptomatic. The risk of complications, mainly that of acute cholecystitis, occurs in around 2% of patients with symptomatic gallstones. Gallstones can be classified depending on their composition. The commonest stones are cholesterol or cholesterol-predominant stones (mixed stones), which make up around 80% to 85% of all gallstones. Mixed stones can be multiple, of varying sizes, and faceted. Most are radiolucent but 10% are radiopaque. Pure cholesterol stones are commonly solitary but may be multiple and are radiolucent. Pigment stones are less common in Western populations and are associated with hemolytic disorders such as hemolytic anemias, malaria and cirrhosis. Risk factors for cholesterol-predominant stone formation are shown in Box 1 . Female patients have a 2 to 8 times greater risk of developing gallstones than male patients. This increased risk appears to decline following menopause. High intake of carbohydrate, high glycemic load, and high glycemic index foods increases the risk of symptomatic gallstone disease by approximately 1.5 times. Other risk factors include a high body mass index (BMI), rapid weight loss (>1.5 kg/week), and history of dieting or gastric bypass surgery. In a 10-year follow-up study, patients who were overweight (defined as BMI >25) were approximately twice as likely to develop gallstones compared with controls. It has also been documented that following antiobesity surgery, 20% to 35% of patients develop gallstones in the postoperative period. BOX 1

Risk Factors for Developing Gallstones Age >50 years (relative risk, 2.5; P 50% in creatinine clearance or doubling of serum creatinine in less than 2 wk; rule out other etiologies of ARF

HRS II

Progressive renal failure, refractory ascites

Hepatopulmonary syndrome

Hypoxia, intrapulmonary vascular dilations, contrast-enhanced echocardiography or technetium-labeled macroaggregated albumin scanningz

Portopulmonary hypertension

Pulmonary hypertension without secondary etiologies other than portal hypertension

Hepatocellular carcinoma

Lesion >2 cm with arterial enhancement or AFP >400 µg/mL, FNA in other suspicious lesions

Abbreviations: AFP = alpha-fetoprotein; ARF = acute renal failure; EGD = esophagogastroduodenoscopy; FNA = fine-needle aspiration; HE = hepatic encephalopathy; HRS = hepatorenal syndrome; PMN = polymorphonuclear neutrophil (leukocyte).

Common Laboratory and Imaging Findings Frequently, tests confirm the clinical suspicion of cirrhosis in the presence of the characteristic physical findings of advanced liver disease. Laboratory studies could help establish the etiologic diagnosis and screen or confirm complications. In general, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated but can be in the normal range. In the absence of chronic alcohol use, cirrhosis may be indicated by a higher AST than ALT. Bilirubin often increases only in advanced stages. High alkaline phosphatase pinpoints to a cholestatic component. Albumin trends to lower levels and the prothrombin time (PT) or international normalized ratio (INR) increases with the severity of the synthetic disturbance. Cytopenias, especially thrombocytopenia, are common. A low platelet count is often the only initial laboratory finding.

CURRENT DIAGNOSIS Symptoms: fatigue, weakness, nausea, abdominal discomfort, loss of appetite with weight loss, pruritus Physical exam (general): jaundice, skin hematomas, spider angiomas, palmar erythema, gynecomastia, testicular atrophy, caput medusae, Dupuytren's contracture, thenar wasting, leukonychia or Terry's nails, clubbing, splenomegaly Physical exam (in decompensation): ascites, hepatic encephalopathy (asterixis) Complications: spontaneous bacterial peritonitis, esophageal/gastric varices, portal hypertensive gastropathy, hepatorenal syndrome, hepatopulmonary syndrome, portopulmonary hypertension, hepatocellular carcinoma Imaging studies such as abdominal ultrasound (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) can suggest the diagnosis by revealing abnormalities in size, shape, and contour of the liver. However, they are not perfect, and liver biopsy remains the gold standard. Liver imaging can be helpful for the evaluation of portal hypertension and biliary tree abnormalities and to look for complications of advanced liver disease such as ascites, vascular thombosis, and HCC. Diagnosis Obtaining adequate tissue from the liver confirms the diagnosis of cirrhosis. Biopsies could be obtained percutaneously except in the presence of a prolonged PT more than 3 seconds, thrombocytopenia of less than 60,000 to 80,000, or the presence of ascites. In these instances, an open biopsy or a transjugular approach can be used. Severity of Cirrhosis Multiple scores have been created to categorize the severity of disease. The Child-Pugh score is the most widely used ( Table 2 ). It incorporates three laboratory values (PT, bilirubin, and albumin) and two clinical features (ascites and encephalopathy). Class A patients have an 85% 2-year survival, compared with 60% and 35% for classes B and C, respectively. The MELD (Model for End-stage Liver Disease) score has now supplanted the Child-Pugh classification for listing the patient for liver transplantation ( Table 2 ) and is calculated by a formula that includes bilirubin, creatinine, and the INR instead of PT.

TABLE 2 -- Classification of Cirrhosis Child-Pugh Points 1

2

3

Bilirubin (mg/dL)

3.0

Prothrombin time (seconds prolonged)

6

Albumin (g/L)

>3.5

2.8–3.5

3

Serum albumin, g/dL

> 3.5

2.8–3.5

< 2.8

Prothrombin, sec

1–3

4–6

>6

Ascites

Absent Slight

Encephalopathy

None

Moderate

Grade 1–2 Grade 3–4

5–6 points = Grade A (compensated liver disease, 1-year survival is 100%). 7–9 points = Grade B (significantly functional compromised liver disease, 1-year survival is 80%). 10–15 points = Grade C (decompensated liver disease, 1-year survival is 45%).

Acute Bleeding From Esophageal Varices Bleeding esophageal varices is one of the common causes of upper GI hemorrhage. It accounts for an estimated one third of diagnoses in patients presenting with upper GI bleeding. In 1985 the diagnosis of bleeding esophageal varices accounted for approximately 62,000 total hospital days in nonfederal, shortstay hospitals in the United States and was without a doubt the most expensive of all GI disorders in terms of average daily cost of hospitalization ($1091/day). Patients with bleeding esophageal varices tend to present with hematemesis and melena. Often there is evidence of large amount volume of bleeding because the high portal pressures precipitate the rupture of esophageal varices. Relevant history of chronic liver disease and thorough physical examination yielding the stigmata of liver cirrhosis can help guide clinicians toward the correct diagnosis. However, clinicians must remember that although esophageal varices are the most common cause of upper GI bleeding in cirrhotic patients requiring emergent endoscopy, peptic ulcer disease, gastric varices, Mallory-Weiss tears, and portal hypertensive gastropathy are also frequent causes of upper GI bleeding in this group of patients. In patients with active bleeding esophageal varices, only approximately half of the patients stop bleeding spontaneously, which is significantly lower than other forms of upper GI bleeding. In addition, more than 50% of the patients will have recurrent bleeding within the first week of the initial bleeding episode.

Because bleeding esophageal varices is a life-threatening medical emergency, patients with bleeding esophageal varices require immediate medical attention with admission to the hospital. All patients with hemodynamic instability (shock, orthostatic hypotension, decrease in hematocrit of at least 6%, or transfusion requirement more than 2 units of packed red blood cell (RBCs) or active bleeding (manifested by hematemesis, bright red blood per nasogastric tube, or hematochezia) should be admitted to the intensive care unit for resuscitation and close monitoring with automated blood pressure monitoring, ECG monitoring, and pulse oximetry. Because signs such as hypotension and/or tachycardia are often found in the patient, hemodynamic resuscitation is the vital first step in the treatment process. Endotracheal intubation should be considered for the severely encephalopathic, uncooperative, or unconscious patient, if the airway could be compromised, to provide adequate ventilation and prevent aspiration. Nasogastric or orogastric tube lavage should be performed to remove particulate matter, fresh blood, and clots to facilitate anticipated endoscopy examination and to decrease the risk of aspiration. Two large-bore intravenous (IV) catheters that are at least 18 gauge in size should be established. For hypotensive patients the IV catheters should be running wide open; and a central catheter should be established as well, in case pressor medications need to be initiated. It is important to remember that the initial hematocrit level poorly reflects the degree of blood loss if the bleeding is acute. Therefore, estimating the patient's volume loss could be more useful in assessing an acutely bleeding patient. Blood loss should be aggressively replaced by packed RBCs to maintain hematocrit above 30%. Patient's hemoglobin and hematocrit should be followed every 2 to 6 hours depending on the status of the patient. Platelet count should be kept above 50,000/mm3 while the patient is actively bleeding. Desmopressin acetate (DDAVP), which is a synthetic analogue of vasopressin, can be considered in patients with concurrent renal failure in which uremia can lead to platelet dysfunction. Endstage liver disease patients often have at least some degree of coagulopathy, so transfusion of clotting factors with fresh frozen plasma should be performed if necessary. The goal is to maintain international normalized ratio (INR) less than 1.5 in these patients. Small-scale studies have suggested that recombinant human factor VIIa could assist in the treatment of coagulopathy by enhancing the normalization of serum prothrombin time. Subcutaneous (SC) administration of vitamin K can be considered if the patient is at risk for vitamin K deficiency, if the bleeding episode does not stop acutely, or if the patient has abnormal prothrombin time. It should be given at 5 to 10 mg SC/day. Three doses of vitamin K administration should adequately replenish a patient's vitamin K supply. It is also important to hold all nonsteroidal antiinflammatory medications, anticoagulants, sucralfate, antacids, iron supplements, and food during the bleeding episode. A synthetic and long-acting analogue of somatostatin, IV octreotide should be given if bleeding esophageal varices is suspected to assist in the reduction of portal venous pressure by indirectly causing splanchnic vasoconstriction and decreased portal flow. It can stop variceal bleeding in up to 80% of the cases. Intravenous octreotide is given as an initial 50 µg bolus followed by continuous infusion of 50 µg/hour. A higher dose of octreotide does not appear to further the lowering of portal venous pressure and perhaps could lead to elevation of systemic venous pressure. Its safety profile is generally excellent with abdominal discomfort and elevated serum glucose that can occasionally occur in patients receiving this medication. Intravenous vasopressin is an alternative medication that reduces portal pressure by directly constricting the mesenteric arterioles and decreasing portal venous inflow. It is administered by an IV bolus of 0.4 U followed by 0.4 to 0.8 U/minute infusions. Unfortunately, vasopressin is associated with potential serious side effects including myocardial, bowel, and limb ischemia because of its systemic vasoconstrictive effects. Administering nitroglycerin by IV is recommended concurrently along with vasopressin to counter the vasopressin-induced systemic vasoconstriction effect. It is administered at a rate of 10 to 40 µg/minute. We use octreotide over vasopressin in the setting of acute bleeding esophageal varices because of the lower

risk of adverse events. The optimal duration of octreotide or vasopressin is unclear, but we recommend either drug to be continued for 2 to 3 days after the esophageal variceal bleeding episode is adequately controlled. Because patients with bleeding esophageal varices are at risk of having concurrent peptic ulcer disease or developing stress-induced peptic ulcers, administration of proton pump inhibitor medication is also recommended. Another important aspect of managing this group of patients is to prevent and decrease the impact of complications associated with bleeding esophageal varices. A patient likely could achieve hemostasis but only to succumb to the associated complications such as infections including aspiration pneumonia, bacterial peritonitis, urinary tract infection, sepsis; hepatic encephalopathy; and renal failure because of acute tubular necrosis or hepatorenal syndrome. Cirrhotic patients who are hospitalized with a GI hemorrhage tend to be at high risk for developing infections. Therefore, it is reasonable to provide prophylactic antibiotic coverage in this group of patients. Most experts tend to use a fluoroquinolone class antibiotic such as ciprofloxacin or levofloxacin for 5 to 7 days total, initially administered by IV and followed by oral route. However, physicians should take the local patterns of antibiotic resistance into consideration when choosing the antibiotic regimen. Furthermore, it is important to elevate the head of the patient's bed to more than 30 degrees to decrease the risk of aspiration. Hepatic encephalopathy should be treated with lactulose to induce three loose bowel movements each day. Close monitoring of the stool output of patients with hepatic encephalopathy is important because too much watery diarrhea from lactulose can deplete these patients intravascularly, whereas too few bowel movements can worsen the encephalopathy. In terms of renal failure, it can be minimized by adequate hydration of the patient as well as avoidance of nephrotoxic drugs. Esophagogastrodudenoscopic therapy is the definitive treatment of choice for bleeding esophageal varices; therefore, this procedure should be performed once the patient is hemodynamically stable for endoscopy exam. Endoscopy is also highly sensitive and specific for locating and identifying bleeding lesions in the upper GI tract. Modern endoscopic therapies can achieve hemostasis in up to 90% of the cases. Combining endoscopic and pharmacologic therapies has made great strides in decreasing the mortality of esophageal variceal bleeding. A complete and thorough endoscopic examination is necessary to rule out other etiologies of upper GI hemorrhage. Bleeding esophageal varices are confirmed on endoscopy if there is active bleeding from esophageal varices, a platelet plug is found on the surface of the varix, or varices are present and no other source of hemorrhage is found. Two types of endoscopic treatments can be carried out: endoscopic band ligation ( Figure 1 ) and endoscopic sclerotherapy ( Figure 2 ), with endoscopic band ligation as the recommended treatment option. Endoscopic band ligation is carried out by placing elastic rubber bands around the esophageal varices located in the distal portion of the esophagus. Endoscopic sclerotherapy involves the injection of a form of sclerosant into the esophageal varices. Both types of treatment measures have similar efficacy in terms of achieving hemostasis, but one study suggested band ligation has better long-term outcome. Sclerotherapy's advantages are that it is easy to use, more widely available, and a less costly procedure to perform. However, endoscopic band ligation is the preferred method mainly because it has lower risk of procedural associated complications. The potential complications of endoscopic sclerotherapy include local ulceration or bleeding, esophageal stricture formation, esophageal perforation, mediastinitis, and aspiration pneumonia. However, some endoscopists still prefer endoscopic sclerotherapy because of the ability to visualize bleeding sites, and because the application of band ligation can sometimes make the endoscopic field difficult to visualize. Endoscopists should also evaluate whether the patient has evidence of portal hypertensive gastropathy, because both treatments could potentially worsen this condition and increase the risk of bleeding from the stomach.

FIGURE 1 Endoscopic band ligation performed with a flexible endoscope. A varix is aspirated into the device using endoscopic suction and ensnared with an elastic band. (From Schaefer J. In GI/Liver Secrets. Philadelphia, Hanley and Belfus, 1996, p 355. Reprinted with permission.)

FIGURE 2 Endoscopic sclerotherapy performed with a flexible endoscope. A flexible injection needle is used to inject sclerosant into the varix. (From Schaefer J. In GI/Liver Secrets. Philadelphia, Hanley and Belfus, 1996, p 355. Reprinted with permission.)

Unfortunately, emergent endoscopic therapy fails to control acute esophageal variceal bleeding in 15% to 20% of patients. Furthermore, early rebleeding can occur after a bleeding-free period of at least 24 hours. In these circumstances the patient may require a transjugular intrahepatic portosystemic shunt (TIPS) or, in rare cases, surgical intervention to decrease portal venous pressure to control bleeding. The TIPS procedure is performed by inserting an expandable wire mesh stent into the hepatic vein via the jugular vein and advancing to the intrahepatic part of the hepatic vein, creating a portosystemic shunt from the portal vein to the hepatic vein without the need for general anesthesia or major surgery. In 80% to 90% of the patients, TIPS can control acute bleeding esophageal varices. However, there is a 30% increased risk of developing new or worsening hepatic encephalopathy after placement of TIPS. In addition it could precipitate liver failure in the patient. Hence, TIPS should solely be reserved for patients who have failed pharmacologic and endoscopic therapies. There are two main types of emergent surgical interventions available: portosystemic

shunt surgery and devascularization procedures such as distal esophageal transection. They both seem effective in controlling bleeding. However, both types of surgical procedures require experienced surgeons, have a wide variety of complications, and have high intraoperative and postoperative mortality rates. Another option for patients who are unresponsive to endoscopic and pharmacologic therapies is balloon tamponade, which is a temporary measure to control acute hemorrhage. Sengstaken-Blakemore and Minnesota tubes are the most common types of balloons used in practice. Balloon tamponade can provide temporary cessation of active bleeding in 30% to 90% of the cases, with rebleeding occurring in 50% of the cases after the balloon is deflated. The balloon typically has three parts: a gastric balloon, an esophageal balloon, and a gastric suction port. Once the tube is inserted into the patient, the gastric balloon is inflated first, once the tube reaches the stomach, and drawn up against the gastroesophageal junction and secured in place. If this maneuver still does not control bleeding, the esophageal balloon is inflated with tension applied to the tube to directly tamponade the esophageal varices. A nasogastric tube should be placed concurrent with this procedure to prevent tracheal aspiration. This procedure requires experienced endoscopists to perform, because it is associated with significant complications including esophageal rupture, esophageal perforation, local ulceration, tracheal aspiration, and accidentally misplacing the tube into the airway. Given the high risk of complications, patients should have endotracheal intubation and mechanical ventilation support before undergoing the balloon tamponade procedure. Balloon tamponade should only be a temporary measure, and patients should have TIPS or surgical interventions performed as soon as possible ( Figure 3 ).

3. Recommended algorithm for the management of acute bleeding esophageal varices. TIPS = transjugular intrahepatic portosystemic shunt.

Prevention of Recurrent Esophageal Variceal Bleeding A history of bleeding esophageal varices is the best predictor of future esophageal variceal bleeding. The risk of rebleeding is 60% to 70% without further therapy after the initial bleeding episode is controlled. The risk of rebleeding is the highest in the first 6 weeks after cessation of active bleeding. The clinical predictors used to classify a patient's risk of developing initial bleeding esophageal varices mentioned earlier can also be used to predict the risk of recurrent bleeding. Therefore, secondary prophylaxis is important to decrease

the risk of rebleeding. Several treatment options are available to prevent recurrent bleeding including pharmacologic, endoscopic, surgical, TIPS, and orthotopic liver transplantation. Nonselective ß-blockers such as nadolol and propranolol can decrease portal pressure and variceal blood flow. Patients who can tolerate nonselective ß-blockers may start propranolol at 20 mg twice a day, or nadolol at 40 mg once a day, gradually titrating the medication dosage up until heart rate decreases by 20% to 30% or reaches 55 to 60 beats per minute. Nadolol has the advantage of being once-a-day dosing, because patient compliance can be an issue in some cirrhotic patients; however, it is a more expensive medication and less widely available. Titrating the dosage of nonselective ß-blockers based on the HVPG has been evaluated by studies and appeared more effective than titration of the dosage based on heart rate alone. Unfortunately, adverse side effects and poor compliance are significant problems in achieving sustained benefit with the nonselective ßblockers. Long-acting nitrates such as isosorbide mononitrate also reduce portal pressure, but no study has demonstrated that it can decrease recurrent bleeding or mortality as a monotherapy. The mechanism of nitrates appears to be its ability to cause a decrease in outflow resistance in the portal system. Combining nonselective ß-blockers and long-acting nitrates has been more effective and better tolerated than using nonselective ß-blockers alone to reduce recurrent bleeding. Endoscopic band ligation is the treatment of choice at most institutes to prevent recurrent esophageal variceal bleeding. Endoscopic band ligation appears to be at least as equally effective as sclerotherapy in preventing recurrence of bleeding and has a better complication profile. Serial endoscopic band ligation treatments are performed on an outpatient basis at 14-day intervals until varices in the distal esophagus are obliterated. Achieving complete obliteration usually requires three to four endoscopy sessions, after which follow-up endoscopy should be performed every 3 to 6 months to evaluate for any recurring varices. The main downside of band ligation is that small varices can be difficult to band and might be hard to obliterate with this technique. Patients treated with endoscopic band ligation alone have approximately 20% to 40% risk of rebleeding from the esophageal varices. However, if sclerotherapy is performed, it should be repeated 3 to 7 days after the initial session, followed by sessions at 1 to 2 weeks until all varices are completely obliterated. Treatment with sclerotherapy can reduce the risk of recurrent bleeding by 50% at 1 year, but data have not shown its ability to reduce patient mortality. Treatment combining endoscopic band ligation and nonselective ß-blockers has an estimated 25% chance of rebleeding. Combination of nonselective ß-blockers and sclerotherapy does not appear to be more effective than sclerotherapy alone. Whether combining nonselective ß-blockers with long-acting nitrates is more effective than endoscopic therapy in decreasing the risk of rebleeding is still to be determined by future studies. Procedures that decompress the portal system are recommended in patients who failed endoscopic and/or pharmacologic therapies. Transjugular intrahepatic portosystemic shunt is more effective at preventing recurrent esophageal variceal bleeding than endoscopic therapies. The risk of rebleeding after TIPS placement is 8% to 18% at 1 year. It also eliminates the risks of operative and postoperative complications. However, the downside of TIPS is that there is the 30% increased risk of developing new or worsening hepatic encephalopathy after placement of TIPS. Furthermore, there is no survival benefit of using TIPS over endoscopic therapies. Another problem with TIPS is that stenosis and dysfunction of the shunt are frequent. As a result, endoscopic balloon dilation or stent replacement is often needed to re-establish patency of the shunt, and frequent monitoring of stent patency is often performed using Doppler ultrasound. Unfortunately, Doppler ultrasound is neither sensitive nor specific in detecting shunt patency. All these potential problems of TIPS can lead to a significantly higher amount of overall cost. Therefore, given all these considerations, TIPS should be used as a bridge to liver transplantation. Rebleeding occurs in 10% to 20% of patients treated with surgical shunts, which is lower in comparison to

endoscopic therapies but also carries a higher risk of developing new or worsening hepatic encephalopathy. Selective shunts (e.g., distal splenorenal shunt) have lower risk of hepatic encephalopathy than nonselective shunts (e.g., portacaval interposition shunt) because it preserves better liver function. However, selective shunts are somewhat less effective in preventing rebleeding. Yet, although nonselective shunts are more effective at decompressing the portal system, it is associated with higher risk of operative and postoperative complications. Decompressive surgical shunt procedures tend to be considered in noncompliant patients, patients who are ineligible for liver transportation, Child-Pugh A and B patients, and for patients who have failed endoscopic therapies. Selective shunt is the preferred method of the two types of shunt surgeries; the nonselective shunt should only be considered in emergency situations in the hands of an experienced surgeon. Nonetheless, the choice of surgical treatment should be individualized with consideration of the surgeon's expertise, patient compliance, and severity of cirrhosis in the patient. Of course, the best and ultimate treatment option for cirrhotic patients with history of bleeding esophageal varices is liver transplantation. Every cirrhotic patient should be evaluated for liver transplant eligibility. Nonetheless, most of the patients with Child-Pugh A and B can be managed with the treatment measures discussed earlier until liver diseases further deteriorate, whereas more severe patients should be treated adequately to control esophageal variceal bleeding in the pretransplant phase. Clinicians should follow all patients with cirrhosis closely, and patient compliance issues should be emphasized.

CURRENT DIAGNOSIS Esophageal varices commonly occur in cirrhotic patients because of portal hypertension. A significant portion of patients with esophageal varices will develop upper GI bleeding episodes that can lead to a high mortality rate if left untreated. The diagnosis of esophageal varices is established by upper endoscopy but the recently developed PillCam ESO video capsule endoscope has the potential to perform rapid screening measure. Abbreviation: GI = gastrointestinal. Primary Prophylaxis for Bleeding Esophageal Varices The annual risk of cirrhotic patients developing varices is approximately 6%. Because of the high mortality rate from bleeding esophageal varices, prevention of the initial bleeding episode is desirable. Therefore, endoscopy screening looking for evidence of esophageal varices is often recommended. We recommend endoscopic screening for the following subgroups of patients: all newly diagnosed cirrhotic patients and all other cirrhotic patients who are medically stable, motivated and willing to be treated prophylactically, and would benefit from medical or endoscopic therapies. Patients who are unlikely to benefit from prophylactic treatments and those with short life expectancy should be excluded from screening endoscopy. Low-risk cirrhotic patients, such as the ones that have no or small esophageal varices, may not require prophylactic treatment and a repeat screening endoscopy may be performed in 2 years. The newly developed PillCam ESO video capsule endoscope (Given Diagnostic System, Yoqneam, Israel) is equipped with miniature cameras on both ends, is approximately the size of a multivitamin, and takes approximately 20 minutes to perform with little patient discomfort; it might be a useful screening tool for monitoring esophageal varices in the near future. Study has already demonstrated PillCam ESO video capsule endoscope to be a sensitive

diagnostic modality for visualization of esophageal mucosal pathology and may provide an effective method to evaluate patients for esophageal disease. Both pharmacologic and endoscopic treatments are available for primary prophylaxis for bleeding esophageal varices. The aim in using pharmacologic therapy in this setting is, again, to reduce portal pressure and, in turn, intravariceal pressure. Nonselective ß-blockers and long-acting nitrates are the main categories of medications that have been used for this purpose. In most randomized studies of prophylactic ß-blocker therapy compared with control, ß-blockers decreased the risk of first esophageal variceal hemorrhage and the risk of death associated with GI bleeding. In a meta-analysis of nine randomized trials comparing prophylactic ß-blockers with no active treatment (i.e., placebo) to prevent first esophageal variceal bleeding, the incidence of bleeding was significantly reduced with ß-blocker therapy versus control. This effect was more pronounced in patients with large- or medium-sized varices or in those with varices and an HVPG greater than 12 mm Hg. However, adverse side effects and poor compliance were significant problems in achieving sustained benefit with ß-blockers. Nevertheless, prophylactic therapy with propranolol or nadolol is the standard of care for the prevention of a first esophageal variceal bleeding episode. Combination therapy with propranolol and long-acting nitrate such as isosorbide mononitrate may be superior to using ß-blocker alone in the primary prevention of variceal bleeding. Unfortunately, because many patients with advanced cirrhosis often have blood pressure on the lower side, it can be difficult for them to tolerate both ß-blocker and nitrate at the same time. Because of the potential to cause systemic vasodilation, nitrates should not be used as monotherapy in cirrhotic patients. However, endoscopic band ligation is an effective endoscopic treatment of active variceal bleeding and secondary prevention of esophageal variceal bleeding. A recent randomized study compared endoscopic band ligation and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices and concluded that prophylactic propranolol had a significantly higher treatment-failure rate than endoscopic banding. This study also concluded that propranolol was not significantly safer than banding but was associated with arithmetically more frequent severe adverse events requiring discontinuation of therapy. The direct costs of the propranolol group were not significantly less than banding. Therefore, the results of this study suggested that prophylactic banding seems to be a more promising treatment than propranolol for preventing initial variceal bleeding for compliant patients who are at high risk of initial variceal hemorrhage and who are candidates for liver transplantation. So, endoscopic band ligation perhaps should be considered as frontline for the primary prophylaxis of bleeding esophageal varices. No studies have addressed the efficacy of the effectiveness in preventing initial variceal bleeding of combining endoscopic band ligation with ß-blocker treatment. Primary prophylaxis with sclerotherapy leads to a higher mortality rate than placebo or ß-blocker therapy and should not be performed.

CURRENT THERAPY Hemodynamic resuscitation is the first step that needs to be performed in patients with actively bleeding esophageal varices. Combination therapy with pharmacologic and endoscopic treatments should be performed in patients with acute bleeding esophageal varices. Primary prophylaxis and secondary prophylaxis are important objectives in preventing initial bleeding episode and recurrent bleeding, respectively.

Conclusions Bleeding esophageal varices occurs frequently in cirrhotic patients and can lead to significant mortality, disability, productivity, and costs. Because of the poor outcomes that can result once the initial bleeding episode occurs, primary prophylaxis should be carried out. It is the responsibility of clinicians to screen out the patients at risk of developing and having esophageal varices. For patients who already had a bleeding episode, secondary prophylaxis is vital in preventing future bleeds. At the present moment, combination therapies appear to be more effective for the prevention and treatment of bleeding esophageal varices. However, patient education and awareness are also important objectives that clinicians must not forget.



REFERENCES Brown and Everhart, 1994. Brown DM, Everhart JE: Cost of digestive diseases in the United States. In: Everhart JE, ed. Digestive Diseases in the United States: Epidemiology and Impact. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. (NIH Publication no. 94–1447.57–82), Washington, DC: US Government Printing Office; 1994. Ejlersen et al., 2001. Ejlersen E, Melsen T, Ingerslev J, et al: Recombinant activated factor VII (rFVIIa) acutely normalizes prothrombin time in patients with cirrhosis during bleeding from oesophageal varices. Scand J Gastroenterol 2001; 36:1081. Eliakim et al., 2005. Eliakim R, Sharma VK, Yassin K: A prospective study of the diagnostic accuracy of PillCam ESO esophageal capsule endoscopy versus conventional upper endoscopy in patients with chronic gastroesophageal reflux diseases. J Clin Gastroenterol 2005; 39:572-578. Everhart, 1994. Everhart JE: Overview. In: Everhart JE, ed. Digestive diseases in the United States: Epidemiology and Impact. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. (NIH Publication no. 94–1447.3–53), Washington, DC: US Government Printing Office; 1994. Imperiale and McCullough, 1992. Imperiale TF, McCullough AJ: Prophylactic beta-blocker therapy: Clinical implications of an aggregate analysis. Hepatology 1992; 15:354-356. Jutabha et al., 2005. Jutabha R, Jensen DM, Martin P: Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices. Gastroenterology 2005; 128:870-881. Kovacs and Jensen, 1997. Kovacs TOG, Jensen DM: Therapeutic endoscopy for upper gastrointestinal bleeding. In: Taylor MB, Gollan J, Peppercorn MA, et al, ed. Gastrointestinal Emergencies, 2nd ed.. Baltimore: Williams & Wilkins; 1997:181-198. Nevens et al., 1998. Nevens F, Bustami R, Scheys I, et al: Variceal pressure is a factor predicting the risk of a first variceal bleeding: A prospective cohort study in cirrhotic patients. Hepatology 1998; 27:15. Stiegman et al., 1992. Stiegman GV, Goff JS, Michaletz-Onody PA, et al: Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med 1992; 326:1527. Thabut et al. Thabut D, de Franchis R, Bendsten F, et al: Efficacy of activated recombinant factor VII (RFVIIA; Novoseven® in cirrhotic patients with upper gastrointestinal bleeding: A randomized placebocontrolled double-blind multicenter trial (abstract). J Hepatol 3;38(Suppl):13.



Chapter 129 – Dysphagia and Esophageal Obstruction

Method of: Philip O. Katz, MD Girish Anand, MD Dysphagia refers to a subjective sensation of the delayed passage of food from the mouth through the esophagus to the stomach. It derives its origin from Greek dys meaning “difficulty” and phagia meaning “eat.” Dysphagia has been reported in about 2% of healthy adults older than 65 years. The incidence increases to 12% to 13% in the hospitalized elderly. Dysphagia has been reported in about 50% to 60% of patients in nursing homes and other chronic care facilities. There may be associated pain with swallowing (odynophagia) if there is coexistent inflammation. Most patients describe dysphagia as a feeling of food getting “stuck” or “not going down right.” The history plays an important role in understanding the anatomic location and the severity of the symptoms. Key questions like the exact location where the food is getting stuck, associated regurgitation, types of foods causing dysphagia, and presence of weight loss or heartburn are crucial in assessing the symptom of dysphagia. Pathophysiology In the swallowing process, the oropharyngeal and esophageal phases transport solid or liquid boluses rapidly from the mouth to the stomach. Primary peristalsis is the classic coordinated motor pattern of the esophagus, combined with almost simultaneous upper and lower esophageal sphincter relaxation initiated by the act of swallowing. The food bolus is transferred by a progressive pharyngeal contraction through the relaxed upper esophageal sphincter (UES) into the esophagus. The UES closure is followed by a progressive circular contraction beginning in the upper esophagus and proceeding distally along the esophageal body to propel the bolus through the relaxed lower esophageal sphincter (LES), which subsequently closes with a prolonged contraction. Secondary peristalsis is a progressive contraction in the esophageal body occurring in response to its distention by stimulation of sensory receptors in the esophageal body. It usually begins at or above a level corresponding to the location of the stimulus and is limited to the esophagus. A local intramural mechanism can at times take over as a reserve mechanism to produce peristalsis in the smooth muscle segment of the esophagus. This has been called tertiary peristalsis. Any problem with either the strength or coordination of the musculature causes difficulty with movement of food, leading to obstruction. Similarly, any narrowing in the path of transit causes obstruction and distention of the lumen, leading to the sensation of dysphagia. The motility abnormalities might not be constant, thus giving intermittent dysphagia. The extent of luminal obstruction guides the diagnosis. Partial obstruction

might initially give only solid food dysphagia related to large food boluses (e.g., steak). When the extent of obstruction progresses to near total occlusion, the symptoms involve both solid and liquid dysphagia. The extent of associated inflammation (esophagitis) determines whether or not odynophagia is an associated symptom. Diagnosis A careful history helps to localize the site of abnormality, and this forms the basis of further work-up. The evaluation of dysphagia begins with a complete history. A problem initiating a swallow and associated coughing or choking indicates a more proximal or oropharyngeal cause for the symptoms. Pure solid food dysphagia suggests a structural lesion, stricture, ring, or malignancy. A problem initially with solids progressing later to liquids suggests a benign or malignant stricture.

CURRENT DIAGNOSIS Differentiate between oropharyngeal and esophageal dysphagia. Pure solid food dysphagia implies a mechanical (obstructive) cause. Mixed solid and liquid dysphagia suggests functional (motility) abnormality. Eosinophilic esophagitis should be considered in young men with solid dysphagia. Barium swallow (with solid bolus) and endoscopy are complementary. Esophageal function testing (manometry) should be performed for nonobstructive dysphagia. Rapidly progressive dysphagia is concerning for malignancy. The presence of other medical problems such as stroke or scleroderma might point to a systemic cause of the symptoms. A careful history of medications is important, because many drugs have been implicated in pill esophagitis and can cause dysphagia as well as odynophagia. The history can also differentiate dysphagia from globus sensation (feeling of a lump in the throat), which has a different evaluation from dysphagia. Dysphagia for all practical purposes can be classified into oropharyngeal and esophageal dysphagia. OROPHARYNGEAL DYSPHAGIA Difficulty in transferring a food bolus from the hypopharyngeal area to the esophageal body across the upper esophageal sphincter gives rise to the suspicion of oropharyngeal or transfer dysphagia. Several clues in the patient's history help to establish the cause. The onset of symptoms in oropharyngeal dysphagia is almost immediate. The patient describes the feeling of choking or coughing on initiation of swallowing and frequently points to the cervical region as the site of dysphagia. Patients might describe regurgitation of food, aspiration, or halitosis, which can point to a structural abnormality such as a Zenker's diverticulum.

Patients might have to resort to certain physical maneuvers, such as extending their arms and neck and using their fingers to move the bolus. There may be associated speech abnormalities such as hoarseness, nasal quality, or dysarthria, which points to a neuromuscular cause for the oropharyngeal dysphagia. The various causes of oropharyngeal dysphagia are listed in Box 1 . BOX 1 Causes of Oropharyngeal Dysphagia Structural (Mechanical)

Carcinoma Cervical and proximal esophageal webs Cricopharyngeal bar Osteophytes and other skeletal abnormalities Prior surgery or radiation therapy Neuromuscular

Amyotrophic lateral sclerosis Brainstem tumors Dermatomyositis, polymyositis Head trauma Idiopathic upper esophageal sphincter dysfunction Multiple sclerosis Myasthenia gravis Myotonic dystrophy Paraneoplastic syndromes Parkinson's disease Postpolio syndrome Sarcoidosis Stroke Infection

Botulism Diphtheria Lyme disease Syphilis

In patients with oropharyngeal dysphagia, the oral cavity, head, and neck should be carefully examined. Special attention should be paid to the neurologic examination, especially the nerves involved in the act of swallowing, namely cranial nerves V, VII, IX, X, XI, and XII. Clues in the physical examination might suggest polymyositis or dermatomyositis as the cause of symptoms. Video fluoroscopy (barium swallow) is a good first test that permits visualization of the swallowing mechanism. It can identify aspiration, pooling, and abnormal motor activities. This examination concentrates on the cervical esophageal region. A barium swallow can delineate the anatomic anomalies and also can show the remainder of the esophagus. The study starts with liquid barium, progressing to a solid phase. Different consistencies of food are used to assess the oropharynx, UES, and proximal esophagus. A structural abnormality found on the barium examination generally requires an endoscopy for confirmation or treatment. Endoscopy is not the first test to use to evaluate oropharyngeal dysphagia, because the chances of missing an abnormality in the upper part of esophagus are higher than in the distal esophagus. A nasopharyngeal laryngoscopy performed by the otolaryngologist provides detailed information of the hypopharynx, larynx, and oropharynx. It also allows a clear visualization of the vocal cords, valleculae, and the pyriform sinuses to assess any pooling of secretions. Patients with oropharyngeal dysphagia who have an unrevealing barium study or endoscopy might need an esophageal manometry study with careful attention to the UES. Incoordination between UES opening and pharyngeal contractions can cause relaxation (opening) or shortening opening may be associated with dysphagia as well. Zenker's diverticulum is an outpouching of the mucosa through an area of muscular weakness between the transverse fibers of the cricopharyngeus and the oblique fibers of the lower inferior constrictor. These generally occur in older adults and can show symptoms of pulmonary aspirations, gurgling, or regurgitation. Rarely, they become large enough to manifest as a mass and even cause esophageal obstruction. ESOPHAGEAL DYSPHAGIA Esophageal dysphagia occurs either from mechanical or motility causes. The abnormality lies within the body of the esophagus or the lower esophageal sphincter. Patients often complain of symptoms localizing to the upper epigastric region or lower sternum although the association is less significant than in oropharyngeal dysphagia. The type of food producing symptoms and its temporal progression help to identify the cause of symptoms. Dysphagia progressing from solids to liquids usually indicates a mechanical cause, and dysphagia to both solids and liquids from the outset favors a motility disorder. Symptoms of associated heartburn, weight loss, anemia, and regurgitation further narrow the differential diagnosis. Other medical conditions such as radiation therapy and medication use may be associated with dysphagia, as may infectious esophagitis. Both are often associated with odynophagia as well. Opportunistic infections—especially in the setting of HIV disease and AIDS—such as candida, cytomegalovirus, and herpes virus, are the most common and can be managed adequately with medical therapy. The various causes of esophageal dysphagia are listed in Box 2 .

BOX 2 Causes of Esophageal Dysphagia Structural (Mechanical) Intrinsic

Benign tumors Carcinoma: Adenocarcinoma and squamous cell cancer Diverticula Eosinophilic esophagitis Esophageal rings and webs: Schatzki's ring Foreign body Infections: Herpes, CMV, EBV, MAI, Candida, Pneumocystis Peptic strictures Pill esophagitis Radiation strictures or esophagitis Extrinsic

Cervical osteophytes Mediastinal masses Vascular compression: Dysphagia lusoria Motility (Neuromuscular)

Achalasia Diffuse esophageal spasm (DES) Hypertensive lower esophageal sphincter Ineffective esophageal motility disorder Nutcracker esophagus Secondary causes like scleroderma, Sjögren's syndrome, Chagas' disease Functional

Functional dysphagia Abbreviations: CMV = cytomegalovirus; EBV = Epstein-Barr virus; MAI = Mycobacterium aviumintracellulare.

The most common initial diagnostic approach to esophageal dysphagia is to perform endoscopy. In addition to the diagnostic value, endoscopy affords an opportunity to obtain tissue samples and do therapeutic intervention. A barium swallow with a solid bolus challenge is a reasonable alternative, especially with patients in whom oropharyngeal causes are a possibility or when the history suggests a complex stricture or achalasia. An endoscopy is required if a structural abnormality is discovered on the barium study. STRUCTURAL CAUSES Patients reporting only solid food dysphagia typically have a mechanical cause for their symptoms. This can progress to both solid and liquid dysphagia in cases of a high-grade obstruction. These patients tend to develop food impaction and might regurgitate. Benign causes for these symptoms include an esophageal web or a distal esophageal ring. The rings, also called Schatzki's rings, are smooth, thin mucosal structures at the gastroesophageal junction covered by squamous mucosa above and columnar epithelium below. Muscular rings, on the other hand, are characterized by hypertrophic esophageal musculature and are generally located about 2 cm above the gastroesophageal junction. Nonprogressive, episodic dysphagia is a characteristic of esophageal rings. Dysphagia becomes prominent when the diameter is smaller than 13 mm. Rings can manifest with acute dysphagia associated with impaction of a piece of meat, often referred to as “steakhouse syndrome.” Esophageal webs, often asymptomatic, have been associated with iron deficiency anemia (Plummer-Vinson syndrome). Peptic strictures occur in 8% to 10% of patients with symptomatic gastroesophageal reflux disease (GERD). Peptic strictures are associated with a long duration of reflux symptoms, male sex, and older age. Symptoms of dysphagia occur when the luminal diameter narrows to 13 mm or less. Radiation-related strictures or esophagitis are seen in persons undergoing radiotherapy for thoracic or head or neck tumors. In the acute setting esophagitis is the predominant finding and can progress to fibrosis and strictures in the chronic phase. Malignancy is the primary concern in patients with rapidly progressive solid food dysphagia associated with weight loss and anorexia. The staging of esophageal cancer involves CT scanning of the chest and abdomen and endoscopic ultrasonography (EUS). EUS provides the most accurate estimate of disease stage and assists with management decisions. The 5-year survival rate for patients with advanced esophageal cancer continues to be less than 5%. Eosinophilic esophagitis is seen more often as a cause of dysphagia, particularly in young adults. Extensive diffuse eosinophilic infiltration (>20 per high power field), particularly in the proximal esophagus, is seen. The disease can manifest for the first time as a food impaction requiring emergency endoscopic therapy. Feline esophagus, concentric mucosal rings, or ringed esophagus is the classic endoscopic description of eosinophilic esophagitis. Pill-induced esophagitis has been shown to occur with a variety of medications including bisphosphonates, doxycycline, potassium chloride, quinidine, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and iron preparations.

Vascular anomalies such as double aortic arch or aberrant right subclavian artery can cause dysphagia. MOTILITY CAUSES Patients reporting both solid and liquid dysphagia are more likely to have a motility disorder. Achalasia is a disease in which there is a loss of peristalsis in the distal esophagus and a failure of LES relaxation. These patients complain of chest pain, regurgitation, heartburn, and weight loss in addition to dysphagia. A barium swallow is the primary screening test when achalasia is suspected and manometry is confirmatory. The characteristic features on manometry include elevated resting LES pressure, incomplete LES relaxation, and aperistalsis. Spastic motility disorders also manifest with dysphagia and often associated chest pain. The group of spastic motility disorders includes distal esophageal spasm, nutcracker esophagus, and hypertensive LES. The clinical relevance of these abnormalities identified during esophageal manometry is debated, and their management can be challenging. Treatment OROPHARYNGEAL DYSPHAGIA Surgical and endoscopic therapeutic options are available, and these should be based on the patient's age and surgical risk. Surgery has been the mainstay of symptomatic Zenker's diverticulum. These involve cricopharyngeal myotomy with or without diverticulectomy or diverticulopexy. The efficacy of myotomy has been observed to be in excess of 80%. More recently, endoscopic techniques involving coagulation or cutting of the bridge, especially the cricopharyngeal muscle, between the esophagus and the diverticulum have been used. This approach is especially good for patients who are poor surgical risks and is now being used widely by experts in this technique. Botulinum toxin injection might be an alternative to cricopharyngeal myotomy, although results are variable. Injection is usually performed under electromyographic guidance and has been shown to relieve dysphagia in small trials.

CURRENT THERAPY Treat the underlying disorder (e.g., GERD). Dilatation and antireflux therapy manage most peptic strictures. Multimodality therapy should be considered for malignant dysphagia. Achalasia can be effectively treated with pneumatic dilatation or surgery. Swallowing rehabilitation is helpful for oropharyngeal dysphagia following stroke. The presence of other structural abnormalities such as proximal strictures, can require endoscopic

measures such as dilatation. A neoplasm requires appropriate intervention with surgical resection, chemotherapy, or radiation therapy. If the oropharyngeal dysphagia is believed to be from nonstructural causes, swallowing rehabilitation may be the best option available. Swallowing rehabilitation is carried out by trained speech and language therapists, who teach patients maneuvers to overcome the risks of aspiration and improve dysphagia. These can involve proper positioning of the head and neck during swallowing, oral motor exercises, and deliberate multiple swallows. Certain diet modifications can improve swallowing and prevent aspirations. The risk of malnutrition or recurrent aspiration can require placement of gastrostomy tubes for managing long-term nutritional needs. ESOPHAGEAL DYSPHAGIA The treatment of peptic strictures can involve dilatation, biopsies to rule out malignancy, and medical therapy for reflux. Proton pump inhibitor therapy has been shown to reduce the development of these strictures and the need for future dilatation. Radiation-related strictures or esophagitis may be difficult to treat and require frequent esophageal dilatation. The treatment of esophageal cancer depends on the stage of the cancer at the time of diagnosis. The various options available include surgery, chemotherapy, radiation therapy, palliative intraluminal stenting, and, more recently, photodynamic therapy. Eosinophilic esophagitis is treated with topical steroid therapy with fluticasone[1] (Flovent), oral methylprednisolone, or montelukast in addition to dietary restrictions. These treatments have been studied in small series and have been shown to be beneficial. Dilatation may be helpful but must be done with care. Treatment of pill-induced esophagitis involves stopping the offending agent and dilatation of strictures as needed. Treatment modalities for achalasia include pneumatic dilatation of the LES, laparoscopic myotomy, botulinum toxin injection, and medical therapy with nitrates and calcium channel blockers. Medical therapy should be considered only for people who are not candidates for other modalities. Good to excellent relief of dysphagia can be achieved in patients with achalasia whether treated with pneumatic dilatation or myotomy. Many patients require multiple approaches and should be managed by experts in the field. Minimally invasive (laparoscopic or thoracoscopic) myotomy is gaining popularity, and in some centers it has become the procedure of choice. Proposed treatments for distal esophageal spasm, nutcracker esophagus, and hypertensive LES include proton pump inhibitors, nitrates, calcium channel blockers, phosphodiesterase inhibitors, and tricyclic antidepressants or selective serotonin reuptake inhibitors.[1] Botulinum toxin[1] application and endoscopic

dilatation have been tried in small series with varying results. 1 Not FDA approved for this indication.

Summary This review outlines the various causes and management of dysphagia. A careful history and examination with use of certain diagnostic tests help in establishing the reason for the symptom of dysphagia. Most of the conditions can be managed by medical therapy, endoscopic therapy, or surgery. A possible approach is outlined in Figure 1 .

FIGURE 1 Diagnostic algorithm for patients with dysphagia. Abbreviations: EGD = esophagogastroduodenoscopy; PPI = proton pump inhibitor.



REFERENCES Cook and Kahrilas, 1999. Cook IJ, Kahrilas PJ: AGA technical review on management of oropharyngeal dysphagia. Gastroenterology 1999; 116(2):455-479. Katz et al., 1998. Katz PO, Gilbert J, Castell DO: Pneumatic dilatation is effective long-term treatment for achalasia. Dig Dis Sci 1998; 43(9):1973-1977. Khazanchi and Katz, 2001. Khazanchi A, Katz PO: Strategies for treating severe refractory dysphagia. Gastrointest Endosc Clin N Am 2001; 11(2):371-386.viii Spechler, 1999. Spechler SJ: American Gastroenterological Association medical position statement on treatment of patients with dysphagia caused by benign disorders of the distal esophagus. Gastroenterology 1999; 117(1):229-233. Trate et al., 1996. Trate DM, Parkman HP, Fisher RS: Dysphagia: Evaluation, diagnosis and treatment. Prim Care 1996;417-432. Tutuian and Castell, 2006. Tutuian R, Castell DO: Esophageal motility disorders (distal esophageal spasm, nutcracker esophagus, and hypertensive lower esophageal sphincter): Modern management. Curr Treat Options Gastroenterol 2006; 9(4):283-294. Yan and Shaffer, 2006. Yan BM, Shaffer EA: Eosinophilic esophagitis: A newly established cause of dysphagia. World J Gastroenterol 2006; 12(15):2328-2334.



Chapter 130 – Diverticula of the Alimentary Tract

Method of: Harris R. Clearfield, MD Diverticula are often asymptomatic but may produce symptoms if they distend with food or liquid and compress the lumen (Zenker's and epiphrenic diverticula), harbor sufficient organisms to produce a bacterial overgrowth syndrome (jejunal diverticula), or become inflamed or bleed (Meckel and colonic diverticula). Esophageal Diverticula HYPOPHARYNGEAL DIVERTICULA The hypopharyngeal diverticulum (Zenker's diverticulum) is found in approximately 2% of patients presenting with dysphagia, and the majority of cases occur in patients beyond the seventh decade of life. The diverticulum generally protrudes between the cricopharyngeus muscle (superior esophageal sphincter) and the inferior constrictor muscles as a result of high pressure produced by transient inadequate or uncoordinated relaxation of the superior esophageal sphincter during swallowing. Because the cervical spine prevents posterior extension, the diverticulum enlarges laterally, usually to the left side. Small diverticula are asymptomatic, but progressive enlargement can occur as a result of food-induced stretching. The opening of the diverticulum may become larger than the lumen of the esophagus, so that food and liquid can preferentially enter the diverticulum and subsequently spill over into the lumen of the esophagus. The progressively enlarging diverticulum may exert sufficient pressure on the esophagus to produce dysphagia and perhaps aspiration. Symptoms include cervical dysphagia, coughing while eating, bad breath from the fermenting food, a swelling in the neck (usually during meals or liquid ingestion) caused by the enlarging diverticulum, and nocturnal wheezing resulting from aspiration. Medications may also accumulate in the diverticulum causing erratic absorption. The symptoms may be suggestive, but barium upper gastrointestinal (GI) tract radiographic films usually establish the diagnosis. If a Zenker's diverticulum is suspected, upper endoscopy, if necessary, should be accomplished by inserting the instrument under direct vision to reduce the likelihood of perforation. Treatment

No treatment is required for asymptomatic diverticula, but those producing symptoms often require surgery. Although external surgery such as diverticulectomy and myotomy of the superior sphincter is an effective therapy, the use of endoscopic staple diverticulotomy has become increasingly popular. It can be accomplished on an outpatient basis with a more rapid convalescence and a lower rate of complications as compared to external surgery, although there is a recurrence rate of approximately 12%. MIDESOPHAGEAL DIVERTICULA Midesophageal diverticula were once thought to result from a fibrotic “pull” or “traction” from an adjacent mediastinal inflammatory reaction, such as tuberculosis. This theory was largely replaced by the observation

that many diverticula are associated with motility abnormalities such as achalasia or esophageal spasm. The diverticula are usually small and wide mouthed, so that food trapping rarely occurs and symptoms are unusual. If chest pain is associated with these diverticula, esophageal motility studies should be performed. No treatment is usually required for the diverticula. EPIPHRENIC DIVERTICULA Epiphrenic diverticula occur in the distal esophagus and are thought to result from high pressure generated by a motility disorder of the lower esophageal sphincter or distal esophagus, such as achalasia, esophageal spasm, or hypertensive lower esophageal sphincter. Most diverticula are asymptomatic, but an occasional diverticulum may progressively distend and begin to trap food and secretions, leading to dysphagia, substernal discomfort, or vomiting (often nocturnal). The diagnosis is usually established by barium upper GI studies, but upper endoscopy also reveals the lesion. Treatment

No treatment or evaluation is required for small asymptomatic outpouchings, but detailed esophageal motility studies should be performed for larger diverticula. Symptomatic diverticula associated with a motility disorder are treated with calcium channel blockers, but medical therapy is usually ineffective. If surgery is required, myotomy of the lower esophageal sphincter down to the cardia of the stomach and proximal to the mouth of the diverticulum may suffice for relatively small diverticula, but diverticulectomy plus myotomy is best for large diverticula. The procedure is most commonly performed by an “open” approach, but increasing evidence supports a laparoscopic approach. Either type of surgery should be combined with an antireflux procedure to prevent reflux resulting from loss of the lower esophageal sphincter's competence. Small Intestinal Diverticula DUODENAL DIVERTICULA Duodenal diverticula are noted in approximately 5% of patients studied with barium upper GI radiographs and in 10% to 20% of patients studied by endoscopic retrograde cholangiopancreatography (ERCP). They are the most common small bowel diverticula and are exceeded in frequency only by colonic diverticula. They usually occur within the “C loop,” often adjacent to the ampulla of Vater (referred to as juxtapapillary diverticula), and are rarely found on the lateral wall of the duodenum. The diverticula increase in frequency with advancing age. They are usually composed of mucosa without muscle fibers, which suggests they are the result of duodenal pressure, but congenital diverticula may also occur. There appears to be no increased incidence of colonic diverticula in patients with duodenal diverticula, thus negating the concept of a general GI predisposition to diverticular formation. The ERCP endoscope, which is side viewing, is best suited for the detection of juxtapapillary diverticula, but they may be observed by standard upper endoscopy and barium radiographs. Because imaging studies are usually obtained related to upper GI symptoms, it is tempting to ascribe such symptoms to the presence of the diverticula. However, it is difficult to establish a correlation between these occasionally encountered diverticula and a variety of dyspeptic or aerophagic complaints. Nevertheless, there does appear to be a correlation between the presence of juxtapapillary diverticula and infected bile, common duct stones, and gallstones. This raises the possibility that the diverticula may compromise flow in the common bile duct by exerting extrinsic pressure, thus promoting stasis and common duct calculi formation. Dysfunction of the

sphincter of Oddi is ascribed to the presence of adjacent diverticula and could lead to reflux of duodenal contents and bacteria into the biliary tree. Rare cases of pancreatitis are thought to be secondary to juxtapapillary diverticula. The presence of juxtapapillary diverticula may complicate diagnostic and therapeutic ERCP procedures. Treatment

Duodenal diverticula rarely produce symptoms and therefore usually require no therapy. Resection should be considered if studies suggest that external pressure on the common bile duct is causing obstruction or stone disease. Upper GI tract bleeding, brisk rather than occult, may rarely arise from these diverticula, but efforts should be made to define some other, more likely etiology. A causal relationship between duodenal diverticula and bleeding should be established only with convincing endoscopic or angiographic findings. The management of the bleeding is similar to that of other causes of upper GI tract hemorrhage, but emergency excision of the diverticulum could be required if supportive measures are unsuccessful. Diverticular perforation and abscess are even more uncommon and would prompt computed tomography (CT) scan, ultrasonography, or surgical exploration to establish the diagnosis. Diverticulectomy would be required for such patients. JEJUNAL AND ILEAL DIVERTICULA Jejunal and ileal diverticula are uncommon and are thought to be primarily of the acquired type. They tend to occur on the mesenteric border of the small bowel where blood vessels penetrate from the serosal surface, thus creating a potential weakness in the musculature. Multiple large diverticula, usually jejunal, may permit sufficient bacterial overgrowth to result in a malabsorption syndrome. This complication may be associated with a more generalized bowel motility disorder, such as scleroderma. The symptoms are those of other malabsorption syndromes and include megaloblastic anemia secondary to vitamin B 12 or folate deficiency, steatorrhea, diarrhea, weight loss, and fat-soluble vitamin deficiency. Jejunal diverticula are also associated with intestinal pseudo-obstruction, although the retrospective nature of the published reports does not permit an estimate of the frequency of this relationship. The diverticula appear to be a manifestation of the pseudoobstruction rather than the cause. The generalized nature of the small bowel motility disorder in these patients is illustrated by such associated findings as esophageal dysmotility, the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), and degenerated smooth muscle cells consistent with a visceral myopathy. Large small bowel diverticula have caused volvulus and are also complicated by hemorrhage and perforation (diverticulitis). Treatment

The bacterial overgrowth of small bowel diverticulosis often responds to antibiotic therapy. Tetracycline, 250 mg four times daily, or other broad-spectrum antibiotics for 7 to 10 days may be effective. Unfortunately, relapse is common and some patients benefit from 1 week of antibiotic therapy each month. A promotility agent such as metoclopramide[1] 250 mg or 500 mg can be taken 30-60 minutes before meals in an attempt to decrease small intestinal stasis. Vitamin B12, folic acid, and fat-soluble vitamins should be provided, and dietary fat and milk products should be reduced. Resection of the small bowel containing the diverticula is suggested for patients with chronic symptoms, but this may prove to be ineffective if the diverticula are the result of a generalized neuropathic or myopathic process. Surgery should be reserved for acute complications such as bleeding, diverticulitis, or volvulus. It is therefore important to consider an associated motility disturbance in patients with symptomatic small bowel diverticula.


MECKEL'S DIVERTICULUM Meckel's diverticulum, which is present in 1% to 3% of the population, represents the failure of the intestinal end of the primitive yolk duct (vitelline duct) to close completely. The diverticula usually occur on the antimesenteric surface of the ileum, approximately 60 to 80 cm from the ileocecal valve, but they may occur as far as 200 cm proximal to the valve. The diverticulum is usually several centimeters in size, but diverticula measuring up to 10 cm are described. The majority of the diverticula are asymptomatic. The major complications of bleeding, inflammation, and obstruction are seen most commonly in infants and young children (60%), with a male predominance. Adult males are also more likely to develop complications from the diverticula. The most common presenting complication in adults is bleeding, whereas the most common childhood presentation is obstruction. Bleeding generally results from the presence of ectopic gastric mucosa within the sac, a finding in approximately 50% to 70% of symptomatic patients. The acid production leads to ulceration and bleeding from within or adjacent to the diverticulum. The bleeding is more frequently maroon or red than tarry and is more likely to be brisk than occult. Obstruction, with or without a fibrous attachment to the umbilicus, can result from volvulus or intussusception and may be of the closed-loop type. Inflammation of the diverticulum (diverticulitis) is less common than appendicitis because of the diverticular wide neck that permits the fecal stream to exit easily. The motility of the ileum decreases the likelihood that the inflammation will be sealed off, increasing the possibility of perforation should diverticulitis occur. The presence of painless, massive lower GI tract bleeding in an infant or child should suggest the possibility of Meckel's diverticulum. Bowel obstruction or peritonitis in this age group should also raise this suspicion. Although less common, the preceding complications can also occur in adults. The diagnosis of Meckel's diverticulum is rarely made by barium small bowel examination, although this study (or small bowel enema) may be useful in selected patients to exclude other disorders. The 99mTc pertechnetate isotope is taken up by Meckel's diverticula containing gastric mucosa and may be helpful for establishing the diagnosis, but a negative examination does not exclude the possibility (many diverticula do not contain gastric mucosa, and even those that have the heterotopic gastric mucosa may not be visualized). Sensitivity is enhanced somewhat by pretreating patients with acid-suppressive therapy prior to isotope scanning. CT scanning has been helpful in diagnosis and should be performed if Meckel diverticulum is suspected, but false negatives also occur. The wireless videocapsule is helpful in a case report, but caution should be exercised if the process is Meckel's diverticulitis because the capsule may become lodged in an area of edema and narrowing. Mesenteric angiography may be useful during an active bleeding episode; intestinal obstruction is diagnosed on the basis of clinical and radiographic criteria; and peritonitis in an infant or child should suggest appendicitis or diverticulitis. Treatment

The treatment of symptomatic Meckel's diverticulum requires blood replacement, localization of the bleeding point if possible by isotope scan, CT scan, angiography, or videocapsule. Diverticulectomy is advised if the symptomatic diverticulum is identified, but one study suggested that the distribution of the heterotopic gastric mucosa may be at the base of short diverticula and thus could require localized small bowel resection. Laparoscopic resection for Meckel's diverticula in adults is reported. Occasionally patients, both young and old, may bleed intermittently posing diagnostic difficulties if the preceding localizing efforts prove

unrewarding. Bowel obstruction requires immediate surgery, and Meckel's diverticulitis usually requires exploration. There is some controversy as to the management of an asymptomatic Meckel's diverticulum discovered during surgery for some other disorder. An analysis of 1476 patients at the Mayo Clinic could not support or reject the recommendation that all Meckel's diverticula found incidentally be removed. Some of the criteria that could be used for selective resection include male sex, patient younger than 50 years, and diverticular length more than 2 cm. Diverticular Disease of the Colon In diverticular disease of the colon, diverticula occur in two rows on either side of the colon, with a distinct clustering in the sigmoid colon. Although diverticula may also be observed in the proximal colon, it is most unusual for patients to have right-sided or transverse colonic diverticula in the absence of sigmoid involvement. The frequency of diverticula formation is almost directly related to age and increases to approximately 50% of individuals in their ninth decade. Although diverticula are uncommon before 40 years of age, complications from diverticular disease do occur in young people. The diminished frequency of diverticula among individuals from Africa, Asia, and certain areas of South America is attributed to a high-fiber diet, which tends to decrease transit time in the gut, to increase stool frequency, and to result in softer, larger stools. This is an attractive hypothesis, but it is difficult to distinguish healthy persons from those with diverticulosis on the basis of stool weight and frequency. Another theory regarding the cause of colonic diverticula is related to the high sigmoid pressure observed in patients with the irritable bowel syndrome or those who strain during defecation. This is the basis of the supposition that increased intraluminal pressure forces the mucosa to protrude through the relatively weak areas of the colonic musculature adjacent to the blood vessels that penetrate from the serosal surface. This explanation seems reasonable, but diverticula are found in patients with no history of irritable bowel symptoms or chronic constipation. Stool weight and sigmoid pressure remain the primary explanations, but there is presently no convinc-ing and unifying explanation for the development of colonic diverticula. DIVERTICULOSIS Uncomplicated diverticula do not produce symptoms, but in patients with the irritable bowel syndrome, colonic diverticula may be revealed by barium enema examination or colonoscopy. Treatment, therefore, should not be directed to the diverticula but should focus on the predominant symptoms, such as pain, diarrhea, or constipation. Consider therapy with a high-fiber diet, psyllium preparations (Metamucil, Konsyl), or methyl cellulose (Citrucel) for constipation. Crampy pain or diarrhea may respond to antispasmodic medications (Bentyl, Levbid) or antidiarrheal agents such as loperamide (Imodium) or diphenoxylate (Lomotil). Patients with diverticula and the irritable bowel syndrome should not be informed that they have diverticular disease or diverticulitis because these labels may induce added anxiety and create confusion for physicians who may subsequently evaluate the patients. DIVERTICULAR BLEEDING Diverticula are one of the major causes of massive colonic hemorrhage. The bleeding is usually painless and rarely accompanies clinical diverticulitis. It is thought to result from the presence of an inspissated diverticular fecalith that erodes or ulcerates into an adjacent penetrating artery. The close relationship of the diverticula to these arteries explains why bleeding is often more severe from diverticula than encountered from an arteriovenous malformation (AVM). Although right-sided diverticula are occasionally cited as the

most common cause of diverticular bleeding, colonoscopy examinations suggest that the AVM is a more common etiology of right colon bleeding. The bleeding site (but not the cause) may be established by a technetium isotope bleeding study (often an initial study) or by angiography, but these studies must obviously be performed during the bleeding episode if localization is to be made with confidence. Cleansing of the colon with a lavage solution (GoLYTELY, Colyte) can be accomplished in selected patients during the bleeding episode if hemodynamic stability can be achieved, permitting a colonoscopic examination that may determine the site of bleeding and the cause (diverticula, AVM, or neoplasm). However, colonoscopy is most often performed after bleeding ceases. Treatment

It is more important to determine which segment of the colon is the site of brisk bleeding (sigmoid, left, transverse, or right colon) than to identify the specific diverticulum or other etiology. Hemodynamic stability should be achieved before time-consuming diagnostic studies are initiated. The most common cause for death resulting from GI hemorrhage is inadequate transfusions. An isotope bleeding study may demonstrate the area of colonic bleeding but is helpful only if the patient is bleeding actively during the study window. Angiography permits the most precise localization of bleeding points if active bleeding is present. If a bleeding diverticulum is identified, angiographic embolization can be performed or vasopressin infusion may result in sufficient local vasoconstriction to permit cessation of bleeding. Colonoscopy during a colonic hemorrhage can be achieved if the patient is stable and capable of tolerating the cleansing preparation. The examination may show evidence of vascular lesions, “oozing” from a presumably culpable diverticulum, or neoplasm (benign polyps rarely bleed massively). It is useful to remember that one of the causes of lower GI bleeding is upper GI bleeding, suggesting that an upper endoscopy or enteroscopy should be considered if a colonic site is not definitely shown. If major bleeding continues and the diagnostic strategies just outlined are unrewarding, a subtotal resection with ileorectal anastomosis should be considered. A “blind” left-sided colectomy in patients with known diverticular disease may be disastrous if the bleeding originates from the right colon. If diverticular bleeding stops with conservative measures, elective surgery need not be immediately considered because there is a reasonable possibility that bleeding will not recur. Recurrent bleeding should be approached surgically if the site is identified. DIVERTICULITIS Diverticulitis results from a microperforation of a single diverticulum, usually into pericolic tissues. The inflammatory reaction is generally walled off by surrounding omentum or adjacent bowel loops but may progress to an abscess or phlegmon (marked cellulites without pus). If the inflammatory process is not sealed, a free perforation may rarely occur. Diverticulitis usually involves the sigmoid colon, but instances of right-sided diverticulitis are encountered. The patient usually complains of left lower quadrant or suprapubic pain that may be accompanied by back pain, nausea, vomiting, dysuria, or fever. Gross rectal bleeding is unusual. Physical examination generally reveals tenderness over the left lower quadrant, suprapubic area, or both. Muscle guarding or rebound tenderness may be elicited. An elevated white blood cell count has little localizing value but can be useful in distinguishing between the irritable colon (normal count) and diverticulitis (leukocytosis is common). A urinalysis may reflect the presence of cystitis secondary to an adjacent inflammatory reaction or a true colovesical fistula (ask the patient about the passage of gas during urination). An obstruction series may provide little information, but a

sigmoid obstruction secondary to edema and inflammation may be noted, or a partial small bowel obstruction may result from a segment of distal jejunum or proximal ileum that becomes surrounded by the pericolonic inflammatory reaction. A CT scan provides the most useful information, such as an abscess, pericolonic inflammation, or air in the bladder if a fistula is present. The CT scan may not demonstrate these findings if obtained very early in the inflammatory process. Blood cultures should be obtained in febrile patients. Sigmoidoscopy and colonoscopy should be avoided during the acute process so that free perforation secondary to air insufflation can be avoided. Contrast radiographic films of the colon are ordinarily deferred for the same reason, but early imaging may be required if the clinical picture is atypical, perhaps raising the possibility of ischemia, acute colitis, or perforated neoplasm. In such circumstances, meglumine diatrizoate (Gastrografin) administration given without air insufflation is usually sufficient to outline the pathology. A CT scan should be considered. This may show a fistula, partial obstruction, or evidence of an extrinsic mass effect on the colon. Colonoscopy is less useful for the diagnosis of recent diverticulitis but can be helpful in the differential diagnosis. The differential diagnosis may include the irritable bowel syndrome, but the presence of fever, leukocytosis, and/or peritoneal signs should suggest an inflammatory reaction. Ovarian pathology, appendicitis (the appendix may extend down into the pelvis), inflammatory bowel disease, and ischemic colitis should be considered. A confined perforation of a colonic carcinoma is more difficult to exclude during the acute process. Even the surgeon may have problems making that distinction during emergency exploration because the surrounding inflammatory reaction may be intense. Complications include fistulas to the bladder (less common in women because the uterus “protects” the bladder), small bowel, or vagina. Free perforation, which is rare but significantly increases the morbidity and mortality rate, abdominal abscess, partial or complete obstruction of the small or large bowel, and septicemia may occur. Another serious complication of diverticulitis is spread of the bacteria through the portal vein to the liver leading to pyelophlebitis (pus in the portal vein) and pyogenic liver abscess. Treatment

Mild cases of diverticulitis with low-grade fever, tenderness without peritonitis, and modest leukocytosis may be treated on an ambulatory basis with clear liquids and a combination of oral levofloxacin (Levaquin) and metronidazole (Flagyl). If the fever subsides and clinical improvement is noted in 72 hours, the diet can be gradually increased. Immunocompromised patients should be treated earlier and more aggressively. More severe cases require hospitalization. The bowel should be kept at rest and intravenous (IV) fluids given. Nasogastric suction should be used if peritonitis or obstruction is present. Parenteral broad-spectrum antibiotic coverage against aerobes and anaerobes is given. Single-therapy agents include piperacillin/tazobactam (Zosyn), ticarcillin/clavulanate (Timentin), or imipenem/cilastatin (Primaxin). Combination IV therapy could include levofloxacin (Levaquin) plus metronidazole or ampicillin/sulbactam (Unasyn) plus metronidazole. Percutaneous CT-guided aspiration of a pericolonic or pelvic abscess, especially if 4 cm or larger, may hasten resolution of the process and perhaps permit a one-stage resection and anastomosis if surgery is subsequently required.

CURRENT DIAGNOSIS Cervical dysphagia associated with bad breath and a swelling in the neck during eating strongly suggests Zenker's diverticulum. Although most duodenal diverticula are asymptomatic, those adjacent to the ampulla of Vater can cause pressure on the bile duct resulting in stasis and common duct calculi. The most common presenting complication of Meckel's diverticulum in adults is bleeding, whereas the most common childhood presentation is obstruction. Patients with the irritable bowel syndrome may present with severe left lower quadrant pain and tenderness, but diverticulitis should be suspected if there is fever, leukocytosis, or peritoneal findings. A negative Meckel's pertechnetate isotope scan does not exclude the diverticulum because many do not contain heterotopic gastric mucosa. Colonic bleeding from diverticular disease is usually more severe than that encountered from arteriovenous malformations, polyps, or neoplasms.

CURRENT THERAPY Symptomatic Zenker's diverticulum requires resection, most recently performed by an endoscopic staple diverticulotomy. Small symptomatic epiphrenic diverticula can be treated with lower esophageal myotomy, but large diverticula may also require diverticulectomy plus myotomy. Both procedures should be accompanied by an antireflux wrap procedure. There is controversy regarding the removal of asymptomatic Meckel's diverticula. Factors that may support excision of such diverticula include size larger than 2 cm, male sex, and patients 60 years and a prior history of peptic ulcer) and also with high doses of NSAIDs and concurrent use of either anticoagulants or high-dose corticosteroids. NSAIDs cause gastric ulcers much more commonly than duodenal ulcers. Up to 40% of these persons remain asymptomatic, and patients commonly present with complications. The most important mechanism by which NSAIDs cause ulcers is by indirectly decreasing prostaglandin production via the inhibition of COX-1. Prostaglandins are important in maintaining mucosal integrity by producing mucus, stimulating bicarbonate production, decreasing acid production, and maintaining mucosal blood flow. The analgesic and anti-inflammatory effects of NSAIDs result from the inhibition of the COX-2

isoenzyme. Nonselective NSAIDs cause inhibition of both COX-2 and COX-1, resulting in considerable GI toxicity. The more recently developed selective COX-2 inhibitors, such as celecoxib (Celebrex), as the name implies, inhibit COX-2 to a much greater extent than COX-1, leading to their better GI safety profile. However, recent reports of cardiovascular complications attributed to COX-2 inhibitors have severely restricted their use. Idiopathic Ulcers

In a specific subgroup of patients who develop ulcers, all the known etiologic factors are excluded. This subgroup should not be confused with patients who have unexplained ulcers, 60% of whom have a history of surreptitious NSAID use. The true incidence of idiopathic ulcers is hard to assess in various studies as a result of false-negative H. pylori tests or surreptitious use of NSAIDs, and the exact pathogenic mechanism that causes these idiopathic ulcers remains unknown. Various abnormalities including genetic predisposition, defective mucosal defense mechanisms, and increased acid production have all been postulated. CLINICAL FEATURES Clinical signs and symptoms are unreliable and are not specific enough to make a diagnosis of a peptic ulcer. Upper abdominal pain (dyspepsia) is present in more than 80% of patients; however, only 15% of patients with dyspepsia have PUD. Pain is typically epigastric, described as burning and nonradiating. Food or antacids can relieve duodenal ulcer pain. Nausea or anorexia can occur with gastric ulcers. Nocturnal symptoms awaken patients in two thirds of duodenal ulcer and one third of gastric ulcer cases. Symptoms usually wax and wane over a period of months. The physical examination is usually normal in PUD patients. Epigastric tenderness may be present on palpation, but it is an unreliable sign with a positive predictive value of less than 50%. Stool tests for occult blood may be positive in one third of patients. DIAGNOSTIC WORK-UP Routine laboratory studies are not helpful in establishing a diagnosis of PUD. Upper endoscopy is the gold standard in making a diagnosis of peptic ulcer. Endoscopy has the advantage of taking biopsies for the presence of H. pylori infection and, in the case of gastric ulcer, to rule out malignancy. However, endoscopy is more expensive and invasive. In the absence of alarm symptoms, double-contrast barium radiography may be a suitable second choice. If barium radiography shows an ulcer (gastric or duodenal), H. pylori must be tested noninvasively. Treatment can be instituted with acid-suppression therapy with or without antibiotics depending on the presence of H. pylori. Gastric pH and fasting gastrin levels should be obtained only if there is clinical suspicion for gastrinoma (see the section on Zollinger-Ellison syndrome). For gastric ulcers, it is advisable to repeat the endoscopy after 6 to 8 weeks of therapy to confirm the healing of the ulcer and rebiopsy if it is not healed, because 5% of gastric ulcers can be malignant.

CURRENT DIAGNOSIS In the majority of cases of dyspepsia, no structural abnormality can be identified after investigation. Patients with dyspepsia who are older than 55 years or who have alarm symptoms (anemia, anorexia, weight loss, early satiety, dysphagia, or gastrointestinal bleeding) should undergo upper endoscopy. Helicobacter pylori infection and NSAIDs are the two most common causes of peptic ulcer disease. Endoscopic biopsy, urea breath test, and stool antigen testing are the most accurate ways to diagnose active H. pylori infection. Zollinger-Ellison syndrome should be suspected if there are multiple duodenal ulcers, ulcers that are refractory to treatment, or peptic ulcers associated with diarrhea. Many tests are available for H. pylori. Testing for H. pylori can be made by either noninvasive or invasive methods ( Table 1 ). An appropriate test should be chosen depending on the clinical situation. For example, testing for serologic antibodies against H. pylori may be appropriate for the initial testing for H. pylori though it is not as accurate as breath or stool tests. Also, serology is not useful to check for eradication after therapy, because it will not distinguish current active infection from prior infection that was treated (antibody levels fall slowly and unpredictably). Office-based qualitative antibody tests are cheaper compared with enzyme-linked immunosorbent assay (ELISA) test done in the laboratory but not as accurate, and they have been superseded by stool antigen and breath testing. Patients with alarm symptoms and all patients older than 55 years who have dyspeptic symptoms should undergo endoscopy, at which time H. pylori testing can be done by biopsy if an ulcer is found. Confirmation of the eradication of H. pylori should be considered after treating this infection in ulcer patients, by either the stool antigen test or the urea breath test, depending on the local resources. Confirmation of eradication by gastric biopsy is only recommended if endoscopy is performed for another reason, for example, to confirm healing of a gastric ulcer.

TABLE 1 -- Diagnostic Tests for H. pylori Diagnostic Test

Sensitivity (%) Specificity (%)

Noninvasive Tests Serum ELISA test for antibody 85

80

Urea breath test (14C or 13C)

95-100

91-98

Stool antigen test

91-98

94-99

Invasive (Endoscopy-Based) Tests Rapid urease test

93-97

95-100

Histology

>95

98-99

Culture

70-80

100

Abbreviation: ELISA = enzyme-linked immunosorbent assay.

DIFFERENTIAL DIAGNOSIS Functional dyspepsia is a major differential diagnostic consideration in all patients with upper abdominal pain (see the section on functional dyspepsia). Other diseases that mimic the symptoms of PUD include cancers of the upper gastrointestinal tract, biliary colic, and mesenteric ischemia. TREATMENT Different classes of drugs are available to treat PUD ( Table 2 ). Antacids heal the ulcers and are cheap but are relatively ineffective, are slow to produce healing, and have many side effects. Both PPIs and H2-RAs block acid secretion, but PPIs inhibit more than 90% of the 24-acid output compared with 65% with H2-RAs; hence, PPIs heal the ulcer and relieve symptoms faster. Ulcer-healing rates of sucralfate (Carafate) are similar to those for H2-RAs. The mechanism of action of sucralfate is unknown; it probably coats the ulcer base, thereby promoting ulcer healing, and might have other effects too. The frequent dosing schedule and large tablet size of sucralfate is not conducive to good compliance. Misoprostol (Cytotec) is a prostaglandin analogue approved for preventing NSAID-induced ulcers. Compliance with misoprostol treatment is also a problem, particularly at high doses, owing to its GI side effects of abdominal cramping and diarrhea.

TABLE 2 -- Treatment Options for Peptic Ulcers[*] Active Ulcer (Gastric or Pharmacologic Agent Duodenal)[†]

Prevention of NSAID-Induced Ulcer Recurrence

Antisecretory Agents H2-Receptor Antagonists Cimetidine (Tagamet)

400 mg bid or 800 mg qhs

Famotidine (Pepcid)


Nizatidine (Axid)


Ranitidine (Zantac)


Double the dose indicated for active ulcer[1]

Proton Pump Inhibitors Esomeprazole (Nexium)

40 mg qd

40 mg qd[1]

Lansoprazole (Prevacid)

30 mg qd

30 mg qd

Omeprazole (Prilosec)

20 mg qd

20 mg qd[1]

Pantoprazole (Protonix) 40 mg qd

40 mg qd[1]

Rabeprazole (Aciphex) 20 mg qd

20 mg qd[1]

Mucosal Protectants Misoprostol (Cytotec)

200 µ g qid

200 g qid or 400 g bid

Sucralfate (Carafate)

1 gm qid

Not effective

1 Not FDA approved for this indication. * All patients should be tested for H.pylori and treated if positive. † Duration of treatment for duodenal ulcer is 4 weeks with proton pump inhibitor (PPI) and 6 weeks with H2-receptor antagonist. Duration of treatment for gastric ulcer is 8 weeks with either PPI or H2-receptor antagonist.

H. pylori eradication is recommended in all ulcer patients who are H. pylori positive, but H. pylori infection should not be assumed without a documented positive test. H. pylori eradication heals ulcers and reduces the ulcer recurrence dramatically, to less than 20% after 2 years. Select H. pylori eradication regimens are summarized in Table 3 . Confirmation of eradication is mandatory for complicated ulcer associated with bleeding, perforation, or obstruction and is recommended in all ulcer patients receiving H. pylori therapy. Treatment of idiopathic ulcers is difficult and often requires indefinite maintenance antisecretory therapy, particularly for a complicated ulcer.

TABLE 3 -- Select FDA-Approved Helicobacter pylori Eradication Regimens Drug Combination Dosing Schedule PPI [*] (omeprazole 20 mg or lansoprazole 30 mg) + amoxicillin 1 g + clarithromycin 500 mg

Each bid for 10-14 d

Esomeprazole[*] 40 mg qd + amoxicillin 1 g bid + clarithromycin 500 mg bid

For 10 d

PPI [*] (omeprazole 20 mg or lansoprazole 30 mg) + amoxicillin 1 g + metronidazole 500 mg

Each bid for 10-14 d

Rabeprazole[*] 20 mg + amoxicillin 1 g + clarithromycin 500 mg

Each bid for 7 d

Bismuth subsalicylate 525 mg + metronidazole 250 mg + tetracycline 500 mg[†]

Each qid for 2 wk plus H2-RA for 4 wk

Abbreviations: FDA = U.S. Food and Drug Administration; PPI = proton pump inhibitor.

* Although not yet approved, pantoprazole (Protonix) can be substituted. † In patients with penicillin allergy, this regimen can be used. Alternatively, PPI + clarithromycin + metronidazole can be used.

PREVENTION Ulcers can recur either with continued use of NSAIDs or with H. pylori infection that persists after the initial antibiotic course. The incidence of antibiotic resistance to H. pylori is rising all over the world. In the United States, approximately 30% of H. pylori strains are now resistant to metronidazole (Flagyl), and 10% to 12% are resistant to clarithromycin (Biaxin), which decreases the cure rates by as much as 50% and 37%, respectively. If the patient has persistent symptoms after therapy, eradication failure should be strongly suspected and noninvasive testing for H. pylori should be performed. If the initial diagnosis of the ulcer was made by radiography, endoscopy is the next reasonable test. Drugs that are clearly shown to be superior to placebo in preventing NSAID-induced ulcers are PPIs and misoprostol (Cytotec). Double the standard doses of H2-RAs used for active ulcers are significantly better than placebo in preventing NSAID-induced

gastroduodenal ulcers (see Table 2 ). PPIs are generally preferred over H 2-RAs given the simplicity of the dosing schedule and comparable cost. Elderly patients who require long-term NSAID therapy should receive H. pylori eradication therapy if they are infected with this bacterium. COMPLICATIONS Hemorrhage

Gastrointestinal bleeding is the most common complication of PUD. Approximately 10% to 20% of ulcer patients develop significant GI bleeding, with overall mortality of up to 10%. Patients generally present with either melena or hematemesis. Endoscopy is indicated for diagnosis, risk stratification, and therapy in all patients with significant bleeding. High-dose oral or intravenous PPIs should be instituted before endoscopy if upper bleeding is suspected. All H. pylori–positive patients must have confirmation of eradication after therapy.

CURRENT TREATMENT In patients with dyspepsia who are younger than 55 years, a Helicobacter pylori test-and-treat strategy, followed by PPI treatment (if the patient remains symptomatic or is not infected by H. pylori) is the management strategy of choice. Long-term acid-suppression therapy with PPIs may be necessary for patients believed to be at high risk for bleeding but in whom chronic NSAID use is necessary. PPIs inhibit more than 90% of the 24-acid output compared with 65% with H2-RAs; hence PPIs heal peptic ulcers and relieve symptoms faster. Elderly patients who require long-term NSAID therapy should receive H. pylori eradication therapy if they are infected with this bacterium. Triple therapy (PPI plus amoxicillin and clarithromycin) is the most widely used treatment strategy for H. pylori in the United States. Abbreviations: H2-RA = H2-receptor antagonist; NSAID = nonsteroidal anti-inflammatory drug; PPI = proton pump inhibitor. Perforation

Perforations occur in approximately 5% to 7% of ulcer patients. The incidence has not changed in spite of decreasing prevalence of H. pylori, because the use of NSAIDs continues to increase. The decision whether to manage operatively or nonoperatively should be made on a case-by-case basis. Obstruction

Duodenal bulb or pyloric channel ulcers cause scarring and gastric outlet obstruction in approximately 2% of patients with PUD. Patients then present with early satiety, vomiting, and weight loss. Management involves H. pylori eradication and acid suppression along with endoscopic dilatation. Surgery is reserved for patients

who do not respond to endoscopic therapy. Zollinger-Ellison Syndrome Less than 1% of PUD is caused by Zollinger-Ellison syndrome (ZES). This syndrome results from a gastrinproducing neuroendocrine tumor (gastrinoma), two thirds of which are malignant. PUD is caused by increased acid production from very high serum gastrin levels. Most gastrinomas arise in the gastrinoma triangle, bounded by the porta hepatis, neck of the pancreas, and third portion of the duodenum. The pancreas and the duodenum are the two organs most commonly involved. Approximately one quarter of gastrinomas are part of the multiple endocrine neoplasia type 1 (MEN-1) syndrome, which is associated with parathyroid hyperplasia, pituitary tumors, and pancreatic endocrine tumors. Gastrinomas commonly manifest between ages 30 and 50 years and have a male-to-female ratio of 2:1. The clinical features include peptic ulcers (90%), diarrhea (60%), and GERD (20%), all of which are due to gastric acid hypersecretion. The majority of ulcers occur in the duodenum. ZES should be suspected if the ulcers are multiple, in unusual locations, refractory to treatment, or associated with diarrhea. Diagnosis is made by measuring fasting gastrin levels and gastric pH. If the gastrin levels are elevated to more than 1000 pg/mL in the right clinical setting, the diagnosis of ZES is established. Hypochlorhydria secondary to gastric atrophy from H. pylori or autoimmune gastritis, or due to acid suppression therapy by H2-RAs and PPIs, can increase gastrin levels. Therefore, gastrin levels should be measured after H2-RAs are held for 24 hours and PPIs for 1 week. The gastric pH should be measured to distinguish ZES from hypochlorhydria. Gastric pH is less than 2 in ZES, whereas in achlorhydria secondary to gastric atrophy, gastric pH is greater than 2. Provocative tests, such as the secretin test, can also be used to diagnose gastrinoma. Intravenous administration of secretin can decrease or slightly increase gastrin levels in normal patients and in patients with antral G-cell hyperplasia. In cases of gastrinoma, gastrin levels are significantly increased (>200 pg/mL) from the basal levels. Tumor localization should be investigated by somatostatin receptor scintigraphy (Octreoscan), computed tomography, magnetic resonance imaging, and endoscopic ultrasound. Treatment involves medical therapy with a high-dose PPI titrated against symptoms, gastric pH, and endoscopic findings. Surgical resection of isolated hepatic metastasis will decrease symptoms and prolongs survival.



REFERENCES Chan and Graham, 2004. Chan FK, Graham DY: Review article: Prevention of non-steroidal antiinflammatory drug gastrointestinal complications: Review and recommendations based on risk assessment. Aliment Pharmacol Ther 2004; 19(10):1051-1061. Chan and Leung, 2002. Chan FK, Leung WK: Peptic-ulcer disease. Lancet 2002; 360(9337):933-941. Stollman and Metz, 2005. Stollman N, Metz DC: Pathophysiology and prophylaxis of stress ulcer in intensive care unit patients. J Crit Care 2005; 20(1):35-45. Suerbaum and Michetti, 2002. Suerbaum S, Michetti P: Helicobacter pylori infection. N Engl J Med 2002; 347(15):1175-1186. Talley and American Gastroenterological Association, 2005. Talley NJ, American Gastroenterological Association : American Gastroenterological Association medical position statement: Evaluation of dyspepsia. Gastroenterology 2005; 129(5):1753-1755. Talley et al., 2005. Talley NJ, Vakil N, Practice Parameters Committee of the American College of Gastroenterology : Guidelines for the management of dyspepsia. Am J Gastroenterol 2005; 100(10):23242337.



Chapter 135 – Acute and Chronic Hepatitis

Method of: Mamta K. Jain, MD, MPH Daniel M. Brailita, MD Viral hepatitis is the most common cause of acute and chronic liver disease worldwide. Given the increasing number of new diagnoses and the risk of chronic liver disease, cirrhosis, and hepatocellular carcinoma, viral hepatitis is a serious health care problem. This article focuses on the epidemiology, diagnosis, prevention, and, in some cases, therapies that are available. Several viruses are considered hepatotropic because viremia is associated with elevation of serum aminotransferases. However, viral hepatitis refers to infections caused by hepatitis viruses A through E. Hepatitis A (HAV) and E (HEV) viruses have a fecal-oral transmission route and do not produce chronic infection; hepatitis B (HBV), C (HCV), and D (HDV) viruses have a parenteral transmission route and can lead to chronic liver disease, hepatocellular carcinoma, and cirrhosis. Other viral infections, which can involve the liver as one manifestation of a systemic infection, include HIV, Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). These viruses can cause acute hepatitis, which can be fatal, especially in immunocompromised patients. Only hepatitis A, B, C, D, and E viral infections (characteristics are outlined in Table 1 ) are discussed in this article.

TABLE 1 -- Characteristics of Hepatitis A through E Virus HAV HBV HCV

HDV

HEV

Family

Picornaviridae Hepadnaviridae

Flaviviridae

Deltavirus (no separate family)

Hepeviridae

Size

27 nm

42 nm

50-55 nm

36 nm

32 nm

Nucleic acid

ssRNA

dsDNA

ssRNA

ssRNA

ssRNA

Transmission

Fecal-oral

Vertical, percutaneous, sexual

Blood products, Mainly percutaneous, sexual percutaneous

Fecal-oral

Incubation

15-45 d

1-6 mo

7 wk

3-20 wk

15-60 d

Chronic infection?

No

Yes

Yes

Yes

No

Vaccine available?

Yes

Yes

No

No

Experimental

Abbreviations: HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; ss = single-stranded; ds = double-stranded.

Acute Hepatitis Versus Chronic Hepatitis ACUTE HEPATITIS Acute hepatitis can be either symptomatic or asymptomatic. Generally, asymptomatic disease occurs in younger children. Symptomatic clinical disease is often seen in adolescents and adults. In the prodromal phase, a person can experience flulike illness with malaise, fever, anorexia, nausea, vomiting, and mild abdominal pain. During the icteric phase, jaundice appears, often accompanied by dark-brown urine and acholic or clay-colored stools. However, these signs may be seen in some persons without jaundice. Less frequent symptoms include arthralgias, rash, diarrhea, and lymphadenopathy. Typical laboratory tests show high elevations of liver enzymes including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (often in the 1000 IU/mL range), an increase in bilirubin, and sometimes an increase in alkaline phosphatase. Fulminant hepatic failure, a rare complication, can be seen, with prolongation of prothrombin time (PT), coagulopathy, encephalopathy, and jaundice. Patients with fulminant hepatic failure, because of the high mortality rate, should be managed in specialized centers with access to liver transplantation and close monitoring of coagulopathy, volume status, and neurologic status. CHRONIC HEPATITIS HBV and HCV can cause acute infection, either symptomatic or asymptomatic, and can progress to chronic liver disease. Most patients with chronic viral hepatitis are asymptomatic or complain of mild fatigue only; progression to cirrhosis, hepatocellular carcinoma, and end-stage liver disease is possible. The clinical examination can be normal or stigmata of chronic liver disease may be observed, such as spider angiomas, palmar erythema, testicular atrophy, and gynecomastia. The laboratory tests might show mild to moderate transaminitis in the chronic phase. The degree of ALT and AST elevation might not reflect the severity of liver fibrosis. Often, patients with cirrhosis have normal ALT and AST levels. The degree of fibrosis in chronic liver disease is based on histologic findings on liver biopsy. Cirrhotic patients can develop portal hypertension leading to an enlarged spleen, variceal bleeding, ascites, and encephalopathy. Other clinical parameters that indicate progressive liver disease include: decrease in serum albumin and platelet count, rise of serum bilirubin, and prolongation of PT. In these patients, transplantation may be necessary. Cirrhotic patients are also at increased risk for developing hepatocellular cancer (HCC) and should be screened by alpha fetoprotein (AFP) and abdominal ultrasound every 6 months. In addition, these patients are at risk for fulminant hepatitis due to other viruses and should be vaccinated for vaccine-preventable infections. For example, patients with HCV-related cirrhosis should be vaccinated for HAV and HBV. Vaccination schedules are shown in Table 2 .

TABLE 2 -- Vaccination Schedules for Hepatitis Vaccines Licensed in the United States Vaccine Type Dose Schedule Hepatitis A Virus Havrix (GlaxoSmithKline) Inactivated HAV

12 mo-18 y: 0.5 mL (720 EL.U)

0 and 6-12 mo

>18 y: 1 mL (1440 EL.U) Vaqta (Merck)

Inactivated HAV

12 mo-18 y: 0.5 mL (25 U)

0 and 6-18 mo

>18 y: 1 mL (50 U) Hepatitis A and B Viruses Twinrix (GlaxoSmithKline)

Inactivated HAV and recombinant HBV

>18 y: 1 mL

0, 1, and 6 mo

0-19 y: 0.5 mL (5 µg)

Infants: birth, 1-4, and 6-18 mo

Hepatitis B Virus Recombivax-HB (Merck) Recombinant HBV

Older children: 0, 1-2, and 4 mo

Engerix-B (GlaxoSmithKline)

Recombinant HBV

>20 y: 1 mL (10 µg)

0, 1, and 6 mo

0-19 y: 0.5 mL (10 µg)

Infants: birth, 1-4, and 6-18 mo Older children: 0, 1-2, and 4 mo

>20 y: 1 mL (20 µg)

0, 1, and 6 mo

Dialysis patients: double adult dose

0, 1, 2, and 6 mo.

Comvax (Merck)

Recombinant HBV, HiB

Approved for 6 wk-4 y of age: 1 dose

2, 4, and 12-15 mo

Pediarix (GlaxoSmithKline)

Recombinant HBV, DTaP, IPV

Approved for 6 wk-6 y of age.: 1 dose

2, 4, and 6 mo

Abbreviations: DTaP = diphtheria, tetanus toxoids, and acellular pertussis vaccine; EL.U = enzyme-linked immunosorbent assay units of HAV antigen; HiB = Haemophilus influenzae group B vaccine; IPV = inactivated polio vaccine; U = units of HAV antigen.

Hepatitis A EPIDEMIOLOGY

HAV is the leading cause of acute viral hepatitis worldwide and is a reportable disease in the United States, but significant shifts in HAV epidemiology have been seen since the introduction of licensed vaccines from 1995 to 1999. In 2004, an estimated 56,000 new infections occurred in the United States, which represents a historically low rate; to compare, more than 356,000 infections occurred in 1995. Higher prevalence of HAV is seen in children in less developed countries where sanitation is poor and infection occurs at an early age. The virus is transmitted mainly by the fecal–oral route via contaminated food or water. In industrialized countries, like the United States, sporadic cases are more common and the prevalence of acute HAV is higher in adults. Populations at risk include children in daycare centers, close contacts of viremic patients, persons with substandard hygiene habits, or eating undercooked food, travelers in endemic areas, and men who have sex with men (MSM). Waterborne outbreaks are rare in developed countries but can be seen in less developed countries. CLINICAL FEATURES Infection with HAV does not lead to chronic liver disease. Acute infection is asymptomatic in most children, especially children younger than 2 years, but it is symptomatic in children older than 5 years. Symptomatic illness occurs after an incubation of 15 to 45 days. The viral prodrome before the onset of jaundice (see acute hepatitis) typically lasts 2 to 7 days. Hepatomegaly is possible. Typically, significant improvement occurs by the end of the third week, with normalization of ALT and AST, fading jaundice, and resolution of hepatomegaly. The clinical patterns include asymptomatic infection without jaundice, symptomatic infection with jaundice but with a limited 8-week course, cholestatic infection with jaundice with usually a longer course, relapsing infection with two or more episodes over a 6- to 10-week period, and, rarely, fulminant hepatic failure. Complete recovery is achieved in most persons by 6 months. The prognosis is excellent, with no progression to chronic disease. Mortality, occurring in less than 0.4%, is more common in the extremes of age (infants and the elderly, especially those with diabetes). DIAGNOSIS Acute HAV infection is diagnosed by detecting anti-HAV immunoglobulin M (IgM) (see Table 3 ) in the acute serum sample, which appears before the onset of clinical symptoms and persists for 3 to 6 months. AntiHAV IgG appears after IgM and persists for years, indicating immunity. Although different variants of HAV have been identified, only one serotype is responsible for cross-reactivity to all variants. HAV antigen is detectable in the stool 1 to 2 weeks before the onset of symptoms, disappears before jaundice, and reappears during relapses. ALT and AST are typically very high and recover in 3 weeks. Bilirubin peaks at 12 to 30 mg/dL and starts declining in 2 to 3 weeks. The patient is no longer infectious 1 week after the onset of jaundice.

TABLE 3 -- Serologic Parameters for Hepatitis A Virus Type Anti-HAV IgM Anti-HAV IgG Acute

+

-

Type

Anti-HAV IgM Anti-HAV IgG

Exposed

±

+

Immunized ±

+

Abbreviation: anti-HAV = antibodies to hepatitis A; HAV = hepatitis A virus; Ig = immunoglobulin.

TREATMENT AND PREVENTION The treatment of HAV is supportive. Hygiene is important in prevention of infection. Persons with documented HAV immunity (previous infection) do not need passive or active prophylaxis. Active prophylaxis, obtained by HAV vaccines, offers prolonged immunity. Prevaccination testing of children is not indicated due to low incidence of infection in the United States, but it may be cost-effective in select adult populations. Currently in the United States three licensed vaccines are available: Havrix, Vaqta, and the combination HAV/HBV vaccine Twinrix. The vaccines are highly effective if used appropriately. Immunity occurs in 1 month.

CURRENT DIAGNOSIS Acute hepatitis is self-limited and does not cause progressive liver disease. Chronic hepatitis can lead to cirrhosis and end-stage liver disease. Hepatitis A is a vaccine-preventable disease, but sporadic outbreaks still occur. Travelers to less developed countries should be vaccinated for hepatitis A. Hepatitis B can cause both acute and chronic liver disease. In most cases, infection resolves through natural immune clearance. For patients with chronic infection, several therapies exist. Hepatitis B is a vaccine-preventable disease. Hepatitis C is a leading cause of chronic liver disease. Combination therapies for hepatitis C with pegylated interferon and ribavirin are available but are only effective in 50% of patients. Hepatitis E is a self-limited disease seen mostly in less developed countries. Travelers should drink bottled or boiled water in endemic countries to avoid infection. Mortality is high in pregnant women who acquire hepatitis E. Hepatocellular cancer is a complication of chronic liver disease and should be screened for regularly. HAV vaccine should be given to all children ages 1 to 18 years, travelers to endemic areas, MSM, recreational drug users, those with chronic liver disease, persons with clotting factor disorders, and persons at risk for occupational exposure. During outbreaks, unvaccinated children should receive both active and

passive prophylaxis. Passive prophylaxis, obtained by administration of pooled immunoglobulins (Ig), offers limited protection, but it is important during HAV outbreaks in daycare centers and among food handlers, household contacts of patients with acute HAV, and persons traveling to HAV-endemic areas within 4 weeks from the first dose of HAV vaccine. A 0.02 mL/kg Ig dose is 80% to 90% effective as postexposure prophylaxis if given within 2 weeks, but it also attenuates the clinical disease if given after 2 weeks. A 0.06 mL/kg Ig dose given before travel confers immunity for 3 to 5 months. (See Table 2 for the vaccination schedules.) Hepatitis B EPIDEMIOLOGY Worldwide, the number of HBV infections exceeds 350 million. In the United States, an estimated 1.25 million people are chronically infected. The number of acute infections in the United States has decreased from 260,000 per year in the 1980s to 60,000 per year in 2004. The decline is largely due to the routine use of HBV vaccine. In areas of high prevalence, such as Southeast Asia, China, and Africa, the most common route of transmission is vertically from mother to child and horizontally among children. However, in the United States and other Western countries, which are considered low-prevalence areas, horizontal spread among adults is the most common, especially through sexual contact or through injection drug use. The virus is transmitted by passage of infectious bodily fluids through percutaneous routes or disrupted mucosal membranes. HBV is 100 times more infectious than HIV and approximately 8 to 10 times more infectious than HCV. Routine testing for HBV should be offered to persons with multiple sexual partners, MSM, parenteral drug users, household contacts of infected persons, children born to infected mothers or to immigrants from highly endemic areas, hemodialysis patients, pregnant women, HIV-positive persons, and health care and public safety workers. CLINICAL FEATURES Acute HBV infection occurs after an incubation period of 30 to 180 days. The age and immune status of the exposed person are correlated with the outcome of the acute infection, but why some patients ultimately clear the viral infection is not known. Acute HBV is subclinical in 90% of young children but 30% to 80% of adults have anicteric or icteric forms (see the discussion of acute hepatitis). Resolution of jaundice generally occurs within 1 to 3 months. Eighty percent of acute HBV resolves with disappearance of hepatitis B surface antigen (HBsAg) by 12 to 24 weeks. As in HAV, less than 1% of the cases progress to fulminant hepatic failure, which generally occurs within 4 weeks of onset of symptoms. Chronic hepatitis following acute infection develops in 90% of infants born to hepatitis B e antigen (HBeAg)positive mothers, 30% of children infected at 1 to 5 years of age, and 6% of those infected after 5 years of age. Immunosuppressed persons are more likely to develop chronic infection. From 15% to 25% of the chronically infected patients die from complications of HBV including cirrhosis and HCC.

Extrahepatic manifestations are common in both acute and chronic HBV infection. Arthritis-dermatitis is manifested with fever, arthralgia, rash, and edema. Polyarteritis nodosa (PAN), a systemic necrotizing vasculitis, is a serious complication of HBV infection. Glomerulonephritis occurs with several different glomerular lesions and can manifest with the nephrotic syndrome. Essential mixed cryoglobulinemia is not seen as commonly as in HCV and is often asymptomatic. DIAGNOSIS The diagnosis of acute HBV infection ( Table 4 ) is made by the presence of HBsAg and antibodies to hepatitis B core antigen (anti-HBcAg). During the replicative phase of the infection, HBV DNA and HBeAg, a marker of viral replication, are also positive. HBsAg appears first, before the onset of symptoms, and disappears 3 to 6 months after the infection in persons who recover without chronic infection. Hepatitis B surface antibodies (anti-HBs) are protective and appear after the clearance of HBsAg. Anti-HBs also appear after successful vaccination. The persistence of HBsAg longer than 6 months usually indicates chronic infection; however, clearance after 6 to 12 months is possible. There is a serologic window between the disappearance of HBsAg and the appearance of HBsAb when the diagnosis of acute infection is only possible by detection of anti-HBcAg IgM. Anti-HBcAg is detectable throughout the course of disease (IgM is replaced by IgG in chronic infection), but it does not give protection and its presence means natural infection.

TABLE 4 -- Serologic Parameters for Hepatitis B Virus Type HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc HBV DNA Acute

±

-

+

-

IgM

+

Immune clearance (recovered)

-

+

-

+

IgG

- [*]

Chronic

+

-

±

±

IgG

+

Vaccination

-

+

-

-

-

-

Abbreviations: anti-HBc = antibodies to hepatitis B core antigen; anti-HBe = antibodies to hepatitis B e antigen; anti-HBs = antibodies to hepatitis B surface; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus.

* May have detectable HBV DNA by more sensitive assays.

HBeAg seroconversion, referring to loss of HBeAg and development of antibodies to HBeAg (anti-HBe), can occur through immune clearance during acute infection or through antiviral therapies in chronic infection. However, mutations in the precore and basal core promoter regions of HBV can give rise to HBeAg mutants in which patients are HBeAg-negative, but produce HBV DNA and can develop progressive liver disease. Inactive carriers are persons who have evidence of HBV DNA by highly sensitive polymerase chain reaction (PCR) methods and also have normal serum aminotransferases. Long-term follow-ups of these persons suggest that they do not develop progressive liver disease. Liver function tests may need to be monitored

every 6 to 12 months. Active carriers have evidence of HBV DNA by non-PCR methods and elevated or intermittently elevated serum aminotransferases. TREATMENT Treatment goals include HBeAg seroconversion, significant decrease in HBV DNA or viral suppression, normalization of aminotransferases, and improvement of fibrosis on liver biopsy. Patients with more than 104 copies/mL of HBV DNA and abnormal liver function tests may need to be considered for therapy, especially if they are cirrhotic (see Table 5 for guidelines). A specialist should evaluate those who do not meet the guidelines outlined in Table 5 but have detectable HBV DNA levels to determine risk of disease progression.

TABLE 5 -- Current Therapies for Chronic Hepatitis B and C Viruses Virus and Type

Treatment Decision Factors

HBV, HBeAgpositive[*]

HBV DNA >20,000 copies/mL, elevated ALT[†]

Treatment Strategy

Therapy Options

Treat until HBV DNA is undetectable and HBeAg seroconversion plus 6 additional mo

Lamivudine (Epivir) 100 mg PO qd

Adefovir (Hepsera) 10 mg PO qd Entecavir (Baraclude) 0.5 mg PO qd for naive, 1 mg PO qd for experienced Telbivudine (Tyzeka) 600 mg PO qd IFN-a-2b (Intron A) 10 million units SC 3 ×/wk for 16 wk PEG-IFN-a-2a (Pegasys) 180 µg SC weekly for 48 wk HBV, liver cirrhosis

Decompensated

Combination therapy with lamivudine or entecavir plus adefovir; place on transplant list

Adefovir plus entecavir or lamivudine (dose as for HBeAg-positive) Interferon therapy is contraindicated

HCV, genotype 1

Compensated

If HBV DNA >2000 copies, treat long term with adefovir or entecavir

Adefovir or entecavir (dose as for HBeAg-positive)

If no contraindications

Treatment for 48 wk

PEG-IFN-a-2a (Pegasys) 180 µg SC weekly or

Discontinue if no virologic response at 12 wk

PEG-IFN-a-2b (PEG-Intron) 1.5 µg/kg SC weekly plus Ribavirin (Rebetol, Ribasphere, Copegus) 1200 mg (>75 kg) or 1000 mg (2000 copies/mL. † Normal ALT may need to have liver biopsy to determine if treatment is necessary

Older therapies such as interferon-a-2b (IFN-a-2b) (Intron A) given three times weekly for 4 months have been replaced with the newer pegylated IFN-a-2a (Pegasys) once-weekly treatment given for 12 months (see Table 5 ), in which one third of patients who are HBeAg-positive at baseline obtain HBeAg loss. Interferon is more effective in patients with high ALT and low HBV DNA. Lamivudine (Epivir), adefovir (Hepsera), and entecavir (Baraclude) are oral agents directed against viral replication. They have few adverse effects in comparison with interferon-based therapies (see discussion of HCV for side effects) but HBeAg loss rates are not as high as with interferon therapies. Lamivudine is also safe for use in decompensated liver disease. For lamivudine, response rates in HBeAg-positive patients have been 16% to 18% in loss of antigen and 49% to 56% in histologic improvement; higher ALT predicted better response. In HBeAg-negative patients, good response rates were offset by the greater than 90% relapse rate after 1 year. Over time, lamivudine resistance (70% with 5 years of therapy) can develop, making lamivudine ineffective. Adefovir can be used either initially in treatment-naive persons or as second-line treatment for those with lamivudine resistance. Long-term therapy with adefovir has revealed development of resistance in 3% with 2 years of therapy and 30% with 5 years of therapy. The relapse rate is high if medication is stopped. Entecavir can suppress HBV replication significantly and is active for both lamivudine- and adefovir-resistant mutations. Entecavir is administered at two doses depending on whether the drug is being used in a naive or treatment-experienced patient. Telbivudine has also received FDA approval for the treatment of chronic HBV, however resistance can develop in one-third of patients after one year. Several other agents including tenofovir (Viread) [1] and emtricitabine (Emtriva)[1] (used in HIV infection) also have activity against HBV. 1 Not FDA approved for this indication.

PREVENTION Vaccination against HBV with newer DNA recombinant vaccines has changed the epidemiology of the disease and significantly decreased the number of new infections. The currently available HBV vaccines are Engerix-B and Recombivax HB (see Table 2 for vaccine schedule and dose). Combination vaccines effective against both HAV and HBV are available (see the discussion of hepatitis A). Due to the high risk of vertical transmission, all infants born to HBsAg-positive mothers should receive a first dose of HBV vaccine and passive prophylaxis with hepatitis B immune globulin (HBIg) 0.5 mL IM, in a separate site from the vaccine, in the first 12 hours after delivery. Vaccination of all other stable infants before hospital discharge is now recommended. All children and adolescents are currently included in a catch-up vaccination program. Vaccination is also recommended for health care workers, persons with chronic liver disease, and all persons considered at risk (i.e., persons recommended to be screened for HBV). Generally, a postvaccine HBsAb titer of greater than 10 IU/mL is considered protective, but postvaccination testing is necessary only for health care workers. Boosting is indicated for hemodialysis patients. The vaccine is more than 95% efficacious in immunocompetent patients. Hepatitis C EPIDEMIOLOGY Worldwide, an estimated 3% of persons have HCV antibodies and more than 170 million people are chronically infected. No available HCV vaccine exists. In the United States, as well as most developed countries, the number of new infections has decreased significantly due to screening of blood products. However, the number of new diagnoses continues to rise, with an estimated burden of 3.2 million chronic infections in the United States; most of these persons were infected through intravenous drug use or receipt of blood products decades ago. Transmission from mother to child is also possible. In 1992, a commercial assay became available for HCV testing and has been used to test blood products since then. Other routes of transmission include tattoos, especially if occurring during incarceration, and intranasal cocaine use. Sexual transmission is rare among heterosexual couples. The Centers for Disease Control and Prevention (CDC) does not recommend changes in sexual practices in monogamous couples. However, risk of sexual transmission might be increased in persons with multiple sexual partners or MSM. The CDC and the American Association for the Study of Liver Diseases (AASLD) recommend HCV testing for parenteral drug users, hemophiliacs, and other persons receiving blood products or organ transplants before 1992, HIV-positive persons, hemodialysis patients, health care workers with occupational exposure to HCV-positive blood, children born to infected mothers, partners of HCV-positive patients, and persons with unexplained liver function test abnormalities. HCV-positive persons should be counseled about how to avoid transmitting the disease to others. CLINICAL FEATURES There are six major genotypes of HCV, and they have a geographic distribution. In the United States, 60% to

70% of persons are infected with genotype 1, whereas genotypes 2 and 3 are more common in Europe. In Egypt, the predominant genotype is 4. The importance of genotype lies in its predictive value for treatment response to combination therapy with PEG-IFN and ribavirin. Following an incubation period averaging 7 weeks, acute hepatitis C usually is asymptomatic; it manifests as a flulike illness or rarely as a mild icteric disease. Following acute infection, 50% to 85% of the patients develop chronic infection. Of these, 70% progress to chronic liver disease. Overall, 1% to 5% of infected persons die of HCV-related complications. Progression to HCC occurs in the setting of cirrhosis, and all HCV-infected cirrhotic patients should be screened for HCC regularly. Extrahepatic manifestations are rare during acute infection but common in chronic infection. Well-described extrahepatic manifestations are essential mixed cryoglobulinemias, membranoproliferative glomerulopathy, leukocytoclastic vasculitis, immune arthropathies, and porphyria cutanea tarda. There may be an increased incidence of non-Hodgkin's lymphoma in HCV-infected patients. DIAGNOSIS The diagnosis ( Table 6 ) is based on detection of antibodies against HCV (anti-HCV). HCV antibodies are not protective and only serve as a marker of infection. The third-generation enzyme immunoassay (EIA) has 97% sensitivity in detecting total antibodies and can be confirmed by direct detection using HCV RNA. If the HCV RNA is negative, a recombinant immunoblot assay (RIBA) can be performed; if RIBA is negative, EIA is a false positive. If the EIA and RIBA are positive but HCV RNA is repeatedly negative, prior infection and natural immune clearance have occurred, which can be seen in 15% to 50% of acute infections, and no further testing is required.

TABLE 6 -- Serologic Parameters for Hepatitis C Virus HCV

Anti-HCV HCV RNA

Acute

+

+

Chronic

+

+

Past Infection

+

-

Abbreviations: anti-HCV = antibodies to hepatitis C; HCV = hepatitis C.

The quantitative HCV RNA assays have lower sensitivity than the qualitative assays. A quantitative assay is obtained to confirm infection (presence of virus) and determine the level of viremia; however, the actual RNA level is only important as a prognostic factor for treatment response. It does not correlate with severity of liver disease. A genotypes should also be ordered because it affects the treatment duration and predicts therapeutic response. Qualitative HCV RNA assays are available with limits of detection of 50 UI/mL. The only FDA-approved quantitative test is Bayer's Versant HCV RNA 3.0, with limits of detection of 615,000 to 7,700,000

copies/mL, but other quantitative assays are available. The same quantitative test should be used to monitor treatment response. TREATMENT The goal of treatment is eradication of infection and prevention of complications from chronic HCV infection such as end-stage liver disease. Sustained virologic response (SVR) is defined as an undetectable HCV RNA by qualitative assays (55 years

2.

White blood cell count >16,000 cells/mm3

3.

Serum glucose >200 mg/dL

4.

Serum lactate dehydrogenase >350 IU/L

5.

Aspartate transaminase >250 U/dL

6.

Hematocrit fall >10% [†]

7.

Serum calcium 4 mEq/L

9.

Blood urea nitrogen increase >5 mg/dL[†]

10. Arterial PO2 6L[‡] * Criteria are modified slightly for gallstone pancreatitis. † Compared to admission values. ‡ Fluid volume infused minus urine and nasogastric tube output.

TABLE 3 -- Atlanta Symposium Clinically Based Classification System for Acute Pancreatitis[*] Mild Acute Pancreatitis (75%) Clinical manifestations (abdominal tenderness, vomiting, hypoactive bowel sounds) Lacks features of severe pancreatitis Patients respond appropriately to fluid administration Minimal organ dysfunction Contrast enhancement of pancreatic parenchyma is usually normal Intrapancreatic pathology: Interstitial edema rarely necrosis Severe Acute Pancreatitis (25%) Clinical manifestations (abdominal tenderness, vomiting, hypoactive bowel sounds) Ranson =3, Acute Physiology and Chronic Health Evaluation (APACHE) II =8 Organ failure Intrapancreatic pathology: Necrosis, less commonly interstitial edema Pancreatic Necrosis

Nonenhanced parenchyma on contrast-enhanced computed tomography >3 cm or involving >30% of the gland Pathology: Macroscopic focal or diffuse areas of devitalized pancreatic tissue and peripancreatic fat necrosis * Adapted from Arch Surg 1993;128:586-990.

MANAGEMENT OF MILD ACUTE PANCREATITIS Although recovery without specific treatment is the rule, all patients are watched closely in a hospital setting because rapid deterioration is not always predictable. Management consists of nothing by mouth, hydration with intravenous crystalloid solution, and analgesia as needed. Prophylaxis against deep venous thrombosis with low-dose subcutaneous heparin and/or sequential calf compression should be routine. Alcoholic patients must be assessed for risk of alcohol withdrawal syndromes. Laboratory tests on admission should include either an arterial blood gas measurement or oxygen saturation measured by pulse oximetry. Oral intake of liquids is resumed when the abdomen is soft and nontender, which usually correlates with a normalized serum amylase level. If the liquids do not exacerbate the attack, the diet can be advanced as tolerated. A right upper quadrant ultrasound is performed in all patients, even alcoholic patients, because they too may harbor gallstones. Nasogastric suction is indicated if ileus and vomiting are present because of the risk of aspiration. Likewise, gastric antisecretory agents are given only if there is concern about peptic ulcer or stress gastritis. MANAGEMENT OF SEVERE ACUTE PANCREATITIS Severe acute pancreatitis is usually evident on initial clinical assessment; if not, the grave situation declares itself within the subsequent 24 to 48 hours. Early mortality from severe acute pancreatitis results from cardiovascular and/or respiratory failure. Thus, patients are managed in an intensive care unit, with urinary, central venous pressure, and arterial catheters, cardiac and pulse oximetry monitoring, and close observation. Profound and ongoing intravascular volume loss results from fluid sequestration within the retroperitoneum as well as a diffuse capillary leak, which causes generalized edema. Intravascular volume is maintained by crystalloid infusion, titrated to maintain adequate tissue perfusion. Inotropic cardiac support is used as needed once intravascular volume repletion is achieved. Packed red blood cells are transfused as needed to maintain adequate oxygen-carrying capacity. Respiratory function frequently worsens precipitously in the first 24 hours, requiring endotracheal intubation and ventilatory support. Analgesia and sedation are liberally administered, as is stress ulcer prophylaxis. At present, no pharmacologic therapy dependably ameliorates the severity of the pancreatitis or decreases the risk of systemic complications. Neither octreotide (Sandostatin),[1] a somatostatin analogue that inhibits pancreatic exocrine secretion, nor various protease inhibitors have improved mortality. Newer therapies targeting mediators of the pancreatic and systemic inflammatory response could in theory improve outcome, especially if administered very early in the attack. One such agent, a platelet-activating factor antagonist called lexipafant, showed promise in initial laboratory investigations but did not prove beneficial in clinical trials. Because retroperitoneal and peritoneal exudates contain activated digestive enzymes and a host of other vasoactive and inflammatory mediators, peritoneal dialysis might logically improve the condition of patients with severe acute pancreatitis. Indeed, several trials report amelioration of the cardiovascular collapse associated with a severe attack, although overall hospital mortality due mainly to late infectious sequela was not altered. Finally, operation has almost no role early in the course of severe acute pancreatitis (first 14 days), except to rule out another suspected cause of the acute abdomen or to resect gangrenous bowel, which has developed as a complication of the severe pancreatitis.

CURRENT THERAPY Acute Pancreatitis MILD ACUTE PANCREATITIS

Supportive therapy: Intravenous fluids, pain control, diet as tolerated If gallstones: Cholecystectomy and cholangiogram during same hospitalization or shortly thereafter Severe Acute Pancreatitis

Admission to intensive care unit Supportive therapy: Intravenous fluids, pain control, antibiotics, enteral or parenteral nutrition Surgical treatment of infected pancreatic necrosis Surgical or endoscopic treatment of pseudocyst 1 Not FDA approved for this indication.

NECROSIS AND INFECTION The presence of pancreatic necrosis can be detected by dynamic CT scanning or by serum markers, if available. The probability of complications and of death correlates with the amount of pancreas that is necrotic. When 20% or less of the gland undergoes necrosis, secondary pancreatic infection is rare, and survival is expected. If 50% or more of the gland is necrotic, secondary infection becomes very probable, and mortality is as high as 50%. Secondary infection of necrotic pancreatic and peripancreatic tissues is relatively common and is the principal cause of mortality from severe acute pancreatitis. Infecting organisms are usually enteric gram-negative bacilli, but infection with gram-positive organisms and fungi is now recognized as well. A trend toward reduced pancreatic infection (as well as other systemic infection) has been shown following the prolonged use of newer antibiotics, which effectively penetrate pancreatic tissue. However, infections that develop in patients treated with prophylactic antibiotics tend to involve resistant organisms. One standard prophylactic antibiotic regimen gaining acceptance uses imipenem-cilastatin (Primaxin) started soon after admission and continued for at least 2 weeks. These patients have many intravenous and invasive monitoring catheters, which are potential portals for entry of gram-positive organisms that can secondarily infect the pancreas. Rigid adherence to appropriate infection control measures is required to minimize this risk. Infected pancreatic necrosis is the most dreaded and lethal complication of severe acute pancreatitis. The condition becomes apparent most frequently during the third and fourth weeks of hospitalization and is marked by fever, increasing pain, tenderness, and fullness in the upper abdomen. The patient usually appears septic. Contrastenhanced CT may reveal extraluminal retroperitoneal gas, which is a radiographic hallmark of infected necrosis. Percutaneous image-guided fine-needle aspiration of the pancreas, with immediate gram stain and culture of the aspirate, can reveal the presence of organisms, which is diagnostic

of infected necrosis. Infected pancreatic necrosis is almost always fatal without aggressive débridement and drainage of the retroperitoneum. The standard for wide débridement is an open laparotomy, although laparoscopic, endoscopic, and percutaneous techniques are being described and developed. Surgical strategy ranges from débridement with closed suction and irrigation of the retroperitoneum to multiple planned operative débridements every 2 to 3 days until all necrotic material is removed. All approaches are time and labor intensive, but they offer the only chance for survival of the majority of patients. Sterile pancreatic necrosis is associated with severe acute pancreatitis but, unlike infected pancreatic necrosis, is usually managed without the need for urgent operation. Acute peripancreatic fluid collections frequently arise. They may include reactive serous effusions but likely represent secondary or even main pancreatic ductal disruption, with resultant leak of pancreatic juice into the lesser peritoneal sac or other anatomic spaces surrounding the pancreas. These acute collections often resorb spontaneously, requiring no specific treatment. If infection of the fluid is suspected or if pain and tenderness are increasing, the collections may be percutaneously aspirated or even drained. In some centers, endoscopically placed transpapillary drains are inserted into the pancreatic duct, occasionally through the disruption into the fluid collection, to accomplish drainage. Finally, if such collections do not spontaneously disappear and do not require early drainage, they may evolve into a pancreatic pseudocyst. A few patients with sterile pancreatic necrosis fail to improve in spite of optimal, protracted conservative care. These patients deserve operative exploration and pancreatic débridement on the grounds of failed nonoperative treatment, coupled perhaps with the suspicion that a smoldering, occult infection has eluded discovery. The operation is delayed as long as is practical, to allow areas undergoing necrosis to demarcate and liquefy. This makes the débridement technically easier. The pancreas and adjacent tissues are débrided and drained, provision for enteric feeding is established, and the abdomen is closed with the expectation that the need for reoperation will be likely. BILIARY (GALLSTONE) PANCREATITIS Gallstone pancreatitis is caused by transient obstruction of the pancreatic duct at the ampulla of Vater. The offending gallstone need not be large; “biliary sludge” and even biliary “microlithiasis” appear to be capable of provoking acute pancreatitis. As a rule, patients with gallstone pancreatitis have multiple small gallstones within the gallbladder, a comparatively wide cystic duct (promoting passage into the common bile duct), and a distinct “common channel” of the bile and pancreatic ducts. Nonalcoholic patients with acute pancreatitis very likely have biliary lithiasis as the underlying cause. The presence of gallstones within the gallbladder virtually makes the diagnosis. A distended common bile duct seen by ultrasound further suggests the recent passage of a stone. Serum bilirubin and/or alkaline phosphatase levels may be mildly elevated, but often both are normal. If the ultrasound fails to reveal gallbladder stones or sludge and other rare causes are excluded, an endoscopic ultrasound may identify sludge or microlithiasis in a stable patient. Endoscopic ultrasound can also complement the pancreatic anatomic findings on CT. If endoscopic ultrasound is not available or is inconclusive, the next diagnostic step includes endoscopic retrograde cholangiopancreatography (ERCP). A sample of bile can be obtained to examine for microscopic crystals (this can be achieved by duodenal drainage as well), and small stones or anatomic anomalies may be identified. Gallstone pancreatitis is usually mild, resolving clinically within 2 to 4 days. Serum bilirubin and alkaline

phosphatase levels are typically normal or return to normal within this period, suggesting a low probability of persistent stone(s) within the common bile duct. Cholecystectomy eliminates the source of further stones and thus prevents recurrent pancreatitis; it should be performed during the same hospitalization or shortly thereafter. An intraoperative cholangiogram is performed, unless it has been undertaken preoperatively. If pancreatitis resolves but liver function tests suggest a persistent stone in the bile duct, then preoperative ERCP with papillotomy and stone extraction is appropriate, followed by prompt cholecystectomy. If the intraoperative cholangiogram shows choledocholithiasis, a laparoscopic or open common bile duct exploration or a postoperative ERCP with papillotomy with stone removal can be performed, depending on the available expertise. Severe gallstone pancreatitis is managed like severe pancreatitis of any cause. Usually, the inciting stone has passed, leaving the bile and pancreatic ducts unobstructed; therefore, routine, early ERCP is not warranted. However, if a stone is persistently obstructing the ampulla of Vater, if the patient has jaundice, or if the patient has signs of cholangitis, urgent ERCP and stone extraction may be necessary. Chronic Pancreatitis Chronic pancreatitis (CP) is an irreversible, progressive inflammatory disease of the pancreas characterized by pain, fibrosis, and progressive loss of exocrine and/or endocrine function. The early course of this disease may often manifest as repeated attacks of acute pancreatitis. It occurs in men more frequently than in women. Excessive alcohol consumption is usually the cause in developed countries. INCIDENCE In several Western industrialized countries, the estimated prevalence of CP is approximately 10 to 15 per 100,000 population, with an annual incidence of 3.5 to 4 per 100,000 population. These rates may actually underestimate the problem because the diagnosis of CP is not based on advanced diagnostic tools such as ERCP and CT scan. In a recent report from Japan using CT and ERCP, the incidence of CP is 12 per 100,000 and prevalence is 45 per 100,000 population, which are much higher than in Western countries. In southern India, the prevalence of CP has been estimated to be 125 per 100,000 with the majority being calcific pancreatitis. The cause of this tropical pancreatitis is thought to be dietary. According to estimates of the Commission on Professional and Hospital Activities, CP ranks as the 27th most common digestive disease in the United States, with a threefold higher prevalence in the black male population. The majority of care for CP is directed toward ameliorating pain, but a substantial amount of resources is also spent on treating complications. More than half of CP patients will develop pancreatic diabetes; one third of these patients will be insulin dependent, and nearly 50% will eventually require surgical intervention for pain or other complications. Optimal care of the patient with CP relies on supportive medical management of endocrine and exocrine insufficiency and of pain. Surgical intervention is generally reserved for intractable pain and specific complications such as pseudocyst and biliary or intestinal obstruction. As many as half of all patients will die within 20 years of their diagnosis of CP, a rate much higher than their age-matched population. ETIOLOGY AND PATHOGENESIS CP appears to be a multifactorial process involving both a genetic predisposition and environmental factors

(see Table 4 ). Alcohol use is by far the number one cause of CP in the Western world, accounting for an estimated 70% of the cases in the United States and Europe. About 10% of chronic alcoholics will develop CP, roughly the same percentage of alcoholics who develop hepatic cirrhosis. Average age at diagnosis of alcoholic pancreatitis is 35 to 45 years with an 11- to 18-year history of 150 to 175 g of alcohol ingestion daily.

TABLE 4 -- Causes of Chronic Pancreatitis Alcohol Obstruction Pancreas divisum Congenital strictures Acquired strictures Acute pancreatitis Trauma Endoscopic retrograde cholangiopancreatography Neoplasm Pancreatic Periampullary Toxic Substances Tropical pancreatitis Hypercalcemia Hyperlipidemia Genetic Autoimmune Idiopathic

Ingested alcohol results in direct damage to the acinar cell with increased concentration of protein secretion, decreased production of bicarbonate, and decreased fluid volume as demonstrated in experimental models and in patients with alcoholic pancreatitis. This combination appears to result in protein and calcium precipitation within the pancreatic duct system, subsequent ductal obstruction, activation of pancreatic enzymes, and autodigestion of the gland. Over time, a fibrotic response results in permanent ductal abnormalities, calcification, and stone formation. Dietary factors, such as high-fat and high-protein intake and trace mineral insufficiency, seem to be epidemiologically associated with CP. Another theory suggests the presence of an acinar cell product, lithostatin or pancreatic stone protein, that prevents calcium precipitation. Decreased concentrations of lithostatin and decreased levels of lithostatin messenger RNA have been found in the pancreatic juice and acini of patients with chronic calcific pancreatitis, suggesting a genetic component of risk for developing the disease. Alcohol-induced derangement of lipid metabolism has also been postulated as inducing the periacinar fibrosis and changes associated with alcoholic pancreatitis. The range of experimentally identified abnormalities supports the multifactorial nature of the disease. Another form of CP, tropical pancreatitis, may be caused by protein malnutrition and cyanogens found in cassava root. The clinical and histologic features of tropical pancreatitis are nearly identical to those of alcoholic CP. Obstructive pancreatitis results from both congenital and acquired ductal obstruction, as in

pancreas divisum, congenital and acquired strictures, and neoplasia. Unlike alcoholic pancreatitis, the obstructed pancreas shows uniform inflammatory changes with preserved ductal epithelium and rare protein plugs. The hypothesis that high intraductal pressure results in pancreatitis has been proposed based partly on the demonstration of high intraductal pressures in these patients. Additional causes of CP include hypercalcemia, hyperlipidemia, autoimmune diseases, and genetic alterations, as seen in hereditary and idiopathic pancreatitis (see section on acute pancreatitis). The mechanism by which pancreatitis develops in these situations is unclear. DIAGNOSIS Patients with CP typically present with persistent midepigastric pain, often with a thoracolumbar component. The pain may be exacerbated by eating and by alcohol consumption. Nausea, vomiting, and hemodynamic instability are less frequent than with acute pancreatitis. Examination often reveals upper abdominal fullness and tenderness with frequent associated signs of malnutrition and occasionally jaundice. The classic triad of CP—pancreatic calcification, diabetes mellitus, and steatorrhea—occurs in fewer than 25% of cases, although two thirds of patients will have an abnormal glucose tolerance test at the time of presentation. Because of the difficulty of obtaining pancreatic tissue for histologic analysis, CP is usually diagnosed by pancreatic imaging with or without tests of exocrine function. Radiologic evidence of pancreatic calcification is pathognomonic and is present in only 30% to 50% of patients. Pain is present in 75% of patients. Initially the pain is characterized by recurrent attacks but tends to become persistent with variable periods of remission. Occasionally it will “burn out” over time. The etiology of pain is uncertain. Table 5 lists some of the proposed factors. The most recent theory suggests hypoxia and damage to local sensory nerves with exposure to inflammatory irritants such as histamine, prostaglandins, and pancreatic enzymes.

TABLE 5 -- Proposed Factors Producing Pain in Chronic Pancreatitis Ductal hypertension Autodigestion Parenchymal ischemia Perineural inflammation

Laboratory values are of limited value in evaluating CP. Pancreatic enzyme levels (amylase, lipase) may be elevated in acute exacerbations but are not a good measure of chronic disease, pancreatic function, or pancreatic reserve, nor do they correlate with symptoms. Functional studies are cumbersome and are rarely required to diagnose CP. However, stimulated pancreatic secretions collected from the duodenum (amylase, lipase, trypsin, chymotrypsin, and bicarbonate), urine tests (nitroblue tetrazolium–para-aminobenzoic acid [NBT-PABA] test, and pancreolauryl test), or serum studies (P-isoamylase and trypsin), provide reliable estimates of pancreatic functional reserve and can be useful in evaluating treatment strategies. Serum liver enzyme levels and leukocyte counts may provide important information regarding complications of the disease. Imaging

Plain abdominal radiographs reveal pancreatic calcification in less than 50% of patients and are otherwise nonspecific in CP. Transabdominal ultrasound can determine the size and consistency of the gland, characteristics of the biliary tree, and the presence of complications. A skilled ultrasonographer may achieve 70% sensitivity in diagnosing the disease.

CURRENT DIAGNOSIS Chronic Pancreatitis CLINICAL MANIFESTATIONS

Persistent midepigastric pain exacerbated by eating or alcohol consumption One or more present: Malnutrition, steatorrhea, glucose intolerance RADIOLOGIC AND LABORATORY TESTS

Computed tomography scan of the pancreas may show calcifications, pancreatic duct dilation, and/or pseudocyst formation Endoscopic retrograde cholangiopancreatography is the gold standard diagnostic test but is used only when computed tomography is not sufficient to make the diagnosis or clarify anatomy Amylase and lipase levels are not useful Functional pancreatic studies are cumbersome and rarely required CT approaches 90% sensitivity and greater than 90% specificity in diagnosing CP and should be considered in all suspected patients to classify their disease and determine the presence of complications and surgically correctable lesions. CT scan is the best radiologic modality for detecting calcifications, pancreatic ductal dilation, and pseudocysts and may be the only imaging study necessary in most cases. ERCP remains the gold standard for diagnosis and staging of CP, with a sensitivity up to 95% and specificity greater than 90%. The small but finite incidence of serious complications related to ERCP should limit its use to those patients who require anatomic definition not provided by other imaging studies and in patients suspected of ampullary or ductal obstruction amenable to ERCP treatment. Magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and CT cholangiopancreatography/angiography are rapidly evolving and can replace diagnostic ERCP in most situations. This technology provides definition of soft tissues and ductal anatomy but remains institutional and operator dependent. Likewise, endoscopic ultrasound is becoming more available and may play a role in the early diagnosis of CP. MEDICAL TREATMENT Medical treatment of CP consists primarily of supportive care. Pain relief, metabolic and nutritional support,

as well as pancreatic endocrine and exocrine support, are the mainstays of medical therapy. Pain control is difficult, often requiring opiate analgesics. Abstinence from alcohol must be the initial goal, as alcohol consumption predicts recurrent pain even after surgical intervention. Oral pancreatic enzyme supplementation and octreotide[1] may provide modest pain relief, probably due to reduced pancreatic secretion. Because opiate addiction increases in proportion to duration of disease, nonsteroidal antiinflammatory drugs should be prescribed early and chronically. Opiates should be reserved for exacerbations and intractable pain. Some authorities recommend surgical intervention prior to the chronic administration of opiates.

CURRENT THERAPY Chronic Pancreatitis MEDICAL TREATMENT

Abstinence from alcohol Pain control, preferably with nonopioid analgesics, pancreatic enzymes, octreotide Nutritional support: Low-fat foods, adequate protein and vitamins Management of diabetes Management of exocrine insufficiency with pancreatic enzymes MEDICAL TREATMENT

Indications: Pain refractory to medical management, inability to exclude malignancy, biliary or enteral obstruction, pseudocyst, pancreatic ascites, pancreatic fistula Dilated pancreatic duct: Internal drainage procedure Nondilated pancreatic duct: Resection Pseudocyst: Internal surgical drainage or endoscopic techniques Malnutrition is common due to fear of pain after eating, as well as poor dietary habits and nutritional problems, in the alcoholic population. Attention should be directed at providing a low-fat diet with adequate protein and calories and vitamin supplementation. Parenteral or jejunal feedings may be required in certain situations, such as preoperative preparation and episodes of acute exacerbation. Pancreatic exocrine insufficiency necessary to produce protein malabsorption does not occur until 90% of acinar mass has been lost. However, steatorrhea, or fat malabsorption, is a common and often troublesome problem in patents with CP. In addition to lipase from the pancreas, digestion of lipids depends on salivary and gastric hydrolysis, alkalinization in the duodenum, and adequate bile acid concentrations, all of which may be diminished in alcoholics. Pancreatic exocrine enzyme replacement is indicated to ameliorate steatorrhea. Present enzyme preparations include enteric-coated and encapsulated forms to aid delivery of active enzymes and decrease the volume of administration. Gastric acid suppression may also be necessary to provide an adequate pH environment for enzyme activity.

Endocrine insufficiency in CP is primarily manifested as pancreatic diabetes. Its treatment is similar to that for other forms of diabetes in that it may be controlled by diet, oral hypoglycemic agents, or insulin. SURGICAL TREATMENT The first line of therapy in CP should be noninjurious; surgical intervention should be reserved for intractable disease. Additional indications for surgical intervention are listed in Table 6 . The choice of operation depends on the anatomic findings in each patient ( Table 7 ). Pancreatic and biliary duct anatomy should be carefully evaluated preoperatively. Improvements in perioperative preparation and care have enabled routine performance of surgical procedures on the pancreas, with very low mortality and morbidity. Contemporary series of operations for CP demonstrate mortality rates less than 3% and complication rates less than 30%, comparable to the rates of other major intra-abdominal operations.

TABLE 6 -- Indications for Surgery in Chronic Pancreatitis Pain refractory to medical management Inability to exclude pancreatic malignancy Complications Pseudocyst Biliary obstruction Duodenal obstruction Splenic vein thrombosis Pancreatic fistula Colonic obstruction Pancreatic ascites Pancreatic abscess

TABLE 7 -- Selection of Operation for Chronic Pancreatitis Disease limited to tail of gland

Distal pancreatectomy

Obstruction in head of gland Dilated pancreatic duct

LR-LPJ

Nondilated pancreatic duct

Whipple, DPPHR

No obstruction in head of gland Dilated pancreatic duct

LPJ

Nondilated pancreatic duct

Distal resection (40%– 95%), total pancreatectomy

Unable to tolerate major operation

Neurolysis?

Failure of primary drainage/resection Additional drainage/resection, neurolysis Inability to rule out malignancy

Resection

Abbreviations: DPPHR = duodenal preserving pancreatic head resection; LR-LPJ = local resection–longitudinal pancreaticojejunostomy.

In a minority of patients, stenosis or stricture of the ampulla of Vater can be treated with simple sphincterotomy or sphincteroplasty. Initial results with this technique revealed improvement in pain, but the results were short lived and correlated with alcohol abstinence. Although these procedures have been successful in limiting recurrent acute bouts of pancreatitis in pancreas divisum, no benefit has been realized for patients with CP. This experience suggests that sphincterotomy and pancreatic duct stenting will have little effect on the long-term management of CP from other etiologies. The pancreatic duct in CP usually is either dilated diffusely or in a beaded (“chain-of-lakes”) pattern. A dilated pancreatic duct is best treated with internal drainage of the pancreatic duct into a Roux-en-Y limb of jejunum. Historically, 8 mm was considered the lower limit of dilation amenable to internal drainage, but the procedure has proved tenable and successful in relieving pain in patients with duct dilation of greater than 5 mm. The Partington-Rochelle modification of the Puestow operation (lateral pancreaticojejunostomy) has resulted in good to excellent relief of pain in 70% to 80% of patients. Concomitant procedures to address complications such as pseudocyst and biliary obstruction can be incorporated into the jejunal limb. There is no evidence that surgery improves pancreatic function, as was hoped by the pioneers of ductal drainage procedures. The Frey procedure is based on the concept that the head of the pancreas and uncinate process may not be completely drained by longitudinal pancreaticojejunostomy. This procedure entails a “coring out” or local resection of the head of the gland combined with lateral pancreaticojejunostomy. Results have been promising; only 13% of patients have reported no pain relief. Another proposed mechanism for the success of this operation is the reversal of ischemia or ductal hypertension that irritates sensory nerves in the head of the gland. When the pancreatic duct is not dilated, decompressing procedures are not feasible. However, patients may obtain relief of pain with pancreatic resection. Debate continues on the merits and complications of partial (40%–80%) distal pancreatectomy, subtotal (95%) distal pancreatectomy (Child's procedure), pancreaticoduodenectomy (Whipple's procedure), and total pancreatectomy. Duodenum-preserving pancreatic head resection (Beger's procedure) performed in the 10% to 30% of CP patients with an inflammatory mass in the head of the gland has shown excellent pain relief, comparable to that of a Whipple procedure. Pancreatic insufficiency resulting from resection procedures is generally proportional to the extent of resection, with severe exocrine insufficiency and a particularly brittle and difficult to control form of pancreatic diabetes at the extreme. Attempts at autologous pancreatic islet cell transplantation at the time of pancreas resection were initially promising, but enthusiasm for the technique has waned because of less than satisfactory long-term results. Several approaches to nerve ablation have been proposed based on the theory that the pain of CP is related to inflammatory involvement of the splanchnic nerves. Extraperitoneal, intraperitoneal, thoracic, and thoracoscopic splanchnicectomy as well as complete denervation procedures have been attempted to treat

the pain of CP. Results have been unpredictable, often unconfirmed, and with limited follow-up. Neurotomy may be considered in patients who have not obtained relief of pain after surgical drainage or resection procedures. PANCREATIC PSEUDOCYST Pancreatic pseudocysts are walled-off collections of fluid and debris resulting from disruption of the pancreatic duct and are most commonly associated with acute and chronic pancreatitis. Pseudocysts will develop in up to 10% of patients after an episode of acute alcoholic pancreatitis. They may also occur after trauma or in association with a neoplasm. The wall is vascularized inflammatory tissue without an epithelial lining and may contain pancreatic parenchyma. Pseudocysts may occur in any region of the gland and are multiple in 10% to 15% of patients. Fluid collections occurring within 3 weeks of an acute episode of pancreatitis are considered acute fluid collections, and 30% to 40% of these collections will resolve spontaneously. The most common presentation is abdominal pain, present in 90% of patients. Physical examination often reveals a tender abdominal fullness or mass. Nonspecific complaints of nausea, vomiting, early satiety, and weight loss are common. More dramatic presentations may result from free intraperitoneal rupture, intracystic hemorrhage or infection, gastric variceal bleeding resulting from splenic or portal vein thrombosis, or intraperitoneal hemorrhage from adjacent pseudoaneurysm rupture. Laboratory findings are nonspecific, although persistent amylase elevation is common. Imaging with CT is preferable, but ultrasound is nearly as sensitive and can be recommended for follow-up to determine interval changes in size. Sampling of a postpancreatitis fluid collection is rarely indicated. However, if there has not been a preceding episode of pancreatitis, fluid cytology and chemistry can help differentiate a pseudocyst from a more likely mucinous or serous cystic neoplasm. The natural history of asymptomatic pseudocysts reveals that nearly half remain stable, decrease in size, or completely resolve at 1-year follow-up, irrespective of size. However, pseudocysts larger than 6 cm are more likely to require operation during follow-up. Pseudocysts present for more than 12 weeks almost never resolve spontaneously and have a high rate of complications. Therefore, current management of pancreatic pseudocysts takes into account the presence or absence of symptoms, the age and size of the pseudocyst, and the presence or absence of complications. Postpancreatitis fluid collections that are asymptomatic in a stable patient can be followed with monthly imaging to evaluate resolution, stability, and enlargement. Failure to resolve and evidence of enlargement are indications for intervention. If, on the other hand, the pseudocyst is symptomatic, early intervention should be considered. Generally, a period of 6 weeks is desired prior to surgical intervention to assure adequate maturation of the cyst wall. The preferred operative management of a pseudocyst is internal drainage into the gastrointestinal tract. This can be accomplished by anastomosis of the opened cyst wall to the stomach (cystogastrostomy), duodenum (cystoduodenostomy), or a Roux-en-Y limb of jejunum (cystojejunostomy), depending on the location of the pseudocyst. Multiple pseudocysts can be addressed simultaneously by connecting the pseudocysts and draining them as one, separately draining each cyst into a Roux-en-Y jejunal limb, or a combination of the internal drainage procedures. A lateral pancreaticojejunostomy should be added when the pancreatic duct is dilated. The cyst wall should be biopsied on all occasions, as cystic neoplasms of the pancreas can mimic a pseudocyst. Infected pseudocysts are generally treated as pancreatic abscesses.

Simple aspiration of pseudocysts will fail to resolve the fluid collection in as many as 80% of patients. Prolonged catheter drainage has demonstrated better resolution rates but may take months of drain maintenance. New endoscopic techniques that place an endoprosthesis through the intestinal lumen into the pseudocyst and that bridge the pancreatic duct disruption with a pancreatic duct stent are currently being analyzed. ENDOSCOPIC THERAPY Endoscopic approaches to ductal decompression have been attempted in CP. These include endoscopic clearance of the main pancreatic duct with pancreatic sphincterotomy and basketing of stones for removal, extracorporeal shock wave lithotripsy, transpapillary drainage of pseudocysts, and dilation and stenting of ductal strictures. Various endoscopic series have reported success rates of 50% to 70% for clearing the pancreatic duct and 60% to 80% for long-term pain relief. The risk of complications is approximately 10%. The early results of endoscopic therapy are comparable with those of surgery, but all endoscopic reports have been case series, some with little long-term follow-up. Randomized controlled studies using adequate and constant methods for evaluating and reporting results and comparing endoscopic, medical, and surgical treatment modalities are now required.



REFERENCES Balthazar et al., 1990. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH: Acute pancreatitis: Value of CT in establishing prognosis. Radiology 1990; 174:331-336. Baron and Morgan, 1999. Baron TH, Morgan DE: Acute necrotizing pancreatis. N Engl J Med 1999; 340:1412-1417. Bradley, 1993. Bradley 3rd EL: A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993; 128:586-590. Howare et al., 1998. Howare J, Idezuki Y, Ihse I, Prinz RA: Surgical Diseases of the Pancreas, 3rd ed.. Baltimore, Williams & Wilkins, 1998. Mitchell et al., 2003. Mitchell RM, Byrne MF, Baillie J: Pancreatitis. Lancet 2003; 361:1447-1455. Tandon et al., 2002. Tandon RK, Sato N, Garg PK, Consensus Study Group : Chronic pancreatitis: AsiaPacific consensus report. J Gastroenterol Hepatol 2002; 17:508-518. Triester and Kowdley, 2002. Triester SL, Kowdley KV: Prognostic factors in acute pancreatitis. J Clin Gastroenterol 2002; 34:167-176. Uhl et al., 2002. Uhl W, Warshaw A, Imrie C, International Association of Pancreatology , et al: IAP guidelines for the surgical management of acute pancreatitis. Pancreatology 2002; 2:565-573. Working Party of the British Society of Gastroenterology et al., 2005. Working Party of the British Society of Gastroenterology , Association of Surgeons of Great Britain and Ireland , Pancreatic Society of Great Britain and Ireland , Association of Upper GI Surgeons of Great Britain and Ireland : UK guidelines for the management of acute pancreatitis. Gut 2005; 54(Suppl. 3):iii1-iii9.



Chapter 138 – Gastroesophageal Reflux Disease

Method of: Sachin Wani, MD Prateek Sharma, MD Gastroesophageal reflux disease (GERD) includes a broad spectrum of upper gastrointestinal (GI) manifestations caused by the reflux of stomach contents. It affects around 20% to 50% of adults in Western countries, and more than 15 million Americans experience heartburn on a daily basis. The annual direct cost for managing this disease is estimated to be more than $10 billion in the United States. Afflicted persons have a significantly decreased quality of life that deteriorates as the severity of GERD symptoms increase. The last two decades have seen major advances in the diagnosis and pathophysiology of GERD combined with a burgeoning use of pharmacologic, surgical, and endoluminal therapies for managing GERD. Definitions and Classification A universally accepted definition of GERD and its various symptoms and complications is lacking, and the use of varied definitions and terminology for GERD is often a source of confusion. Such definitions have made a pragmatic distinction between persons whose reflux-induced symptoms justify the diagnosis of GERD and the many persons in the general population who experience a clinically insignificant level of reflux-induced symptoms. A recent international consensus group defined GERD as a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications. Determination of whether symptoms were troublesome should be patient centered; mild symptoms occurring 2 or more days a week and moderate or severe symptoms occurring more than once a week are often considered troublesome by patients. Based on the findings at upper endoscopy, GERD patients are categorized into those with erosive esophagitis and those with nonerosive reflux disease (NERD). Less than 50% of patients with typical GERD symptoms have endoscopic evidence of erosive esophagitis characterized by mucosal breaks ( Figure 1 ). NERD describes patients who have no mucosal breaks and who have reflux symptoms with or without abnormal esophageal acid exposure during ambulatory 24-hour esophageal pH monitoring. Recently, a conceptual change in the classification of GERD-related disease manifestations has been proposed ( Box 1 ). This allows symptoms to define the disease but also permits further characterization if mucosal injury is identified. It is aimed at improving disease management, making studies more generalizable and ultimately assisting patients and physicians to manage the disease.

FIGURE 1 Endoscopic image of erosive esophagitis (Los Angeles grade C).

BOX 1

Clinical Spectrum of Gastroesophageal Reflux Disease Esophageal Syndromes Symptomatic Syndromes

•

Reflux chest pain syndromes

•

Typical reflux syndrome (heartburn, regurgitation)

Syndrome with Esophageal Injury

•

Barrett's esophagus

•

Esophageal adenocarcinoma

•

Reflux esophagitis

•

Reflux stricture

Extraesophageal Syndromes Established Associations

•

Reflux asthma syndrome

•

Reflux cough syndrome

•

Reflux dental erosion syndrome

•

Reflux laryngitis syndrome

Proposed Associations

•

Idiopathic pulmonary fibrosis

•

Pharyngitis

•

Recurrent otitis media

•

Sinusitis

Adapted from Vakil N, van Zanten SV, Kahrilas P, et al: The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. Am J Gastroenterol 2006;101:19001920 (with permission). Epidemiology According to U.S. population surveys, 44% of all Americans experience heartburn at least once a month, 14% at least once a week, and up to 7% daily. In a recent population-based study in Sweden, reflux symptoms were reported by 40% and erosive esophagitis was diagnosed in nearly 16%. There appears to be little difference between the prevalence of GERD in North America and in Europe. Data suggest that the prevalence of GERD is on the rise in several Asia-Pacific regions that were once considered a zone of low

prevalence of GERD. Although there is a lack of epidemiologic data for GERD in the pediatric age group, it is increasingly clear that symptoms suggesting GERD are not uncommon in children. GERD appears to affect about 7% of all infants during the first year of life to the extent that they are brought to medical attention. Data on the incidence of GERD are limited. Genetic factors have been implicated, because the prevalence of reflux symptoms is high in the parents of affected patients, and concordance of reflux disease is higher in monozygotic than in dizygotic twins. The relation between age and GERD is unclear, although data suggest that advancing age is a risk factor for severe esophagitis and fewer reflux symptoms. Male gender is a risk factor for erosive esophagitis, and men typically have more severe reflux disease. Lifestyle factors associated with GERD include obesity and consumption of tobacco, alcohol, coffee, chocolate, mint, citrus fruits and juices, carbonated beverages, fatty foods, and high-calorie late meals. The data on these factors are not conclusive in spite of some evidence linking them to the main mechanism of the disease, transient relaxation of the lower esophageal sphincter. A high body mass index (BMI) has been associated with an elevated risk of GERD and a specific dose-response relationship between increasing BMI and GERD prevalence has been demonstrated. Studies have found little or no overall effect of Helicobacter pylori eradication on GERD. Some studies, especially from East Asia and in patients with chronic atrophic gastritis, have shown a negative association between H. pylori and GERD. Pathophysiology The structure and function of the lower esophageal sphincter (LES) are of paramount importance in GERD. The LES is a segment of smooth muscle in the distal esophagus that maintains a pressure of at least 15 mm Hg above the intragastric pressure by tonic contractions. The main pathophysiologic mechanisms that contribute to the development of GERD are frequent transient relaxation of the LES, impaired clearance of regurgitated gastric acid, hiatal hernia, and delayed gastric emptying. Obesity is believed to increase the risk of GERD by imposing mechanical stresses on the esophagogastric junction by increased intragastric pressure and anatomic disruption of the esophagogastric junction, which results in a hiatal hernia. Hiatal hernia has broad pathophysiologic implications in GERD pathogenesis: increased incidence of straininduced reflux, reduced threshold for distention-induced transient LES relaxations, swallow-induced reflux, reduced LES pressure, and impaired acid clearance. Key factors in removing refluxed material (esophageal peristalsis) and neutralizing acid (salivary secretions, esophageal epithelium, and bicarbonate secretion), as well as the characteristics and quantity of gastric fluids, are believed to play roles in the pathogenesis of GERD. Clinical Features Heartburn and acid regurgitation are well established classic or typical symptoms of GERD. Heartburn is defined as a burning sensation in the retrosternal area, and regurgitation is defined as the perception of flow of refluxed gastric content into the mouth or hypopharynx. Upper abdominal or lower retrosternal symptoms

such as bloating or abdominal pain are not definitive for GERD and are grouped under the umbrella of the current definition of dyspepsia. Other possible symptoms include globus (lump in the throat) and water brash (excessive salivation). In addition to these symptoms, many manifestations of GERD involve extraesophageal organs (extraesophageal syndromes), and established associations include chronic cough, laryngitis, bronchial asthma, and dental erosions. The proposed associations are pharyngitis, sinusitis, idiopathic pulmonary fibrosis, and recurrent otitis media. Alarm symptoms include dysphagia, odynophagia, progressive unintentional weight loss, GI bleeding, anemia, anorexia, and persistent vomiting ( Box 2 ). In the presence of alarm symptoms, prompt endoscopy is strongly indicated. BOX 2 Alarm Symptoms of GERD that Require Prompt Referral for Upper Endoscopy •

Gastrointestinal bleeding (occult or overt)

•

Iron deficiency anemia

•

Pain while swallowing (odynophagia)

•

Persistent vomiting

•

Progressive difficulty swallowing (dysphagia)

•

Unintentional weight loss

•

Anorexia

Abbreviation: GERD = gastroesophageal reflux disease. Diagnosis SYMPTOM ASSESSMENT Symptom pattern evaluation, by structured interview or validated questionnaires, is the single most important diagnostic step, because a high percentage of patients with reflux disease are not recognized by endoscopy. Diagnosis, treatment, and assessment of outcomes rely heavily on symptom evaluation. Symptom severity has no consistent relation to the severity of mucosal injury, and hence endoscopic findings cannot be used as a surrogate for determining symptom severity.

CURRENT DIAGNOSIS Heartburn and acid regurgitation are well-established cardinal symptoms of GERD. Several ear, nose, and throat, respiratory, and sleep disorders; oral diseases; and symptoms such as chest pain have been associated with GERD (extraesophageal syndromes). Complications of GERD are esophageal strictures, ulcers, Barrett's esophagus, and esophageal adenocarcinoma. Alarm symptoms that prompt urgent endoscopy include dysphagia, odynophagia, progressive unintentional weight loss, gastrointestinal bleeding, anemia, anorexia, and persistent vomiting. There is no gold standard for the diagnosis of GERD. Symptom pattern evaluation, by structured interview or validated questionnaires, is the single most important diagnostic step because endoscopy does not diagnose a high percentage of reflux disease. Based on the findings at upper endoscopy, GERD is categorized into two groups: erosive esophagitis and nonerosive reflux disease. The identification of erosive esophagitis at endoscopy is highly specific (90%-95%) for the diagnosis of GERD, but endoscopy per se has a low sensitivity. Empiric treatment with proton pump inhibitors (PPIs) in patients with a history suggesting typical or uncomplicated GERD is recommended. Alleviation of symptoms serves as an adequate diagnosis. Esophageal pH monitoring may be useful for patients with atypical symptoms or in patients who respond poorly to an adequate trial of acid-suppression therapy. UPPER GASTROINTESTINAL ENDOSCOPY The identification of erosive esophagitis at endoscopy is highly specific (90%-95%) for the diagnosis of GERD; however, endoscopy itself has a low sensitivity. The Los Angeles classification is used to categorize the extent of mucosal injury ( Box 3 ). Upper endoscopic evaluation is recommended for evaluating alarm symptoms to look for complications such as esophageal ulcers, strictures, or malignancy. It is only indicated in patients who do not respond to adequate acid-suppression therapy and for screening for Barrett's esophagus (although this indication is controversial). At present, routine esophageal biopsies are not recommended for the assessment of GERD. BOX 3

Los Angeles Classification of Esophagitis LA Grade A

•

One mucosal break (or more) no longer than 5 mm

•

Does not extend between the tops of two mucosal folds

LA Grade B

•

One mucosal break (or more) more than 5 mm long

•

Does not extend between the tops of two mucosal folds

LA Grade C

•

One mucosal break (or more) that is continuous between the tops of two or more mucosal folds

•

Involves less than 75% of the circumference

LA Grade D

•

One mucosal break (or more) that involves at least 75% of the esophageal circumference

Abbreviation: LA = Los Angeles.

Several recent advances have improved the diagnostic yield of endoscopy in GERD. These include magnification endoscopy, magnification chromoendoscopy, video capsule endoscopy, and narrow band imaging. Currently, these are being evaluated in clinical trials and are not established options in routine clinical practice. Reliability of histologic assessment, especially in NERD patients (increases in polymorphonuclear and mononuclear white cells, basal cell hyperplasia, papillary elongation, and dilated intercellular spaces), has been explored and appears promising. EMPIRIC TREATMENT WITH ACID-SUPPRESSION THERAPY If the patient's history appears to be typical of uncomplicated GERD, alleviation of symptoms with an initial trial of empiric acid-suppressive therapy is recommended and can serve as an adequate diagnosis. Proton pump inhibitors (PPIs) are effective in healing esophagitis and controlling symptoms; thus, a poor response to a trial of empiric therapy should prompt referral for further investigations, and an alternative diagnosis should be considered. AMBULATORY ESOPHAGEAL pH MONITORING Twenty-four-hour esophageal pH monitoring is not an appropriate initial diagnostic method because diagnosis can be reached with a high level of accuracy without pH monitoring. Although initially proposed as a gold standard for diagnosiing GERD, it is probably not a gold standard because sensitivity does not

exceed 75%. It is also relatively expensive, inconvenient, uncomfortable, and not widely available. It is useful for the minority of patients with atypical symptoms or in patients who poorly respond to an adequate trial of acid-suppression therapy. Multichannel intraluminal impedance monitoring with pH sensors can detect acidic, weakly acidic, and nonacidic reflux; its usefulness in the clinical setting needs further research and validation. BARIUM ESOPHAGRAM The barium esophagram has a low diagnostic yield in the diagnosis of GERD and should not be used in patients with typical GERD symptoms without dysphagia. It can detect severe cases of erosive esophagitis and is useful for the initial evaluation of patients with dysphagia. It can identify esophageal strictures, esophageal motor abnormalities, and diverticula. Treatment The goals of treatment are to relieve symptoms, promote healing, and prevent complications. LIFESTYLE MODIFICATIONS Experts typically recommend lifestyle modifications in patients with GERD, although supporting data are sparse. Lifestyle changes that have been recommended include smoking cessation; weight loss; avoiding late-evening meals; avoiding foods such as citrus fruits, coffee, chocolate, mint, spicy foods, and fatty foods; avoiding alcohol; and sleeping with the head of the bed elevated. Lifestyle interventions should not be recommended as the primary treatment in patients with bothersome GERD symptoms, but they can play an adjunctive role with acid-suppression therapy or antireflux surgery.

CURRENT THERAPY Lifestyle changes such as smoking cessation, weight loss, avoidance of late-evening meals, avoiding foods such as chocolate, avoiding alcohol, and sleeping with the head of the bed elevated can play an adjunctive role with acid-suppression therapy or antireflux surgery, but evidence is sparse. Pharmacologic options include antacids, histamine type 2–receptor antagonists (H2-RAs), and proton pump inhibitors (PPIs). PPIs are unequivocally the most cost-effective pharmacologic agents for treating GERD and have become the mainstay of medical GERD management. GERD is predominantly a chronic relapsing disorder, and most patients with healed erosive esophagitis (80%-90%) relapse within 6 to 12 months without treatment. The fraction of patients with nonerosive reflux disease (NERD) responding to a standard dose of PPI is approximately 20% to 30% lower than has been documented in patients with erosive esophagitis, along with a longer lag-time to sustained symptom response. Most patients with severe esophagitis (Los Angeles grade C or D) or with nocturnal or extraesophageal manifestations of GERD probably require long-term maintenance therapy.

PPIs may be suitable for intermittent and on-demand therapy in patients with uncomplicated symptomatic GERD (NERD and Los Angeles grade A or B). Antireflux surgery may be appropriate for young, otherwise healthy patients in whom medical management is not tolerated or who refuse to take medications chronically. PHARMACOLOGIC THERAPY Pharmacologic options include over-the-counter medications such as antacids, histamine type 2–receptor antagonists (H2-RAs), and PPIs. Systematic reviews have confirmed that PPIs, by blockade of the gastric acid proton pump—H+,K+-ATPase (adenosine triphosphatase)—are more effective than H 2-RAs at healing esophagitis and maintaining remission from mucosal injury and symptoms. PPIs are unequivocally the most cost-effective pharmacologic agents for treating GERD and have become the mainstay of medical GERD management. The management plan should acknowledge that GERD is predominantly a chronic relapsing disorder in most patients and usually reoccurs once treatment is discontinued. Most patients with healed erosive esophagitis (80%-90%) relapse within 6 to 12 months without treatment. Most patients with nocturnal or extraesophageal manifestations of GERD are likely to require long-term maintenance therapy. Several guidelines have been published for the management of GERD. Current evidence lends support to initial therapy with a PPI once daily for 4 to 8 weeks. When initial therapy fails to control symptoms, either the diagnosis is incorrect or the chosen treatment has not been sufficiently effective. Treatment needs to be intensified if, on review of the patient, it is concluded that reflux disease is still the most likely diagnosis. Doubling the dose of PPI may be required. If severe erosive esophagitis (Los Angeles grade C or D) has been documented, full-dose PPI therapy is indicated. If symptoms resolve, stopping therapy can be considered, although the chances for relapse are present. This approach is not recommended in patients with severe erosive esophagitis. If symptoms persist despite PPI use, endoscopy followed by 24-hour esophageal pH monitoring should be considered. Factors associated with lack of response to PPIs include inadequate compliance or dosing, incorrect diagnosis, and nonacid reflux. The goal of long-term treatment is to step down management to the lowest level of medical therapy that controls symptoms. Recent data suggest that PPIs may be suitable for intermittent and on-demand therapy in patients with uncomplicated symptomatic GERD (NERD and Los Angeles grade A or B). This is not recommended in patients with severe esophagitis, complicated GERD (e.g., esophageal stricture, ulcer, or Barrett's esophagus), nocturnal GERD, or extraesophageal manifestations. Such therapy has been shown to be a cost-effective therapeutic option in symptomatic GERD patients, but patients who relapse should resume the dose that controlled their symptoms previously. The management algorithm is shown in Figure 2 .

FIGURE 2 Management pathway for patients with typical reflux symptoms. Abbreviation: PPI = proton pump inhibitor.

Other medications such as baclofen have been studied in the management of GERD. It acts by inhibiting transient LES relaxation via the -aminobutyric acid B receptor (GABA-B) and has been shown to reduce reflux. However, the side effects of this drug limit its application for treating GERD. SURGICAL MANAGEMENT Antireflux surgery augments the reflux barrier by a full or partial wrap of the gastric fundus (fundoplication) around the lower esophagus and can be performed laparoscopically. Recent reports confirm that laparoscopic antireflux surgery has similar outcomes to the open procedure. Antireflux surgery has an operative mortality rate of 0.5% to 1%; mortality is reduced with laparoscopic surgery and the experience of the surgeon.

Some patients managed with surgery still require acid-suppression therapy, and there is no convincing evidence that fundoplication reduces the risk of esophageal adenocarcinoma in the long term. Nevertheless, antireflux surgery may be appropriate for young, otherwise healthy patients in whom medical management is not tolerated or who refuse to take medications chronically. It is imperative to confirm a diagnosis of GERD before subjecting a patient to this procedure. Combinations of diagnostic tools like endoscopy, 24-hour pH monitoring, and manometry can identify patients who are likely candidates for surgery. ENDOSCOPIC ANTIREFLUX PROCEDURES Endoscopic techniques have been developed to treat GERD because long-term PPI therapy is expensive and does not affect the main abnormality in reflux disease: abnormal relaxation of the LES. Endoscopic procedures can be divided into three main approaches: endoscopic application of radiofrequency to the lower esophagus, suturing devices for the LES, and injection or implantation of inert material into the muscle layer of the distal esophagus. Results have been inconsistent with regard to symptom relief, PPI use, and effects on 24-hour pH results. Several endoscopic antireflux devices (Enteryx, Gatekeeper technique, endoscopic suturing device) have recently been withdrawn from the market for safety reasons or insufficient efficacy. Prolonged follow-up is required, and future devices and studies should be rigorously conducted with endpoints including efficacy, safety, and cost-effectiveness. Currently, these procedures are not advocated in routine practice. Complications Complications that could develop in GERD patients include esophageal strictures, esophageal ulceration, Barrett's esophagus, and rarely esophageal adenocarcinoma. Esophageal strictures ( Figure 3 ) and ulcers have a prevalence of approximately 0.1% and 0.05%, respectively. Both are associated with white race, male gender, and increasing age.

FIGURE 3 Esophageal stricture secondary to chronic gastroesophageal reflux disease.

Barrett's esophagus is an acquired condition resulting from chronic GERD and is a well-recognized premalignant condition leading to esophageal adenocarcinoma ( Figure 4 ). It is estimated that 10% to 15% of patients with GERD have Barrett's esophagus. It is characterized by a metaplastic transformation of the squamous epithelium to a columnar type highlighted by the presence of goblet cells appreciated on histologic evaluation. The condition entails a 30- to 50-fold greater risk of developing esophageal adenocarcinoma and has an incidence of development of adenocarcinoma that approaches 0.5% annually.

FIGURE 4 Endoscopic image of Barrett's esophagus.

Endoscopic screening of patients with chronic GERD symptoms has been proposed as a method for detecting Barrett's esophagus and early cancer. Patients with Barrett's esophagus are then typically enrolled in surveillance programs to monitor the lesion for progression. Although data in support of screening and surveillance are lacking, the practice is widespread and endorsed by many international gastroenterologic societies, with the ultimate aim of preventing deaths from esophageal adenocarcinoma. Epidemiologic studies suggest that patients with more frequent, severe, and long-lasting symptoms of reflux are at the greatest risk for development of Barrett's esophagus.



REFERENCES Donnellan et al., 2004. Donnellan C, Sharma N, Preston C, Maoayyedi P: Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2004; 4:CD003245. DeVault et al., 2005. DeVault KR, Castell DO, American College of Gastroenterology : Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190200. Dent et al., 2004. Dent J, Armstrong D, Delaney B, et al: Symptom evaluation in reflux disease: Korkshop background, processes, terminology, recommendations, and discussion outputs. Gut 2004; 53(suppl 4):iv1iv24. Kaltenbach et al., 2006. Kaltenbach T, Crockett S, Gerson LB: Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006; 166(9):965971. Klinkenburg-Knol et al., 1987. Klinkenburg-Knol EC, Jansen JM, Festen HP, et al: Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987; 1:349-351. Lagergren et al., 1999. Lagergren J, Bergström R, Lindgren A, Nyrén O: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340:825-831. Lundell et al., 1999. Lundell LR, Dent J, Bennett JR, et al: Endoscopic assessment of oesophagitis: Clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45:172-180. Sampliner and Practice Parameters Committee of the American College of Gastroenterology, 2002. Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology : Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol 2002; 97:1888-1895. Shaw et al., 2001. Shaw MJ, Talley NJ, Beebe TJ, et al: Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001; 96:52-57. Spechler et al., 2001. Spechler SJ, Lee E, Ahnen D, et al: Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: Follow-up of a randomized controlled trial. JAMA 2001; 285:2331-2338. Vakil et al., 2006. Vakil N, van Zanten SV, Kahrilas P, et al: The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. Am J Gastroenterol 2006; 101:1900-1920. Wiklund et al., 2006. Wiklund I, Carlsson J, Vakil N: Gastroesophageal reflux symptoms and well-being in a random sample of the general population of a Swedish community. Am J Gastroenterol 2006; 101:18-28.



Chapter 139 – Tumors of the Stomach

Method of: Scott A. Hundahl, MD Gastric Adenocarcinoma From earliest cancer registry activity through World War II, adenocarcinoma of the stomach ranked number one among solid organ neoplasms in the United States. Since that time, both incidence and mortality have declined. Worldwide, however, gastric adenocarcinoma remains a common neoplasm, eclipsed only by lung cancer in incidence and mortality. Several pathology classification schemes have been proposed for gastric adenocarcinoma, including the Borrmann morphologic classification, the Broder differentiation classification, the histologic World Health Organization (WHO) classification, the Nagayo-Komagome classification, the Ming classification, and the Goseki classification. None is more widely used than the 1951 Jarvi-Lauren (aka “Lauren”) classification, which divides gastric adenocarcinoma into intestinal-type (gland-forming tumors) and diffuse-type (discohesive) tumors. The Jarvi-Lauren classification, when combined with epidemiologic information, identifies three main histoepidemiologic patterns:

1.

Intestinal-type tumors arising from the distal stomach, associated with preexisting atrophic gastritis and intestinal metaplasia (Helicobacter pylori–associated),

2.

Diffuse-type tumors involving the body of the stomach (H. pylori–associated) but usually not associated with significant intestinal metaplasia, and

3.

Intestinal-type tumors of the gastroesophageal junction

In high-incidence regions of the world, such as Japan and Korea, up to two thirds of gastric adenocarcinomas are of the first type and are strongly associated with chronic multifocal atrophic gastritis and intestinal metaplasia from chronic H. pylori infection. The process usually begins at the antral-corpus junction along the lesser curvature and predisposes to cancers of the intestinal type occurring in the sixth and seventh decades of life. The second type of gastric adenocarcinoma, also associated with H. pylori, afflicts younger individuals in the fourth and fifth decades of life. The last type, seen in lower-incidence regions of the world, such as the United States, is associated with chronic gastroesophageal reflux and Barrett's esophagitis. It has been estimated that 42% of gastric adenocarcinomas worldwide can be attributed to chronic H. pylori infection. Strains containing the cagA gene appear more dangerous. The infection usually starts by the second or third decade and, unless successfully treated, gives rise to chronic inflammation, atrophic gastritis, and eventually intestinal metaplasia, which is a premalignant histologic condition. Dietary factors,

such as high-salt and high-nitrate intake, can accentuate this progression. As the condition progresses, acidproducing oxyntic mucosa is progressively eliminated, gastric pH increases, and bacterial overgrowth with non–H. pylori bacteria is facilitated. The original H. pylori, which requires an acid environment to thrive, often disappears at this point. Once intestinal metaplasia is established, dietary factors become particularly important in mitigating the risk of cancer development. Protective factors include intake of vitamin C, fresh fruits and vegetables, and antioxidants. The association of H. pylori infection with the development of intestinal metaplasia suggests that early detection and elimination of this infection might prevent gastric cancer. Unfortunately, in high-incidence areas, reinfection from contaminated water supplies and other sources is common, thus undermining the strategy. In addition, in prevention trials to date, any benefit is restricted to the subgroups without preexisting intestinal metaplasia. General risk factors for gastric cancer include low socioeconomic status, smoking, a diet deficient in fresh fruits and vegetables or high in salt-preserved, nitrate-laden foods, previous gastric ulcer, ionizing radiation, family history, and previous gastric resection. Blood group A is associated with higher risk of developing a diffuse-type tumor. Predisposing genetic conditions include the Lynch syndrome (i.e., hereditary nonpolyposis colorectal cancer, a condition with microsatellite instability due to deficient DNA repair enzymes) and, for diffuse tumors, specific germline mutations in the E-cadherin gene, as first detected in certain New Zealand Maori kindreds. In Western populations, by the time gastric cancer causes symptoms, the disease is often relatively advanced. In a large National Cancer Data Base survey of U.S. patients, presenting ascribable symptoms included weight loss (62%), abdominal/epigastric pain (52%), nausea (34%), anorexia (32%), early satiety (32%), dysphagia (26%), and melena (18%). Mass screening combining upper GI series, endoscopy, and serum pepsinogen I/II ratio have proven beneficial in high-incidence areas, such as Japan, but cannot be justified in the United States, where incidence is low. However, for defined risk groups, such as those with established atrophic gastritis and established intestinal metaplasia, a strong family history, or hereditary nonpolyposis colorectal cancer syndrome, surveillance screening should definitely be considered. In the United States, diagnosis is usually made by upper endoscopy. One should be aware that diffuse-type cancers presenting as linitis plastica are often associated with minimal visible mucosal changes, and deep biopsies are often required for establishing the diagnosis. Furthermore, small, “early” gastric cancers (“early” defined by the Japanese as in situ and T1 cancers, with or without node involvement) can be associated with particularly subtle mucosal changes, presenting a challenge for even the most experienced endoscopist. Extent-of-disease studies for gastric adenocarcinoma include endoscopic ultrasound, which is good for estimating depth of tumor and visualizing immediately adjacent nodes, and helical CT scanning, which is good for evaluating extraluminal extent of disease, intra-abdominal and/or mediastinal extension/spread, and liver/lung metastases. Because even high-resolution CT scanning can miss small peritoneal implants, extraregional nodal spread, and small liver metastases, staging laparoscopy and minilaparotomy are valuable adjuncts and should be considered mandatory if any preoperative treatment is considered.

CURRENT DIAGNOSIS Chronic Helicobacter pylori infection gives rise to atrophic gastritis and intestinal metaplasia, which predispose to cancer. Surveillance issue. Mucosal changes in diffuse-type gastric cancer presenting as linitis plastica can be minimal. Deep mucosal biopsies are required. Helical computed tomography, endoscopic ultrasound, and minilaparotomy or laparoscopy for pretreatment staging of gastric cancer. In early growth, gastrointestinal stromal tumors are rarely associated with mucosal changes.

CURRENT THERAPY For local-regional cancer, complete surgical resection remains the key component of curative treatment. Total gastrectomy and splenectomy/pancreatectomy should not be routine but performed only when required for negative-margin resection. Surgical goal with respect to node dissection for cancer is a low Maruyama index operation (see references). For fit patients with good postoperative caloric intake, postoperative adjuvant chemoradiation is considered standard for all but stage IA cases. Node dissection is not required for gastrointestinal stromal tumors. Although a long-established, much-modified Japanese staging system, the “General Rules,” finds widespread use in many areas of the world, the American Joint Committee on Cancer and the Union Internationale Contre le Cancer (AJCC/UICC) TNM system is by far the dominant staging system used. T stage is defined a bit differently than for colorectal cancer: muscularis propria penetration short of serosal penetration is still considered T2 disease; a serosal breach is required for T3 disease; and a T4 designation requires direct involvement of adjacent structures. Optimally accurate nodal “N” designation requires that more than 15 nodes be examined by the pathologist. N1 disease means metastases in one to six regional nodes, N2 disease means metastases in 7 to 15 regional nodes, and N3 disease means metastases in more than 15 nodes. Any N3 disease, any node-positive T4 disease, any M1 distant metastatic disease, and any involved extraregional M1 nodes translate in the staging matrix to stage IV disease. The reader is referred to the AJCC staging manual referenced at the end of this article. Curative treatment of gastric cancer involves, as main therapy, complete negative-margin surgical resection of disease. Various experts have shown endoscopic mucosal resection and minimally invasive techniques to be appropriate for some selected in situ and T1 tumors, but most tumors in the United States are discovered at a stage where formal open surgery is required. To secure a negative intramural margin of resection, a gross margin of 2 cm is usually adequate for exophytic, noninfiltrating tumors, and a margin of at least 6 cm of grossly normal tissue is recommended for ulcerated or infiltrating tumors or diffuse histology. Closest mural margins are generally checked by frozen section at the time of surgery to confirm adequacy of resection. Total gastrectomy is not indicated as a routine procedure, except in linitis plastica, but is

warranted whenever required for a negative-margin resection. Routine splenectomy for treatment of gastric cancer, as well as routine distal pancreatectomy (performed in the past to clear splenic nodes), should be avoided unless definitely required for complete resection of visible/palpable disease. The extent of lymph node dissection in this disease has generated—and continues to generate—international controversy. Although several prospective, randomized trials of non-Asian populations—none perfect—fail to demonstrate that routine extensive lymphadenectomy increases survival, insufficient lymphadenectomy has also been shown to definitely compromise survival. A prospectively planned analysis of a large U.S. adjuvant chemoradiation trial and a blinded reanalysis of a large Dutch surgical trial have shown that the adequacy of lymphadenectomy for a given case can be quantified using the “Maruyama index of unresected disease” (the Maruyama index), and that this measure independently correlates with survival in a “dose-response” proportional fashion. Prospectively using the Maruyama Computer Program to predict the extent of nodal spread for a given cancer case is one way to assure a low Maruyama index surgical resection. Sentinel node biopsy, an established technique for treatment of other cancers, has failed to win support for cancer of the stomach, because of the organ's lymphatic complexity and the relatively high reported falsenegative rates. A large North American prospective, randomized trial of postoperative adjuvant 5-fluorouracil (5-FU)–based chemoradiation in completely resected gastric cancer revealed a significant increase in disease-free and overall survival with this treatment. The postoperative nature of this trial thwarted implementation of surgical guidelines, and the extent of node dissection for most patients in the trial was minimal, with survival compromise for such patients demonstrated. Practitioners in some countries, such as Japan, dismiss the necessity of adjuvant postoperative adjuvant chemoradiation with the (unproven but reasonable) argument that this is only a salvage technique for inadequate surgery. A separate Korean chemoradiation series has shown benefit even for radically treated cases, however. For patients with good postoperative performance status, good organ function, and adequate nutrition, postoperative adjuvant chemoradiation therapy is considered standard in North America. Recently, survival data from a U.K. study of preoperative plus postoperative epirubicin, cisplatinum, and continuous-infusion 5-FU (ECF) chemotherapy versus surgery alone have shown encouraging results. However, results of other preoperative chemotherapy studies have been negative. This approach, although promising, is still considered investigational in North America. In Korea, a positive trial of adjuvant perioperative intraperitoneal chemotherapy has been reported. Considerable morbidity and mortality are associated with this adjuvant treatment, however, and this therapy likely will not be implemented without refinement and independent duplication of results. For localized disease deemed not resectable to negative margins, chemotherapy and chemoradiotherapy have been used to convert such tumors to potentially resectable status. With successful, negative-margin resection, some of these patients survive long term. Without any surgery, administration of 5-FU–based

concomitant chemoradiotherapy to patients with residual, unresected local-regional disease can also result in some degree of 5-year survival (reported in excess of 10%). Other Gastric Tumors Gastrointestinal stromal tumors (GISTs) present as submucosal spindle cell tumors in the sarcoma family. In contrast to leiomyosarcomas and other spindle cell sarcomas, they express the antigen CD117 and most (>80%) tumors have activating mutations of c-kit. Formerly considered rare, approximately 5000 of these tumors per year are now diagnosed in the United States. Owing to the pattern of growth in the gastric wall, deep to the mucosa, early symptoms are unusual, and these tumors will often grow to massive size before mucosal ulceration and hemorrhage (or other major symptoms) finally develop. GISTs are classified as sarcomas. Treatment of localized primary tumors consists of complete surgical resection, which usually can be accomplished with a 2-cm margin of grossly normal tissue. Specific lymph node dissection is not indicated for this histology. Surgical series indicate that approximately 50% of primary gastric tumors will metastasize and recur within 5 years, with risk factors including size greater than 5 cm and more than one mitosis per high-power field. For patients with widespread metastases, generally located in the peritoneal cavity or the liver, first-line therapy is now the well-tolerated oral agent imatinib mesylate (Gleevec or STI571) at an initial dose of 400 mg daily, which generates partial responses in more than 50% of cases and stable disease in an additional 25% of cases. Side effects are minimal, and 1-year survival in treated patients is approximately 85%. Carcinoid tumors of the stomach have a similar behavior to small-bowel carcinoids. When small (i.e., 100, attenuated 20-100)

•

Not based on family history

•

At-risk relatives identified for FAP if one or more adenomas are found before age 50 years or with extracolonic manifestations

•

Genetic testing is useful if FAP is an attenuated form or if diagnosis is unclear (80% FAP patients test positive for a genetic marker)

Abbreviations: FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colon cancer.

Familial adenomatous polyposis is more easily diagnosed than HNPCC (see Box 1 ). More than 100 adenomatous polyps must be present in the colon, and diagnosis does not depend on family history. Severe polyposis may be found (>1000 polyps) or an attenuated FAP variant (20-100 polyps). Unfortunately, the development of colorectal cancer is certain. Patients also suffer from noncolorectal manifestations, such as osteomas and desmoid tumors in Gardner's syndrome, brain tumors in Turcot's syndrome, and duodenal adenomas. Less stringent criteria are used to diagnose at-risk relatives: one or more polyps found at early age (130/80 on = 3 occasions (whichever is lower)

Above, plus pharmacologic therapy titrated to achieve target BP

Note: Urine collection should not be performed following vigorous exercise, during an acute infection, during a female patient's menstrual cycle, or following an episode of severe hypoglycemia. Once angiotensin-converting enzyme (ACE) inhibitor is started, microalbumin excretion should be monitored q3–6 mo. Target BP is 85th percentile, or weight >120% of puberty occurs at a ideal for height younger age

Frequency Method q2y

Fasting plasma glucose

Plus 2 of the following risk factors: Family history of T2D in 1st- or 2nd-degree relative Race/ethnicity (American Indian, African American, Hispanic, Asian/Pacific Islander) Signs of or conditions associated with insulin resistance (acanthosis nigricans, PCOS, HTN, dyslipidemia) Adapted from American Diabetes Association: Type 2 diabetes in children. Diabetes Care 2000;23(3):381-389. Note: Clinical judgment should be used to test for diabetes in high-risk patients who do not meet these criteria. Abbreviations: BMI = body mass index; T2D = type 2 diabetes; HTN = hypertension; PCOS = polycystic ovarian syndrome.

As noted earlier, the diagnosis of T2D is based on fasting plasma glucose (FPG), 2-hour glucose value during an OGTT, or a casual glucose level. Because T2D often goes without symptoms, individuals who are overweight, have a positive family history of T2D, come from one of the high-risk racial and ethnic minority groups, and/or have markers of insulin resistance warrant screening for T2D. Screening can be performed with a FPG or OGTT when clinical concerns are high and the FPG is normal. Currently one oral medication is approved for the treatment of T2D in youth. This medication is metformin (Glucophage), which is also available in a liquid formulation. The maximum recommended daily dose of metformin (Glucophage) in youth is 2000 mg/day divided as 1000 mg twice daily. Often patients with T2D present in ketoacidosis and require initial insulin therapy. The goal of management of the child with T2D is initial stabilization often with insulin therapy, metformin (Glucophage) directed at managing the insulin resistance, and education. Once glucose levels are stabilized, insulin dosage may be lowered along with continued treatment with metformin (Glucophage) and approaches to lifestyle management. Lifestyle

management involves a healthy diet, increasing exercise, and decreasing sedentary behaviors. Other medications used to treat T2D include second-generation sulfonylureas, meglitinides, thiazolidinediones, and a-glucosidase inhibitors, none of which is currently approved for use in pediatric patients. There is ongoing studies to assess the efficacy and safety of these medications ( Table 6 ).

TABLE 6 -- Medications to Treat Type 2 Diabetes Class Mechanism of Action Biguanides (metformin)[*]

Sulfonylureas (glimepiride, glyburide, glipizide)

Adverse Effects

Decrease hepatic glucose production

Gastrointestinal upset

Increase peripheral glucose disposal

Lactic acidosis

Insulin secretagogues

Hypoglycemia Weight gain

Meglitinides (repaglinide, nateglinide)

Insulin secretagogues

Hypoglycemia Weight gain

a-Glucosidase inhibitors (acarbose)

Decrease gut carbohydrate absorption

Gastrointestinal upset

Thiazolidinediones (rosiglitazone and pioglitazone)

Decrease hepatic glucose production

Weight gain

Increase peripheral glucose disposal

Edema Increased liver enzymes Anemia

* Metformin (Glucophage) is the only medication with FDA approval for use in children.



REFERENCES American Diabetes Association, 2005. American Diabetes Association : Diagnosis and classification of diabetes mellitus. Diabetes Care 2005; 28(Suppl 1):S37-S42. American Diabetes Association, 2000. American Diabetes Association : Type 2 diabetes in children. Diabetes Care 2000; 23(3):381-389. Barroso, 2005. Barroso I: Genetics of type 2 diabetes. Diabet Med 2005; 22:517-535. Dunger et al., 2004. Dunger DB, Sperling MA, Acerini CL, et al: ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004; 89:188-194. Fox et al., 2005. Fox LA, Buckloh LM, Smith SD, et al: A randomized controlled trial of insulin pump therapy in young children with type 1 diabetes. Diabetes Care 2005; 28:1277-1281. Glaser et al., 2001. Glaser N, Barnett P, McCaslin I, et al: The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med 2001; 344(4):264-269. Goodwin et al., 2006. Goodwin G, Volkening LK, Laffel LM: Younger age at onset of type 1 diabetes in concordant sibling pairs is associated with increased risk for autoimmune thyroid disease. Diabetes Care 2006; 29(6):1397-1398. Hannon et al., 2005. Hannon TS, Rao G, Arslanian SA: Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005; 116(2):473-480. Hirsch, 2005. Hirsch IB: Insulin analogues. N Engl J Med 2005; 352:174-183. Laffel et al., 2003. Laffel LM, Vangsness L, Connell A, et al: Impact of ambulatory, family-focused teamwork intervention on glycemic control in youth with type 1 diabetes. J Pediatr 2003; 142(4):409-416. Rosenbloom, 2005. Rosenbloom AL: Cerebral edema in diabetic ketoacidosis and other acute devastating complications: Recent observations. Pediatr Diabetes 2005; 6:41-49. Silverstein et al., 2005. Silverstein J, Klingensmith G, Copeland K, et al: American Diabetes Association: Care of children and adolescents with type 1 diabetes. Diabetes Care 2005; 28(1):186-212. Wysocki et al., 2003. Wysocki T, Harris MA, Mauras N, et al: Absence of adverse effects of severe hypoglycemia on cognitive function in school-aged children with diabetes over 18 months. Diabetes Care 2003; 26(4):1100-1105.



Chapter 144 – Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome

Method of: Robert A. Kreisberg, MD Elizabeth D. Ennis, MD Hyperglycemic crisis includes the disorders of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar syndrome (HHS). They are often severe and life threatening, requiring prompt and appropriate therapy. Both are characterized by hyperglycemia and moderate to severe deficits of water, electrolytes, and minerals. They differ in the severity of the hyperglycemia and ketoacidosis and in the deficits of water and electrolytes. Patients often have features of both syndromes so that classification as one or the other might not be possible ( Figure 1 ). Successful treatment of these disorders requires an understanding of their pathophysiology, appropriate use of insulin, correction of volume and electrolyte deficiencies, and a compulsive approach to patient management. Although mortality from hyperglycemic crisis may be declining, there are still about 2500 deaths per year attributable to these disorders, with an overall age-adjusted rate of 23.8 per 100,000 people with diabetes. The profiles of patients with DKA and HHS have changed. Although many with DKA continue to be young patients with type 1 diabetes (T1DM), a new group of patients with DKA has emerged. Many patients from minority ethnic groups who have type 2 diabetes (T2DM) present with DKA (a presentation sometimes referred to as type 1.5 diabetes). This group constitutes as much as 40% to 50% of minority patients with DKA and is characterized by severe obesity. After recovering from decompensated diabetes, these patients can often achieve subsequent control with diet, with or without oral agents. The average age for DKA is 43 years, emphasizing the changing demographics of this disorder. Young patients can also present with HHS.

FIGURE 1 Severity of hyperglycemic and ketoacidosis in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS). Classic metabolic profiles are expressed at the extreme left and right of the diagram. A continuum of combinations of hyperglycemia and ketoacidosis is possible, which is consistent with the observation that approximately 33% of patients with decompensated diabetes mellitus have features of both syndromes. (Redrawn with permission from LeRoith D, Taylor SI, Olefsky JM: Diabetes Mellitus: A Fundamental and Clinical Text, 3rd ed. Lippincott Williams & Wilkins, 1996.)

Precipitating Factors Decompensated diabetes invariably occurs as a result of intercurrent illness, omission or discontinuation of insulin, or new-onset diabetes. Acute intercurrent illness is an important precipitant for both DKA and HHS. In the elderly with HHS it may be difficult to know if myocardial infarction, stroke, mesenteric thrombosis, intestinal obstruction, or other conditions are the cause of HHS or are the effect of the predisposition to thrombosis that occurs as a result of the severe hemoconcentration. Numerous drugs are associated with DKA and HHS, many of which include newer psychiatric agents. Thus, all medications should be reviewed for their potential to precipitate clinical diabetes mellitus or diabetic decompensation. Pathophysiology A relative or absolute deficiency of insulin, in the presence of increased levels of glucose counterregulatory hormones (cortisol, catecholamines, glucagon, and growth hormone) that occur with intercurrent illness,

stress, or just severely decompensated diabetes, sets the stage for DKA and for HHS. This loss of balance between insulin and glucagon coupled with predicted changes in glucose counterregulatory hormones leads to glycogenolysis, protein breakdown, gluconeogenesis, lipolysis, increased levels of free fatty acids, and ketogenesis. Free fatty acids released from adipose tissue and amino acids released from body protein stores provide the substrates for ketogenesis and gluconeogenesis. Hydrogen ion, due to ketoacid production, titrates bicarbonate and other body buffers, leading to acidosis. It is not entirely clear why patients with decompensated diabetes and HHS have less intense ketogenesis and milder ketoacidosis than those with DKA. The less severe ketoacidosis has been attributed to lower concentrations of glucose counterregulatory hormones, less severe insulin deficiency, and reduced responsiveness of tissues to insulin deficiency and glucose counterregulatory hormone excess as a consequence of age. DKA and HHS, often discussed as two separate entities, constitute ends of a continuum of severe diabetic decompensation and hyperglycemia (see Figure 1 ). Patients with severe decompensation can have features of both disorders. The older age of patients with HHS probably contributes to alterations in central nervous system (CNS) function. The sequence of events leading to presentation differs depending on the rates of ketogenesis. Those with accelerated ketogenesis (characteristic of DKA) quickly become acidemic, leading to an earlier presentation (usually within 1-3 days), because the acidosis makes them ill. If the rates of ketogenesis are low, the prodrome is more protracted (7-10 days), allowing greater water and electrolyte loss and the development of more severe hyperglycemia. In HHS there is greater hyperosmolality due to the very high glucose levels and to the normal or increased serum sodium levels. When the effective osmolality (Eosm) is 320 mOsm/L or more, mental function declines and patients are often lethargic, confused, obtunded, or comatose. Effective osmolality is calculated with the following equation:

where Na+ and K+ are in mEq/L and glucose is in mg/dL. Urea is omitted from the calculation, because urea is distributed in total body water and does not contribute to the osmotic gradient. The initial response to the increase in extracellular osmolality due to hyperglycemia is for intracellular water to follow the osmotic gradient and shift into the extracellular compartment. This accounts for the mild hyponatremia characteristic of DKA. This increase in the extracellular volume leads to an increase in glomerular filtration rate (GFR) and enhanced excretion of water in the urine due to the osmotic diuresis from glucosuria. The early presentation of patients with DKA dictates a smaller loss of free water. However, only about two thirds of patients with DKA have classic hyponatremia, and one third has normal or high serum sodium concentrations consistent with greater free water loss, which is characteristic of HHS. The evolution of changes in the serum sodium concentration in decompensated diabetes is dynamic and is influenced by the duration of the hyperglycemia and access to free water. Older patients, often in nursing homes, are at particular risk. It is no surprise that their water needs are often unmet as a consequence of an age-related blunting of thirst and their dependency on others to meet their free water requirements. As the duration of decompensation lengthens, the initial early shift of free water into the vascular compartment and resultant hyponatremia disappears and the serum sodium concentration returns to normal. When the

prodrome is prolonged there is volume contraction, reduced filtration, and excretion of glucose in the urine and the development of hypernatremia. The increased effective osmolality in HHS is primarily due to hyperglycemia, but hypernatremia can also contribute to this finding. The classic anion-gap acid-base abnormalities in DKA are due to the loss of bicarbonate and its replacement by ketoacid anions (acetoacetate and ß-hydroxybutyrate). However, many patients with DKA also have a hyperchloremic component, particularly if fluid intake has been maintained during the prodrome. This leads to enhanced filtration and loss of ketoacid anions in the urine and increased tubular reasborption of chloride. On admission, only about one half of the patients with DKA have a classic anion-gap acidosis and another 40% have a mixed acidosis (a combination of anion-gap ketoacidosis and hyperchloremic metabolic acidosis). In these patients the increase in the anion gap accounts for only 0.4 to 0.8 of the reduction in bicarbonate concentration. Classically, patients with HHS are much less acidemic (by definition, pH =7.30 and bicarbonate >15 mEq/L). Urinary ketones are only weakly positive and the degree of ketoacidosis is generally defined as mild. Often, the acidosis is attributed to coexisting renal dysfunction or lactic acidosis occurring in the setting of severe intravascular volume depletion. Relatively little is known about the extent of ketoacidosis in HHS because these patients often have concomitant metabolic alkalosis due to preceding treatment with diuretic agents and because the frequency of concomitant extreme hypovolemia compromises oxygen delivery, leading to lactic acidosis and preferential formation of ß-hydroxybutyrate. Because ß-hydroxybutyrate is not detected by the qualitative nitroprusside reagents used for detecting ketone bodies, the degree of ketoacidosis is often underestimated. Direct measurement of ß-hydroxybutyrate could be helpful in resolving this question and in the management of DKA. Diagnosis The diagnostic features of DKA and HHS are shown in Table 1 . The glucose concentration is not a defining characteristic of DKA. Euglycemic DKA (glucose 6.8 mg/dL), sudden fluctuations, up or down, of the serum urate level can provoke acute attacks of gout. Such fluctuations can be caused by many things including alcohol ingestion, starvation, fluid shifts during surgery, medications, and interventions specifically directed at lowering the serum urate level. Acute and Chronic Arthritis

Acute gouty arthritis typically occurs in men from the third decade onward and in postmenopausal women. However, due to the myriad of reasons, including genetic enzymopathies, that patients can become chronically hyperuricemic, it can occur in patients of both sexes at all ages. Generally, patients are exposed to several years of serum urate levels greater than 6.8 mg/dL before the first attack of gout. Initial attacks are often extremely acute in onset and are dramatic in terms of the degree of pain and signs of inflammation. Some patients recall multiple twinges of discomfort before the first attack. Initial attacks often involve the lower extremities, including the base of the great toe, midfoot, or knee, but virtually any joint, tendon sheath, or bursa can be involved. Attacks can occur during the night or first appear during the day, and it is not uncommon that patients attribute the first attack to twisting their ankle or stepping off a curb wrong and selfmedicate without seeing a physician. Attacks are self-limited; the initial attacks can last 3 to 10 days even without anti-inflammatory therapy. Perhaps 10% of patients do not have another attack for many years or never again. However, the overwhelming majority of patients experience recurrent attacks, although not necessarily at the same anatomic site. Over years, if hyperuricemia persists and the patient is not on an anti-inflammatory medication to prevent attacks, gouty flares can occur more frequently, involve more joints, and persist for longer periods if not treated. Tophaceous nodules, usually asymptomatic, can appear around joints, at areas of friction or microtrauma, and particularly within the olecranon bursae, along the ulnar aspect of the forearms, around bunions, along the Achilles tendons, and within the finger pads. Gout occasionally evolves into a chronic polyarthritis that is characterized by multiple deformed joints. There is often asymmetric joint involvement in these patients, with a nodular component to the joint swelling that is greater than that observed in rheumatoid arthritis. Involvement of the distal interphalangeal joints of the hands, particularly in postmenopausal women with osteoarthritis and Heberden's nodes, also distinguishes this from rheumatoid (but not psoriatic) arthritis. Chronic gouty polyarthritis tends to occur with less severe pain than acute attacks, but it has chronic discomfort, stiffness, and loss of joint mobility. Patients who have received organ transplants and are on chronic therapy with calcineurin antagonists (e.g., cyclosporine), are prone to develop particularly aggressive, rapidly progressing tophaceous gout. They can develop gout in the upper extremities, fingers, shoulders, and tendon sheaths earlier than is normally expected. Patients with acute gouty arthritis often have fever, especially if the attack involves more than a single joint. Although the pain may be more severe in gout, it is impossible to distinguish with certainty gout from septic arthritis (or pseudogout) on the basis of history, symptoms, physical findings, or laboratory results other than synovial fluid analysis and culture. The definitive diagnosis of gouty arthritis is made by identifying negatively elongating birefringent needleshaped crystals in the synovial fluid of an inflamed joint, with the exclusion of infection by fluid culture. Routinely, in the appropriate setting consistent with an acute gout attack in the absence of a concurrent or antecedent bacterial infection or exposure, the finding of urate crystals is sufficient to warrant specific treatment for crystal-induced arthritis. However, crystals can persist for years in joints that have been previously affected by a gout attack unless the serum urate has been lowered. These joints rarely become infected, with crystals still evident in the fluid. Thus, full clinical assessment is warranted, looking for any

clues that heighten concern for bacteremia or locally acquired bacterial infection. It is never inappropriate to send inflammatory synovial fluid for microbiological culture while treating the patient for gout based on a positive crystal analysis. If crystals are not seen, the diagnosis of gout should not be made until cultures return as negative and reaspiration identifies crystals. Although the first episodes of gout should be documented by synovial fluid analysis if at all possible, at times it may be impossible to aspirate fluid due to the location of the apparent attack (e.g., midfoot) or the logistics of the examination (patient refusal for reaspiration, dry aspirates, or inadequate equipment). In these cases, especially with a prior history of documented attacks of gout and no special concern for infection, it may be appropriate to treat empirically for crystal-induced arthritis, with close follow-up and communication with the patient.

CURRENT DIAGNOSIS Gouty arthritis is characterized by the acute onset of articular and/or periarticular pain accompanied by objective signs of inflammation. Initial attacks of gout are often monoarticular, in the lower extremities, self-limited, and very responsive to high-dose anti-inflammatory therapy. Diagnosis is ideally made by documenting the presence of urate crystals in the affected joint or bursal fluid. The serum urate level should not be relied on as a diagnostic test for acute gout. Hyperuricemia may be clinically significant when it is >6.8 mg/dL; this is the approximate level at which urate begins to precipitate in biological fluids. Some patients with years of inadequately treated gout develop chronically swollen painful arthritis and tissue deposits of uric acid (tophi), which can resemble rheumatoid arthritis. Hyperuricemia A longstanding asymptomatic serum urate level higher than 6.8 mg/dL is almost invariable in patients as a prodrome to gouty arthritis, and hyperuricemia is the strongest independent risk factor for the development of gout. However, the urate level may be lower than this at the time of an acute attack. This can occur either because something has transiently lowered the urate level (often a medication, crash diet, or intravenous fluid) and thus precipitated the attack, or cytokines such as interleukin-6 released during an acute attack have lowered the serum urate level due to effects on urinary excretion of uric acid. Whether hyperuricemia is an independent direct contributor to the risk of atherosclerotic cardiovascular disease (ASCVD) is controversial. Up until the past few years the prevalent perspective was that asymptomatic hyperuricemia is benign, and that the epidemiologic association of hyperuricemia with ASCVD was on the basis of shared comorbidities (diuretic use, hypertensive renal disease, insulinresistance syndromes, and high red meat Western diet). However, analysis of several large patient registries and the data from large ASCVD intervention trials using multiregression analyses suggest that hyperuricemia may be an independent risk factor for cardiovascular events. In parallel with these analyses there is increased recognition of potential pathophysiologic links between

urate levels and vascular disease. Data from a rat model of acute mild hyperuricemia strongly suggest a direct link between hyperuricemia and renin-related hypertension and endothelial dysfunction. Other studies, also in rats, indicate that dietary fructose–induced hyperuricemia can directly induce resistance to some of the effects of insulin, thus leading to the development of components of the metabolic syndrome. Hyperinsulinemia also can directly perpetuate hyperuricemia via suppression of renal uric acid excretion. At present there is not enough evidence or adequate interventional outcome data in humans to support the treatment of asymptomatic hyperuricemia with the hope of reducing cardiovascular events or progression of renal disease, congestive heart failure (CHF), or ASCVD. Treatment ANTI-INFLAMMATORIES The treatment of patients with gout can be conceptually and practically divided into three discrete areas: treating the acute attack, preventing the next attack with anti-inflammatory therapy (prophylaxis), and treating the underlying root cause of gout, hyperuricemia. Although the management of these three areas overlaps, it is useful to specifically address and periodically reevaluate each one at every gouty patient's visit. Acute gout can be extremely painful and can severely hamper the patient's ability to pursue normal activities. Fortunately, attacks respond fairly quickly to high-dose anti-inflammatory therapy. Pure analgesic therapy is less effective. Attacks generally respond to any one of several classes of medications; the choice of therapeutic agent is usually dictated by the patient's comorbidities ( Box 1 ) and relative contraindications to the different medications. Many experienced clinicians believe, although no controlled trials or high-quality observational data have been collected, that patients respond more rapidly to therapy the earlier in an attack that therapy is initiated. Thus, many clinicians advise patients who suffer from recurrent (documented) gout attacks to initiate therapy at the first twinge of what they recognize as an attack. Difficulty in completely resolving an acute attack is often the result of using a too-low dose of anti-inflammatory therapy, discontinuing it as soon as the patient begins to experience relief, or failing to recognize that changes in the serum urate level at the time of the attack can predispose the patient to rebound flares unless some form of continued anti-inflammatory therapy is provided. BOX 1

Therapy of Acute Gouty Arthritis •

Confirm the diagnosis by arthrocentesis if possible; exclude septic arthritis.

•

Avoid changes in drugs that affect the serum urate level, if possible.

•

Any nonsteroidal anti-inflammatory drugs (NSAIDs) may be prescribed in high doses. Relative and absolute contraindications include dyspepsia or prior history of treated PUD (can consider using with a PPI), renal insufficiency, thrombocytopenia or platelet dysfunction, recent gastric ulcer with bleed (absolute contraindication), coumadin therapy (strong contraindication), and uncontrolled CHF. Some options include: •

Indomethacin (Indocin) 50 mg tid (avoid in elderly patients, particularly gastric toxic; decreases renal blood flow and increases confusion in the elderly)

•

Diclofenac (Voltaren) 75 mg bid or 50 mg tid

•

Naproxen (Naprosyn) 500 mg bid

•

Ibuprofen (Motrin) 600-800 mg qid (can negate effect of cardioprotective aspirin)

•

Celecoxib (Celebrex) 200-400[1] mg bid (off label at the higher dose; has no antiplatelet effect; not totally GI safe)

•

Colchicine 0.6 mg hourly until relief or GI intolerance, maximum 6 pills. Not generally recommended since diarrhea is extremely common with this regimen. Avoid in setting of renal insufficiency or biliary dysfunction.

•

Corticosteroids can be given by oral, parenteral, or intra-articular route, for example: •

Prednisone 40-60 mg PO once daily until several days of total relief, then slow taper to off (or to baseline dose) over 10 d

•

Methylprednisolone 40-60 mg IV or IM daily as above.

•

ACTH (corticotropin) 40 IU q12-24h as above.

•

Intraarticular methylprednisolone acetate (Depo-Medrol 80 mg/mL) 80 mg into a knee, 8-16 mg into first MTP, 40 mg into ankle or wrist.

1Exceeds

dosage recommended by the manufacturer.

Abbreviations: CHF = congestive heart failure; GI = gastrointestinal; MTP = metatarsophalangeal joint; NSAID = nonsteroidal anti-inflammatory drug; PPI = proton pump inhibitor; PUD = peptic ulcer disease.

Likely, a full dose of any nonsteroidal anti-inflammatory drug (NSAID) will be effective. Some response may be noticeable at 4 to 6 hours after the first dose. Treatment ideally should be continued until several days after the attack has completely resolved. Concerns with using NSAID therapy in this fashion include gastric damage, potentially serious interactions with medications (warfarin, diuretics, aspirin, and nephrotoxins), decreased renal blood flow, fluid retention, and confusion (indomethacin). Cotreatment with a proton pump inhibitor (PPI) should provide some gastric

protection, but this protection is likely insufficient to permit NSAID use in the setting of a recent bleed or gastric ulcer. Parenteral administration of an NSAID offers no safety advantage. A selective COX-2 NSAID (etoricoxib)[2] has been shown to be effective, and thus high-dose celecoxib (Celebrex) will also likely be effective. Celecoxib, because it does not affect platelet function, may have some safety advantage in the patient at risk for bleeding due to recent surgery or reduced platelet number or function. Gastric safety advantage in this setting has not been evaluated; it has no renal safety advantage.

CURRENT THERAPY Acute gouty arthritis responds to treatment with high-dose anti-inflammatory therapy: nonsteroidal anti-inflammatory drugs, systemic corticosteroids, intraarticular corticosteroids, or colchicine. Choice of therapy for acute gout must take into consideration the patient's specific comorbidities and potential drug side effects and interactions. The serum urate level should not be manipulated at the time of an acute attack. The serum urate level is most effectively treated with drugs inhibiting xanthine oxidase (i.e., allopurinol), which should be titrated to a dose that decreases the serum urate to 6.8 mg/dL) is necessary for gout to develop, and because chronic reduction of the serum urate to levels below this have been shown to reduce the frequency of gout attacks and detectable urate deposits (tophi), it is reasonable to consider hypouricemic therapy in all patients with gout. However, because some significant complications are associated with hypouricemic therapy (800 mg on a standard diet). Allopurinol, a xanthine oxidase inhibitor of urate synthesis, is generally used to lower the level of serum urate.

There is no set dose of allopurinol. As with the use of antihypertensive medications, which are dosed based on the target BP response, allopurinol dosing should be adjusted to reach the target urate level (often recommended at approximately 6 mg/dL). In clinical practice, it has been inappropriately assumed that 300 mg is the correct dose of allopurinol; however only 20% to 47% of patients (in different studies) attain an appropriately lowered serum urate level with 300 mg dosing. Guidelines have been offered suggesting that the dose of allopurinol should be reduced based on renal function; however, this is an opinion based recommendation based on drug levels, not on prospective dosing observational studies. It is reasonable to initiate allopurinol at a dose of 50 to 100 mg/day, checking the serum urate and increasing the dose of allopurinol by 100-mg increments every 3 to 4 weeks (still in once-daily dosing). Unfortunately, in many practices it seems that urate levels are not repetitively measured and allopurinol doses are not adjusted; in one study, doses were appropriately measured and adjusted in less than 30% of patients! Allopurinol labeling permits dosing to 800 mg daily, but many clinicians increase the dose above this if necessary in select patients, with appropriate monitoring for any safety concerns. In patients taking allopurinol, any new rash must be promptly evaluated because a rare but potentially lifethreatening complication of therapy with this drug is the Stevens-Johnson reaction. Rare patients also develop a systemic hypersensitivity reaction (fever, hepatitis, vasculitis, rash, and eosinophilia). Extreme care must be exercised when starting allopurinol in patients taking azathioprine, because the active metabolite of azathioprine can rapidly increase and cause toxicity. Patients started on any hypouricemic therapy are at high risk for developing an acute attack of gout; this can occur in about 30% of patients, accompanying the acute lowering of serum urate level. Thus, it is appropriate before lowering the urate level to initiate a prophylactic anti-inflammatory regimen to protect against an acute gout attack. Colchicine 0.6 mg once or twice daily is a commonly used regimen, NSAIDs can also be used; the choice should be dictated by patient tolerance and comorbidities. Prophylaxis should be continued for many months, if tolerated. Twenty-four-hour urine collections are used to detect patients with increased production of urate as the etiology for their hyperuricemia. Hyperproduction as the primary contributor to hyperuricemia is rare (enzymopathies) in the absence of readily recognized proliferative disorders. Unless a uricosuric agent is to be used as the primary hypouricemic drug, a 24-hour collection is not usually required because allopurinol is equally effective in the setting of hyperproduction or inefficient uric acid excretion (likely >90% of the time). If a 24-hour collection is required, it can be done on a standard diet, but should be done at least twice. If hyperproduction is documented, collection should be repeated while the patient is on a purine-restricted diet. Losartan (Cozaar),[1] an angiotensin receptor blocker, has some uricosuric activity, as does fenofibrate (Tricor)[1]; these medications can be useful adjuncts in appropriate patients. In rare patients with extremely severe tophaceous gout and in whom traditional therapy is not tolerated or inefficacious, intravenous uricase therapy is available (rasburicase [Elitek]) off label, but it might not be tolerated on repeat dosing. Current trials are under way with pegylated uricase [5] preparations that may be tolerated on a chronic intermittent basis. These drugs can drop the serum urate to less than 1 mg/dL and dramatically dissolve urate deposits.

Education is a critically important part of the management of gouty arthritis. Once gouty arthritis has been confirmed, patients should know to take an anti-inflammatory medication (NSAID; steroid; colchicine tablets taken one per hour up to a predefined number that does not cause diarrhea in the patient) at the first sign of an attack. Patients and their physicians should recognize the risk factors for gout (beer and mineral spirit ingestion, excess weight, eating a diet with high nonvegetable purine content), and hospitalization for surgical or medical problems. Current data indicate that hyperuricemia and gout are strongly associated with ASCVD and the metabolic syndrome. Although insufficient information exists to warrant hypouricemic therapy in an effort to reduce this risk, at the least the diagnosis of gout warrants a full evaluation for, and aggressive treatment of, known modifiable risk factors including diabetes, hyperlipidemia, hypertension, smoking, and physical inactivity. 1 Not FDA approved for this indication. 5 Investigational drug in the United States.



REFERENCES Baker et al., 2005. Baker JF, Krishnan E, Chen L, Schumacher HR: Serum uric acid and cardiovascular disease: Recent developments, and where do they leave us?. Am J Med 2005; 118:816-826. Becker et al., 2005. Becker MA, Schumacher HP, Wortmann RL, et al: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353:2450-2461. Borstad et al., 2004. Borstad GC, Bryant LR, Abel MP, et al: Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004; 31:2429-2432. Choi et al., 2005. Choi HK, Mount DB, Reginato AM: Pathogenesis of gout. Ann Intern Med 2005; 143:499516. Craig et al., 1994. Craig MH, Poole GV, Hauser CJ: Postsurgical gout. Am Surgeon 1994;56-59. Hande et al., 1984. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984; 76:47-56. Johnson et al., 2005. Johnson RJ, Feig DI, Herrera-Acosta J, Kang D-H: Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005; 45:18-20. Nakagawa et al., 2006. Nakagawa T, Hu H, Zharikov S, et al: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006; 290:F625-F631. Nuki, 2006. Nuki G: Treatment of crystal arthropathy—history and advances. Rheumatic Dis Clin North Am 2006; 32:333-357. Sarawate et al., 2006. Sarawate CA, Brewer KK, Yang W, et al: Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc 2006; 81:925-934. Stamp et al., 2005. Stamp L, Searle M, O'Donnell J, Chapman P: Gout in solid organ transplantation: A challenging clinical problem. Drugs 2005; 65:2593-2611.



Chapter 147 – Dyslipoproteinemias

Method of: Peter P. Toth, MD, PhD The complications of atherosclerotic disease remain the number one cause of death and disability for men and women in industrialized nations. Atherosclerosis is a complex, chronic disease with a multifactorial etiology. Considerable investigation demonstrates an unequivocal relationship between disturbances in cholesterol and lipoprotein metabolism and risk for atherogenesis within the coronary, peripheral, renal, and cerebral vasculature. Dyslipoproteinemias frequently develop in response to genetic and environmental factors and are modifiable through pharmacologic intervention and lifestyle changes. As demonstrated in the Framingham Study, Multiple Risk Factor Intervention Trial and the Seven Countries Study, when serum levels of cholesterol increase, the lifetime risk for developing coronary artery disease (CAD) rises steadily. Consequently, cholesterol is one of the most important endogenous and exogenous toxins that humans are exposed to. The identification and aggressive management of dyslipidemias in both the primary and secondary prevention settings is pivotal to continued efforts to significantly reduce the prevalence of atherosclerotic disease and its clinical sequelae in populations throughout the world. Lipoprotein Metabolism and Atherogenesis Although it is pathogenic, cholesterol is also a critical modulator of cell membrane fluidity and is a precursor for steroid hormone biosynthesis. Consequently, a pool of cholesterol must be available for a variety of physiologic functions. Cholesterol, monoglycerides, free fatty acids, and phospholipids are absorbed from micelles in the intestinal lumen via a series of translocators located within the brush border of jejunal enterocytes. Absorbed cholesterol and lipid are assimilated with apolipoprotein (apo) B48 into chylomicrons. Chylomicrons are released into the lymph and ultimately transported to the central circulation via the thoracic duct. In serum, the triglycerides in chylomicrons are hydrolyzed by lipoprotein lipase. This lipolytic reaction produces chylomicron remnant particles that are taken up by the low-density lipoprotein (LDL) receptorrelated protein and metabolized by the liver. The liver secretes very-low-density lipoprotein (VLDL), a lipoprotein enriched with triglycerides, cholesterol, and apoprotein B100. As the triglycerides in VLDL are hydrolyzed by lipoprotein lipase, the size of the lipoprotein particle decreases, eventually forming LDL. LDL particles are concentrated with cholesterol and cholesterol esters and relatively depleted of triglycerides. As the VLDL is progressively converted to LDL, it releases constituents from its surface coat (apoproteins AI, AII, and phospholipids) that are used to form high-density lipoprotein (HDL) in serum. Patients with hypertriglyceridemia can have elevations in either serum chylomicron or VLDL levels, or both. Patients who consume very high fat diets or who are hyperabsorbers of dietary fat can be hyperchylomicronemic. In contrast, patients with excessive fat storage depots (most notably visceral adiposity) can develop elevated VLDL. Naturally occurring mutations in lipoprotein lipase and an insulinresistant state can yield hypertriglyceridemia secondary to reduced lipolysis of chylomicrons and VLDL. Reduced lipolysis results in the formation of incompletely digested chylomicrons and VLDL, or “remnant particles” that are widely believed to be atherogenic. Patients with hypertriglyceridemia tend to have reduced serum levels of HDL because:

•

There is a decreased release of surface coat constituents from chylomicrons and VLDL.

•

As HDL becomes progressively more enriched with triglyceride, it becomes a better substrate for hepatic lipase, an enzyme that catabolizes HDL.

Serum VLDL remnant particles and LDL function as delivery vehicles of cholesterol to peripheral tissues, including blood vessel walls. These lipoproteins are atherogenic because they can traverse the endothelial cell barrier. Macrophages resident within the subendothelial space exposed to LDL oxidized by such enzymes as lipoxygenase or myeloperoxidase upregulate the expression of scavenger receptors (SR-A, CD36) on their surface and actively take up excessive amounts of cholesterol. This process promotes foam cell and fatty streak development—events that precede atheromatous plaque formation. The activation of macrophages also promotes an inflammatory response with the elaboration of cytokines, interleukins, Creactive protein, cell mitogens, matrix metalloproteinases, and reactive oxygen species that facilitate lesion progression and instability. LDL and VLDL remnants not taken up by peripheral tissues can be cleared from the circulation by hepatic LDL receptors. Therapies targeted at the upregulation of hepatic LDL receptors are antiatherogenic by virtue of their ability to reduce circulating levels of atherogenic lipoproteins. HDL particles appear to protect the vasculature from progressive injury and atherogenesis. With few exceptions, in prospective epidemiologic and case-control studies conducted throughout the world, high HDL levels are protective against the development of CAD. For instance, patients with familial hypoalphalipoproteinemia (low HDL) have increased risk for premature CAD, whereas patients with familial hyperalphalipoproteinemia are relatively resistant to atherosclerotic disease. In contrast to LDL, which promotes cholesterol delivery to, and uptake by, vessel wall macrophages, HDL extracts excess cellular cholesterol and delivers it back to the liver for elimination through the gastrointestinal tract in a process referred to as “reverse cholesterol transport.” HDL does the following: •

Reduces endothelial cell adhesion molecule (vascular cell adhesion molecule-1, intercellular adhesion molecule-1) expression

•

Augments endothelial nitric oxide and prostacyclin production

•

Reduces oxidized fatty acid components of LDL

•

Decreases platelet aggregability

•

Inhibits endothelial cell apoptosis

Recent studies suggest that among the elderly, low HDL is a better predictor of risk for cardiovascular disease than is high LDL. An HDL greater than 60 mg/dL is a negative risk factor. The higher the level of serum HDL, the lower the risk for CAD. Therapeutic maneuvers should not be undertaken to reduce circulating levels of HDL. Identification of Lipoprotein Targets Dyslipoproteinemias constitute a highly prevalent and heterogeneous class of disorders. Derangements in circulating levels of specific lipoprotein classes can be the result of abnormalities in gastrointestinal absorption, enzyme activities, and/or receptor expression. A complete fasting (12 to 14 hours) lipoprotein profile should be obtained from any patient being evaluated for dyslipidemia. Because of the relationship between specific lipoprotein fractions and risk for CAD, a total cholesterol level has little practical clinical utility.

The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) has systematically defined risk-stratified target levels for atherogenic serum lipoproteins based on the best available evidence to date ( Table 1 ). Risk stratification is performed by evaluating a patient's cardiovascular risk factor burden (number of risk factors) and, if two or more risk factors are present, calculation of the Framingham risk score. Among patients being treated for primary prevention, low risk is defined as a 0-1 risk factor. Moderate and moderately high risk are defined as 2 or more risk factors and a 10-year Framingham risk of less than 10% and 10% to 20%, respectively. In the high-risk category, patients either have CAD (defined as a history of myocardial infarction [MI], stable/unstable angina, revascularization with coronary artery bypass grafting, or percutaneous angioplasty) or a CAD risk equivalent (defined as diabetes mellitus, peripheral vascular disease, significant carotid artery disease [transient ischemic attack or stroke from carotid origin or greater than 50% obstructive atheromatous plaque in a carotid artery], abdominal aortic aneurysm, and a 10-year Framingham risk that exceeds 20%). Among patients with multiple risk factors and no history of CAD or a CAD risk equivalent, it is important to calculate the Framingham risk score so as to differentiate moderate, moderately high, and high risk. An electronic version of a Framingham risk calculator for men and women can be downloaded at www.nhlbi.nih.gov/guidelines/cholesterol . Risk factors recognized by NCEP are summarized in Box 1 .

TABLE 1 -- Low-density Lipoprotein Cholesterol Goals and Thresholds for Initiating Lifestyle Change and Pharmacologic Intervention LDLC Level at Which LDLC Level at Which to Risk Category[*],[†] LDLC Goal to Initiate TLC Consider Drug Therapy CHD or CHD risk equivalents 20%) goal 500 mL/day), and nutritional status. There is no consensus that outcomes in these conditions are improved with bowel rest and TPN. In fact, in comparison with enteral feeding, PN results in more complications, such as hyperglycemia, infection, and sepsis. For these reasons, PN should not be routinely started. However, despite the lack of supportive trials, it does seem prudent to initiate PN if a patient cannot tolerate oral or enteral nutrition after 7 to 10 days, to

prevent malnutrition. PN lipid administration is safe in patients with acute pancreatitis. For patients with proximal jenunal fistulas, enteral feeding can lead to further complications from malabsorption, and PN is suggested. COMPROMISED BOWEL FUNCTION In patients who have undergone major intestinal resection, short gut syndrome can develop if the remaining functional length of the small bowel is less than 100 cm (20

1500 mL + 20 mL/kg/d for every kg >20

60 mL + 1 mL/kg/h for every kg >20

* Assuming normal renal function and usual insensible losses.

Maintenance fluids are designed only to replace, or input, naturally occurring output when oral fluids are

contraindicated or not tolerated. Output includes urinary losses, in addition to insensible water loss from the skin and lungs. If renal function is abnormal, maintenance fluids by definition do not apply; in this case, fluid requirement is better estimated by calculating insensible water loss ( Table 2 ) and adding it to urine output and any other significant losses (e.g., diarrhea, nasogastric suction). Similarly, factors such as raised body temperature increase insensible water losses and need to be considered when determining appropriate fluid volume.

TABLE 2 -- Insensible Fluid Losses by Body Surface Area Insensible Losses Body Surface Area (m2) 400 mL/m2 BSA/d (spontaneously breathing) 300 mL/m2 BSA/d (ventilated) 500-600 mL/m2 BSA/d (neonates) Abbreviation: BSA = body surface area.

ELECTROLYTE REQUIREMENTS Sodium

In the same 1957 paper, Holliday and Segar proposed maintenance sodium requirements for children to be 30 mmol/L. This requirement translates to the use of a hypotonic saline solution for maintenance fluids, equivalent to 0.2% NaCl in 5% dextrose in water (D5W). Although this solution, or similar hypotonic composites, continues to be widely used in pediatric practice, there is good reason to question its appropriateness. Holliday's water requirements were based on caloric expenditure in healthy children, and electrolyte composition was derived from that of human and cow's milk. The recommended sodium concentration is less than the average dietary salt intake, and the guideline fails to account for impaired water excretion, an important factor in hospitalized children. Several case reports have raised concern about the routine use of hypotonic solutions in hospitalized children, because reports of potentially fatal hyponatremia have come to light. Factors implicated in the development of hyponatremia include the action of antidiuretic hormone (ADH) preventing water excretion as well as the input of electrolyte-free water (EFW). There are several reasons for ADH secretion to be elevated in hospitalized children. Apart from osmotic forces, stimuli for ADH release include malignancies, central nervous system disorders (including meningitis), pulmonary disorders (including pneumonia), and several medications, including commonly used drugs such as morphine sulfate (morphine). Additionally, nonspecific symptoms such as pain, nausea, and stress, as well as a postoperative state and hypovolemia, all result in an increase in ADH. Given the illness of hospitalized children in the 21st century, it is rare to care for a patient who does not have at least one of these risk factors for elevated ADH, making water retention an essential consideration in the prescription of IV fluids.

With respect to EFW, the routine use of hypotonic maintenance fluids provides the major source for hospitalized patients. There is 154 mmol/L of sodium in 0.9% NaCl (normal saline), which is isotonic with respect to the cell membrane. Ringer's lactate provides a similar sodium concentration. Solutions with less sodium content are hypotonic ( Table 3 ). Holliday's historic prescription of 0.2% NaCl contributes a large degree of EFW (78%). This contribution of free water via IV fluids, compounded by an impaired ability to excrete water, place the hospitalized child at risk for developing acute hyponatremia. Consequently, IV solutions that are less hypotonic, or even isotonic, are starting to be used in pediatric hospital wards.

TABLE 3 -- Source of Electrolyte-Free Water IV Solution

Tonicity

Na (mmol/L) EFW (%)

D5W/0.9% NaCl

Isotonic

154

0

D5W/0.45% NaCl Hypotonic 77

50

D5W/0.2% NaCl

78

Hypotonic 34

Abbreviation: EFW = electrolyte-free water.

Potential risks of using isotonic fluids as maintenance solutions include fluid overload in children with an impaired ability to excrete sodium and hypernatremia in patients with renal concentrating defects, significant water loss, or prolonged fluid restriction. In the absence of these factors, the risks of isotonic fluids are largely theoretical. Potassium

Maintenance potassium requirements have similarly been derived at 20 mmol/L. In most clinical situations, maintenance potassium should be added to the IV solution. Exceptions include uncertainty regarding the patient's renal function, poor urine output, or any other risk factors for hyperkalemia. In these scenarios, the addition of potassium is not advised, and renal function and electrolytes should be closely monitored. Ongoing losses of potassium (e.g., diarrheal losses) or other reasons for hypokalemia (e.g., prolonged use of albuterol (salbutamol [Ventolin]) can require higher concentrations of potassium, along with appropriate electrolyte monitoring. GLUCOSE Dextrose should routinely be added to maintenance fluids as a carbohydrate source when children are in a fasting state in order to provide some calories (albeit minimal) and prevent ketosis. Generally, a child with normal glucose metabolism requires a 5% dextrose solution (D5W), which can be safely combined with either hypotonic or isotonic solutions. Unlike sodium, glucose can freely cross the cell membrane and thus does not contribute to the osmotic force. METHOD FOR PRESCRIBING MAINTENANCE FLUIDS: A PRACTICAL APPROACH No prospective studies have evaluated the risks or benefits of hypotonic versus isotonic IV fluids. Clearly,

the routine use of 0.2% saline requires reconsideration, and it is likely inappropriate for use in pediatric wards. A case-control study by Hoorn and colleagues, the most rigorous on the topic to date, recommends that isotonic fluids be used perioperatively as well as in children with a plasma sodium less than 138 mmol/L. Practically, a decision regarding IV fluid composition must be made on a case-by-case basis. The choice may be viewed as a prescription, taking details about the patient, the clinical scenario, and the baseline laboratory values into account, and monitoring and reevaluating the child's fluids and electrolytes on a regular basis. Rather than following strict rules, judgment is required for each patient. The following scenarios provide some guidance about IV fluid composition. A normal sodium value (=136 mmol/L) in a patient who is relatively well should lead one to consider halfnormal saline (0.45% NaCl) in D5W a good choice. This solution provides more sodium (and contributes less EFW) than 0.2% saline while still providing the patient with some free water. A second patient with the same sodium value, however, might require a different fluid prescription. For example, a child with a low-normal sodium of 137 mmol/L in the clinical context of severe pain, meningitis, or pneumonia—all risk factors for elevated ADH—is likely a good candidate for an isotonic solution such as 0.9% NaCl in D5W. If this same patient presented with a sodium of 132 mmol/L, 0.9% NaCl in D5W should almost certainly be instituted. In any of these solutions, 20 mmol/L of potassium could be added provided that the patient's urine output is appropriate and no other risk factors for hyperkalemia are present. With respect to the surgical patient, the recent literature would suggest that isotonic fluids (0.9% NaCl in D5W, Ringer's lactate) be routinely used in the perioperative period. Postoperatively, approximately 1% of patients develop a serum sodium less than 130 mmol/L. The development of hyponatremia in this clinical context is not surprising, given the multiple factors placing these patients at risk for increased ADH secretion, namely, pain, nausea, stress, narcotic medications, and volume depletion. A NOTE ABOUT VOLUME Provided that a patient has normal renal function and usual insensible losses, maintenance fluid guidelines may be followed, estimated by the rules noted in Table 1 . It is crucial to note, however, that in studies examining the question of IV fluids in children, excess fluid volume—greater than maintenance requirements—was an important factor associated with development of acute hyponatremia. Often clinicians prescribe maintenance IV fluids when the child is unwell and not taking anything by mouth. In most cases, when the patient's clinical condition improves, oral intake is initiated. Be mindful that oral fluid is hypotonic and can add significantly to the patient's free water load. To prevent the development of hyponatremia and its significant clinical consequences in these children, IV fluid prescriptions should be reevaluated on a regular basis, taking oral intake into account and adjusting the IV volume to maintain an appropriate total fluid intake. Rehydration ASSESSMENT OF DEHYDRATION Gastroenteritis and Dehydration

Acute gastroenteritis accounts for more than 1.5 million outpatient visits, 10% of all pediatric hospitalizations (200 000), and approximately 300 deaths per year in the United States. This pales in comparison with the estimated 30% of worldwide deaths among infants and toddlers, amounting to 8000 children younger than 5 years dying per day, from diarrhea and dehydration in the developing world. Young children with diarrhea are more prone to dehydration than older children and adults because of their higher body surface–to–volume ratio, a higher metabolic rate, and smaller fluid reserves. In addition, they are often dependent on others to provide fluid. Viruses, primarily rotavirus, are responsible for 70% to 80% of infectious diarrhea in the developed world. There are also many other causes of dehydration not involving diarrhea, including poor oral intake (e.g., stomatitis), increased insensible losses (e.g., fever, tachypnea), and renal losses (e.g., diabetes mellitus, diabetes insipidus). Classification of Dehydration

The American Academy of Pediatrics (AAP) classifies dehydration as mild (3%-5% fluid deficit), moderate (6%-9%), and severe (=10%). The first signs of dehydration are believed to appear when the fluid deficit is 3% to 4%. Dehydration can be further classified based on the serum sodium concentration. Isotonic dehydration (Na 130-150 mmol/L) accounts for the vast majority, and hypotonic (Na 150 mmol/L) dehydration account for less than 5% of the total cases. Inaccurate assessment of dehydration can result in permanent injury and death if fluid deficits are underestimated, and overestimation likely leads to unnecessary interventions and inappropriate use of resources. Accuracy of Historic Factors and Physical Examination

Traditional teaching regarding the assessment of dehydration is empiric and based on clinical experience ( Table 4 ). The gold standard for measuring dehydration is considered to be acute body weight change over the course of the illness. Unfortunately, this information is seldom available due to a lack of an accurate preillness weight.

TABLE 4 -- Signs Associated with Dehydration Minimal or No Dehydration (2 sec

•

Dry mucous membranes

•

Absent tears

•

Abnormal general appearance

indicate a fluid deficit of at least 5%. This subset of four factors predicted dehydration as well as the entire set. In addition, a clinical dehydration scale has been developed by Friedman and coworkers using formal measurement methodology. A score of 0 reflects no dehydration, and a maximum score of 8 reflects severe dehydration as per Table 5 .

TABLE 5 -- A Dehydration Score Characteristic 0 1

2

General appearance

Normal Thirsty, restless, lethargic, but irritable when touched

Drowsy, limp, cold, sweaty, ± comatose

Eyes

Normal Slightly sunken

Very sunken

Mucous membranes (tongue)

Moist

Dry

Tears

Present Decreased

Eliciting Signs of Dehydration

Sticky

Absent

As is true in the physical examination of any young child, opportunism is the operative word! Start with the least-invasive part, which involves observing the child's overall appearance and interaction with the caregiver. This also allows you to record the respiratory rate over a 30-second period, looking for hyperpnea suggesting a metabolic acidosis. To assess capillary refill time, sufficient pressure should gradually be applied to blanch the palmar surface of the distal fingertip, and then immediately released. Less than 1.5 to 2 seconds for restoration of normal color is considered normal. The examining room should be at a warm ambient temperature. Autonomic nervous system abnormalities or extremes in patient temperature can affect measurement. Dryness of the mucous membranes is best assessed by examination of the tongue because the lips are often dry in mouth breathers and in children with conditions other than dehydration. If the child does not cry during your examination, the presence of tears may need to be inquired about on history. Skin turgor is usually assessed by pinching a small skin fold on the lateral abdominal wall at the level of the umbilicus. This is then released, and return to its normal position is classified as immediate, slightly delayed, or prolonged. False negatives can be seen in hypernatremia and obese children, and malnutrition can cause false positive results. Although decreased blood pressure and severe tachycardia should be examined for, they are late signs and only tend to become evident in severe dehydration. Remember that the degree of dehydration may be underestimated in hypertonic dehydration as a result of the movement of water from the intracellular to the extracellular space, which helps to preserve the intravascular volume. In hypotonic dehydration the opposite occurs, and an overestimation of dehydration can result. Usefulness of Blood Tests

There is a tendency to want to use blood test results to help in the assessment of dehydration because they are perceived to be more reliable than the features on history and physical examination. Unfortunately their usefulness has not been supported by data in the literature. In his systematic review, Steiner reviewed six studies that looked at blood urea nitrogen (BUN), BUN–to–serum creatinine ratio, and acidosis in children. The only laboratory measurement that seemed to be helpful was serum bicarbonate. A normal serum bicarbonate concentration of more than 17 mEq/L reduced the likelihood of 5% dehydration. Why are the laboratory findings so unhelpful? A number of reasons have been suggested. In cases of isolated vomiting or nasogastric drainage, either a metabolic alkalosis can result from gastric acid losses or a metabolic acidosis can result from volume contraction and lactic acidosis. Volume depletion without renal insufficiency should cause a disproportionate rise in the BUN with little or no change in creatinine. This is caused by increased passive reabsorption of urea in the proximal tubule as a result of appropriate renal conservation of sodium and water. But BUN results may be misleading because children with gastroenteritis can have decreased protein intake during their illness, which can cause hypouremia. Not knowing the child's baseline BUN means that it could double but still remain in the normal range. Finally, if dehydration is rapid, BUN, which is a waste product that builds up gradually with decreased renal excretion, might not have the chance to increase significantly. What Are the Lessons for the Clinician?

Acute change in weight is the best indicator of dehydration. If a child was seen the day before with a weight of 10 kg and returns the next day with a weight of 9 kg, then by definition the child is 10% dehydrated. Unfortunately, this information is not often available, and based on current data, the empiric classification

systems suggested in the past are not particularly accurate or reliable. There are more than 30 different potential tests for assessing dehydration but no conclusive way to approach this. A general classification of a child's dehydration status as none (23 µg/dL (635 nmol/L), adrenal function is considered adequate if the response is >20 µg/dL (550 nmol/L). Low-Dose ACTH Stimulation Test The serum cortisol concentration is measured 60 min following IV administration of 1 µg cosyntropin diluted in normal saline. The minimum normal response is reported by various investigators to be 18-22 µg/dL (500-600 nmol/L). Insulin-Induced Hypoglycemia Test This test is more sensitive than cosyntropin testing in the setting of recent-onset secondary adrenal insufficiency. Under the supervision of an endocrinologist or other experienced physician, regular insulin (0.1-0.15 U/kg) is administered intravenously. Serum glucose and cortisol concentrations are measured at 0, 10, 20, 30, 45, 60, and 90 min following the injection. If adequate hypoglycemia is attained (serum glucose 60% Useful mg/d additive to metyrapone

Lethargy, somnolence, dizziness, rash, fever, nausea, anorexia, hyopthyroidism

50012,000 mg/d

83%

Gastrointestinal, impaired mentation, dizziness, hyperlipidemia, gynecomastia, transient rash, hepatotoxicity

Mitotane (o, p'-DDD, Blocks side-chain Lysodren)[1][*] cleavage Adrenolytic

ACTH Release Inhibitors Cyproheptadine (Periactin)[1]

Impairs ACTH secretion

24 mg/d

30%-50%

Somnolence, hyperphagia, weight gain

Bromocriptine (Parlodel)[1]

Impairs ACTH secretion

3.75-30 mg/d

25%-42%

Nausea, dry mouth, postural hypotension

Octreotide (Sandostatin)[1]

Inhibits ACTH release 100-600 µ g/d

Limited experience, additive to ketoconazole

Diarrhea, gallstones

Valproic acid (Depakene)[1]

Potentiates GABA 1-2 g/d inhibition of CRH and ACTH release

Limited experience, additive to metyrapone

Sedation, nausea, hepatotoxicity, pancreatitis

Glucocorticoid Receptor Antagonist Mifepristone (RU486, Mifeprex)[1]

Glucocorticoid receptor antagonist

10-25 mg/kg/d

Limited experience Nausea, vomiting, irregular menses

Abbreviations: ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone;GABA = gamma-aminobutyric acid.

1 Not FDA approved for this indication. * FDA approved for treatment of adrenocortical carcinoma.

CURRENT DIAGNOSIS The clinical presentation of Cushing's syndrome is nonspecific and overlaps that of other more common diseases such as polycystic ovary syndrome, the metabolic syndrome, and depression. Signs and symptoms more specific for Cushing's syndrome include unexplained osteoporosis, muscle weakness, spontaneous ecchymoses, hypokalemia, central obesity, and plethora. Children present with growth failure, generalized obesity, and menstrual irregularities. A stepwise approach to the diagnosis helps avoid pitfalls in the interpretation of diagnostic tests. The first step is to confirm the diagnosis of Cushing's syndrome. The second step is to determine if the patient has ACTH-dependent or ACTH-independent disease. The final step is to determine if the ACTH source is eutopic (from the pituitary gland) or ectopic (the ectopic ACTH syndrome). The 1 mg ON dex test is easy to perform and has good sensitivity for diagnosing Cushing's syndrome. However, because of its poor specificity, confirmatory testing with measurement of urine free cortisol, midnight serum or salivary cortisol or the dex-CRH test is required. Random or CRH-stimulated ACTH levels greater than 10 pg/mL indicate ACTH-dependent disease. Biochemical testing is inadequate for distinguishing pituitary tumors from the ectopic ACTH syndrome. Jugular venous sampling has a high positive predictive value, but if negative, inferior petrosal or cavernous sinus sampling with CRH stimulation is required. Pituitary MRI is positive in only approximately one half of patients with corticotroph adenomas. Abbreviations: ACTH = adrenocorticotropic hormone; CRH = corticotrophin-releasing hormone; dex = dexamethasone; MRI = magnetic resonance imaging; 1 mg ON dex test = 1 mg overnight dexamethasone suppression test.

CURRENT THERAPY Treatment for Cushing's syndrome is primarily surgical and targeted to the pathologic lesion. Transsphenoidal adenomectomy is recommended for pituitary-dependent Cushing's disease, but has a long-term success rate of only 60% to 80%. Laparoscopic adrenalectomy has replaced open approaches in the management of primary adrenal lesions except for adrenocortical carcinoma, and for second-line treatment after failed pituitary surgery or failure to localize an occult ectopic tumor. Definitive secondary treatments for failed pituitary surgery include pituitary irradiation and bilateral adrenalectomy. Medical therapy for Cushing's syndrome is difficult, and reserved for surgical failures awaiting benefit from radiation therapy or in preparation for surgical therapy. * FDA approved only for adrenocortical carcinoma.



REFERENCES Bochicchio et al., 1995. Bochicchio D, Losa M, Buchfelder M: Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: A retrospective study by the European Cushing's disease survey group. J Clin Endocrinol Metab 1995; 80:3114-3120. Hammer et al., 2004. Hammer GD, Tyrrell JB, Lamborn KR, et al: Transsphenoidal microsurgery for Cushing's disease: Initial outcome and long-term results. J Clin Endocrinol Metab 2004; 89:6348-6357. Ilias et al., 2004. Ilias I, Chang R, Pacak K, et al: Jugular venous sampling: An alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing's syndrome. J Clin Endocrinol Metab 2004; 89:3795-3800. Leinung and Zimmerman, 1994. Leinung MC, Zimmerman D: Cushing's disease in children. Endocrinol Metab Clin North Am 1994; 23:629-639. Mahmoud-Ahmed and Suh, 2002. Mahmoud-Ahmed AS, Suh JH: Radiation therapy for Cushing's disease: A review. Pituitary 2002; 5:175-180. Nieman, 2002. Nieman LK: Medical therapy of Cushing's disease. Pituitary 2002; 5:77-82. Oldfield et al., 1991. Oldfield E, Doppman J, Nieman L, et al: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 1991; 325:897-905. Papanicolaou et al., 2002. Papanicolaou DA, Mullen N, Kyrou I, Nieman LK: Nighttime salivary cortisol: A useful test for the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2002; 87:4515-4521. Reincke, 2000. Reincke M: Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am 2000; 29:4356. Yanovski et al., 1993. Yanovski J, Cutler G, Chrousos G, Nieman L: Corticotropin-releasing hormone stimulation following low-dose dexamethasone (Decadron) administration. JAMA 1993; 269:2232-2238.



Chapter 156 – Diabetes Insipidus

Method of: Jennifer Kelly, DO Arnold M. Moses, MD General Principles of Treating Central (Neurogenic) Diabetes Insipidus The hormonal treatment of diabetes insipidus is accomplished using the synthetic nanopeptide desmopressin (1-deamino [8-d-arginine] vasopressin; DDAVP). Arginine vasopressin (AVP) is the natural hormone of humans. Desmopressin is a synthetic analogue of AVP that does not constrict smooth muscle and has a longer antidiuretic action than does the natural hormone. Because of its lack of vasoactivity, desmopressin can be used without precipitating angina, abdominal cramps, or headaches. It can also be used to treat diabetes insipidus during pregnancy because it resists inactivation by placental vasopressinase. The available preparations of vasopressin are listed in the table above. The durations of antidiuretic responses to the different preparations are listed in Table 1 .

TABLE 1 -- Mean Time That Urine Remains Hypertonic in Adults with Diabetes Insipidus[*] Route of Administration Amount Administered Mean Duration of Action (hr) Intranasal desmopressin

10 µg (0.1 mL)

12

15 µg (0.15 mL)

16

20 µg (0.2 mL)

20

Subcutaneous or intravenous desmopressin 0.5 µg

10

1.0 µg

14

2.0 µg

18

4.0 µg

22

0.1 mg

6–8

0.2 mg

8–12

0.4 mg

16–20

5U

4

Oral desmopressin

Subcutaneous arginine vasopressin

* Note: Onset of antidiuretic action of subcutaneous or intravenous preparation is 30–45 minutes. Onset of antidiuretic effect of tablets is about 60 minutes.

For most patients with diabetes insipidus, the treatment of choice is intranasal desmopressin (100 µg/mL). Two delivery systems are available: a nasal (rhinal) tube, which the patient uses to blow measured amounts (0.05-0.2 mL) into the nose, and a compression pump system, which delivers 0.1 mL (see Current Therapy). Treatment is usually initiated with 10 µg of intranasal desmopressin. Patients are instructed to repeat this

dose when polyuria recurs. Some patients respond better if the hormone is administered on a more defined schedule. The dose administered can be increased or decreased in accordance with the patient's response. Patients should be told to drink only when they are thirsty. Some patients prefer to start therapy with oral desmopressin; others can be switched to the oral preparation when absorption of the intranasal form is decreased in the presence of nasal congestion. The starting dose of the tablet is usually 0.05 mg (half of a 0.1-mg tablet) twice per day. The maintenance dose is gradually adjusted to provide an adequate limitation of water turnover. The daily oral dose may range from 0.1 to 1.2 mg in divided doses. We do not currently recommend the use of nonhormonal agents such as chlorpropamide (Diabinese),[1] clofibrate,[1,][2] or carbamazepine.[1]

CURRENT DIAGNOSIS Central diabetes insipidus (DI) can be diagnosed as follows: 1.

Ensure urine volume is increased to ×3 L/day in adults.

2.

Rule out glycosuria (dipstick will suffice).

3.

Measure serum sodium concentration during ad libitum fluid intake.

4.

If the serum sodium concentration is above normal while urine osmolality is less than 3 00 mOsm per kilogram of water, injection of desmopressin (DDAVP) at least doubles the urine osmolality in patients with central DI. If the urine osmolality response is less, the patient may have nephrogenic DI.

5.

If the serum sodium concentration is normal while urine osmolality is less than 300 mOsm per kilogram of water, additional procedures, including a water deprivation or saline infusion test, may be required. Refer to an experienced specialist.

6.

Magnetic resonance imaging to detect the presence or absence of the pituitary hyperintense signal may be helpful in differentiating central DI from primary polydipsia. Plasma arginine vasopressin levels do not differentiate these two polyuric conditions.

In the uncooperative or unconscious patient with diabetes insipidus, desmopressin should be injected subcutaneously, usually starting with 0.5 or 1.0 µg (see Table 1 for duration of action). Subcutaneous AVP is sometimes used in patients with acute onset of diabetes insipidus after head trauma or neurosurgical procedures. Its short duration of action might help prevent water intoxication in patients receiving poorly monitored intravenous fluids. As with desmopressin, it is safest to administer subsequent doses of AVP when polyuria reappears. As long as untreated patients with diabetes insipidus are conscious, retain normal thirst, and have enough fluid to drink, they seldom become dehydrated. However, severe dehydration with extremely high serum sodium concentrations may occur acutely when patients with untreated diabetes insipidus do not receive adequate fluids (orally or intravenously). The most common and important problem in the hospitalized patient with diabetes insipidus is iatrogenic hyponatremia. Particularly when it occurs rapidly, hyponatremia may cause severe neurologic problems.

Hyponatremia in this setting is caused by overhydration (only rarely does sodium loss contribute) in patients receiving vasopressin and can be prevented by allowing patients to self-regulate their oral intake of fluids whenever possible. When such self-regulation is not feasible because the patient is obtunded, has a defective thirst mechanism, or cannot drink, extreme care must be taken in ordering intravenous fluids to prevent hyponatremia. The patient can be maintained in an antidiuretic state by giving vasopressin when the urine becomes dilute. The intravenous fluid should consist largely of 5% dextrose in water with amounts of normal saline gauged to replace daily urinary sodium losses. The volume of intravenous fluid for every 8hour period should replace 8-hour urine volumes plus estimated 8-hour insensible losses and fluid losses through perspiration and other routes. The amount of intravenous fluid should be adjusted according to plasma sodium, blood urea nitrogen, and creatinine levels. If hypernatremia occurs, the amount of intravenous fluids should be increased accordingly.

CURRENT THERAPY

Trade Name

Chemical Composition

Concentration Size

Pharmaceutical Company

Intranasal Preparations Desmopressin Rhinal Tube

Desmopressin acetate

100 µ g/mL

2.5-mL bottle with rhinal tube Ferring delivering sprays of 10–20 µg

DDAVP Rhinal Tube


100 µ g/mL

2.5-mL bottle with rhinal tube Aventis delivering sprays of 10–20 µg

DDAVP Nasal Spray


100 µ g/mL

5.0-mL bottle with spray pump delivering 50 sprays of 10 µg each


Not applicable 0.1-mg, 0.2-mg tablets

Aventis

Oral Preparation DDAVP Tablets

Aventis

Injectable Preparations (Subcutaneous, Intravenous) DDAVP Injection


4 µ g/mL

1.0,10.0 mL/vials

Aventis

Pitressin Injection

Arginine vasopressin

20 U/mL

1 mL/vial

Monarch

Arginine

Arginine vasopressin

20 U/mL

0.5,1, and 10 mL/vials

American Regent

Vasopressin Injection

Caution: Stimate Nasal Spray (desmopressin acetate) is marketed by Aventis Pharmaceuticals in a 2.5mL nasal spray bottle. It is designed for treating bleeding disorders and contains 1.5 mg/mL desmopressin. Stimate can be confused easily with the less concentrated preparations of desmopressin acetate that are used for treating diabetes insipidus.

If a major decrease in serum sodium concentration occurs, intravenous fluids should be temporarily discontinued, and, if necessitated by clinical manifestations, the patient should be given 200 to 300 mL of 3% saline, perhaps with 40 mg of furosemide (Lasix) intravenously. Temporary discontinuation of vasopressin should also be considered. To emphasize, the patient with central diabetes insipidus whose fluid intake is maintained intravenously presents a major medical problem and must be followed up carefully to maintain normonatremia. Pregnancy is associated with significant alterations in water metabolism. The osmotic threshold for secretion of vasopressin is lowered and the threshold for thirst reduced, with a resulting decrease in plasma osmolality by about 10 mOsm per kilogram of water. A deficiency of plasma vasopressin can also result from increased degradation of the hormone by placental vasopressinase. This disorder is referred to as gestational diabetes insipidus because the symptoms of diabetes insipidus occur only during pregnancy and remit soon after delivery. An underlying subclinical deficiency in vasopressin secretion may also be involved. Gestational diabetes insipidus is treated successfully with desmopressin, which is not degraded by vasopressinase. The dose of desmopressin should be about the same as that used in the nonpregnant state, but the normal range for serum sodium is about 5 mEq/L lower. 1 Not FDA approved for this indication. 2 Not available in the United States.

Principles of Treating Specific Problems THE ALERT PATIENT WITH INTACT THIRST When antidiuretic therapy is initiated in the alert patient with diabetes insipidus, the patient must consciously avoid excessive drinking for at least several days. By that time, the thirst mechanism usually adapts to the more normal urine volume. However, some patients must be reminded to avoid excessive drinking, which causes the syndrome of inappropriate antidiuresis. Thirst may be perceived with normal or low serum sodium concentration because of a dry mouth, as might occur with mouth breathing, anticholinergic drugs, ß-adrenergic blockers, or cigarette smoking. An occasional patient is hyperdipsic because of increased circulating angiotensin II levels or from hypothalamic involvement, as may occur with sarcoidosis involving the hypothalamus. Use of ice may help limit fluid intake. THE ALERT PATIENT WITH ADIPSIA The alert patient with adipsia presents a difficult management problem in the hospital and particularly after the patient is discharged from the hospital. Because of the loss of thirst perception, normal serum sodium

concentration is maintained only with great difficulty. The patient and family must closely and continuously monitor the patient's intake and output of fluids, body weight, and vital signs. Serum sodium concentration and blood urea nitrogen, uric acid, and creatinine levels should be checked often. Such a patient must always relate fluid intake to volume of urine plus fluid losses through perspiration and the gastrointestinal tract. Failure to properly monitor these patients may allow their condition to go unrecognized until they develop severe dehydration. This may require the infusion of normal saline to restore pulse and blood pressure and then water orally or dextrose in water intravenously. Appropriate antidiuretic therapy should be instituted along with the fluids. THE CONFUSED, OBTUNDED, OR UNCONSCIOUS PATIENT When confused, obtunded, or unconscious, such as postoperatively or after head trauma, the patient with diabetes insipidus is monitored in the same ways described for the alert patient with adipsia. The only major difference is that vasopressin must be given by injection or infusion and the fluids given intravenously. In the presence of hypernatremia and associated hypovolemia, normal saline is required to help restore pulse and blood pressure to normal. Otherwise, patients with hypernatremia should be treated with dextrose in water (see later) while antidiuretic therapy is instituted and maintained. Postoperative hypernatremia should be prevented by the early recognition of diabetes insipidus before, during, and after surgery and by avoidance of osmotic diuretic use during surgery. The patient should be switched to oral fluids as soon as possible, and the adequacy of the patient's thirst mechanism to control fluid intake appropriately should be evaluated. Diabetes insipidus that occurs postoperatively or after head trauma may be variable (biphasic or triphasic), and frequently the diabetes insipidus is transient. Therefore, hormonal treatment should be withheld periodically to determine whether the symptoms of diabetes insipidus recur. After 6 months of diabetes insipidus, remission is very unlikely. Special Problems of Fluid Balance THE HYPERNATREMIC PATIENT Hypernatremia in patients with diabetes insipidus is usually associated with normal total body sodium. The hypernatremia is due to loss of free water by way of the kidneys, but losses from the skin and lungs can aggravate the problem. Alterations in the composition of water and solutes in the brain cells may contribute to the symptoms of hypernatremia. An abrupt increase in plasma sodium concentration causes more severe symptoms than does a gradual rise to the same sodium level. The goal of treating hypernatremia in patients with diabetes insipidus is restoration of normal plasma volume and tonicity. Desmopressin should be injected to maintain concentrated urine. If the patient has circulatory disturbances due to hypovolemia, isotonic saline should be given until systemic hemodynamics are stabilized. In fact, isotonic saline is relatively hypotonic to plasma in patients with severe hypernatremia and simultaneously corrects both volume and water deficits. After volume deficits are corrected, the hypernatremia can be treated intravenously with 5% dextrose in water, or water can be given by mouth if the patient is able to drink. The water deficit in these patients can be calculated on the basis of the serum sodium concentration and on the assumption that 60% of body weight is water. For example, if the patient's usual weight is 75 kg, total

body water would normally be 75 kg × 0.6 = 45 L. If the serum sodium value is 154 mEq/L, the patient has a 10% deficit of water (154 - 140) ÷140 and theoretically requires 4.5 L of water to correct the deficit. Continuing losses of water must also be replaced. Despite inaccuracies, including the assumption that body water is always 60% of the body weight and the postulate that water is lost uniformly throughout all body cells, this approach provides an approximate value that can be used in planning therapy. The major problem is determining the appropriate rate at which to lower serum sodium concentration to normal. Because seizures or even fatal cerebral edema may occur when serum sodium concentration is lowered rapidly, the best recommendation is to correct the hypernatremia over 48 to 72 hours and at a rate not exceeding 0.5 to 2.0 mEq/L/hr. As total body water expands, the serum sodium concentration may fall proportionately. Serum electrolyte values should be monitored frequently to ensure an appropriate response. Treatment of the hypernatremia due to water loss, as occurs in untreated patients with diabetes insipidus, must also address associated electrolyte abnormalities and underlying medical and surgical conditions. An example is the patient with diabetes insipidus with coexisting hyperglycemia. In this case, the “corrected” serum sodium concentration should be used to calculate the water deficit. Slightly low or abnormal serum sodium concentrations in the presence of high serum glucose often result, when corrected, in hypernatremic values. The corrected serum sodium concentrations can be calculated by increasing the sodium concentration by 1.5 mEq/L for every 100 mg/dL increment in the serum glucose concentration above 100 mg/dL. For example, in a patient with a sodium level of 138 mEq/L and a glucose level of 700 mg/dL, the corrected serum sodium concentration is 138 + (1.5 × 6), or 147 mEq/L. THE HYPONATREMIC PATIENT Hyponatremia in diabetes insipidus occurs almost exclusively in patients who are overhydrated orally or parenterally while they are being treated with desmopressin. The severity of hyponatremia correlates closely with the magnitude of fluid overload. The amount of excessive body water can be calculated using the same approach as described for hypernatremia. Rarely, the hyponatremia is aggravated by large amounts of sodium in the urine, probably related to increased levels of atrial natriuretic peptide and glomerular filtration rate and inhibition of aldosterone. The hyponatremia due to natriuresis in the water-overloaded patient can be corrected only partially with saline infusions, because the natriuresis continues until the hypervolemic state is corrected. Hyponatremia can be caused or aggravated by adrenal or thyroid insufficiency. A large body of literature on the appropriate rate at which to correct hyponatremia is available. Rapidly occurring (acute) and marked hyponatremia can be lethal and should be treated urgently. Under these conditions, and when neurologic symptoms are severe, initial therapy should raise the serum sodium concentration by 1 to 2 mEq/L/hr regardless of the duration of the electrolyte abnormality. Most authorities agree that the rate of change in serum sodium concentrations should not exceed 12 to 20 mEq/L/day. However, in patients with chronic hyponatremia, correction of serum sodium concentration approximating this rate occasionally causes serious, even fatal complications by inducing central pontine myelinolysis. Fluid restriction is adequate for treatment of the asymptomatic mildly hyponatremic patient. Urine should be analyzed every 4 to 8 hours for volume and osmolality, and fluid replacement should be ordered in relation to urine volume. Remember that insensible fluid losses of about 600 mL of free water per day occur in the usual adult. It is NOT appropriate to write for a fixed amount of fluid replacement. Plasma sodium concentration should be checked frequently and fluid replacement adjusted according. The complaint of thirst by a water-restricted patient should not be ignored. Long-term management is usually less disrupted

by adjusting fluid intake than by discontinuing hormonal therapy and allowing the patient to “break through.” Alternatively, when the patient has symptomatic or severe hyponatremia (serum sodium concentration 250 mg in women or >300 mg in men) is seen in 30% to 40% of patients. PHPT may be associated with a reduction in creatinine clearance, in the absence of any other cause. Classic associations exist between PHPT and other organs, such as the neuromuscular system, the gastrointestinal tract, and the cardiovascular and articular systems, but such panopleistic features of PHPT are rarely seen today. More vexing are nonspecific elements associated with PHPT, such as easy fatigability, a sense of weakness, and a feeling that the aging process is advancing faster than it should be. This is sometimes accompanied by an intellectual weariness and a sense that cognitive faculties are less sharp. Whether these nonspecific features of PHPT are truly part of the disease process, reversible upon successful parathyroid surgery, remains under active investigation. CLINICAL FORMS OF PRIMARY HYPERPARATHYROIDISM Asymptomatic PHPT with serum calcium levels within 1 mg/dL above the upper limits of normal is the most common clinical presentation. Most patients do not have specific complaints and do not show evidence of any target organ complications. In parts of the world where severe vitamin D deficiency is common, more symptomatic PHPT is seen. Unusual clinical presentations of PHPT include MEN-I and MEN-II, familial PHPT not associated with any other endocrine disorder, familial cystic parathyroid adenomatosis, jaw tumor syndrome, and neonatal PHPT. A new presentation of PHPT is being described, namely, in individuals with normal serum calcium concentrations but elevated PTH levels. Potential secondary causes of elevated PTH levels are considered but have not been found. It is considered likely that these patients represent the earliest stage of PHPT, when there is glandular overproduction of hormone, before hypercalcemia becomes evident. DIAGNOSIS AND EVALUATION Hypercalcemia and elevated levels of PTH establish the diagnosis. The serum phosphorus concentration tends to be in the lower range of normal. Serum alkaline phosphatase activity may be elevated. More specific markers of bone formation (bone-specific alkaline phosphatase, osteocalcin) and bone resorption (urinary deoxypyridinoline, N-telopeptide of collagen) tend to be in the upper range of normal. In some patients, the actions of PTH in altering renal acid-base handling leads to a small increase in the serum chloride concentration and a concomitant small decrease in the serum bicarbonate concentration. Urinary calcium excretion, when elevated, is not generally excessively high. The circulating 25-hydroxyvitamin D

concentration is low, and the 1,25-dihydroxyvitamin D concentration is high in some patients. ROLE OF BONE MASS MEASUREMENT Dual-energy x-ray absorptiometry shows a pattern of skeletal involvement that is consistent with the physiologic actions of PTH, that of eroding cortical bone while sparing cancellous sites. The typical patient with PHPT shows reductions in bone density that are most marked in the distal third of the forearm, a cortical site, with much less involvement of the lumbar spine, a cancellous site. The hip region, a mixture of cortical and cancellous bone, shows changes that are intermediate between changes in the forearm and the lumbar spine. TREATMENT Localization Tests Prior to Surgery

Imaging of abnormal parathyroid tissue is accomplished most accurately with technetium-99m sestamibi. Sestamibi is taken up by both thyroid and parathyroid tissue, but it persists in the parathyroid glands. Various approaches to the use of technetium-99m sestamibi include using the imaging agent alone, and thereby depending upon a difference in uptake kinetics between thyroid and parathyroid tissue, or in combination with iodine 123 (123I). Some believe that use of dual isotopic methods provides better definition of the thyroid from which the image obtained with sestamibi can be subtracted. Even more sophisticated approaches have been developed using sestamibi imaging with single-photon emission computed tomography. Ultrasound, computed tomography, and magnetic resonance imaging are also used to localize abnormal parathyroid tissue. Invasive localization tests with arteriography and selective venous sampling for PTH are used when noninvasive studies have not been successful. In the past, parathyroid imaging was reserved for patients who had undergone neck surgery. With greater success in parathyroid imaging and the increasing popularity of minimally invasive parathyroid surgery, preoperative imaging is becoming routine in all patients.

CURRENT DIAGNOSIS Primary Hyperparathyroidism Most common cause of hypercalcemia. Diagnosis established by elevated serum calcium concentration and parathyroid hormone level that is frankly elevated or is in the upper range of normal. In some patients, the parathyroid hormone level is elevated but the serum calcium concentration is normal. Hypoparathyroidism Much less common than primary hyperparathyroidism. Most often due to destruction or removal of the parathyroid glands. Diagnosis is established by hypocalcemia and low parathyroid hormone levels.

CURRENT THERAPY Primary Hyperparathyroidism When symptoms are present, parathyroid surgery is indicated. In the absence of symptoms, surgery is recommended if any one of five criteria are met (see Table 2 ). Preoperative localization testing prior to surgery has become routine. Medical management is reserved generally for those who do not meet surgical criteria. Prudent use of calcium, hydration, and ambulation is encouraged. Pharmacologic agents, such as bisphosphonates and calcimimetics, show promise. Hypoparathyroidism Acute management of hypocalcemia is a medical emergency and requires intravenous administration of calcium. Chronic treatment is based upon adequate calcium, vitamin D, and, in some cases, the active vitamin D metabolite 1,25-dihydroxyvitamin D. TABLE 2 -- Guidelines for Surgical Management of Asymptomatic Primary Hyperparathyroidism[*] Serum calcium >1 mg/dL above normal Hypercalciuria >400 mg/day Reduced creatinine clearance by >30% Reduced bone density below T score of - 2.5 at any site Age 30 µg/24 h; >83 nmol/d) of aldosterone, and they are younger (< 50 years) than those with IHA. Patients fitting these descriptors are considered to have a high probability of APA (see Figure 2 ). However, these factors are not absolute predictors of unilateral versus bilateral

adrenal disease. With the addition of adrenal venous sampling (AVS), we have found unilateral APAs in 36% of patients with clinically high-probability APA who had normal findings or unilateral adrenal limb thickening on CT. AVS is essential to direct appropriate therapy in patients who have primary aldosteronism and who want to pursue a surgical treatment option. Treatment PRINCIPLES The treatment goal is to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage. Determining the cause of the primary aldosteronism helps to determine the appropriate treatment. Normalization of blood pressure should not be the only goal in managing the patient who has primary aldosteronism. In addition to the kidneys and colon, mineralocorticoid receptors are present in the heart, brain, and blood vessels. Excessive secretion of aldosterone is associated with increased cardiovascular morbidity. Therefore, normalization of circulating aldosterone or mineralocorticoid receptor blockade should be part of the management plan for all patients with primary aldosteronism. SURGERY Unilateral laparoscopic adrenalectomy is an excellent treatment option for patients with APA or unilateral hyperplasia. Although blood pressure control improves in nearly 100% of patients postoperatively, average long-term cure rates of hypertension after unilateral adrenalectomy for APA range from 30% to 60%. Persistent hypertension following adrenalectomy is correlated directly with having more than one first-degree relative with hypertension, use of more than two antihypertensive agents preoperatively, older age, increased serum creatinine, and duration of hypertension and is most likely due to coexistent primary hypertension.

CURRENT DIAGNOSIS Most patients with primary aldosteronism are not hypokalemic and typically present with asymptomatic hypertension, which may be mild or severe. Case finding can be completed with a simple morning (8-10 am) blood test (PAC/PRA ratio) in a seated ambulant patient. A high PAC/PRA ratio is a positive screening test result, a finding that warrants confirmatory testing. The subtype evaluation can require one or more tests, the first of which is imaging the adrenal glands with computed tomography. Adrenal vein sampling is essential to direct appropriate therapy in patients with primary aldosteronism who want to pursue a surgical treatment option. Abbreviations: PAC = plasma aldosterone concentration; PRA = plasma renin activity.

Laparoscopic adrenalectomy is the preferred surgical approach and is associated with shorter hospital stays and less long-term morbidity than the conventional open approach. To decrease the surgical risk,

hypokalemia should be corrected with spironolactone or eplerenone preoperatively; treatment with these drugs should be discontinued postoperatively. PAC should be measured shortly after the operation. For the first few weeks postoperatively, serum potassium levels should be monitored weekly and a generous sodium diet should be followed to prevent the hyperkalemia of hypoaldosteronism that can occur because of chronic suppression of the renin-angiotensin-aldosterone axis. Typically, the hypertension resolves in 1 to 3 months postoperatively. It has been found that adrenalectomy for APA is significantly less expensive than long-term medical therapy alone. PHARMACOLOGIC TREATMENT IHA and GRA should be treated medically. APA patients may be treated medically if the medical treatment includes mineralocorticoid receptor blockade. A sodium-restricted diet (100 µg/L). Alternatively, prolactin can be secreted by the normal pituitary gland through different mechanisms (see Table 1 ), and the associated serum levels will be lower, depending on the cause. In patients with pituitary tumors, the

manifestations of hyperprolactinemia can vary depending on the type and size of the tumor under discussion. For example, patients with large pituitary tumors often have headaches and visual deficits in addition to signs and symptoms of hypopituitarism. Prolactinomas vary in size at presentation. Most women with prolactinomas present with microadenomas, oligomenorrhea and/or amenorrhea, and galactorrhea. Men often present with macroadenomas and erectile dysfunction.

TABLE 1 -- Causes of Hyperprolactinemia in Patients with Pituitary Tumors Mechanism

Expected Serum Prolactin Levels

Pure prolactin-secreting

Secretes prolactin only

>100 µg/L

Mixed-cell tumors

Secretes prolactin and other hormones (e.g., growth hormone)

30-100 µg/L

Non–prolactin-secreting

Prolactin is secreted by the normal pituitary through compression of portal vessels and pituitary stalk

25-75 µg/L

Nonfunctioning tumors

Prolactin is secreted by the normal pituitary through compression of portal vessels and pituitary stalk

25-75 µg/L

Functioning and nonfunctioning tumors

Prolactin is secreted by the normal pituitary through other mechanisms (e.g., dopamine antagonists, estrogen)

25-75 µg/L

Tumor Type Functioning Tumors

Other Pituitary Tumors

Clinical Features When produced in excessive quantities, prolactin has effects in addition to its influence on lactation. Hyperprolactinemia causes inhibition of the pulsatile gonadotropin-releasing hormone (GnRH) release from the hypothalamus, leading to decreased gonadotropin release and subsequently to impaired gonadal steroidogenesis and infertility. Other effects of significant hyperprolactinemia include possible loss of bone mineral greater than what can be attributed to the associated hypogonadism. From a pathophysiologic standpoint, clinical manifestations of hyperprolactinemia can be classified as either signs and symptoms from the hyperprolactinemia itself, regardless of its cause, or those related to the underlying causes of the hyperprolactinemia. In women, symptoms and signs resulting from the hyperprolactinemia include amenorrhea or oligomenorrhea, galactorrhea, diminished libido, hypogonadism (vaginal dryness and dyspareunia), and infertility. In men, signs and symptoms of hypogonadism (diminished libido and potency) predominate, although up to 20% of men also have galactorrhea. With prolonged hyperprolactinemia and hypogonadism, osteoporosis is an additional feature of hyperprolactinemia in both men and women. In patients whose hyperprolactinemia is caused by primary hypothyroidism there are significant signs and symptoms related to the primary diagnosis (hypothyroidism).

Diagnosis The diagnostic significance of hyperprolactinemia is determined, to a large extent, by the degree of elevation in serum prolactin levels and the associated clinical presentation. Although it is safe to conclude that a serum prolactin level of greater than 200 µg/L is almost certainly due to a small or larger prolactin-secreting pituitary adenoma (prolactinoma), many other potential diagnostic possibilities exist when the level is minimally (25-50 µg/L) or moderately (50-100 µg/L) elevated. Similarly, serum prolactin levels that are greater than 100 µg/L are most often caused by prolactinomas, although other possibilities can be associated with such levels. Particularly in patients whose serum prolactin level is less than 100 µg/L, one needs to integrate all available clinical data to achieve a working diagnosis. Some patients have multiple causes of hyperprolactinemia. In general, drug-induced hyperprolactinemia (e.g., antipsychotic dopamine antagonists) is associated with serum prolactin levels of 40 to 100 µg/L. In such patients, an additional cause for hyperprolactinemia (e.g., estrogen therapy) might be associated with serum prolactin levels of 100 to 150 µg/L and thus overlap with the potential possibility of a prolactinoma. The same argument can be made in patients with other diseases or illnesses independently associated with hyperprolactinemia. A major diagnostic challenge is a patient with mild hyperprolactinemia (25-75 µg/L) who also has clinical symptoms such as those that can be associated with partial or complete loss of pituitary function (hypopituitarism). In such patients, two distinct possibilities should be considered, and both require a magnetic resonance imaging (MRI) scan of the sella turcica. The first possibility includes a nonsecreting pituitary tumor or parasellar mass (e.g., meningioma, pituitary tumor, hypothalamic mass) that is compressing the pituitary stalk and portal vessels and thus results in hyperprolactinemia and loss of all other pituitary function. The second possibility includes prolactinomas that exhibit the hook effect. In such patients, measurements of prolactin level in a serially diluted (1:10, 1:100) serum sample address that possibility. A common feature of either of these possibilities is the associated presence of headaches and visual symptoms.

CURRENT DIAGNOSIS History and Physical Examination Review the medication list Look for signs and symptoms related to specific causes of hyperprolactinemia: Pregnancy, renal failure, hypothyroidism, pituitary or hypothalamic disease. Look for subtle features of hypopituitarism Inquire about symptoms and signs caused by hyperprolactinemia: Hypogonadism, osteoporosis, galactorrhea. Testing

Laboratory: prolactin, renal and thyroid function tests, anterior pituitary hormones in cases of pituitary adenomas Be aware of the pitfalls in serum prolactin measurements: The hook effect in patients with pituitary macroadenomas and moderate hyperprolactinemia The possibility of macroprolactinemia in patients without significant symptoms or signs MRI of the sella with and without gadolinium enhancement should be done in patients with significant hyperprolactinemia, those who have evidence for other pituitary hormone deficits, and others without an obvious cause for hyperprolactinemia. It is important to incorporate the clinical picture in deciding the extent of the work-up for hyperprolactinemia. Whereas an MRI of the sella is necessary in practically all patients with a prolactin level higher than 100 µg/L, an MRI is also important in patients with even mild degrees of hyperprolactinemia when they have headaches, visual complaints, or symptoms or signs suggesting other pituitary hormone abnormalities. Similarly, an MRI of the sella might be necessary in patients who have no obvious reason for the hyperprolactinemia (regardless of its degree), especially when they have symptoms. Caution should be exercised in asymptomatic patients who have mild hyperprolactinemia and are recently discovered to have pituitary microadenomas. In such instances, the microadenoma might be an incidental finding and therefore requires no treatment but only continued follow-up. An incidentally discovered mild hyperprolactinemia without any obvious known cause and without other clinical signs or symptoms (particularly reproductive), is likely the benign entity, macroprolactinemia. Macroprolactinemia accounts for 10% of all cases of hyperprolactinemia, and it can be followed without any intervention. Laboratory studies used to identify patients with macroprolactinemia include gel filtration or precipitation by polyethylene glycol before the measurement is made. Treatment Patients with no signs and symptoms related to hyperprolactinemia might not require treatment even when the cause is a microprolactinoma. These microadenomas rarely grow, and thus, in the absence of symptoms, no treatment is indicated, but continued follow-up is warranted. The ultimate goal of therapy is to restore gonadal function and fertility. In patients with pituitary adenomas, an additional goal of therapy is to eliminate the mechanical effects of the tumor on surrounding tissue. Eliminating or treating the underlying cause of hyperprolactinemia is the primary approach in managing patients with this biochemical abnormality. For example, treating an underlying hypothyroid state or eliminating an implicated medication corrects the hyperprolactinemia. In most instances of drug-induced hyperprolactinemia, one can treat the symptoms caused by hyperprolactinemia (estrogen in women and testosterone in men) even though the serum prolactin level after such therapy might increase even further. Treatment of idiopathic hyperprolactinemia can follow the same approach outlined for the management of microprolactinomas.

CURRENT THERAPY The decision to treat the hyperprolactinemia should be based on the cause and associated symptoms. Treat and/or eliminate the probable underlying cause whenever possible. Treatment of the hyperprolactinemia: Dopamine agonists are the first and best approach for treating prolactin-secreting pituitary adenomas. Therapy works, regardless of the cause. Cabergoline (Dostinex) (best available option), pergolide (Permax), quinagolide (Norprolac),[1] bromocryptine (Parlodel) (leastfavored option). Resection of a hypothalamic or pituitary lesion, if applicable Adjunctive radiation therapy for tumors that are invasive or unresectable and others that are not responsive to surgery or medical therapy, if applicable 1 Not FDA approved for this indication.

At times, antipsychotic dopamine antagonists cannot be easily discontinued because of significant psychiatric illness. Furthermore, patients receiving antipsychotic drugs might experience worsening of their psychiatric symptoms when given dopamine agonists to correct the hyperprolactinemia. In such instances, clinical judgment should be exercised as to which is more clinically beneficial for the patient's well-being. Treatment is indicated for all patients with symptoms, particularly those with hypogonadism. Patients with no signs or symptoms might not require treatment unless their adenoma is large. They should be followed carefully because they are likely to present with symptoms at some point. PHARMACOLOGIC THERAPY Most authorities in the field believe that dopamine agonists are the treatment of choice for patients with prolactinomas. Patients with macroprolactinomas are managed in a manner similar to that for patients with microadenomas. Currently, three dopamine agonists are available for clinical use: bromocriptine (Parlodel), pergolide (Permax) [*], and cabergoline (Dostinex). These agents are effective in their ability to decrease serum prolactin levels and shrink tumor sizes. However, theoretically and practically, cabergoline is believed to be the most effective because it has more D2-receptor specificity and a longer half-life. The three dopamine agonists have different half-lives, and consequently the frequency of their administration is different for optimal benefit. Bromocriptine has to be used three or four times daily (5-30[3] mg/day; average dose, 7.5 mg), pergolide can be used once or twice daily (0.05-0.25 mg/day; average dose, 0.1 mg), and cabergoline is used two to four times weekly (0.5-2.0[3] mg/week). A recent study suggested that of the three dopamine agonists, cabergoline was the most effective in reducing tumor size. Although cabergoline was effective in all patients, it appears to be most effective in those who never received dopamine agonists previously. In most patients, tumor shrinkage occurs over

several months, although rapid changes were reported in occasional patients. Serum prolactin levels are normalized over several weeks in approximately 80% to 90% of patients given any of the three dopamine agonists at optimal dosing schedules. Of these patients, shrinkage of the tumor can be noted in about 70% within 3 to 6 months. In 30% to 40% of patients, the adenoma can no longer be visualized on imaging studies. Patients with persistent hyperprolactinemia should be given the highest tolerable dose recommended. The dose of the dopamine agonist can be increased every 6 to 8 weeks until the serum prolactin level is normal or until adverse effects are encountered. One can use serum prolactin levels to monitor and follow patients being treated without having to do frequent MRIs. However, infrequently, patients develop cystic changes in their tumors with dopamine therapy and therefore might have an increase in size of the pituitary mass despite low serum prolactin levels. For these reasons, a follow-up MRI is necessary in all patients with dopamine therapy, especially those who presented with macroadenomas. We usually do not get the MRI until the serum prolactin level is normal or, alternatively, when patients have mechanical symptoms such as headaches and visual disturbances. Common side effects from all dopamine agonists include nausea, vomiting, constipation, dizziness, postural hypotension, and nasal congestion. These side effects can be minimized by introducing the drug very slowly and mixing it with food. In using cabergoline, we prefer to distribute the total weekly dose so that the drug is given on a daily or every-other-day schedule. Duration of therapy in patients with prolactin-secreting pituitary microadenomas is still not clear. We recommend at least 5 to 6 years of continuous therapy before the therapy can be slowly tapered and discontinued. If during that period a rise in serum prolactin level is observed, the dose can be increased and treatment prolonged. Even in patients with suprasellar extension and chiasmal compression, dopamine agonist therapy is the treatment of choice in patients with macroprolactinomas. Patients should be monitored carefully to ensure tumor regression with medical therapy. * Recently withdrawn from the U.S. market. 3 Exceeds dosage recommended by the manufacturer.

SURGICAL THERAPY Patients with chiasmal compression who do not respond to medical therapy within the first 3 to 4 months should have surgery to debulk the tumor and alleviate pressure from the optic chiasm. RADIATION THERAPY Although radiation therapy was commonly used in the past as an alternative treatment, it is now reserved for patients with tumors that cannot be controlled medically or surgically. Only a small number of patients require radiation treatment.

Follow-up Regardless of the therapeutic choice, patients need to be followed up regularly and for indefinite periods. Occasional patients whose tumors are resistant to dopamine agonists and radiation require multiple surgical procedures, including transfrontal craniotomy. Prolactinomas and Pregnancy A potential area of concern in patients with prolactinoma is pregnancy. It is commonly known that once serum prolactin decreases, fertility is restored in men and women within a few weeks. It is important for women to use contraception to avoid pregnancy. Initially, patients interested in getting pregnant are asked to use mechanical contraception for several months until two or three menstrual cycles are reported. This helps patients recognize the possibility of potential pregnancy once mechanical contraception is discontinued. The rationale for this approach is to minimize the use of dopamine agonists during pregnancy. In addition, it is advisable, but not necessarily essential, for patients to switch to bromocriptine[1] from the newer, longeracting agents during the time from when mechanical contraception is discontinued until pregnancy. Bromocriptine[1] has been used during all stages of pregnancy to suppress compressive symptoms. Bromocriptine crosses the placenta and suppresses pituitary prolactin secretion, but it has not been associated with increased fetal abnormalities. Although other agents such as pergolide and cabergoline were occasionally used during pregnancy without side effects, the experience with bromocriptine is more extensive, and thus it is the preferred drug during pregnancy if treatment with dopamine agonists becomes necessary. In the absence of any form of contraception, patients often get pregnant before menses are resumed. Because estrogens normally stimulate lactotrophs, it was initially believed that a prolactinoma might increase in size during pregnancy. This, however, was not found to be a clinically relevant issue in most patients. It is estimated that less than 5% of microadenomas slightly increase in size during pregnancy. The risk is somewhat higher in patients with macroadenomas, especially with suprasellar extension, and is estimated to be 15%. Measurement of serum prolactin during pregnancy in these patients is not helpful in identifying those with potential tumor growth. In women who had a minimal to moderate decrease in tumor size with initial medical therapy, some authorities use a surgical debulking procedure before pregnancy to decrease the chance of tumor expansion during pregnancy. If compressive symptoms develop during pregnancy, and surgery is not recommended, bromocriptine[1] is an effective agent in such instances. Summary Hyperprolactinemia is often reported in the general population and its cause is often easy to recognize. Identifying the pathophysiologic basis of hyperprolactinemia and its associated clinical presentation should precede any therapeutic intervention. Eliminating the offending drug or treating the primary cause is effective and rewarding. The most significant cause of hyperprolactinemia is prolactinoma, and these are effectively treated with dopamine agonists. Such treatments lower serum prolactin levels to normal and shrink existing tumors so that surgical therapy is not often used in these patients. Surgical resection can be an alternative approach in the small percentage of patients who are resistant to dopamine agonists' therapy and in the few who are unable to tolerate these drugs.



REFERENCES Arafah, 1986. Arafah BM: Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1986; 62:1173-1179. Arafah and Nasrallah, 2001. Arafah BM, Nasrallah M: Pituitary tumors: Pathophysiology, clinical manifestations and management. Endocr Relat Cancer 2001; 8:287-305. Barlier and Jaquet, 2006. Barlier A, Jaquet P: Quinagolide: A valuable treatment option for hyperprolactinemia. Eur J Endocrinol 2006; 154:187-195. Gibney et al., 2005. Gibney J, Smith TP, McKenna TJ: Clinical relevance of macroprolactin. Clin Endocrinol (Oxf) 2005; 62:633-643. Gillam et al., 2006. Gillam MP, Molitch ME, Lombardi G, Colao A: Advances in the treatment of prolactinomas. Endocr Rev 2006; 27:485-534. Honbo et al., 1978. Honbo KS, Van Herle AJ, Kellett KA: Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978; 64:782-787. Schlechte, 2003. Schlechte JA: Prolactinomas. N Engl J Med 2003; 349:2035-2041. Sievertsen et al., 1980. Sievertsen GD, Lim VS, Nakawatase C, Frohman LA: Metabolic clearance and secretion rates of human prolactin in normal subjects and patients with chronic renal failure. J Clin Endocrinol Metab 1980; 50:846-852.



Chapter 161 – Hypothyroidism

Method of: John T. Nicoloff, MD Jonathan S. LoPresti, MD, PhD Diagnosis and treatment of hypothyroidism is an extremely rewarding experience both for the patient and clinician because lifelong restoration of a euthyroid state can be safely and economically achieved with the appropriate use of oral l-thyroxine (T4) replacement therapy. Although there are many potential causes for hypothyroidism ( Table 1 ), autoimmune thyroiditis (chronic thyroiditis, lymphocytic thyroiditis, Hashimoto's thyroiditis) represents most spontaneously occurring cases of primary hypothyroidism. The initial phases of the disease often start in early adolescence; the incidence of hypothyroidism often reaches its peak in older patient populations in which some degree of biochemical hypothyroidism becomes demonstrable in approximately 8% of males and 20% of females by the age of 70 years. This pattern is the result of the inherently slow, progressive, and unremitting nature of the underlying destructive autoimmune process. Unfortunately, establishing a clinical diagnosis of hypothyroidism generally is a difficult task, especially during the early stages of the disease. The insidious character of thyroid destruction and the lack of specific symptoms that raise suspicion in either the patient or physician make the diagnosis of hypothyroidism problematic. However, this diagnostic limitation can be overcome by establishing the presence of what is most often termed biochemical or subclinical or mild hypothyroidism as defined by consistent elevations in serum thyroid-stimulating hormone (TSH) concentrations when serum free thyroxine (FT4) levels still remain within the normal range. This diagnosis may be further bolstered by the additional findings of detectable serum antithyroperoxidase (anti-TPO) antibodies and the presence of a small, firm goiter. Therefore, the diagnosis of hypothyroidism secondary to chronic autoimmune thyroiditis can definitively be diagnosed at the earliest stages of the disease before the development of significant morbidity occurs. Furthermore, advances in technology have both reduced the cost and improved the accuracy of serum TSH measurements, thereby making it possible to perform cost-effective serum TSH screening on large at-risk populations. Therefore, the challenge for the clinician is to identify populations that are likely to be at risk for developing hypothyroidism, establish a diagnosis of subclinical disease, and initiate oral T4 therapy before overt signs and symptoms of hypothyroidism become clinically apparent.

TABLE 1 -- Etiology of Hypothyroidism

Primary Hypothyroidism •

Chronic autoimmune thyroiditis (Hashimoto's, lymphocytic)

•

Iatrogenic: 131I therapy, thyroidectomy, external radiation

•

Drugs: methimazole (Tapazole), PTU, perchlorate, lithium, amiodarone

•

Immune modulators: interferon-a, interleukins, postpartum period

•

Congenital: complete or partial thyroid gland absence, peroxidase deficiency

•

Severe dietary iodine deficiency

•

Thyroid infiltrative diseases (rare): lymphoma, Riedel's struma, amyloidosis, hemochromatosis

Central Hypothyroidism •

Pituitary TSH deficiency (secondary hypothyroidism): Sheehan's syndrome, pituitary tumors, hypophysitis, trauma (surgery, radiation, head injury), empty sella syndrome

•

Hypothalamic TRH deficiency (tertiary hypothyroidism): tumor, craniopharyngioma, Sheehan's syndrome, infiltrative diseases (sarcoidosis, tuberculosis, histiocytosis, lymphoma, eosinophilic granuloma)

Transient Hypothyroidism •

Subacute thyroiditis

•

Postpartum thyroiditis

Congenital Thyroid Hormone Resistance (Genetic) •

Peripheral variant

•

Central variant

Abbreviations: 131I = iodine-131; PTU = propylthiouracil; TRH = thyrotropin releasing hormone; TSH = thyroid-stimulating hormone.

Etiology PRIMARY HYPOTHYROIDISM Chronic autoimmune thyroiditis is responsible for most spontaneously occurring cases of thyroid gland failure. As its name implies, chronic autoimmune thyroiditis results from an immunologic process characterized by the insidious, cell-mediated destruction of the thyroid gland. Lymphocytic thyroiditis and Hashimoto's thyroiditis represent specific pathologic terms that describe histologic variants of this autoimmune thyroid gland destruction. The disorder is characterized by progressive infiltration of the thyroid by lymphocytes, lymphoid follicles, and other inflammatory cells over many years, ultimately producing a remnant scar where the gland was located. The onset of the disease commonly occurs in early adolescence and primarily in females (5:1 female-to-male ratio) who display a small, irregular, firm, nontender goiter (so-

called adolescent goiter) in an otherwise healthy young adult. Even in this initial phase of the disease, serum TSH concentrations can become persistently elevated; and serum anti-TPO antibodies are frequently detectable. The former is responsible for the compensatory goiter formation, and the latter serving as a nonspecific marker of the underlying thyroid autoimmunity. With advancing age, the cumulative incidence of hypothyroidism gradually rises in both females and males with the female-to-male ratio declining from an initial value of 5:1 to a 2:1 ratio by age 70 years. This latter finding is consistent with the concept of a genetic predisposition for developing autoimmune thyroiditis with thyroid dysfunction displayed earlier in the female population. It is noteworthy that this same age/sex pattern is commonly observed with other autoimmune diseases as well. Exposure to iodine-containing drugs such as intravenous (IV) contrast dyes and to immune modulating agents such as interferon can precipitate or exacerbate this underlying autoimmune process in susceptible individuals, occasionally producing an abrupt onset of thyroid gland failure and development of hypothyroidism. However, on withdrawal of these agents, thyroid function usually returns to the pretreatment status. In a similar context, postpartum thyroiditis represents a transient autoimmune exacerbation of thyroid dysfunction occurring during early postpartum in women with either preexisting or the genetic tendency for autoimmune thyroid disease. Although most of these women subsequently experience a spontaneous resolution of this mild and transient form of biochemical hypothyroidism within a few weeks, they should be considered to be an at-risk population for developing spontaneous hypothyroidism in the future. UNCOMMON CAUSES OF PRIMARY HYPOTHYROIDISM Severe dietary iodine deficiency, surgical thyroidectomy, iodine-131 (131I) ablation, and excessive antithyroid drug administration represent obvious and anticipated causes of primary hypothyroidism and therefore should not represent either a diagnostic or therapeutic problem for the clinician. Approximately one third of patients with subacute thyroiditis will experience a mild to moderate primary hypothyroidism from 6 weeks to 6 months following the onset of this virally mediated destruction of the thyroid. However, in contrast to chronic autoimmune thyroiditis, this form of hypothyroidism is transient in character; eventual full recovery of thyroid gland function and histology is the norm. Neonatal hypothyroidism, or cretinism, represents a rare but important treatable cause of infant mental retardation. Although clinically difficult to recognize at birth, the widespread use of neonatal thyroid screening testing and early T4 replacement therapy has essentially abolished this form of hypothyroidism in medically advanced countries. Fortunately, thyroid neonatal screening programs are also rapidly spreading to the underdeveloped regions of the world to address this treatable form of hypothyroidism. CENTRAL HYPOTHYROIDISM Central hypothyroidism is a rarely encountered entity representing less than 1% of all cases of hypothyroidism. It results from a wide variety of pathologic conditions that impair pituitary TSH, secondary hypothyroidism, and/or hypothalamic thyrotropin-releasing hormone (TRH), tertiary hypothyroidism production, or secretion resulting in a decline in function of the thyroid gland. Common causes of central hypothyroidism include pituitary tumors, empty sella syndrome, trauma, postpartum pituitary necrosis (Sheehan's syndrome), hypophysitis, whole-brain radiation, and a variety of infiltrative diseases (see Table 1 ). Of considerable diagnostic importance is that the biologic properties of the TSH secreted in secondary hypothyroidism are often altered (because of impaired TRH action on TSH formation) resulting in forms of TSH that have markedly reduced bioactivity while retaining normal immunoactivity. This phenomenon often results in falsely normal TSH values reported in patients who are otherwise biochemically and clinically hypothyroid. Therefore, the utility of serum TSH measurements by immunoassay in accurately assessing thyroid status is essentially lost either for establishing the initial diagnosis or monitoring the adequacy of T4 replacement therapy in patients with secondary hypothyroidism.

Diagnosis The clinical diagnosis of hypothyroidism is inherently difficult to establish because the classic features of this condition only become fully evident in the latest stages of the disease. Furthermore, the classic signs and symptoms of hypothyroidism such as weight gain, hypertension, dry skin, hair loss, cold intolerance, chronic fatigue, constipation, and fluid retention are nonspecific in character and commonly occur in populations without hypothyroidism. Only the presence of an asymptomatic, small, firm goiter and delayed deep tendon reflexes provide findings of some diagnostic utility and specificity. However, these signs are usually not routinely assessed unless a suspicion that the patient is at risk for developing hypothyroidism is present. Common risk factors include a positive family history of thyroid or other autoimmune diseases and the detection of an elevated serum TSH value with routine blood tests.

CURRENT DIAGNOSIS Hypothyroidism presents with nonspecific signs and symptoms. Therefore, hypothyroidism requires biochemical diagnosis. Screening of all adults older than 35 years of age should be considered. Definitive indications for screening include a positive family history and/or the presence of a goiter on exam. Routine screening tests include a serum TSH level and anti-TPO titer. Primary hypothyroidism is confirmed by elevated serum TSH levels and low T4 values. Secondary hypothyroidism is diagnosed by low serum T4 levels. Subclinical hypothyroidism is defined as a normal T4 and a minimally elevated TSH level. Abbreviations: anti-TPO = antithyroperoxidase; T4 = l-thyroxine; TSH = thyroid-stimulating hormone. AT-RISK POPULATIONS FOR PRIMARY HYPOTHYROIDISM Because the propensity for the development of autoimmune diseases is strongly influenced by genetic factors, it is not surprising to find that hypothyroidism secondary to chronic thyroiditis is a familial disorder. Therefore, eliciting a family history either of an underactive or overactive thyroid condition, the use of thyroid medications, or the presence of a goiter all point toward the possibility of the patient harboring an occult thyroid disorder. If any of these conditions are present in the family, undertaking of a more careful neck examination palpating for a goiter, eliciting deep tendon reflexes evaluating for a slow relaxation phase, and measuring serum TSH and anti-TPO levels can be justified. A positive family history for other autoimmune disorders such as vitiligo, pernicious anemia, myasthenia gravis, Addison's disease, and type 1 diabetes mellitus increases the risk of developing autoimmune hypothyroidism. The discovery of such a history of familial autoimmunity is considerably useful because it raises the probability of detecting subclinical hypothyroidism. LABORATORY DETECTION OF SUBCLINICAL HYPOTHYROIDISM

Measurement of serum TSH levels occupies a central role in establishing the laboratory diagnosis of primary hypothyroidism, especially in its earliest subclinical stage. Because thyroxine secretion declines as a result of the progressive destruction of the thyroid gland from chronic thyroiditis, even a small decrease in serum FT4 concentration within the normal range promptly produces a reciprocal increase in the serum TSH value. Importantly, the relative magnitude of this serum TSH rise far exceeds the fall in FT4 resulting from an amplified hypothalamic–pituitary negative feedback response, for example, a two-fold change in FT4 produces a 100-fold change in TSH. Therefore, this isolated elevation in serum TSH not only serves as an early marker for impending thyroid gland failure but also acts to stimulate the preferential secretion of more biologically active triiodothyronine (T3) by the thyroid gland, thereby masking the onset of the signs and symptoms of hypothyroidism. This latter phenomenon helps, in part, to explain the subclinical character of this syndrome. When such an isolated elevation in serum TSH is detected, the serum TSH determination should be repeated along with a serum anti-TPO measurement for diagnostic verification and as an indicator of the underlying autoimmune nature of the process. If not already performed, complete a careful family history, as characterized earlier; a careful neck examination for the presence of a goiter; and an assessment of deep tendon reflexes. WHEN ARE SERUM THYROID-STIMULATING HORMONE ELEVATIONS SIGNIFICANT? In ambulatory, clinically well individuals, any persistent serum TSH elevation should be considered as strong evidence for the presence of primary hypothyroidism, even when the serum FT4 values remain within the normal range. With a normal reference range of serum TSH concentration of 0.5 to 3.5 mU/L, individuals displaying TSH increases from 3.5 to 10 mU/L or even higher are often remarkably free of hypothyroid symptoms, particularly in younger patients. However, bolstered by the additional findings of detectable antiTPO antibodies, a positive family history for thyroid or other autoimmune diseases as well as the presence of a small firm goiter, this suspicion evolves into the realm of diagnostic certainty, even with modest rises in serum TSH levels. If, however, these additional confirmatory findings are absent but serum TSH elevations persist, some clinicians may choose to defer making a diagnosis of primary hypothyroidism, especially if the rise in serum TSH is minimal (less than 10 mU/L). In this case, the physician should continue to monitor serum TSH concentrations at 6- to 12-month intervals to ascertain the persistence and progression of hypothyroidism rather than to initiate lifelong oral T 4 therapy. Keep in mind, however, that many patients with mild subclinical hypothyroidism may experience unexpected symptomatic benefit as well as lowering of serum lipid levels following the initiation of T4 replacement therapy. In this sense, subclinical hypothyroidism may represent a misnomer. TRANSIENT SERUM THYROID-STIMULATING HORMONE ELEVATIONS ASSOCIATED WITH SYSTEMIC ILLNESSES In contrast to the relatively stable serum TSH values encountered in healthy ambulatory populations, serum TSH values can become quite labile with acute illnesses where serum TSH values are commonly in the range characteristic of both hyper- and hypothyroidism. Generally, as the illness worsens, serum TSH concentrations become suppressed whereas during recovery they can rebound to elevated values. Obviously, these transient changes in serum TSH levels greatly impair the utility of serum TSH determination as a diagnostic tool. Therefore, greater reliance must be placed on serum FT4 measurements in sick patients. Interestingly, the therapeutic use of both glucocorticoids and dopamine will also cause dramatic transient reductions in serum TSH levels during their acute administration, followed by rebound elevations when these agents are withdrawn. It is believed that this results from direct inhibitory action on the release of TSH from the pituitary. Presumably, a similar inhibitory action from the endogenous cortisol increase on TSH secretion in response to major stress is responsible for the spontaneous decline in serum

TSH in acute illness. When such transient changes in serum TSH occur in ambulatory patient populations, acute therapeutic glucocorticoid administration most often proves to be the culprit, such as asthma therapy. However, when chronic glucocorticoid therapy is employed, serum TSH concentrations generally remain in the normal range in the euthyroid patient. THYROID-STIMULATING HORMONE SCREENING OF ADULT POPULATIONS Serum TSH screening of adult populations is cost effectively performed because of technological advances made in the automation of TSH assay methods. This fact has led the American Thyroid Association to recommend screening of the entire population for thyroid disease starting at age 35 years and at 5-year intervals thereafter if initial screening results are normal. Other more restrictive population screening recommendations include testing the entire prenatal population and all the adult population starting at age 60 years. Certainly, all individuals providing a familial history of thyroid or other autoimmune diseases also make up a logical group deserving of TSH screening, as well. In the final analysis, it comes down to what is perceived to be the cost-to-benefit ratio of such an undertaking. Presently, a broad consensus in the medical community on this subject has not yet been formed regarding screening for thyroid disease in the population. Treatment ORAL L-THYROXINE ALONE AS THE SOLE FORM OF THYROID HORMONE REPLACEMENT THERAPY The advantages of employing oral LT4 (Synthroid) as the sole thyroid replacement therapy are many and include the following: •

The availability of several well-standardized, competitively priced brands of synthetic oral LT 4 ( Table 2 )

•

A long biological half-life approximating 7 days, thereby making day to day compliance less critical

•

Production of remarkably stable circulating levels of FT4, which can be easily and accurately measured by routine laboratory testing methods

•

Production of stable physiologic circulating levels of triiodothyronine (T3), the active form of thyroid hormone, derived from the peripheral tissue conversion from T4

•

Allows the physiologically adaptive regulation of T4 to T3 conversion to occur in response to alterations in nutrition and stresses associated with illness and injury

TABLE 2 -- Thyroid Hormone Preparations Generic Name Brand Name Levothyroxine sodium (LT4)

•

Levothroid

•

Levoxyl

•

Unithroid

Liothyronine sodium (LT3)

Cytomel

Liotrix (LT4 and LT3 combination)

Thyrolar

Thyroid USP (LT3 and LT4 extract) Armour Thyroid

Abbreviations: LT 4 = levothyroxine; LT 3 = liothyronine.

In contrast, the use of oral LT3 (Cytomel) alone or in combination with LT4 possesses none of these important advantages and therefore is not recommended for use as standard hormone replacement therapy. INITIATION AND MAINTENANCE OF OPTIMAL LT4 REPLACEMENT THERAPY IN PRIMARY HYPOTHYROIDISM It is important to initiate oral LT4 replacement therapy slowly, starting with a LT4 dose of 25 µg daily and subsequently increasing the dose by 25 µg every 6 weeks until the serum FT4 levels reach the midnormal range. A total daily LT4 dose ranging between 50 and 125 µg usually is required to achieve this goal of a normal FT4 value (a daily dose of 125 mg of LT 4 is needed for full replacement in an adult with no residual thyroid function). This deliberate treatment approach is essential to allow sufficient time for the myriad of metabolic alterations produced by T4 therapy to take place. After achieving this initial goal of normal serum FT4 levels, serial serum TSH levels can be measured to achieve an optimal individualized TSH target value ranging between 0.5 to 2.0 mU/L. However, with each LT4 dosage adjustment, it is important to allow a period of at least 6 weeks for a new metabolic equilibrium to be achieved before serum TSH is remeasured. As noted, this LT4 titration process requires that considerable time and patience be practiced by both by the clinician and patient. Once the final optimal serum TSH level is achieved, this daily oral LT4 dose requirement rarely changes as long as the patient remains compliant and the brand of T4 medication is not altered. One possible exception to this rule is that a slight reduction in LT 4 dose requirement often occurs after the age of 60 years presumably in association with a general slowing of overall metabolism.

CURRENT THERAPY Treatment of choice for hypothyroidism should be a nongeneric levothyroxine preparation. Interchanging of brands is contraindicated because each levothyroxine preparation has a unique absorption profile. Levothyroxine sodium (Synthroid) dosing should start at 25 µg daily and be increased slowly until the ideal dose is reached as determined by a serum TSH level. Goal of levothyroxine therapy in primary hypothyroidism is a serum TSH value between 0.5 mU/L and 2.0 mU/L. Goal of therapy in secondary hypothyroidism is a normal T4 level. Treatment of subclinical hypothyroidism should be determined on a case-by-case basis. Abbreviations: T 4 = l-thyroxine; TSH = thyroid-stimulating hormone. TREATMENT OF CENTRAL HYPOTHYROIDISM

The initiation of oral LT4 therapy in patients with central hypothyroidism is essentially the same as detailed previously for primary hypothyroidism. However, before starting LT4 therapy, special care must be exercised to ensure adequate glucocorticoid replacement as thyroid hormone may accelerate glucocorticoid disposal and thereby may precipitate an Addisonian crisis. Additionally, because the measurement of serum TSH concentrations cannot serve as a useful therapeutic end-point in patients with central hypothyroidism, the adequacy of LT 4 replacement therapy must then rely on normalizing serum FT4 values. COMMON PITFALLS IN OPTIMAL ORAL L-THYROXINE THERAPY The clinician should become suspicious that a problem likely exists in the management of LT4 therapy when marked variability in serum TSH values occurs on a fixed LT4 maintenance dose. The three most likely causes for this phenomenon are as follows: 1.

Noncompliance: Poor compliance represents the most commonly encountered problem causing suboptimal LT4 maintenance therapy. The principal reason for noncompliance usually relates to the fact that patients do not experience any immediate change in their state of health when stopping LT4 therapy. This often results in patients missing their daily LT4 dose or when they run out of their T4 supply, not promptly replacing it. To compound the problem, when the patients are asked, “Are you taking your thyroid medication?” they can honestly say, “Yes,” because they may have recently restarted therapy in anticipation of the next physician visit. Therefore, one might ask, “How often do you forget to take your thyroid medication?” to remove the stigma from noncompliance. Patients often look puzzled when queried in such a manner but they then rapidly understand when their physician reassures them, “We all forget to take our medication at some time—I certainly do.” Experience indicates that such misinformation is the most common cause for physicians inadvertently prescribing excessive dosages of oral LT4 therapy

2.

Drugs and other factors altering T 4 absorption and metabolism: Table 3 lists some of the most common causes leading to a need for an increase in oral LT4 dose requirements. Drugs or conditions that reduce gastric acidity also decrease T4 absorption because the hormone is more readily absorbed in its acidic form. Because T4 is highly lipophilic, drugs that interfere with fat absorption also will impair thyroxine absorption, as well. Still other drugs act to accelerate hepatic T4 disposal by the so-called hepatic “first pass effect.” Administering oral LT 4 separately in the morning before taking drugs that interfere with GI absorption can mitigate this problem. Otherwise, compensatory increases in the oral LT4 dosing schedule will be required.

3.

Switching oral LT4 brands: The T4 content of oral thyroxine preparations is well standardized and carefully monitored by the FDA. However, variations in tablet dissolution characteristics and other features of the tablet structure appear to influence the efficiency of T 4 gastrointestinal absorption. These facts make it desirable not to switch the brand of an oral LT 4 preparation once the optimal dose has been ascertained for any given patient. For the same reason, generic T4 brands should be avoided because the source of the T 4 tablets may vary over time.

TABLE 3 -- Common Causes Requiring Oral Levothyroxine Dosage Adjustment

Increased LT4 Administration Required •

Poor compliance

•

Decreased gastrointestinal absorption: oral iron, lipid-binding drugs, sucralfate, calcium carbonate, achlorhydria, proton-blocking drugs

•

Altered T4 metabolism: phenobarbital, phenytoin, carbamazepine, rifampin, HAART

•

Pregnancy

•

Nephrotic syndrome

Decreased LT4 Administration Required •

Aging

Abbreviations: HAART = highly active antiretroviral therapy; LT4 = levothyroxine; T4 = L-thyroxine.

Special Situations PREGNANCY Women with hypothyroidism who become pregnant usually require substantial increases in their oral LT4 maintenance dose. Such upward dose adjustments must be performed very early in pregnancy because normal fetal brain development in the first 12 weeks of gestation depends on maternal thyroxine as its source of thyroid hormone. Furthermore, there is strong circumstantial evidence that a deficiency in maternal T 4 at this stage of pregnancy is associated with a subsequent reduction in intelligence quotient in the offspring. It is noteworthy that one possible cause for this increased oral LT 4 requirement results from the concurrent use of oral iron supplements, which interfere with T4 absorption ( Table 3 ). To reduce this effect of iron on T4 absorption, it is advisable to take the oral LT4 dose and the iron at separate times. SURGICAL PROCEDURES Surgery usually does not present a special problem for hypothyroid patients who have received adequate preoperative oral LT4 replacement therapy. The failure to receive oral medications for a few days postoperatively also is not a therapeutically important problem by virtue of the long 7-day half-life of thyroxine. However, in rare cases of prolonged restriction of oral intake, LT4 can then be administered as a 500 µg IV bolus every 5 days until oral intake can be restarted. In the untreated or inadequately treated hypothyroid patient requiring elective surgery, surgery should be deferred until a euthyroid state is restored with LT4 therapy to significantly reduce operative and postoperative morbidity. In those instances of surgical emergenciesor in patients with severe coronary artery disease, surgery should proceed because such surgery is reasonably well tolerated if IV LT4 therapy is administered in the immediate postoperative period. MYXEDEMA COMA Myxedema coma is a somewhat imprecise term in that this syndrome should be more appropriately termed

decompensated hypothyroidism. Myxedema coma does not simply represent the natural progression of severe hypothyroidism but signifies an instance where intervening illness or events are responsible for precipitating a significant deterioration in mental status (i.e., acute psychosis, confusion, stupor, and coma) and producing cardiovascular collapse in the patient. The key to therapy is determining the precipitating cause and promptly initiating appropriate therapy. Occult infection and sepsis represent the most common etiologies of decompensation, but a long list of primary and contributing causes includes blood loss, excessive use of diuretics, carbon dioxide retention, oversedation with medications, overuse of tranquilizers and narcotics, and so forth. The use of IV LT4 at an initial dose of 500 µg undoubtedly plays a positive role in marshalling an improved host response but is only useful in conjunction with the identification and reversal of the precipitating event(s).



REFERENCES Foley, 2004. Foley Jr TP: Hypothyroidism. Pediatr Rev 2004; 25:94-100. Green, 2005. Green WL: New questions regarding bioequivalence of levothyroxine preparations: A clinician's response. AAPS J 2005; 7:54-58. LoPresti, 1996. LoPresti JS: Thyroid function tests. In: Shindo M, Singer P, ed. Clinics in Otolaryngology, Philadelphia: WB Saunders; 1996:557-576.1996. LoPresti and Nicoloff, 1993. LoPresti JS, Nicoloff JT: Myxedema coma: A form of decompensated hypothyroidism. In: Ober KP, ed. Endocrinology and Metabolism Clinics of North America, WB Saunders: Philadelphia; 1993:279-290. Roberts and Ladenson, 2004. Roberts CG, Ladenson PW: Hypothyroidism. Lancet 2004; 363:1558-1594. Surks et al., 2005. Surks MI, Goswami G, Daniels GH: The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab 2005; 90:5489-5496. Wartofsky and Dickey, 2005. Wartofsky L, Dickey RA: The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab 2005; 90:5483-5488.



Chapter 162 – Hyperthyroidism

Method of: Peter A. Singer, MD Hyperthyroidism encompasses a heterogeneous group of disorders, all of which have two features in common. Firstly, all of the types of hyperthyroidism include a ß-adrenergic–mediated symptom complex of varying degrees of severity characterized by symptoms of nervousness, heat intolerance, irritability, palpitations, and increased bowel motility, with frequency of movements. Secondly, hyperthyroidism is associated with the catabolic effects of excess circulating levels of thyroid hormone; such effects can include weight loss, fatigue, muscle weakness, increased appetite, and bone loss. The symptoms and signs of hyperthyroidism depend on a number of variables, including levels of circulating thyroid hormone, duration of disease, the age of the patient, and concurrent illnesses. Hyperthyroidism can be classified according to the capacity of the thyroid gland to trap radioactive iodine ( Box 1 ). Disorders with increased radioiodine uptake have thyroid gland autonomy (with the exception of thyroid-stimulating hormone [TSH]-secreting pituitary tumors) and require specific treatment, whereas those with suppressed radioiodine uptake include conditions that are usually self-limited and might require only symptomatic treatment. Physical examination of the hyperthyroid patient generally reveals a person who is somewhat anxious and has a rapid pulse. In the elderly, atrial fibrillation is common, and many elderly patients have widened pulse pressure, warm skin, and palpable thyroid gland findings, depending on the underlying etiology. Examination of the eyes in all types of hyperthyroidism might show eyelid retraction, which is mediated by ß-adrenergic stimulation. Infiltrative ophthalmopathy is seen almost exclusively in patients with thyrotoxic Graves' disease. BOX 1

Causes of Hyperthyroidism[*] Hyperthyroidism with Elevated RAIU

•

Graves' disease

•

Toxic multinodular goiter

•

Toxic adenoma

•

TSH-secreting pituitary tumor

•

Hydatiform mole

•

Choriocarcinoma

•

Pituitary resistance to thyroid hormone

Hyperthyroidism with Low RAIU

•

Factitious

•

Subacute granulomatus thyroiditis

•

Subacute lymphocytic (postpartum or sporadic)

•

Amiodarone-induced thyroiditis

•

Iodine-induced hyperthyroidism

•

Radiation-induced thyroiditis

•

Metastatic functioning follicular tumor

•

Struma ovarii

Abbreviations: RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone. * In probable decreasing order of frequency.

Diagnosis Because many of the symptoms of hyperthyroidism may be compatible with some nonthyroid disorders, such as anxiety or the perimenopausal state, TSH, should be measured in patients in whom hyperthyroidism is suspected. TSH suppressed in hyperthroidism, although in patients with rare TSH-secreting pituitary tumors, TSH levels may be normal or even slightly elevated. TSH levels may be suppressed in hospitalized patients, especially those who are seriously ill or who are receiving pharmacologic doses of glucocorticoids or dopamine, thus limiting the usefulness of serum TSH measurements in such patients. A suppressed TSH level in patients suspected to have hyperthyroidism should be complemented with a serum free thyroxine (T4) or its estimate to confirm the diagnosis. Patients with normal thyroid hormone levels and suppressed TSH concentrations have what is termed subclinical hyperthyroidism, a disorder usually free of overt symptoms of hyperthyroidism.

After the diagnosis of hyperthyroidism is confirmed, its etiology should be determined by obtaining a thyroid radioactive iodine uptake. Patients with obvious Graves' disease (such as those with infiltrative ophthalmopathy or large goiters with bruits), may forgo the radioactive iodine uptake test. It is important, however, to differentiate between Graves' disease and low radioactive iodine uptake conditions, which usually are self-limited. In addition to the radioactive iodine uptake, a scan may be helpful in establishing the diagnosis in patients with suspected toxic multinodular goiter, a condition encountered more commonly nowadays due to increasing immigration into the United States from endemic goiter regions. Treatment Because approximately 80% of patients with hyperthyroidism in the United States have thyrotoxic Graves' disease, most of the comments in this article pertain to that disorder. Among patients with high radioactive iodine–uptake hyperthyroidism, only Graves' disease may be associated with remission following the use of thionamide drugs.

CURRENT DIAGNOSIS Symptoms of Graves' Hyperthyroidism Emotional lability Eye irritation, photophobia, diplopia Fatigue Heat intolerance Increased appetite Increased frequency of bowel movements Increased perspiration Menstrual irregularities Muscle weakness Nervousness Palpitations Shortness of breath Sleep disturbances Weight loss Signs of Graves' Hyperthyroidism

Diffuse goiter Eye stare Hyperreflexia Infiltrative dermopathy (~5%) Proptosis Proximal muscle weakness Systolic hypertension Tachycardia Thyroid bruit Warm, smooth skin Widened pulse pressure DEVELOPING A TREATMENT STRATEGY General Measures and Patient Education

Essential in the early management of Graves' hyperthyroidism is emphasizing to the patient that strict adherence to the treatment regimen is essential in alleviating symptoms and restoring health. Persons with hyperthyroidism commonly tend to be impatient, likely due to their symptoms, and it must be stressed that compliance with treatment advice is essential for a successful outcome. If family members or friends accompany the patient to the appointment, it is helpful to make them familiar with the treatment plan as well. Initial Treatment of Symptoms

Because many of the symptoms of hyperthyroidism are related to enhanced ß-adrenergic stimulation, I routinely employ ß-adrenergic–blocking drugs, although mild symptoms might not warrant their use. I prefer propranolol (Inderal),[1] even though it must be given approximately every 6 hours to be completely effective. Propranolol's relatively short half-life makes this agent preferable, because patients learn to titrate their own medication, depending on their symptoms. As patients improve during the course of thionamide therapy (see later), they can omit more doses of propranolol. The usual starting dose of propranolol[1] is between 20 and 40 mg approximately every 6 hours (or four times a day), and the desired target heart rate is approximately 80 beats per minute. Some physicians prefer longer acting ß-blockers, such as atenolol (Tenormin), [1] which may be given as a single daily dose. In patients in whom compliance may be problematic, or in those who prefer once-daily dosing, atenolol 50 to 100 mg a day is an excellent alternative. Other long-acting ß-blockers are nadolol (Corgard)[1] and metoprolol (Lopressor).[1] Long-acting ß-blockers are cardioselective and are not contraindicated in patients with coexisting asthma, as propranolol is.

CURRENT THERAPY

Treatment Modality

Advantages

Disadvantages

Thionamide drugs

Chance of remission

Relapse (40%)

Relatively inexpensive

Side effects (5-10%)

Rapid, permanent cure

Surgical complications (hypocalcemia, recurrent nerve injury ~1%–3%)

Surgery

Hypothyroidism Radioactive iodine Permanent cure

Expensive Hypothyroidism

In my experience, patients who are treated with adequate doses of ß-adrenergic blocking drugs have significant relief of symptoms within a few days after the medication is initiated. 1 Not FDA approved for this indication.

Reduction of Serum Thyroid Hormone Levels

Unfortunately, there have been few advances in the management of hyperthyroidism in recent years. Treatment basically consists of lowering the concentrations of serum thyroxine (T4) and triiodothyronine (T3), which may be accomplished either with thionamide drugs or with ablative therapy, either radioiodine or surgery. In the United States, radioiodine ablation with 131I is the preferred method of treatment of most practicing endocrinologists. Indeed, in a survey of thyroid experts completed in 1991, 69% of respondents chose radioiodine as the primary form of therapy for a prototypic 43-year-old woman with uncomplicated Graves' disease. Only 1% of physicians recommended surgery, and 30% selected thionamide drugs as the primary form of therapy. The responses were in sharp contrast to thyroid experts in both Europe and Japan, where a similar survey revealed that the majority of physicians favored thionamide drugs as the primary form of therapy. The rationale provided by physicians in the United States who selected radioiodine therapy was the fact that the remission rate following 1 to 2 years of thionamide drugs was only approximately 30%. Before recommending a specific type of therapy for a patient with Graves' disease, it is essential that the patient be aware of the benefits and pitfalls of each type of treatment. THIONAMIDE DRUG THERAPY Initial Treatment

Currently, there are two thionamide drugs available for clinical use in the United States, methimazole (MMI, Tapazole) available in 5-mg and 10-mg tablets, and propylthiouracil (PTU) available in 50-mg tablets. Both agents inhibit the synthesis of thyroid hormone by blocking organification of iodine. PTU also inhibits

peripheral conversion of T4 to T3, although clinically this may be more of a theoretical than a practical advantage. I generally prefer MMI, rather than PTU, because of its longer biological half-life and its potency. For uncomplicated hyperthyroidism, MMI may initially be given 2 to 3 times a day in a total dose of 20 to 30 mg, whereas PTU is usually administered 3 to 4 times a day in a total dose of 300 to 400 mg. When biochemical euthyroidism is achieved, usually after 6 to 8 weeks of therapy, MMI may be given once a day, or PTU twice a day, and the total dose may be halved. The relative simplicity of using MMI versus PTU can render it more suitable for patients in whom compliance may be difficult. It must be stressed to the patient that omitting medication doses can result in a rebound of the hyperthyroid state, because the intrathyroid deficiency of iodine produced by thionamide drugs results in more avid trapping of exogenous iodide. In general, I obtain serum T4 and T3 levels about 6 to 8 weeks after initiating thionamide drug therapy to ensure adequacy of treatment response. If there has been little clinical or biochemical improvement, the likeliest scenario is that doses of medication are being omitted. A serum TSH provides no additional information at this point, because TSH suppression is common for up to 3 or 4 months after euthyroidism has been achieved. Patients with very large goiters and fairly severe hyperthyroidism often take somewhat longer than 6 to 8 weeks to become euthyroid and can require larger doses of MMI (e.g., 40 mg/day) or PTU (e.g., 400-600 mg/day). I stress to patients that any improvement with thionamide drugs can take several weeks, and I recommend that they defer, if possible, making definitive decisions regarding long-term thionamide versus ablative therapy until they have improved to the extent that they are better able to make more reasoned choices. I always discuss the various forms of treatment of hyperthyroidism with patients during our first appointment, however, and reiterate the options after they have improved. Although the overall remission rate of patients treated with thionamide drugs in the United States is approximately 30%, some patients are more likely than others to go into remission. Patients with mild hyperthyroidism, small goiters, and a negative family history for hyperthyroidism are more likely to respond favorably, as are patients who respond quickly to thionamide drugs in terms of thyroid gland shrinkage and biochemical improvement. Conversely, patients with severe thyrotoxicosis and those with a strong family history of Graves' disease infrequently go into remission. Some clinicians have advocated serologic markers, such as thyroid-stimulating immunoglobulin or anti-TPO antibodies, to predict the likelihood of remission, but there has been no confirmation of their usefulness for such a purpose. Continuing Treatment

I reevaluate patients taking thionamide drugs approximately every 3 months, and in addition to the clinical examination, I obtain a serum free T4 (estimate) and TSH. If hypothyroidism occurs while on medication, I often add levothyroxine (Synthroid) rather than reduce the dose of thionamide drug. Most patients can be maintained euthyroid on 20 mg of MMI and 0.1 mg of levothyroxine taken in a single daily dose. If PTU is employed, it usually must be given twice daily. Combined therapy with thionamide drugs and levothyroxine resulted in a considerable amount of controversy several years ago, following the publication of an article from a Japanese group of researchers

who reported that 98% of patients taking both MMI and levothyroxine achieved remission. The researchers maintained serum TSH levels in the suppressed range and theorized that TSH inhibition with levothyroxine resulted in less stimulation of antigen release. Unfortunately, their findings have not been confirmed in subsequent studies, either in Japan or elsewhere. Some physicians, however, have reported improved remission rates following longer durations of thionamide administration, of up to 10 years. The practical aspects of such prolonged therapy however, might be open to question. Side Effects of Thionamide Drugs

The most common allergic side effects of thionamide drugs range from mild maculopapular rashes to urticarial eruptions and occur in approximately 5% of patients. Allergic reactions usually do not occur until 2 to 4 weeks after initiation of therapy. Mild symptoms may be managed with antihistamines, although complete resolution of itching and rash is uncommon. Therefore, I routinely switch patients from the type of medication they are taking (e.g., MMI) to PTU. Approximately 20% of patients are also allergic to the other thionamides, preventing their continued use. The most serious side effect of thionamide drugs is agranulocytosis, and although it is rare (0.2%-0.5% of patients), it is potentially fatal. It is usually manifested by fever and symptoms of infection, such as a severe sore throat. Patients must be instructed that if they develop fever and signs and symptoms of infection, they must stop the thionamide drug and call their physician immediately. A white blood cell count and differential must be performed, and if agranulocytosis is diagnosed, hospital admission is required. Successful reversal of agranulocytosis, sometimes employing granulocyte colony stimulating factor (G-CSF), should occur within a few days to a week. Some physicians obtain periodic white blood cell (WBC) counts, although this practice is probably unnecessary because the WBC does not predict agranulocytosis. Nevertheless, before initiating therapy with thionamide drugs, it is helpful to have a baseline WBC because leukopenia is common in patients with Graves' disease, and if a subsequent WBC is obtained, it is useful for comparison. Other potential side effects of antithyroid drugs include arthralgias and, rarely, hepatitis. Hepatitis is also potentially fatal. Stopping Antithyroid Drug Therapy

If therapy with thionamide drugs is used to induce remission, an endpoint of therapy should be determined. I usually treat for 12 to 18 months and then discontinue the thionamide agent. Patients are reevaluated approximately 4 to 6 weeks later, and a serum TSH is obtained. If the serum TSH is suppressed during thionamide therapy, the likelihood of remission is poor. If the patient is euthyroid at 4 to 6 weeks, the next visit is scheduled for approximately 3 months later and at increasing intervals thereafter, but at intervals no longer than 1 year. Most relapses of hyperthyroidism occur within the first year after stopping thionamide drugs, but they can occur at any time. If relapse occurs, a second course of thionamide drugs does not appear to increase the likelihood of remission, and ablation with radioiodine is then recommended. Some patients, however, prefer to take antithyroid drugs for several, or even many years and often can be maintained on a very small dose

of thionamide drug (e.g., 2.5-5 mg/day of MMI). Although such extended therapy is not my preference, there is no absolute contraindication to it. Patients on such a regimen need to be instructed that periodic follow-up, perhaps every 3 to 6 months, is necessary. RADIOACTIVE IODINE THERAPY Therapy with radioiodine (131I) is the preferred method of treatment for hyperthyroidism among other thyroid specialists practicing in the United States. Radioiodine has distinct advantages: It is effective, relatively inexpensive, and predictable, and it appears to be free of side effects other than the development of hypothyroidism. Radioiodine has been used to treat hyperthyroidism for approximately 45 years in the United States, and careful follow-up has failed to show an increased incidence of cancer in patients so treated or in genetic defects in offspring of 131I-treated patients. Radioiodine is contraindicated during pregnancy, which should be ruled out in women of childbearing age before its administration. In addition, women who are breast-feeding should not be treated with radioiodine, because the isotope can recirculate in breast milk for up to several weeks after administration. Selection of Radioiodine Dose

Some clinicians advocate administering a 131I dose that is sufficient to control hyperthyroidism without resulting in hypothyroidism. Various strategies have been employed over the years in an effort to achieve this goal, but they generally have failed. Therefore, I prefer administering a dose large enough to result in hypothyroidism, which usually occurs within 3 to 6 months after 131I administration. A dose of 15 mCi of 131I is usually sufficient to achieve this goal, but the appropriate dose depends on the radioactive iodine uptake and size of the thyroid gland. A 24-hour radioactive iodine uptake should be measured before the treatment dose is administered to ensure that adequate quantities of 131I will be absorbed by the thyroid. A dose of 100-150 fCi/g of thyroid tissue is generally an adequate ablative dose. Some patients are resistant to an initial dose of 131I and require a second or even third treatment. In my experience, male patients, Asians, and patients with large goiters appear to require larger or additional doses. If patients continue to be hyperthyroid 6 months after an initial treatment with 131I, a second dose is administered. Before administering radioiodine, I usually pretreat patients with thionamide drugs until they are euthyroid, because depletion of thyroid hormone from the thyroid prevents release of excess of thyroid hormone from the gland, thereby preventing exacerbation of hyperthyroidism. This is especially important for older patients or those with cardiovascular risk factors. Antithyroid drugs should be discontinued 3 to 5 days before radioiodine treatment. Patients receiving 131I without having been pretreated with antithyroid drugs (for example, patients who are allergic to thionamides) benefit from administration of propranolol [1] or other ßblockers after treatment, because their underlying hyperthyroidism may be transiently exacerbated by 131Iinduced thyroiditis. Follow-up after Radioiodine Treatment

I usually evaluate patients approximately 6 weeks following radioiodine administration in order to assess the clinical and biochemical responses. If the thyroid gland has not decreased in size by 6 weeks, a beneficial response from radioiodine is unlikely. If patients are euthyroid at 6 weeks, they return 4 to 6 weeks later, and if they are hypothyroid by that time, levothyroxine therapy is begun. If patients are still euthyroid (or hyperthyroid) 3 months after therapy, they are reevaluated in another 3 months. Nearly all patients are hypothyroid by 6 months after radioiodine treatment, and those who are still hyperthyroid require another

treatment dose. As experience with radioiodine has increased over the years, age limits for patients believed to be appropriate for treatment have decreased. It appears to be safe to treat teenagers with radioiodine, although I defer treatment in those who have not completed linear growth. There is little concern for developing thyroid nodularity in teenagers following 131I treatment provided ablative doses are administered. Radioiodine Treatment and Graves' Ophthalmopathy

Some clinicians think the administration of 131I to patients with Graves' ophthalmopathy can worsen the eye disease and administration of pharmacologic amounts of glucocorticoids for a period of one month to 6 weeks following radioiodine treatment will lessen the likelihood of this occurrence. The data concerning efficacy of steroids are not conclusive, however. I believe that patients with moderate symptoms and signs of eye disease should be evaluated by an ophthalmologist with expertise in Graves' ophthalmopathy before administration of 131I. Indeed, it is often helpful to involve the ophthalmologist in the care of patients with ophthalmopathy, regardless of the type of treatment for hyperthyroidism. SURGERY Surgery for Graves' hyperthyroidism is infrequently employed in the United States. Candidates for such treatment include children and teenagers, especially those who have difficulty complying with antithyroid drugs. Other indications include patients with very large goiters, especially those likely to be resistant to radioiodine because of large goiter size. In addition, surgery is the only choice for patients who are allergic to thionamide drugs and who refuse to take radioiodine. Surgery is also indicated for pregnant patients who are allergic to thionamide drugs (see later). Patients who have a coexistent thyroid nodule suspicious for cancer on fine-needle aspiration should be treated surgically. Before surgery, it is preferred to render the patient euthyroid with thionamide drugs. Some surgeons prefer to administer exogenous iodides for 10 days before surgery. Exogenous iodides produce benefit both by inhibiting thyroid hormone release and by decreasing thyroid gland vascularity. Potassium iodide or Lugol's solution, 10 drops in a glass of water daily for 10 days, is sufficient. Patients electing to undergo thyroidectomy should be made aware that permanent hypothyroidism will most likely result and that they will require the same type of follow-up as those treated with radioiodine. If insufficient thyroid tissue is removed, persistent or recurrent hyperthyroidism will result, which will necessitate radioiodine ablation. Although surgery has the advantage of being rapidly curative, it also has potential complications. One is injury to the recurrent laryngeal nerve and the other is the possibility of permanent hypoparathyroidism. In skilled hands, these complications occur no more than 1% to 3% of the time, yet these potential risks must be explained fully to the patient beforehand. Other Forms of Hyperthyroidism TOXIC NODULAR GOITER

Toxic multinodular goiter increases in prevalence with increasing age. In elderly persons it is a more common cause of hyperthyroidism than is Graves' disease. The diagnosis should be documented with a radioactive iodine uptake and thyroid scan. Patients with toxic multinodular goiter will not go into remission on thionamide drugs, limiting definitive treatment to either radioiodine or surgery. Before radioiodine is employed in elderly patients, thionamide drugs should be administered to minimize the risk of exacerbating hyperthyroidism. Radioiodine is the treatment of choice for most patients with toxic multinodular goiter, although surgery may be preferred for patients with especially large glands or with symptoms of compression who are good operative risks. If radioiodine is used for treatment of toxic nodular goiter, the dose required is usually greater than that employed for Graves' disease. A single thyroid nodule producing hyperthyroidism occurs much less often than toxic multinodular goiter, and it generally occurs in persons younger than those with multinodular goiter. Although radioiodine is commonly employed for such patients, surgery is usually recommended for patients younger than 25 to 30 years. HYPERTHYROIDISM AND PREGNANCY Hyperthyroidism during pregnancy can lead to adverse outcomes both for mother and fetus. Adequate control of hyperthyroidism during pregnancy is essential. Either MMI or PTU may be used during pregnancy, but most clinicians favor PTU because it does not cross the placenta as easily as does MMI. For hyperthyroidism that is difficult to control, or if the patient is allergic to antithyroid drugs, thyroidectomy should be performed during the second trimester. ß-Adrenergic blocking agents may be given safely during pregnancy to control symptoms. Patients who continue to be treated with thionamide drugs during pregnancy should have a thyroidstimulating immunoglobulin level drawn during the last trimester to predict the possible occurrence of neonatal hyperthyroidism. Hyperthyroid pregnant patients should be followed carefully at least every 4 to 6 weeks, and close communication should be maintained between the endocrinologist and obstetrician. It is advisable to use the lowest dose of thionamide drug that maintains maternal euthyroidism. THYROID STORM Thyroid storm (or crisis) is characterized by severe manifestations of hyperthyroidism, fever, and altered mental status. The disorder is usually precipitated by a concurrent illness. Early recognition and treatment of thyroid storm are essential because it is life threatening. Patients must be managed in the intensive care unit, and, in addition to general supportive measures and treatment of concurrent illness, aggressive pharmacologic management of the hyperthyroidism is necessary. Either MMI or PTU may be used, although PTU has the potential advantage of reducing production of T3 from T4. A dose of 150 mg of PTU every 6 hours or 15 to 20 mg of MMI every 8 hours is usually sufficient. For patients unable to take medication orally, MMI may be crushed and given by nasogastric tube or may be prepared by the pharmacy as a rectal suppository. In addition to thionamide drugs, exogenous iodides should be administered. Iopanoic acid may be used for

this purpose, because it not only inhibits thyroid hormone release but also has the advantage of being a potent inhibitor of T4 to T3 conversion. A dose of 500 mg to 1 g orally daily is sufficient. However it is not currently available in the United States. Alternatively, iodine can be administered in the form of Lugol's solution or saturated solution of potassium iodide, 10 drops in water three times daily, or sodium iodide, 500 mg intravenously every 12 hours. It is essential to administer the first dose of thionamide drug a few hours before administration of iodides to prevent further organification of iodide with resultant additional thyroid hormone production. Some clinicians also use pharmacologic doses of glucocorticoids to further inhibit T4 to T 3 conversion, although the clinical efficacy of this treatment has not been shown convincingly. ß-Blocking agents, preferably propranolol,[1] are essential in the management of thyroid storm and may be given either orally or intravenously. If the latter route is used, 1 mg every 5 to 10 minutes is given intravenously until the heart rate is less than 100 bpm. Once adequate control of the heart rate is achieved, oral propranolol may be given, and doses of 160 mg or more every 6 hours are not uncommon. Heart failure, which may be due in part to uncontrolled tachycardia, must be treated with adequate digitalis. If diuretics[1] are used, they must be administered very cautiously, because patients with thyroid storm are peripherally vasodilated and can suffer vascular collapse if conventional doses of diuretics are given. Plasmapheresis has been described as a treatment for thyroid storm, although I have neither used it nor seen it employed.



REFERENCES Auer et al., 2001. Auer J, Scheibner P, Mische T, et al: Subclinical hyperthyroidism is a risk factor for atrial fibrillation. Am Heart J 2001; 142:838-842. Baldini et al., 2002. Baldini M, Gallazzi M, Orsatti A, et al: Treatment of benign nodular goiter with mildly suppressive doses of L-thyroxine: Effects on bone mineral density and on nodule size. J Intern Med 2002; 251:407-414. Bauer et al., 2001. Bauer DC, Ettinger B, Nevitt MC, Stone KL: Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med 2001; 134:561-568. Charkes, 1996. Charkes ND: The many causes of subclinical hyperthyroidism. Thyroid 1996; 5:391-396. Cooper, 1984. Cooper DS: Antithyroid drugs. N Engl J Med 1984; 311:1353-1362. Cooper, 1994. Cooper DS: Antithyroid drugs and radioiodine therapy: A grain of (iodized) salt. Ann Intern Med 1994; 121:612-614. Cooper, 1996. Cooper DS: Treatment of thyrotoxicosis. In: Braverman LE, Utiger RD, ed. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text, 7th ed.. Philadelphia: Lippincott-Raven; 1996:708734. Cooper, 1998. Cooper DS: Antithyroid drugs for the treatment of hyperthyroidism caused by Graves' disease. Endocrinol Metab Clin North Am 1998; 27:225-247. Franklyn, 1994. Franklyn JA: The management of hyperthyroidism. N Engl J Med 1994; 130:1731-1738. Franklyn, 1994. Franklyn JA: Drug therapy: The management of hyperthyroidism. N Engl J Med 1994; 330:1731-1738. Klein et al., 1994. Klein I, Becker D, Levey G: Treatment of hyperthyroid disease. Ann Inter Med 1994; 121:281-288. Klein and Ojamaa, 1992. Klein I, Ojamaa K: Cardiovascular manifestations of endocrine disease. J Clin Endocrinol Metab 1992; 75:339-342. McIver and Morris, 1998. McIver B, Morris JC: The pathogenesis of Graves' disease. Endocrinol Metab Clin North Am 1998; 27:73-89. Mestman, 2004. Mestman JH: Hyperthyroidism and pregnancy. Best Pract Res Clin Endocrinol Metab 2004; 18:267-288. Motomura and Brent, 1998. Motomura K, Brent GA: Mechanisms of thyroid hormone action. Endocrinol Metab Clin North Am 1998; 27:1-23. Papi et al., 2005. Papi G, Pearce EN, Braverman LE, et al: A clinical and therapeutic approach to thyrotoxicosis with thyroid-stimulating hormone suppression only. Am J Med 2005; 118:349-361. Roti et al., 1996. Roti E, Minelli R, Salvi M: Management of hyperthyroidism and hypothyroidism in the

pregnant woman. J Clin Endocrinol Metab 1996; 81:1679-1682. Sawin, 1991. Sawin CT: Thyroid dysfunction in older persons. Adv Intern Med 1991; 37:223-249. Sawin et al., 1994. Sawin CT, Geller A, Wolf P, et al: Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249-1252. Singer et al., 1995. Singer PA, Cooper D, Levy E, et al: Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1995; 273:808-812. Surks et al., 1990. Surks MI, Chopra I, Mariash C, et al: American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990; 263:1529-1532. Torring et al., 1996. Torring O, Tallstedt L, Wallin G, et al: Graves' hyperthyroidism: Treatment with antithyroid drugs, surgery, or radioiodine a prospective, randomized study. J Clin Endocrinol Metab 1996; 81:2986-2993. Wing et al., 1994. Wing DA, Millar LK, Koonings PP, et al: A comparision of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994; 170:90-95.



Chapter 163 – Thyroid Cancer

Method of: Marlon A. Guerrero, MD Nancy D. Perrier, MD Thyroid cancer is the most common endocrine malignancy and accounts for approximately 2% of all cancers. The incidence of thyroid cancer has increased more than 50% since 1975, but mortality remains relatively constant at 0.5 deaths per 100,000 persons annually. In 2006, approximately 30,180 new cases of thyroid cancer were diagnosed in the United States—an 8% increase from 2005. Thyroid cancer has a female predominance, and the lifetime risk of developing thyroid cancer is 1.02% for women and 0.36% for men. Thyroid cancer accounts for 3% of malignancies in women and is now the seventh most common cancer among women. Classification Thyroid cancer is classified according to the cells of origin as either follicular or parafollicular. Cancers originating from follicular cells are further subdivided into differentiated and undifferentiated cancers. Papillary (PTC) and follicular (FTC) thyroid carcinomas are of follicular origin and are collectively referred to as differentiated thyroid cancers. They account for 90% of thyroid cancers (80% PTC and 10% FTC). The aggressive Hürthle cell variant (HCC) of FTC constitutes 3% of thyroid cancers; 8% of HCCs are found to have anaplastic differentiation. Undifferentiated anaplastic thyroid carcinomas (ATC), also of follicular cell origin, have a particularly poor prognosis but fortunately account for only 2% of thyroid cancers. Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of parafollicular cell origin and accounts for 5% of thyroid cancers. Two forms have been identified: sporadic (80% of MTC) and hereditary (20%). The hereditary form occurs in association with multiple endocrine neoplasia (MEN) types 2a and 2b and as familial (non-MEN) MTC. All hereditary forms are autosomal dominant and are associated with early C-cell hyperplasia and a germline mutation in the RET proto-oncogene. Approximately 50% of patients with MTC present with regional lymph node disease, and an additional 13% have distant metastases. Another rare cancer of the thyroid is lymphoma, which represents less than 1% of all thyroid cancers. Its development is closely associated with Hashimoto's thyroiditis. The majority of cases are the non-Hodgkin's B-cell type. Clinical Presentation and Evaluation Thyroid cancer typically manifests as an asymptomatic solid thyroid nodule. The work-up of a thyroid nodule commences with a detailed history. The clinician must be cognizant of the risk factors associated with thyroid cancer ( Box 1 ). The greatest risk is exposure to ionizing radiation during childhood (90% of radiation-induced thyroid cancers are PTC). A strong family history or a personal history of thyroid cancer also increases the risk. Several familial syndromes are associated with thyroid cancer. Differentiated

cancers can occur as part of a constellation of diseases in familial adenomatous polyposis, Gardner's syndrome, and Cowden disease. MTC is known to occur as part of MEN-2a (MTC, pheochromocytoma, and hyperparathyroidism) and MEN-2b (MTC, pheochromocytoma, marfanoid habitus, and mucosal neuromas). BOX 1 Risk Factors for Thyroid Cancers Differentiated Carcinoma

•

Cowden disease (multiple hamartomas)

•

Familial adenomatous polyposis

•

Familial nonmedullary thyroid cancer

•

Gardner's syndrome (gastrointestinal polyps, osteomas, soft tissue tumors)

•

Ionizing radiation

Anaplastic Carcinoma

•

Differentiated thyroid cancer Endemic goiter Previous or concurrent thyroid disease

Medullary Carcinoma

•

Familial (RET proto-oncogene mutation) MEN-2a (pheochromocytoma, hyperparathyroidism, MTC)

•

MEN-2b (pheochromocytoma, MTC, mucosal neuromas, marfanoid habitus)

Abbreviations: MEN = multiple endocrine neoplasia; MTC = medullary thyroid cancer.

A complete physical examination should entail meticulous examination of the head and neck region and lymphatic basins. A firm, fixed thyroid nodule that moves vertically with swallowing is suspicious for cancer. An enlarging nodule or cervical lymphadenopathy also suggests malignant disease. Though rare, obstructive symptoms such as dysphagia, hoarseness, stridor, and pain may be evident at initial presentation. This uncommon presentation occurs predominantly with ATC or advanced disease. The recommended tests for patients with a dominant, solid thyroid nodule are outlined in Figure 1 . In general, only incidentally identified nodules larger than 1 cm or those clinically palpable should be evaluated. Evaluation for nodules smaller than 1 cm may be considered in patients considered at high risk (see Box 1 ). All patients should undergo evaluation of thyroid function by measurement of serum thyroid-stimulating hormone (TSH). A low TSH level (suggesting hyperthyroidism) should be assessed with either an iodine-123 (123I) or technetium-99m (99mTc) scan. A hot nodule (with high radiotracer uptake) denotes autonomous thyroid function (hyperthyroidism) and is more likely to be benign. On the other hand, a cold nodule (with

radiotracer uptake less than the surrounding thyroid tissue) is more likely to be malignant. A patient with a normal or elevated TSH level or a cold thyroid nodule should be further evaluated with neck ultrasonography, usually followed by fine-needle aspiration (FNA). Nodules larger than 1 cm or those with suspicious ultrasound findings should undergo FNA.

FIGURE 1 Tests recommended for thyroid nodules. Abbreviations: 123I, iodine-123; FNA, fine-needle aspiration; 99mTc, technetium 99m; TSH, thyroid-stimulating hormone.

Ultrasonography increases the diagnostic accuracy of FNA compared with palpation-guided FNA, permits

identification of solid components within a cystic nodule, allows simultaneous assessment of cervical lymph nodes, and identifies characteristics suspicious for malignancy (irregular border, microcalcifications, tissue invasion, and increased vascularity). The finding of MTC on FNA warrants a full preoperative evaluation to identify MEN-2a or 2b. Serum calcitonin and carcinoembryonic antigen (CEA) are usually elevated in MTC, and levels should be checked before surgical intervention so that the values can be used as markers for follow-up care. It is also imperative to check serum levels of calcium and parathyroid hormone and plasma metanephrines (to rule out coexisting pheochromocytoma) to identify MEN. Positive results or a high suspicion of MEN-2a or MEN-2b is an indication for RET proto-oncogene testing. For MEN-2b patients, the stereotypic phenotype of mucosal neuromas or marfanoid facies should prompt suspicion of the disease and a full work-up. Genetic testing should also be offered to even those with seemingly sporadic disease because of the possibility of carrying a germline RET proto-oncogene mutation. If the gene is found, then family members should be screened because there is a 50% penetration of this autosomal dominant gene. The specific RET proto-oncogene mutation is further stratified by codon mutations into incrementing levels of clinical importance (low, moderate, high risk) to direct timing of intervention in otherwise asymptomatic carriers. Computed tomography of the chest, abdomen, and pelvis is indicated to evaluate for pheochromocytoma or pancreatic tumors. If pheochromocytoma is identified, it should be surgically treated before addressing the thyroid disease. Thyroid cancer is staged using the TNM classification system ( Table 1 ). ATCs are almost universally fatal. Because of this lethality, all are categorized as stage IV in the TNM classification system.

TABLE 1 -- AJCC TNM Staging System for Thyroid Cancer Stage Characteristic Tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor 2 cm or less in greatest dimension limited to the thyroid

T2

Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the thyroid

T3

Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroidal extension

T4a

Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve Intrathyroidal anaplastic carcinoma—surgically resectable

T4b

Tumor invading prevertebral fascia or encasing carotid artery or mediastinal vessels Extrathyroidal anaplastic carcinoma—surgically unresectable

Stage Characteristic Regional Lymph Nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

N1a

Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)

N1b

Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes

Distant Metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Cytology The cytologic results of FNA are classified as benign, malignant, indeterminate, or nondiagnostic. FNA is 95% accurate in diagnosing PTC, ATC, and MTC. Indeterminate cytology is found in 15% to 30% of FNA specimens. Approximately 10% to 20% of FNA results are nondiagnostic. This can result from inadequate sampling, areas of necrosis or calcification, or cystic degeneration. Repeat aspiration is warranted, specifically under ultrasound guidance. Nodules with a continual nondiagnostic FNA warrant close observation. Surgery should be strongly considered if the nondiagnostic nodule is solid. Occasionally, ATC is confused with lymphoma. Core-needle biopsy with immunohistochemical staining and flow cytometry is used to exclude lymphoma if differentiation cannot be made by FNA. A cytologic finding consistent with PTC is a monolayer sheet of cells forming papillae, with occasional calcifications (psammoma bodies). The nuclei are typically enlarged, irregular, and overlapping, with peripheral margination of the chromatin (Orphan Annie eyes), nuclear grooves, and inclusion bodies. Unlike the other thyroid cancers, follicular thyroid cancer (FTC) and Hürthle cell carcinoma (HCC) cannot be diagnosed by FNA and can only be designated as “neoplasms” on cytologic assessment. An assembly of hypercellular follicular cells with minimal colloid favors FTC, but distinction from an adenoma cannot be made by FNA alone. Capsular or vascular invasion must be identified on permanent histologic sections following surgical resection for both neoplasms to be diagnosed as malignant. Hürthle cell carcinoma is typically found to have large polygonal follicular cells with eosinophilic cytoplasm. The overall rate of malignancy associated with these indeterminate thyroid lesions on permanent histology is 20%. The diagnosis of ATC is confirmed by identifying numerous mitotic figures and marked cellular pleomorphism on FNA. In ATC, three histologic patterns have been identified: spindle cell, giant cell, and squamoid. In addition, high mitotic activity, vascular invasion, necrosis, and paucity of staining for thyroglobulin are also common. Anaplastic cells do not transport iodine or produce thyroglobulin and do not contain thyrotropin receptors.

A cytologic finding of eosinophilic cells interspersed with amyloid and a vascular stroma is representative of MTC. Immunohistochemical staining for calcitonin confirms the diagnosis of MTC. Treatment and Follow-up DIFFERENTIATED THYROID CANCERS A preoperative neck ultrasound to evaluate the entire thyroid and bilateral cervical lymph nodes should be performed for proper staging ( Table 2 ). Total thyroidectomy is the surgical treatment of choice for differentiated thyroid cancer.

TABLE 2 -- Staging of Papillary or Follicular Carcinoma Classification Stage 5 days).

•

Renal scarring or impaired renal function is known to be present.

•

Diabetes, AIDS, sickle cell, or other serious chronic disease is present.

Once on antibiotic therapy, defervescence may be expected in approximately 68% of children younger than 2 years by 24 hours and in 89% by 48 hours. The 11% who remain febrile at 48 hours were no more likely to have renal abscesses or hydronephrosis than the others, and they may be discharged after sensitivities are known. It is convenient to the family to perform the cystogram, if indicated, during hospitalization and it greatly improves compliance. Prophylaxis There is expert agreement that further prospective studies of antibiotic prophylaxis for childhood UTI are needed. In adult women, the cost-to-benefit ratio favors prophylaxis with three or more UTIs per year. In children, because young age is the major risk for renal scarring, studies are lacking, but expert opinion favors 6 months of prophylaxis after a febrile UTI, with or without VUR. Guidelines from the American Urological Association also suggest prophylaxis for all children with VUR, but the Swedish experts suggest stopping at age 24 months in boys and 5 years in girls. Table 1 lists suggested agents. Unfortunately, the choice of antibiotic is becoming limited as trimethoprim (Proloprim) resistance rates rise.

TABLE 1 -- Prophylactic Antibiotics for Childhood Urinary Tract Infections Drug

Dose

Timing

Trimethoprim-sulfamethoxazole (TMP-SMX) (Bactrim)

2 mg/kg of TMP component (up to 40 mg)

Bedtime Rash in ~6%

Nitrofurantoin (Macrodantin capsules 25, 50, or 100 mg preferred over oral suspension)

1-2 mg/kg/d up to 100 mg

Bedtime Vomiting, abdominal pain

Trimethoprim (Primsol oral solution 50 mg/mL or 100 2 mg/kg up to 40 mg mg tablets)

Side Effects

Bedtime Rash in ~1%

CURRENT DIAGNOSIS A high level of suspicion is required in all febrile infants. Boys outnumber girls 10:1 in the neonatal period. Girls are at highest risk for UTI when younger than 12 months of age and again at 3 to 5 years of age. Urine for culture should not be obtained with a bag, but requires a catheterization or suprapubic aspiration, if the child is not toilet trained. The colony count cutoff to define a UTI differs with the method used for collection. With a negative urinalysis, febrile UTI becomes much less likely, but an afebrile UTI cannot be ruled out. Abbreviations: UTI = urinary tract infection. Radiologic Evaluation

No area of childhood UTI evaluation is as controversial as determining which children merit sonography, radionuclide scans, and cystograms. Two recent studies have helped clarify these issues, and several professional academies have agreed on guidelines for febrile children younger than 2 years of age (Pediatrics, Family Practice, Emergency Physicians, Urological, and College of Radiology). These associations recommend a renal sonogram and a voiding cystogram soon after the first febrile UTI. Figure 2 indicates that the initial cystogram should be a standard fluoroscopic examination to permit accurate grading of VUR. Follow-up cystograms may be radionuclide studies, which carry less risk of gonadal radiation.

FIGURE 2 Radiologic management of a child with vesicoureteral reflux.

Hoberman and colleagues also question the value of the initial renal sonogram. In a cohort of 309 febrile children who had paired dimercaptosuccinic acid (DMSA) radionuclide renal scans and sonography performed within 48 hours of diagnosis, neither study changed management. All had had an antenatal sonogram after 30 weeks of gestation, and anomalies were presumably corrected before UTI could occur. The argument in favor of doing this painless and medically safe study is that children with “dilating reflux” (i.e., grades III-V) would be identified, and the doctor could track down these children if they fail to keep an appointment for a cystogram. In other words, in the absence of a cystogram, a sonogram with

hydronephrosis or pelvic caliectasis will change management. In the patient with no health insurance who cannot afford both studies, the more important study is the voiding cystogram, not the sonogram.

CURRENT THERAPY Outpatient therapy of febrile UTIs is usually appropriate in infants older than 2 months of age. A single dose of intramuscular ceftriaxone (Rocephin) will cover the first 24 hours after diagnosis when emesis is most likely to occur and antibiotic sensitivities are unknown. Febrile girls should be seen between 36 and 48 hours after diagnosis to assess clinical improvements and check urine culture results. A voiding cystogram remains essential for febrile girls younger than 5 years of age and all boys. Abbreviations: UTI = urinary tract infection.



REFERENCES Abelson Storby et al., 2004. Abelson Storby K, Osterlund A, Kahlmeter G: Antimicrobial resistance in Escherichia coli in urine samples from children and adults: A 12 year analysis. Acta Paediatr 2004; 93:487491. Bollgren, 1999. Bollgren I: Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr 1999;48-52. Gauthier et al., 2004. Gauthier M, Chevalie I, Sterescu A, et al: Treatment of urinary tract infections among febrile young children with daily intravenous antibiotic therapy at a day treatment center. Pediatrics 2004; 114:469-476. Hellerstein, 2002. Hellerstein S: Urinary tract infections in children. Infections in Medicine 2002; 19:554560. Hoberman et al., 2003. Hoberman A, Charros M, Hickey RW, et al: Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348(3):195-202. Hoberman et al., 1999. Hoberman A, Wald ER, Hickey RW, et al: Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 1999; 104(1):79-86. Jakobsson et al., 1999. Jakobsson B, Esbjorner E, Hansson S: Minimum incidence and diagnostic rate of first urinary tract infection. Pediatrics 1999; 104(2 Pt):222-226. Johnson, 2004. Johnson CE: Dysuria. In: Kliegman RM, Greebaum LA, Lye PS, ed. Practical Strategies in Pediatric Diagnosis and Therapy, 2nd ed.. Philadelphia: WB Saunders; 2004:397-411. Lin et al., 2000. Lin D-S, Huang F-Y, Chiu N-C, et al: Comparison of hemocytometer leukocyte counts and standard urinalysis for predicting urinary tract infections in febrile infants. Pediatr Infect Dis J 2000; 19:223227. Lowe et al., 2004. Lowe LH, Patel MN, Gatti JM, Alon US: Utility of follow-up renal sonography in children with vesicoureteral reflux and normal initial sonogram. Pediatrics 2004; 113:548-550. Roberts, 1999. Roberts KB: A synopsis of the American Academy of Pediatrics' practice parameter on the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatr Rev 1999; 20(10):1-4. Rushton, 1997. Rushton HG: Urinary tract infections in children: Epidemiology, evaluation, and management. Pediatr Clin North Am 1997; 44(5):1133-1169.



Chapter 169 – Childhood Enuresis

Method of: Frank R. Cerniglia Jr., MD In general, enuresis is associated with purely nighttime wetting. The term, however, means involuntary wetting (day or night) beyond the age of anticipated control. Childhood enuresis includes both day (diurnal) and night (nocturnal) wetting. The latter is further subdivided into primary and secondary nocturnal enuresis. Enuresis is one of the most common problems seen by the pediatric primary care physician and is referred to the pediatric urologist. The problem, which dates back to as early as 1500 bc, has been the subject of many dissertations on diagnosis, causes, and remedies. Childhood wetting problems, or voiding dysfunctions, affect 5% to 10% of school-aged children and can be a profound source of distress for the child and family as a whole. The number of potential causes for abnormal voiding include anatomic, neuropathic, and functional disorders. Most children who present with day and/or nighttime wetting have a non-neurologic functional voiding abnormality requiring no complex evaluation or invasive study. Development of Bladder Control Urinary continence develops in an ordered process of sequenced maturation that requires no teaching. To attain continence, one needs a low-pressure storage vessel surrounded by smooth muscle to “squeeze” out the urine from the bladder, an “involuntary” internal sphincter, and a complex external sphincteric mechanism with intertwined smooth and skeletal muscle that is under voluntary control. These three mechanisms work in accord to accomplish bladder emptying. The neonate voids by reflex through the sacral spinal cord. The bladder reaches a functional capacity stretch point, and afferent signals are sent to the spinal cord to activate sympathetic outflow to the bladder and urethra. The result is relaxation of the external sphincter and contraction of the detrusor; bladder emptying ensues. Urinary frequency, incontinence, and nocturnal enuresis are all normal occurrences in the very young child. Infants are asleep approximately 60% of the time with 40% of their voiding episodes occurring during sleep. In year 1 of life, the child voids approximately 20 times per day. During the next 2 years, voiding frequency decreases by as much as 50% while the voided volumes (and bladder capacity) increase by as much as three to four times. Beginning at age 2 years, conscious sensation of bladder fullness develops, although control is not yet mastered. By 4 years, most children have achieved an adult pattern of voiding in which micturition can occur at less than total bladder capacity or be postponed until absolute functional bladder capacity is reached. For the transition to this pattern, three separate events must occur: 1.

Capacity of bladder must increase so it can function as a reservoir.

2.

The child must gain control over the external sphincter so urination can be allowed or terminated at will.

3.

Direct voluntary control over the voiding reflex must develop to allow the child to initiate or inhibit bladder contraction voluntarily.

Simply put, urinary control is obtained when the bladder fills under low pressure to an adequate capacity and then can be emptied, with a detrusor contraction coordinated with complete relaxation of the external sphincter. However, one needs to understand this happens on a continuum. Nocturnal bowel control occurs first, followed by daytime bowel control, daytime urine control, and finally nighttime dryness. Most, but not all, children achieve these functions by the 4th year. Evaluation Pure voiding dysfunction is urinary incontinence without any underlying structural or obvious neurologic abnormality. On the whole, patients with an anatomic abnormality usually have leaked their entire lives, unable to gain continence at any point. The incontinence, instead of being diurnal or nocturnal only, is a combination of both. Children with suspected anatomic defects should be evaluated with imaging of both the kidneys and bladder by ultrasound and voiding cystogram with or without a fluoroscopic urodynamics study. Children with voiding dysfunction are able to gain continence for a varying period of time followed by incontinence. It is important during history taking to ask the child's primary caregiver for valuable insight into the general aspects of the child's voiding habits. One should ask precise questions, understandable to the child, in order to get accurate answers. This information can be augmented with a voiding diary because many parents may not be totally aware of the specifics and finer points of the child's voiding habits. ONSET At what age was the child toilet trained? If the child was trained, at what point did he or she start wetting? Were there any occurrences in the child's life coinciding with the onset of wetting? Has the child ever been able to be toilet trained? Is the wetting new over the last few days, weeks, or months? FREQUENCY Voiding diaries can be very helpful in diagnosing and treating voiding abnormalities. They can be kept over a 3- to 4-day period and include voiding times, volumes, wet versus dry, and any associated symptoms. Appropriate volumes can be calculated as age (in years) plus 2 oz. One should determine if the volumes are less than expected. Does the child void infrequently with larger-than-anticipated amounts? How many voids per day? How many accidents per week? Does the child wet multiple times during the day or only at night? CHARACTER OF VOIDING Does the male child compress his urethra while or after voiding? Does he sit or stand to void? Can the parent hear him voiding (good forceful stream) or does he dribble? Does the little girl void with her legs tightly closed? Does she sit back on the toilet or perch on the edge of the seat to help maintain balance (causing pelvic contraction)? Is the child in a rush? Does he or she delay voiding? Is there posturing (squatting, crossing legs)? DEGREE

Does the child wet enough to require clothes to be changed, or does the wetting consist of only spotting in the underwear? Is the wetting before voiding (unstable bladder) or after voiding (vaginal pooling)? Two other important aspects of the history are bowel habits and family history of wetting. Any bowel dysfunction must be corrected before one can treat any wetting abnormality successfully. One should obtain a family history because it is now evident that a genetic component is linked to conditions such as primary nocturnal enuresis. One should also ask about other associated urologic, neurologic, or nephrologic conditions (valves, reflux, renal insufficiency) or any previous surgeries. Physical Examination Once the history is taken, the physical examination should be performed, taking into account not only vitals (height, weight, blood pressure), as a basic starting point, but the general appearance of the child. Uncleanliness, poor hygiene, or poor dentition may suggest neglect or abuse. An abdominal examination should seek to identify masses, a palpable bladder, or stool in the colon. Careful inspection of the child's back for occult spinal dysraphisms includes looking for lipomas, scoliosis, hair patches, cutaneous lesions, sacral or coccygeal defects, or gluteal asymmetry. A basic neurologic examination is essential and should include such points as gait, reflexes, and brief examination room maneuvers to substantiate that no nerve deficits are contributing to the incontinence. Examination of the rectal area is important, but often passed over, and should incorporate assessing sphincter tone, ruling out pelvic masses, and looking for signs of fecal soiling. Additionally, one should inspect the external genitalia to diagnose labial adhesions in young girls, female epispadias (causing total incontinence), and signs of vaginal pooling (butterfly “rash” and irritation of the labia and perineal and perianal areas). In boys, one should look for narrowing or inflammation of the meatus, unretractable foreskin, hypospadias, or epispadias. If the physician can observe the child void, valuable information can be gained about the quality and pattern of the urinary stream. Laboratory/Radiograph Examination A urinalysis should be performed to check for infection, glucosuria, and proteinuria. A specific gravity test can exclude polyuria as a cause for incontinence and indicates if the kidneys concentrate properly. If indicated, a urine culture should be done. If all of the tests just mentioned are normal, no further testing is needed at this initial stage. After the history, physical examination, and urinalysis, the abnormality is classified as anatomic, functional, or neurogenic. When an anatomic problem is suspected, imaging of the upper tract as well as the bladder is needed. Usually a renal ultrasound and voiding cystourethrogram is performed. The same is required if the urine is infected, a neurologic disorder is diagnosed, or there is history of either. More complex testing (magnetic resonance imaging [MRI] or computed tomography [CT] scan) may need to be done if abnormal physical findings of the lower spine or sacrum are found. Although urodynamics testing may be invasive and is not done routinely as a screen, it may be valuable in those select patients with severe symptoms refractory to standard treatment or in the child with a neurologic lesion. Diurnal Enuresis Daytime wetting, or diurnal enuresis, is much more troubling to the school-aged child and adolescent because it is often obvious to family, friends, and peers as well as being socially unacceptable and a source of embarrassment and ridicule. Children who are wet during the day generally experience urge and urge incontinence and may be wet at night as well. They may posture, and when the urine volume is measured, a small bladder capacity may be found. Children generally outgrow daytime wetting as they mature, but until

that time treatment can be offered, which parents generally expect. Initial treatment measures are usually directed toward placing the child on a timed voiding schedule (every 2 to 3 hours to empty the bladder before the child has an uninhibited bladder contraction), practicing good hygiene, and, of utmost importance, correcting constipation with stool softeners and a high-fiber diet. The next step commonly is pharmacologic treatment of the voiding dysfunction. This must be tailored to the type of abnormality and whether there is associated infection or vesicoureteral reflux. For many years, the drug of choice has been oxybutynin (Ditropan) because the mainstay of treatment has been long-term anticholinergic use. Once the underlying bladder overactivity or instability is quashed and the overactivity of the external sphincter lessened, the result is diminished or eliminated elevated intravesical pressure. Another preparation used recently is tolterodine (Detrol).[1] Both of these drugs are now available in once-aday long-acting formulations (Ditropan XL, Detrol LA). Both have been reported to have side effects in varying degrees such as facial flushing, dry mouth, diminished sweating, occasional blurred vision, and constipation. Other drugs, which have been used with varying levels of success, include hyoscyamine sulfate (Levsin),[1] propantheline (Pro-Banthine), [1] and dicyclomine hydrochloride (Bentyl).[1] The child who fails initial treatment may need a further workup with fluoroscopic urodynamics studies to assess bladder function, filling pressure, and sphincter coordination with voiding. 1 Not FDA approved for this indication.

Nocturnal Enuresis Nocturnal enuresis (NE) has been described in early literature dating back to the Ebers papyrus with various documented causes and remedies across the centuries. It continues to be a very common problem affecting 15% to 20% of school-aged children. The prevalence falls to 5% at 10 years old and affects 1% of 15-yearold teenagers. Fifteen percent of children with monosymptomatic primary nocturnal enuresis experience spontaneous resolution each year. NE can have a serious impact on the child, leading to shame, guilt, and diminished self-esteem. Only about one third of parents seek medical attention; about the same number punish the child for wetting, mistakenly thinking laziness or purposeful behavior has caused the problem. It is therefore incumbent on anyone who treats young children to screen for bed-wetting, educate the parents, and offer treatment if appropriate. There is no one isolated cause for bed-wetting. It has been attributed to a multifactorial maturational delay in arousal to a full bladder, a delay in maturation of the bladder resulting in a diminished nocturnal bladder capacity, and a diminished circadian rhythm of antidiuretic hormone production. Even a genetic component is implicated because bed-wetting has been shown to run in families.

CURRENT DIAGNOSIS Obtain a good voiding history, including family history of wetting, history of all elimination habits, and dietary history. Do a thorough physical examination, including neurologic and rectal if appropriate and indicated. Educate the family and debunk any myths about wetting. Give the family multiple treatment options, both pharmacologic and nonpharmacologic, including observation. Although bed-wetting is considered benign from a physical standpoint, because of the previously described negative impact, treatment options should be offered to the child age 6 years and older. The focus of the physician treating NE should be to ensure the child has no physical abnormality causing the bed-wetting. The child who has pure monosymptomatic nocturnal enuresis needs no further evaluation than a good history and physical examination and a urinalysis. Treatment should be first directed at treating constipation or any daytime frequency or wetting component, which can be a benign association in 15% to 25% of cases. Treatment measures should include patient education because once the child (and parents) have an understanding of the mechanisms behind bedwetting, compliance and success of treatment often improve. Initial therapy should also center on evening fluid restriction, avoidance of caffeine and artificial dyes (particularly red number 40), and motivational therapy with rewards and praise for dry nights. The child has no control over wet nights and should never be punished for a wet bed. If the parents decide treatment is desirable, they can choose between pharmacologic and nonpharmacologic options. For those wishing to avoid medication, conditioning therapy with a moisture-sensitive alarm is an option. Several enuresis alarms are available on the market, all with the goal of awakening the child at or shortly after the time of micturition. The first drops of urine complete a circuit, activating a buzzer designed to awaken the child. It is important for a family member to be involved in the process to ensure the child wakes up and completes the voiding process in the toilet. Over time a conditioned response develops, and the child awakens voluntarily to a full bladder without help from the alarm. This process can take weeks to months, therefore requiring a patient and dedicated family and child to achieve success. The overall success rate has been stated as 50%, but with family involvement and proper use it can be as high as 70% to 90%. Additional nonpharmacologic treatments offered include motivational therapy, bladder training exercises, hypnotherapy, bladder training, night wakening, and fluid restriction and diet therapy. All except motivational therapy have shown disappointing results. The alternative to the alarm is pharmacologic treatment. The most commonly used drug now is desmopressin acetate (DDAVP) in tablet form and less commonly nasal spray. Desmopressin acetate is a synthetic analogue of vasopressin, a potent antidiuretic hormone produced by the pituitary gland. Desmopressin acetate tablets are dosed starting at 0.2 mg 1 hour before bed (food and drink should be withheld 1 hour before dosing) and increased by one tablet per week up to 0.6 mg or until dryness is achieved at a lower dose. Success rates increase with higher doses and can be as high as 60% to 70%. Side effects are rare even at the higher doses. If a child responds, that dose is continued for 3 to 6 months

before structured weaning by one less tablet a night per week. The drug can also be used long term without reservation. Another advantage is its ability to be used intermittently in situations like nightly or weekend sleepovers at a friend's house or overnight trips. Another acceptable alternative is imipramine (Tofranil), a tricyclic antidepressant that has generalized effects on the bladder including weak a-adrenergic and anticholinergic effects. It weakly increases arousal and additionally may have some antidiuretic properties. Dosage begins at 25 mg at bedtime and is increased if necessary to 50 mg at bedtime in preadolescents and 75 mg per night in adolescents. There has been some hesitancy recently using imipramine because of certain profound side effects that have been observed. These include insomnia, weight loss, extrapyramidal symptoms, anxiety, and personality changes. Fatal cardiac dysrhythmias have been reported with overdosage. If dosed properly, imipramine can be an effective and safe drug. If effective, medicine is dosed for 6 months before attempts to wean.

CURRENT THERAPY Treatment of constipation is the initial measure. Children should not be punished for wet nights. For the bed-wetting alarms to be effective, family involvement is critical. Patience and understanding of the process are important for compliance with therapy and attaining success.



REFERENCES Cendron, 1999. Cendron M: Primary nocturnal enuresis: Current concepts. Am Fam Physician 1999; 59(5):1205-1214.1219-1220 Hinsl and Hurwitz, 1991. Hinsl KK, Hurwitz RS: Urol Clin North Am 1991; 18(2):283-293. Roth, 2003. Roth DR: Enuresis. In: Rakel RE, Bope ET, ed. Conn's Current Therapy 2003, 55th ed.. Philadelphia: Elsevier Science; 2003. Rushton, 1995. Rushton HG: Wetting and functional voiding disorders. Urol Clin North Am 1995; 22(1):7593. Rushton and Belman, 1999. Rushton HG, Belman AB: Enuresis and voiding dysfunction: A national kidney foundation guide to the child who wets, Washington, DC, Children's National Medical Center, 1999.



Chapter 170 – Urinary Incontinence

Method of: E. Ann Gormley, MD Urinary incontinence is a significant problem that affects millions of Americans. Patients may not report incontinence to their primary care providers because of embarrassment or misconceptions regarding treatment. Because incontinence is often treatable, it behooves the health care professional to identify patients who might benefit from treatment. Given that the treatment of incontinence varies depending on the etiology, the aim of evaluation is to identify the etiology. Etiology Urinary incontinence is generally the result of either bladder or urethral dysfunction ( Table 1 ). Incontinence also may result from a nonurologic cause and is usually reversible when the underlying problem is treated ( Table 2 ). More uncommon causes of incontinence are urinary fistulae and ectopic ureteral orifices.

TABLE 1 -- Etiology of Incontinence Bladder Dysfunction 1.

Urge incontinence •

• 2.

Detrusor overactivity •

Idiopathic

•

Neurogenic origin

Poor compliance

Overflow incontinence

Urethral Dysfunction 3.

Stress incontinence •

Anatomic

•

Intrinsic sphincter deficiency

TABLE 2 -- Transient Causes of Incontinence (DIAPPERS) Cause

Comment

Delirium

Incontinence may be secondary to delirium and will often stop when acute delirium resolves.

Cause

Comment

Infection

Symptomatic infection may prevent a patient from reaching the toilet in time.

Atrophic vaginitis

Vaginitis may cause the same symptoms as an infection.

Pharmacologic • Sedatives

Alcohol and long-acting benzodiazepines may cause confusion and secondary incontinence.

• Diuretics

A brisk diuresis may overwhelm the bladder's capacity and cause uninhibited detrusor contractions, resulting in urge incontinence.

• Anticholinergics

Many nonprescription and prescription medications have anticholinergic properties. Side effects of anticholinergics include urinary retention with associated frequency and overflow incontinence.

• a Adrenergics

Tone in the bladder neck and proximal sphincter is increased by a-adrenergic agonists and can cause urinary retention, particularly in men with prostatism.

• a Antagonists

Tone in the smooth muscles of the bladder neck and proximal sphincter is decreased with a-adrenergic antagonists. Women treated with these drugs for hypertension may develop or have an exacerbation of stress incontinence.

Psychological

Depression may be occasionally associated with incontinence.

Excessive urine production

Excessive intake, diabetes, hypercalcemia, congestive heart failure, and peripheral edema can all lead to polyuria, which can lead to incontinence.

Restricted mobility

Incontinence may be precipitated or aggravated if the patient cannot get to the toilet quickly enough.

Stool impaction

Patients with impacted stool can have urge or overflow urinary incontinence and may also have fecal incontinence.

From Resnick NM: Urinary incontinence in the elderly. Med Grand Rounds 1984;3:281–290.

BLADDER DYSFUNCTION Bladder dysfunction causes urge or overflow incontinence. Urge incontinence occurs when the bladder pressure is sufficient to overcome the sphincter mechanism. Elevated bladder or detrusor pressure tends to open the bladder neck and urethra. An elevation in detrusor pressure may occur from intermittent bladder contractions (detrusor overactivity) or because of an incremental rise in pressure with increased bladder volume (poor compliance). Detrusor overactivity may be idiopathic, or it may be associated with a neurologic disease (detrusor overactivity of neurogenic origin). Detrusor overactivity is common in the elderly and may be associated with bladder outlet obstruction. Poor bladder compliance results from loss of the viscoelastic features of the bladder or because of a change in neuroregulatory activity. The patient with urge incontinence may appreciate a sudden sensation to void but then is unable to suppress the urge fully. In severe cases, the patient may not be aware of the sensation of needing to void until he or she is actually leaking. The amount of leakage in patients with urge incontinence is variable, depending on the patient's ability to suppress the contraction. Patients with urge incontinence will often have frequency and nocturia in addition to urgency and urge incontinence. They may also have nocturnal enuresis.

Overactive bladder is a newer term that describes patients with frequency and urgency with or without urge incontinence. Overflow incontinence occurs at extreme bladder volumes or when the bladder volume reaches the limit of the bladder's viscoelastic properties. The loss of urine is driven by an elevation in detrusor pressure. Overflow incontinence is seen in the case of incomplete bladder emptying caused by either obstruction or poor bladder contractility. Obstruction is rare in women but can result from severe pelvic prolapse or following surgery for stress incontinence. Patients with overflow incontinence complain of constant dribbling, and they may also describe extreme frequency. URETHRAL-RELATED INCONTINENCE Urethral-related incontinence, or stress incontinence, occurs because of either urethral hypermobility or intrinsic sphincter deficiency (ISD). Incontinence associated with urethral hypermobility has been called anatomic incontinence because the incontinence is due to malposition of the sphincter unit. Displacement of the proximal urethra below the level of the pelvic floor does not allow for transmission of abdominal pressure that normally aids in closing the urethra. Some women with mobility of the bladder neck or urethra do not experience incontinence. ISD was initially believed to occur after failure of one or more operations for stress incontinence. Other causes of ISD include myelodysplasia, trauma, and radiation. Some authors have theorized that all incontinent patients must have an element of ISD in order to actually leak. The patient with stress incontinence leaks urine with any sudden increase in abdominal pressure. In patients with severe ISD, the increase in abdominal pressure required to cause leakage is small, so patients may leak urine with minimal activity. Evaluation of the Incontinent Patient The evaluation of the incontinent patient includes a history, physical examination, laboratory tests, and possibly urodynamic testing. The onset, frequency, severity, and pattern of incontinence should be sought, as well as any associated symptoms such as frequency, dysuria, urgency, and nocturia. Incontinence may be quantified by asking the patient if he or she wears a pad and how often the pad is changed. Obstructive symptoms, such as a feeling of incomplete emptying, hesitancy, straining, or weak stream, may coexist with incontinence, particularly in males and in female patients with previous incontinence procedure, cystoceles, or poor detrusor contractility. Female patients should be asked about symptoms of pelvic prolapse, such as recurrent urinary tract infection, a sensation of vaginal fullness or pressure, or the observation of a bulge in the vagina. All incontinent patients should be asked about bowel function and neurologic symptoms. Response to previous treatments, including drugs, should be noted. Important features of the history include previous gynecologic and urologic procedures, neurologic problems, and past medical problems. A list of the patient's current medications, including over-the-counter medications, should be obtained.

CURRENT DIAGNOSIS Urge Incontinence Symptoms

Urgency Frequency Nocturia Unable to reach the toilet with urge Stress Incontinence Symptoms Leakage with physical activity Signs Bladder neck mobility Positive stress test Mixed Incontinence Symptoms Urgency Frequency Nocturia Unable to reach the toilet with urge Leakage with physical activity Signs Bladder neck mobility Positive stress test Overflow Incontinence Symptoms Frequency Nocturia Urgency Leakage with physical activity Signs High postvoid residual Although the history may define the patient's problem, it may be misleading. Urge incontinence may be triggered by activities such as coughing, so according to the patient's history, he or she seems to have stress incontinence. A patient who complains only of urge incontinence may also have stress incontinence. Mixed

incontinence is very common; at least 65% of patients with stress incontinence have associated urgency or urge incontinence. A complete physical examination is performed, with emphasis on the neurologic assessment and on the abdominal, pelvic, and rectal examinations. In females, the condition of the vaginal mucosa and the degree of urethral mobility are determined. Simple pelvic examination with the patient supine is sufficient to determine if the urethra moves with straining or coughing. The degree of movement is not as important as the determination of whether movement occurs. The presence of associated pelvic organ prolapse should be noted because it can contribute to the patient's voiding problems and may have an impact on diagnosis and treatment. A rectal examination in both males and females includes the evaluation of sphincter tone and perineal sensation. A urinalysis is performed to determine if there is any evidence of hematuria, pyuria, glucosuria, or proteinuria. A urine specimen is sent for cytologic examination if there is hematuria and/or irritative voiding symptoms. The urine is cultured if there is pyuria or bacteriuria. Infection should be treated prior to further investigations or interventions. Hematuria consisting of more than three red cells per high-power field warrants further investigation. A postvoid residual (PVR) should be measured either with pelvic ultrasound or directly with a catheter. A normal PVR is less than 50 mL, and a PVR greater than 200 mL is abnormal. A significant PVR urine may reflect either bladder outlet obstruction or poor bladder contractility. The only way to distinguish outlet obstruction from poor contractility is with urodynamic testing. Urodynamic testing is used to accurately diagnose the etiology of a patient's incontinence; however, many patients can be successfully treated without urodynamic testing. The purpose of urodynamic testing is to examine compliance, diagnose stress incontinence, and rule out obstruction as a cause of either overflow or urge incontinence. Urodynamic testing should ideally be performed prior to invasive therapies and certainly in patients who are undergoing repeat procedures following failed procedures. Treatment of Urinary Incontinence URGE INCONTINENCE Patients with urge incontinence need to understand that they leak urine because their bladder contracts with little or no warning. The first line of treatment is timed voiding. Often, reminding patients to void every 1 to 2 hours during the day, before they get an urge to void, will result in them staying dry. Other behavioral interventions, such as modification of fluid intake, avoidance of bladder irritants, and bladder retraining, where the patient attempts to consciously delay voiding and to increase the interval between voids, may also have a role in the treatment of urge incontinence. Anticholinergics are the mainstay of medical therapy in achieving continence. The side effects of anticholinergics include urinary retention, dry mouth, constipation, nausea, blurred vision, tachycardia, drowsiness, and confusion. They are contraindicated in patients with narrow-angle glaucoma. Anticholinergics are also used to decrease bladder pressure in patients with poor compliance. Anticholinergics are combined with clean intermittent catheterization in patients who have a significant PVR

prior to treatment and in patients who develop retention while taking anticholinergics. Patients with intractable detrusor overactivity may require surgical intervention, consisting of neuromodulation with a sacral nerve stimulator or various forms of bladder augmentation. The primary goal in caring for the patient with poor compliance is treating the high bladder pressure. Complete bladder emptying with clean intermittent catheterization combined with anticholinergics will often lower bladder pressure to a safe range. Some patients may require a combination of anticholinergics and a agonists. Bladder augmentation is required when medical management fails. OVERFLOW INCONTINENCE Overflow incontinence is treated by emptying the bladder. If the cause of overflow is obstruction, then relieving the obstruction should lead to improved emptying. Anatomic obstruction in males derives from either urethral stricture disease or prostatic obstruction. Depending on the severity of urethral stricture disease, the patient may require urethral dilation, internal urethrotomy, or urethroplasty. Prostatic obstruction may be treated in a variety of ways, but transurethral resection remains the gold standard. If a woman is obstructed from previous surgery or from pelvic prolapse, she may benefit from urethrolysis or surgical correction of the prolapse. Clean intermittent catheterization is an option in the obstructed patient who does not want or could not tolerate further surgery. The patient with overflow incontinence secondary to poor detrusor contractility is best treated with clean intermittent catheterization.

CURRENT THERAPY Urge Incontinence Behavioral Changes Avoidance of bladder irritants Timed voiding Pelvic muscle exercises Anticholinergics—Antimuscarinics—Nonselective for M3 Receptor Propantheline (Pro-Banthine)[1] 7.5 to 30 mg orally, three to five times daily Tolterodine (Detrol LA) 4 mg orally, daily Trospium (Sanctura) 20 mg orally, two times daily Solifenacin (Vesicare) 5-10 mg orally, daily Anticholinergics—Antimuscarinics—Selective for M3 Receptor Darifenacin (Enablex) 7.5-15 mg orally, daily

Anticholinergics—Antimuscarinics/Smooth Muscle Relaxants Oxybutynin Regular (Ditropan) 2.5-5 mg orally, one to three times daily Extended-release (Ditropan XL) 5-30 mg orally, daily Transdermal (Oxytrol) 3.9-mg patch, twice per week Hyoscyamine (Levsin) 0.125-0.375 mg orally, two to four times daily Anticholinergics/a Agonist—For Urge or Mixed Incontinence Imipramine (Tofranil)[1] 10-25 mg, once to three times daily Stress Incontinence Behavioral Changes Weight loss Quitting smoking Pelvic muscle exercises a Agonists Pseudoephedrine (Sudafed)[1] 30-60 mg, up to four times daily Surgery Anatomic Retropubic suspensions Burch Marshall-Marchetti-Krantz Slings Pubovaginal Midurethral Obturator Intrinsic Sphincter Deficiency Slings Pubovaginal Midurethral Obturator Artificial sphincter Submucosal Injections with Bulking Agents

Collagen (Contigen) Carbon-coated zirconium oxide beads (Durasphere) Ethylene vinyl alcohol copolymer (Tegress) 1 Not FDA approved for this indication.

Indwelling catheters are not an optimum treatment modality for treatment of incontinence. All patients with indwelling catheters will have infected urine, which predisposes them to bladder calculi and ultimately to squamous cell carcinoma of the bladder. Any foreign object in the bladder can cause or exacerbate elevated bladder pressure that is associated with hydronephrosis, ureteral obstruction, renal stones, and eventually renal failure. STRESS INCONTINENCE The amount of incontinence and how it affects the patient often determines the aggressiveness of treatment. The patient who is severely restricted because of severe leakage with minimal movement may not want to try medical therapy but may opt for surgical treatment, whereas the patient who leaks small amounts infrequently may choose conservative treatment. Pelvic floor exercises can improve anatomic stress urinary incontinence by augmenting closure of the external urethral sphincter and by preventing descent and rotation of the bladder neck and urethra. To benefit from the exercises, women must be taught to do the exercises properly, and they must do them. Adjuncts to learning pelvic floor exercises include weighted vaginal cones, a perineometer, and electrical stimulation. a Agonists such as phenylpropanolamine[1] and pseudoephedrine (Sudafed)[1] can be used for treatment of stress incontinence. The bladder neck and proximal urethra have abundant a receptors. Activation of these receptors by a agonists leads to an increase in smooth muscle tone. The usual dose is twice daily, but some women who are incontinent with exercise may benefit from taking an a agonist 1 hour before exercise. Tricyclic antidepressants, such as imipramine (Tofranil),[1] have both a-agonist and anticholinergic properties. Surgical therapy for stress incontinence is indicated when a patient does not wish to pursue nonsurgical therapy, or if such therapy has failed. The type of surgical therapy depends on the diagnosis. Patients who have anatomic stress incontinence can benefit from a variety of surgical repairs that restore the bladder neck to its normal retropubic position or improve urethral support. Patients with ISD usually have a well-supported bladder neck. These patients require a procedure that will close or coapt the proximal urethra. Coaptation may be achieved with a variety of bulking agents that are injected into the bladder neck or proximal urethra. A pubovaginal sling is the ideal procedure for the patient with both ISD and anatomic stress incontinence, as a sling will coapt the proximal urethra and restore the bladder neck to its normal location. Synthetic midurethral slings are ideal for the patient with anatomic stress incontinence who wishes surgery with minimal recovery time. In one of the rare randomized surgical trials for stress incontinence, the result with tension-free vaginal tape has been shown to be comparable to that of a Burch colposuspension at 6, 12, and 24 months. The newest sling is a transobturator sling that is placed transversely underneath the urethra from one obturator foramina to the other. The advantage of this sling is that the retropubic space is avoided, with low risk of bladder, bowel, and major vessel injury.

Randomized trials comparing midurethral or transobturator slings to pubovaginal slings have not been performed. MIXED INCONTINENCE Stress and urge incontinence often coexist. Burgio et al. advocate pelvic muscle exercises with biofeedback for treatment of stress and urge incontinence. Behavioral therapy can result in a reduction in incontinence episodes and patient-perceived improvement. Imipramine (Tofranil)[1] is beneficial in patients with mixed (stress and urge) incontinence. The recommended dose is 10 to 25 mg, three times daily. Seventy percent of patients with combined incontinence (stress and urge) will be relieved of urge incontinence following a procedure for stress incontinence. Patients whose urge incontinence does not respond to anticholinergics preoperatively may have a good response to anticholinergics once their stress incontinence is treated. Box 1 provides an overview of treatments. BOX 1 Overview of Treatments Behavioral Changes

•

Avoidance of bladder irritants

•

Weight loss

•

Quitting smoking

•

Pelvic muscle exercises

Medical Therapy

•

•

a Agonists •

Stress incontinent patients

•

Mixed incontinent patients

Anticholinergics •

•

Urge incontinent patients

Anticholinergics/a agonists •

Mixed incontinent patients

Surgical Therapy

•

Stress incontinent patients

•

Rare patients with urge incontinence



REFERENCES Blaivas and Groutz, 2002. Blaivas JG, Groutz A: Urinary incontinence: Pathophysiology, evaluation, and management overview. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, ed. Campbell's Urology, vol 2. 8th ed.. Philadelphia: WB Saunders; 2002:1027. Burgio et al., 1998. Burgio KL, Locher JL, Goode PS, et al: Behavioral vs drug treatment for urge urinary incontinence in older women: A randomized controlled trial. JAMA 1998; 280:1995-2000. Leach et al., 1997. Leach GE, Dmochowski RR, Appell RA, et al: Female Stress Urinary Incontinence Clinical Guidelines Panel summary report on surgical management of female stress urinary incontinence. The American Urological Association. J Urol 1997; 158:875. Ward and Hilton, 2001. Ward KL, Hilton P: A randomized trial of colposuspension and tension-free vaginal tape (TVT) for primary genuine stress incontinence: 2 year follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2001; 12(Suppl. 2):S7-S8.



Chapter 171 – Epididymitis

Method of: John N. Krieger, MD Epididymitis is the inflammatory reaction of the epididymis to infection or to local trauma. Epididymitis causes major morbidity, accounting for more than 600,000 visits to physicians per year in the United States. Acute epididymitis is responsible for more days lost from military service than any other disease and is responsible for 20% of urologic admissions in the military. A survey of ambulatory patients documented epididymitis as a cause of 1 in 345 visits (0.3%), representing the fifth most common urologic condition, after prostatitis, urinary tract infections, urinary stones, and sexually transmitted infections. Clinical Presentation Painful swelling of the scrotum is the characteristic clinical presentation. In most patients the pain and swelling are unilateral. The onset may be acute over 1 or 2 days or more gradual. Pain can radiate along the spermatic cord or into the lower abdomen. Symptoms of cystitis or urethritis are common. Dysuria or irritative lower urinary tract symptoms are characteristic. Many sexually active men have a urethral discharge. Thus, particular attention should be directed to eliciting a history of genitourinary tract disease or sexual exposure. Some men may have only a nonspecific finding of fever or other signs of infection. This is especially common in hospitalized men who have had urinary tract manipulation or catheterization and may be obtunded by medication. Tender swelling can occur in the posterior aspect of the scrotum. Usually, the swelling is unilateral and is often accompanied by erythema of the scrotal skin. Early in the course, swelling may be localized to one portion of the epididymis. However, the swelling often progresses to involve the ipsilateral testis, producing an epididymo-orchitis. At this point it is difficult to distinguish the testicle from the epididymis within the inflammatory mass. Scrotal examination reveals the characteristic inflammatory hydrocele caused by secretion of fluid between the layers of the tunica vaginalis. Urethral discharge may be apparent on inspection or on stripping of the urethra. Ideally, evaluation for urethritis should be done before the patient voids because micturition can make mild urethritis difficult or impossible to detect. The nursing staff should be taught to instruct patients with urogenital tract complaints not to void until after the physical examination. This is a common problem when we are asked to consult on patient management in the emergency department or in primary care settings. Patients with no sexual risk factors or evidence of urethritis should have microscopic evaluation of their midstream urine. Pathogenesis Acute epididymitis occurs when uropathogens overcome the host defenses of the male lower genitourinary tract to establish infection of the epididymis. Most cases result from retrograde ascent of organisms through

the urethra, prostate, ejaculatory duct, and vas deferens to reach the epididymis. Structural or functional abnormalities of the lower urinary tract increase the risk of epididymitis. The risk factors for epididymitis vary substantially in different patient populations. In children and older men, anatomic abnormalities are critical risk factors for development of epididymitis. These include congenital anatomic abnormalities, such as an ectopic ureter draining into the vas deferens in children, and acquired anatomic abnormalities, such as bladder outflow obstruction in older men. In contrast, most sexually active younger men with epididymitis have normal urinary tracts. Thus, urologic investigations are indicated in children and older men with epididymitis but are seldom needed for management of epididymitis in young sexually active men. Infections of the urethra, bladder, or prostate are important risk factors for development of epididymitis. In children and older men, the most common organisms are the typical bacteria that cause urinary tract infections, especially Escherichia coli, other enterics, and pseudomonads. In sexually active men, the most common pathogens are Chlamydia trachomatis and Neisseria gonorrhoeae. Men who practice insertive anal intercourse are also at risk for epididymitis caused by E. coli and other enteric bacteria. In addition to the usual causative organisms, immunocompromised patients are at higher risk for epididymitis caused by mycobacteria and fungi. Diagnosis and Treatment ACUTE EPIDIDYMITIS Most patients with acute epididymitis can be considered in two categories, nonspecific bacterial epididymitis or sexually transmitted epididymitis. Unusual patients develop epididymitis after genital trauma or with disseminated infections.


Exposure to sexually transmitted infection Urologic abnormalities or genitourinary tract instrumentation Symptoms of dysuria or urethral discharge Physical Examination

Pain or swelling on palpation of the epididymis Inflammatory hydrocele Scrotal skin erythema Urethral discharge Abnormal genitourinary tract anatomy Elevated temperature Laboratory Studies

Urethral swab specimen or first-void urine for pyuria Midstream urine for evidence of bacteriuria or pyuria Urine culture and sensitivity testing Samples for evaluation of sexually transmitted infections, as appropriate Doppler scrotal ultrasound may be helpful to differentiate epididymitis from testicular torsion or tumor Clinical evaluation begins with a history, with specific attention to eliciting recognized risk factors, and a thorough physical examination. Initial laboratory tests include urinalysis, culture, and sensitivity testing for men with presumed nonspecific bacterial epididymitis. Men at risk for sexually transmitted epididymitis should also have a gram-stained urethral smear, culture for N. gonorrhoeae, and testing for C. trachomatis. In the latter group, serologic testing is also recommended for syphilis and for HIV infection.

CURRENT THERAPY Age Younger than 35 Years with No History of Allergy

Ceftriaxone (Rocephin) 250 mg IM once plus Doxycycline (Vibramicin) 100 mg PO bid for 10 days or Azithromycin (Zithromax) 1 g PO as a single dose Age Older than 35 Years or Patient with a History of Allergy to Cephalosporins or Tetracyclines

Ofloxacin (Floxin) 300 mg PO bid for 10 days or Levofloxacin (Levaquin) 500 mg PO qd for 10 days All Patients

Anti-inflammatories Decreased activity Scrotal elevation Pain control Follow-up

Failure to improve within 3 days: Reevaluate initial diagnosis and therapy For persistent swelling and tenderness after therapy, consider: Testicular tumor Abscess Testicular infarction Tuberculosis Fungal epididymitis NONSPECIFIC BACTERIAL EPIDIDYMITIS Infection with coliform or Pseudomonas species is the most common cause of epididymitis in men older than 35 years. In most series, gram-negative rods caused more than two thirds of cases of bacterial epididymitis. However, gram-positive cocci are also important pathogens and constituted the most common organisms in other reports. Patients with bacterial epididymitis often have underlying urologic pathology or have a history of genitourinary tract manipulation. Epididymitis can occur weeks or rarely months after genitourinary tract surgery or urethral catheterization. Epididymitis constitutes a special risk for men who undergo urinary tract surgery or instrumentation while they are bacteriuric. Acute and chronic bacterial prostatitis represent other important predisposing conditions for development of bacterial epididymitis. Medical management is appropriate for most patients with bacterial epididymitis. Typical patients are managed as outpatients. Initial empiric treatment is initiated with agents appropriate for both gram-negative rods and gram-positive cocci pending urine culture and sensitivity results. Fluoroquinolones represent our first choice for management of nonspecific epididymitis in outpatients. Agents of choice include ofloxacin (Floxin) and levofloxacin (Levaquin). Ciprofloxacin (Cipro) represents a reasonable alternative quinolone. In areas where the rate of bacterial resistance is low, trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim, Septra) represents another reasonable alternative. Initial empiric therapy may be changed, if necessary, after culture results are available. A standard course of therapy is 10 days. More prolonged therapy may be needed for select patients such as those with evidence of bacterial prostatitis, whose antimicrobial therapy is continued for 6 to 12 weeks. Indications for hospitalization include systemic symptoms, such as leukocytosis and fever, complications, or associated medical conditions. In these severe cases, parenteral antimicrobial therapy is used until the patient defervesces. Choices for empiric therapy of severe cases include the combination of an

aminoglycoside plus either a ß-lactam agent or a third-generation cephalosporin. After resolution of the acute systemic infection, therapy is continued with oral agents, guided by the culture and sensitivity results. Nonspecific measures are worthwhile, including bedrest, scrotal elevation, analgesics, and local ice packs. A spermatic cord block with bipuvicaine (Marcaine) may be helpful for managing severe pain. We recommend urologic evaluation, because structural or functional abnormalities are common among men and boys with nonspecific bacterial epididymitis. SEXUALLY TRANSMITTED EPIDIDYMITIS Sexually transmitted epididymitis is most common in young men. C. trachomatis and N. gonorrhoeae are the major pathogens. In most series, chlamydia was identified as the most common cause of epididymitis in younger, sexually active populations. For example, in our institution, C. trachomatis infections were documented in 17 (50%) of 34 cases of epididymitis in men younger than 35 years but in only 1 (6%) of 16 cases of epididymitis in men older than 35 years. In the past, these patients were considered to have “idiopathic” nonspecific epididymitis. Sexually transmitted E. coli infection also occurs among men who are the insertive partners during anal intercourse. Often patients with chlamydial epididymitis do not complain of urethral discharge. However, 11 (65%) of 17 patients with epididymitis caused by Chlamydia had demonstrable discharge. In most cases, the discharge was scant and watery, characteristic of nongonococcal urethritis. The median interval from the last sexual exposure was 10 days and ranged from 1 to 45 days. Thus, urethral C. trachomatis may be carried for long periods before overt epididymitis develops. In the preantibiotic era, epididymitis occurred in 10% to 30% of men with gonococcal urethritis. However, in current series, N. gonorrhoeae was identified in 16% of men with epididymitis in military populations and in 21% of men with epididymitis in civilians younger than 35 years. Many patients with epididymitis do not have a history of urethral discharge, and a discharge may be demonstrable in only 50% of such patients. Diagnosis depends on a high index of clinical suspicion, evaluation for presence of urethritis (which may be asymptomatic), appropriate cultures, or antigen detection tests. Empiric therapy is recommended before culture results are available. Appropriate therapy includes coverage for both N. gonorrheae and C. trachomatis infections. The first choice regimen is the combination of ceftriaxone (Rocephin) plus doxycycline (Vibramycin) for 10 days. Allergic patients are treated with one of the quinolone regimens described earlier. Alternatives for coverage of N. gonorrhoeae include cefixime (Suprax), ciprofloxacin, ofloxacin, levofloxacin, or spectinomycin (Trobicin). Azithromycin (Zithromax) represents an effective alternative for coverage of C. trachomatis. Nonspecific measures are helpful, including bedrest, scrotal elevation, analgesics, and local ice packs. A spermatic cord block with bipuvicaine can reduce the need for analgesics in men with severe pain. Patients should be evaluated for other sexually transmitted infections, and treatment of sexual partners is important. Patients should be instructed to avoid intercourse until symptoms have resolved completely and to refer all sex partners within the previous 60 days for evaluation and treatment. Underlying genitourinary tract abnormalities are uncommon in this population. Thus, a complete urologic work-up is indicated rarely for patients with uncomplicated sexually transmitted epididymitis.

UNCOMMON CAUSES Tuberculous epididymitis is the most common manifestation of genital tuberculosis in men, with orchitis and prostatitis less common. The usual symptom is heaviness or swelling. Scrotal swelling with bead-like enlargement of the vas deferens is characteristic. Chronic draining scrotal sinuses can occur. The systemic mycoses rarely cause epididymitis; blastomycosis is the most common pathogen and can also cause a draining sinus through the scrotal wall. Men with HIV infection and uncomplicated epididymitis should receive the same treatment as those without HIV. However, fungal and mycobacterial causes of epididymitis are more common among patients who are immunocompromised. In the pediatric population, epididymitis can occur with congenital anatomic abnormalities, such as ectopic ureter or posterior urethral valves. Epididymitis occasionally occurs after testicular trauma. Many of these men have evidence of genitourinary tract infections with organisms outlined earlier, but occasional men develop traumatic epididymitis that is not associated with positive cultures or inflammation. We also described an unusual syndrome of noninfectious epididymitis associated with amiodarone (Cordarone) therapy for refractory ventricular arrhythmias. Rare patients develop epididymitis as a complication of collagen vascular disorders, such as Wegener's granulomatosis or Behçet's disease. Differential Diagnosis Severe inflammation can lead to an enlarged indurated epididymis that is indistinguishable from the testicle. This can present difficulties in the differential diagnosis of epididymitis from testicular torsion or testicular cancer. Normally, the epididymis lies posterior to the testis. This demarcation is often preserved in cases of epididymitis. Reactive hydrocele formation can render palpation of intrascrotal structures difficult. Although transillumination often identifies hydroceles, color-flow Doppler ultrasonography is my preferred imaging study when the diagnosis is in doubt. Acute epididymitis must be distinguished from testicular torsion at the initial evaluation because uncorrected torsion results in testicular death within 24 hours. Men with swelling and tenderness that persist after completing therapy should be reevaluated for testicular cancer, tuberculosis, or fungal epididymitis. Complications Most patients experience relief of their symptoms within 48 hours. However, swelling and discomfort can persist for weeks or months following eradication of the infecting organism. In some cases, the epididymis remains enlarged or indurated indefinitely. Such men can develop chronic epididymitis, which is characterized by pain and occasionally by recurrent swelling. Bacterial epididymitis may be an important focus of organisms causing both local morbidity and bacteremia in men with indwelling transurethral catheters. Genitourinary tract complications of acute epididymitis include testicular infarction, scrotal abscess, pyocele of the scrotum, a chronic draining scrotal sinus, chronic epididymitis, and infertility. Ultrasonography, particularly color-flow Doppler ultrasonography, is useful for the differential diagnosis of complicated cases. Surgery may be necessary for complications of acute epididymal infections.



REFERENCES Centers for Disease Control and Prevention, 2006. Centers for Disease Control and Prevention : Sexually transmitted diseases treatment guidelines, 2006. MMWR Morb Mortal Wkly Rep 2006; 55:1-94. Collins et al., 1998. Collins MM, Stafford RS, O'Leary MP, Barry MJ: How common is prostatitis?. A national survey of physician visits. J Urol 1998; 159:1224-1228. Furuya et al., 2004. Furuya R, Takahashi S, Furuya S, et al: Is seminal vesiculitis a discrete disease entity? Clinical and microbiological study of seminal vesiculitis in patients with acute epididymitis. J Urol 2004; 171:1550-1553. Karmazyn et al., 2005. Karmazyn B, Steinberg R, Kornreich L, et al: Clinical and sonographic criteria of acute scrotum in children: A retrospective study of 172 boys. Pediatr Radiol 2005; 35:302-310. Krieger, 2004. Krieger JN: Sexually transmitted diseases. In: Tanagho EA, McAninch JW, ed. Smith's Urology, 16th ed.. New York: Lange Medical Books/McGraw-Hill; 2004:245-255. Mittemeyer et al., 1966. Mittemeyer BT, Lennox KW, Borski AA: Epididymitis: A review of 610 cases. J Urol 1966; 95:390-392. Naber et al., 2001. Naber KG, Bergman B, Bishop MC, et al: EAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol 2001; 40:576-588. Nickel et al., 2002. Nickel JC, Siemens DR, Nickel KR, Downey J: The patient with chronic epididymitis: Characterization of an enigmatic syndrome. J Urol 2002; 167:1701-1704. Nickel et al., 2005. Nickel JC, Teichman JM, Gregoire M, et al: Prevalence, diagnosis, characterization, and treatment of prostatitis, interstitial cystitis, and epididymitis in outpatient urological practice: The Canadian PIE Study. Urology 2005; 66:935-940. Stehr and Boehm, 2003. Stehr M, Boehm R: Critical validation of colour Doppler ultrasound in diagnostics of acute scrotum in children. Eur J Pediatr Surg 2003; 13:386-392.



Chapter 172 – Primary Glomerular Diseases

Method of: Manuel Praga, MD Enrique Morales, MD Clinical Presentation And Diagnosis The clinical manifestations of primary glomerular diseases are very variable, ranging from asymptomatic urinary abnormalities to severe forms of rapidly progressive glomerulonephritis. The different clinical presentations are summarized and defined in Box 1 . BOX 1 Clinical Presentations of Glomerular Diseases Nephrotic Syndrome

•

Proteinuria >3.5 g/d in adults and >40 mg/h/m2 in children

•

Hypoalbuminemia

•

Hyperlipidemia

•

Edema

Nephritic Syndrome

•

Hypertension

•

Oliguria

•

Edema

•

Hematuria (usually macroscopic)

•

Red cell casts

•

Non-nephrotic proteinuria

•

Mild and nonprogressive GFR decrease

Rapidly Progressive Glomerulonephritis

•

Acute or subacute progressive worsening of renal function

•

Hematuria (usually macroscopic)

•

Red cell casts

•

Proteinuria (usually 40%

•

Nephritic or nephrotic syndrome in 2 U packed red blood cells per 24 hours), incomplete radiographic staging, and laparotomy for associated injuries. The presence of more than one relative indication often warrants surgical treatment. The selective embolization of hemorrhage via interventional radiology, used more commonly in splenic and hepatic injuries, is a promising new modality for nonoperative management of select renal injuries.

CURRENT THERAPY Renal Trauma Observation with close monitoring of vital signs and hematocrit Renal exploration and attempted reconstruction Ureteral Trauma Urinary diversion (via a ureteral stent or percutaneous nephrostomy tube) Ureteral exploration and repair (immediate or delayed) Bladder Trauma Catheter drainage Bladder exploration and repair Genital Trauma in Males Surgical exploration and repair Urethral Trauma Transurethral catheterization Suprapubic urinary diversion Endoscopic realignment Urethral suturing

Operative renal exploration is performed through a midline transperitoneal abdominal approach. The renal vessels are identified prior to opening Gerota's fascia. Vascular control becomes important when confronted with deep renal parenchymal or vascular bleeding. Once the kidney is exposed and all injuries are identified, the appropriate reconstructive technique can be performed. Simple lacerations can be managed with renorrhaphy. Polar injuries are best treated by partial nephrectomy. Attempts at vascular repair should be made provided these injuries are discovered promptly. OUTCOME Aggressive accurate staging of renal trauma and careful attention to reconstruction are paramount in avoiding renal loss. Although most renal injuries can be managed nonoperatively, renal salvage can be expected in approximately 70% to 90% of cases requiring exploration. Early complications of renal trauma include bleeding, infection, abscess formation and persistent urinary extravasation. Late complications include hypertension and decreased renal function. Hypertension occurs in approximately 5% of cases and is believed to be caused by mechanisms that activate the renin-angiotensin system. It usually manifests within the first few months of injury, but further delayed onset has been documented. Blood pressure should be measured regularly for the first year and annually thereafter. Ureteral Trauma ETIOLOGY Ureteral injuries from external trauma constitute approximately 1% to 3% of all genitourinary injuries. The ureter's mobility and anatomic characteristics protect it from trauma; its narrow diameter and retroperitoneal location between the spine, major muscle groups, and the peritoneal contents make it an unlikely target. Most external ureteral injuries occur from gunshot wounds. The bullet need not physically transect the ureter to cause significant damage. If the bullet's path is simply near the ureter, the temporary cavitation created by the missile can cause significant tissue destruction and delayed necrosis. Such injuries can be difficult to identify initially and often present with delayed sequelae. Penetrating ureteral injuries are almost always associated with multiple organ injuries. The most common sites, in order of decreasing frequency, are the small bowel, colon, liver, and iliac vessels. Ureteral injuries from blunt trauma are rare. They usually occur in children during rapid deceleration, causing excessive hyperextension of their flexible vertebral column with disruption at the ureteropelvic junction. Blunt ureteral injuries also are associated with multiple organ injuries, most commonly to the liver, spleen, and skeletal system. Iatrogenic ureteral injuries are the most common. They most frequently occur during ureteroscopy, hysterectomy, low anterior colon resection, vaginal surgery, and abdominal aneurysm repair and usually involve the lower ureteral segment. DIAGNOSIS Prompt diagnosis is the first step toward a successful outcome. This may be complicated by the presence of multiple organ injuries and the absence of clinical and laboratory findings specific for ureteral trauma. Indeed, hematuria, which is a reliable indicator of renal trauma, is absent in 30% to 45% of ureteral injuries. These limitations frequently result in delayed recognition manifested by fever, flank pain, urinoma, fistula formation, and eventually sepsis. To avoid this additional morbidity, it is imperative that the evaluating

physician maintain a high index of suspicion based on the injury mechanism and location. Essentially any patient with penetrating abdominal trauma should be suspected of having a ureteral injury and evaluated radiographically. Similarly, children with significant blunt abdominal trauma and multiple associated injuries should undergo radiographic ureteral assessment regardless of findings on urinalysis. Urinary tract imaging can be obtained using either a CT scan or an IVP. Extravasation of contrast is the sine qua non of a ureteral injury. On CT, the extravasated contrast usually will be confined to the medial perirenal space. With complete ureteral disruption, no contrast material will be seen in the distal ureter on delayed images. Extravasation may be seen on an IVP, but frequently the findings are more subtle, such as delayed renal function or mild ureteral dilation or deviation. If the results of the CT or IVP are inconclusive, a retrograde ureterogram can be performed. Although this is the most accurate ureteral imaging test, it is often impractical in the acute trauma setting. Most penetrating ureteral injuries are diagnosed intraoperatively during the initial exploratory laparotomy performed for management of the associated abdominal injuries. In this setting, direct visual inspection is the most reliable method for assessing ureteral integrity. Intravenous or intraureteral injection of indigo carmine or methylene blue may aid in injury recognition ( Figure 4 ).

FIGURE 4 Algorithm for the diagnosis and management of ureteral trauma (abdominal or rapid deceleration injury). Abbreviations: CT = computed tomography; IVP = intravenous pyelogram.

Iatrogenic ureteral injuries are usually discovered more than 24 hours after the insult. Often they present with signs of acute infection from prolonged urinary extravasation or with incisional urinary leakage. MANAGEMENT Selection of the appropriate management of a ureteral injury depends on the patient's condition, the site and extent of injury, and the time of diagnosis. Most patients with ureteral injuries from external trauma require prompt operative exploration for management of the associated abdominal injuries. Concomitant intraabdominal organ or vascular injuries should not preclude ureteral reconstruction in a stable patient. Ureteral repair can be performed using a variety of reconstructive techniques, depending on the level and length of the injured segment. Regardless of the location, successful surgical repair includes the use of healthy ureteral segments (taking thermal effect into consideration) and a watertight, tension-free anastomosis. Injuries to the distal lower third of the ureter are best managed by bladder reimplantation. For injuries involving the entire lower third of the ureter, a psoas hitch can be used. However, in patients with insufficient bladder capacity or with severe pelvic scarring, a transureteroureterostomy can be fashioned. Injuries encompassing the lower half of the ureter are best managed with an anterior bladder wall (Boari-Ockerblad) flap. Short mid or upper ureteral defects can be bridged with a primary ureteroureterostomy. Complete ureteral avulsions are managed with an ileal interposition or renal autotransplantation. Ureteral injuries in a patient in whom diagnosis was significantly delayed or in an unstable patient are best managed initially by percutaneous nephrostomy drainage or endoscopic ureteral stenting. Definitive repair can be scheduled electively, if necessary. Approximately 50% of iatrogenic ureteral injuries heal simply with temporary urinary diversion. OUTCOME Early diagnosis and careful reconstruction of ureteral injuries are important in minimizing complications and preserving renal function. Complications are rare but include prolonged extravasation, infection, fistula formation, and stricture. Bladder Trauma ETIOLOGY The bladder is second to the kidneys in frequency of injury, accounting for 20% to 25% of all genitourinary injuries. Bladder injuries are caused by either blunt or penetrating trauma to the lower abdomen, pelvis, or perineum. Blunt trauma is the more common mechanism, usually by a severe external force such as a motor vehicle accident, fall, or crush injury. Associated injuries include pelvic and long bone fractures as well as central nervous system and chest injuries. Factors that contribute to bladder rupture include pelvic fracture, bladder distention, and any previous pelvic surgery. The location of the bladder deep within the bony pelvis protects it from most penetrating trauma; however, the possibility of bladder trauma should be considered with any lower abdominal gunshot or stab wound. Iatrogenic bladder injuries usually occur during transurethral or gynecologic procedures. DIAGNOSIS

A bladder injury should be suspected after any external lower abdominal or pelvic trauma. The patient usually complains of abdominal pain and distention and may be unable to urinate. Hemodynamic instability is common because of extensive blood loss in the pelvis. Physical examination should include carefully performed pelvic and rectal examinations. Gross hematuria occurs in 95% of bladder ruptures from blunt injuries; the remainder have microscopic hematuria. With penetrating injuries, most patients present with microscopic hematuria. Urine is best obtained by urethral catheterization, which must be performed only after inspection of the urethral meatus. Blood at the meatus is a contraindication to urethral catheterization because this finding strongly suggests a urethral injury and requires confirmation by retrograde urethrography. Cystography is the most accurate imaging test to diagnose a bladder injury. With conventional cystography, a plain film of the pelvis is first obtained and then 350 mL of water-soluble contrast material is infused through a catheter by gravity to distend the bladder; anteroposterior and drainage films should be taken. Alternatively, CT cystography can be used, provided the bladder is filled in a retrograde manner (via a transurethral catheter). In most cases, extravasation of contrast is not seen, and the injury is classified as a contusion. Such injuries result in damage to the mucosa or muscularis without loss of bladder wall continuity. With extravasation of contrast material, the distinction between an extraperitoneal and intraperitoneal bladder rupture must be made. Extraperitoneal bladder ruptures are more common. On cystography, these injuries are characterized by extravasation confined to the perivesical soft tissues. With intraperitoneal bladder ruptures, the contrast extravasates in the peritoneal cavity, outlining the bowel loops. Although cystography can accurately diagnose bladder injuries, the amount of contrast extravasated does not correlate with the extent of injury ( Figure 5 ).

FIGURE 5 Algorithm for the diagnosis and management of bladder trauma (lower abdominal or pelvic injury).

MANAGEMENT The choice of management depends on the overall status of the patient, the type of bladder injury sustained, and the extent of associated injuries. Bladder contusions can be treated by transurethral catheter drainage alone, which should be maintained until the hematuria completely resolves. Extraperitoneal bladder ruptures in patients who do not require laparotomy can also be managed nonoperatively, provided the urine is sterile at the time of injury and the existing hematuria does not obstruct catheter drainage. Usually the catheter can be removed after approximately 10 to 14 days after a repeat cystogram shows adequate healing. Extraperitoneal ruptures that involve the bladder neck or drain with difficulty should be surgically repaired. All intraperitoneal bladder ruptures require surgical exploration. This is accomplished through a midline infraumbilical incision, avoiding dissection of the pelvic hematoma. The peritoneum is opened and the abdominal viscera inspected; the bladder injury is then repaired from within the bladder lumen, and a transurethral catheter is maintained for 7 to 10 days. OUTCOME

Mortality in patients with bladder trauma approaches 20% and is due to the associated injuries rather than the bladder rupture. Short-term complications of the bladder injury include persistent bleeding, urinary extravasation, and infection. Long-term complications are rare but can include fistula formation, urinary incontinence, and bladder instability. Genital Trauma in Males ETIOLOGY Injuries to the male genitalia constitute 5% to 7% of all civilian genitourinary injuries. However, in some wartime series, they were the most common genitourinary injuries (60%). This high incidence was the result of the widespread use of ground-level explosives during combat. Genital injuries include those occurring to the testes, scrotum, and penis. Most testicular injuries result from blunt trauma and are usually unilateral; penetrating testicular injuries from gunshot and stab wounds are less common. Similarly, scrotal trauma from gunshot or stab wounds occurs infrequently; most scrotal injuries occur as a consequence of burns or avulsions. Penile injuries have diverse mechanisms, including ruptures (usually occurring during sexual intercourse), amputations (usually self-inflicted or from entrapment of clothes by heavy machinery), and strangulations (usually from constricting penile rings used to enhance erections). Penetrating injuries (mostly gunshot wounds) can occur, although they usually cause little tissue destruction apart from the entrance and exit wounds. DIAGNOSIS Accurate determination of the extent of a testicular injury by clinical means alone may be difficult; the diagnosis is enhanced by scrotal ultrasonography. A heterogeneous intratesticular echo pattern is the most common ultrasonographic finding of a testicular rupture. In addition, extruded testicular tissue or disruption of the tunica albuginea can be seen occasionally but is not a required sonographic criterion to confirm a rupture. Penile and scrotal injuries can be accurately diagnosed by visual inspection in conjunction with a thorough history. Any patient with trauma to the penis should undergo a retrograde urethrogram because the incidence of a concomitant urethral injury approaches 80%, depending on the mechanism of injury ( Figure 6 ).

FIGURE 6 Algorithm for the diagnosis and management of genital trauma.

MANAGEMENT All penetrating testicular injuries and any blunt testicular injury suggestive of a rupture should be surgically explored. Attempts at testicular repair should be made, with orchiectomy limited to extensive unreconstructable injuries. Similarly, penile ruptures and penetrating injuries should be explored promptly and the defect repaired, sparing unnecessary débridement, which could further compromise valuable erectile tissue. Penile amputations should be managed by microsurgical reimplantation, provided the amputated segment is viable. The management of scrotal burns or avulsions requires surgical excision of all nonviable tissue and meticulous wound care. Techniques for delayed scrotal closure include split-thickness skin grafts, rotational thigh flaps, and tissue expanders. OUTCOME Genital injuries usually can be diagnosed easily and should be managed promptly. The goal is preservation of genital function and maintenance of cosmesis. Untoward sequelae can be minimized by limiting excessive débridement of penile and testicular tissues and instituting prompt aggressive local wound care with scrotal trauma. Complications of penile and testicular injuries include erectile and reproductive dysfunction, infection, tissue necrosis, and urethral stricture. Urethral Trauma ETIOLOGY Urethral injuries compose approximately 7% to 10% of all genitourinary injuries. These injuries are anatomically subdivided into posterior and anterior injuries. In males, the posterior urethra is proximal and the anterior urethra distal to the external (striated) sphincter. Only the posterior urethra exists in females. Injuries to the posterior urethra occur almost exclusively with pelvic fractures. Specifically, with a crush or

deceleration-impact injury, the severe shearing forces necessary to fracture the pelvis are transmitted to the prostatomembranous junction, the weakest portion of the urethra. Overall, the male posterior urethra is injured in up to 10% of all pelvic fractures and the female urethra in up to 4% of all pelvic fractures. In contrast to posterior urethral trauma, injuries to the anterior urethra are not associated with pelvic fractures. External anterior urethral injuries result from blunt or penetrating trauma. Blunt injuries are more common and are caused by vehicular accidents (often bicycles), falls (straddle-type injuries), and direct blows to the perineum or penis. Penetrating anterior urethral injuries, usually from gunshot wounds, are less frequent but often occur in conjunction with penetrating penile or testicular trauma. Iatrogenic urethral injuries are by far the most frequent cause of urethral trauma. Examples include inadvertent Foley catheter balloon inflation in the urethra and traumatic lower urinary tract endoscopy (cystoscopy, transurethral surgery). These injuries are often minor and tend to be underreported. DIAGNOSIS The diagnosis of urethral trauma should be suspected from the history. A pelvic fracture or any external penile or perineal injury can be suggestive of urethral trauma. In a conscious patient, a thorough voiding history should be obtained to establish the time and characteristics of the last urination. A urinalysis is an important laboratory adjunct. The following clinical indicators of urethral trauma warrant a complete urethral evaluation: 1.

Blood at the urethral meatus. This is the most consistent and accurate clinical indicator of urethral trauma. Its presence should preclude any attempts at urethral instrumentation until the entire urethra is adequately imaged.

2.

Blood at the vaginal introitus. In female patients following pelvic fracture, this finding is highly suggestive of a urethral injury.

3.

Hematuria. Although this finding is nonspecific, it is a reliable indicator of urethral trauma. All patients who are able to urinate after a urethral injury will have some degree of hematuria on a first-voided specimen.

4.

Pain on urination or inability to void. Painful urination occurs after urethral trauma from edema or urinary extravasation. The inability to void suggests urethral disruption.

5.

High-riding prostate. This may be palpated after a posterior urethral injury because of superior displacement of the prostate, but it is not a very reliable finding.

Assessment of concomitant rectal and genital injuries is mandatory in every case of external urethral trauma. All patients should have a rectal examination with stool Hemoccult testing. In addition, a complete pelvic examination should be performed on female patients. Retrograde urethrography is the cardinal diagnostic procedure in male patients suspected of having sustained urethral trauma. This must be performed prior to any attempt at transurethral catheterization. Urethroscopy should not be used in the initial diagnosis of urethral trauma in males. In females, however, the short urethra precludes adequate imaging with retrograde urethrography, making urethroscopy the

diagnostic modality for identification and staging of these injuries. Urethral injuries are simplistically classified as follows: 1.

Contusion, whereby the urethral mucosa remains intact

2.

Partial disruption, with segmental maintenance of mucosal continuity

3.

Complete disruption with separation of both urethral ends

The distinction is made by retrograde urethrography. Although any degree of urethral disruption will result in contrast extravasation, the absence of contrast material in the bladder suggests a complete disruption ( Figure 7 ).

FIGURE 7 Algorithm for the diagnosis and management of urethral trauma (penile or perineal injury, pelvic fracture).

MANAGEMENT The goal of initial treatment of any urethral trauma is avoidance of any maneuver that can potentiate the injury. Only urethral contusions can be managed safely with transurethral catheterization. With a urethral disruption, the blind passage of a transurethral catheter should be avoided because this can extend the urethral tear, introduce infection, and disrupt a pelvic hematoma. Urinary diversion by means of a suprapubic cystostomy is the easiest and safest option for the initial management of any urethral disruption (partial or complete). After the patient has adequately recovered from the associated injuries and the urethral injury

has stabilized, the urethra can be thoroughly evaluated radiographically and the appropriate reconstructive procedure planned when necessary. Immediate repair of the acutely traumatized urethra by means of endoscopic realignment or urethral suturing is technically more difficult than suprapubic cystostomy placement. In select cases, however, it may be successful in minimizing the need for subsequent extensive reconstructive surgery by limiting scar formation. Examples in which primary urethral repair may be considered include most penetrating urethral injuries (by suturing), urethral injuries associated with penile fractures (by suturing), and select partial posterior urethral disruptions (by realignment). A urethral disruption in a female requires immediate surgical repair because any tear involving the short female urethra likely will extend to the bladder neck and disrupt the sphincteric mechanism. Prompt urethral and bladder neck reconstruction is necessary in order to limit posttraumatic incontinence. OUTCOME Urethral injuries from external trauma are some of the most devastating and difficult genitourinary injuries. Major long-term complications, which include urinary incontinence, erectile dysfunction, stricture formation, and recurring infections, are often a result of the initial injury. Adhering to the principles outlined earlier can minimize additional complications.



REFERENCES Brandes et al., 2004. Brandes S, Coburn M, Armenakas NA, McAninch JW: Diagnosis and management of ureteric injury: an evidence-based analysis. BJU Int 2004; 94:277-289. Chapple et al., 2004. Chapple C, Barbagli G, Jordan G, et al: Consensus statement on urethral trauma. BJU Int 2004; 93:1135-1202. Gomez et al., 2004. Gomez RG, Ceballos L, Coburn M, et al: Consensus statement on bladder injuries. BJU Int 2004; 94:27-32. Morey et al., 2004. Morey AF, Metro MJ, Carney KJ, et al: Consensus on genitourinary trauma: External genitalia. BJU Int 2004; 94:507-515. Santucci et al., 2004. Santucci RA, Wessells H, Bartsch G, et al: Evaluation and management of renal injuries: Consensus statement of the renal trauma subcommittee. BJU Int 2004; 93:937-954.



Chapter 175 – Prostatitis

Method of: Andrea Gallina, MD Pierre I. Karakiewicz, MD The clinical entity termed prostatitis affects 2% to 10% of men during their lifetime. Moreover, prostatitis symptoms are the most common cause for urologic consultation in men 50 years of age. The definition of prostatitis includes a large variety of clinical and nonclinical entities with a common underlying background. To standardize the diagnostics and the therapeutic approaches, the National Institutes of Health (NIH) proposed a classification system of prostatitis syndromes. It consists of four categories that reflect the wide variety of clinical manifestations of this syndrome ( Box 1 ). BOX 1 National Institutes of Health Classification of Prostatitis Category I

•

Acute bacterial prostatitis

Category II

•

Chronic bacterial prostatitis

Category III

•

Chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS) •

III A: Inflammatory CP/CPPS

•

III B: Noninflammatory CP/CPPS

Category IV

•

Asymptomatic inflammatory prostatitis

Category I: Acute Bacterial Prostatitis Acute bacterial prostatitis affects 2% to 5% of prostatitis patients. It typically represents an ascending infection of the prostate with uropathogenic bacteria (Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia marcescens, Pseudomonas aeruginosa). The classic presentation includes systemic (fever, chills and malaise) and local symptoms. Local symptoms consist of dysuria and perineal and prostatic pain, and they may be associated with complete or partial bladder outlet obstruction (urinary frequency, incomplete

emptying, urgency, hesitancy, or retention). The onset may be sudden. The severity of systemic symptoms determines the need for hospitalization. On history, recent urinary tract infections and urologic instrumentation (e.g., prostate biopsies, urinary catheters) should be ruled out. A gentle digital rectal examination (DRE) (to avoid local or systemic exacerbation of symptoms) assesses the extent of tenderness (acute infection), and rules out masses (abscess formation or associated prostatic or nonprostatic lesions). Postvoid residual is best assessed ultrasonically, because passage of catheters should be avoided. Presence of significant residual (>20% of voided volume) represents a relative indication for catheter drainage. Size 14 F or smaller catheters represent a valid alternative for suprapubic drainage. Urinalysis, midstream specimen for urine culture, and blood cultures (if systemic symptoms are present) complete the assessment. Patients with systemic symptoms usually require hospitalization. Intravenous antibiotics (ampicillin and gentamicin) and hydration represent the mainstay of therapy. Ciprofloxacin and levofloxacin are alternatives if allergies or other contraindications exist. Once the patient is afebrile for 24 hours or according to blood culture results, oral fluoroquinolones or trimethoprim-sulfamethoxazole (TMP-SMX) may be initiated. Persistent fever and symptoms after 48 hours of IV antibiotic therapy can indicate an abscess formation, which may be identified with computed tomography (CT), magnetic resonance imaging (MRI), or transrectal ultrasonography. Antibiotic-refractory prostatic abscesses might require drainage with transurethral prostatic resection. Periprostatic abscesses may be drained transrectally. Category I prostatitis represents a complicated urinary tract infection (UTI). Once symptoms have subsided and antibiotic therapy has been completed, a careful investigation of the upper and lower urinary tract is in order to identify any potentially predisposing causes. Imaging studies (ultrasound, CT, MRI), cystoscopy, and urodynamic studies can reveal an underlying cause, such as prostatic hypertrophy with urinary retention, bladder stone or diverticulum, or urethral stricture, among others. Category II: Chronic Bacterial Prostatitis NIH category II prostatitis is defined as a chronic or persistent pathogenic infection (culture proven) of the prostate without systemic symptoms. It accounts for 2% to 5% of patients with prostatitis. It is characterized by intermittent episodes of cystitis-like urinary symptoms, which only rarely involve appreciable discomfort or pain. Recurrent infectious episodes are highly suggestive of chronic bacterial prostatitis, especially if the same pathogen is documented in either a midstream urine specimen or a postprostatic massage urine specimen. E. coli (which represents 80% of the infectious agents), Klebsiella species, P. aeruginosa, and Proteus species represent the most commonly seen pathogens. History and physical and laboratory examinations are virtually the same as those for category I prostatitis. The more protruded nature of category II prostatitis requires 4 to 8 weeks of antimicrobials (fluoroquinolones or TMP-SMX). This therapy is effective in 60% to 80% of patients. However, in cases of recurrent infections, long-term (3-6 months) antibiotic therapy is an alternative treatment. Other modal-ities have been investigated (for example intraprostatic injection of antibiotics) but have met with limited success. Category III: Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome

Category III prostatitis (CP/CPPS) accounts for 90% to 95% of prostatitis cases and is the most challenging subgroup. Symptoms include pelvic or perineal (or both) pain or discomfort, as well as urinary or ejaculatory symptoms. Pain may be perineal, suprapubic, coccygeal, rectal, urethral, or testicular or scrotal. Urinary frequency, dysuria, urgency, or incomplete emptying and ejaculatory pain affect a significant proportion of patients. Ejaculatory pain suggests worse prog-nosis. Presence or absence of inflammatory cells in the ejaculate distinguishes between category IIIA (inflammatory) and category IIIB (noninflammatory) prostatitis. However, the clinical presentation and therapeutic approaches are the same for these two groups, and the reliability of this distinction is suboptimal. Only in up to 5% of patients is a pathogen successfully isolated from urine or semen. The clinical heterogeneity of category III prostatitis and the absence of a diagnostic marker add complexity to the classification and treatment of this syndrome. A multifactorial etiology, which includes infectious, traumatic, inflammatory, hormonal, neurologic, and psychological triggers, is the most likely cause. DIAGNOSIS The evaluation of patients with category III prostatitis should include a detailed history (focusing on previous infections, trauma, surgery, or neurologic problems). It should be complemented with the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire, which is a standardized assessment of the type and severity of symptoms. Physical examination should include the same elements as in categories I and II prostatitis. Urine analysis and midstream culture are mandatory. Urinary cytology is recommended to rule out irritative symptoms of bladder cancer. Urine flow rate and residual urine determination can also help in the diagnostic work-up. In rare instances, abdominal, pelvic, or neurologic imaging, urodynamic studies, cystoscopy, or prostate-specific antigen testing may be useful.

CURRENT DIAGNOSIS Category I (Acute Bacterial Prostatitis)

History Physical examination (including gentle DRE) Urinalysis Urine culture Blood cultures (if systemic symptoms are present) Postvoid residual Category II (Chronic Bacterial Prostatitis)

History Physical examination Urinalysis Urine culture Postprostatic massage urine culture Evaluation of complicated UTI (optional) Category III (Chronic Pelvic Pain Syndrome)

History Physical examination NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire Urinalysis Midstream culture Optional tests (cytology, urine flow, postvoid residual, etc) Category IV (Asymptomatic Inflammatory Prostatitis)

No further evaluation Abbreviations: DRE = digital rectal examination; NIH = National Institutes of Health; UTI = urinary tract infection.

In most men, the disease has a protracted natural history. Symptom severity predicts recurrence in 30% of men, and previous symptoms predict recurrence in 50% of men. Unfortunately, in most category III prostatitis patients, the cause of pelvic pain cannot be identified. Thus, the diagnosis of CP/CPPS remains a diagnosis of exclusion. TREATMENT Several treatments have been investigated and studied for category III prostatitis, with mixed results ( Figure 1 ). These include a-blockers, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and pentosan polysulfate, among others.

FIGURE 1 Management of NIH category III prostatitis.

Mehik's group tested the efficacy of an a-blocker, alfuzosin (Uroxatral)[1] 5 mg, against placebo for symptom relief in 70 patients. At 6 months, the pain score was lower in the alfuzosin group (P = 0.02). Similar results were obtained by Cheah and colleagues in a cohort of 86 patients treated with terazosin (Hytrin),[1] with dose escal-ation from 1 to 5 mg/day compared with placebo. The a-blocker significantly improved the quality of life and significantly reduced pain at 14 weeks (P = 0.03). Nickel and colleagues randomized 58 men younger than 55 years to 0.4 mg tamsulosin (Flomax)[1] or placebo. At 45 days, tamsulosin significantly reduced symptoms. However, these benefits were not always replicated, especially in pretreated men. A 4- to 6-week trial of antibiotics is one of the key management options for patients with category III prostatitis, despite absence of benefit in placebo-controlled trials. Lack of efficacy at 6 and 12 weeks was shown by Nickel's group, who randomized 80 patients with category III prostatitis to either levofloxacin or placebo for 6 weeks. Alexander's group recapitulated these findings with ciprofloxacin. NSAIDs were tested in a placebo-controlled trial of 161 patients. Rofecoxib (Vioxx) (50 mg) significantly improved pain and NIH-CPSI scores. It has been withdrawn from the market. Pentosan polysulfate (Elmiron)[1] was tested in a placebo-controlled, randomized trial of 100 men. Three daily 100-mg doses of Elmiron for 16 weeks resulted in a significant improvement in NIH-CPSI quality-of-life scores. Several other therapeutic approaches are available. These include prostatic massage, which should be considered once or twice weekly, in men who report some degree of symptom relief. Finasteride (Proscar)[1] 5 mg daily and phytotherapy (e.g., cernilton[7] and quercetin[7]) showed some, albeit limited, efficacy. Tricyclic antidepressants (amitriptyline [Elavil][1]), anticholinergics (oxybutynin [Ditropan][1]), anticonvulsants, lifestyle changes (e.g., nutrition, stress reduction), biofeedback, pelvic floor training, and thermal therapy reduced symptoms in some category III prostatitis patients. The multitude of trials addressing CP/CPPS

patients emphasizes the high failure rate (~66%) of sequential monotherapy. It suggests the need for structured assessment of multimodality approaches.

CURRENT THERAPY Category I (Acute Bacterial Prostatitis)

Admission Intravenous antibiotics (ampicillin or gentamicin) Bladder drainage, if urinary retention Oral antibiotics for 3 to 4 weeks (fluoroquinolones or TMP-SMX) Category II (Chronic Bacterial Prostatitis)

Outpatient treatment Antibiotics for 4 to 8 weeks (fluoroquinolones or TMP-SMX) Long-term antibiotic therapy Category III (Chronic Pelvic Pain Syndrome)

Antibiotics for 4 to 6 weeks (fluoroquinolone or TMP-SMX) a-Blockers (e.g., tamsulosin [Flomax],[1] alfuzosin [Uroxatral],[1] terazosin [Hytrin][1]) Anti-inflammatory medications Finasteride (Proscar),[1] pentosan polysulfate (Elmiron),[1] and phytotherapies (e.g., cernilton,[7] quercetin[7]) Nonpharmacologic therapies (biofeedback, pelvic floor training, thermal treatments) Repeat treatment if relief is noted. Combine therapies if partial relief is noted. Category IV (Asymptomatic Inflammatory Prostatitis)

No treatments Abbreviation: TMP-SMX = trimethoprim-sulfamethoxazole. 1 Not FDA approved for this indication. 7 Available as dietary supplements.

Category IV: Asymptomatic Inflammatory Prostatitis

Category IV prostatitis is defined as incidental observation of leukocytes in prostatic secretions or tissue obtained during evaluation for other disorders, (e.g., leukocytes noted in prostate biopsies performed for elevated prostate-specific antigen [PSA]). Epidemiologic studies estimate the prevalence of category IV prostatitis to be as high as 32.2% in a population of men with elevated PSA levels. Category IV prostatitis needs no further evaluation or treatment. Acknowledgments Pierre I. Karakiewicz is partially supported by the Fonds de la Recherche en Santé du Québec, the Centre hospitalier de l'Université de Montréal (CHUM) Foundation, the Department of Surgery, and Les Urologues Associés du CHUM.



REFERENCES Clemens et al., 2006. Clemens JQ, Meenan RT, O'Keeffe-Rosetti MC, et al: Prevalence of prostatitis-like symptoms in a managed care population. J Urol 2006; 176(2):593-596. Dimitrakov et al., 2006. Dimitrakov JD, Kaplan SA, Kroenke K, et al: Management of chronic prostatitis/chronic pelvic pain syndrome: an evidence-based approach. Urology 2006; 67(5):881-888. Fowler, 2002. Fowler Jr JE: Antimicrobial therapy for bacterial and nonbacterial prostatitis. Urology 2002; 60(6 Suppl):24-26. Habermacher et al., 2006. Habermacher GM, Chason JT, Schaeffer AJ: Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 2006; 57:195-206. Krieger et al., 1996. Krieger JN, Egan KJ, Ross SO, et al: Chronic pelvic pains represent the most prominent urogenital symptoms of “chronic prostatitis.”. Urology 1996; 48(5):715-721. Krieger et al., 1999. Krieger JN, Nyberg Jr L, Nickel JC: NIH consensus definition and classification of prostatitis. JAMA 1999; 282(3):236-237. Krieger et al., 2002. Krieger JN, Ross SO, Riley DE: Chronic prostatitis: Epidemiology and role of infection. Urology 2002; 60(6 Suppl):8-12. Litwin et al., 1999. Litwin MS, McNaughton-Collins M, Fowler Jr FJ, et al: The National Institutes of Health chronic prostatitis symptom index: Development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network. J Urol 1999; 162(2):369-375. Pontari and Ruggieri, 2004. Pontari MA, Ruggieri MR: Mechanisms in prostatitis/chronic pelvic pain syndrome. J Urol 2004; 172(3):839-845. Rothman et al., 2004. Rothman I, Stanford JL, Kuniyuki A, Berger RE: Self-report of prostatitis and its risk factors in a random sample of middle-aged men. Urology 2004; 64(5):876-879. Schaeffer et al., 2002. Schaeffer AJ, Datta NS, Fowler Jr JE, et al: Overview summary statement: Diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Urology 2002; 60(6 Suppl):1-4. Wagenlehner et al., 2005. Wagenlehner FM, Weidner W, Sorgel F, Naber KG: The role of antibiotics in chronic bacterial prostatitis. Int J Antimicrob Agents 2005; 26(1):1-7.



Chapter 176 – Benign Prostatic Hyperplasia

Method of: Gopal H. Badlani, MD Matthew E. Karlovsky, MD Epidemiology Bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) is one of the most common medical conditions in older men and represents up to a 40% clinical risk for urinary retention in a man's lifetime. It is the most prevalent condition in the aging male, affecting 14 million men in the United States, with an annual cost of $4 billion to treat. Age and normal androgenic function are two of the better established risk factors. Whereas BPH is rare before the age of 40, the prevalence of histologic BPH at autopsy is 50% by 60 years of age and 90% by 85 years of age. Approximately 40% of males 70 years of age or older have lower urinary tract symptoms (LUTS) secondary to BPH, and with age, the prevalence increases. Symptomatically, approximately 25% of 55-year-old men experience decreased urinary flow rate and other symptoms of BPH. By 75 years of age, the appearance of this symptom increases to 50%. Age, however, is not a causative factor of BOO. Although the risk for developing symptoms from BPH doubles for each decade of life between 60 and 90 years of age, clinical symptoms of the individual patient do not necessarily progress with age. BPH is more commonly diagnosed because of increased life expectancy and a greater tendency today to seek medical advice at an earlier disease stage. Normal androgenic function is required for development of BPH. Both androgenic and estrogenic hormonal stimulation can induce prostatic hypertrophy. Other factors, such as race, sexual activity, smoking, socioeconomic status, vasectomy, alcohol intake, and diet, have been implicated in BPH development. Identifying men at clinical risk for BPH and its progression has clinical usefulness in selecting the appropriate intervention when necessary. Pathophysiology The pathophysiology of BPH is poorly understood because no direct correlation can be made between prostatic glandular enlargement and the symptomatology of BPH. Because the condition is rare in those younger than 40 years of age and does not develop in castrated men, it is accepted that BPH development requires aging and functional testes for androgen production. BPH is believed to originate in the trans-itional zone of the prostate, which surrounds the prostatic urethra between the bladder neck and the verumontanum, and is progressive. Both a static and a dynamic component are involved in BPH development. The static component relates to epithelial and stromal cell proliferation in the prostatic transitional zone (TZ); enlargement is evident as median or lateral lobe hypertrophy. Proliferation is induced by testosterone and its biologically active conversion product, dihydrotestosterone. Conversion of testosterone to dihydrotestosterone occurs via the enzyme 5a-reductase. Two forms of this enzyme have been described, type 1 and type 2. Type 1 is present in liver, skin, and other organs. Type 2 is present in urogenital tissues. Individuals lacking 5a-reductase type

2 do not develop genitalia and prostates. Conversely, the dynamic component relates to prostatic smooth muscle. High concentrations of a1adrenergic receptors occur in the prostatic capsule and bladder neck. An increase in smooth muscle tone is responsible for increased urethral resistance and pressure. Pharmacologic blockade with a1 antagonists blocks prostatic smooth muscle contraction and decreases urethral resistance and pressure, subsequently relaxing the dynamic component of BPH. Symptoms The diagnosis of BPH is presumptive, based on symptoms. These symptoms, commonly referred to as lower urinary tract symptoms (LUTS), are not specific for BPH. LUTS include frequency, retention, intermittency, decreased force of stream (FOS), straining, urgency, and nocturia. Individuals with LUTS should be carefully assessed to determine the cause, to confirm diagnosis of BPH, and to exclude other bladder and prostate processes. Normal prostate size on digital rectal examination (DRE) does not rule out a diagnosis of BPH because palpable prostate size does not correlate with degree of obstruction or severity of LUTS. However, the odds of having moderate to severe symptoms are five times higher for men with enlarged prostates compared with those with normal prostates. Symptoms of BPH are difficult to assess and quantify, yet they are the keys to proper diagnosis and treatment. Because the vast majority of procedures performed for BPH are to provide symptomatic relief, it is necessary to quantify the level of interference in the quality of life of the patient. Assessment of interference on quality of life can be reliably accomplished using the well-validated International Prostate Symptom Score (IPSS) ( Figure 1 ). Symptoms based on overall score are classified as mild (0 to 7), moderate (8 to 19), and severe (20 to 35). The subjective impact of these symptoms on overall quality of life must also be taken into account. The patient with a severe-range IPSS may feel the symptoms are less bothersome than a patient with a lower IPSS, and this subjective impact on quality of life can direct therapeutic options.

FIGURE 1 International prostate symptom score (IPSS).

Diagnosis Diagnosis of BPH relies on an accurate medical history eliciting the specific voiding complaints, as well as quantification of these symptoms using the IPSS. Other possible causes of LUTS also must be ruled out, including urinary tract infection (UTI), urolithiasis, diabetes, urethral stricture, overactive or neurogenic bladder, prostate/bladder cancer, or congestive heart failure. Medications that can exacerbate obstructive symptoms include tricyclic antidepressants, anticholinergic agents, diuretics, narcotics, and first-generation antihistamines and decongestants. Physical examination should include DRE for prostatic abnormalities,

such as palpable nodules, induration or irregularities of malignancy, or infection. On DRE, the posterior lobes, not the transition zone, are palpable. Abdominal examination may detect a suprapubic or low abdominal mass in a patient with BPH-induced retention. The American Urological Association and the American Cancer Society recommend all men older than age 50 receive an annual prostate-specific antigen (PSA) serum level to screen for prostate cancer. In black men or men with a family history of prostate cancer in a first-degree relative, PSA screening should begin at 40 years of age or younger. The normal range for PSA is up to 4.0 µg/mL. Other valuable laboratory data include urinalysis to rule out infection or hematuria, a serum creatinine level to determine renal function, and urine cytologic studies if irritative voiding symptoms are present. More sophisticated studies, such as urinary flow rate, postvoid residual, and pressure flow urodynamic studies, are appropriate for evaluation of men with more severe symptoms (IPSS >8) or with more complex comorbidities. These tests are often used to determine baseline function prior to initiation of therapy or to determine subsequent response to therapy. In patients who fail medical therapy, urodynamic pressure-flow studies and cystoscopy may be appropriate to evaluate the need for operative intervention and to rule out other urologic pathologies. Cystoscopy is also reserved for situations in which invasive treatment is strongly considered. If watchful waiting or noninvasive therapies are appropriate, invasive diagnostic tests are usually not necessary. The variables of importance of disease progression in an artificial neural network analysis were PSA, obstructive symptom score, and transitional zone volume. The Olmsted County study showed risk progression of acute urinary retention (AUR) with age. Overall, a 60-year-old man has a 23% chance of AUR if he survives the next 20 years. The average annual change in prostate volume was 1.6% for all ages. The annual increase was not significantly related to baseline age but was significantly related to baseline prostate volume. Treatment WATCHFUL WAITING Indications for treatment of BPH rely, in large part, on the subjective nature of the symptoms. For the majority of patients with BPH, symptoms are not severe or bothersome enough to warrant long-term medical or surgical intervention. Men with an IPSS of less than 8 are usually treated with expectant management. Advising the patient toward lifestyle modifications, such as minimizing evening fluid intake, avoiding caffeine, and avoiding decongestants, anticholinergics, and other medications that impair voiding, often provides an effective resolution of symptoms. In a study of 556 men with moderate symptoms of BPH comparing outcomes following transurethral resection of the prostate (TURP) with watchful waiting for more than 3 years, 8% of men randomized to TURP and 17% of men with watchful waiting failed treatment. Treatment failure with watchful waiting was mostly because of high postvoid residuals and significant increases in IPSS symptoms. Patients who respond poorly to watchful waiting have multiple medical and surgical options for treatment of BPH. a1 -ADRENERGIC BLOCKING AGENTS The a1-adrenergic antagonists have been shown in numerous randomized placebo-controlled trials to be safe and effective in the treatment of BPH. The most commonly prescribed a1-adrenergic blockers appear to have similar safety profiles and clinical efficacy and are the common first approach for urologists. Terazosin (Hytrin) and doxazosin (Cardura) were the first a antagonists available for treatment of BPH; however, orthostatic hypotension was a significant concern, requiring careful dose titration. Tamsulosin (Flomax), a highly selective a-blocker, does not induce orthostatic hypotension and so does not require dose titration. Overall, the most common side effects include headaches, dizziness, asthenia, and drowsiness. Sexual side effects are limited to retrograde ejaculation. Alfuzosin (Uroxatral), a newer nonspecific a-blocker, has

minimal vasoactive or retrograde ejaculation side effects. Table 1 provides a list for medication dosing and schedules.

TABLE 1 -- Common Medications for Benign Prostatic Hyperplasia Medication Class Dose Schedule Alfuzosin (Uroxatral) a-1 Blocker

10 mg

Once daily

Doxazosin (Cardura) a-1 Blocker

1-8 mg, titrated

Once daily at bedtime

Tamsulosin (Flomax) a-1a Blocker

0.4 mg

Once daily

Terazosin (Hytrin)

1-10 mg, titrated Once daily at bedtime

a-1 Blocker

Dutasteride (Avodart) 5-a Reductase inhibitor 0.5 mg

Once daily

Finasteride (Proscar) 5-a Reductase inhibitor 5 mg

Once daily

5a-REDUCTASE INHIBITION Finasteride (Proscar) and dutasteride (Avodart) are 5a-reductase inhibitors (type 1 and type 1/2, respectively) that block conversion of testosterone to dihydrotestosterone, the androgen involved in development of BPH. These medications represent the paradigm for androgen suppression of BPH. They have their greatest therapeutic effect in men with prostates greater than 40 g, and treatment for 6 months or more is usually required for a clinical response. The first randomized, multicenter, double-blind, placebocontrolled trial investigating the efficacy of finasteride demonstrated significant improvements in maximum flow rate and decreased prostatic volume. Since then, further studies have confirmed a reduced risk of acute urinary retention and surgical intervention with finasteride use. Finasteride can reduce BPH-associated hematuria. It is effective as adjuvant therapy, following other treatments, and as neoadjuvant therapy prior to minimally invasive therapy. Adverse effects include decreased libido, ejaculatory dysfunction, and gynecomastia. In the patient being monitored for prostate cancer with PSA testing, finasteride therapy must be taken into account when interpreting PSA values; finasteride decreases PSA values by 50%, leading to a false-negative result. Efficacy of Medical Therapy The Medical Therapy of Prostate Symptoms (MTOPS) study evaluated the efficacy of doxazosin and finasteride to determine if medical therapy delays or prevents disease progression. At 4 years, combination therapy was most effective for reducing risk of clinical progression (AUR) and improving symptom score and urinary flow rate. Fina-steride and combination therapy significantly reduced the risk of AUR and invasive therapy over 4 years. Monotherapy with either medication reduced symptom score and improved flow significantly, but to a lesser degree than combination therapy. Doxazosin delayed time to progression of AUR and invasive therapy but not the risk. Without treatment, the risk of BPH progression was 20% more during the trial. Risk factors for progression include baseline prostate volume (>40 g) and higher serum PSA value (>2 µg/mL). Phytotherapy Saw palmetto (Serenoa repens)[1,][2] extract is the most popular phytotherapeutic agent. Its likely mechanism

is inhibition of 5a-reductase. A recent meta-analysis of numerous randomized trials using saw palmetto described a mild to moderate improvement in flow and LUTS; however, because of small study sample, varying products, short treatment times, and varying outcomes, these study conclusions are difficult to interpret. Other popular preparations are African plum (Pygeum africanum)[1,][2] and South African star grass (Cynodon nlemfuësis). [1,][2] The former has been shown to have several in vitro effects, such as antiestrogen effects, leukotriene blockade, and inhibition of fibroblast growth factors. The latter has been shown in vitro to increase plasminogen activators, as well as to stimulate release of transforming growth factor-ß, an inducer of apoptosis, yet these in vitro effects have not been shown to occur in vivo. A meta-analysis of four clinical trials of South African star grass extract, ß-sitosterol, concluded that ß-sitosterol improved urologic symptoms and flow rates in men. There is no standard of care for management of patients using phytotherapy. Nor have the long-term safety effects been established. Patients should be cautioned that doses, efficacy, side effects, and drug interactions with phytotherapy are unknown. For the patient refusing medical therapy of a-blockers and 5areductase inhibitors, phytotherapy may be attempted as long as the patient understands the limitations of these agents. If retention, UTI, calculi, or decreased renal function occurs, phytotherapy should be discouraged and more aggressive medical and surgical management undertaken. 1 Not FDA approved for this indication. 2 Available as a dietary supplement.

Minimally Invasive Therapies The most commonly employed surgical procedure, and the gold standard for BPH, is transurethral resection of the prostate (TURP), involving endoscopic resection of the obstructive component of the prostate. TURP is highly effective, improving symptoms in up to 95% of patients. Common complications include inability to void postoperatively, clot retention, incontinence, impotence, and retrograde ejaculation. A number of new minimally invasive therapies have been developed to reduce the complications associated with TURP, as well as provide alternatives for the unfavorable surgical candidate. Most minimally invasive therapies use energy, such as radio waves, laser, ultrasound, microwaves, or electrical current. Transurethral incision of the prostate (TUIP) involves endoscopic placement of one to two incisions into the prostate and capsule to reduce urethral constriction. This procedure is highly effective on prostate glands less than 30 g and is well documented and safe, with efficacy comparable with TURP. TUIP is associated with a 78% to 83% improvement of symptoms. Because TUIP is associated with fewer retrograde ejaculations, less morbidity, and a reoperation rate of less than 1% in 10 years, this procedure is the treatment of choice for small gland BPH in men concerned with fertility and ejaculation. Intransurethral needle ablation (TUNA), low-level energy is transferred by radiofrequency to the prostate, creating a well-defined necrotic lesion within the prostatic parenchyma while preserving the urethral mucosa. A cystoscope-like instrument with two needles set at 90 degrees from each other ablates tissue in 3 to 5 minutes when needles reach temperatures of 27° to 38°C (80° to 100°F). Urethral and rectal temperatures are also vigorously monitored as the device adjusts. Preliminary studies show an increase in peak flow and a decrease in symptom score following TUNA, with no major complications. Transient urinary retention is reported in 10% to 40% of patients. In a prospective study, TURP was superior to TUNA in increasing flow

rates but demonstrated comparable improved symptoms at 1 year postoperatively. Transurethral microwave thermotherapy (TUMT) heats prostatic transitional zone tissue to between 60° and 80°C (140° to 176°F), inducing tissue damage. Thermotherapy preferentially destroys smooth muscle by coagulative necrosis while water-conductive cooling of the urethral mucosa preserves periurethral tissues. Although prospective studies indicate that TURP produces more pronounced urinary improvements versus TUMT, thermotherapy consistently improves symptom scores by 75% and increases peak flow rates by 75%. Furthermore, TUMT is a procedure done under local anesthesia. Retrograde ejaculation and urinary retention with prolonged catheterization occurs in greater than one third of patients. Ultimately, therapeutic decisions depend in large part on symptom scores. Men with low symptom scores without bother are appropriately managed through watchful waiting. As scores increase, or if progression with clinical morbidity develops, more aggressive management is appropriate.



REFERENCES Bhargava et al., 2004. Bhargava S, Canda AE, Chapple CR: A rational approach to benign hyperplasia evaluation: Recent advances. Curr Opin Urol 2004; 14:1-6. Djavan et al., 2004. Djavan B, Waldert M, Ghawidel C, Marberger M: Benign prostatic hyperplasia progression and its impact on treatment. Curr Opin Urol 2004; 14:45-50. Fong et al., 2005. Fong YK, Milani S, Djavan B: Role of phytotherapy in men with lower urinary tract symptoms. Curr Opin Urol 2005; 15:45-48. Hoffman et al., 2004. Hoffman RM, MacDonald R, Monga M, Wilt TJ: Transurethral microwave thermotherapy vs. transurethral resection for treating benign prostatic hyperplasia: A systematic review. BJU Int 2004; 94:1031-1036. Walsh et al., 2002. In: Walsh PC, Retik A, Vaughan D, ed. Campbell's Urology, 8th ed.. Philadelphia: Saunders Elsevier Science; 2002.



Chapter 177 – Erectile Dysfunction

Method of: Luciano Kolodny, MD The term erectile dysfunction (ED) is relatively new, having replaced impotence approximately a decade ago. ED is defined as the “inability of the male to attain or maintain an erection sufficient for satisfactory sexual intercourse.” ED affects millions of men worldwide with implications that go far beyond sexual activity alone. ED is now recognized as a sentinel event in cardiovascular disease, diabetes mellitus (DM), and depression. It can also be damaging to interpersonal relationships and self-esteem. Epidemiology The Massachusetts Male Aging Study is one of the pivotal studies on the prevalence of ED. Between 1987 and 1989, men between the ages of 40 and 70 years received questionnaires inquiring about several aspects of their sexual health. Of the 1790 men who received the questionnaires, 1290 responded. They revealed that 52% of them had some degree of dysfunction, 17% with minimal, 25% with moderate, and almost 10% with complete absence of erectile function. It also showed the extremely detrimental link between coronary artery disease (CAD), DM, and ED. A few years later another group used the same patient database and followed up on these subjects. The risk of ED was 26 cases per 1000 men annually, which increased with age, lower education, DM, heart disease, and hypertension. Physiology of Erection The penile erection requires intact vascular, neuronal, and hormonal systems. The intricate details of this process are beyond the scope of this article, but in summary, after any sensorial stimulation, which can be visual, tactile, auditory, or olfactory, nitric oxide (NO) and other neurotransmitters are released at the cavernous nerve terminals. The endothelial cells then release vasoactive relaxing factors, which lead to vasodilatation of the penile blood vessels and increased blood flow. As blood flow increases, compression of the subtunical venular plexuses will substantially decrease venous outflow and finally cause the penis to change from flaccid to erect ( Figure 1 ).

FIGURE 1 The biochemical process involved in erections and the mechanism of action of sildenafil citrate (Viagra). The cavernous nerves (S2-S4) innervate the penis and release NO. NO stimulates the production of cGMP in the smooth muscle cells of the penis. cGMP is directly responsible for increasing smooth muscle relaxation, which leads to increased arterial inflow and an erection. When cGMP is metabolized by PDE5, the penis undergoes detumescence. Sildenafil citrate (Viagra) inhibits PDE5 and increases the available cGMP, thereby leading to an enhanced erection. cGMP = cyclic guanosine monophosphate; NO = nitric oxide; PDE5 = phosphodiesterase 5.

NO is the principal neurotransmitter involved in penile erection, but other vasoactive substances such as vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide (CGRP), substance P, and serotonin also play roles. High levels of intrapenile NO facilitate the relaxation of intracavernosal trabeculae, thereby maximizing blood flow and penile erection. Nonadrenergic, noncholinergic neurons have been found to release NO, leading to increased production of cyclic guanosine monophosphate (cGMP). Through a series of reactions, cGMP will lead to relaxation of the smooth muscle, directly impacting the ability to go from a flaccid to an erect penile state. The return from erect to flaccid requires the hydrolysis of cGMP to guanosine monophosphate (GMP) by phosphodiesterase 5 (PDE5) (see Figure 1 ). Testosterone and Erectile Function Testosterone provides intrapenile nitrous oxide synthase (NOS), which has an important role in enhancing the production of NO, subsequent local vasodilatation, and penile erection. There is no correlation between serum testosterone levels and the degree of ED. However, hypogonadal men may experience significantly reduced libido. Hypogonadism is associated with decreased self-esteem, depression, osteoporosis, insulin resistance, increased fat mass, decreased lean body mass, and cognitive dysfunction.

Pathophysiology of Erectile Dysfunction ED can be classified as psychogenic, organic (hormonal, vascular, drug-induced, or neurogenic), or mixed psychogenic and organic. Up to 80% of ED cases have an organic origin. The most common cause of ED is vascular disease ( Box 1 ). BOX 1 Classification of Erectile Dysfunction Endocrine

•

Hypogonadism

•

Hyperprolactinemia

Drug Induced

•

ß-Blockers

•

Calcium channel blockers

•

Alcohol

•

Nicotine

•

Antiandrogens

•

Cocaine

•

Heroin

•

Marijuana

•

Cimetidine

•

Metoclopramide

•

Antidepressant medications

•

Antipsychotic medications

Vascular

•

Coronary artery disease

•

Peripheral vascular disease

•

Hypertension

•

Diabetes mellitus

Psychogenic

•

Depression

•

Performance anxiety

Neurogenic

•

Spinal cord injury

•

Neuropathy (diabetic, hypertensive)

•

Cerebrovascular disease

•

Radical prostatectomy

•

Pelvic surgery

Multifactorial

•

Aging

•

End-stage renal disease

•

Pelvic trauma (neurogenic and vasculogenic)

•

Diabetes mellitus (neurogenic, vasculogenic, drug induced)

Atherosclerosis is the most common cause of vasculogenic ED, whereas endothelial damage is the most common mechanism. Aging is a well-known risk factor for ED, and it is hypothesized that there are alterations in the levels of NO that occur as a consequence of the aging endothelium. Additionally, chronic illness, depression, and lack of a sexual partner are all prevalent in this age population. Chronic tobacco use is a major risk factor for the development of vasculogenic ED because of its effects on the vascular endothelium. Additionally, blood nicotine levels rise after smoking, which increases sympathetic tone in the penis and leads to nicotine-induced, smooth-muscle contraction in the cavernosal body. Chronic smoking also leads to decreased penile NOS activity and neuronal NOS content. DM is a major risk factor for ED. In the Massachusetts Male Aging Study, the diabetic subset had a threefold increased prevalence of ED compared with nondiabetic subjects (28% versus 9.6%). In the same study, the overall incidence rate of ED was 26 cases per 1000 man-years in nondiabetics and 50 cases per 1000 manyears in the diabetic population. The pathogenesis of ED in the diabetic patient is related to accelerated atherosclerosis, alterations in the corporal erectile tissue, and neuropathy. Hypertension is another major risk factor for ED. Whether ED in patients with hypertension is related to the disease itself or to the use of antihypertensive medications has been debated for years. In a study looking at 104 subjects, the differences in incidence or severity of ED were minor between distinct types of antihypertensive medications or the number of agents being used simultaneously. This favors the concept that antihypertensive agents as well as the disease itself contribute to the appearance of ED. There are, however, classes of antihypertensive medications that are notorious for their negative impact on erectile function such as thiazides and ß-blockers. The only ß-blocker not associated with significant incidence of ED is carvedilol (Coreg).

Hyperlipidemia is another etiologic factor for ED. It is believed to contribute to ED by its relationship to endothelial dysfunction. One study showed that decreasing total cholesterol to less than 200 mg/dL by using atorvastatin (Lipitor) led to significant improvement of ED as measured by the International Index of Erectile Function (IIEF). ED may be a sentinel manifestation of vascular disorders. In a study of 980 subjects seeking ED advice, 18% were suffering from undiagnosed hypertension, 16% had DM, 5% had ischemic heart disease, 15% had benign prostatic hyperplasia, 4% had prostate cancer, and 1% had depression. ED can itself be an independent marker for CAD. In addition, the extent of CAD correlates with the prevalence of ED. Quantification of the Severity of Erectile Dysfunction and Improvement There are several tools designed to assess the severity of ED, as well as to measure the efficacy of different treatments. We discuss three different measures, the IIEF, the Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ) ( Box 2 ). BOX 2 Tools Used to Quantify Erectile Dysfunction Severity Tools used in the quantification of the severity of erectile dysfunction (ED) include the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ). International Index of Erectile Function The IIEF is a standardized questionnaire designed to measure ED and detect treatment-related changes. It is a 15-item questionnaire addressing five different domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. The IIEF is the most frequently used efficacy measurement employed in ED drug trials. Using a scale from 1 (never/almost never) to 5 (almost always/always), men grade each domain. It is very sensitive and specific, and has been validated in 20 languages to assess treatment-related changes in sexual function. The questions 1-5 and 15 are used to quantify erectile dysfunction severity and are as follows: 1.

How often were you able to get an erection during sexual activity?

2.

When you had erections with sexual stimulation, how often were your erections hard enough for penetration?

3.

When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?

4.

During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?

5.

During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?

15. How do you rate your confidence that you could get and keep an erection? And it is scored as follows:

26-30 Normal ED 22-25 Mild ED 17-21 Mild to moderate ED 11-16 Moderate ED =10

Severe ED

Sexual Encounter Profile SEP is a five-question survey provided to patients with ED in clinical studies of oral therapies. The survey is completed after each sexual attempt. The questions are as follows: 1.

Were you able to achieve at least some erection?

2.

Were you able to insert your penis into your partner's vagina?

3.

Did your erection last long enough to have successful intercourse?

4.

Were you satisfied with the hardness of your erection?

5.

Were you satisfied with the overall sexual experience?

Answers to questions 2 and 3 are the ones most often used in the literature. Global Assessment Questions GAQ is usually administered at the end of the treatment period during efficacy studies. Question 1: Has the treatment taken during the study improved your erections? Question 2: If yes, has the treatment improved your ability to engage in sexual activity? This is very subjective, and its responses tend to be valued less than SEP and IIEF. PATIENT HISTORY When assessing sexual dysfunction, it is important to inquire about a number of issues:

1.

Differentiate between decreased libido and ED: assess whether the patient has one or both

2.

Tobacco use: type, amount, duration

3.

Alcohol intake

4.

History of depression or anxiety disorder

5.

Presence of social/relationship stressors

6.

Ability to have erections while masturbating versus when with partner

7.

List of all prescription, over-the-counter, and herbal medications

8.

Knowledge of whether nocturnal erections are present

9.

History of drug use: marijuana, cocaine, other recreational drugs

10. History of genitourinary trauma 11. History of prostatic disease, or possible related symptoms 12. History of hypertension, hyperlipidemia, CAD, peripheral vascular disease, cerebrovascular disease 13. History of DM 14. History of spinal cord injury 15. History of penile plaques: possible Peyronie's disease 16. Frequency of intercourse or attempted intercourse 17. Ability to ejaculate PHYSICAL EXAMination The physical examination should include a careful testicular examination to assess testicular size, asymmetries, presence of hernias, or varicoceles. Additionally, a digital rectal examination to assess the prostatic size, consistency, and presence of nodules is warranted. Penile inspection and palpation should be performed, with special attention to possible fibrotic plaques. Palpation and auscultation of femoral arteries for possible bruits is another important part of the examination. LABORATORY STUDIES Laboratory workup on a patient with ED should include total and bioavailable testosterone levels drawn in the morning, prolactin, prostate-specific antigen, fasting glucose, and fasting lipid panel. Further studies may be warranted depending on the results of the aforementioned. Management of Erectile Dysfunction The landscape of ED was revolutionized with the introduction of sildenafil citrate (Viagra), the first oral medication for the treatment of this condition. Since then, oral agents have become the preferred mode of treatments by patients in surveys worldwide. There are three oral agents that inhibit PDE5 currently on the market:

1.

Sildenafil citrate (Viagra)

2.

Vardenafil (Levitra)

3.

Tadalafil (Cialis)

All three drugs work by inhibiting PDE5, which maintains intracavernosal levels of cGMP, subsequently producing vasodilatation and penile erection (see Figure 1 ). SILDENAFIL CITRATE (VIAGRA) Sildenafil citrate (Viagra) is an orally active, potent, and selective inhibitor of cGMP-specific PDE5. The predominant phosphodiesterase isoform in the penile tissue is type 5. The selectivity of sildenafil citrate (Viagra) for PDE5 is approximately 4000-fold greater than its selectivity for phosphodiesterase 3 (PDE3), the isoform involved in the control of cardiac contractility. Sildenafil citrate (Viagra) is absorbed rapidly after oral administration, with an absolute bioavailability of 40%. The time of maximal (T-max) plasma after oral dosing in the fasting state is between 30 and 120 minutes. A high-fat meal increases the time to peak plasma concentration by 60 minutes and reduces the peak plasma concentration by 29%. The half-life of the drug is from 3 to 5 hours. Sildenafil citrate (Viagra) is metabolized by hepatic microsomal cytochrome P450 isoenzyme 3A4 for the most part. Cytochrome P450 3A4 inhibitors, cimetidine (Tagamet), erythromycin, ketoconazole (Nizoral), and protease inhibitors may retard the metabolism of sildenafil citrate (Viagra). The recommended dose is from 25 to 100 mg as needed approximately 1 hour before sexual activity. In some individuals, the onset of activity may be seen as early as 11 to 19 minutes, but this is not the norm. The usual starting dose is 50 mg. The maximum recommended dose is 100 mg, and the maximum dosing frequency is once daily. A starting dose of 25 mg can be considered for patients older than age 65 years as well as for patients with severe hepatic cirrhosis or severe renal impairment. There are more than two dozen, randomized, double-blind, placebo-controlled studies involving this agent. It produces positive results regardless of the etiology of ED. It has been studied in patients with DM, CAD, postcoronary artery bypass graft (post-CABG), spinal cord injury, depression, hypertension, prostate cancer post-prostatectomy, benign prostate enlargement post-transurethral resection of the prostate (TURP), patients on hemodialysis, as well as recipients of renal transplants. Results vary according to the underlying condition causing ED in the first place, ranging from 50% to 85%. The most common side effects of sildenafil citrate (Viagra) include vasodilatory effects such as headaches, flushing, and nasal congestion caused by hyperemia of the nasal mucosa, as well as dyspepsia. Up to 30% of patients may get at least one side effect. Another side effect that presents on occasion is blurred or bluegreen vision because of inhibition of phosphodiesterase 6 (PDE6) in the retina. It is absolutely contraindicated in men taking long-acting or short-acting nitrate drugs, and men taking any form of nitrates should be informed about the dangerous interaction. Do not prescribe sildenafil citrate (Viagra) to patients with unstable CAD who need nitrates. Assess the need for ordering treadmill testing in select patients. Initial monitoring of blood pressure (BP) after the

administration of sildenafil citrate (Viagra) may be indicated in men with complicated congestive heart failure (CHF). a-Blockers should not be used in combination with sildenafil citrate (Viagra) because of possible orthostatic hypotension. VARDENAFIL (LEVITRA) Vardenafil (Levitra) is a highly potent inhibitor of PDE5. It was approved for use in the United States in late 2003. It is a more selective PDE5 inhibitor than sildenafil citrate (Viagra). The absorption of vardenafil (Levitra) is delayed by a fatty content of more than 30% in a meal. However, that does not seem to affect its effectiveness in different trials. The half-life of vardenafil (Levitra) is 4.4 to 4.8 hours, and the clinical effectiveness may be as long as 12 hours. The time for maximum plasma concentration is between 42 and 54 minutes. The first trial using the agent included 580 patients, excluding patients with spinal cord injury, radical prostatectomy, hypogonadism, thyrotoxicosis, or DM. The successful rates of intercourse were 71% to 75% on patients taking 5 or 10 mg at a time. Those taking 20 mg had a success rate of 80%. The placebo groups had an average success rate of 30%. Vardenafil (Levitra) has been tested in patients with type 2 DM; 452 patients were enrolled in a double-blind, placebo-controlled trial. The success rate in the vardenafil (Levitra) group ranged from 57% to 72%. In a different study involving 736 subjects including men with DM and stable CAD, the success rates were 28% for the placebo group, 65% for those taking 5 mg, 80% for those taking 10 mg, and 85% for the 20-mg group. Patients who were unresponsive to sildenafil citrate (Viagra) at a dose of 100 mg on several attempts were given vardenafil (Levitra) in doses of 10 and 20 mg (proved in trial). Vardenafil (Levitra) produced statistically and clinically significant results compared with placebo in men who were historically unresponsive to sildenafil citrate (Viagra). The dose that offers the best clinical results is 20 mg. It should not be taken more than once every 24 hours. Safety studies have shown no deleterious effects with long-term daily use of this drug for up to 12 months. The most common side effects include headaches (10% to 21%), flushing (5% to 13%), rhinitis (9% to 17%), and dyspepsia (1% to 6%) because vardenafil (Levitra) does not inhibit PDE6. Unlike sildenafil citrate (Viagra), it does not produce problems of blurred vision or blue-green visual disturbances. The same warning regarding the use of nitrates as sildenafil citrate (Viagra) applies to vardenafil (Levitra). Patients taking vardenafil (Levitra) may use a-blocking agents with caution. TADALAFIL (CIALIS) The third oral agent of this class is tadalafil (Cialis). It has a half-life of 17.5 hours, with two thirds of patients experiencing clinical benefits of this drug up to 36 hours after its use. The clinical onset of action occurs in less than 1 hour. There is no interaction between food and alcohol on the absorption of the drug. There have been numerous phase II and III studies in Europe, Canada, and the United States using doses

of 2, 5, 10, and 25 mg of the drug in comparison with placebo. The average success rates on these studies averaged 17% for placebo, 51% for the 2-mg dose, and 80% for the other doses, as well as up to 88% on the 25-mg dose in one study. In one study looking at 216 subjects with type 2 DM, improved erections were reported in 56% to 64% of the patients. A recent article looking at all the previously published patient data showed that among 2102 men studied in 11 randomized placebo-controlled trials lasting 12 weeks, each mean improvement in IIEF at 20 mg of tadalafil (Cialis) was 8.6. Mean positive Sexual Encounter Profile Diary Question 3 (SEP3) response was 68% versus 31% in placebo groups. Mean GAQ was 84% versus 33% in placebo group. In a multicenter, randomized, double-blind, crossover study looking at 181 men who received either sildenafil citrate (Viagra) or tadalafil (Cialis), 73% (132) preferred tadalafil (Cialis) at 20 mg instead of sildenafil citrate (Viagra) at 50 or 100 mg. The most clinically effective dose of tadalafil (Cialis) is 20 mg. It should be taken at least 30 minutes before intercourse. It may be used with caution in patients using a-blocking agents. Nitrates are absolutely contraindicated for use in patients taking tadalafil (Cialis). The most common side effects include headaches, dyspepsia, back pain, rhinitis, and flushing. There are no visual side effects reported. APOMORPHINE (UPRIMA)[1] Apomorphine (Uprima)[1] is a potent emetic that acts on central dopaminergic receptors. The stimulation of central dopaminergic receptors transmits excitatory signals down the spinal cord to the sacral parasympathetic nucleus, stimulating activity of the sacral nerves supplying the penis. It has been used successfully in up to 67% of patients when administered through a sublingual preparation. Subcutaneous injections[2] of apomorphine (Uprima)[1] produce almost a 100% erectile response, but nausea and vomiting are limiting factors to this mode of administration. The most common side effects are headache, nausea, and dizziness. Rare syncopal episodes have been reported. 1 Not FDA approved for this indication. 2 Not available in the United States

PHENTOLAMINE (REGITINE) Phentolamine (Regitine) is an a1- and a2-adrenergic receptor antagonist. The sympathetic system via the release of noradrenaline (NA) is the primary determinant of cavernosal smooth muscle contraction and detumescence. A relative predominance of NA-induced contraction over NO-induced smooth muscle relaxation may contribute to ED. In large phase III studies, 55% to 59% of patients receiving 40 and 80 mg were able to achieve vaginal

penetration. Adverse effects include nasal congestion (10%), headaches (3% to 5%), dizziness (3% to 5%), tachycardia (3%), and nausea. TRAZODONE (DESYREL)[1] Trazodone (Desyrel)[1] is a serotonin reuptake inhibiting agent. Its action in ED is believed to be the result of central serotonergic and peripheral a-adrenolytic activity. The efficacy of trazodone is poorly demonstrated; however, it may have a place in those with performance anxiety. Side effects include drowsiness, insomnia, headaches, and weight loss. DIETARY SUPPLEMENTS AND ERECTILE DYSFUNCTION Yohimbine[1] is an a2-adrenoreceptor antagonist with short duration of action. It is administered orally, and it is believed to have a central effect at adrenergic receptors in brain centers associated with libido and penile erection. A meta-analysis of seven studies established that it is superior to placebo, although results can be very erratic. Side effects include palpitations, tremors, and anxiety. Yohimbine should not be recommended as part of the management of ED. A study with 60 patients who had failed papaverine[1] injections (50 mg or less) were treated with an extract of Ginkgo biloba, 60 mg for 12 to 18 months. After 6 months, 50% of the patients reported improvement in erectile function. A placebo-controlled randomized trial using 240 mg of Ginkgo biloba extract daily for 24 weeks in patients with vasculogenic ED did not demonstrate significant differences between the groups. l-Arginine[1] is an amino acid that is the precursor to NO. Three small studies are looking at this drug. There are encouraging results in one study. Zinc is found in high concentrations in seminal fluid. Anecdotal reports of improvement in ED. ALPROSTADIL (PROSTAGLANDIN E1, CAVERJECT, MEDICATED URETHRAL SYSTEM FOR ERECTION) Prostaglandin E1 (PGE1) exerts a number of pharmacologic effects including systemic vasodilatation, inhibitory actions on platelet aggregation, and relaxation of smooth muscle. PGE1 binds to PGE receptors and causes a relaxation response mediated by cyclic adenosine monophosphate (cAMP). It can be administered intracavernosally or intraurethrally. It has been used in combination with papaverine,[1] and the combination was superior to PGE1 alone. The intracavernosal administration seems to be more effective than transurethral (medicated urethral system for erection [MUSE]). MUSE should be administered in 1-mg doses, applied intraurethrally. Responses to intracavernosal injections (Caverject) as high as 80% may be expected in patients with organic ED with a dose of 20 µg, and much lower to MUSE (35% to 43%). Injections are given with 27- to 30-gauge needles. The administration of PGE1 is usually relegated as an alternative in patients who have contraindications to the use of phosphodiesterase 5 (PDE5) inhibitors. The possible side effects include penile fibrosis, priapism, urethral bleeding, hypotension, or syncopal episodes.

Papaverine[1] is a nonspecific phosphodiesterase inhibitor that increases cAMP and cGMP levels in penile erectile tissue. It produces smooth muscle relaxation and vasodilatation. It decreases the resistance to arterial inflow and increases the resistance to venous outflow. It is highly effective in psychogenic and neurogenic ED but not vasculogenic. It has been commonly used in combination with phentolamine (Regitine). Major side effects include priapism, corporeal fibrosis, and possible elevation of liver transaminases. Moxisylyte chlorohydrate[2] is an a-blocking agent. In a study where 156 subjects received either alprostadil or moxisylyte in a dose-escalating fashion, alprostadil had much better success rates (46% versus 81%). Chlorpromazine (Thorazine)[1] is useful when given in combination with alprostadil or papaverine. It has ablocking properties, and it is cheaper than phentolamine (Regitine). Decreased concentration of vasoactive intestinal polypeptide (VIP)[*] has been reported in the penile tissue of men with ED. VIP is believed to play a role in the erectile process. It is ineffective when administered alone but can be quite effective in combination with phentolamine (Regitine). In a small study of 52 subjects with organic ED, 100% of them achieved an erection sufficient for intercourse. Further studies into the effectiveness of VIP may be needed. * Investigational drug in the United States.

PENILE PROSTHESES This surgical approach used to be quite common before the advent of oral agents. The use of prostheses is still a suitable alternative for those who are unresponsive to less invasive treatments. Prostheses can be classified as rod, one-piece inflatable, two-piece inflatable, and three-piece inflatable. Postsurgical infections and malfunctions are the most common complications. Patients are usually satisfied with the results of prosthetic placement.

CURRENT DIAGNOSIS The risk factors for ED include tobacco, alcohol, and drug use, as well as DM, hypertension, hyperlipidemia, and prostate disease. ED is widely prevalent, and incidence sharply increases with age. ED is a cardiovascular sentinel event, and its occurrence warrants a cardiac workup. The workup of ED should include checking testosterone levels, prolactin, glucose, and lipid levels. First-line therapies include the use of PDE5 inhibitors such as sildenafil citrate (Viagra), vardenafil (Levitra), and tadalafil (Cialis). Abbreviations: DM = diabetes mellitus; ED = erectile dysfunction; PDE5 = phosphodiesterase 5.

CURRENT THERAPY PDE5 Inhibitors Sildenafil citrate (Viagra) 25-100 mg Vardenafil (Levitra) 10-20 mg Tadalafil (Cialis) 10-20 mg Alprostadil (PGE1) Intracavernosal injections (Caverject) 20 µg Intraurethral application (MUSE) 1-mg pellet Papaverine injections[1] 30-60 mg Agents not yet approved for use by the FDA: Apomorphine (Uprima)[1] 3, 4, 6 mg Phentolamine (oral)[1] 40, 60, 80 mg Abbreviations: MUSE = medicated urethral system for erection; PDE5 = phosphodiesterase 5; PGE 1 = prostaglandin E1. Vacuum Constrictive Device

Vacuum constrictive device is a plastic cylinder that is placed over the penis and connected to a pump that creates a partial vacuum. After achieving penile rigidity, a band is placed around the base of the penis to maintain the erection. This is a safe, noninvasive, and effective method of treating ED. It requires an understanding partner and the quality of the erection is not ideal; but patients are usually satisfied. Testosterone

Patients who have low testosterone levels may benefit substantially from replacement. Men may expect significant improvements in libido, self-esteem, and overall energy levels. Additionally, testosterone is necessary for NO generation in the penile tissue. The different testosterone preparations include injections such as testosterone enanthate (Delatestryl), cypionate (Depo-Testosterone) given as an intramuscular (IM) injection in doses of 100 to 200 mg, every 2 weeks on average. They also include transdermal testosterone patches (Androderm and Testoderm, 5 mg/d) or transdermal gel (AndroGel 5-g packets, one daily; or Testim 1% testosterone gel, one packet daily). Testosterone gel preparations provide physiologic replacement of testosterone and are preferred more than depot IM injections. Future Trends In the next few years we will see a sharp rise in the use of combination drugs, such as PDE5 inhibitors and apomorphine (Uprima),[1] PDE5 inhibitors and phentolamine (Regitine), and combinations of PDE5 inhibitors and intraurethral and intracavernosal agents. ED will be recognized universally as a cardiovascular sentinel event and also as a risk factor for vascular disease in general.



REFERENCES Archer, 2002. Archer SL: Potassium channels and erectile dysfunction. Vascul Pharmacol 2002; 38:61-71. Burchardt et al., 2000. Burchardt M, Burchardt T, Baer L, et al: Hypertension is associated with severe erectile dysfunction. J Urol 2000; 164(10):1188-1191. Carson et al., 2004. Carson CC, Rajfer J, Eardley I, et al: The efficacy and safety of tadalafil: An update. BJU Int 2004; 93:1276-1281. Crowe and Streetman, 2004. Crowe SM, Streetman DS: Vardenafil treatment for erectile dysfunction. Ann Pharmacother 2004; 38:77-85. Feldman et al., 1994. Feldman HA, Goldstein I, Hatzichristou DG, et al: Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994; 151(1):54-61. Jackson et al., 2002. Jackson G, Betteridge J, Dean J, et al: A systematic approach to erectile dysfunction in the cardiovascular patient: A consensus statement—Update 2002. Int J Clin Pract 2002; 56(9):663-671. Jaynat and Shepherd, 2002. Jaynat D, Shepherd MD: Evaluation and treatment of erectile dysfunction in men with diabetes mellitus. Mayo Clin Proc 2002; 77(3):276-282. Johannes et al., 2000. Johannes CB, Araujo AB, Feldman HA, et al: Incidence of erectile dysfunction in men ages 40 to 69 years old: Longitudinal results from the Massachusetts Male Aging Study. J Urol 2000; 163(2):460-463. Kirby et al., 2002. Kirby M, Jackson G, Betteridge J, et al: Is erectile dysfunction a marker for cardiovascular disease?. Int J Clin Pract 2002; 55(9):614-618. Lue, 2000. Lue TF: Drug therapy: Erectile dysfunction. N Engl J Med 2000; 342(24):1802-1813. Michelakis et al., 2000. Michelakis E, Tymchak W, Archer S: Sildenafil: From the bench to the bedside. CMAJ 2000; 163(9):1171-1175. NIH Consensus Development Panel on Impotence, 1993. NIH Consensus Development Panel on Impotence : Impotence (NIH Consensus Conference). JAMA 1993; 270(1):83-90. Padma-Nathan, 1999. Padma-Nathan H: Intra-urethral and topical agents in the management of erectile dysfunction. In: Carson III CC, Kirby RS, Goldstein I, ed. Textbook of Erectile Dysfunction, Oxford: Isis Medical Media; 1999:323-326. Rhoden et al., 2002. Rhoden EL, Teloken C, Mafessoni R, et al: Is there any relation between serum levels of testosterone and the severity of erectile dysfunction?. Int J Impot Res 2002; 14:167-171. Shokeir et al., 1999. Shokeir AA, Alserafi MA, Mutabagani H: Intracavernosal versus intraurethral alprostadil: A prospective randomized study. BJU Int 1999; 83:812-815. Spahn et al., 1999. Spahn M, Manning M, Juenemann KP: Intracavernosal therapy. In: Carson III CC, Kirby RS, Goldstein I, ed. Textbook of Erectile Dysfunction, Oxford: Isis Medical

Media; 1999:345-353. Sullivan et al., 1999. Sullivan ME, Thompson CS, Dashwood MR, et al: Nitric oxide and penile erection: Is erectile dysfunction another manifestation of vascular disease?. Cardiovasc Res 1999; 43:658-665.



Chapter 178 – Acute Renal Failure

Method of: Steven D. Weisbord, MD, MSc Paul M. Palevsky, MD Definition, Epidemiology, and Outcomes of Acute Renal Failure Acute renal failure (ARF) is a clinical syndrome broadly defined as an abrupt decline in renal function over a period of hours to days. Its clinical characteristics relate to the retention of nitrogenous and metabolic waste products and of extracellular fluid resulting from a reduction in the glomerular filtration rate (GFR). Although the initial manifestation of ARF may be decreased urine output, urine volume may remain normal or even increase, with the decline in renal function manifested by increases in blood urea nitrogen and serum creatinine concentrations. Despite a clear conceptual understanding of the syndrome, a universally accepted, operational definition of ARF does not exist, leading to the use of a variety of definitions in clinical studies and confounding efforts to characterize its epidemiology. Definitions have been based on absolute or proportional changes in the serum creatinine concentration, as direct measurement of GFR in the clinical setting is technically difficult. Commonly used definitions have included absolute increases in serum creatinine concentration of 0.5 to 1.0 mg/dL and relative increases of 25% to 100% over 1 to several days. Although expert panels have been convened to develop consensus definitions, the lack of sensitive and easily measured biomarkers of early renal damage has limited such efforts. The reported incidence of ARF is dependent on both the patient population studied and the definition of renal failure used. ARF develops in as many as 7% of hospitalized patients and complicates up to 30% to 50% of admissions to intensive care units. Its incidence among ambulatory patients is substantially lower. Unfortunately, outcomes associated with ARF have changed little over the past several decades. In-hospital mortality rates in excess of 50% continue to be reported in critically ill patients with ARF despite technologic advances in renal replacement therapies and other supportive care. Multiple studies have identified demographic and clinical factors that portend adverse outcomes from ARF. Older age, male gender, and respiratory, liver, and hematologic failure have all been directly correlated with in-hospital mortality, whereas serum creatinine and urea nitrogen concentrations (presumably reflecting nutritional factors) as well as urine output have inverse relationships with in-hospital mortality. Whereas associated comorbidities contribute to the high mortality associated with ARF, multiple studies have demonstrated that the development of ARF, in and of itself, is a strong predictor of mortality independent of concomitant comorbid conditions. The impact of a change in renal function on hospital outcomes is underscored by a recent study that found that even very small elevations in serum creatinine concentration (0.1-0.2 mg/dL) following cardiac or thoracic aortic surgery were associated with increased 30-day postoperative mortality. Classification of Acute Renal Failure ARF can be broadly classified into prerenal, postrenal, and intrinsic renal etiologies ( Table 1 ). Prerenal ARF is the most common cause of acute renal dysfunction, resulting from hemodynamically mediated reductions in renal blood flow. The hallmarks of prerenal azotemia are the absence of demonstrable

pathologic damage to the renal parenchyma and the prompt restoration of renal function following correction of the hemodynamic abnormality.

TABLE 1 -- Classification of Etiologies of Acute Renal Failure Prerenal Acute Renal Failure •

•

•

Decreased Absolute Blood Volume •

Blood loss: Hemorrhage

•

Cutaneous losses: Burns, sweating

•

Gastrointestinal losses: Diarrhea, vomiting, drainage from intestinal, pancreatic or biliary fistulas

•

Renal losses: Diuretics, osmotic diuresis

Decreased Effective Blood Volume •

Heart failure

•

Cirrhosis

•

Nephrotic syndrome

Intrarenal Hemodynamic Effect •

Nonsteroidal anti-inflammatory drugs

Postrenal Acute Renal Failure •

•

Upper Tract Obstruction: Bilateral obstruction or unilateral obstruction with single functioning kidney •

Intrinsic: Nephrolithiasis, papillary necrosis, blood clot, transitional cell carcinoma

•

Extrinsic: Retroperitoneal or pelvic malignancy, retroperitoneal adenopathy, retroperitoneal fibrosis, endometriosis, abdominal aortic aneurysm

Lower Tract Obstruction •

Transitional cell carcinoma of the bladder, prostate cancer, benign prostatic hypertrophy, urethral stricture, neurogenic bladder, bladder stones

Intrinsic Acute Renal Failure

•

Acute Tubular Necrosis •

Ischemic

•

Nephrotoxic

• •

•

•

•

•

Exogenous: Radiocontrast media, aminoglycosides, amphotericin B (Fungizone), cisplatinum (Platinol), acetaminophen (Tylenol)

•

Endogenous: Rhabdomyolysis, hemolysis

Sepsis

Acute Interstitial Nephritis •

Medications: Penicillins, cephalosporins, sulfonamides, rifampin (Rifadin), phenytoin (Dilantin), furosemide (Lasix), nonsteroidal anti-inflammatory drugs

•

Infections: Bacterial, viral, rickettsial, mycobacterial

•

Autoimmune disorders: Systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis

Acute Glomerulonephritis •

Poststreptococcal glomerulonephritis

•

Postinfectious glomerulonephritis

•

Endocarditis-associated glomerulonephritis

•

Vasculitis/autoimmune disease

•

Thrombotic microangiopathy (hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)

•

Rapidly progressive glomerulonephritis

Acute Vascular Syndromes •

Large-vessel disease: Bilateral renal artery thromboembolism or dissection, bilateral renal vein thrombosis

•

Small-vessel disease: Atheroembolic disease

Intratubular Obstruction •

Crystals: Calcium oxalate, uric acid, acyclovir (Zovirax), indinavir (Crixivan)

•

Protein: Light-chain nephropath

The second broad category of ARF is postrenal, which is characterized by obstruction of the urinary collecting system. ARF may develop with obstruction of either the lower urinary tract (bladder or urethra) or the upper urinary tract (ureters and kidneys). Upper tract obstruction must, however, be bilateral or affect a solitary functioning kidney in order to cause ARF. Intrinsic ARF involves renal parenchymal injury. The most common form of intrinsic ARF is acute tubular necrosis (ATN), which develops as the result of nephrotoxic, ischemic, or septic injury to the kidney. With

ATN there is renal tubular epithelial cell injury, apoptosis and necrosis of the tubular epithelium, denuding of the epithelial basement membrane, and obstruction of tubular lumens by sloughed epithelial cells and debris. Glomerular histology is preserved, and the decline in renal function is mediated by a combination of intrarenal vasoconstriction, back-leak of glomerular ultrafiltrate across the denuded epithelium, and tubular obstruction. Acute interstitial nephritis, acute glomerulonephritis, rapidly progressive GN, and macrovascular- and microvascular-mediated injury are less common forms of intrinsic ARF. ARF can also be categorized based on urine volume as nonoliguric, oliguric, or anuric. Oliguria is defined as daily urine output less than 400 mL and anuria as daily urine output less than 50 mL, the latter most commonly encountered in the setting of bilateral urinary tract obstruction or severe ATN associated with shock. In general, nonoliguric ARF is associated with a better prognosis than is oliguric or anuric disease, reflecting lesser degrees of renal injury. Diagnostic Features of Specific Syndromes of Acute Renal Failure PRERENAL ACUTE RENAL FAILURE Prerenal ARF results when hemodynamic factors lead to renal hypoperfusion. Prerenal ARF may occur in the setting of true hypovolemia, as may result from diarrhea, vomiting, decreased oral intake, and overly aggressive use of diuretics, or it may occur in relation to clinical conditions associated with decreased effective circulating volume, such as congestive heart failure and chronic liver disease. Clinical findings of volume depletion may include absolute or relative hypotension, orthostatic changes in pulse and/or blood pressure, decreased jugular venous pressure, dry mucous membranes, and tenting of the skin. However, many of these physical findings are nonspecific, especially in the elderly and in chronically ill patients. The utility of these physical findings may be diminished in patients with cardiac or liver disease, in whom effective circulating volume may be decreased despite extracellular volume overload with edema. Assessment of urine chemistry may be helpful in the diagnosis of prerenal azotemia. The urine sodium concentration is usually low (1.015) and a bland urine sediment without casts. In prerenal states, the ratio of blood urea nitrogen to serum creatinine may be increased to greater than 20:1 as a result of increased tubular reabsorption of urea. Table 2 provides a summary of diagnostic findings associated with various etiologies of ARF.

TABLE 2 -- Diagnostic Findings in Acute Renal Failure BUN/Cr UNa Ratio (mEq/L) FENa Urinalysis Prerenal Acute Renal Failure

>20:1

2%[*]

Muddy-brown casts, tubular epithelial cells

FEUrea 20

>1%

Hematuria, WBCs, WBC Eosinophilia casts, eosinophils

Acute glomerulonephritis

20

Variable Variable

Fluctuating urine output

Postrenal Acute Renal Failure

>20:1

—

Abbreviations: BUN = blood urea nitrogen; Cr = creatinine; FEUrea = fractional excretion of urea; UNa = urine concentration of sodium; RBC = red blood cell; WBC = white blood cell.

* Fractional excretion of sodium (FENa) can be low in cases of radiocontrast nephropathy and pigment nephropathy. † Calcium oxalate crystals with ethylene glycol intoxication; uric acid crystals with uric acid nephropathy; Bence-Jones proteins, associated with multiple myeloma, can be detected using the sulfosalicylic acid test of urine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can precipitate or exacerbate prerenal ARF. In settings of decreased absolute or effective circulatory volume, local synthesis of vasodilatory prostaglandins opposes the vasoconstrictive effects of angiotensin II on the afferent (preglomerular) arteriole in order to maintain GFR. In settings in which the renin-angiotensin axis is activated, inhibition of prostaglandin synthesis by the kidney results in unopposed vasoconstriction, markedly diminishing GFR. NSAID use, particularly in the setting of chronic kidney disease, older age, concomitant use of angiotensin-converting enzyme inhibitors, use of angiotensin receptor blockers or diuretics, and clinical conditions associated with decreased effective circulating volume (e.g., heart failure and advanced liver failure), is associated with a markedly increased risk of prerenal ARF and an increased risk of developing ATN. POSTRENAL ACUTE RENAL FAILURE The second broad category of ARF is postrenal or obstructive disease, which is characterized by obstruction of the urinary collecting system. ARF develops only when obstruction affects both kidneys or with unilateral

upper urinary tract obstruction in the setting of a solitary functioning kidney. The disorders that cause postrenal ARF are usually categorized by the level of urinary tract obstruction. Obstruction to the lower urinary tract (bladder outlet and urethra) commonly results from benign or malignant prostate disease, bladder cancer, or urethral stricture. Obstruction to the upper urinary tract commonly stems from pelvic and retroperitoneal malignancy, retroperitoneal lymphadenopathy, transitional cell carcinoma of the renal pelvis and ureters, bilateral kidney stones, or retroperitoneal fibrosis. The clinical findings depend on the degree and level of obstruction to urinary flow. Anuria can be seen with complete obstruction, whereas normal urine volume, polyuria, or fluctuating urine output may occur with partial obstruction. Gender-related anatomic differences, notably a longer urethra and periurethral prostatic tissue, make postrenal ARF more common in men. Careful abdominal examination may reveal a tender, distended bladder, suggesting the presence of bladder outlet obstruction. The gold standard diagnostic test is the renal ultrasound, which demonstrates dilation of the renal collecting system (hydronephrosis and/or hydroureter). However, in up to 20% of cases, particularly early in the clinical course or in cases associated with intravascular volume contraction or retroperitoneal fibrosis, ultrasound may fail to demonstrate hydronephrosis despite the underlying presence of obstructive ARF. Documentation of a postvoid bladder urine volume of at least 100 mL by bedside ultrasound or catheterization suggests lower urinary tract obstruction. Outcomes with postrenal ARF depend greatly on the duration and degree of obstruction. With complete obstruction, the likelihood of recovery of renal function decreases after approximately 1 week. Recovery from partial obstruction is more difficult to predict and depends on the severity and duration of obstruction along with other complicating factors. INTRINSIC RENAL DISEASE Acute Tubular Necrosis

Most cases of ATN can be linked to renal ischemia, use of nephrotoxic agents, or sepsis. Unlike prerenal azotemia, ATN is characterized by tubular epithelial cell injury leading to impaired reabsorption of sodium with a urine sodium concentration greater than 40 mEq/L and a fractional excretion of sodium greater than 2%. Urine in patients with ATN is typically isosthenuric (isotonic with plasma), with a specific gravity of approximately 1.010. The urine sediment typically demonstrates “muddy brown” coarse granular casts on microscopic analysis. The blood urea nitrogen concentration usually rises in proportion to the serum creatinine concentration, leading to maintenance of the normal ratio of approximately 10:1. Radiocontrast-Associated Acute Tubular Necrosis

The administration of intravascular radiocontrast media results in one of the most common forms of ATN, accounting for approximately 10% of hospital-acquired ARF. The administration of intravascular radiocontrast often results in a transient and clinically insignificant (0.1-0.2 mg/dL) rise in the serum creatinine concentration. Radiocontrast nephropathy (RCN) develops when more pronounced reductions in kidney function follow radiocontrast administration. The pathogenesis of RCN is multifactorial and is mediated by both renal vasoconstriction, particularly affecting the renal medulla, and direct epithelial cell toxicity. Clinically, RCN manifests as an abrupt decline in kidney function 24 to 72 hours after radiocontrast administration. The serum creatinine concentration typically peaks within 3 to 5 days and returns to baseline by 7 to 10 days. Several clinical factors increase the risk for RCN, including preexisting chronic kidney disease, diabetes mellitus with or without diabetic nephropathy, congestive heart failure, volume depletion, and increasing dose of radiocontrast media. In contradistinction to other forms of ATN, the fractional

excretion of sodium may be low in RCN. Aminoglycoside-Associated Acute Tubular Necrosis

Aminoglycoside antibiotics are associated with nephrotoxicity in 10% to 15% of patients. Aminoglycosides are actively taken up and accumulate in proximal tubular cells, leading to toxicity as intracellular concentrations rise. ARF usually develops 7 to 10 days after the initiation of therapy. Because aminoglycosides are renally excreted, dosing of these agents is central to their nephrotoxicity. Aminoglycoside-induced ATN is typically nonoliguric, and near-complete or full recovery of renal function is common, although the course of ARF may be protracted. Myoglobinuric Acute Tubular Necrosis

Rhabdomyolysis develops from injury to skeletal muscle and results in the release of cellular constituents, such as creatine phosphokinase and myoglobin, into the systemic circulation. When myoglobin is filtered in large quantities by the kidney, tubular damage and ATN can ensue. Although the classic description of rhabdomyolysis involves severe trauma with crush injuries, an increasing number of cases are linked to nontraumatic etiologies, including use of medications, such as statins, and use of illicit drugs, primarily cocaine. Typical symptoms include muscle soreness and weakness. A dramatically elevated creatine phosphokinase level is the sine qua non of this condition. Commonly, hyperphosphatemia, hyperuricemia, and hyperkalemia complicate rhabdomyolysis due to release of the respective components from damaged muscle. Additionally, hypocalcemia may occur, resulting primarily from calcium deposition in the injured muscle. Subsequent release of deposited calcium during the recovery phase may result in hypercalcemia. Urine findings include heme-pigmented casts and a positive dipstick for heme pigment in the absence of red blood cells on microscopic examination. Postoperative Acute Renal Failure

ARF is a relatively common complication following vascular, cardiac, and major abdominal surgical procedures and is associated with particularly high mortality rates. Its development can usually be linked to perioperative episodes of hypotension and/or sepsis. Depending on the definition of ARF and the risk profile of the patient population, ARF develops in 1% to 40% of patients undergoing cardiac surgery, with 1% to 7% of these patients requiring dialysis. Specific clinical factors that increase the risk for ARF following cardiac surgery include cardiogenic shock, decreased baseline renal function, emergent surgery, left ventricular dysfunction, age greater than 70 years, peripheral vascular disease, and left main coronary artery disease. Additionally, valve surgery, particularly of the aortic valve, is associated with greater risk than is coronary artery bypass surgery, with the greatest risk in patients undergoing combined procedures. Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) results from inflammatory damage to the renal interstitium. Antibiotics and NSAIDs are the most common etiologic agents, although the list of drugs that can precipitate AIN is extensive. Less commonly, infections and autoimmune diseases lead to AIN. Eosinophilia, fever, and rash classically accompany AIN, although the presence of this complete triad is seen in only approximately one third of patients. Examination of the urine reveals hematuria and sterile pyuria with or without white blood cell casts. Although eosinophiluria is associated with AIN, the sensitivity and positive predictive value of this finding are poor. In contrast, the negative predictive value of this finding is high, making the absence of

eosinophiluria a useful test for ruling out AIN. The clinical features of AIN typically develop several days to weeks after exposure to the offending agent, and recovery is common following discontinuation of the agent. Acute Glomerulonephritis

Acute GN and rapidly progressive GN are uncommon causes of ARF that can result from myriad conditions and are characterized by primary injury to the glomerulus. The hallmark findings of GN-associated ARF are dysmorphic red blood cells and red blood cell casts on microscopic examination of the urine sediment. The prototypic form of acute GN is poststreptococcal GN; however, acute GN may also develop in the setting of endocarditis and other infections, systemic vasculitis, and autoimmune disease, or it may present as an idiopathic renal-limited disease. Serologic assays for complement levels (C3 and C4), hepatitis markers, antistreptococcal antibodies (ASO), antinuclear antibodies (ANA), antiglomerular basement membrane antibodies (anti-GBM), and antineutrophil cytoplasmic antibodies (ANCA) may be helpful in making a diagnosis; however, renal biopsy is commonly required to determine the specific etiology. Intratubular Obstruction

Intratubular obstruction to the flow of urinary filtrate can occur in certain clinical settings and result in an acute decline in renal function. The obstruction may result from precipitation of either crystals or protein within the tubular lumen. Ethylene glycol ingestion is associated with intratubular precipitation of calcium oxalate crystals. This diagnosis should be suspected when ARF develops in the setting of acute intoxication and high anion-gap metabolic acidosis and is usually accompanied by a preponderance of calcium oxalate crystals on examination of the urine sediment. Tumor lysis syndrome is a term applied to a constellation of metabolic and clinical findings that may occur after treatment of rapidly proliferative neoplastic disorders, usually of hematologic origin. Marked hyperuricemia leads to intratubular precipitation of uric acid crystals in the distal nephron. Other associated findings include hyperphosphatemia, hyperkalemia, and hypocalcemia. This form of ARF is typically oliguric or anuric. The urine sediment usually demonstrates abundant uric acid crystals or amorphous urates in the setting of an acidic urine. Characteristically, the ratio of urine uric acid to creatinine is greater than 1 in acute uric acid nephropathy, compared to values of less than 0.6 to 0.75 in ARF of other etiologies. Intratubular precipitation of acyclovir and indinavir is the major mechanism of ARF with use of these drugs. Tubular obstruction is also one of the well-recognized complications of multiple myeloma. Monoclonal immunoglobulins and/or light chains precipitate in distal tubules, leading to intratubular obstruction and ARF. Acute Vascular Syndromes

Acute vascular syndromes that cause ARF can be broadly divided into large-vessel disease and smallvessel disease. Although uncommon, etiologies for large-vessel disease include bilateral thromboembolism, renal vein thrombosis, and large vessel vasculitis leading to renal infarction. More common is small-vessel disease resulting from atheroemboli that involve the distal renal vasculature. Cholesterol crystals released from atheromatous plaques deposit in small arteries and arterioles. Although nonobstructive, these emboli induce an inflammatory reaction that ultimately leads to fibrosis and obliteration of vessels. Acute and/or subacute renal failure are common sequelae. Along with renal involvement, cutaneous manifestations such as livedo reticularis, abdominal pain from intestinal ischemia and pancreatitis, myositis, and neurologic involvement from emboli to the central nervous system and spinal cord can complicate the clinical picture. Renal atheroemboli should be suspected in any case of ARF that occurs subsequent to instrumentation of the vasculature. Laboratory clues to the diagnosis include eosinophilia, eosinophiluria, and

hypocomplementemia, although these findings are not universally present. Prevention and Treatment of Acute Renal Failure PRERENAL ACUTE RENAL FAILURE Treatment of prerenal azotemia is directed at augmenting renal perfusion. With true hypovolemia, administration of intravascular isotonic fluid is the primary therapy. Treatment directed at the cause of volume loss, such as diarrhea or vomiting, should also be implemented. In cases of overdiuresis, diuretics should be discontinued and judicious intravascular volume expansion provided. With severely decompensated heart failure, renal perfusion can be optimized using intravenous inotropic agents, although this is usually only a temporizing measure. Cautious intravascular volume expansion can be beneficial in prerenal azotemia in advanced liver disease; however, this must be balanced against the risk of total body volume overload. No data support the routine use of intravenous albumin for expansion of the intravascular space in the majority of patients with advanced liver disease. However, use of intravenous albumin has proved beneficial in preventing renal dysfunction in the treatment of spontaneous bacterial peritonitis and in patients undergoing large volume paracentesis. Prevention of NSAID-related prerenal azotemia hinges on avoiding these agents in patients with chronic kidney disease or other factors that predispose to renal underperfusion. To prevent the evolution of NSAID-associated prerenal ARF into ischemic ATN, prompt discontinuation of the offending NSAID, along with other potentially nephrotoxic agents, is essential. POSTRENAL ACUTE RENAL FAILURE Treatment of postrenal ARF hinges on the prompt relief of obstruction. Placement of a bladder catheter provides relief of functional or anatomic bladder outlet obstruction. Upper tract obstruction requires the placement of ureteral stents or percutaneous nephrostomy tubes. INTRINSIC ACUTE RENAL FAILURE Acute Tubular Necrosis General Therapeutic Considerations

In the majority of patients, the development of ARF is unpredictable. For this reason, with the exception of specific clinical settings discussed later, preventive measures are limited to broad recommendations for avoidance of nephrotoxic agents when possible, for cautious dosing of such agents when they must be used, particularly in the elderly and in patients with underlying chronic renal insufficiency, and for avoidance of hypovolemia and hypotension. Similarly, the pharmacologic management of established ATN is ineffective. Although multiple agents, including diuretics, renal vasodilators, natriuretic peptides, and growth factors, have shown promise in animal models and preliminary clinical trials, none has proved to be clinically effective when rigorously evaluated. The role of loop diuretics in the management of ATN has been controversial. It was hypothesized that decreased oxygen demand resulting from inhibition of sodium transport might reduce the extent of renal injury; however, this benefit has not been substantiated in clinical trials. In addition, diuretics have been used to convert oliguric to nonoliguric ARF in the hope that this will improve prognosis. Although the increased urine volume simplifies fluid management, there is no evidence that the conversion to a nonoliguric state

actually impacts outcomes. Rather, the response to diuretics merely identifies patients with less severe renal injury. A recent observational study suggested that diuretic use was associated with an increased risk of death and with nonrecovery of renal function, although these findings were not confirmed in a subsequent trial. Nevertheless, these findings highlight the concern that diuretic therapy may result in delays in initiation of renal replacement therapy. Therefore, we believe that a trial of high-dose furosemide (Lasix; 160-200 mg intravenously) or an equivalent dose of other loop diuretics is reasonable in oliguric patients who are not intravascularly volume depleted, but that diuretic therapy should not be used to delay the initiation of otherwise indicated renal replacement therapy. Repeated dosing of diuretics is not warranted in patients who do not respond. Dopamine (Intropin) increases renal plasma flow, GFR, and sodium excretion when administered at doses of 0.5 to 2 µg/kg/min. Although such “renal-dose” dopamine has been widely used in the management of ARF, clinical trials have not established any benefit with regard to survival or need for renal replacement therapy with this agent. Given the risk of complications, especially cardiac tachyarrhythmias, there is no role for low-dose dopamine in the management of ARF. Similarly, there is no established role for fenoldopam mesylate[1] (Corlopam), a selective dopamine-1 receptor agonist, in the management of ARF. 1 Not FDA approved for this indication.

Renal Replacement Therapy

In the absence of effective pharmacologic therapy, renal replacement therapy remains the primary treatment of severe ARF, providing an effective means for managing hyperkalemia, metabolic acidosis, volume overload, and uremic manifestations. Multiple forms of renal replacement therapy, including intermittent hemodialysis, continuous renal replacement therapy, newer hybrid forms of slow hemodialysis such as sustained low-efficiency dialysis, and peritoneal dialysis, can be used in patients with ARF. Only limited data are available to guide selection of modality of renal replacement therapy. Specifically, no data support improved outcomes associated with continuous renal replacement therapy compared to intermittent hemodialysis, although continuous renal replacement therapy and sustained low-efficiency dialysis both are associated with less hemodynamic instability and more effective volume removal than is intermittent hemodialysis. Therefore, selection of modality should be based on local capabilities and expertise. Generally accepted indications for initiation of renal replacement therapy in patients with ARF include volume overload, hyperkalemia, metabolic acidosis, and overt uremic manifestations such as encephalopathy and pericarditis. An optimal threshold for initiation of therapy based on level of azotemia is not established, although preemptive initiation of therapy prior to the development of uremic symptoms is well recognized to be associated with improved outcomes. Therefore, it is generally accepted that, in the absence of other indications, renal replacement therapy should be initiated when the blood urea nitrogen concentration reaches approximately 90 to 100 mg/dL, although some data suggest that earlier initiation of therapy may be associated with improved outcomes. Despite substantial technologic advancements in the dialysis apparatus, the optimal dose of renal replacement therapy in ARF remains uncertain. Although daily intermittent hemodialysis was associated with improved survival compared to alternate-day dialysis in a prospective study, several methodologic issues related primarily to the relatively low dose of dialysis provided with each treatment raise questions regarding the applicability of the results of this study to general practice. Similarly, although two single-center

randomized controlled trials have demonstrated improved survival with increased intensity of continuous renal replacement therapy, results have not been consistent across all studies. It is hoped that ongoing clinical trials will resolve this issue in the near future. Therapeutic Considerations for Specific Etiologies of Acute Tubular Necrosis RADIOCONTRAST NEPHROPATHY.

Most radiographic procedures that utilize intravascular radiocontrast are planned in advance, making RCN one of the forms of ARF most amenable to preventive measures. Three strategies have been conclusively shown to decrease the risk for RCN in high-risk patients. First is intravascular volume expansion with intravenous fluids. Volume expansion with isotonic saline (1 mL/kg/hr for 12 hours before and 12 hours after the administration of radiocontrast) is more effective than the same volume of hypotonic saline. Several recent studies have suggested that administration of isotonic sodium bicarbonate may be superior to sodium chloride for the prevention of radiocontrast nephropathy. However, confirmation of these results across broader populations of patients and in larger studies is required before the superiority of sodium bicarbonate can be definitively established. Second, low-osmolar radiocontrast agents are associated with less nephrotoxicity than are older high-osmolar agents, and additional protection may be provided by the use of iodixanol (Visipaque), an iso-osmolar radiocontrast agent, in high-risk patients, particularly in patients with chronic kidney disease and diabetes mellitus. Third, minimizing the dose of radiocontrast decreases renal damage. Along with these measures, the administration of N-acetylcysteine[1] (Mucomyst), an antioxidant agent, may be associated with protection from RCN. Although clinical trials have yielded conflicting results and metaanalyses have failed to conclusively demonstrate a beneficial effect, this agent is inexpensive and free of deleterious side effects. Therefore, use of N-acetylcysteine (600-1200 mg orally twice daily on the day before and on the day of the procedure) is not inappropriate, albeit not in lieu of proven preventive strategies. Similarly, with the well-recognized relationship between intravascular volume depletion/renal underperfusion and risk for RCN, discontinuation of diuretics and NSAIDs prior to radiocontrast administration is advisable. Mannitol,[1] dopamine[1] (Intropin), fenoldopam[1] (Corlopam), calcium channel blockers, and human ß-type natriuretic peptide[1] (Natrecor) are not effective and have no role in the prophylaxis of RCN. Likewise, prophylactic intermittent hemodialysis and continuous hemofiltration have no role in the prevention of RCN. An algorithm for the prevention of RCN is shown in Figure 1 .

FIGURE 1 Management algorithm for the prevention of radiocontrast nephropathy (RCN).[1]Not FDA approved for this indication. Abbreviations: COX-2 = cyclooxygenase-2; NaCl = sodium chloride; NaHCO2 = sodium bicarbonate; NSAIDs = nonsteroidal antiinflammatory drugs.

AMINOGLYCOSIDE-ASSOCIATED ACUTE TUBULAR NECROSIS.

Based on the observation that proximal tubule uptake of aminoglycosides is saturable, use of once-daily dosing of these antimicrobial agents may be less nephrotoxic than multiple-daily dosing schemes. Although conclusive data are lacking, a series of studies and meta-analyses support the use of once-daily dosing. Therefore, it is not unreasonable to consider once-daily dosing in clinically appropriate circumstances to

reduce the risk of ARF. Additional preventive strategies that should be implemented include monitoring of drug levels, discontinuing concomitant nephrotoxic agents, limiting the duration and total dose of therapy, and switching to non-nephrotoxic agents guided by antibiotic sensitivities. MYOGLOBINURIC ACUTE RENAL FAILURE.

Rhabdomyolysis is associated with sequestration of large volumes of fluid in the injured muscle. Because the risk of ARF in rhabdomyolysis is associated with intravascular volume depletion, patients with rhabdomyolysis should be aggressively administered large volumes of isotonic electrolyte solutions to maintain intravascular volume. In patients with crush injuries, the use of aggressive fluid resuscitation with administration of normal saline at 1 L/hr has been shown to minimize the risk of ARF. Optimally, this strategy should be initiated in the field, prior to extraction of the patient. Although use of mannitol as an osmotic diuretic and urinary alkalinization with bicarbonate have been recommended, data supporting the superiority of these agents over isotonic saline alone are inconclusive. Hypocalcemia should not be treated unless the patient is symptomatic because calcium administration increases the risk of hypercalcemia during the recovery phase of rhabdomyolysis. POSTOPERATIVE ACUTE RENAL FAILURE.

No specific therapies have been demonstrated to be effective for the prevention or treatment of postoperative ATN. Acute Interstitial Nephritis

The primary treatment of AIN is discontinuation of the offending agent. In most patients, renal function recovers, although this can take several weeks. Use of glucocorticoids for treatment of AIN remains controversial. Although case series have suggested a potential benefit of glucocorticoids, their use has not been evaluated in prospective randomized trials. Nonetheless, a trial of glucocorticoids is a reasonable therapeutic option in patients with biopsy-proven AIN in whom renal function fails to improve after discontinuation of the offending drug. ACUTE GLOMERULONEPHRITIS Therapy for acute GN is dependent upon the specific diagnosis. The treatment of poststreptococcal GN is supportive. In patients with endocarditis-associated GN and other forms of infection-associated GN, treatment is directed at the underlying infection. Plasma exchange should be initiated in patients with hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. High-dose glucocorticoids and cytotoxic or immunosuppressive therapy are usually required in patients with vasculitis-associated GN and rapidly progressive GN. In patients with anti-GBM disease, plasmapheresis is often required in addition to high-dose glucocorticoids and cytotoxic therapy. INTRATUBULAR OBSTRUCTION Oxalate Nephropathy

Fomepizole (Antizol), a competitive inhibitor of alcohol dehydrogenase, and intravenous ethanol[1] are the primary therapies for ethylene glycol intoxication. By inhibiting formation of oxalate, these therapies can

prevent the development or arrest the progression of acute oxalate nephropathy. Maintenance of high urinary flow rates with intravenous fluids may help minimize calcium oxalate precipitation. Mannitol can be used as an osmotic diuretic to maintain urine flow rates. Intravenous sodium bicarbonate may be necessary to treat the metabolic acidosis that commonly complicates this form of ARF. Dialysis may be beneficial for rapidly lowering plasma ethylene glycol levels and acutely decreasing the concentrations of plasma oxalate and other metabolites. Acute Uric Acid Nephropathy

Tumor lysis syndrome and acute uric acid nephropathy characteristically develop after the initiation of chemotherapy, allowing initiation of treatment to prevent this form of ARF. Volume expansion with intravenous saline to maintain high urine flow rates minimizes the intratubular precipitation of uric acid crystals and is the mainstay of therapy. The role of urinary alkalinization with intravenous sodium bicarbonate is less certain. Although the solubility of uric acid is increased in alkaline urine, the benefit of alkalinization compared to saline alone has not been demonstrated, and it may promote the deposition of calcium phosphate in patients with concomitant hyperphosphatemia. Allopurinol (Zyloprim; 600-900 mg/day) should be initiated in advance of chemotherapy to inhibit xanthine oxidase and block the generation of uric acid. In patients unable to take oral medications, an intravenous form of allopurinol (200-400 mg/m2/day) is available. Alternatively, rasburicase (Elitek; 0.15-0.2 mg/kg/day), a recombinant form of uricase, rapidly metabolizes uric acid to the more soluble allantoin and is approved for use in children. Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. In patients who develop ARF, hemodialysis may rapidly lower uric acid concentrations and facilitate recovery of renal function. Multiple Myeloma

Acute light-chain nephropathy should be treated with aggressive intravascular volume expansion. Concomitant hypercalcemia, which increases the risk of acute nephropathy, should be treated. Chemotherapy should be initiated to decrease the light-chain burden. Plasmapheresis may be of benefit in some patients by rapidly lowering the filtered light-chain burden. Although it has previously been suggested that plasmapheresis is of benefit in some patients with light-chain nephropathy by rapidly lowering the filtering light-chain burden, this has not been borne out by a more recent multicenter study. For this reason, plasmapheresis is no longer recommended in this setting. Atheroembolic Disease

No specific therapy for atheroembolic disease exists. Treatment with antiplatelet agents, steroids, and iloprost[1] (Ventavis), a prostacylin analogue, have all been investigated, with no definitive benefit seen. Supportive care, including the withdrawal of anticoagulants, avoidance of additional intravascular manipulation, and therapy to lower serum cholesterol concentrations with statins, may improve outcomes. Overall mortality from renal atheroembolic disease remains greater than 60% to 80% in some series, underscoring the importance of primary prevention. Complications and Additional Therapeutic Considerations Electrolyte and Acid-Base Complications

Hyperkalemia is a common complication of ARF, developing as a result of decreased renal excretion,

particularly in patients with oliguric ARF. If severe, hyperkalemia can lead to life-threatening arrhythmias. Therapy depends on the degree of elevation of the serum potassium concentration, with severe hyperkalemia requiring urgent therapy. In patients with electrocardiographic changes of hyperkalemia, the initial therapy is intravenous calcium (10-20 mL of 10% calcium gluconate or 10 mL of 10% calcium chloride). This should be followed by intravenous insulin (10-20 U regular insulin), combined with an infusion of dextrose (250 mL of 20% dextrose in water over 1 hour) to prevent hypoglycemia and inhaled albuterol[1] (Proventil) (10-20 mg by nebulizer) to translocate potassium from the extracellular to intracellular compartments. Potassium removal from the body can be achieved by administration of oral or rectal polystyrene sulfonate (Kayexalate) or by initiation of dialysis. In patients with serum potassium concentrations greater than 6 mEq/L but without electrocardiographic changes, intravenous calcium is not required, and treatment should begin with insulin/glucose and/or albuterol to translocate potassium into the intracellular compartment, followed by dialysis or potassium-binding resin. Less severe degrees of hyperkalemia need only be treated with dialysis or binding resins. Metabolic acidosis is another frequent complication of ARF, manifested initially by a decline in serum bicarbonate concentration. Concomitant pulmonary disease may result in the development of mixed acidbase disorders; hence, confirmation of the presence of acidemia by blood gas analysis is necessary prior to initiation of therapy. The role of bicarbonate therapy in patients with anion-gap metabolic acidosis remains controversial. Although severe acidemia (pH 7 mg/dL), short-term administration of aluminum hydroxide[1] (Alu-Cap) rapidly lowers the serum phosphate concentration. Once the serum phosphate concentration is less than 7 mg/dL, calcium-based binders should be used (calcium acetate [PhosLo] 667-1364 mg or calcium carbonate[1] [Tums] 0.5-1.0 g administered with meals). Sevelamer (Renagel), a newer non–calciumcontaining polymer that binds intraintestinal phosphate, can be used in patients with hypercalcemia or an elevated calcium-phosphate product. Hemodialysis and renal replacement therapy are highly effective in lowering the plasma phosphate concentration and may lead to hypophosphatemia. Hypermagnesemia can occur with ARF and is usually due to exogenous magnesium administration in the setting of impaired renal excretory capacity. Extreme caution should be used when administering magnesium to patients with severely decreased GFR. Hemodialysis can be used in severe cases to lower the serum magnesium level. Hematologic Complications

ARF can result in platelet dysfunction, predisposing to bleeding complications. The uremic platelet defect is manifested by prolongation of the bleeding time in the setting of a normal platelet count, normal prothrombin time (PT), and normal activated partial thromboplastin time (aPTT). This defect is usually corrected, at least in part, by dialysis. If the platelet dysfunction is severe and is complicated by active bleeding, administration of 1-deamino (8-D-arginine) vasopressin (DDAVP[1]; 0.3 µg/kg intravenously) may be of benefit; however, tachyphylaxis usually develops after two to three doses. Intravenous estrogens (conjugated estrogen[1] [Premarin] 0.6 mg/kg) administered daily for 5 days has been shown to correct the platelet defect for up to

14 days. Pooled cryoprecipitate is of benefit but is associated with risk of transmission of viral diseases. Anemia is a common occurrence with ARF; however, the role of recombinant human erythropoietin [1] (Procrit) and other erythropoietic agents in the management of this complication is not well characterized. Infectious Complications

Infection is a common comorbidity in patients with ARF. Intravascular and bladder catheters frequently serve as routes of infection. Whenever possible, bladder catheters should be removed and intermittent bladder catheterization used. Temporary dialysis catheters are a frequent source of bacteremia. To reduce the risk of infection, femoral dialysis catheters should be avoided whenever possible and should remain in place for as brief a duration as possible. In patients with prolonged ARF, the use of tunneled dialysis catheters will decrease the risk of infection. In a single small clinical trial, use of antibiotic-impregnated dialysis catheters was associated with a reduced risk of catheter-associated bacteremia. Additional studies confirming these results are needed before this approach can be recommended. Early recognition and initiation of systemic antimicrobial therapy for blood-borne infections related to central venous catheters are essential, as is the appropriate dosing of antibiotics in the setting of reduced GFR. Removal of central venous catheters in the setting of bacteremia is highly dependent on the clinical status of the patient, the pathogenic organism, and the need for short-term vascular access. Cardiopulmonary Complications

Cardiac and pulmonary problems are protean in patients with ARF. Arrhythmias, hypertension, pericarditis, and pericardial effusion can be seen with ARF. Pericarditis, which can be life-threatening, should be treated with intensification of renal replacement therapy. Pulmonary vascular congestion or overt pulmonary edema resulting from impaired diuresis and natriuresis may precipitate the need for renal replacement therapy. In patients with acute lung injury or the acute respiratory distress syndrome who are mechanically ventilated using low-tidal volumes as a lung-protective strategy, the dialysis prescription may require adjustment to provide adequate control of the acidemia resulting from hypercapnia. Nutritional Management

The optimal approach to nutritional therapy in the setting of ARF remains a matter of debate. ARF is usually a catabolic state. Although caloric and protein requirements should be individualized based on the overall clinical condition of the patient, protein intake should not be restricted and generally should range from 1.2 to 1.6 g/kg/day, with a minimum daily caloric intake of 30 kcal/kg. Enteral routes of nutritional supplementation are greatly preferred. Renal replacement therapy can be associated with loss of proteins and amino acids, necessitating adjustments in the nutritional prescription. Among nondialysis patients, close attention should be paid to limit intake of potassium (90% of patients who have a relapse after radiation therapy. Thus, approximately 99% of patients with low-stage seminomas are cured. NSGCTs include embryonal cell carcinoma, choriocarcinoma, yolk sac carcinoma, teratoma, and mixed germ cell tumors. The rate of cure for patients with NSGCTs in clinical stage 1 exceeds 95%. Surveillance and RPLND are both standard treatment options for this group of patients. Twenty percent of clinical stage 1 NSGCT patients have lymph node involvement, and those with vascular invasion or predominance of embryonal cell carcinoma are at increased risk (50%). RPLND is a major abdominal operation in which lymph nodes from the retroperitoneum are removed from the renal hilum down to the level of the common iliac artery, with lateral margins being confined by the ureters. Patients found to have node-positive disease are generally recommended for chemotherapy with usually two cycles. Patients with persistently increased concentrations of AFP, ß-hCG, or both but without other clinical evidence of disease following orchiectomy usually have systemic disease and are treated with chemotherapy. Testicular Cancer

Initial chemotherapy is required in approximately one third of patients with germ cell tumors. Because relapse is frequent in patients with clinical stage 2c disease or in patients with primary retroperitoneal or mediastinal seminomas who receive radiation alone, these patients are treated initially with chemotherapy. Patients also receive initial chemotherapy if they have stage 3 NSGCTs or multifocal retroperitoneal lymph node involvement, lymph nodes >3 cm in diameter, or tumorrelated back pain. Postchemotherapy RPLND is usually reserved for residual masses (>3 cm) in patients after treatment for seminoma. In NSGCT, the need for postchemotherapy RPLND is controversial. Some advocate surgery in all patients with initial bulky retroperitoneal disease, whereas others advocate observation rather than surgery in patients with >90% shrinkage of retroperitoneal nodes, no residual nodes >1.5 cm, and no teratomatous elements in the primary tumor. Owing in part to the multimodality approach to these tumors, 90%–95% of patients are ultimately cured of their disease. Abbreviations: AFP = a-fetoprotein; ß-hCG = ß-chorionic gonadotropin; CT = computed tomography; NSGCT = nonseminomatous germ cell tumor; RPLND = retroperitoneal lymph node dissection.

RPLND is a major abdominal operation in which lymph nodes from the retroperitoneum are removed from the renal hilum down to the level of the common iliac artery, with lateral margins confined by the ureters. In the past, this procedure resulted in lack of ejaculation and infertility in 100% of patients. By performing a modified-template RPLND, the contralateral area of aorta below the inferior mesenteric artery is not manipulated. This maneuver serves to preserve the confluence of sympathetic fibers along the aorta that are responsible for ejaculation, with a 60% to 88% rate of preservation of ejdculation and no reports of recurrence for stage 1 disease. Patients with persistently increased concentrations of a-fetoprotein, ß-hCG, or both but without other clinical evidence of disease following orchiectomy usually have systemic disease. These patients should undergo three or four cycles of standard chemotherapy rather than surgery. Patients with stage 2 NSGCTs are treated initially with either RPLND or chemotherapy depending on the extent of the disease, serum tumor marker concentrations, and the presence or absence of tumor-related symptoms. Asymptomatic patients with solitary retroperitoneal lymph nodes less than 3 cm in diameter as assessed by CT imaging generally undergo retroperitoneal lymph node dissection, whereas bulky stage 2 disease (more than 5 cm) undergo initial chemotherapy. Recurrences within the retroperitoneum are rare after a properly performed operation. Adjuvant chemotherapy is an important consideration when any lymph node is more than 2 cm in diameter, at least six nodes are involved, or there is extranodal invasion. The majority of patients in this group who relapsed did not receive adjuvant chemotherapy. Although the rate of cure is the same when chemotherapy is withheld until relapse, patients who received adjuvant therapy require fewer cycles of chemotherapy and avoid additional surgery. Initial chemotherapy is required in approximately one third of patients with germ cell tumors. Because relapse is frequent in patients with clinical stage 2c disease or in patients with primary retroperitoneal or mediastinal seminomas who receive radiation alone, these patients are treated initially with chemotherapy. Patients also receive initial chemotherapy if they have stage 3 NSGCTs or multifocal retroperitoneal lymph node involvement, lymph nodes more than 2 cm in diameter, or tumor-related back pain.

Postchemotherapy RPLND is usually reserved for residual masses (more than 3 cm) in patients after treatment for seminoma. In NSGCT, the need for postchemotherapy RPLND is controversial. Some groups advocate surgery in all patients with initial bulky retroperitoneal disease, whereas others advocate observation rather than surgery in patients with greater than 90% shrinkage of retroperitoneal nodes, with no residual nodes greater than 1.5 cm, and with no teratomatous elements in the primary tumor. There is no debate, however, concerning the need for removal of any significant postchemotherapy residual mass. The first combination chemotherapy regimens containing cisplatin (Platinol), vinblastine (Velban), and bleomycin (Blenoxane) resulted in complete remission in 70% to 80% of patients with metastatic germ cell tumors. Subsequent studies show that prolonged maintenance chemotherapy was unnecessary, and vinblastine was replaced by etoposide (Vepesid), which is less toxic and probably more efficacious. Serious adverse effects of combination chemotherapy include neuromuscular toxic affects, death from myelosuppression for bleomycin-induced pulmonary fibrosis, and Raynaud's phenomenon. Leydig cell tumors make up between 1% and 3% of all testicular tumors. Although the majority of cases are recognized in men between 20 and 60 years of age, approximately a fourth are reported before puberty. The prognosis for Leydig cell tumors following radical inguinal orchiectomy is good because of their generally benign nature. Gonadoblastoma is a rare tumor occurring almost exclusively in patients with some form of gonadal dysgenesis. Gonadoblastomas constitute approximately 0.5% of all testicular neoplasms and occur in all age groups from infancy to beyond 70 years, although the majority occur in individuals younger than 30 years. Radical orchiectomy is the first step in therapy. The high incidence of bilaterality (50%) mandates a contralateral gonadectomy when gonadal dysgenesis is present. The prognosis is excellent for patients with gonadoblastoma. The most common secondary neoplasm of the testis and the most frequent of all testicular tumors in patients older than 50 years is lymphoma. The median age is approximately 60 years of age. As with lymphomas elsewhere, patients with poorly differentiated lymphocytic types tend to survive longer than those with the histocytic type. Survival is poor with bilateral disease and among patients presenting with lymphoma at other sites who later experience a testicular tumor relapse. However, among those patients with disease apparently confined to the testis, survival appears to be good.



REFERENCES Carver and Sheinfeld, 2005. Carver BS, Sheinfeld J: Germ cell tumors of the testis. Ann Surg Oncol 2005; 12:871. Cohen and McGovern, 2005. Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005; 353:2477. Cooperberg et al., 2005. Cooperberg MR, Moul JW, Carroll PR: The changing face of prostate cancer. J Clin Oncol 2005; 23:8146. Jemal et al., 2005. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 2005; 55:10. Stein et al., 2001. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001; 19:666.



Chapter 181 – Management of Urethral Stricture Disease[*]

Method of: Andrew C. Peterson, MD Urethral strictures are defined as an area of narrowing in the urethra, usually occurring from scar tissue formation. The strictures may occur anywhere in the urethra from the bladder to the meatus of the penis. They are well documented in ancient literature dating from the Greek and Egyptian period. Urethral stricture disease is relatively common today, mostly acquired from injury or infection. Recently, iatrogenic causes, including urologic instrumentation and placement of indwelling catheters, that cause strictures anywhere in the urethra are the most common cause. The urethra is commonly described as having two sections: the posterior urethra (starting at the bladder neck, including the prostatic urethra and membranous urethra) and the anterior urethra (starting at the bulbar urethra, including the pendulous urethra and the fossa navicularis and meatus). Posterior urethral strictures are commonly caused by trauma with pelvic fractures and concomitant urethral injuries. Anterior urethral injuries commonly result from direct, blunt penile or perineal trauma, instrumentation, catheterization, and infections. * The views expressed in this article are those of the author and do not reflect the official policy or position of the United States Army, Department of Defense, or the U.S. government.

Diagnosis and Preoperative Evaluation Obstructive voiding symptoms are the most common complaints causing patients to seek medical attention, including decreased force of stream, hesitancy, urgency, nocturia, and sometimes acute urinary retention. Urinary tract infections, urethral bleeding, and, rarely, urethrocutaneous fistula and periurethral abscess may develop. Young men diagnosed with recurrent epididymitis and so-called prostatitis should be completely evaluated for urethral strictures because this is often a missed diagnosis in these cases.

CURRENT DIAGNOSIS Young men with recurrent so-called prostatitis and epididymitis should be considered for workup of urethral stricture disease. Obstructive voiding symptoms are the most common complaints causing patients to seek medical attention for urethral stricture disease. The retrograde urethrogram is the key diagnostic study for evaluation of urethral stricture disease. Retrograde urethrography (RUG) is the study of choice for diagnosis. An antegrade voiding study through a previously placed suprapubic tube combined with a RUG often helps define the length and complexity of the

stricture. Penile ultrasound may also help define the extent of spongiofibrosis and aid in planning for a surgical reconstruction. Cystourethroscopy allows for identification of the true caliber of a urethral stricture, and a small flexible ureteroscope may be used to determine the length of the stricture and the quality of the proximal urethra. It may be important to examine the bladder through a suprapubic tract as well for concomitant injury and bladder calculi. Magnetic resonance imaging (MRI) studies can be invaluable in some cases of posterior urethral strictures after pelvic fracture. This is an important study to define the post-traumatic anatomy, allowing the surgeon to plan the reconstructive approach. MRI should always be used in conjunction with RUG and cystogram and not as a sole technique for evaluation. Management After the final diagnosis and staging of the urethral stricture are completed, the choice of treatment depends heavily on location, etiology, and length. Treatment options for urethral strictures continue to include simple dilation, incision of the urethral stricture using endoscopes (urethrotomy), the UroLume stent, and a wide spectrum of reconstructive surgical techniques that include possible use of skin flaps, skin grafts, and more complex reconstructive techniques. Although no single procedure is appropriate for all strictures, dilation and urethrotomy continue to be most commonly employed. However, these interventions have high recurrence rates, and many patients eventually progress to surgical repair.

CURRENT THERAPY Office/clinic dilation of urethral stricture continues to be the most common initial treatment and is often the first treatment attempted. Both dilation and internal urethrotomy have equivalent long-term outcomes for the treatment of short urethral strictures. Surgical options for urethral stricture disease are based primarily on the location and length of the stricture. In treatment of lichen sclerosis, all of the native surrounding genital skin is subject to this disease so the entire affected urethra must often be excised and replaced with extragenital tissue for reconstruction DILATION AND URETHROTOMY Office/clinic dilation of urethral stricture continues to be the most common initial treatment and is often the first treatment attempted. Techniques used in the office include filiforms and followers, serial dilators, and balloon dilation under endoscopic control. Afterward, patients can be taught self-calibration with a soft catheter for ongoing management. Few patients, however, accept this option in the long term. Visual internal urethrotomy is performed using local, spinal, or general anesthesia and is ideally aided by a

guidewire placed through the stricture under direct vision. The incision is made at either the 12 o'clock or at the 3 and 9 o'clock positions with a cold knife, laser, or cautery. Urethrotomy is especially suited for short strictures in the bulbar urethra and has high failure rates for long strictures associated with significant spongiofibrosis and those located in the pendulous urethra. Although both of these procedures may be curative, most often the patient requires retreatment. Both dilation and internal urethrotomy have equivalent long-term outcomes for the treatment of short urethral strictures. In those who ultimately require formal operative repair, there is not a higher failure rate if that patient first underwent a prior endoscopic treatment. Therefore, this practice of initial treatment of short urethral strictures with repeat dilations or internal urethrotomies may be reasonable. UROLUME STENTS The UroLume stent (American Medical Systems, Minnetonka, MN) is a permanent, self-expanding metal stent that is FDA approved for the treatment of bulbar urethral strictures. Enthusiastically introduced in 1988, postplacement problems, including postvoid dribbling, perineal pain, erectile pain, and recurrent stricture, significantly limited the use of this device. It is helpful to manage recalcitrant anastomotic bladder neck contracture following radical prostatectomy and in the very elderly who may not be able to tolerate an open operative repair of a urethral stricture. SURGICAL INTERVENTION Surgical options for urethral stricture disease are based primarily on the location and length of the stricture. Tissue, including local grafts or flaps from the penis or scrotum and grafts from remote sources such as mouth, thigh, and preauricular areas, often are needed to reconstruct the urethra. Buccal graft harvested from the mouth currently has the most support. Management of Strictures in the Pendulous Urethra Optimal management of strictures of the pendulous urethra consists of onlay flap repairs using penile skin as described by Orandi, Quartey, McAninch, Turner-Warwick, and Mundy. Strictures from lichen sclerosis, however, require significantly different treatment (see later). The stricture is opened on the ventral side of the penis and the incision carried into healthy urethra on either side. It is then patched with an island of skin carried on a vascular pedicle. Although the ideal skin consists of hairless penile skin, island flaps can be made in the longitudinal or a transverse orientation and may reach up to 15 cm in length and 2 cm in width. Even circumcised men invariably have ample penile skin for these flaps. Bulbar Strictures Historically, flap-based repairs and tubularized single-staged graft urethroplasties were often performed for these strictures. However, these had a failure rate up to 56%, and currently the interest has shifted to excision of tight segments of the stricture and use of grafts (ideally buccal) to augment the anastomosis or to address the stricture in its entirety. For strictures less than 2 cm long, stricture excision and primary reanastomosis remains the ideal procedure with excellent reported long-term results exceeding 90% success rates ( Figure 1 ). For strictures measuring

2 to 4 cm, the latest evolution is the excisional augmented anastomotic urethroplasty. In this procedure, the worst section of the stricture is excised and the repair is augmented with a buccal graft or other onlay ( Figure 2 ). Long strictures where segmental excision is not feasible are best managed with a dorsal onlay alone without excision ( Figure 3 ). Occasionally, very long and dense strictures require a staged repair. Depending on the clinical situation, the entire urethra may need to be excised, replacing with a flat grafted area of buccal mucosa tissue, split-thickness skin graft from the thigh or other areas such as preauricular skin, and rarely bladder or rectal mucosa. The graft is allowed to heal for 6 to 12 months after which the patient is brought back to the operating room for tubularization.

FIGURE 1 Retrograde urethrogram showing a short bulbar urethral stricture amenable to excision with primary anastomosis.

FIGURE 2 Retrograde urethrogram showing a longer, more complex, bulbar urethral stricture needing excision of the most significant area of stricture and onlay of the remaining stricture: the excisional, augmented anastomotic urethroplasty.

FIGURE 3 Retrograde urethrogram showing a very long and complex stricture needing repair with dorsal onlay.

Strictures from Lichen Sclerosis (Balanitis Xerotica Obliterans) Balanitis xerotica obliterans, first described in 1928, is a form of lichen sclerosis (LS) and occurs in up to 1 in 300 men. The cause is unclear, and changes from LS most commonly occur in the glans penis and prepuce, causing phimosis with more extensive disease affecting the urethra as far back as the midbulb ( Figure 4 ).

FIGURE 4 Retrograde urethrogram (A) showing a pan-pendulous urethral stricture from lichen sclerosis. These may be repaired with complex staged reconstruction. However, a simple perineal urethrostomy (B) may be appropriate for some patient populations.

Management includes medications and surgery. Topical steroids, such as clobetasol (Temovate),[1] 0.05% cream applied two to four times daily, may cause significant regression of the scarring process. Surgical therapy ranges from extended simple meatotomy for distal strictures to complex staged repairs for more extensive disease. Because all of the native surrounding genital skin is subject to progression of LS, the entire affected urethra must often be excised and replaced with extragenital tissue for reconstruction. These can be morbid procedures fraught with complications and high failure rates up to 71%. Placement of a perineal urethrostomy may provide a good alternative to complex staged repair ( Figure 4 ). 1 Not FDA approved for this indication.

Posterior Urethral Strictures Traumatic injury to the prostatomembranous urethra occurs in approximately 10% of pelvic fractures. This injury may range from urethral elongation without tearing of the urethra to complete transection. With any suspicion of urethral injury in a pelvic trauma patient, a RUG should be performed. If no extravasation is seen, a Foley catheter may be inserted and a cystogram or upper tract study performed as indicated. When a catheter cannot be placed into the bladder through the urethra because of a posterior urethral injury, bladder drainage should be managed acutely with a suprapubic (SP) catheter. Definitive treatment after 3 to

6 months of recovery allows resolution of hematoma and shortening of the defect. Acute surgical intervention is indicated only in the uncommon situations where there is an associated rectal, bladder, or bladder neck injury or when there is another indication for laparotomy. Immediate (primary) realignment is performed without the preceding indications using a variety of techniques. All involve the acute placement of a catheter across the urethral defect with magnetic guides, interlocking guides, or an open surgical procedure. Long-term restricturing occurs in 50% to 100% of patients, requiring additional future endoscopic procedures, intermittent catheterization, or reconstruction. Delayed (primary) management is an alternative in cases whose recovery allows for return to the operating room 5 to 10 days after injury. An SP tube is placed acutely and realignment accomplished endoscopically when the patient is stable. An antegrade placed flexible endoscope negotiates the bladder neck and emerges in the injured area. A second retrograde endoscope is placed through the urethra to allow for hematoma irrigation, visualization of the defect, and antegrade passage of a stenting catheter across the defect.Delayed (secondary) repair is delayed for 3 or more months following the injury; in the interim the patient is managed by SP catheter drainage. Most of these defects can be repaired with a one-stage perineal anastomotic urethroplasty. This remarkably versatile procedure manages long obliterative strictures well in more than 95% of cases. The progressive perineal anastomotic repair involves the mobilization of the urethra with transection at the point of obliteration. The bulbar urethra is then reconnected to the prostatomembranous urethra proximal to the obliteration. Depending on the length of the repair needed, one to four of the following well-described sequential steps are used to accomplish a tension free anastomosis: 1.

Circumferential mobilization of the distal urethra provides 2 to 3 cm of length sufficient for anastomosis in 8% of cases.

2.

Separation of the proximal corporal bodies shortens the distance by 1 to 2 cm and is sufficient for anastomosis in another 41% of cases.

3.

Inferior pubectomy with resection of a wedge of bone from the inferior surface of the pubis further shortens the defect by 1 to 2 cm, facilitating anastomosis in another 28% of cases.

4.

Rerouting the urethra around the lateral surface of a corporal body provides another 1 to 2 cm of length and is needed for the remaining 23% of cases.

Future Trends The current evolution is pointing toward development and acceptance of artificial tissue replacements, allografts, and xenografts for the urethra, obviating the need for graft harvesting. These include Apligraf, a bioengineered product composed of a bovine-collagen fibroblast-containing matrix integrated with a sheet of stratified human epithelium that is similar to human skin. Also, many are currently developing a promising off-the-shelf collagen matrix based on cultured human cadaveric bladder mucosa.



REFERENCES Attwater, 1943. Attwater HL: History of urethral stricture. BJU Int 1943; 15:39. Barbagli et al., 2001. Barbagli G, Palminteri E, Lazzeri M, et al: Long-term outcome of urethroplasty after failed urethrotomy versus primary repair. J Urol 2001; 165(6 Pt 1):1918-1919. Barbagli et al., 1996. Barbagli G, Selli C, Tosto A, Palminteri E: Dorsal free graft urethroplasty. J Urol 1996; 155(1):123-126. Depasquale et al., 2000. Depasquale I, Park AJ, Bracka A: The treatment of balanitis xerotica obliterans. BJU Int 2000; 86(4):459-465. El Kassaby et al., 2003. El Kassaby AW, Retik AB, Yoo JJ, Atala A: Urethral stricture repair with an off-theshelf collagen matrix. J Urol 2003; 169(1):170-173. Flynn et al., 2003. Flynn BJ, Delvecchio FC, Webster GD: Perineal repair of pelvic fracture urethral distraction defects: Experience in 120 patients during the last 10 years. J Urol 2003; 170:1877-1880. Glass et al., 1978. Glass RE, Flynn JT, King JB, Blandy JP: Urethral injury and fractured pelvis. Br J Urol 1978; 50(7):578-582. Guralnick and Webster, 2001. Guralnick ML, Webster GD: The augmented anastomotic urethroplasty: Indications and outcome in 29 patients. J Urol 2001; 165(5):1496-1501. Iselin and Webster, 1999. Iselin CE, Webster GD: Dorsal onlay graft urethroplasty for repair of bulbar urethral stricture. J Urol 1999; 161(3):815-818. Kane et al., 2002. Kane CJ, Tarman GJ, Summerton DJ, et al: Multi-institutional experience with buccal mucosa onlay urethroplasty for bulbar urethral reconstruction. J Urol 2002; 167(3):1314-1317. McAninch, 1993. McAninch JW: Reconstruction of extensive urethral strictures: circular fasciocutaneous penile flap. J Urol 1993; 149(3):488-491. Orandi, 1968. Orandi A: One-stage urethroplasty. Br J Urol 1968; 40(6):717-719. Quartey, 1985. Quartey JK: One-stage penile/preputial island flap urethroplasty for urethral stricture. J Urol 1985; 134(3):474-475. Santucci et al., 2002. Santucci RA, Mario LA, McAninch JW: Anastomotic urethroplasty for bulbar urethral stricture: Analysis of 168 patients. J Urol 2002; 167(4):1715-1719. Steenkamp et al., 1997. Steenkamp JW, Heyns CF, de Kock ML: Internal urethrotomy versus dilation as treatment for male urethral strictures: A prospective, randomized comparison. J Urol 1997; 157(1):98-101. Venn and Mundy, 1998. Venn SN, Mundy AR: Urethroplasty for balanitis xerotica obliterans. Br J Urol 1998; 81(5):735-737. Webster and Ramon, 1991. Webster GD, Ramon J: Repair of pelvic fracture posterior urethral defects using an elaborated perineal approach: Experience with 74 cases. J Urol 1991; 145(4):744-748.

Webster and Sihelnik, 1985. Webster GD, Sihelnik S: The management of strictures of the membranous urethra. J Urol 1985; 134(3):469-473.



Chapter 182 – Renal Calculi

Method of: Sujeet S. Acharya, MD Glenn S. Gerber, MD Nephrolithiasis is a common condition affecting 5% to 10% of the U.S. population. Roughly 2 million patients a year present with kidney stones on an outpatient basis, an increase of 40% from 1994. Stone disease results in pain, loss of time at work, and medical costs in excess of $2 billion a year. Nephrolithiasis is more common in the industrialized world, but with changes in dietary habits, the incidence is increasing worldwide. Epidemiology Most kidney stones occur in patients between 20 and 50 years old, with peak onsets of disease between the third and fifth decades of life. Patients with recurrent stones often have their first case of nephrolithiasis in their teens or 20s. The recurrence rate of urinary calculi is roughly 50% within 5 years. In general, male patients are more commonly affected with kidney stones than female patients by a ratio of 2:1. Stones due to infection (struvite stones), however, are more common in women than in men. About 6% of men have onset of disease after age 50 years, compared with 25% in female patients. Stones caused by metabolic or hormonal defects and stone disease in children occur equally between the sexes. Kidney stones are more prevalent in whites, Latin Americans, and Asians than in African Americans and Native Americans. Geographic variation influences frequency as stones are more common in hot and dry areas. Pathophysiology Supersaturation of urine by constituents such as calcium oxalate and uric acid is necessary for stone formation. If the concentration of an ion reaches a level beyond which it is not soluble, it has reached the level of supersaturation. Crystals and foreign bodies in the bladder serve as nidi for ions from the supersaturated urine to form microscopic lattice structures. These then increase in size by crystal growth and aggregation. Three quarters of renal calculi contain calcium. The majority of the rest contain uric acid. Cystine, struvite, and other stones occur less often. Although geography, fluid intake, and diet influence the rate of calculi formation, metabolic derangements and heredity are the major causes of kidney stones. Hypercalciuria, whether absorptive, resorptive, or renal, is the most commonly noted metabolic abnormality. Absorptive hypercalciuria is the most common of the three forms of hypercalciuria. Severe (type 1) absorptive hypercalciuria has excess calcium in the urine independent of diet, whereas the calciuria of mild (type 2) absorptive hypercalciuria normalizes on a calcium-restricted diet. Renal hypercalciuria is caused by impaired renal tubular reabsorption of calcium. To

balance calcium losses from urine, parathyroid function increases and eventually causes further mobilization of calcium from bone and increased intestinal absorption. As a result, patients with renal hypercalciuria have normal serum calcium. Resorptive hypercalciuria results from primary hyperparathyroidism, causing both serum and urine calcium levels to be high ( Table 1 ).

TABLE 1 -- Hypercalciuric States Test Type 1 AH Type 2 AH RH

Resorptive

Serum Calcium

Normal

Normal

Normal

Elevated

Phosphorus

Normal

Normal

Normal

Low

PTH

Normal

Normal

Elevated Elevated

1,25(OH) 2D3

Normal

Normal

Elevated Elevated

Fasting urine

Normal

Normal

Elevated Elevated

24-h restricted[*]

Elevated

Normal

Elevated Elevated

Elevated

Elevated Elevated

Urinary Calcium

Post-Ca 2+ load [†] Elevated

Abbreviations: 1,25(OH)2D3 = vitamin D3; AH = absorptive hypercalciuria; PTH = parathyroid hormone; RH = renal hypercalciuria.

* Urine while patient is on a diet restricted in calcium (400 mg/day) and sodium (10 mEq/day). † Four-hour urine collection after an oral bolus of 1 g calcium.

Other causes of calcium stones include hyperuricosuria (dietary causes, overproduction), hyperoxaluria (enzyme defects, increased vitamin C, inflammatory bowel disease [IBD], bowel resection), gout, and decreased urine levels of the stone inhibitors citrate and magnesium. Urate stones result from hyperuricosuria (malignancy, myeloproliferative states, glycogen storage disease) and from the net alkali deficit and dehydration during chronic diarrhea states. Cystine stones result from an autosomal recessive disorder in cystine metabolism, leading to cystinuria. Struvite stones result from urinary tract infection with urea-splitting organisms such as Proteus and Klebsiella species. These cause the formation of magnesium-ammonium-phosphate crystals, which can rapidly coalesce to form stones. Diagnosis HISTORY AND PHYSICAL EXAMINATION Patients with urinary calculi present with pain, fever, dysuria, or hematuria. Stones passing into the ureter cause acute obstruction, with proximal urinary tract dilation and are associated with renal colic. Renal colic is

marked by cramping, severe flank pain, nausea, and vomiting. While the stone moves distally through the ureter, pain moves from the flank to the abdomen, then to the groin, and finally the scrotal or labial area. Staghorn calculi are kidney stones occupying the renal pelvis and the calyceal system. These stones are often asymptomatic, and when they do manifest it is usually with hematuria and infection rather than with acute onset of pain. Uncommonly, patients with asymptomatic bilateral obstruction present with renal failure.

CURRENT DIAGNOSIS Nephrolithiasis affects 5% to 10% of the U.S. population, male patients more than female patients. The majority of renal calculi contain calcium. Patients usually have pain, nausea, vomiting, fever, dysuria, or hematuria. Physical findings include costovertebral angle and/or abdominal tenderness. Laboratory tests should include urinalysis, complete blood count, and chemistry profile. Recurrent stone formers should undergo metabolic evaluation including a 24-hour urine collection. This helps in classifying their nephrolithiasis and directs their long-term therapy. The standard means to evaluate for a suspected kidney stone is noncontrast computed tomography. During the history it is important to ask about the quality, location, and duration of pain. Prior history of urinary tract infections, urinary calculi, and their management should be noted as well. Other areas useful in stone management include past medical history (hyperparathyroidism), dietary habits, fluid consumption, medications, family history of calculi, loss of renal function, and history of solitary or transplanted kidney. On physical examination, significant costovertebral angle tenderness is quite common and often moves to the abdomen as the stone migrates. Patients rarely present with peritoneal signs, which is important in distinguishing renal colic from other sources of flank and abdominal pain. LABORATORY STUDIES The initial studies useful for stone patients include urinalysis (with or without culture), complete blood count (CBC), and a chemistry profile. Urinalysis evaluates the urine for hematuria and infection and can also assess for pH and crystals ( Table 2 ). An elevated white blood cell (WBC) count indicates renal or systemic infection. A decreased red blood cell (RBC) count and hemoglobin indicate a chronic disease state or significant ongoing hematuria.

TABLE 2 -- Crystal Shapes in Kidney Stones Stone Crystal

Shape under Microscope

Calcium oxalate dihydrate

Envelope or bipyramidal

Calcium oxalate monohydrate Dumbbell or hourglass

Stone Crystal

Shape under Microscope

Calcium phosphate apatite

Amorphous

Cystine

Hexagonal

Struvite

Coffin lid

Uric acid

Rhomboid Irregular plates or rosettes Amorphous

A chemistry profile including serum electrolytes, creatinine, calcium, phosphorus, uric acid, and PTH is necessary to assess a patient's renal and metabolic functions. Acidosis and elevations in serum calcium or urate can help reveal the etiology of the stone(s). The same can be said for alterations in PTH or phosphorus. Finally, an acute significant rise in creatinine from baseline can indicate urgent or emergent surgical intervention to relieve obstruction. This is especially true in patients with a solitary kidney or baseline renal dysfunction. Patients who are recurrent stone formers and high-risk first-time stone formers (patients younger than 30 years and those with renal failure, struvite stones, multiple stones, intestinal disease, or solitary or transplanted kidney) warrant a more extensive laboratory evaluation, including a 24-hour urine collection. The 24-hour urine collection measures calcium, uric acid, creatinine, sodium, oxalate, citrate, pH, and volume. Elevation of the 24-hour excretion rate of calcium, oxalate, or uric acid indicates predisposition to stone formation. Other tests include the 24-hour urine collection after 1 week of a diet restricted in calcium, sodium, and oxalate; the fasting urine study; and the calcium load study ( Table 3 ).

TABLE 3 -- Classification of Nephrolithiasis Category

General Features

Urine Study Findings

Normal serum calcium

Hypercalciuria: Urine calcium > 200 mg/24 h

Normal serum phosphorus

Type 1: Hypercalciuria independent of diet

Hypercalciuria Absorptive hypercalciuria

Type 2: Normocalciuria with low-calcium diet Renal hypercalciuria Normal serum calcium

Hypercalciuria independent of diet

Normal serum phosphorus Increased PTH and Vitamin D (2° hyperparathyroidism) Resorptive hypercalciuria

Hypercalcemia

Hypercalciuria independent of diet

Category

General Features

Urine Study Findings

Hypophosphatemia Increased PTH and Vitamin D (1° hyperparathyroidism) Other Causes Cystinuria

Urine cystine > 250 mg/d

Gouty diathesis

Calcium, uric acid, or mixed stones

Persistently acidic urine (pH 45 mg/d

Dehydration and low urine citrate due to Oxalate >80 mg/d: primary or enteric acidosis contribute Oxalate 45-80 mg/d: dietary causes Hyperuricosuria

Normal serum calcium

Urine uric acid >600 mg/24 h Normal urinary calcium and oxalate Normal fasting and calcium load responses Calcium stones with urine pH >5.5

Hypocitraturia

Associated with distal RTA

Urine citrate 7.0 or risk calcium phosphate stones

Hyperoxaluria Calcium citrate

150 mg PO qd

Binds oxalate in gut, preventing absorption Raises urinary pH and urine citrate levels Add thiazide if hypercalciuria develops

Hypocitraturia Potassium citrate

30-90 mEq/d divided Same therapy whether hypocitraturia is due to distal tid-qid with food RTA or chronic diarrhea or is idiopathic Large doses (120 mEq/d[3]) may be needed for severe acidosis

Cystinuria High fluid intake

Try to reduce urine cystine to 6.5-7.0 tid-qid with food

D-Penicillamine (Cuprimine)

125 mg PO qod

Increases cystine solubility Associated with the nephrotic syndrome, dermatitis, and pancytopenia

Infection Stones Various antibiotics Acetohydroxamic acid (Lithostat)

Control infection 250 mg PO tid

Works by inhibiting urease of struvite stone-forming organisms

Abbreviations: AH = absorptive hypercalciuria; HCTZ = hydrochlorothiazide; RTA = renal tubular acidosis.

1 Not FDA approved for this indication. 3 Exceeds dosage recommended by the manufacturer.


SURGICAL CARE The indications for surgery are pain, infection, and obstruction. Contraindications to definitive stone manipulation include uncorrected bleeding diathesis and pregnancy (relative contraindication). Treatment for most renal calculi is noninvasive (e.g., lithotripsy); open surgical excision is limited to isolated atypical cases.

In an obstructed and infected collecting system secondary to a stone, emergent relief of obstruction is necessary by ureteral stent or percutaneous nephrostomy placement. Nearly 85% of kidney stones requiring intervention are treated with extracorporeal shock-wave lithotripsy (ESWL). Shocks are generated via an electrohydraulic, electromagnetic, or piezoelectric source and are focused on the calculus. As the stone is hit by the shockwave, it breaks into smaller fragments that can pass in the urine. ESWL is less successful if the stone is larger than 1.5 cm or is in the lower pole of the kidney. In these cases, fragmentation does take place, but due to either the large volume of fragments or their location, the fragments do not pass completely. Cystine stones do not fragment well with ESWL. Do not perform ESWL in pregnant patients or if there is ureteral obstruction distal to the stone. Ureteroscopic management is the second most common management option. Either a flexible or rigid endoscope is passed into the bladder and up the ureter to visualize the stone. The stone is either extracted with a grasper or basket device or is fragmented via laser, ultrasonic, or electrohydraulic lithotripsy. Commonly, a ureteral stent is placed at the end of the procedure to prevent obstruction secondary to ureteral spasm or edema. Percutaneous nephrostolithotomy (PCNL) affords fragmentation and removal of large stones from the kidney and ureter, particularly after failed ESWL. Percutaneous access to the kidney is achieved, and a sheath with a 1-cm lumen allows use of larger and more powerful lithotrites. Due to its morbidity, PCNL is generally reserved for large or complex stones that are refractory to management by ureteroscopy or ESWL. CONSULTATIONS Consultation with a urologist is recommended when stones are present in the settings of infection and obstruction. Referral is required when medical management fails, for stones refractory to outpatient management, and for stones that do not pass spontaneously.



Follow-up The postoperative course after minimally invasive stone removal usually consists of discomfort, which is best handled with oral pain medications. If pain continues or worsens, it is important to evaluate for complications such as infection, ureteral obstruction, and hemorrhage. Repeat urine cultures and imaging should be performed to assess for ureteral obstruction or perforation. Antibiotic choice is dictated by urine culture results. A follow-up examination with abdominal x-ray is often sufficient after uncomplicated stone removal. In patients with stones having unusual characteristics and after difficult or complicated procedures, imaging evaluating renal drainage (IVP, ultrasound, CT scan) may be important. In patients older than 40 years who have a single stone that passed either spontaneously or after intervention, follow-up for recurrent stones is generally not necessary. These patients have a low recurrence risk, especially if they maintain increased fluid intake. For patients at risk for recurrence, annual radiograph or ultrasound and 24-hour urine analyses are adequate.



REFERENCES Menon and Resnick, 2002. Menon M, Resnick MI: Urinary lithiasis: Etiology, diagnosis, and medical management. In: Walsh PC, Retik AB, Vaughan ED, et al ed. Campbell's Urology, 8th ed.. Philadelphia: WB Saunders; 2002:3229-3305. Preminger, 1995. Preminger GM: Medical management of urinary calculus disease. Part 1: Pathogenesis and evaluation. AUA Update Series, lesson 5 1995; 14:37-44. Preminger, 1995. Preminger GM: Medical management of urinary calculus disease. Part 2: Classification of metabolic disorders and selective medical management. AUA Update Series, lesson 5 1995; 14:45-52. Stoller and Bolton, 2000. Stoller MLS, Bolton DM: Urinary stone disease. In: Tanagho EA, McAninch JW, ed. Smith's General Urology, 15th ed.. New York: McGraw-Hill; 2000:291321.



SECTION 11 – The Sexually Transmitted Diseases

Chapter 183 – Chancroid

Method of: Stanley M. Spinola, MD Chancroid is caused by the gram-negative bacillus Haemophilus ducreyi. Chancroid is endemic in resourcepoor countries in Africa, Asia, South America, and the Caribbean and occurs in sporadic outbreaks in industrialized nations. The annual global prevalence of chancroid is estimated to be 6 million cases, but diagnostic tests for H. ducreyi are not routinely performed and its epidemiology is poorly defined. The maleto-female ratio ranges from 3:1 to 25:1. Lack of circumcision is associated with infection in men. Like other agents of genital ulcer disease (GUD), H. ducreyi facilitates both acquisition and transmission of HIV-1, and chancroid contributes substantially to the HIV-1 pandemic in Asia and sub-Saharan Africa. H. ducreyi has a short duration of infection, and chancroid can be perpetuated only by highly sexually active populations such as commercial sex workers (CSWs). Infected men usually report intercourse with CSWs. In the United States, chancroid is now rare; less than 100 cases were reported annually from 2000 to 2004. However, outbreaks occurred as recently as 1995 in New Orleans and Jackson, Mississippi. In these outbreaks, additional risk factors for infection included crack cocaine use, exchange of drugs for sex, or sex with a partner who used crack. Elimination of chancroid from CSWs controls outbreaks and reduces endemic disease.

CURRENT DIAGNOSIS Patients usually develop 1–4 soft painful ulcers with ragged edges on the foreskin or at the entrance of the vagina. Infected women may also have painless internal vaginal and cervical ulcers. Regional lymphadenitis occurs in 10%–50% of cases. Infected men have usually had contact with CSWs. Diagnosis is typically made by culture after exclusion of HSV and syphilis. Abbreviations: CSWs = commercial sex workers; HSV = herpes simplex virus. Diagnosis H. ducreyi enters the skin through breaks in the epithelium that occur during sex, and erythematous papules form at each entry site within hours to days. Papules evolve into pustules in 2 to 3 days. After several weeks, the pustules ulcerate, and patients usually develop one to four soft painful ulcers with ragged edges. The

ulcer may be covered by a yellow or gray purulent exudate and frequently bleeds when scraped. The most frequent sites of the ulcer are the foreskin and the entrance of the vagina. Internal vaginal and cervical ulcers may be painless and go unnoticed by infected women. Suppurative inguinal lymphadenopathy occurs in up to 50% of patients with ulcers. The classic presentation of chancroid occurs in a minority of patients, and chancroid cannot be reliably distinguished from syphilis or herpes on clinical grounds. Mixed infections with H. ducreyi, Treponema pallidum, and herpes simplex virus (HSV) are common, occurring in approximately 17% of proven chancroid cases. Mixed infection may account for the variable clinical presentations of chancroid and treatment failures. Confirmation of chancroid is difficult because culture is at best 80% sensitive. A highly sensitive multiplex polymerase chain reaction assay for GUD was developed but not marketed. Culture is the only reliable diagnostic test available for most settings. In practice, the diagnosis of chancroid is typically made by exclusion of HSV and syphilis. If patients with GUD and inguinal lymphadenitis or treatment failures for presumed primary syphilis appear in a community, public health authorities should be notified and diagnostic testing initiated. Treatment H. ducreyi is usually resistant to ampicillin, chloramphenicol (Chloromycetin), tetracyclines, trimethoprim (Proloprim), and sulfonamides and is susceptible to macrolides, quinolones, and third-generation cephalosporins. The Centers for Disease Control and Prevention (CDC) recommends single-dose azithromycin (Zithromax), 1 g orally, or ceftriaxone (Rocephin[1]), 250 mg intramuscularly (IM), ciprofloxacin (Cipro[1]), 500 mg orally twice a day for 3 days, or erythromycin base,[1] 500 mg orally three times a day for 7 days. Low-dose erythromycin (250 mg three times a day for 7 days) may be as effective as the standard 500 mg regimen. Single-dose oral ciprofloxacin, 500 mg, may be as effective as the single-dose azithromycin and multiple-dose ciprofloxacin regimens.

CURRENT THERAPY CDC recommends single-dose azithromycin (Zithromax), 1 g orally, or ceftriaxone (Rocephin[1]), 250 mg IM, ciprofloxacin (Cipro[1]), 500 mg PO bid for 3 days, or erythromycin base, [1] 500 mg PO tid for 7 d. Low dose erythromycin (250 mg tid for 7 d) may be as effective as the standard 500 mg regimen. Single-dose oral ciprofloxacin, 500 mg, may be as effective as single-dose azithromycin and multiple-dose ciprofloxacin regimens. Even if H. ducreyi is successfully treated, ulcers may persist if HSV or syphilis is present and not treated. Recommend HIV testing and syphilis serology at time of presentation and 3 mo later if initial tests are negative. Abbreviations: IM = intramuscularly; HSV = herpes simplex virus; PO = orally.

Within 1 week of treatment, there should be no purulence and the ulcers should be less tender. Most ulcers

heal in 2 weeks, but large ulcers may take 4 weeks to heal. Patients co-infected with HIV and H. ducreyi may have a greater number of ulcers that do not heal as quickly as patients infected with H. ducreyi alone. However, the antibiotic treatment efficacy of single-dose azithromycin or ciprofloxacin for chancroid in HIV seropositive and seronegative patients is similar. When evaluating the response to treatment, one must distinguish between bacteriologic and clinical cure. Even if H. ducreyi is successfully treated, ulcers may persist if HSV or syphilis is present and not treated. Fluctuant buboes may be treated by incision and drainage or needle aspiration; the former lessens the need for repeated procedures. All patients with chancroid should undergo testing for HIV at the time of presentation and 3 months later if the initial test is negative. All sexual contacts should be examined and treated even if GUD is not present. 1 Not FDA approved for this indication.



REFERENCES Ballard et al., 1996. Ballard RC, Ye H, Matta A, et al: Treatment of chancroid with azithromycin. Int J STD AIDS 1996; 7(Suppl 1):9-12. Bong et al., 2002. Bong CTH, Bauer ME, Spinola SM: Haemophilus ducreyi: Clinical features, epidemiology, and prospects for disease control. Microbes Infect 2002; 4:1141-1148. Ernst et al., 1995. Ernst A, Marvez-Valls E, Martin D: Incision and drainage versus aspiration of fluctuant buboes in the emergency department during an epidemic of chancroid. Sex Transm Dis 1995; 22(4):217220. Kimani et al., 1995. Kimani J, Bwayo JJ, Anzala AO, et al: Low dose erythromycin regimen for the treatment of chancroid. East Afr Med J 1995; 72:645-648. Lewis, 2000. Lewis DA: Diagnostic tests for chancroid. Sex Transm Infect 2000; 76:137-141. Malonza et al., 1999. Malonza IM, Tyndall MW, Ndinya-Achola JO, et al: A randomized, double-blind, placebo-controlled trial of single-dose ciprofloxacin versus erythromycin for the treatment of chancroid in Nairobi, Kenya. J Infect Dis 1999; 180:1886-1893. Martin et al., 1995. Martin DH, Sargent SJ, Wendel Jr GD, et al: Comparison of azithromycin and ceftriaxone for the treatment of chancroid. Clin Infect Dis 1995; 21:409-414. Moodley et al., 2003. Moodley P, Sturm PDJ, Vanmali T, et al: Association between HIV-1 infection, the etiology of genital ulcer disease, and response to syndromic management. Sex Transm Dis 2003; 30:241245. Trees and Morse, 1995. Trees DL, Morse SA: Chancroid and Haemophilus ducreyi: An update. Clin Microbiol Rev 1995; 8:357-375. Tyndall et al., 1994. Tyndall MW, Agoki E, Plummer FA, et al: Single dose azithromycin for the treatment of chancroid: A randomized comparison with erythromycin. Sex Transm Dis 1994; 21:231-234.



Chapter 184 – Gonorrhea

Method of: David M. Bamberger, MD Gonorrhea is a common sexually transmitted disease of epithelial tissue that usually causes urethral infection in men and cervical infections in women. Conjunctival infections, proctitis, and pharyngeal infections are also observed. Neisseria gonorrhoeae is a gram-negative, aerobic, piliated but nonmotile coccus that grows in pairs with adjacent, flattened sides. Epidemiology In 2005, 339,353 cases of gonorrhea were reported in the United States. The rate of 115.6 per 100,000 people reflects a large decrease in incidence from 1976 to 1996 but only a small decrease from 1996 to 2005. Infection rates are much higher in the southeastern states. Rates among women and men are almost equal. The highest rates are observed among women 15 to 19 years of age and men 20 to 24 years of age. Rates among blacks are higher than in whites, Hispanics, Asian/Pacific Islanders, or American Indians/Alaskan natives. Although rates are highest among blacks and those living in the South, the rates have been declining over the past 5 years in these populations and have been increasing among whites and those living in the West. Rates in developing countries are estimated to be substantially higher than in the United States. An estimated 60 million cases of gonorrhea occur worldwide every year. Cases reported to state and local health departments are under-reported. On the basis of a populationbased study performed in 2001-2002 in adults 18 to 26 years of age, the prevalence of gonococcal infections was 0.43%. This rate was approximately 10-fold less than for chlamydial infections, the other common cause of urethritis and cervicitis. The population-based study confirmed the substantially higher rate among blacks than whites and a lower rate in the West compared to the South. Most men and women with gonococcal infections in the survey were asymptomatic. Rates of gonococcal infection are also high among men who have sex with men, lower socioeconomic and educational attainment, users of illicit drugs, and commercial sex workers. Among men having sex with men, the rate of infection increased between 1999 and 2003, particularly from western U.S. cities. Acquisition of infection is more related to differences in sex partner networks, societal factors, and access to health care than the number of sexual partners. Transmission usually occurs among those with no or minimal symptoms. The risk of transmission from a single sexual encounter from an infected woman to her male partner is approximately 20% and is approximately 50% from an infected man to his female partner. The U.S. Preventive Services Task Force recommends that clinicians screen all sexually active women under the age of 25, including those who are pregnant, for gonorrhea infection if they have a history of sexually transmitted infections, new or multiple sex partners, inconsistent condom use, sex work, or drug use. Clinical Manifestations

In men, the usual incubation is 2 to 5 days, followed by a urethral discharge that is typically purulent, as opposed to the clear or whitish discharge of chlamydial urethritis. Extragenital infections, such as proctitis or pharyngitis, are more likely to be asymptomatic. Symptoms of proctitis may include tenesmus, rectal discharge, and pain. Acute epididymitis is the most common complication of urethral infection. In women, the usual symptoms are vaginal discharge or pruritus and dysuria. Pelvic pain is often because of ascending infection. On cervical exam, a mucopurulent discharge is often observed. Vaginal involvement, including periurethral (Skene's) glands and involvement of the Bartholin ducts, is more common in postmenopausal women and prepubertal girls. Rectal involvement is often asymptomatic and caused by contamination with cervicovaginal secretions. Pelvic inflammatory disease (PID) (see the appropriate article) is estimated to occur in 10% to 20% of women with cervical infections. Perihepatitis (Fitz-Hugh-Curtis syndrome) is caused by involvement of the liver capsule. Pharyngeal involvement in both men and women may be a source of transmission and is usually asymptomatic. Autoinoculation of the eye is the usual cause of adult gonococcal conjunctivitis. Bacteremic dissemination is estimated to occur in 0.5% to 3% of patients, but these estimates may be high because of declining prevalence in strains associated with dissemination (serotype IA, auxotype AHU, failure to express outer membrane protein II). It occurs more often in women or in men who have sex with men; in women it is associated with menstruation or pregnancy, and it may be associated with deficiencies in the terminal components of complement. During the initial phase of illness, patients usually develop fever and polytenosynovitis of the knees, elbows, wrists, and joints of the hands and feet. Discrete papulopustular skin lesions on an erythematous base occur. As the illness continues, septic arthritis manifests in one or two joints, typically the knees, elbows, ankles, or wrists. Microbiology and Diagnosis In men with symptomatic purulent urethritis, a Gram stain of the purulent discharge revealing intracellular gram-negative diplococci is both sensitive and specific. The use of a Gram stain in the diagnosis of cervical infection has lower sensitivity and specificity. Cultures of urethral specimens from men and cervical specimens from women should be plated directly onto media to improve yield and transported promptly to the microbiology laboratory. A special medium such as Thayer-Martin, which inhibits the growth of contaminating organisms, is used for nonsterile sites such as the urethra, cervix, rectum, or pharynx. Plates are incubated at 35°C to 36°C (95°F to 97°F) in 3% to 5% carbon dioxide (CO 2). Nonculture methods are increasingly replacing cultures in the diagnosis of gonococcal infections. Three commercially available nucleic acid amplification tests are currently marketed: the polymerase chain reaction (PCR) assay (Amplicor, Roche), a transcription mediated amplification assay (Aptima, Gen-Probe), and the DNA strand displacement assay (Probe-Tec, Becton Dickinson). These assays are highly sensitive and specific in testing male urethral, female cervical, and male urine specimens. An important advantage of the assays is their utility in testing urine specimens from both men and women and self-collected vaginal specimens from women. The PCR assay was only 55% to 65% sensitive when testing urine samples from women. The strand displacement and transcription mediated amplification assay are moderately more sensitive in testing female urine specimens but sensitivity remains less than 95%. Although most of the current nonculture assays have a specificity of approximately 99%, there is a suboptimal positive predication if testing a population with very low prevalence. Cultures are still considered the gold standard test in forensic settings and offer the advantage of preserving the specimen for antimicrobial testing, which has

become increasingly important in an era of increasing antimicrobial resistance. Cultures remain the only approved diagnostic testing methodology for pharyngeal and rectal specimens.

CURRENT DIAGNOSIS Urethral discharge in men and vaginal discharge and dysuria in women are the common symptoms of gonococcal infections, but many women and some men have asymptomatic or minimally symptomatic infections. Urethral Gram stain is an inexpensive sensitive and specific test in men but not women. Newer generation nucleic acid amplification tests are highly sensitive and specific in cervical specimens in women and in urethral and urine specimens in men, but some lack sensitivity in urine specimens from women. Nucleic acid amplification tests should not be used in testing specimens from pharyngeal or rectal sources. Treatment Treatment for gonococcal infections is best provided at the time of initial presentation with a regimen that is highly effective with single-dose therapy. Adherence with therapy wanes with prolonged outpatient treatment courses. Antimicrobial resistance rates are increasing, and susceptibility testing results are generally not available at the time treatment is provided. In the U.S. Gonococcal Isolate Surveillance Project (GISP) report in 2005, 19.6% of isolates were resistant to penicillin, tetracycline, or both, and 10.5% of isolates demonstrated resistance to ciprofloxacin (Cipro). Chlamydial infection is detected in approximately 20% of men and 42% of women with laboratory-documented gonococcal infections, necessitating the need for cotreatment of Chlamydia trachomatis (see Obstetrics and Gynecology section) in patients with gonococcal infections, unless a nucleic acid amplification test is negative for the presence of chlamydia at the time of treatment. Patients with gonococcal infections should also be screened and counseled regarding other sexually transmitted diseases, including HIV and syphilis, and offered hepatitis B vaccination. An ideal treatment regimen for gonococcal infections of the urethra, cervix, or rectum is inexpensive, welltolerated, and a single dose. Ceftriaxone (Rocephin), 125 mg given intramuscularly (IM) as a single dose, is highly efficacious for urogenital and rectal infections. It may be reconstituted in 1% lidocaine (Xylocaine) to reduce injection site pain. The 2007 Update to the 2006 STD Treatment Guidelines from the Centers for Disease Control and Prevention (CDC) includes only cefixime (Suprax) at 400 mg as a recommended oral regimen. Manufacture of cefixime (Suprax) as an oral tablet ceased in 2002 but may be reintroduced. An oral suspension (100 mg/5 mL) is marketed. Since 2002 quinolone resistance has increased. Several countries in Southeast Asia have rates of fluoroquinolone resistance that exceed 50%. Within the United States, data from the GISP in 2005 indicated a rate of greater than 5% resistance in most Western U.S. cities, and in Atlanta, Philadelphia, New Orleans, and Miami. Outside of the GISP, high rates of fluoroquinolone resistance are also reported in Massachusetts, Michigan, New York, and New Hampshire. The rate of fluoroquinolone resistance in men who have sex with men is 29% compared with 3.8% in heterosexuals. Because of the higher rates of fluoroquinolone resistance, the CDC no longer recommends use of fluoroquinolones for the treatment of gonococcal infections and associated conditions, such as pelvic inflammatory disease. Consequently, only cephalosporins are recommended and available.

CURRENT THERAPY Uncomplicated urethritis, cervicitis, or rectal infections should be treated with a single dose of: Ceftriaxone (Rocephin), 125 mg IM or Cefixime (Suprax), 400 mg PO Alternative therapies include: Azithromycin (Zithromax), 2 g PO Cefpodoxime (Vantin), 200-400 mg PO Patients should be treated for concomitant chlamydial infection with Azithromycin (Zithromax), 1 g PO or Doxycycline (Vibramycin), 100 mg PO bid for 7 d Sexual partners of infected patients should be evaluated and treated for gonorrhea and chlamydia and evaluated and counseled for other sexually transmitted diseases. Oral cefpodoxime (Vantin) is an alternative to cefixime but is slightly less active in vitro. At a dose of 200 mg, the efficacy is 96.5% (95% confidence interval [CI], 94.8 to 98.9) and is approved for urethritis in males and females and rectal infections in females by the FDA, but not recommended by the CDC because the lower limit of the 95% CI was less than 95%. Use of a 400 mg oral dose is recommended by some state health departments as an alternative, but published efficacy data are limited. A 2 g single oral dose of azithromycin (Zithromax) is highly efficacious but associated with more gastrointestinal intolerance, and azithromycin resistance is increasing and occurs among 2.9% of isolates. Spectinomycin (Trobicin), given as a single 2 g IM dose, is another alternative to ceftriaxone (Rocephin) in patients with a history of allergy to cephalosporins or anaphylaxis to penicillin, but is not available in the United States as of May 2007. Pharyngeal infections are generally less responsive to treatment. Recommended treatment is 125 mg IM ceftriaxone (Rocephin). A 2-g dose of oral azithromycin (Zithromax) is an alternative in documented cases of cephalosporin allergy. Conjunctival infections in adults are treated with a single dose of 1 g IM ceftriaxone (Rocephin); ophthalmia neonatorum is treated with 25 to 50 mg/kg, not to exceed 125 mg, of intravenous (IV) or IM ceftriaxone. All neonates should receive ocular prophylaxis against gonococcal ophthalmia with 0.5% erythromycin (Ramycin), or 1% tetracycline. Sexual partners of infected patients should be evaluated and treated for gonorrhea and chlamydia and evaluated and counseled for other sexually transmitted diseases. Expedited partner therapy involves a strategy in which patients deliver treatment and counseling information with medication or a prescription to their partner. This strategy reduces recurrent infections. Operational issues regarding the patient–physician relationship with uncertain current legal status in some states are a barrier in the use of this strategy. Patients who have uncomplicated gonorrhea and are treated with any of the CDC-recommended regimens do not need to return for a confirmation of cure testing. Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility.

Disseminated gonococcal infection is treated with 1 g of ceftriaxone (Rocephin) daily, and once a response has occurred may be switched to oral therapy with cefixime (Suprax) or cefpodoxime (Vantin) at 400 mg orally twice daily to finish one week of therapy. Fluoroquinolones may be an alternative treatment option if antimicrobial susceptibility can be documented by culture. Gonococcal endocarditis is treated with 4 weeks of ceftriaxone (Rocephin), and meningitis with 10 to 14 days of ceftriaxone (Rocephin). Treatment of PID is described in the appropriate article.



REFERENCES Centers for Disease Control and Prevention, 2006. Centers for Disease Control and Prevention : Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep 2006; 55(No. RR-11):42-49. Centers for Disease Control and Prevention, 2007. Centers for Disease Control and Prevention : Update to CDC's Sexually Transmitted Diseases Treatment guidelines, 2006: Fluoroquinolones No Longer Recommended for Treatment of Gonococcal Infections, 2007. MMWR Wkly Rep 2007; 56:332-336. Centers for Disease Control and Prevention, January 2007. Centers for Disease Control and Prevention : Sexually transmitted disease surveillance 2003 Supplement: Gonococcal Isolate Surveillance Project (GISP) annual report—2005, Atlanta, Ga, U.S. Department of Health and Human Services, January 2007. Centers for Disease Control, 2004. Centers for Disease Control and Prevention: STD Surveillance 2004: Accessed December 2, 2004, at http://www.cdc.gov/std/stats/04pdf/NatProfileAll.pdf Cook et al., 2005. Cook RL, Hutchison SL, Ostergaard L, et al: Systematic review: Noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med 2005; 142:914-925. Golden et al., 2005. Golden MR, Wrightington WLH, Handsfield HH, et al: Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection. N Engl J Med 2005; 352:676-685. Miller et al., 2004. Miller WC, Ford CA, Morris M, et al: Prevalence of chlamydia and gonococcal infections among young adults in the United States. JAMA 2004; 291:2229-2236.



Chapter 185 – Nongonococcal Urethritis

Method of: John N. Krieger, MD Urethritis is defined as inflammation of the urethra and is commonly caused by urogenital infection. Urethritis is classified as either gonococcal, in patients whose inflammation is caused by Neisseria gonorrhoeae, or nongonococcal (NGU), in patients with inflammation that is not related to infection with N. gonorrhoeae. Clinical Presentation More than 4 million NGU cases are estimated to occur among men in the United States every year. Urethritis is characterized by symptoms of urethral discharge and dysuria, often accompanied by increased urinary frequency or pruritis. Signs of urethritis include urethral discharge that can occur spontaneously or after stripping of the urethra, erythema, and urethral tenderness. Although the clinical presentation varies, the incubation of NGU averages 7 to 14 days from exposure to an infected partner. Typically the onset is gradual, with mild dysuria and mucoid discharge. In some high-risk populations, up to 50% of infections are asymptomatic. Etiology NGU should be considered infectious until proven otherwise. Most infectious cases of urethritis are sexually transmitted. Chlamydia trachomatis remains the most important pathogen, accounting for 15% to 40% of NGU cases. The prevalence of C. trachomatis is lower in older patients and in referral populations. Other infectious causes of NGU include Mycoplasma genitalium, Trichomonas vaginalis, and herpes simplex virus. The etiologic roles are less well defined for other infectious agents including Ureaplasma urealytimum, enteric bacteria, anaerobes, and Candida species. Occasionally, patients with other urologic conditions (e.g., prostatitis, urethral stricture disease, or, rarely, bacterial urinary tract infection) present with symptoms of NGU. Other unusual causes of NGU include chemical, allergic, and autoimmune processes. Diagnosis It is important to document the presence of urethral inflammation. This may be done by finding mucoid or mucopurulent discharge on physical examination or by diagnostic testing. The Gram stain is the preferred rapid diagnostic test. Urethral inflammation may also be documented by a positive leukocyte esterase test on first-void urine or by finding pyuria on microscopic examination of the first-void urine sediment. Diagnostic testing for both N. gonorrhoeae and C. trachomatis organisms is strongly recommended. Specific

etiologic diagnosis may guide therapy and can improve compliance and partner notification. These infections are both reportable to state health departments. Patients at risk for N. gonorrhoeae and C. trachomatis should receive appropriate counseling and should receive testing for HIV and syphilis. Clinical evaluation and treatment of sex partners are critical for preventing complications and interrupting sexual transmission. Pathogens responsible for NGU are associated with cervicitis, pelvic inflammatory disease, and tubal infertility. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis because it provides high sensitivity and specificity. Gonococcal infection can be established by documenting the presence of white blood cells (WBCs) containing intracellular gram-negative diplococci. Presence of gram-negative rods should raise the suspicion for enteric bacteria.

CURRENT DIAGNOSIS Documenting urethral inflammation is critical for diagnosis of urethritis. One or more of the following techniques can provide documentation: Physical examination showing urethral discharge, either present spontaneously at the meatus or after stripping the urethra. This discharge may be either mucoid or purulent in character. Gram stain of urethral exudate showing five or more WBCs per oil immersion field (×1000). The Gram stain is the preferred rapid diagnostic test. Urine leukocyte esterase dip stick test positive on first-void urine First-void urine sediment microscopic examination demonstrating 10 or more WBCs per high-power field (×400). Abbreviation: WBC = white blood cell.

Confirmatory tests should be employed to identify a specific etiology. N. gonorrhoeae and C. trachomatis can be detected using culture, DNA hybridization tests on a urethral specimen, or nucleic acid amplification tests on a urethral or urine specimen. Because of their increased sensitivity, nucleic acid amplification tests are recommended for diagnosing chlamydial infection. For urine testing, 10 to 15 mL of first-void urine is collected then evaluated using nucleic acid amplification testing. Diagnostic tests for the genital mycoplasmas (M. genitalium, U. urealyticum, and other genital mycoplasmas) are available in research settings. Such tests are usually unavailable for routine clinical use. T. vaginalis may be cultured, but specific media are necessary for isolation. To increase sensitivity, cultures of both a urethral swab sample and a urine specimen are recommended. Treatment If gonorrhea cannot be ruled out by Gram stain of urethral secretions, potentially noncompliant patients should be treated for both gonorrhea and chlamydial infection. Both azithromycin (Zithromax) and

doxycycline (Vibramycin) are highly effective for treating chlamydial NGU. Azithromycin also provides convenient single dosing and the opportunity for directly observed therapy. Doxycycline is inexpensive but requires twice-daily dosing for a full week. Alternatives include erythromycin and fluoroquinolones regimens.

CURRENT THERAPY Recommended Regimens

Azithromycin (Zithromax) 1 g PO in a single dose Doxycycline (Vibramycin) 100 mg PO bid × 7 days Alternative Regimens

Erythromycin base (E-Mycin, ERYC, E-Base) 500 mg PO qid × 7 days Erythromycin ethylsuccinate (EES) 800 mg PO qid × 7 days Ofloxacin (Floxin) 300 mg PO bid × 7 days Levofloxacin (Levaquin)[1] 500 mg PO qd × 7 days If an erythromycin regimen is the only possibility and the patient cannot tolerate high-dose schedules, then one of the following regimens should be considered. Erythromycin base (E-Mycin, ERYC, E-Base) 250 mg PO qid × 14 days Erythromycin ethylsuccinate (EES) 400 mg PO qid × 14 days 1 Not FDA approved for this indication.

For patients with erratic health care–seeking behavior in whom poor compliance is anticipated, azithromycin offers the easiest administration. Further, M. genitalium appears to respond better to macrolides than to tetracyclines. Patients should be advised to abstain from sex until therapy is completed, symptoms have resolved, and sex partners have been treated. Follow-up Routine follow-up is not recommended for patients whose symptoms resolve after therapy. Patients with persistent or recurrent symptoms should return for reevaluation. Symptoms alone should not prompt a second course of therapy unless the patient has documented urethritis or a positive test for a urogenital pathogen. Patients should return for evaluation and treatment if their symptoms persist or recur after completion of therapy. Patients with NGU should refer all sex partners in the past 60 days for evaluation and treatment. Chronic Urethritis Chronic urethritis is defined as persistent or recurrent urethritis within 6 weeks following treatment. An

estimated 20% to 40% of NGU cases do not respond to first-line therapy. Although up to 20% of men with chlamydial NGU have chronic urethritis, up to 50% of men with nonchlamydial NGU have chronic urethritis. Noncompliance and reinfection are important considerations. Other causes include organisms that do not respond to the standard treatment regimens, such as T. vaginalis, tetracycline-resistant mycoplasmas, viral etiologies, and other bacteria. Up to 30% of NGU has no identifiable infectious etiology. These cases can involve allergy and postinfectious immunologic responses. Before administering therapy, presence of urethral inflammation should be documented. Patients with persistent or recurrent urethritis who did not comply with therapy or who had exposure to an untreated sex partner should be re-treated with the initial drug regimen. Otherwise, recommended treatment regimens include metronidazole (Flagyl),[1] 2 g orally in a single dose, plus either erythromycin base (E-Base), 500 mg orally four times a day for 7 days, or erythromycin ethylsuccinate (EES), 800 mg orally four times a day for 7 days. Complications For infected men, complications of untreated NGU include epididymitis in less than 3% of cases and, rarely, Reiter's syndrome. Patients with a history of NGU also appear to be at increased risk for developing chronic prostatitis/chronic pelvic pain syndrome. Female sex partners are at risk for pelvic inflammatory disease, tubal infertility, and ectopic pregnancy. Prompt and appropriate therapy and treatment of sexual partners decrease the risk of complications substantially.



REFERENCES Aydin et al., 2005. Aydin D, Kucukbasmaci O, Gonullu N, Aktas Z: Susceptibilities of Neisseria gonorrhoeae and Ureaplasma urealyticum isolates from male patients with urethritis to several antibiotics including telithromycin. Chemotherapy 2005; 51:89-92. Bradshaw et al., 2006. Bradshaw CS, Tabrizi SN, Read TR, et al: Etiologies of nongonococcal urethritis: Bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006; 193:336-345. Centers for Disease Control and Prevention, 2002. Centers for Disease Control and Prevention : Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections. MMWR Recomm Rep 2002; 51(RR-15):3-19. Centers for Disease Control and Prevention, 2002. Centers for Disease Control and Prevention : Sexually transmitted disease treatment guidelines 2002. MMWR Recomm Rep 2002; 51(RR-6):30-42. Deguchi et al., 2004. Deguchi T, Yoshida T, Miyazawa T, et al: Association of Ureaplasma urealyticum (biovar 2) with nongonococcal urethritis. Sex Transm Dis 2004; 31:192-195. Falk et al., 2004. Falk L, Fredlund H, Jensen JS: Symptomatic urethritis is more prevalent in men infected with Mycoplasma genitalium than with Chlamydia trachomatis. Sex Transm Infect 2004; 80:289-293. Geisler et al., 2005. Geisler WM, Yu S, Hook 3rd EW: Chlamydial and gonococcal infection in men without polymorphonuclear leukocytes on Gram stain: Implications for diagnostic approach and management. Sex Transm Dis 2005; 32:630-634. Jensen, 2004. Jensen JS: Mycoplasma genitalium: The aetiological agent of urethritis and other sexually transmitted diseases. J Eur Acad Dermatol Venereol 2004; 18:1-11. Kaydos-Daniels et al., 2004. Kaydos-Daniels SC, Miller WC, Hoffman I, et al: The use of specimens from various genitourinary sites in men, to detect Trichomonas vaginalis infection. J Infect Dis 2004; 189:19261931. Leung et al., 2006. Leung A, Eastick K, Haddon LE, et al: Mycoplasma genitalium is associated with symptomatic urethritis. Int J STD AIDS 2006; 17:285-288. O'Mahony, 2006. O'Mahony C: Adenoviral non-gonococcal urethritis. Int J STD AIDS 2006; 17:203-204. Ozgül et al., 2006. Ozgül A, Dede I, Taskaynatan MA, et al: Clinical presentations of chlamydial and nonchlamydial reactive arthritis. Rheumatol Int 2006; 26:879-885. Pontari et al., 2005. Pontari MA, McNaughton-Collins M, O'Leary P, et al: A case-control study of risk factors in men with chronic pelvic pain syndrome. BJU Int 2005; 96:559-565. Swygard et al., 2004. Swygard H, Sena AC, Hobbs MM, Cohen MS: Trichomoniasis: Clinical manifestations, diagnosis and management. Sex Transm Infect 2004; 80:91-95. Taylor, 2005. Taylor SN: Mycoplasma genitalium. Curr Infect Dis Rep 2005; 7:453-457.

Taylor-Robinson et al., 2004. Taylor-Robinson D, Gilroy CB, Thomas BJ, Hay PE: Mycoplasma genitalium in chronic non-gonococcal urethritis. Int J STD AIDS 2004; 15:21-25. Yasuda et al., 2005. Yasuda M, Maeda S, Deguchi T: In vitro activity of fluoroquinolones against Mycoplasma genitalium and their bacteriological efficacy for treatment of M. genitalium–positive nongonococcal urethritis in men. Clin Infect Dis 2005; 41:1357-1359.



Chapter 186 – Syphilis

Method of: Mrunal Shah, MD One of the oldest infections known, syphilis dates back more than 500 years. It was known as “The Great Pox” because of its skin manifestations; in contrast to the “small pox” seen around the same time. Studies were done before the use of antibiotics, which is where most of our natural history information comes from. The most recent epidemic occurred in 1990 (20.3 cases per 100,000 population) and has fallen steadily each year since. In the year 2000, the rate was at an all time low of 2.2 cases per 100,000 population. This was a 9.6% drop since 1999. The Centers for Disease Control and Prevention (CDC) hopes to eradicate the disease completely by 2005, but this may be difficult. Peak ages are 30 to 39 years of age in men and 20 to 24 years of age in women. African Americans have always had higher incidences than whites. In the 1990s, it was 60:1, but the incidence has since declined to 30:1. Microbiology Treponema pallidum is the bacterium responsible for causing syphilis. It is very small and cannot be detected by ordinary microscopy, a feature that complicates diagnosis. The organism can be seen with darkfield microscopy, a technique that uses a special condenser to cast an oblique light. This allows visualization of a corkscrew-shaped organism with tightly wound spirals. This organism is extremely sensitive to penicillin, as is discussed later in the article. It has a very slow doubling rate, therefore requiring longer courses of treatment. Pathophysiology T. pallidum initiates infection when it gains access to subcutaneous tissues through microabrasions that can occur during sexual intercourse. Even though it has a slow doubling time (30 hours), it escapes host immune defenses and leads to the initial ulcerative lesion, the chancre. These can be seen anywhere around the genitalia including the cervix, perianal and rectal areas, and the oral mucosa. Regional lymphadenopathy also can be seen. As the host immune system fights the initial infection, T. pallidum is disseminated throughout the host. This is known as latency, as the patient will have no symptoms. There is also vertical spread in utero or during delivery, which is why prenatal panels include screening tests for syphilis. Clinical Manifestations The initial clinical manifestation is also called primary syphilis. This usually consists of a painless chancre at the site of inoculation. Primary syphilis represents a local infection, but it quickly becomes systemic with widespread dissemination of the spirochete. Because it is painless, most people do not seek medical attention. Even without treatment, the chancre will resolve in 4 to 6 weeks. It is this painlessness that helps

separate it from herpes simplex virus (genital herpes) and Haemophilus ducreyi (chancroid). In approximately weeks to months after the resolution of the chancre, patients will develop secondary syphilis, which includes systemic symptoms of rash, fever, headache, malaise, anorexia, and diffuse lymphadenopathy. The rash typically involves the palms and soles but can also include mucosal surfaces. Many patients do not realize that they had these lesions. These symptoms usually resolve spontaneously but can relapse for up to 5 years. After symptoms resolve, and for up to many years later, the disease goes into latent syphilis, which is characterized by a lack of symptoms but seropositive test results. This can be separated into early and late latent phases based on being potentially infectious in the early phase. This is defined by the United States Public Health Service (USPHS) as infection of 1 year's duration or less. Anything longer is late latent. Finally, for the next 1 to 30 years, untreated patients have a 25% to 40% risk of developing late or tertiary syphilis. It may involve many tissue types, so the spectrum of disease can be very confusing. Moreover, patients need not have had symptoms of primary or secondary syphilis prior to developing late syphilis. Tissues involved include cutaneous (gumma formation), cardiovascular (aortic disease), and central nervous system (CNS) (tabes dorsalis, meningitis, neurosyphilis) diseases ( Table 1 ).

TABLE 1 -- Clinical Manifestations and Treatment of Syphilis Stage Clinical Manifestation

Treatment

Primary

Painless ulcer (chancre), adenopathy

Benzathine penicillin G (Bicillin LA), 2.4 million U IM × 1

Secondary (weeks to months)

Rash, mucocutaneous lesions, adenopathy, Benzathine penicillin G, 2.4 million hepatitis, arthritis, glomerulonephritis, condyloma lata U IM × 1

Latent

Asymptomatic

Early (35 y and those with a history of DVT, with cardiovascular disease, or with active liver disease. Progestin-only birth control methods (pills, injections, or the progestin-releasing IUD) represent appropriate contraceptive options for women who have medical problems contraindicating combination birth control methods. Women with menorrhagia or dysmenorrhea may benefit from extended-cycle oral contraceptive pills (Seasonique and Seasonale). Plan B, a progestin-only formulation, is the only oral formulation currently marketed for emergency contraception. Although package labeling indicates it should be taken within 72 hours, effective postcoital contraception is provided if Plan B is taken up to 5 d following unprotected intercourse. Copper and progestin-releasing IUDs offer users convenient birth control as effective as sterilization yet completely reversible. The copper IUD (ParaGard) may increase menstrual flow and thus may not be a good method for women with menorrhagia. Use of the progestin (levonorgestrel)-releasing IUD (Mirena) is associated with noncontraceptive benefits including reduction in heavy menstrual flow because of fibroids or adenomyosis and decreased pain in women with endometriosis. Surgical tubal sterilization is associated with a 10-y cumulative failure rate of 1.8%-3%. A device for occlusion of the fallopian tubes using hysteroscopy (Essure) was approved for use in the United States in 2002.

The failure rate associated with vasectomy is 0.94% at 1 y and 1.1% at 5 y, representing pregnancy rates higher than previously reported. Abbreviations: DVT = deep vein thrombosis; IUD = intrauterine device. Estrogen/Progestin Combination Oral Contraceptive Pills Oral contraceptive (OC) use is safe for the majority of users with many noncontraceptive benefits, such as decreasing the risk of endometrial cancer, ovarian cancer, ectopic pregnancy, and pelvic inflammatory disease and treating dysmenorrhea, menorrhagia, and acne. Although OCs represent a highly effective birth control method for correct consistent users, inconsistent or incorrect use accounts for the annual failure rate of 8% experienced overall by OC users. OCs are usually initiated on the first day of menses or the first Sunday after menses starts. In these cases, a backup method of contraception is not needed. It is helpful to associate pill taking with a daily routine such as tooth brushing to improve compliance. Conventional combination OC formulations include 21 active and 7 inactive tablets. The progestin component of the OCs suppresses the pituitary secretion of luteinizing hormone (LH), preventing ovulation. The estrogen component (ethinyl estradiol) suppresses secretion of follicle-stimulating hormone (FSH) and enhances cycle control (regular withdrawal bleeding with minimal unscheduled or so-called breakthrough bleeding). If 1 or 2 tablets are missed, the patient should take 1 tablet as soon as possible. Then 1 tablet should be taken twice a day until all the missed tablets are taken. Breast tenderness and nausea, common OC side effects, are related to the estrogen dose. Accordingly, if these side effects persist for more than several cycles, changing to a lower estrogen dose (e.g., switching from a 30- to 35-µg to a 20- to 25-µg) formulation may be useful. Breakthrough (unscheduled) bleeding and spotting occurs more often in women taking 20-µg estrogen OCs than in those taking 30- to 35-µg formulations. Box 1 lists medical contraindications to all estrogen-progestin contraceptives. BOX 1

Contraindications to Combination Hormonal Methods •

Smokers: =35 y

•

Hypertension: Uncontrolled or =35 y

•

Diabetes: Vascular disease or =35 y

•

Migraines: Focal neurologic symptoms or =35 y

•

Vascular disease: Associated with systemic lupus erythematosus

•

Personal history of breast cancer or thromboembolism

•

Coronary artery or cerebrovascular disease

•

Acute or chronic hepatocellular disease with abnormal liver function

•

Cholestatic jaundice with prior pregnancy or contraceptive use

Adapted from http://www.arhp.org/healthcareproviders/cme/onlinecme/wellwoman/TOC.cfm?ID=336 Combination Oral Contraceptives with Reduced Pill-Free Intervals and/or Extended Cycles OC formulations with reduced pill-free intervals appear to achieve superior cycle control (less unscheduled or breakthrough bleeding/spotting) despite use of very low doses of estrogen and may achieve higher contraceptive efficacy than conventional 21/7 OC formulations. Three 28-day OC formulations are formulated with 20 µg ethinyl estradiol and have fewer than 7 hormone-free days. One (Mircette), formulated with the progestin desogestrel, includes 2 days of inactive tablets and 5 ethinyl estradiol tablets in place of the 7 inactive tablets. Two recently approved formulations contain 24 active tablets followed by 4 days of inactive pills. One (Yaz) is formulated with the progestin drospirenone. Yaz has been approved by the FDA for the treatment of premenstrual dysphoric disorder. The other (Loestrin 24) is formulated with the progestin norethindrone acetate and has a shorter duration of withdrawal bleeding than other OCs. The first extended-cycle OC (Seasonale) to be marketed in the United States includes 84 (12 weeks) of active pills followed by 7 placebo pills, rather than the conventional 21 active tablets followed by 7 placebos. Each active pill contains 150 µg of levonorgestrel and 30 µg of ethinyl estradiol. Over time, this extended approach to OC leads to 4 rather than 13 withdrawal bleeding episodes each year. Women considering extended OC use should be counseled to expect an initially higher rate of breakthrough bleeding and spotting, which declines over time. Women with a history of menorrhagia or dysmenorrhea may be candidates for extended-cycle OC use. In the future, extended-cycle OC formulations with no hormone-free days may become available. A recently approved OC (Seasonique) is identical to Seasonale but substitutes 10 µg of estrogen in place of the 7 placebo tablets that follow the 12 weeks of active tablets in each pack. Breakthrough bleeding and spotting appear to occur less frequently with the use of seasonique than with Seasonale Progestin-Only Oral Contraceptives Also known as minipills, the progestin-only OC formulation (Micronor) contains even lower doses than combination OCs. The documented rates of failure for progestin-only pills are comparable to those of combination OCs in women who are meticulous about taking the pill at the same time every day. If one pill is

taken 3 or more hours late, backup contraception is needed for 48 hours. Most commonly in the United States, minipills are used by lactating women who intrinsically have low fecundability; in this subgroup of women, contraceptive failures with progestin-only OC use are not common. Emergency Contraception With the manufacturer no longer making a dedicated combination emergency contraception (EC) formulation (Preven) as of summer 2004, the only dedicated EC formulation currently available is the progestin-only formulation (Plan B), which consists of two levonorgestrel 750 µg tablets. Progestin-only EC is more effective and causes less nausea and emesis than combination EC. Package labeling for Plan B indicates that 1 tablet should be taken within 72 hours of unprotected intercourse, followed 12 hours later by a second tablet. Taking the 2 tablets together, however, may be as effective in preventing pregnancy as dividing the dose. Furthermore, Plan B may retain its efficacy in pregnancy prevention when taken up to 5 days after unprotected intercourse. EC is available over the counter at pharmacies for those 18 years of age and older and is also available by prescription for women of any age. Injectable Contraception PROGESTIN ONLY Depomedroxyprogesterone acetate (DMPA) (Depo-Provera) is an injectable contraceptive that provides long-acting reversible birth control, as effective as sterilization. The standard dose is 150 mg (1 mL) of DMPA intramuscularly every 3 months (or every 12 to 13 weeks). As with combination OC use, DMPA suppresses ovulation and ovarian estradiol production. In contrast with combination OC use, DMPA includes no estrogen component. Therefore, bone mineral density (BMD) declines during prolonged use of DMPA. In 2004, the FDA placed a black box in DMPA package labeling warning of the risk of significant loss of bone density during DMPA use. Fortunately, in adolescents as well as adult users, BMD rapidly recovers after discontinuation of DMPA, and no evidence indicates that DMPA use causes postmenopausal osteoporosis or fractures. The short-term impact that DMPA has on BMD appears analogous to that of lactation (which also lowers background estrogen levels). Lactation is not a risk factor for osteoporosis later in life. Skeletal health concerns should not restrict use of DMPA in adults or teens, nor should use of DMPA be considered by itself an indication for testing BMD. Although concerns regarding weight gain may discourage some women, small randomized clinical trial data found that DMPA did not cause weight gain or increased appetite in short-term users. A subcutaneous DMPA formulation that should facilitate self-administration became available in 2005 and is approved both for contraception and treatment of pain associated with endometriosis. Combination Patch Ortho Evra is a once-a-week transdermal contraceptive patch applied for 3 consecutive weeks, followed by a patch-free week during which withdrawal bleeding is anticipated. The patch can be applied to the lower abdomen, upper outer arm, buttock, or upper torso (except for the breast). The patch delivers a daily systemic dose of 150 µg of norelgestromin and 20 µg of ethinyl estradiol. In a randomized clinical trial, the contraceptive efficacy of the patch was comparable to that of oral contraception. If the patch is detached for

greater than 24 hours, the user should start a new patch cycle and use a backup contraceptive method (such as condoms) for 1 week. A recent randomized pharmacokinetic trial found that serum ethinyl estradiol exposure was lower in the users of the vaginal contraceptive ring compared to oral contraceptives and the transdermal patch. This led to the concern that the risk of venous thromboembolus may be higher in women using the transdermal patch. Findings of epidemiologic studies have conflicted regarding whether the risk of venous thromboembolism is higher with the contraceptive patch than with OCs. Combination Vaginal Ring NuvaRing is worn for 3 weeks, then removed for 1 week, during which withdrawal bleeding is anticipated. The ring is composed of a flexible ethylene vinyl acetate copolymer, which releases approximately 120 µg of etonogestrel and 15 µg of ethinyl estradiol per day. The ring is self-inserted and removed. In comparative clinical trials, rates of breakthrough bleeding and spotting were lower with the ring than with OCs. As with the patch, contraceptive efficacy of the ring is similar to that of combination OCs in clinical trials. Backup contraception is needed for 7 days if the ring remains outside of the vagina for more than 3 hours. Intrauterine Devices Intrauterine devices (IUDs) offer users convenient birth control as effective as sterilization yet completely reversible. In women in the United States, use of IUDs has declined from approximately 10% in the mid1970s to 1% today. Concerns among clinicians and women that IUDs cause salpingitis and tubal infertility account for much of this decline. A systematic review found that if any increased risk in salpingitis is associated with IUD use, it is small and appears confined to the first month postinsertion. Likewise, use of an IUD is not associated with a subsequent increased risk of tubal infertility. The copper IUD (ParaGard) is approved for up to 10 years of use. It is appropriate for women who prefer regular cycles. Because use of the copper IUD can increase flow and cramps, it is appropriate for women who have no excess menstrual flow or cramps at baseline. The Food and Drug Administration (FDA) approved liberalized safety labeling revisions for the copper IUD in 2005. The revised labeling states that although the IUD may now be used in women with a history of pelvic inflammatory disease (PID) or sexually transmitted disease, it is contraindicated in those with acute PID or current behavior suggesting a high risk thereof. The prior language discouraging use of the IUD in nulliparous women was likewise removed. The levonorgestrel-releasing IUD (Mirena) is approved for up to 5 years of use. It releases 20 µg of levonorgestrel a day. This progestin-releasing IUD reduces menstrual flow and is therefore appropriate for women who would like their birth control method to reduce flow. Women interested in using the levonorgestrel-releasing IUD should be aware, however, that initial irregular spotting or bleeding is common after insertion of this device. Hormonal side effects, including acne and ovarian cysts, also occur in some users. Box 2 details the important noncontraceptive benefits associated with use of the levonorgestrel IUD. BOX 2

Noncontraceptive Health Benefits of the Levonorgestrel-Releasing Intrauterine Device •

Reduces menorrhagia, including when caused by uterine fibroids or adenomyosis and as an alternative to endometrial ablation or hysterectomy

•

Relieves pain caused by endometriosis

•

Prevention of endometrial hyperplasia in menopausal women using estrogen therapy; also, treatment of endometrial hyperplasia/cancer

•

Prevention of endometrial proliferation and polyps in patients taking tamoxifen (Nolvadex)

Progestin-Releasing Implants Progestin-releasing contraceptive implants provide highly effective, convenient birth control. Although Norplant and Jadelle are approved by the FDA, neither is currently marketed in the United States. Norplant levonorgestrel consists of six capsules and provides contraception up to 5 years. The difficulty with insertion and, in particular, removal of the six capsules, along with frequent complaints of irregular bleeding among users, explains why U.S. clinicians, women, and the manufacturer lost interest in this contraceptive system, which initially was in great demand when introduced in 1991. Jadelle consists of an implant of two rods each containing 150 mg of levonorgestrel. A single-rod progestin (Etonogestrel) implant (Implanon) is easier and quicker to insert and remove than Norplant, and its use is associated with less bleeding. This highly effective single-rod implant system received FDA approval in 2006. Female Sterilization Tubal sterilization involves using rings (Falope), clips (Filshie or Hulka), electrocautery, or ligature/segmental excision (Pomeroy) to interrupt the patency of the fallopian tubes surgically. In the United States, approximately 700,000 tubal sterilizations are performed annually. Approximately half of them follow delivery, and half of these are performed as outpatient interval procedures. Sterilization is associated with a 10-year cumulative failure rate of 1.8% to 3%. The failure rate is higher in women younger than 28 years. Although sterilization can be reversed in some women and assisted reproductive technology can also be used to achieve pregnancy in many women following sterilization, this procedure should nonetheless be considered permanent. Hysteroscopic tubal occlusion (Essure) is a device developed and approved for use in the United States in 2002. This device (2 mm in diameter and 4 cm long) is made of titanium, stainless steel, and nickel, and it contains Dacron fibers that induce an inflammatory reaction and fibrosis in the tubal lumen. A hysterosalpingogram is recommended following placement of the Essure device to confirm bilateral tubal occlusion. Male Sterilization Vasectomy involves interruption of the vas deferens, preventing passage of sperm into seminal fluid. This

office-based surgical procedure does not interfere with male sexual performance. After vasectomy, couples should use backup contraception until the sperm count reaches zero. According to Jamieson, recent data indicate the failure rate following vasectomy is 9.4 per 1000 procedures at 1 year and 11.3 at 5 years, higher than the previously estimated failure rate.



REFERENCES Anderson et al., 2006. Anderson FD, Gibbons W, Portman D: Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception 2006; 73(3):229-234. Anderson and Hait, 2003. Anderson FD, Hait H: A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003; 68:89-96. Audet et al., 2001. Audet MC, Moreau M, Koltun WD, et al: Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs. an oral contraceptive: A randomized controlled trial. JAMA 2001; 285:2347-2354. Bjarnadottir et al., 2002. Bjarnadottir RI, Tuppurainen M, Killick SR: Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol 2002; 186:389-395. Cole et al., 2007. Cole JA, Norman H, Doherty M, Walker AM: Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007; 109(2 pt 1):339-346. Edelman et al., 2006. Edelman AB, Koontz SL, Nichols MD, Jensen JT: Continuous oral contraceptives: Are bleeding patterns dependent on the hormones given?. Obstet Gynecol 2006; 107(3):657-665. Hubacher et al., 2001. Hubacher D, Lara-Ricalde R, Taylor DJ, et al: Use of copper intrauterine devices and the risk of infertility among nulligravid women. N Engl J Med 2001; 345:561-567. Jain et al., 2004. Jain J, Jakimiuk AJ, Bode FR, et al: Contraceptive efficacy and safety of DMPA-SC. Contraception 2004; 70:269-275. Jamieson et al., 2004. Jamieson DJ, Costello C, Trussell J, et al: US Collaborative Review of Sterilization Working Group: The risk of pregnancy after vasectomy. Obstet Gynecol 2004; 103:848-850. Jensen, 2007. Jensen JT: Don't forget the other benefits of the levonorgestrel IUS. Contemp OB/GYN 2007; 50:46-50. Jick et al., 2006. Jick SS, Kaye JA, Russmann S, Jick H: Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 micrograms of ethinyl estradiol. Contraception 2006; 73(3):223-228. Jones et al., 2002. Jones RK, Darroch JE, Henshaw SK: Contraceptive use among U.S. women having abortions in 2000–2001. Perspect Sex Reprod Health 2002; 34:294-303. Kaunitz, 1997. Kaunitz AM: Revisiting progestin-only OCs. Contemp OB/GYN 1997; 42:91-108. Kaunitz, 2005. Kaunitz AM: Beyond the pill: New data and options in hormonal and intrauterine contraception. Am J Obstet Gynecol 2005; 192:998-1004. Kaunitz, 2005. Kaunitz AM: Depo-Provera's black box: Time to reconsider?. Contraception 2005; 72:165167.

Ubeda et al., 2004. Ubeda A, Labastida RM, Dexeus S: Essure: A new device for hysteroscopic tubal sterilization in an outpatient setting. Fertil Steril 2004; 82:196-199. Van den Heuvel et al., 2005. Van den Heuvel MW, Van Bragt AJ, Alnabawy AK, Kaptein MC: Comparison of ethinyl estradiol pharmacokinetics in three hormonal contraceptive formulations: The vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005; 72(3):168-174. Westhoff, 2003. Westhoff C: Depot-medroxyprogesterone acetate injection (Depo-Provera): A highly effective contraceptive option with proven long-term safety. Contraception 2003; 68(2):75-87. Westhoff, 2003. Westhoff C: Emergency contraception. N Engl J Med 2003; 349:1830-1835. Westhoff and Davis, 2000. Westhoff C, Davis A: Tubal sterilization: Focus on the U.S. experience. Fertil Steril 2000; 73:913-922. Yonkers et al., 2005. Yonkers KA, Brown C, Pearlstein TB, et al: Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005; 106(3):492-501.



SECTION 12 – Diseases of Allergy

Chapter 188 – Anaphylaxis and Serum Sickness

Method of: Stephen F. Kemp, MD Anaphylaxis Anaphylaxis, an acute and potentially lethal multisystem allergic reaction, is virtually unavoidable in medical practice. Health care professionals must be able to recognize the signs of anaphylaxis, treat an episode promptly and appropriately, and be able to provide preventive recommendations. Epinephrine, which should be administered immediately, is the drug of choice for acute anaphylaxis. Anaphylaxis is not a reportable disease, and both its morbidity and mortality are probably underestimated. A variety of statistics on the epidemiology of anaphylaxis have been published, but the lifetime risk per person in the U.S. is presumed to be 1% to 3%, with a mortality rate of 1%. There is no universally accepted definition of anaphylaxis. An international and interdisciplinary group of representatives and experts from thirteen professional, governmental, and lay organizations proposed the following working definition: “Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.” Clinically, anaphylaxis is considered likely to be present if any one of the following three criteria is satisfied within minutes to hours: Acute onset of illness with involvement of skin, mucosal surface, or both, and at least one of the following: respiratory compromise, hypotension, or end-organ dysfunction; two or more of the following occurring rapidly after exposure to a likely allergen: involvement of skin or mucosal surface, respiratory compromise, hypotension, or persistent gastrointestinal symptoms; hypotension develops after exposure to a known allergen for that patient: age-specific low blood pressure or decline of systolic blood pressure of greater than 30% compared with baseline. In clinical practice, however, waiting until the development of multiorgan symptoms is risky because the ultimate severity of anaphylactic reaction is difficult to predict from the outset. Anaphylaxis has varied clinical presentations, but respiratory compromise and cardiovascular collapse cause the most concern because they are the most frequent causes of fatalities. Urticaria and angioedema are the most common manifestations (more than 90% in retrospective series) but may be delayed or absent in rapidly progressive anaphylaxis. The previous severity of anaphylaxis is not predictive of the severity of a future reaction. The more rapidly anaphylaxis occurs after exposure to an offending stimulus, the more likely the reaction is to be severe and potentially life threatening. Anaphylaxis often produces signs and symptoms within 5 to 30 minutes, but reactions sometimes may not develop for several hours. PATHOPHYSIOLOGY

The chemical mediators that cause anaphylaxis are preformed and released from granules (histamine, tryptase, and others) or are generated from membrane lipids (prostaglandin D2, leukotrienes, and plateletactivating factor) by the activated mast cell or basophil. Tryptase is concentrated selectively in the secretory granules of all human mast cells. Its plasma levels during mast cell degranulation correlate with the clinical severity of anaphylaxis but need not be elevated in all forms of anaphylaxis (e.g., food-associated anaphylaxis). Histamine exerts its pathophysiologic effects via both H1 and H2 receptors. Erythema (flushing), hypotension, and headache are mediated by both H1 and H2 receptors, whereas tachycardia, pruritus, bronchospasm, and rhinorrhea are associated with H1 receptors alone. Increased vascular permeability during anaphylaxis can produce a shift of 50% of intravascular fluid to the extravascular space within 10 minutes. This shift of effective blood volume causes compensatory catecholamine release, activates the renin-angiotensin-aldosterone system, and stimulates production of endothelin-1. Mast cells accumulate at sites of coronary plaque erosion and rupture and they may contribute to coronary artery thrombosis. Because antibodies attached to mast cells can trigger mast cell degranulation, some investigators suggest that anaphylaxis may promote plaque rupture.

CURRENT DIAGNOSIS Cutaneous: urticaria, angioedema, diffuse erythema, generalized pruritus Respiratory: tachypnea, bronchospasm, laryngeal or tongue edema, dysphonia Cardiovascular: tachycardia, bradycardia, hypotension, angina, cardiac arrhythmias Gastrointestinal: nausea, emesis, diarrhea, abdominal cramps, dysphagia Other: rhinitis, conjunctivitis, uterine cramps, headache, dizziness, syncope, blurred vision, seizure AGENTS THAT CAUSE ANAPHYLAXIS Cause and effect often is confirmed historically in subjects who experience recurrent, objective findings of anaphylaxis upon inadvertent reexposure to the offending agent. Diagnostic testing, where appropriate, may confirm the presence of specific IgE and/or the degranulation of mast cells and basophils. Virtually any agent capable of activating mast cells or basophils may potentially precipitate anaphylactic or anaphylactoid reactions. Table 1 lists common causes of anaphylaxis classified by pathophysiologic mechanism. Idiopathic anaphylaxis, anaphylaxis with no identifiable cause, has accounted for approximately a third of cases in most retrospective studies of anaphylaxis. However, of 601 patients evaluated more than two decades in a university-affiliated practice (the largest retrospective series), 59% of subjects were

deemed to have idiopathic anaphylaxis.

TABLE 1 -- Representative Agents That Cause Anaphylaxis IgE dependent: •

Foods (such as peanuts, tree nuts, and crustaceans)

•

Medications (such as antibiotics)

•

Venoms (fire ants, yellow jackets, others)

•

Allergen extracts

•

Latex

•

Exercise (where food or medication dependent)

•

Hormones

IgE independent: •

•

Nonspecific degranulation of mast cells and basophils •

Opioids

•

Muscle relaxants

•

Idiopathic

•

Physical factors Cold, heat

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

Intravenous immunoglobulin

Cytotoxic •

•

•

Immune aggregates •

•

Exercise

Disturbance of arachidonic acid metabolism •

•

•

Transfusion reactions to cellular elements (IgM, IgG)

Multimediator complement activation/activation of contact system •

Radiocontrast media

•

Angiotensin-converting enzyme (ACE) inhibitor administered during renal dialysis with selected dialysis membranes

•

Protamine (possibly)

Psychogenic Modified and abridged from Kemp SF, Lockey RF: Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341-348.

Idiopathic anaphylaxis remains a diagnosis of exclusion, however. Serial histories and diagnostic tests for foods, spices, and vegetable gums occasionally identify a specific culprit in subjects previously presumed to have idiopathic anaphylaxis. The most common identifiable causes of anaphylaxis are foods, medications, insect stings, and immunotherapy injections. Anaphylaxis to peanuts and/or tree nuts causes the greatest concern because of its life-threatening severity, especially in subjects with asthma, and the tendency for subjects to develop lifelong allergic responsiveness to these foods. RECURRENT ANAPHYLAXIS Depending on the report, recurrent (biphasic) anaphylaxis occurs in 1% to 20% of subjects who experience anaphylaxis. Signs and symptoms experienced during the recurrent phase of anaphylaxis may be equivalent to or worse than those observed in the initial reaction and may occur 1 to 78 hours (most within 8 hours) after apparent remission. Thus, it may be necessary to monitor subjects up to 24 hours after apparent recovery from the initial phase. Observation periods after apparent recovery from the initial phase should be individualized and based on such factors as comorbid conditions and distance from the patient's home to the closest emergency facility, particularly because there are no reliable predictors of biphasic anaphylaxis DIFFERENTIAL DIAGNOSIS Several systemic disorders share clinical features with anaphylaxis. The vasodepressor (vasovagal) reaction probably is the condition most commonly confused with anaphylactic reactions. In vasodepressor reactions, however, urticaria is absent, dyspnea is generally absent, the blood pressure is usually normal or elevated, and the skin is typically cool and pale. Tachycardia is the rule in anaphylaxis. Bradycardia may be underrecognized in anaphylaxis, however. Brown and others conducted sting challenges in 19 subjects known to be allergic to jack jumper ants (Myrmecia). All eight subjects who became hypotensive developed bradycardia after an initial tachycardia. Systemic mastocytosis, a disease characterized by mast cell proliferation in multiple organs, usually features urticaria pigmentosa (brownish macules that transform into wheals upon stroking them) and recurrent episodes of pruritus, flushing, tachycardia, abdominal pain, diarrhea, syncope, or headache. Other diagnostic considerations include myocardial dysfunction, pulmonary embolism, foreign body aspiration, acute poisoning, and seizure disorder. MANAGEMENT OF ANAPHYLAXIS Table 2 outlines a sequential approach to management. Assessment and maintenance of airway, breathing, circulation, and mentation are necessary before proceeding to other management steps. Subjects are monitored continuously to facilitate prompt detection of any treatment complications. The recumbent position is strongly recommended. In a retrospective review of prehospital anaphylactic fatalities in the United Kingdom, the postural history was known for 10 individuals. Four of the 10 were associated with assumption of an upright or sitting posture and postmortem findings consistent with “empty heart” and pulseless electrical activity.

TABLE 2 -- Management of Anaphylaxis

Immediate intervention: •

Assessment of airway, breathing, circulation, and adequacy of mentation.

•

Administer aqueous epinephrine 1:1000 dilution, 0.2–0.5 mL (0.01 mg/kg in children; maximum dose, 0.3 mg) intramuscularly q5 min, as necessary, to control symptoms and blood pressure.

Possibly appropriate, subsequent measures depending on response to epinephrine: •

Place subject in recumbent position and elevate lower extremities.

•

Establish and maintain airway.

•

Administer oxygen.

•

Establish venous access.

•

Use normal saline IV for fluid replacement.

Specific measures to consider after epinephrine injections, where appropriate: •

An epinephrine infusion might be prepared. Continuous hemodynamic monitoring is essential (see reference for specific details).

•

Diphenhydramine (Benadryl). Note: In the management of anaphylaxis, a combination of diphenhydramine and ranitidine (Zantac)[1] is superior to diphenhydramine alone.

•

For bronchospasm resistant to epinephrine, use nebulized albuterol (Proventil).

•

For refractory hypotension, consider dopamine (Intropin), 400 mg in 500 mL D5W, administered IV at 2–20 µ/kg/min titrated to maintain adequate blood pressure. Continuous hemodynamic monitoring is essential.

•

Where use of ß-blockers complicates therapy, consider glucagon,[1] 1–5 mg (20–30 µg/kg; maximum: 1 mg in children), administered IV over 5 min followed by an infusion, 5–15 µg/min. Aspiration precautions should be observed.

•

For patients with a history of asthma and for those who experience severe or prolonged anaphylaxis, consider methylprednisolone (Solu-Medrol) (1.0–2.0 mg/kg/d).

•

Consider transportation to the emergency department or an intensive care facility.

Interventions for cardiopulmonary arrest occurring during anaphylaxis: •

High-dose epinephrine and prolonged resuscitation efforts are encouraged, if necessary, because efforts are more likely to be successful in anaphylaxis where the subject (often young) has a healthy cardiovascular system (see reference for specific details).

Observation and subsequent outpatient follow-up: •

Observation periods after apparent resolution must be individualized and based on such factors as the clinical scenario, co-morbid conditions, and distance from the patient's home to the closest emergency department. After recovery from the acute episode, patients should receive epinephrine syringes (EpiPen or TwinJect) and be instructed in proper technique. Everyone postanaphylaxis requires a careful diagnostic evaluation in consultation with an allergist-immunologist.

Modified from Lieberman P, Kemp SF, Oppenheimer J, et al (chief eds). Joint Task Force on Practice Parameters. The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol 2005;115:S483-S523.

Abbreviation: IV = intravenous.


Epinephrine is the treatment of choice for acute anaphylaxis. Aqueous epinephrine 1:1000 dilution, 0.2 to 0.5 mL (0.01 mg/kg in children; maximum dose, 0.3 mg) administered intramuscularly every 5 minutes, as necessary, should be used to control symptoms and sustain or increase blood pressure. Comparisons of intramuscular injections to subcutaneous injections during acute anaphylaxis are not available. However, absorption is more rapid and plasma levels are higher in asymptomatic individuals who receive epinephrine intramuscularly in the anterolateral thigh. All subsequent therapeutic interventions depend on the initial response to epinephrine and the severity of the reaction. Development of toxicity or inadequate response to epinephrine injections indicates that additional therapeutic modalities are necessary. The a-adrenergic effect of epinephrine reverses peripheral vasodilation, which alleviates hypotension and also reduces angioedema and urticaria. It may also minimize further absorption of antigen from a sting or injection. The ß-adrenergic properties of epinephrine increase myocardial output and contractility, cause bronchodilation, and suppress further mediator release from mast cells and basophils. Fatalities during witnessed anaphylaxis usually result from delayed administration of epinephrine and from severe respiratory and/or cardiovascular complications. There is no absolute contraindication to epinephrine administration in anaphylaxis. Oxygen should be administered to subjects with anaphylaxis who require multiple doses of epinephrine, receive inhaled ß2 agonists, have protracted anaphylaxis, or have preexisting hypoxemia or myocardial dysfunction. Antihistamines (H1 and H2 antagonists) support the treatment of anaphylaxis. However, these agents act much slower than epinephrine and should never be administered alone as treatment for anaphylaxis. Antihistamines thus should be considered as second-line treatment. Systemic corticosteroids have no role in the acute management of anaphylaxis because even intravenous administration of these agents may have no effect for 4 to 6 hours after administration. Although corticosteroids traditionally are used in the management of anaphylaxis, their effect has never been evaluated in placebo-controlled trials. Corticosteroids administered during anaphylaxis might provide additional benefit for patients with asthma or other conditions recently treated with corticosteroids. Numerous cases of unusually severe or refractory anaphylaxis are reported in subjects receiving ß-blocking agents. Greater severity of anaphylaxis observed in usual doses of epinephrine administered during

anaphylaxis to subjects taking ß-blockers may not produce the desired clinical response. In such situations, both isotonic volume expansion and glucagon[1] administration are recommended. Glucagon may potentially reverse refractory hypotension and bronchospasm because it bypasses the ß-adrenergic receptor and directly activates adenyl cyclase. Persistent hypotension despite epinephrine injections should first be treated with intravenous crystalloid solutions. Saline is generally preferred. One to 2 L of normal saline might need to be administered to adults at a rate of 5 to 10 mL/kg in the first 5 minutes. Children should receive up to 30 mL/kg in the first hour. Large volumes (e.g., 7 L) are often required. Vasopressors should be administered if epinephrine injections and volume expansion fail to alleviate hypotension. Dopamine (Intropin) frequently increases blood pressure while maintaining or enhancing renal and splanchnic perfusion. These agents would not be expected to work as well in patients already maximally vasoconstricted by their internal compensatory response to anaphylaxis. 1 Not FDA approved for this indication.

PREVENTION OF ANAPHYLAXIS Table 3 outlines the basic principles for the prevention of future anaphylactic episodes in high-risk individuals. An allergist-immunologist can provide comprehensive professional advice on these matters.

TABLE 3 -- Preventive Measures for Subjects with Anaphylaxis General measures: •

Obtain thorough history to diagnose life-threatening food or drug allergy.

•

Identify cause of anaphylaxis and those individuals at risk for future attacks.

•

Provide instruction on proper reading of food and medication labels, where appropriate.

•

Patient should avoid exposure to antigens and cross-reactive substances.

•

Manage asthma and coronary artery disease optimally.

Specific measures for high-risk subjects: •

Individuals at high risk for anaphylaxis should carry self-injectable syringes of epinephrine (EpiPen or TwinJect) at all times and receive instruction in proper use with placebo trainer.

•

Individuals should wear a Medic Alert bracelet or chain.

•

Other agents for ß-adrenergic antagonists, angiotensin-converting enzyme (ACE) inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors should be substituted whenever possible.

•

Agents suspected of causing anaphylaxis should be administered slowly, supervised, and orally if possible

•

Where appropriate, use specific preventive strategies, including pharmacologic prophylaxis, short-term challenge and desensitization, and long-term desensitization.

Modified from Kemp SF: Anaphylaxis: Current concepts in pathophysiology, diagnosis, and management.

Immunol Allergy Clin N Am 2001;21: 611-634.

All subjects at high risk for recurrent anaphylaxis should carry epinephrine syringes and know how to administer them. An EpiPen (Dey Laboratories) is a spring-loaded, pressure-activated syringe with a single 0.3 mg dose (1:1000 dilution) of epinephrine. It is easy to use and injects through clothing. An EpiPen Jr, which delivers 0.15 mg (1:2000 dilution) epinephrine, is appropriate for children weighing less than 30 kg. The TwinJect (Verus Pharmaceuticals) is a prefilled, pen-sized, epinephrine auto-injector with two doses of either 0.3 or 0.15 mg. Serum Sickness Serum sickness is a clinical syndrome of fever, malaise, and urticarial and/or morbilliform cutaneous eruption that is often preceded by generalized erythema and pruritus. Arthralgias or arthritis (mainly large joints), neuropathy, lymphadenopathy, nephritis, abdominal pain (emesis or melena are possible), or vasculitis (cutaneous or systemic) may occur in some cases. Cutaneous vasculitis, also known as hypersensitivity vasculitis, is often manifested by palpable purpura, which most commonly are found on the lower extremities of ambulatory individuals or on the sacral or gluteal region of patients with restricted mobility. These purpura reflect vascular leakage from inflamed postcapillary venules. Systemic vasculitis may occur in association with autoimmune diseases, infection, or malignancy. Many agents may produce serum sickness or serum sickness–like reactions ( Table 4 ). Serum sickness classically refers to the immune complex syndrome caused by immunization with heterologous serum proteins (often equine or murine). The most frequent cause is immune complex-mediated drug hypersensitivity. A serum sickness–like drug reaction generally develops 6 to 21 days after the culprit medication is started, but it can occur within 12 to 48 hours in previously sensitized individuals.

TABLE 4 -- Representative Agents That Cause Serum Sickness Medications: ß-lactam antibiotics, sulfonamides, ciprofloxacin (Cipro), metronidazole (Flagyl), rifampin (Rifadin), allopurinol (Zyloprim), carbamazepine (Tegretol), phenytoin (Dilantin), fluoxetine (Prozac), bupropion (Wellbutrin), methimazole (Tapazole), propylthiouracil, thiazide diuretics, captopril (Capoten), propranolol (Inderal), verapamil (Calan), streptokinase (Streptase), others Heterologous (animal-derived) antisera: •

Horse: snake and spider venom, tetanus, botulism, diphtheria

•

Horse or rabbit: anti-lymphocyte globulin

Mouse: monoclonal antibodies (muromonab-CD3 [Orthoclone OKT3], rituximab [Rituxan], infliximab [Remicade]) Homologous (human-derived) antisera: cytomegalovirus, hepatitis B, rabies, tetanus, perinatal RH0(D) PATHOGENESIS AND LABORATORY ABNORMALITIES Healthy individuals regularly generate low levels of circulating immune complexes, which are either excreted by the kidneys or extracted in the liver and spleen by monocytes and macrophages. It is hypothesized that serum sickness results when a drug (hapten) binds to plasma protein and antibodies are generated in

response to the drug-protein complex. Complement activation occurs when large quantities of soluble antigen-antibody (immune) complexes fix to vascular endothelial receptors. Complement fragments attract and activate neutrophils, which release proteases that induce tissue injury. The urticaria in serum sickness probably results from immune complex necrotizing vasculitis and complement activation that induces mast cell degranulation. IgE-dependent mechanisms likely are also contributory in some individuals. Laboratory abnormalities include elevated erythrocyte sedimentation rate, leukopenia (acute phase), occasional plasmacytosis, and decreased total hemolytic complement (CH50), C3, and C4. Slight albuminuria, hyaline casts, and microscopic hematuria may also occur. TREATMENT Stoppage of the culprit agent, when identified, is recommended. Serum sickness is usually self-limited and rarely life threatening when the offending drug or protein is stopped or removed. Symptoms generally improve over 2 to 4 weeks as patients clear their immune complexes. Evidence-based treatment recommendations for serum sickness are very limited. Long-acting, less-sedating H1 antihistamines such as cetirizine (Zyrtec), desloratadine (Clarinex), fexofenadine (Allegra), or loratadine (Claritin) generally control urticaria. Systemic corticosteroids (e.g., prednisone, 0.5 to 1.0 mg/kg/day) may help severe symptoms. Fever and arthralgias typically resolve within 48 to 72 hours of treatment, and the formation of new cutaneous eruptions usually ceases within the same time frame. Antihistamine therapy is continued for 1 week after apparent resolution of symptoms and then slowly discontinued. Skin testing with heterologous antisera is performed routinely to avoid anaphylaxis to future administration of heterologous serum.



REFERENCES American Heart Association in collaboration with International Liaison Committee on Resuscitation, 2005. American Heart Association in collaboration with International Liaison Committee on Resuscitation : 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Anaphylaxis. Circulation 2005; 112(Suppl 4):143-145. Brown et al., 2004. Brown SGA, Blackman KE, Stenlake V, Heddle RJ: Insect sting anaphylaxis: Prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21:149154. Kemp and Lockey, 2002. Kemp SF, Lockey RF: Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 2002; 110:341-348. Lieberman, 2005. Lieberman P: Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005; 95:217-226. Lieberman et al., 2005. Lieberman P, Kemp SF, Oppenheimer J, et al: (cheif eds). Joint Task Force on Practice Parameters. The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol 2005; 115:S483-S523. Project Team of the Resuscitation Council (UK), 1999. Project Team of the Resuscitation Council (UK) : Emergency medical treatment of anaphylactic reactions. J Accid Emerg Med 1999; 16:243-247. Pumphrey, 2003. Pumphrey RSH: Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003; 112:451-452. Pumphrey, 2004. Pumphrey RSH: Fatal anaphylaxis in the UK, 1992–2001. Novartis Found Symp 2004; 257:116-128. Sampson et al., 2006. Sampson HA, Muñoz-Furlong A, Campbell RL, et al: Second symposium on the definition and management of anaphylaxis: Summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391-397. Simons et al., 2001. Simons FER, Gu X, Simons KJ: Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001; 108:871-873. Simons et al., 1998. Simons FER, Roberts JR, Gu X, Simons KJ: Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998; 101:33-37. Wener. Wener M: Serum sickness and serum sickness-like reactions. In: Rose BD (ed): UpToDate, www.uptodateonline.com , Version 15.1 (current through December 2006), Wellesley, Ma.



Chapter 189 – Asthma in Adolescents and Adults

Method of: Michael Schatz, MD, MS Asthma is an extremely common chronic medical condition that causes substantial morbidity among its sufferers. In addition to discomfort, asthma can cause sleep disruption, missed school and work, limitations of recreational activities, and acute episodes requiring emergency hospital care. Although the past 30 years have seen the introduction of increasingly effective and convenient medications, recent surveys continue to suggest that asthma remains suboptimally controlled in the majority of patients. The purpose of this article is to describe an approach to assessment and therapy that leads to optimal asthma control. It is based on the recently released National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3: Guidelines for the Management of Asthma (http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf ). Diagnosis The first step in evaluating a patient with asthma is to confirm the diagnosis. This is particularly important in patients with atypical symptoms or a poor response to asthma therapy. Asthma is confirmed by the demonstration of reversible airways obstruction, which most commonly is an increase in forced expiratory volume in 1 second (FEV1) by 12% or more and at least 200 cc after an inhaled bronchodilator. For some patients, 2 to 4 weeks of chronic inhaled asthma therapy or 2 weeks of oral corticosteroid therapy is necessary to demonstrate reversibility. The latter is particularly important in adults with a history of smoking in whom chronic obstructive pulmonary disease (COPD) is a diagnostic consideration. In patients with normal pulmonary function, asthma can also be confirmed by means of methacholine (Provocholine) or exercise challenge. Particularly important masqueraders of asthma include vocal cord dysfunction, panic attacks, hyperventilation, and cough due to postnasal drip, reflux, or angiotensin-converting enzyme (ACE) inhibitor therapy. All of these can also coexist with asthma, so their presence does not exclude asthma. Even when these conditions coexist with asthma, their diagnosis and appropriate therapy usually reduce the patient's respiratory symptoms. Assessment Assessment of asthmatic patients involves assessment of past severity, identification of aggravating factors, and definition of current status regarding treatment and clinical severity or control. PAST SEVERITY Asthma can be a mild, infrequent illness or a daily severe one. Certain severity markers identify patients who are more likely to experience severe exacerbations or to have symptoms that are more difficult to control and who thus require more careful surveillance. These include histories of asthma hospitalization, especially

requiring intensive care or intubation, past requirement for oral corticosteroids, and exacerbation by aspirin or other NSAIDs. In patients with prior severe exacerbations, the rapidity of the onset of the exacerbation should be ascertained. AGGRAVATING FACTORS Factors that appear to trigger asthma symptoms should be assessed because they may be targets for avoidance therapy. Certain aspects of the patient's environment that can contribute to asthma triggering should be specifically ascertained, including occupational exposures, age of the home, pets, carpeting, visible mold, passive smoke, and cockroach exposure. Patients with persistent asthma should have in vitro or skin tests to identify allergic sensitization to pollens, house dust mites, mold spores, animal dander, and cockroaches that can contribute to the maintenance of asthma inflammation or can trigger episodes. The presence of comorbidities that can aggravate asthma, including cigarette smoking, obesity, rhinitis, sinusitis, reflux, and COPD, should be identified and treated. Finally, psychosocial factors to assess include a history or symptoms of anxiety or depression, attitudes toward asthma and asthma therapy, adherence to therapy, and social support. These may be targets for therapy or may be necessary to understand in order to create an effective therapeutic plan and therapeutic alliance. CURRENT STATUS Assessment of the current therapy the patient is actually taking is necessary for understanding the asthma's severity and to appropriately initiate or change therapy. It is particularly important to determine if the patient is taking long-term control medications, such as inhaled corticosteroids, long-acting ß-agonists, leukotriene modifiers, cromolyn (Intal), nedocromil (Tilade), or theophylline (Theo-Dur). If the patient is not taking controllers, severity should be assessed, as described in Table 1 , based on symptom frequency, nocturnal awakenings, rescue therapy use, activity limitation, spirometry, and exacerbation history. If the patient is already taking controllers, control should be assessed ( Table 2 ). Normal FEV 1/FVC (forced vital capacity) by age is shown in Table 3 .

TABLE 1 -- Classifying Asthma Severity and Initiating Treatment in Patients 12 Years and Older Not Currently Taking Long-Term Control Medications

TABLE 2 -- Assessing Asthma Control and Adjusting Therapy in Patients 12 Years and Older

TABLE 3 -- Normal FEV1/FVC by Age Age Range (y) Normal FEV1/FVC (%) 8-19

85

20-39

80

40-59

75

60-80

70

Abbreviations: FEV 1 = forced expiratory volume in one second; FVC = forced vital capacity.

CURRENT DIAGNOSIS Confirm the diagnosis by demonstrating an increase in FEV1 by 12% or more after asthma therapy. Assess past severity by a history of exacerbations requiring hospitalization, intubation, or oral corticosteroids. Identify environmental exposures, allergic sensitization, and comorbidities that may be aggravating asthma. Assess current severity in patients not taking long-term control medications and assess control in patients who are taking long-term control medications based on symptom frequency, nocturnal awakenings, rescue therapy use, activity limitation, spirometry, and recent exacerbation history. Abbreviation: FEV 1 = forced expiratory volume in 1 second. Long-Term Management The goals of long-term management are to achieve and maintain well-controlled asthma. Both nonpharmacologic and pharmacologic therapy must be considered. NONPHARMACOLOGIC THERAPY The first tenet of nonpharmacologic therapy in the long-term management of asthma is education. Patients need to understand the inflammatory pathophysiology of asthma and the relationships among airway inflammation, bronchospasm, and symptoms. Patients should be informed that the cause of asthma is unknown and there is no cure but that triggers can be identified and asthma can be controlled. They should receive education regarding self-assessment, either based on symptoms or peak flow monitoring, and regarding the recognition of early signs of an impending exacerbation. The next step is to discuss and agree on the goals of therapy. The NAEPP has defined the following goals: •

Prevent chronic and troublesome daytime and nighttime symptoms.

•

Maintain optimal pulmonary function for that patient.

•

Maintain normal activity, including work, school, leisure activity, and exercise.

•

Prevent recurrent exacerbations, especially those requiring urgent medical visits.

•

Provide pharmacotherapy with minimal or no adverse effects.

•

Achieve patient and family satisfaction with asthma care.

The physician should let the patient know that these are the expectations of optimal management and confirm that those are the patient's goals as well. A very important component of nonpharmacologic therapy is reduction of relevant environmental triggers. Information should be given regarding environmental control of pollen, mite, mold, animal dander, and cockroach antigens ( Box 1 ) that appear to be relevant based on the history and results of skin or in vitro specific IgE tests. Inhalant allergen immunotherapy should be considered for patients who have persistent asthma when there is clear evidence of a relationship between symptoms and exposure to an allergen to which the patient is sensitive. BOX 1 Measures to Control Environmental Factors that Can Make Asthma Worse Allergens Reduce or eliminate exposure to the allergen(s) the patient is sensitive to: Animal Dander

•

Remove animal from house or, at a minimum, keep animal out of the patient's bedroom and keep the bedroom door closed.

House-dust Mites

•

•

Recommended •

Encase mattress in a special dust-proof cover

•

Encase pillow in a special dust-proof cover or wash it weekly in hot water.

•

Wash sheets and blankets on the patient's bed in hot water weekly. water must be hotter than 130°F to kill the mites. Cooler water used with detergent and bleach can also be effective.

Desirable •

Reduce indoor humidity to 60% or less.

•

Remove carpets from the bedroom.

•

Avoid sleeping or lying on cloth-covered cushions or furniture.

•

Remove carpets that are laid on concrete.

Cockroaches

•

Keep all food out of the bedroom.

•

Keep food and garbage in closed containers.

•

Use poison baits, powders, gels or paste (e.g., boric acid). Traps can also be used.

•

If a spray is used to kill cockroaches, stay out of the room until the odor goes away.

Pollens (from Trees, Grass, or Weeds) and Outdoor Molds

•

Try to keep windows closed

•

If possible, stay indoors, with windows closed, during periods of peak pollen exposure, which are usually during the midday and afternoon.

Indoor Mold

•

Fix all leaks and eliminate water sources associated with mold growth.

•

Clean moldy surfaces.

•

Dehumidify basements if possible.

Tobacco Smoke

•

Advise patients and others in the home who smoke to stop smoking or to smoke outside the home.

•

Discuss ways to reduce exposure to other sources of tobacco smoke, such as from daycare providers and the workplace.

Indoor and Outdoor Pollutants and Irritants

•

if possible, do not use a wood-burning stove, kerosene heater, fireplace, unvented gas stove, or heater

•

Try to stay away from strong odors and sprays, such as perfume, talcum powder, hair spray, paints, new carpet, or particle board.

Finally, psychosocial issues should be considered and addressed. For many patients, the education and therapeutic alliance described earlier adequately addresses psychosocial concerns. For other patients, poor past adherence requires identifying the barriers to adherence and finding solutions together. Resources for patients with poor social support should be identified. Clinically significant anxiety or depression that can make asthma harder to control should be treated. PHARMACOLOGIC STEP THERAPY The main principle of asthma pharmacologic step therapy is to add therapy in steps until control is achieved (step up) and decrease therapy in reverse steps (step down) to established the lowest effective dose necessary to maintain control.

There are two types of asthma medications: quick-relief medications ( Table 4 ) and long-term control medications ( Table 5 ). Systemic corticosteroids can be used either short-term to treat an exacerbation (see Table 4 ) or as long-term maintenance therapy for patients with severe disease (see Table 5 ). The generally recommended steps of pharmacologic therapy are shown in Table 6 . Definitions of low, medium, and high dose inhaled corticosteroids for each of the available preparations are given in Table 7 . At each therapeutic step level, the NAEPP Expert Panel has indicated preferred medications, which generally identify medications with the best balance of efficacy and safety in clinical trials for patients at that level of severity. However, these recommendations are based on population data and must be tailored to individual patient needs, circumstances, and responsiveness to therapy.

TABLE 4 -- Usual Dosages for Quick-Relief Medications for Patients 12 Years and Older Medication Dosage Form Adult Dose Comments Inhaled Short-Acting ß2-Agonists (SABA) Metered-Dose Inhaler

Applies to all four SABAS

Albuterol CFC

90 µ g/puff, 200 puffs/canister

Albuterol HFA (Proventil, Ventolin)


Pirbuterol CFC (Maxair)


Levalbuterol HFA (Xopenox)


2 puffs 5 min An increasing use or lack of expected effect before indicates diminished control of asthma. exercise Not recommended for long-term daily treatment. Regular use exceeding 2 d/wk for symptom control (not prevention of EIB) indicates the need for additional long-term control therapy or 2 puffs q46h prn Differences in potencies exist, but all products are essentially comparable on a per puff basis. May double usual dose for mild exacerbations. Should prime the inhaler by releasing 4 actuations prior to use. Periodically clean HFA activator, as drug may block/plug orifice. Nonselective agents (epinephrine [Primatene Mist], isoproterenol [Isopro Aerometer], metaproterenol [Alupent]) are not recommended due to their potential for excessive cardiac stimulation, especially in high doses.

Nebulizer Solutions Albuterol (Accuneb, Proventil)

Levalbuterol (Ralbuterol) (Xopenex)

0.63 mg/3 mL 1.25 1.25-5 mg in mg/3 mL 2.5 mg/3 3 mL saline mL 5 mg/mL q4-8h prn (0.5%) 0.31 mg/3 mL

May mix with budesonide (Pulmicort) inhalant suspension, cromolyn (Intal) or ipratropium (Atrovent) nebulizer solutions. May double the dose for severe exacerbations.

0.63 mg-1.25 Compatible with budesonide (Pulmicort) inhalant mg q8h prn suspension.

Medication

Dosage Form

Adult Dose

0.63 mg/3 mL

Comments The product is a sterile-filled, preservative-free, unitdose vial.

1.25 mg/0.5 mL 1.25 mg/3 mL Anticholinergics Metered-Dose Inhalers Ipratropium HFA (Atrovent)

17 µ g/puff 200 puffs/canister

2-3 puffs q6h Multiple doses in the emergency department (not hospital) setting provide additive benefit to shortacting beta agonists Treatment of choice for bronchospasm due to beta blocker Dose not block EIB Reverses only cholinergically mediated bronchospasm; does not modify reaction to antigen May be alternative for patients who do not tolerate short-acting beta-agonist Evidence is lacking for anticholinergics producing added benefit to ß2 agonists in long-term control asthma therapy.

Ipratropium with 18 µ g/puff of albuterol (Combivent) ipratropium bromide and 90 µ g/puff of albuterol 200 puffs/canister

2-3 puffs q6h

Nebulizer Solutions Ipratropium bromide

0.25 mg/mL (0.025%)

0.25 mg[*] q 6 Contains EDTA to prevent discoloration of the h solution.

Ipratropium bromide with albuterol (DuoNeb)

0.5 mg/3 mL ipratropium bromide and 2.5 mg/3 mL albuterol

3 mL q4-6h

Systemic Corticosteroids

This additive does not induce bronchospasm.

Medication Methylprednisolone (Medrol)

Dosage Form 2, 4, 6, 8, 16, 32 mg tab

Prednisolone (DeltaCortef, Prelone)

5 mg tabs, 5 mg/5 mL, 15 mg/5 mL

Prednisone 1, 2.5, 5, 10, 20, 50 (Deltasone, Orasone) mg tabs; 5 mg/mL, 5 mg/5 mL

Adult Dose Comments Short course Short courses (bursts) are effective for (burst): 40-60 establishing control when initiating therapy or mg/d as during a period of gradual deterioration. single or 2 Action may be begin with-in an hour. The divided doses burst should be continued until symptoms for 3-10 d resolve. This usually requires 3-10 d but can require longer. There is no evidence that tapering the dose following improvement prevents relapse in asthma exacerbations.

Repository Injection Methylprednisolone acetate (DepoMedrol)

40 mg/mL 80 mg/mL

240 mg[2][†] IM once

May be used in place of a short burst of oral steroids in patients who are vomiting or if adherence is a problem.

Abbreviations: CFC = chlorofluorocarbon; EIB = exercise-induced bronchospasm; HFA = hydrofluoroalkane; PEF = peak expiratory flow; tab = tablet;.

2 Exceeds dosage recommended by the manufacturer. * 0.5 mg per package insert. † 80-120 mg per package insert.

TABLE 5 -- Usual Dosages for Long-Term Control Medications for Patients 12 Years and Older Medication Dosage Form[*] Adult Dose Comments Systemic Corticosteroids Methylprednisolone (Medrol)

2, 4, 8, 16, 32 mg tab

7.5-60 mg qd in a single dose in AM or qod as needed for control

For long-term treatment of severe persistent asthma, administer single dose in AM either daily or on alternate d (alternate-day therapy may produce less adrenal suppression).

Prednisolone (DeltaCortef, Prelone)

5 mg tab 5 mg/5 mL, 15 mg/5 mL

Short-course (burst) to achieve control, 40-60 mg/d as single or 2 divided doses for 3-10 d

Short courses (bursts) are effective for establishing control when initiating therapy or during a period of gradual deterioration. There is no evidence that tapering the dose following improvement in symptom control and pulmonary function prevents relapse.

Medication

Dosage Form[*]

Adult Dose

Prednisone 1, 2.5, 5, 10, 20, 50 (Deltasone, Orasone) mg tab 5 mg/mL, 5 mg/5 mL Inhaled Long-Acting ß2-Agonists

Comments control and pulmonary function prevents relapse.

Should not be used for acute symptoms relief or exacerbations. Use only with ICS.

Salmeterol (Serevent)

DPI µ g/blister

1 blister q12h

Decreased duration of protection against EIB may occur with regular use.

Formoterol (Foradil)

DPI 12 µ g/single-use capsule

1 cap q12h

Each cap is for single use only; additional doses should not be administered for at least 12 h. Caps should be used only with the Aerolizor inhaler and should not be taken orally.

Inhaled Combined Medications Fluticasone and salmeterol (Advair)

Budesonide and formoterol (Symbicort)

DPI 100 g/50 µ g, 250 1 inhalation bid; g/50 µ g, or 500 g/50 µ dose depends on g HFA 45 g/21 µ g 115 level of control g/21 µ g 230 g/21 µ g

100/50 DPI or 45/21 HFA for patients not controlled on low-to-medium dose ICS

HFA MDI 80 g/4.5 µ g 160 g/4.5 µg

2 inhalations bid; dose depends on level of control

80/4.5 for patients not controlled on low-tomedium dose ICS

MDI 0.8 mg/puff

2 puffs qid

One dose before exercise or allergen exposure provides effective prophylaxis for 1-2 h.

Nebulizer

1 amp qid

Not as effective for EIB as SABA.

250/50 DPI or 115/21 HFA for patients not controlled on medium-to-high dose ICS

160/4.5 for patients not controlled on medium-to-high dose ICS

Inhaled Cromolyn and Nedocromil Cromolyn (Intal)

4-6 wk trial of cromolyn or nedocronil may be needed to determine maximum benefit Dose by MDI may be inadequate to affect hyperresponsiveness Nedocromil (Tilade)

20 mg/ampule MDI 1.75 mg/puff

2 puffs qid

Once control is achieved, the frequency of dosing may be reduced.

4 mg or 5 mg chewable tab 10 mg tab

10 mg qhs

Montelukast exhibits a flat dose-response curve. Doses >10 mg do not produce a.greater response in adults

Leukotriene Modifiers Leukotriene Receptor Antagonists Montelukast (Singulair)

Medication

Dosage Form[*]

Zafirlukast (Accolate) 10 or 20 mg tab

Adult Dose

Comments

40 mg/d (20 mg tab For zafirlukast: Administration with meals bid) decreases bioavailability; take at least 1 h before or 2 h after meals. Zafirlukast is a microsomal p450 enzyme inhibitor that can inhibit the metabolism of warfarin and theophylline. Doses of these drugs should be monitored accordingly Monitor for signs and symptoms of hepatic dysfunction.

5-Lipoxygenase Inhibitor Zileuton (Zyflo)

600 mg tab

2400 mg daily (600 Monitor hepatic enzymes (ALT). mg qid) Zileuton is a microsomal p450 enzyme inhibitor that can inhibit the metabolism of warfarin and theophylline. Doses of these drugs should be monitored accordingly

Methylxanthines Theophylline (Slophyllin, Theobid, TheoDur)

Liquids, sustainedrelease tab, cap

Starting dose 10 Adjust dosage to achieve serum mg/kg/d up to 300 concentration of 5-15 µg/mL at steadymg max Usual max state (=48 h on same dosage). 800 mg/d Due to wide interpatient variability in theophylline metabolic clearance, routine serum theophylline level monitoring is essential. Patient should be told to discontinue if they experience symptoms of toxicity Various factors (diet, food, febrile illness, age, smoking, and other medications) can affect serum concentration

Immunomodulators Omalizumab (AntiIgE)

Subcutaneous (SQ) injection 150 mg/1.2 mL following reconstitution with 1.4 mL sterile water for injection

150-375 mg SQ every 2-4 wk, depending on body weight and pretreatment serum 1 gE level

Do not administer more than 150 mg per injection site Monitor patient following injections; be prepared and equipped to indentify and treat anaphylaxis that may occur Whether patients will develop significant antibody titers to the drug with long-term administration is unknown

Abbreviations: ALT = alanineaminotransferase; amp = ampule; cap = capsule; DPI = dry powder inhaler; EIB = exercise-induced bronchospasm; HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting ß2-agonist; max = maximum; MDI = metered-dose inhaler; SABA = short-acting ß2-agonist; tab = tablet.

* See Table 7 for estimated comparative daily dosages for inhaled corticosteroids.

TABLE 6 -- Stepwise Approach For Managing Asthma in Patients 12 Years and Older[a] Step Preferred Therapy

Alternative Therapy

1

Short-acting ß-agonist prn.

—

2

Low-dose ICS

Cromolyn (Intal), LTRA, nedocromil (Tilade), theophylline (Theo-Dur)

3

Low-dose ICS plus LABA or Medium-dose ICS

Low-dose ICS plus LTRA or theophylline or zileuton (Zyflo)

4

Medium-dose ICS plus LABA

Medium-dose ICS plus LTRA or theophylline or zileuton

5

High-dose ICS plus LABA Consider omalizumab (Xolair) for patients who have allergies

—

6

High-dose ICS plus LABA plus oral corticosteroid[b] Consider omalizumab for patients who have allergies

—

Abbreviations: ICS = inhaled corticosteroid; LABA = long-acting ß agonist; LTRA = leukotriene receptor antagonist.

a The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. b In step 6, before oral corticosteroids are introduced, a trial of high-dose ICS +LABA+either LTRA, theophylline or zilecton may be considered, although this approach has not been studied in clinical trials.

TABLE 7 -- Estimated Comparative Daily Dosages for Inhaled Corticosteroids for Patients 12 Years and Older Daily Dose Drug

Dosage Form

Medium Low (µg) (µg)

High (µg)

Beclomethasone HFA (QVAR)

40 or 80 µg/puff

80-240

>240-480

>480

Budesonide DPI (Pulmicort)

90,180, or 200 µg/inhalation

180-600

>600-1,200

>1,200

Daily Dose Medium Low (µg) (µg)

High (µg)

250 µg/puff

5001,000

>1,0002,000

>2,000

Flunisolide HFA (AeroSpan)

80 µg/puff

320

>320-640

>640

Fluticasone-HFA (Flovent HFA, Flovent Diskus)

MDI: 44, 110, 220 µg/puff

88-264

>264-440

>440

DPI: 50, 100, 250 µg/inhalation

100-300

>300-500

>500

Mometasone DPI (Asmanex)

200 µg/inhalation

200

400

>400

Triamcinolone acetonide (Azmacort)

75 µg/puff

300-750

>750-1500

>1500

Drug

Dosage Form

Flunisolide (AeroBid)

Abbreviations: DPI = dry powder inhaler; HFA = hydrofluoroalkane.

All patients with asthma should have an action plan that describes their pharmacologic self-management. Aspects of pharmacologic self-management include the maintenance medication schedule, rescue therapy doses for increased symptoms, when and how to increase control medication therapy, when and how to use prednisone, how to recognize a severe exacerbation, and when and how to seek urgent or emergency care. Control medications should be increased with an upper respiratory infection or with symptoms requiring more than two doses of rescue therapy in 12 hours. Although doubling the dose of inhaled corticosteroids does not appear to generally be sufficient to provide clinical benefit under these circumstances, higher-fold increases may be effective (e.g., three- or fourfold increases). The increased dose of control medications should be maintained at least until increased symptoms resolve. Prednisone is usually needed for patients with incomplete or temporary responses to adequate doses of ß-agonists (4 puffs with a spacer, waiting at least 1 minute between puffs), substantial interference with sleep every night, requirement for 12 or more puffs of ß-agonist in a 24-hour period, or a peak flow less than 60% predicted. Home treatment of exacerbations is further discussed later. For patients not on long-term control medications, assess severity and select the level of treatment that corresponds to the patient's level of severity (see Table 1 ). Persistent asthma is most effectively controlled with daily long-term control medications, specifically anti-inflammatory therapy. For patients receiving longterm control medications, identify their current step of therapy, based on what they are actually taking (see Table 6 ), and their level of control (see Table 2 ). In general, step up one step for patients whose asthma is not well controlled. For patients with very poorly controlled asthma, consider increasing by two steps, a course of oral corticosteroids, or both. Before increasing pharmacologic therapy, consider adverse environmental exposures, poor adherence, or comorbidities as targets for intervention. For patients with troublesome or debilitating side effects from asthma therapy, explore a change in therapy. Follow-up

Patients whose asthma is not controlled should be seen every 2 to 6 weeks (depending on their initial level of severity or control) until control is achieved. Once control is achieved, follow-up contact at 1- to 6-month intervals is recommended. These checkups should ensure continued control, identify other changes in the patient's status, and update the patient's action plan. When well-controlled asthma has been maintained for at least 3 months, a step down in therapy can be considered to determine the minimal amount of medication required to maintain control or reduce the risk of side effects. Reduction in therapy should be gradual because asthma can deteriorate at a highly variable rate and intensity. Doses of inhaled corticosteroids may be reduced about 25% to 50% every 3 months to the lowest dose possible to maintain control. Most patients with persistent asthma relapse if inhaled corticosteroids are totally discontinued. Patients should be encouraged to contact their asthma physician for signs of loss of asthma control, such as nocturnal symptoms, increasing ß-agonist use, or activity limitation. The Expert Panel recommends consultation with an asthma specialist if the patient has difficulties achieving or maintaining control of asthma, immunotherapy or omalizumab (Xolair) is being considered, the patient requires step 4 care or higher, or the patient has had an exacerbation requiring hospitalization.

CURRENT THERAPY Nonpharmacologic therapy includes asthma education (especially regarding inhaler technique, selfmonitoring, and self-management), reduction in environmental triggers, addressing any relevant psychosocial issues, and immunotherapy for select patients. Preferred step therapy for long-term asthma management is (in order): low-dose inhaled corticosteroids; medium-dose inhaled corticosteroids or low-dose inhaled corticosteroids plus longacting ß-agonists; medium-dose inhaled corticosteroids plus long-acting ß-agonists; high-dose inhaled corticosteroids plus long-acting ß-agonists; and oral prednisone. Asthma exacerbations should be treated with high-dose inhaled ß-agonists and early use of systemic corticosteroids. Treatment of Exacerbations Asthma exacerbations are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, or chest tightness associated with decreases in expiratory airflow. HOME MANAGEMENT Patients' action plans should direct their home therapy of asthma exacerbations according to the following recommendations. Initial therapy should be with inhaled short-acting ß-agonists (2-6 puffs by metered-dose inhaler [MDI] or nebulizer). This may be repeated in 20 minutes. With a good response (minimal or no symptoms and peak expiratory flow (PEF) =80% predicted or personal best), the patient may continue ß-agonists every 3 to 4

hours for 24 to 48 hours. If repeated ß-agonists are needed, a short course of oral corticosteroids should be considered. With an incomplete response to initial therapy (persistent wheezing and dyspnea and PEF 50% to 79% predicted or personal best), oral corticosteroids should be added, ß-agonists should be repeated, and the clinician should be contacted that day. With a poor response (marked wheezing and dyspnea at rest, PEF 40% predicted), initial therapy is oxygen to achieve oxygen saturation greater than 90% and inhaled short-acting ß-agonist by nebulizer or MDI (4-8 puffs) with holding chamber, which may be repeated up to three times in the first hour. Oral corticosteroids (prednisone 40-80 mg) are recommended if there is no immediate response to therapy or if the patient had been recently treated with oral corticosteroids. In patients with severe exacerbations (PEF 70%). When this response is sustained at least 60 minutes after the last treatment, the patient may usually be discharged on a course of oral corticosteroids (generally prednisone 40-60 mg for 5-10 days), initiation or continuation of medium-dose inhaled corticosteroids, and arrangement for outpatient follow-up.

In patients who are not improving with the above therapy, adjunctive therapy, such as with intravenous magnesium sulfate[1] (2 g) or heliox, may be considered. Intubation and mechanical ventilation may be required for patients with respiratory failure in spite of treatment. Summary Asthma is a very common problem with the potential to cause substantial interference with quality of life. Although there is no cure for asthma, asthma can be well controlled in the majority of patients with proper management and an effective patient-physician relationship. I hope that the method described herein for assessing and managing asthma will help physicians help their patients to achieve well-controlled asthma.



Chapter 190 – Asthma in Children

Method of: Gerald B. Kolski, MD, PhD, FAAAAI, FAAP Asthma is the most common cause of significant childhood morbidity. This includes school absenteeism, hospitalizations, emergency department visits, and acute care visits. Its prevalence has been increasing throughout the 1990s and into this century. An estimated 5 million children younger than 15 years have asthma as identified by the National Health Interview Survey of 2003. According to this survey, the prevalence of asthma in the general population is somewhere between 6% and 10%. Prevalence in innercity populations and especially in African Americans is closer to 14% to 15%. Pediatricians and family practitioners are often reluctant to make the diagnosis because of difficulty with giving prognostic information to parents. Wheezing during the first few years of life can often be associated with acute viral infections, especially respiratory syncytial virus (RSV). Longitudinal studies suggest there are three patterns to wheezing in children. There are a group of children who wheeze during infancy associated with viral infections, a second group that wheeze during infancy and also as they get older, and a third group that only develops wheezing later after sensitization with allergens. Because of these groups it is oftentimes difficult to give prognostic information to parents until you have seen the pattern that a child will follow. Despite tremendous improvement in medications and treatments for asthma, deaths from asthma continue to occur. Most recently, however, the mortality rates seem to have leveled off or decreased slightly. One theory for the high prevalence of asthma is the “hygiene hypothesis.” Studies done in homogeneous populations in Europe and Scandinavian countries have noted less asthma and allergies in rural populations versus those that live in urban environments. Attempts have been made to correlate this with endotoxin exposure during infancy and/or infections during this period of time that turn on immune responses that do not promote allergies. This concept favors an immune response, which postulates that certain infections and endotoxin exposure promote a TH1 T cell response in which interferon gamma and interleukin(IL)-2 predominate, whereas a lack of these infections promotes a TH2 response where there is an IL-4, IL-13, and IL-5 predominance with increased IgE production. Pathophysiology Over the last several decades the idea that reversible bronchoconstriction is the main element in asthma has changed. It has become apparent that in addition to bronchoconstriction there is considerable inflammation involving increased mucus production, inflammatory cell infiltrates, and airway thickening. With longitudinal studies it has become apparent that there may in fact be some fibrosis that leads to “airway remodeling.” The increased inflammatory infiltrates lead to increasing airway reactivity characterized by hyperresponsiveness to various stimuli. The inflammatory cell infiltrates can include eosinophils, lymphocytes, basophils, neutrophils, and macrophages depending on the stimulus. Unchecked inflammation is believed to be the cause of the fibrosis. Clearly it is important to try and identify the triggers in an individual patient that are causing the inflammation as well as treating the inflammation.

Differential Diagnosis Determining the cause of wheezing in infancy can often be difficult. During the first year of life if the wheezing is associated with a viral infection, a diagnosis of bronchiolitis is often made. A clinical response to bronchodilators might be helpful in assessing whether this is going to be a child with asthma. Recurrent wheezing in an atopic child with a strong family history of asthma would strongly suggest that the child has underlying asthma. An association with eczema and/or other allergic manifestations might also be suggestive of asthma. Because of the difficulty in doing pulmonary functions during the first few years of life, clinical assessment is the key. In addition to asthma, Table 1 lists the other diagnoses that have to be considered. Cystic fibrosis, gastroesophageal reflux disease, and foreign body aspiration probably are the most common diagnoses that have to be entertained. Recurrent infiltrates should make you worry about immune deficiencies including hypogammaglobulinemia and ciliary defects such as immotile cilia syndrome.

TABLE 1 -- Differential Diagnosis of Wheezing Infants Older Children Laryngomalacia

Asthma

Tracheomalacia

Cystic fibrosis

Vascular rings

Gastroesophageal reflux disease

Subglottic stenosis

Foreign body aspiration

Airway congenital masses Airway tumors Gastroesophageal reflux

Viral infections (RSV, adenovirus)

Bronchiolitis Pneumonia

Tuberculosis

Abbreviations: RSV = respiratory syncytial virus.

Diagnostic tests such as a sweat test, immunoglobulins, skin or radioallergosorbent assay test (RAST), barium swallow, bronchoscopy, or chest radiograph may be indicated. In older children asthma may be diagnosed by doing pulmonary functions. Spirometry can often be done in the office and can be a reproducible way to measure the extent of airway disease in known asthmatics as well as diagnostic by looking at pre- and postbronchodilator responses. The forced expiratory volume at 1 second (FEV1) is often thought to be a measure of large airway obstruction. The FEF25-75 or expiratory flow between the 25th and 75th percentile of the forced vital capacity (FVC) is often thought to be a measure of small airway disease. A 15% increase in FEV1 pre- and postbronchodilator or 25% increase in FEF25-75 is thought to be diagnostic of asthma. Inhalation challenges with methacholine (Provocholine) or histamine are often used to measure airway reactivity in experimental studies. Bronchoconstriction with these inhalation challenges can determine the degree of airway hyperreactivity. Similar results can also be obtained with exercise challenges or cold air challenges. These tests are often used to diagnose asthma in children whose pulmonary functions at baseline are not significantly depressed. In children with asthma, peak expiratory flow rates (PEFRs) are often used to monitor the asthma as well as the management. This test is effort

dependent. Key Diagnostic Points Consistent with Asthma

•

Recurrent wheezing responding to bronchodilators

•

Coughing or wheezing shortly after exercise

•

Pulmonary functions that show obstruction responding to bronchodilators

•

Strong family history of asthma

•

Associated allergic symptoms including seasonal rhinitis, eczema, or urticaria

History Once a diagnosis of asthma is made, it is important to determine the trigger for this individual's asthma symptoms or exacerbations. The history is very important in determining treatment. Box 1 lists the most common causes for asthma exacerbations. BOX 1 Asthma Triggers •

Allergies: perennial or seasonal

•

Viral infections

•

Irritants, especially cigarette smoke and air pollution

•

Exercise

•

Weather changes

•

Gastroesophageal reflux

•

Medications including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs)

•

Sinusitis

The most common perennial allergens are dust mites, cockroaches, mold, and pets. In the inner cities, cockroaches and dust mites are very common causes for allergic sensitization. They are extremely common and very difficult to control. Dust mites need moisture and thus are much more common in humid areas. With increased humidity, molds also can play a significant role. Children are often treated with humidifiers or vaporizers for upper respiratory infections, which may exacerbate dust mite and mold exposure. In drier climates, pets, especially indoor animals, are often exacerbating causes. Recent studies have indicated that more than two or three pets decreased the likelihood of sensitization, whereas an isolated pet is more likely to be associated with the development of allergy. This may have to do with endotoxin and the previously discussed hygiene hypothesis.

CURRENT DIAGNOSIS Always focus on the ABCs (airway, breathing, and circulation). Start prescription early and aggressively (titrate ß-agonist to effect). Reevaluate frequently (try to avoid intubation at all cost). Lack of wheezing is not always a good thing. Plan ahead in case things go bad. Ensure adequate hydration. Children who only have difficulty with their asthma in the spring and fall may have sensitization to the pollens. This is very regional and often associated with being outdoors. Pollination and dissemination is most problematic with dry windy days. Keeping the windows closed at night as well as air conditioning may benefit individuals with seasonal allergies. These children may need medications at particular times of the year but not throughout the year. Airway reactivity often continues even 4 to 6 weeks after the allergen is no longer present. Children who have trouble with viral infections may also have increased reactivity from perennial or seasonal exposures that exacerbate the asthma with infection. It is often helpful to reduce allergy exposure in these individuals so as to reduce their response to viral infections. Parents may be alerted to signs of upper respiratory infection so that they can increase asthma treatment at those times. At all times cigarette smoke causes increased mucus production as well as decreases mucociliary clearance. Children with asthma thus are especially prone to having difficulty around cigarette smoke. During infancy, cigarette smoke exposure is associated with a two- to threefold increase in risk of asthma as well as upper respiratory infections, ear infections, and pneumonia. Smoking during pregnancy is also associated with a sustained decrease in infant pulmonary functions. Smoke is a form of indoor air pollution. Outdoor air pollution, especially small particles, ozone, nitrogen dioxide, and sulfur dioxide, all can be exacerbating factors in asthma. Exercise is associated with asthma exacerbations because of the inhalation of cold dry air. Exercise is often associated with mouth breathing. The nose normally moisturizes, filters, and warms the air. Nasal congestion secondary to allergies, viral infections, or nasal obstruction can all lead to more difficulty with exercise as well as with breathing cold dry air at any time. Weather changes are often a problem secondary to what is in the air or the changes in temperature of the air. Children who have trouble with weather changes are often responding to changes in pollen distribution or other allergens or irritants. Children who have reflux as the exacerbating cause of their asthma often have difficulty at night when they lie down, shortly after meals, or when ingesting very acidic substances. Often there will be considerable coughing and if the child is old enough to talk some significant heartburn. Reflux is often worse when the asthma is a problem because the lower esophageal sphincter tone decreases with hyperinflation at that

time. Children with sensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) often have associated sinusitis, nasal polyps, and profuse rhinorrhea with aspirin exposure. It often goes undiagnosed until adulthood. Nasal polyps should always raise this possibility in addition to a diagnosis of cystic fibrosis. Sinusitis can be associated with significant exacerbations of asthma. Often treating the sinusitis treats the asthma exacerbation. Purulent nasal discharge for 5 to 7 days associated with significant coughing and maxillary tenderness may be suggestive of underlying sinusitis. In children with allergic rhinitis, complications of sinusitis often occur. In all children with asthma it is very important that you try and assess severity of disease. There should be questions asked about whether the patient has ever been intubated or had an intensive care unit admission. In addition questions about recent use of oral corticosteroids should be asked to determine the recent course of asthma. Children with underlying seizure disorders are also important to identify because they are at greater risk for mortality. Signs of mental illness or depression should also be noted because this predisposes children to significant morbidity and mortality. Physical Examination In examining a patient with asthma, the complete physical is extremely helpful. Children with skin findings of eczema or hives associated with an exacerbation of asthma may often lead to a search for an allergy exposure that is responsible for symptoms. Nasal examination may show boggy turbinates suggestive of allergy or erythematous turbinates suggestive of infection. Purulent discharge associated with sinus tenderness may suggest sinusitis. Nasal polyps should also be looked for to ascertain whether the patient may have underlying cystic fibrosis or aspirin-sensitive asthma. Enlarged tonsils and adenoids may predispose to mouth breathing and exacerbate underlying asthma. Examination of the chest may show whether there is a pectus suggesting chronic disease or whether there is hyperinflation with a barrel chest. Supraclavicular, intercostal, and subcostal muscular activity give information as to the work of breathing. The cardiac examination should focus on heart rate as well as any sign that might indicate this is cardiac wheezing instead of asthma. Abdominal examination is important to evaluate any signs of liver or spleen enlargement that might indicate evidence of pulmonary hypertension or cardiac disease. Examination of the extremities is important to look for clubbing and/or cyanosis. The neurologic exam is especially important acutely to ascertain whether the patient is having any change in mental status secondary to hypoxia. Treatment Treatment for asthma has changed considerably since the mid 90's. The chronic management of asthma has focused on assuring that the patient functions as normally as possible with the following goals of asthma management:

•

No nocturnal asthma

•

Full exercise activity

•

No emergency department visits or hospitalizations

•

No lost time from school or work

•

No or minimal side effects from medication

Asthma treatment has focused on the anti-inflammatory nature of the disease to eliminate long-term damage to the lungs. Asthma treatment has followed the National Heart, Lung, and Blood Institute (NHLBI) guidelines with assessment of asthma severity and management based on the classifications ( Table 2 ). We developed a color-coded questionnaire that gives an indication of asthma control.

TABLE 2 -- Stepwise Approach for Managing Asthma in Children Classify Severity: Clinical Features Before Treatment or Adequate Control

Medications Required to Maintain Long-Term Control

Symptoms/Day PEF or FEV1 PEF Symptoms/Night Variability

Daily Medications

Step 4

Continual

30%

•

High-dose inhaled corticosteroids, and

•

Long-acting inhaled ß2-agonists (combination preferred) and, if needed,

•

Corticosteroid tablets or syrup long term (2 mg/kg/d, generally do not exceed 60 mg/d). (Make repeat attempts to reduce systemic corticosteroids and maintain control with high-dose inhaled corticosteroids.)

Step 3:

Daily

>60%–1 night/wk

>30%

•

Low- to medium-dose inhaled corticosteroids.

•

Alternative treatment (listed alphabetically):

•

Increase inhaled corticosteroids within medium-dose range or

Classify Severity: Clinical Features Before Treatment or Adequate Control



Daily Medications •

Low to medium–dose inhaled corticosteroids and either leukotriene modifier or theophylline. If needed (particularly in patients with recurring severe exacerbations):

•

•

Preferred treatment:

•

Increased inhaled corticosteroids within medium-dose range and add long-acting inhaled ß2-agonists (combination inhaler preferred).

Alternative treatment (listed alphabetically): •

Step 2

>2/wk but 80%

Mild persistent

>2 nights/mo

20%–30%

•

Increase inhaled corticosteroids within medium-dose range, and add either leukotriene modifier or theophylline.

Preferred treatment: •

Low-dose inhaled corticosteroids.

Classify Severity: Clinical Features Before Treatment or Adequate Control



Daily Medications •

Step 1

320 µg

200–400 µ g 400–800 mcg

>800 µg

Budesonide inhalation suspension for nebulization (Pulmicort Respules)

0.5 mg

2.0 mg

Flunisolide (AeroBid)

500–750 µ g 1000–1250 µcg 1250 µg

40 or 80 µ g/puff Budesonide DPI (Pulmicort) 200 µ g/inhalation 1.0 mg

250 µ g/puff Fluticasone (Flovent)

88–176 µ g

176–440 µg

>440 µg

MDI: 44, 110, or 220 µ g/puff

100–200 µg 200–400 µg

>400 µg

400–800 µ g 800–1200 µg

>1200 µg

220 µ g

880 µg

DPI: 50, 100, or 250 µ g/inhalation Triamcinolone acetonide (Azmacort) 100 µ g/puff Mometasone fumarate (Asmanex) 220 mg

440 µg

Notes: The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. Classify severity: Assign patient to most severe step in which any feature occurs (PEF is percentage of personal best; FEV1 is percentage predicted). Gain control as quickly as possible (consider a short course of systemic corticosteroids); then step down to the least medication necessary to maintain control. Minimize use of short-acting inhaled ß2-agonists. Overreliance on short-acting inhaled ß2-agonists (e.g., use of approximately 1 canister/mo even if not using it every day) indicates inadequate control of asthma and the need to initiate or intensify long-term control therapy. Provide education on self-management and controlling environmental factors that make asthma worse (e.g., allergens and irritants). Refer to an asthma specialist if there are difficulties controlling asthma or if step 4 care is required. Referral may be considered if care at level step 3 is required. Abbreviations: DPI = daily permissible intake; FEV1 = forced expiratory volume at 1 second; MDI = metered-dose inhaler; PEF = peak expiratory flow (rate).

Medications Asthma medications are classified according to medications that are used for acute relief of symptoms called relievers and those that are used for chronic control of symptoms characterized as controllers. This classification was established to give patients a better understanding of the role of their individual medications. It is also a better way to educate patients as to why they have to continue to take medications even when they are not having symptoms. It is important to discuss these individual classifications and medications for both acute and chronic management. RELIEVERS Various bronchodilators are used for acute management of asthma. These bronchodilators are predominantly ß-agonists such as albuterol (Proventil) and terbutaline (Brethine) that are selective for ß2receptors. Table 3 gives the generic as well as trade names for these medications. The short-acting ßagonists are used for acute relief in most circumstances. In children anticholinergics such as ipratropium bromide (Atrovent) are often used in the emergency department and hospital setting acutely but are rarely

given chronically. Chronic use of ß-agonists is avoided because of a decrease in effectiveness as well as an increase in airway reactivity with their chronic use. With chronic use there is also a decrease in both the number and affinity of ß-receptors for these bronchodilators. The affinity as well as number of ß-receptors is increased with the use of corticosteroids.

TABLE 3 -- Medications for the Acute Relief of Symptoms Generic ß-agonist Brand Name[*] Albuterol

Ventolin, Ventolin HFA, Proventil HFA, Proventil

Pirbuterol

Maxair, Maxair Autohaler

Terbutaline

Brethaire, Brethine, Bricanyl

Metaproterenol

Alupent

Levalbuterol

Xopenex

Albuterol is also available in an inhaler in combination with ipratropium bromide (Combivent).

* Many of these drugs are available in liquid, tablet, inhalation aerosol, as well as metered-dose inhalers.

CURRENT THERAPY Severe: ABCs, oxygen, monitors, POX, IV, isotonic fluids to maintain volume. Start with (consider SC epinephrine if really tight):

Albuterol, 0.5% inhalation solution, 0.5 mL (20 kg) q20 min × 3 (may give as mini-Nebs or start continuous at 2-3 mL/h). After initial stabilization patient will likely need q2h Nebs or continuous albuterol. Methylprednisolone (Solu-Medrol), 2 mg/kg IV (maximum, 125 mg) then start 1 mg/kg q6h (maximum, 80 mg/dose). Ipratropium bromide (Atrovent), 250 µg (5 y) × 2, then q4h. If minimal improvement:

Magnesium sulfate,[1] 45 mg/kg IV over 20 min (maximum, 2 g). If still severe, consider terbutaline drip:

Terbutaline (Brethine), 2-10 µg/kg loading dose, then start infusion at 0.1-0.4 µg/kg/min (maximum, 6 µg/kg/min). Needs pediatric intensive care unit (PICU). At any time if minimal air entry, use:

Epinephrine (1:1000), 0.01 mL/kg SC (maximum, 0.3 mL) or Terbutaline, 0.01 mg/kg SC (maximum, 0.25 mg) Note: Adequate volume can be critical in maintaining circulatory volume (preload), so use volume freely. Also buffering with THAM for severe acidosis can be useful. These two strategies may help you avoid intubation. If you really need to intubate (impending respiratory failure), use atropine, 0.02 mg/kg IV (minimum), 0.1 mg (maximum, 1 mg); ketamine (Ketalar), 1-2 mg/kg IV; or vecuronium (Norcuron), 0.1-0.2 mg/kg IV. Moderate: ABCs, POX, oxygen, monitors. ± IV Start with

Albuterol, 0.5 mL (20 kg) q20 min × 3 (may start with mini Nebs or continuous). Then patient will likely need q2h Nebs or continuous albuterol (2 mL/h 10 kg) Ipratropium bromide, 250 µg (5 y) × 2, then q4h Prednisone, 2 mg/kg (maximum, 80 mg) if tolerating PO or Methylprednisolone, 2 mg/kg (maximum, 80 mg) (continue steroids for 5 d, 2 mg/kg/d) If minimal improvement: Consider magnesium sulfate as above. Mild: ABCs, POX Start with

Albuterol Nebs or MDI with spacer q2-4h Prednisolone, 2 mg/kg loading dose (maximum, 80 mg), then 2 mg/kg/d divided bid × 5 d For mild to moderate exacerbation, discharge home may be considered if patient shows good improvement, is no longer dyspneic or hypoxic, tolerates Nebs q4h, and has good supervision at home. CXR: Consider for a first-time wheezer; a condition other than asthma (i.e., FB); a febrile child with clinical signs of pneumonia; or no clinical improvement or worsening condition (pneumothorax, pneumomediastinum). Continuous albuterol: To calculate the total amount of albuterol and normal saline, remember that the total amount of solution per hour must equal 30 mL. Example: For a child >10 kg, the albuterol dose for continuous Nebs is 3 mL/h so you need to add 27 mL of NSS to run for 1 h (to set it up for 4 h, total mL = 120 with 12 mL albuterol + 108 mL NSS).

Abbreviations: ABCs = airway, breathing, and circulation; CXR = chestradiograph; FB = foreign body; IV = intravenous; Nebs = nebulized; NSS = normal saline solution; POX = pulse oximter; SC = subcutaneous; THAM = tromethamine. 1 Not FDA approved for this indication.

In the management of acute episodes of asthma, an algorithm is used (see Current Therapy box). ßagonists are given either by nebulizer or inhaler. In addition to albuterol, a selective stereoisomer levalbuterol (Xopenex) is also available but is more expensive. This isomer may cause fewer side effects and have a slightly longer duration of action. In the acute setting, treatments are often given every 20 minutes times three and then are continued every 2 to 3 hours for hospitalized patients. In critical situations, albuterol may also be given continuously. It is during the acute situation where ipratropium bromide is beneficial for the first 24 to 48 hours of treatment. It can be given by nebulizer every 4 to 6 hours. Injectable epinephrine is still recommended especially in the acute attack if it is thought to be secondary to allergies or anaphylaxis. It also can be used in the acute situation to make sure that inhaled drugs can reach the lower airway. Magnesium sulfate[1] is used intravenously in severe asthmatics for its bronchodilator properties to prevent intubation or respiratory failure. This is outlined again in the acute management algorithm (Current Therapy box). Theophylline (Theolair) was often the mainstay of asthma management in the 1980s, but its toxicity and the difficulty in having to monitor levels has reduced its use. Nausea, vomiting, abdominal pain, and an increase in hyperactivity often lead to noncompliance. With the selective ß-agonists their use has been minimal. They can be used for chronic management in patients to decrease corticosteroid need. Oral or systemic corticosteroids are always indicated in acute management of episodes of asthma exacerbation. The usual recommended starting dose is 2 mg/kg and should be continued during the episode. Prolonged use of corticosteroids may require a taper, but a short course of 4 to 5 days does not usually require a taper. Any patient who was admitted for an acute exacerbation of asthma should go home on a controller with an action plan for future attacks. In the chronic management of asthma, albuterol is still the mainstay of acute attacks, pre-exercise, and for any reduction in peak flow or pulmonary functions. Albuterol (Proventil) is usually given by metered-dose inhaler and for most patients it is recommended that it be given with a spacer. Spacers increase the deposition in the lower airway and increase the effectiveness of inhaled drugs. In the chronic management of asthma, the NHLBI guidelines recommend that if albuterol is being used more than two or three times a week a step up in controller medications is suggested ( Table 2 ). CONTROLLERS Inhaled corticosteroids are established as the mainstay of chronic management of asthma. Various preparations are available either by dry powder inhaler or metered-dose inhaler. Table 2 outlines the doses

and route. Side effects of growth suppression and decreases in bone mineralization are dose related as well as preparation dependent. Individuals on any of the corticosteroids need to have their growth monitored and also to have instructions on mouth rinsing after inhalation to reduce fungal colonization in the oropharynx. Leukotriene antagonists are available in oral preparations. These offer some advantage in pediatric patients in that they do not require good inhalation technique and can be given once a day. This may improve compliance and offer benefit in asthma as well as allergic rhinitis. They are not as effective as inhaled corticosteroids but offer some benefit in mild disease or as an adjunct to inhaled corticosteroids. Cromolyn (Intal) and nedocromil (Tilade) are available as inhaled medications. Both of these drugs are mast cell stabilizers and appear to be most effective in allergic patients. These drugs should be taken three to four times a day, which makes their compliance more difficult. There are no significant side effects to these medications, however, and they are used in children because of their safety profile. They are used primarily in the mildest of patients and as pretreatment before allergy exposure. Long-acting ß-agonists are characterized as controllers, but these medications cannot be taken as antiinflammatory agents. They have an increased risk of mortality when taken alone. For this reason only the preparations that are in combination with inhaled corticosteroids should be used in children. The drug preparations contain varying doses of inhaled corticosteroid with one standard dose of long-acting ß-agonist. Oral corticosteroids have been used for asthma since they were developed. They were used for patients with severe or chronic asthma before inhaled steroids were available. Because oral corticosteroids have significant side effects they should be used with caution. Prolonged use of systemic steroids leads to adrenal suppression, osteoporosis, and growth suppression. With prolonged use the dose should be reduced gradually. Inhaled corticosteroid effects can be similar to the systemic corticosteroids, especially if they are used at doses higher than recommended. OMALIZUMAB Omalizumab (Xolair) is a monoclonal antibody that is humanized and was developed against IgE. It is expensive and requires monthly injections. It is most effective when allergies are the main trigger for asthma. It is also used in patients with severe anaphylaxis.[1] It is indicated for children with moderate to severe persistent asthma that is exacerbated by significant documented allergies. Because it is nonspecific it does not reduce specific allergies and cannot be used in patients who have no significant atopy. IMMUNOSUPPRESSIVE AGENTS Various experimental studies in patients with chronic steroid-dependent asthma have used immunosuppressive agents such as methotrexate[1] (Trexall), IV gammaglobulin[1] (Gamimune N), and antiinflammatory monoclonal antibodies against cytokines. None of these produced dramatic results and none is available or can be recommended at this time. IMMUNOTHERAPY Specific injections of extracts of allergens to which the patient is allergic is effective for allergic rhinitis that is

secondary to certain allergens. Therapy with allergy extracts is effective for pollens, and by reducing allergic rhinitis symptoms it can affect nasal breathing and therefore benefit asthma. Because of the risk of reactions to immunotherapy it should be used cautiously when the patient is having significant asthma symptoms at the time of injection. Studies in Europe suggest that in the future sublingual immunotherapy may be effective. Well-documented studies in this country have not been done and it is not approved as an FDA procedure. Education and Environmental Control Education of the individual asthmatic is important. Action plans in which treatment of acute episodes is outlined is recommended. Parents and patients should be taught about the patient's triggers as well as steps they should take to increase or decrease their medications depending on symptoms. Environmental precautions such as dust mite avoidance have had some success. Pet avoidance has not worked unless the pet is totally eliminated.



REFERENCES Castro-Rodriguez et al., 2000. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD: A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162:1403-1406. National Institutes of Health/National Heart, Lung, and Blood Institute, 1997. National Institutes of Health/National Heart, Lung, and Blood Institute : NAEPP expert panel report 2: Guidelines for the diagnosis and management of asthma. Publication no. 97-4051, Bethesda, Md, The Institutes, 1997. O'Connor, 2005. O'Connor GT: Allergen avoidance in asthma: What do we do now?. J Allergy Clin Immunol 2005; 116:26-30. Romagnani, 2004. Romagnani S: Immunologic influences on allergy and the TH1/TH2 balance. J Allergy Clin Immunol 2004; 113:395-400. Spahn and Szefler, 2002. Spahn JD, Szefler SJ: Childhood asthma: New insights into management. J Allergy Clin Immunol 2002; 109:3-13.



Chapter 191 – Allergic Rhinitis Caused by Inhalant Factors

Method of: Richard W. Weber, MD Atopy is an inherited disposition manifested by any or all of allergic rhinitis, asthma, or atopic eczema. It is closely, but not invariably, linked to the ability to generate specific allergic antibody, IgE, in greater than normal amounts. Allergic rhinitis is the most prevalent of the atopic diseases, affecting 25% to 35% of persons, depending on the population studied. The atopic disorders have become steadily more prevalent over the past century, although the exact reason for this increase is not clear. Although allergic rhinitis is considered by nonsufferers to be a trivial disease, it delivers a significant personal impact on quality of life. It is responsible for an enormous economic burden in terms of direct medical costs for physician visits and medication and indirect costs of missed work and school and lost productivity. This cost in the United States was recently estimated at more than $2 billion annually and is now presumably even greater. Pathogenesis IgE, like IgA, is a mucosal antibody, produced by plasma cells beneath the mucosal surfaces of the eyes, upper and lower airways, and the gut. IgE is a homocytotropic antibody, binding to specific high-affinity receptors on basophils in the circulation and mast cells in various tissues. Bridging by allergen of two specific IgE molecules on the cell surface is sufficient to cause activation of the basophils or mast cells. This is followed by the release of vasoactive mediators such as histamine, tryptase, leukotrienes, and prostaglandins, as well as several chemokines and cytokines. The former mediators are responsible for the immediate allergic (early-phase) reaction, manifested by sneezing, itching, rhinorrhea, and nasal congestion. Chemotactic factors result in the recruitment of inflammatory cells such as basophils, eosinophils, and polymorphonuclear leukocytes. The influx of these cells is accompanied by fresh release of vasoactive substances, culminating in the delayed (late-phase) reaction with a recrudescence of symptoms. With a single allergen exposure, the early and late phases are easily discernible, the latter occurring 4 to 6 hours after the initial reaction. With persistent exposure, such as with indoor allergens such as dust mite or animal dander, the late-phase inflammatory process is ongoing, resulting in chronic symptoms. With outdoor allergens such as pollens, the persistence of inflammation from prior exposure results in greater sensitivity to further exposures, with lesser pollen amounts resulting in greater symptoms. This is called the priming effect. The proclivity to produce IgE is caused by a shift of helper T-cells cytokine release to a T H2 profile. Two central cytokines to this allergic phenotype are IL-4 and IL-5. The former causes isotype switch in B-cells to IgE production. The latter cytokine is crucial for eosinophil activation and longevity. Once this shift to a T H2 profile occurs, it tends to self-perpetuate. Atopic persons are presumably genetically predisposed to the TH2 phenotype.

In the great majority of instances, allergic rhinitis sensitization is to an airborne, inhalant factor. These aeroallergens may emanate from indoor or outdoor sources and be perennial, relatively constant, or with seasonal peaks. Outdoor sources are usually of plant or fungal origin, namely, pollen grains or spores. These frequently have seasonal peaks whose timing frequently aids in diagnosing the airborne culprit. Depending on the region, tree pollens pollinate in the winter into the early spring, although certain trees shed pollen in the fall. Grasses generally pollinate from May into July, with longer seasons in the southern states, and year round in Hawaii and southern Florida. Although some weeds overlap with the grasses, most pollinate from July into the fall. Aeroallergens indoors are more likely animal in origin: dust mite or cockroach emanations or animal dander. Mold spores are possible, especially with water damage or high humidity, but less likely. The exposures are usually perennial, but there are seasonal peaks in these as well: dust mite in late summer to early fall, cat and dog dander in late winter, and cockroach in summer. A recent study showed that the allergens from dog and cat dander can be found in the dust of essentially all homes, whether pets are present or not. Differential Diagnosis and Co-Morbid Conditions Irritant rhinitis was previously referred to as vasomotor rhinitis, with nasal symptoms driven by perturbations in the environment, and is as frequent as allergic rhinitis. The cause of the increased susceptibility to irritants is not fully understood, although the resultant release of mediators is similar to that seen with allergic rhinitis. A variant of irritant rhinitis is “gustatory rhinitis,” where the act of eating triggers rhinorrhea. Viral infection (upper respiratory infection [URI]) is perhaps the most common cause of nasal symptoms; other infectious agents are distinctly less common. Hormonal factors such as hypothyroidism and pregnancy can lead to increased nasal congestion. Medication-induced nasal congestion was commonly seen with older hypotensive agents and is certainly seen with topical a-adrenergic agonist abuse. Intolerance to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may manifest as asthma, chronic sinusitis, or both. Vasculitides such as Wegener's can present with chronic sinusitis. An expert panel convened by the World Health Organization developed a position statement, “Allergic Rhinitis and Its Impact on Asthma (ARIA).” This document emphasized several important issues. Its scope is not just industrialized countries, but developing countries as well, and it discusses resources with a global perspective. One of the major messages is the frequent concordance of allergic rhinitis and asthma. It is crucial to suspect rhinitis and inflammation of the upper airway as an aggravant in asthma, just as the lower airway should be evaluated in patients with rhinitis. The position statement also suggests that the terms seasonal and perennial be replaced by intermittent and persistent in keeping with the phraseology recommended by the National Asthma Education and Prevention Program (NAEPP) and the Global Initiative for Asthma (GINA) guidelines for management of asthma. Evaluation Evaluation of rhinitis is greatly aided by a careful history: presence of itching and sneezing, severity, seasonality, and progression of symptoms, identifiable triggers, occupational exposures, alleviating factors, and medication usage. A positive family history of atopic disease is helpful. The impact of disease and medication on daily activity is likewise important. The presence of co-morbid conditions is suggested by a history of headache, loss of smell and taste, purulent discharge, cough, chest tightness or wheezing, snoring, and sleep disturbance. Physical examination of the head may reveal characteristic findings. Dennie's lines are folds under the eyes

caused by edema. Dark discoloration under the eyes, or so-called allergic shiners, is caused by venous engorgement. A transverse crease across the nose may be seen in children who chronically push their palm upward under the nose because of rhinorrhea or itching. The turbinates appearing edematous with a bluish mother-of-pearl hue is believed to be pathognomonic but may be seen in nonallergic rhinitis also. Likewise, turbinates may be engorged and erythematous. Lymphoid hyperplasia, or cobblestoning, may be seen on the posterior pharynx. Chronic mouth breathing in children caused by nasal obstruction can cause the allergic facies in the developing facial features. These include open mouth with receding chin and overbite, elongation of the face, and arching of the hard palate. Diagnosis is frequently determined by the appropriate history and findings and supported by demonstration of specific IgE antibodies against a variety of airborne agents. Percutaneous (prick or puncture) skin testing remains the most specific and cost-effective diagnostic modality, although newer CAP-RAST (radioallergosorbent assay) testing is approaching similar sensitivity. Intradermal skin testing is more sensitive but introduces a higher false-positive rate and is not believed to add any diagnostic value to prick testing of potent pollen extracts. There may, however, be a role for intradermal testing with less potent extracts. Pharmacotherapy Pharmacotherapy for allergic rhinitis is the most used mode of treatment, although perhaps not the most effective. H1 antihistamines have the largest market share of rhinitis remedies, although, again, they are not the most effective. Oral first-generation H1 receptor antagonists have been available for more than a half century, and many are obtainable as over-the counter (OTC) preparations. Typical benefits are inhibition of sneezing, itching, and rhinorrhea; oral antihistamines are notoriously ineffective for nasal congestion. Drawbacks are sedation and anticholinergic effects of overdrying. Second-generation antihistamines have the advantage of less anticholinergic effects and little to no sedation. Loratadine (Claritin) is available as an OTC formulation, whereas others such as fexofenadine (Allegra) are still prescription items. Cetirizine (Zyrtec), the active metabolite of hydroxyzine (Atarax), possesses potential for sedation. Topical azelastine (Astelin) is a twice-daily nasal spray as well as an ophthalmic preparation (Optivar). In addition to typical antihistaminic effects, it is modestly anti-inflammatory, improving nasal congestion, presumably through inhibition of ICAM-1, lipoxygenase, and leukotriene C4 synthase. It can cause sedation. Several topical ophthalmic antihistamine preparations are available for associated allergic conjunctivitis.

CURRENT DIAGNOSIS Appropriate history of exacerbants: Perennial or seasonal symptoms, with timing to identify pollens or spores Symptom triggering with identifiable agents such as animals Familial history of asthma, allergic rhinitis, or atopic eczema Medication and medical history: Oral aggravants such as ASA, NSAIDs, hypotensive agents Topical aggravants such as a-agonists Hypothyroidism Pregnancy Physical findings: Rhinorrhea Nasal congestion So-called allergic facies Corroborative findings: Immediate hypersensitivity skin testing Serum-specific IgE Co-morbid conditions: Sinusitis Nasal polyposis Asthma Eustachian tube dysfunction and serous otitis media Abbreviations: ASA = acetylsalicylic acid (aspirin); NSAIDs = nonsteroidal anti-inflammatory drugs.

Leukotriene receptor antagonists were initially approved by the Food and Drug Administration (FDA) for use in asthma, but montelukast (Singulair) was more recently approved for allergic rhinitis therapy as well. However, a recent systematic review and meta-analysis showed these agents to be modestly better than placebo, as effective as antihistamines, and inferior to nasal corticosteroids in improving symptoms and quality of life in patients with seasonal allergic rhinitis. There seems little reason to use leukotriene modifier for treatment of uncomplicated allergic rhinitis. There may be some rationale for using montelukast or zafirlukast1 (Accolate) with zileuton1 (Zyflo) in the treatment of rhinitis complicated by sinusitis with polyposis, although evidence-based data are still missing.

Topical glucocorticoids are the most effective pharmacotherapy for allergic rhinitis. Topical corticosteroids decrease nasal TH2 cytokines, IgE, and eosinophils. A meta-analysis showed superiority over antihistamines in 15 of 16 controlled trials, evaluating symptoms such as rhinorrhea, congestion, and sneezing. Another meta-analysis of nine studies again showed superiority of intranasal corticosteroids over topical antihistamines for nasal symptoms and no difference for ocular symptoms. Even if used on an as-needed basis only, nasal corticosteroids are superior for symptom relief to oral antihistamines. In a short-term 2week study, the combination of montelukast with cetirizine each once daily was shown to be as effective as once-daily intranasal mometasone in improvement of nasal peak flow and total nasal symptoms. Although steroid potency based on receptor affinity is very important in the management of asthma, the dose-response curves for most topical nasal corticosteroids are such that all preparations appear to be equally effective. Choice is therefore predicated on patient preference, which is usually affected by effects of expedients. The most common side effect is epistaxis. Septal perforation is reported, presumably caused by topical vasoconstriction, but is exceedingly uncommon and appears to be adverted by proper administration technique. Concern over systemic side effects is generally not warranted. Fluticasone (Flonase) and mometasone (Nasonex) have very low levels of systemic bioavailability via the nasal route; the levels of budesonide (Rhinocort), triamcinolone (Nasacort), beclomethasone (Vancenase AQ), and flunisolide (Nasalide) are higher. Even so, reports of adverse effects are not common with nasal preparations. For severe symptoms, oral steroids such as prednisone are sometimes used for very short periods to achieve quick improvement. The well-known complications of long-term therapy are not justifiable in the management of rhinitis. In some parts of the United States, intramuscular corticosteroids are considered standard of care for severe symptoms induced by large exposures such as seen with mountain cedar fever. The wisdom of this practice is debatable. An anticholinergic topical preparation, ipratropium bromide (Atrovent 0.06% Nasal Spray), is useful for rhinitis associated with more profuse rhinorrhea. It may be beneficial in allergic rhinitis but has a larger role in nonallergic irritant rhinitis such as cold air–induced, gustatory rhinitis, and the profuse rhinorrhea associated with viral URIs. Ipratropium has no effect on nasal congestion. Methscopolamine (Pamine) is an oral quaternary ammonium anticholinergic used as a drying agent and found primarily in combination with antihistamines such as chlorpheniramine and decongestants such as phenylephrine (Dura-vent/DA). Cromolyn (NasalCrom), a mast cell stabilizer, can be used as a topical nasal spray for allergic rhinitis but needs to be used every 4 hours for optimal efficacy. The use of decongestants is problematic: data on oral efficacy are wanting, and benefit may be overridden by side effects. Potential for significant adverse reactions with overuse resulted in removal of phenylpropanolamine from the U.S. market. Similar problems are arising with pseudoephedrine. Phenylephrine is most often found in combination products. Overuse of topical decongestants like phenylephrine (Neo-Synephrine) and oxymetazoline (Otrivin) results in well-described rebound nasal congestion. The use of saline nasal washes is highly recommended. A commercially available clear squeeze bottle with packets of sodium chloride and baking soda (Neilmed) is effective. This modality is especially useful in patients with complicating chronic sinusitis but is helpful for perennial allergic rhinitis as well. Avoidance and Environmental Controls

Although avoidance of outdoor aeroallergens can be frequently only achieved by remaining indoors, avoidance of indoor allergens is more amenable to intervention. Pets can be removed from the home, although levels of allergenic proteins may take months to subside. And many pet owners choose not to remove an allergenic animal. The value of allergen-impermeable bedding linens is either supported or disavowed by contradictory studies. Control of indoor humidity may provide the best avenue for dust mite and mold abatement. Cockroach control is very difficult to achieve, and sublethal boric acid treatment may actually increase the release of cockroach allergen. Allergen Immunotherapy Allergen vaccine immunotherapy, administered via subcutaneous route, was shown by double-blind placebo-controlled studies to be effective in the treatment of allergic rhinoconjunctivitis. Extracts used include pollens such as short ragweed, timothy grass, other northern grasses, mountain cedar, and pellitory, fungi such as Alternaria and Cladosporium, house dust mites, and cat and dog dander. Immunologic changes include induction of specific lgG, blunting of specific IgE, decreased end-organ responsiveness, decreased recruitment of effector cells, shift from TH2 to TH1 cytokine profile, and induction of T regulatory cells. Sublingual/oral route of administration was studied extensively in Europe, requires high dose of allergen, and appears to have an excellent safety profile but is less effective than subcutaneous immunotherapy and is slower in onset of benefit. Biologic Modifiers Omalizumab 1 (Xolair), the chimeric monoclonal antibody directed against IgE, is effective for allergic rhinitis, although presently approved only for use in steroid-requiring perennial allergic asthmatics. It would be an exceedingly costly way of treating hayfever, but those patients using it for asthma control could expect benefit in concomitant allergic rhinitis symptoms. Considerations in Pregnancy Older antihistamines like chlorpheniramine (Chlor-Trimeton), hydroxyzine (Atarax), and tripelennamine (Pyribenzamine, PBZ) are safe in pregnancy, and data are likewise reassuring for loratadine (Claritin) and cetirizine (Zyrtec). Topical corticosteroids, especially after the first trimester, appear safe; budesonide (Rhinocort) is category B. Cromolyn (NasalCrom) is category B also and can be used for mild disease. Pseudoephedrine (Sudafed) carries a category C, and oral decongestants are best avoided if possible. Allergen immunotherapy with stable maintenance dosing is safe. In conclusion, pharmacotherapy is the most used therapeutic modality in allergic rhinitis because of inhalant factors. Second-generation antihistamines are preferable because of decreased sedation and anticholinergic effects. Topical corticosteroids remain the best and preferred method of treatment, both for seasonal and perennial allergic rhinitis. Addition of antihistamines and antileukotrienes to topical steroids may be beneficial because of a more rapid onset of effect, and they may be withdrawn as control is achieved. Allergen avoidance is recommended but may be difficult depending on the incriminated agent. Allergen vaccine immunotherapy is effective and should be strongly considered in the face of poor response to pharmacotherapy and avoidance.

CURRENT THERAPY Allergen avoidance Pharmacotherapy Topical corticosteroids as first-line monotherapy: Mometasone (Nasonex) Fluticasone (Flonase) Budesonide (Rhinocort Agua) Triamcinolone (Nasocort AQ) Flunisolide (Nasalide) Oral antihistamines used as add-on therapy or alone for mild symptoms: Fexofenadine (second generation) (Allegra) Cetirizine (second generation) (Zyrtec) Loratadine(second generation) (Claritin) Hydroxyzine (Atarax) Chlorpheniramine (Chlor-Trimeton) Diphenhydramine (Astelin) Topical antihistamine (azelastine) Oral leukotriene modifiers (montelukast [Singulair]) as add-on only Oral decongestants: Pseudoephedrine (Sudafed) Phenylephrine (Ah-Chew D) Topical cromolyn (NasalCrom) Nasal saline irrigation (Ocean) Allergen immunotherapy



REFERENCES Benson et al., 2000. Benson M, Strannegård I-L, Strannegård Ö, Wennergren G: Topical steroid treatment of allergic rhinitis decreases nasal fluid Th2 cytokines, eosinophils, eosinophil cationic protein, and IgE but has no significant effect on IFN- , IL-1ß, TNF-a, or neutrophils. J Allergy Clin Immunol 2000; 106:307-312. Bousquet et al., 2001. Bousquet J, Van Cauwenberge P, Khaltaev N: Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108:S147-S334. Frew, 2003. Frew AJ: Immunotherapy of allergic disease. J Allergy Clin Immunol 2003; 111:S712-S719. Incaudo and Takach, 2006. Incaudo GA, Takach P: The diagnosis and treatment of allergic rhinitis during pregnancy and lactation. Immunol Allergy Clin N Am 2006; 26:137-154. Kaszuba et al., 2001. Kaszuba SM, Baroody FM, deTineo M, et al: Superiority of an intranasal corticosteroid compared with an oral antihistamine in the as-needed treatment of seasonal allergic rhinitis. Arch Intern Med 2001; 161:2581-2587. Pedersen, 2001. Pedersen S: Assessing the effect of intranasal steroids on growth. J Allergy Clin Immunol 2001; 108:S40-S44. Weber, 1997. Weber RW: Immunotherapy with allergens. JAMA 1997; 278:1881-1887. Weiner et al., 1998. Weiner JM, Abramson MJ, Puy RM: Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: Systematic review of randomized controlled trials. BMJ 1998; 317:16241629. Wilson et al., 2004. Wilson AM, O'Byrne PM, Parameswaran K: Leukotriene receptor antagonists for allergic rhinitis: A systematic review and meta-analysis. Am J Med 2004; 116:338-344. Wilson et al., 2001. Wilson AM, Orr LO, Sims EJ, Lipworth BJ: Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotrienes receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy 2001; 31:61-68. Yanez and Rodrigo, 2002. Yanez A, Rodrigo GJ: Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: A systematic review with meta-analysis. Ann Allergy Asthma Immunol 2002; 89:479-484.



Chapter 192 – Allergic Reactions to Drugs

Method of: Donald McNeil, MD Drug allergic reactions fall under the broader category of adverse drug reactions (ADRs), which also include toxic drug effects, drug interactions, drug intolerance, and, finally, allergic (or immunologic) drug reactions. Adverse drug reactions are common and often result in only trivial consequences. Some may be severe and life-threatening, and may result from both allergic and nonallergic causes. The incidence of adverse drug effects is unknown but estimates of 20% of hospital admissions are not unreasonable. A skin rash is the most common manifestation; more importantly, however, severe lifethreatening reactions occur, of which only a small portion have an allergic etiology. Most drug reactions are the result of unknown mechanisms. Drug intolerance, drug overdose, and side effects of drugs, as well as drug interactions, all play a significant role. These reactions should be considered both common and predictable. Although allergic drug reactions are potentially severe, they are also the least common and least predictable. Allergic drug reactions are given particular attention because of the unpredictable, costly, and severe consequences that occasionally arise. Several mechanisms may play a role in the underlying etiology of immunologic drug reactions. Immediate IgE-mediated reactions represent the classic allergic reaction. This is well characterized and the best understood, but other mechanisms also exist, for example, a cytotoxic reaction in which drug-induced antibodies result in hemolytic anemia. Another example is immune complex formation resulting in organ damage. This is commonly referred to as a “serum sickness” reaction and is characterized by fever, rash, and arthralgia beginning 2 to 4 weeks after initiation of drug. Finally, a delayed-type hypersensitivity reaction occurs when drug-specific T-lymphocytes react. This completes the picture of the four types of immunologicmediated drug reactions according to the original Gell and Coombs classification. These are referred to as Type I, II, III, or IV reactions, respectively. Cutaneous reactions comprise the most frequent type of allergic drug reaction. Approximately 94% cause a morbilliform rash and only 5% cause an urticarial reaction. Idiosyncratic reactions are still the most likely cause for a rash and occur much more frequently than a true drug-induced allergic reaction. Ampicillins in conjunction with a viral hepatitis or sulfa drugs taken in the AIDS population are common examples. Both allergic and nonallergic reactions are known to be associated with severe reactions, including fatalities. Contrast media agents, allergic extracts, anesthetics, and antibiotics are the most commonly implicated drugs. Penicillin remains the most common cause of fatal drug reactions and accounts for up to 75% of these severe drug reactions in the United States.

An allergy to penicillin is the most frequently reported, but as many as 90% of patients labeled “penicillin allergic” are able to tolerate penicillin. This allergy is often mislabeled because of underlying illness or interaction between antibiotic and illness. Unfortunately one third to half of vancomycin (Vancocin) prescriptions in hospitals are given because of a history of “penicillin allergy.” This raises the incidence of drug-resistant bacteria because of broad-spectrum antibiotic overuse. The economic impact of treating antibiotic-resistant infections is roughly $4 billion annually. Pathophysiology Some drugs are capable of reacting in the body without further alteration in chemical structure, whereas others must first be metabolized to become immunogenic. Many drugs are too small to be immunogenic alone and are incapable of eliciting an immune allergic response. These drugs require binding to a highmolecular-weight protein followed by antigen processing and presentation by the macrophage in the presence of major histocompatibility complex (MHC)-specific antigen to appropriate T-cell receptors. Penicillin is capable of inducing an allergic reaction in more than one manner. Benzylpenicilloyl, the major penicillin determinant, is able to produce a strong antigenic response. A commercially available product, benzylpenicilloyl-polylysine (PPL) (Pre-Pen), provides the means to reproduce the same allergic response by simple skin testing. Minor determinants are metabolic derivatives of penicillin that may also produce an immune response. The diagnostic capabilities of a penicillin allergy are strengthened by including some measure of the allergic response to the minor determinants when skin testing is conducted for penicillin ( Figure 1 ).

FIGURE 1 Penicillin allergy evaluation.x

Patients with a history of penicillin allergy but negative skin testing to PPL and the minor determinants rarely experience allergic reactions on re-exposure. If they should occur, these are not fatal, but rather mild and self-limited. PPL alone will potentially miss a significant percentage of allergic reactions to penicillin. Allergy testing with fresh benzylpenicillin G, aged penicillin (reconstituted more than 24 hours) as well as skin testing with the specific penicillin in question will greatly enhance the likelihood of uncovering of penicillin allergy in a patient with a positive history. Cephalosporins do not provide the same degree of certainty with respect to an allergic evaluation. Crossreactivity with penicillin allergy patients is known to exist, and although uncommon, it is also unpredictable. To err on the side of safety, a patient with a known penicillin allergy should not be treated with a cephalosporin. A patient with a previous cephalosporin reaction with a negative penicillin skin test cannot safely receive penicillin or another cephalosporin unless further diagnostic measures are taken. This patient may be allergic to a side chain on the cephalosporin that has not been identified by penicillin skin testing. Others recommend a graded oral challenge using a cephalosporin with a different side chain. The latter should be done realizing that standardized procedures have not been developed for this and therefore false negative results may occur. Successful desensitization to penicillin has permitted a similar approach with other drugs. If the drug in question is required, either intravenous or oral drug administration is possible by incremental doses given usually every 15 minutes. A 10,000-fold dilution of the initial dose is usually sufficient to begin, followed by higher doses, 2-fold or greater. The vital signs are monitored throughout the procedure with timely medical intervention if problems arise. Sulfonamides typically cause cutaneous reactions, infrequently in healthy individuals but extremely common in AIDS patients. Reactions may be relatively benign in nature such as urticaria or fixed-drug eruption, but may also cause more serious reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). A variety of mechanisms may exist, alone or in combination, using IgE antibody response, T-lymphocytes, and inflammatory cytokines. Because of our inadequate understanding of these mechanisms, there are no universally acceptable means of evaluating sulfonamide hypersensitivity. Unless there has been previously severe reaction, a graded challenge with the drug in question is considered a reasonable alternative ( Box 1 ). Although a theoretical risk exists between sulfonamides and drugs with sulfonamide derivatives (diuretics, COX-2 inhibitors), little data show this is actually true. BOX 1

Graded Challenge 1.

Cautious administration of medications to patient not likely allergic to drug.

2.

Not to be considered equivalent to desensitization.

3.

Used when insufficient evidence available to exclude drug allergy.

4.

Medication administered in incremental doses beginning at 1:100 dilution of final dose.

5.

Adequate medical resources exist to treat allergic reaction.

Radiographic contrast media (RCM) produce an anaphylactoid reaction by an unknown mechanism. Conventional RCM is hypertonic. The newer nonionic RCM with lower osmolarity are associated with fewer anaphylactoid or allergic-like reactions. Complement system activation, which is capable of causing histamine release, is thought to be the method by which this reaction occurs. In the continuum of adverse drug effects with suspected hypersensitivity, exposure to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) rarely exhibits features that are IgE mediated and allergic in nature, and are more often nonimmunologic mediated. A non–IgE-mediated event must still be approached with caution because the consequences are potentially life-threatening. More commonly, NSAIDs are associated with the asthma triad syndrome associated with nasal polyps or rhinitis, and severe asthma. This is not an allergic drug reaction, but it represents a largely unrecognized subpopulation of asthmatics who will benefit by avoiding the use of NSAIDs. The antibiotic vancomycin (Vancocin) causes a reaction referred to as red man syndrome. Histamine and other mast cell mediators are released, but not through vancomycin-induced IgE antibody (rare cases have been reported). Most, but not all, cases of the red man syndrome are related to the rate of the infusion, and most will subside once the medication is stopped. A graded challenge with the drug or a full course of desensitization usually permits resumption of treatment. Angiotensin-converting enzyme (ACE) inhibitors are well known to be associated with cough and angioedema, but like NSAIDs, the mechanism is unknown. Newer ACE inhibitors have been described to cause similar reactions but at a much lower incidence. The symptoms of cough and angioedema may continue to recur for several months and up to a year after the discontinuation of the drug. As seen from the discussion above, IgE-mediated allergic drug reactions represent only a portion of immune-mediated drug reactions. To assist in the diagnosis, a 7- to 10-day delay in the appearance of the drug reaction after initial treatment or immediate reactivation on re-exposure suggests an immunologic etiology. Oftentimes, only the history will provide this index of suspicion. Confirmation by positive skin testing with the drug in question is highly predictive of IgE-mediated hypersensitivity. Attempts to label reactions as either IgE- or non–IgE-mediated may prove to be costly, time-consuming, and of no immediate benefit. Non-IgE reactions are capable of eliciting changes in vital signs, pulmonary function, and cutaneous effects similar to anaphylaxis and are referred to as anaphylactoid. These need to

be regarded with the same degree of caution as IgE-mediated reactions. Narcotics, radiographic contrast media, and chemotherapeutic agents may directly affect mast cell mediator release with the consequences listed above. Antihistamines and corticosteroids given prior to administration of these drugs are usually sufficient to prevent a reoccurrence, or at least to minimize these reactions. Drug desensitization is indicated for those patients with positive skin tests who must receive the drug, but should not be assumed to be universally safe or protective. Some chemotherapeutic agents, such as etoposide (VePesid) and teniposide (Vumon), have a much higher incidence of anaphylactoid reactions. Readministration of these drugs in the face of a previous reaction and in spite of prophylactic measures often leads to disappointing results. Current biologic response modifier agents, as well as others soon to arrive, are associated with adverse reactions. Monoclonal antibodies, T- and B-cell inactivators, and others may prove to have adverse immunologic effects that will only become more apparent with the experience of increased use. Evaluation of Drug Allergy in Practice The importance of a reliable history in a medical evaluation is never more evident than during the initial workup of a suspected drug allergy. The timing of exposure, with the first allergic reaction occurring within days of the priming dose or immediately upon re-exposure, strongly points to an allergic etiology. Multiple exposures to the same drug on previous occasions do not preclude an allergic reaction de novo. Similarly, a previous history of an allergic drug reaction does not by itself predict a reoccurrence on re-exposure. The allergic diathesis may wane over time for drugs just as it may occur for other allergens. Armed with this suggestive drug history and clinical findings such as a rash, fever, bronchospasm, or anaphylaxis, the evaluation becomes more straightforward. In the appropriate clinical setting, eosinophilia will also support a drug-allergic reaction. Avoiding the implicated drug may be the simplest approach because confirmation of the diagnosis with appropriate skin testing is often unavailable. (Standardized skin testing exists only for penicillin, but even this does not provide 100% reliability.) Skin testing with the drug is questionable, but using both a positive and negative control of histamine and saline may still provide useful information. A positive skin test would certainly discourage use of this drug unless adequate precautions were taken. If a non–life-threatening history of a reaction exists and the drug cannot be appropriately substituted, the option exists for a graded oral challenge to confirm the diagnosis. This should not be considered to be the same as desensitization because it involves higher doses and exposure over a shorter period of time than would be considered safe in a truly allergic individual. A challenge such as this should be conducted in suitable medical facilities under close medical supervision. If the drug in question has been shown to cause an allergic reaction but still must be used, then a carefully monitored drug desensitization program should be considered. Under medical supervision, the drug should be administered orally or intravenously beginning with doses that are tenfold more dilute than the final strength. Incrementally higher doses of the drug should be administered every 15 minutes, increasing the

dose twofold each time. Drug-induced skin reactions are common and warrant particular attention. Early recognition is necessary to avoid an incorrect diagnosis and to institute appropriate interventional measures as soon as possible. The following points will assist the physician in arriving at a correct diagnosis. The timing of the onset of the reaction in relation to the time the drug was given provides an important clue. Often signs and symptoms develop 1 to 2 weeks after time of initial drug exposure. Symptoms may develop rapidly on repeat exposure. Pruritic urticarial lesions strongly suggest an adverse drug reaction. A symmetrical or truncal distribution or a rash that occurs only in sun-exposed areas (polymorphous light eruption) also supports an ADR finding. The morphology of the reaction is helpful, although many types occur (lichenoid, morbilliform, eczematous). The histopathology of the lesion on skin biopsy may reveal eosinophils, which may also be detected in the peripheral blood. Drugs that commonly cause ADRs tend to be antibiotics. The most common is the morbilliform rash when ampicillin is given in the presence of a viral infection such as infectious mononucleosis or cytomegalovirus. Rarely is this IgE mediated and it should not be regarded as a basis for a history of penicillin allergy. It should also be noted that not all ADRs are caused by prescription medications. A patient may fail to disclose over-the-counter medications that might be responsible (e.g., St. John's wort). The response to treatment may aid in the recognition of an ADR. An incomplete response to topical steroids is typical of an ADR and systemic steroids may turn out to be the therapy of choice. Finally, the response to withdrawal of drug may range from a rapid recovery to slow clearing over many weeks, but a favorable response nonetheless. Table 1 lists several drugs used to treat AIDS/HIV that are worthy of mention. Not all should be considered to be an allergic cause of ADR.

TABLE 1 -- Drugs Used to Treat AIDS/HIV Drug

Reaction

Zidovudine, AZT (Retrovir)

Hyperpigmentation

Zalcitabine, ddC (Hivid)

Oral ulcers

Abacavir (Ziagen)

Severe rash/anaphylaxis

Nevirapine (Viramune)

Toxic epidermal necrolysis

Foscarnet

Urethral ulceration

Trimethoprim-sulfamethoxazole (TMP-SMX) (Bactrim) Morbilliform rash or erythema multiforme

A careful and systematic approach to the patient with a suspected drug allergy will provide valuable information for both the immediate and the long-term management of the patient. A suspected drug allergy that is disproved will facilitate good medical care because unnecessary expense and the risk of further

sensitizing the patient to a new medication will be spared if the patient is not allergic. On the other hand, a positive screen for a suspected drug allergy will result in a safe alternative. It should be emphasized, however, that neither a family history of a drug allergy nor a patient requesting a “test” for a possible drug allergy without other reason is an indication for further drug allergy evaluation because of the risk of falsenegative results.



Chapter 193 – Allergic Reactions to Insect Stings[*]

Method of: David B.K. Golden, MD Insect bites and stings normally cause temporary localized swelling, redness, pain, and itching. Allergic swelling can also result from insect bites or stings, but stinging insects of the order Hymenoptera can cause anaphylaxis. Allergic reactions to stings from honeybees, vespids (yellow jackets, hornets, wasps), and fire ants are caused by IgE antibodies directed against the protein allergens in the venoms (but not in the bodies or saliva) of these insects. Yellow jacket and hornet venoms are almost identical and are partially cross reactive with wasp venoms, but honeybee venom and fire ant venom are each unique. Commercial venom vaccines are available for honeybee, yellow jacket, yellow hornet, white-faced hornet, and Polistes wasps (ALK Laboratories; Hollister-Stier Laboratories). For fire ant sting allergy, imported fire ant whole body extract is the only commercial available material. Although it contains sufficient venom allergens for diagnostic use and for immunotherapy, evidence indicates that venom is superior. Allergic reactions may be localized or systemic. Large local reactions have a late-phase inflammatory mechanism that progresses for 24 to 48 hours after the sting, causing a painful induration that is often larger than 6 inches in diameter and lasts for 5 to 10 days. A large local reaction to a sting can mimic laryngeal edema (from a sting in the mouth or throat) or cellulitis (lymphangitic drainage from the reaction on an extremity). Systemic reactions are immediate hypersensitivity reactions with manifestations distant from the site of the sting, which can include any one or more of the signs or symptoms of anaphylaxis including urticaria, angioedema, flushing, throat or chest tightness, dyspnea, dizziness, or hypotensive shock. The reported frequency of 50 to 100 fatal reactions per year in the United States is certainly an underestimate. Elevated serum tryptase and venom-specific IgE antibodies are reported in postmortem blood samples in cases of unexpected death in young individuals. Half of fatal reactions occurred in persons with no prior history of reactions to stings, and most occur in individuals older than 45 years. The population at risk is greater than generally appreciated: 3% of adults in the United States have a history of a systemic allergic reaction to insect stings, and more than 20% have IgE antibodies to venom allergens detectable in the skin or blood. * This work was supported by National Institutes of Health (NH) grant A108270.

Diagnosis A detailed history provides the most important diagnostic information. The exact features and time course of the reaction can distinguish large local, systemic, and nonallergic reactions. Objective signs and documented clinical observations are more reliable than subjective descriptions. Venom-specific IgE antibodies can be demonstrated by skin testing or serologic methods (radioallergosorbent assay test [RAST]) but must be interpreted in the context of the clinical history. Skin testing with the five Hymenoptera venoms (or fire ant whole body extract) is recommended for patients who have had systemic allergic reactions to a sting but is not required for large local reactions. Skin tests are performed with superficial intradermal injection of 0.02 mL of each venom at concentrations starting at 0.001 µg/mL and increasing

incrementally up to 1.0 µg/mL, if needed, until a positive wheal and flare reaction is elicited. Diagnostic laboratory measurement of venom-specific IgE antibodies (RAST) may be useful when skin testing is inconclusive or cannot be performed but is less sensitive than skin testing. The venom RAST is positive in 10% of affected patients with negative skin tests, and conversely, the RAST is negative in 20% of patients with positive skin tests. A positive venom skin test in an individual with no history of sting reaction is associated with a 17% frequency of systemic reaction to a subsequent sting. The level of sensitivity on skin test or RAST is not correlated consistently with the severity of the sting reaction. Assessing the risk of a systemic reaction to a future sting is based on the detailed history of previous reactions, the presence of venom-specific IgE antibodies, and the known natural history of the condition ( Table 1 ). In adults with positive venom skin tests and a prior history of systemic reactions, the risk of systemic reaction is 30% to 60%, with the higher risk in patients with the most severe reactions (airway obstruction, unconsciousness) and the lower frequency in patients who had cutaneous systemic signs (urticaria, angioedema) and/or mild dizziness or throat tightness. The risk declines with time, but remains at 15% to 20% even after 20 to 30 years. The risk of systemic reaction is known to be low in the general population and in some subgroups of sensitized individuals ( Table 2 ). The majority of affected children (16 years and younger) have had systemic reactions limited to skin manifestations, including generalized hives and angioedema of the face or lips but with no tongue or throat swelling and no dyspnea or hypotension. In these children, subsequent stings cause no systemic reaction in 90%, mild cutaneous systemic reactions in 5%, and more severe systemic reaction in less than 5% of cases. Patients with large local reactions generally have strongly positive venom skin tests but have only a 5% risk of systemic reaction to future stings.

TABLE 1 -- Clinical Recommendations Based on History of Sting Reactions, Age, and Results of Venom Skin Test (or RAST) Reaction to Previous Sting Skin Test (or RAST) Risk of Systemic Reaction Clinical Recommendation No reaction

Positive

10%–15%

Avoidance

Large local

Positive

5%–10%

Avoidance

Cutaneous systemic

Positive: child

5%–10%

Avoidance

Positive: adult

15%–20%

Venom immunotherapy

Positive

30%–60%

Venom immunotherapy

Negative

5%–10%

Repeat skin test/RAST

Anaphylaxis

Abbreviations: RAST = radioallergosorbent assay test.

TABLE 2 -- Considerations in Stopping Venom Immunotherapy

Severity/pattern of systemic reaction Age (child/teen, adult, senior) Skin tests/RAST (persistent strong) Time/duration of venom immunotherapy Systemic reaction during venom immunotherapy(to injection or sting) Quality of life/exposure Abbreviation: RAST = radioallergosorbent assay test.

CURRENT DIAGNOSIS History of systemic allergic reactions to sting Positive venom skin tests or radioallergosorbent assay test (RAST) Degree of test reaction not correlated with severity of sting reaction Low risk if previous large local sting reactions Low risk in children with mild systemic reactions Quality of life and frequency of exposure a consideration Treatment and Avoidance of Sting Reactions Local sting reactions can be treated symptomatically with ice and oral antihistamines. Large local reactions may require a burst of oral prednisone (e.g., 40 to 60 mg the first day, tapering over 4 to 7 days) but almost never require antibiotic treatment. Systemic reactions generally require the intramuscular administration of epinephrine (1:1000), 0.3 mg in an adult (0.01 mg/kg in children), with the availability of oxygen, intravenous fluids, or airway support if needed. Corticosteroids have no benefit in the acute stage, but despite a lack of supporting evidence are often administered in the hope of preventing late-phase manifestations. The patient should be monitored for 3 to 6 hours because more than 20% of severe cases develop biphasic or protracted anaphylaxis. Any patient judged to have a risk for anaphylaxis to future stings should have a prescription for an epinephrine injection kit and detailed instructions on when to use or not use it. Commercial kits include the EpiPen (0.3 mg epinephrine) and EpiPen Jr (0.15 mg epinephrine) (Dey Laboratories) and the Twinject (two doses of either 0.15 or 0.3 mg epinephrine) (Verus Pharmaceuticals). Such individuals should also be referred to a specialist for evaluation and discussion of risks and treatment options. Sting-allergic patients should avoid nesting areas, trash receptacles, eating or drinking outdoors, lawn mowing, or going barefoot. Prevention of Sting Reactions (Venom Immunotherapy) Systemic reactions to insect stings can be prevented with up to 98% efficacy with venom immunotherapy. The indications for therapy are simply a positive history (of systemic reaction to stings) and positive venom skin tests (or RAST), although the severity of previous reactions and the patient's age at the time are also important variables ( Table 3 ). Venom immunotherapy, and therefore skin testing, is not considered

necessary for low-risk patients because more than 90% will never have a systemic reaction, such as in patients with large local reactions and in children with cutaneous systemic reactions.

TABLE 3 -- Patients with Low Risk for Anaphylaxis Minimal (60 years of age), anemia, evidence of significant cardiac or pulmonary involvement, tendon friction rubs, and the presence of antitopoisomerase antibodies. In general, therapies fall into two groups: those that target the underlying pathophysiologic process, and those that alleviate or reverse target organ complications. Because major internal organ involvement develops early, disease-modifying interventions should be considered before tissue damage becomes established. Because SSc is invariably a multisystem disease, a coordinated approach to evaluation and management by an integrated multidisciplinary team including a rheumatologist, pulmonologist, cardiologist,

gastroenterologist, vascular or orthopedic surgeon, and physical therapist is desirable. Patients should also be given the opportunity to participate in controlled clinical trials on novel therapeutic agents. DISEASE-MODIFYING THERAPIES To date, no therapy is shown conclusively to be disease modifying in SSc. Nonetheless, based on historical or anecdotal evidence or empirical considerations, many agents are used widely in an attempt to reverse or halt the progression of the immunologic, vascular, and fibrotic damage ( Box 3 ). In light of the potential toxicities associated with these therapies and their lack of proven benefit, decisions regarding their use must be considered carefully. In patients with limited SSc and stable disease, organ-based treatments directed toward specific complications of the disease (see later) are generally more appropriate than these generalized disease-modifying treatment strategies. BOX 3 Potentially Disease-Modifying Interventions for Systemic Sclerosis (SSc) Immunomodulatory

•

•

Methotrexate[*]

•

Cyclophosphamide[*]

•

Mycophenolate mofetil[*]

•

Antithymocyte globulin

•

Autologous stem cell therapy (with or without immune oblation)

Antifibrotic •

d-Penicillamine[*]

•

Interferon

* Although commonly used, to date these interventions have not been demonstrated in controlled clinical trials to be of unequivocal benefit in the treatment of SSc.

ORGAN-BASED TREATMENT APPROACHES Therapy for Skin Involvement

Skin induration can be progressive and widespread in diffuse cutaneous SSc, whereas it is generally not prominent in limited cutaneous form. Extensive skin involvement often, but not invariably, predicts severe internal organ involvement. In diffuse SSc, skin induration generally peaks in the first 2 to 4 years of SSc, after which it regresses with spontaneous softening. In early disease, inflammation of the skin dominates, with edema, erythema, and pruritus. Patients at this stage benefit form antihistamines such as hydroxyzine (Atarax),[1] 25 mg at bedtime. Low-dose glucocorticoids such as prednisone,[1] 5 mg daily, provide substantial symptomatic relief for inflammation in early SSc but should be used with caution in light of the increased risk of scleroderma renal crisis (see later); patients taking low-dose prednisone[1] should be instructed to monitor their blood pressure daily. Digital ulcers can be managed using Duoderm[1] application to promote healing and topical povidone-iodine (Betadine)[1] solution for cleansing.

Therapy for Vascular Involvement Raynaud's Phenomenon and Its Complications

Widespread damage of small and medium-sized peripheral blood vessels is virtually universal in SSc. Endothelial cell injury is associated with release of vasoconstrictors such as thromboxane and endothelin 1 (ET1), impaired production of vasodilators such as nitric oxide and prostacyclin, and platelet aggregation and thrombosis. What starts out as a reversible dysfunction of vascular smooth muscle often progresses to irreversible structural alterations characterized by intimal layer proliferation, medial hypertrophy, and adventitial fibrosis. Reduced blood flow and repeated episodes of ischemic reperfusion in the digits, kidneys, lungs, heart, and other involved organs cause tissue ischemia, progressive vascular damage, and fibrosis. Cold-induced Raynaud's phenomenon is the most common presenting problem in SSc and may precede other manifestations of the disease by years. Repeated and increasingly severe Raynaud's episodes lead to digital ischemia, resulting in painful ulcers and nonhealing pitting scars and, in extreme cases, digital infarction and gangrene. Patients should be counseled to stop smoking and to avoid cold exposure, which triggers vasoconstriction; not only the hands but the whole body should also be kept warm. Mild Raynaud's phenomenon can be effectively treated with orally active vasodilators ( Table 2 ) and treatment is most commonly started with calcium channel blockers. Infection complicating digital ulcers should be treated aggressively with antibiotics; such ulcers may take months to heal and may progress to osteomyelitis. The ET1 receptor blocker bosentan (Tracleer),[1] 125 mg twice daily, is effective in preventing digital ulcers. Patients with impending digital infarction may respond tointravenous epoprostenol (Flolan),[1] 0.5 to 6 µg/kg body weight per minute for 6 to 24 hours, or nonpharmacologic interventions such as sympathetic ganglion blockade and surgical digital sympathectomy. The role of statin drugs, antioxidants such as tocopherol (vitamin E)[1] (400 IU daily), and diets rich in fish oils in preventing vascular damage in Raynaud's phenomenon are not yet adequately studied.

TABLE 2 -- Oral Vasodilator Therapy for Raynaud's Phenomenon in Systemic Sclerosis Agent Dose Calcium Channel Blockers Nifedipine (Procardia) 10-30 mg three times daily Diltiazem (Cardizem) 30-120 mg three times daily Amlodipine (Norvasc) 5-20 mg daily Felodipine (Plendil)

2.5-10 mg daily

Angiotensin II Receptor Antagonists Losartan (Cozaar)

25-100 mg daily

Valsartan (Diovan)

80-320 mg daily

Sympatholytic Agents Prazosin (Minipress)

1-5 mg daily

Doxazosin (Cardura) 1-16 mg daily Nitroglycerin

2% ointment topically once daily

Adapted from Wigley FM: Raynaud's phenomenon. N Engl J Med 2002;347(13):1001-1008.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH), which occurs in at least 15% of SSc patients, has a major impact on survival. PAH may complicate interstitial pulmonary fibrosis or may occur in the absence of parenchymal lung disease; the latter is indistinguishable from primary (idiopathic) and familial pulmonary hypertension. Because PAH may be asymptomatic until advanced, it was historically underdiagnosed in SSc. Moderately severe PAH is associated with exertional dyspnea, chest pain, and syncope; right-sided heart failure is seen in late-stage disease. Emphasis must be placed on early preclinical recognition of PAH. A combination of pulmonary function testing and Doppler echocardiography is appropriate for screening and should be performed yearly. Right heart catheterization is the gold standard for determining pulmonary arterial pressures and cardiac index and for excluding pulmonary embolism. Several new classes of agents provide at least short-term symptomatic and hemodynamic improvement in PAH. Patients with New York Heart Association functional class III or IV symptoms (ordinary activity causing dyspnea, chest pain, or near syncope) should start an orally active ET1 receptor blocker such as bosentan (Tracleer). In addition, warfarin anticoagulation (to achieve an INR [international normalized ratio] of 1.5 to 2.0), low-flow oxygen therapy, diuretics, and digitalization are generally indicated. Patients who fail to respond to ET1 antagonists may benefit from parenteral prostacyclin analogues such as inhaled iloprost (Ventavis), every 2 hours up to 45 µg daily, or continuous infusions of subcutaneous treprostinil (Remodulin) 1.25 µg/kg per minute, or intravenous epoprostenol (Flolan), 2 to 10 µg/kg per minute. A major limitation of these therapies is their cost, now exceeding $30,000 per year. Furthermore, because of their short half-lives, prostacyclin analogues must be administered by continuous infusion or frequent inhalations. Epoprostenol requires long-term ambulatory central venous catheterization, which may be complicated by line sepsis and pump failure with potentially catastrophic consequences. Combinations of a prostacyclin analogue together with an ET1 antagonist or a phosphodiesterase type 5 inhibitor such as sildenafil (Viagra),[1] up to 50 mg three times daily, appear to be well tolerated and provide added benefit. Surgical options for patients unresponsive to pharmacologic therapies include atrial septostomy and lung transplantation. In light of the complexity involved, the evaluation and management of PAH in SSc patients should be coordinated by specialized centers having appropriate expertise. Therapy for Interstitial Lung Disease

Some degree of interstitial lung disease is present in most patients with SSc and is a leading cause of death. The extent and progression of pulmonary fibrosis are major determinants of outcome. Combined with pulmonary function testing, high-resolution computed tomography (HRCT) scan of the chest is more sensitive for interstitial lung disease screening than chest radiography. A ground-glass appearance generally correlates with active inflammation (alveolitis). Patients with alveolitis may benefit from cyclophosphamide (Cytoxan)[1] (orally up to 50 mg daily, or intravenously as pulse therapy up to 1000 mg/m2 monthly) to stabilize lung function. Low-dose prednisone[1] (up to 20 mg daily) is often used in combination with cyclophosphamide. The optimal duration of cyclophosphamide[1] treatment is uncertain, but some experts recommend at least a year. General supportive measures include pneumococcal vaccination and yearly influenza immunization, avoidance of smoking, prevention of gastroesophageal reflux, nasal oxygen supplementation, and bronchodilators. Respiratory tract infections should be treated with empirical antibiotics. For selected patients with progressive respiratory decline, lung transplantation remains an option.

Therapy for Gastrointestinal Tract Involvement

Gastrointestinal involvement is common, can be extensive, and significantly contributes to the morbidity of SSc. Gastroesophageal reflux may be associated with dyspepsia, dysphagia, and regurgitation and can lead to chronic esophagitis and its complications ( Box 4 ). Reflux should be managed by elevating the head of the bed, eliminating triggers such as chocolates, alcohol, and tobacco, and restricting food intake before going to sleep. Most patients require long-term treatment with proton pump inhibitors such as omeprazole (Prilosec)[1] in doses sufficient to suppress reflux symptoms (up to 160 mg daily). Prokinetic agents such as metoclopramide (Reglan)[1] (10 mg four times daily) or erythromycin [1] (250 mg three times daily) may be effective for gastroparesis. Chronic diarrhea and malabsorption caused by small bowel bacterial overgrowth can be treated with periodic courses of tetracycline[1] (500 mg four times daily) or metronidazole (Flagyl)[1] (500 mg three times daily). Some patients benefit from subcutaneous octreotide injections (Sandostatin,)[1] (50 mg one to four times daily). Nutritional assessment and support are important aspects of management. Gastric vascular ectasia (watermelon stomach) is frequent in SSc and causes recurrent occult gastrointestinal bleeding. It can be effectively treated with laser argon ablation. BOX 4 Gastrointestinal Tract Complications of Systemic Sclerosis (SSc) Esophageal dysmotility leading to dysphagia and chronic gastroesophageal reflux; dyspepsia, esophagitis, strictures, ulcers, pulmonary aspiration; Barrett's esophagus and esophageal adenocarcinoma •

Watermelon stomach with upper gastrointestinal bleeding

•

Gastroparesis and small bowel hypomotility

•

Blind loop syndrome with malabsorption, weight loss, diarrhea

•

Large bowel pseudo-obstruction

•

Colonic perforation

•

Pneumatosis cystoides intestinalis

Therapy for Renal Involvement

Scleroderma renal crisis, which develops in up to 15% of patients with SSc, was uniformly fatal in the pre–angiotensin-converting enzyme(ACE)[1] inhibitor era. Risk factors include progressive skin induration, male sex, and glucocorticoid use. Renal crisis characteristically manifests with an abrupt rise in blood pressure, frequently associated with retinal hemorrhages, and occasionally with seizures and pulmonary hemorrhage, microangiopathic hemolysis, and rapidly progressive oliguric renal insufficiency. The key to controlling this dreaded complication of SSc is early recognition. Accordingly, high-risk patients should monitor their blood pressure daily, and if there is a rise in blood pressure, a new onset of proteinuria, or a rise in creatinine, patients should be hospitalized for close monitoring and aggressive management. Some patients ( 10 cm2)

•

Liquid nitrogen applied on a large, loosely wound piece of cotton on a wooden stick; or with a cryoprobe, by the spray technique

•

Freeze the wart and 1- to 2-mm surrounding border

Treatment Mechanism Podophyllin Arrest in mitosis resin leading to tissue necrosis

Good Choice for •

Moist warts

Poor Choice for •

Dry wart areas

•

Do not exceed 10 cm2 treatment area

•

TCA (TriChlor)[1]

Surgery

Chemical coagulation of wart proteins

Direct removal of lesions

Procedure •

Use a cotton tip and apply a thin layer to wart and allow to airdry before the patient assumes a normal anatomic position

•

Leave on overnight and avoid washing, bathing, and sexual contact

•

Repeat treatment 1 week later, as needed

•

Apply sparingly to the lesion, being careful not to let the solution run onto normal skin

•

Repeat weekly or every other week, as needed

Not for pregnancy

•

Small, moist, few warts

•

Large wart areas (> 10 cm2)

•

Pregnancy OK

•

Dry warts

•

Large or small treatment areas

•

Bleeding disorders

•

•

Rectal lesions OK

Superficial tangential scissor excision, electrodesiccation, hot cautery, curettage, or CO2 laser may be used

•

Pregnancy OK

•

Moist warts

•

Do not exceed 10 cm2 treatment area

•

Apply bid for 3 days following by a 4-day treatment-free period

•

Repeat weekly cycles four to six times, as needed

Patient applied Podofilox (Condylox)

Arrest in mitosis tissue necrosis

•

Not for pregnancy

•

Poor compliance

Treatment Imiquimod (Aldara)

Mechanism Good Choice for Poor Choice for Immunomodulator • Moist warts • Large wart areas (> 10 cm2) •

Dry warts

•

Poor compliance

Procedure •

Apply every other night on moist warts or intertriginous areas, or every night on dry warts

•

May be used for up to 16 weeks, as tolerated

Abbreviations: TCA = trichloroacetic acid.


TREATMENT MODALITIES Current treatments are divided into provider-administered and patient-applied therapies. Provideradministered therapies include cryotherapy, podophyllin resin (Podocon-25), trichloroacetic acid (TriChlor)[1], and surgery. Patient-applied therapies allow the patient greater control and include podofilox (Condylox) and imiquimod (Aldara). However, these require good compliance and that the patient be able to view and reach the warts. PROVIDER-ADMINISTERED THERAPIES Cryotherapy

Cryotherapy works well for small, flat, few warts in dry or moist areas. It can be used on the penile shaft and vulva with little scarring. It can be used during pregnancy. It is not recommended for large wart areas, which can be quite painful and cause wound-care issues. A small, tightly wound cotton swab (Q-tip) that holds inadequate amounts of liquid nitrogen cannot effectively freeze a wart. Apply liquid nitrogen with a large, loosely wound piece of cotton on a wooden stick or with a cryoprobe. A few small warts can be frozen without an anesthetic. Patients with more warts should be offered local anesthesia, with either injection of 1% lidocaine[1] or topical application of a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA cream).[1] Freeze the wart and 1- to 2-mm surrounding border. For larger warts, two freeze-thaw cycles are effective. How hard to freeze the warts can be learned with experience. Cryotherapy requires proper training. Complications are rare but inexperienced clinicians often underfreeze areas, reducing efficacy. Overfreezing increases pain and the probability of scarring and other complications. Warn patients about post-treatment pain and blistering. 1 Not FDA approved for this indication.

Podophyllin Resin

Podophyllin resin (Podofin, Podocon-25, Podofilm) is from the plant species Podophyllum peltatum or Podophyllum emodii. This resin contains podofilox (podophyllotoxin), 4-dimethylpodophyllotoxin, a-peltatum, and ß-peltatum, which cause cellular mitotic arrest and lead to tissue necrosis. It is a good choice for moist warts and up to a 10 cm2 surface area. It is ineffective in dry areas, such as the scrotum, penile shaft, and labia majora. Podophyllin resin lacks a standardized preparation, but it is commonly used as a 10% to 25% solution in tincture of benzoin. Use a cotton tip and apply a thin layer directly to the wart and allow to air dry before the patient assumes a normal anatomic position. Traditionally, patients were advised to wash off podophyllin 2 to 4 hours after application, but benzoin is water insoluble and cannot be removed simply with soap and water. Another ill-advised but not uncommon practice is to create a barrier around the wart with Vaseline or K-Y jelly, and apply podophyllin resin to the central wart. Body temperature thins the barrier, which mixes with the podophyllin resin, and spreads over the entire area, creating an impressive irritant reaction. I advise patients to leave the podophyllin resin on overnight and avoid washing, bathing, or sexual contact until the next day. Local side effects include erythema, pain, and irritation. Systemic side effects are caused by increased toxic absorption and are associated with large treatment area (>10 cm2) or allowing the resin to absorb for an extended time. Avoid podophyllin resin in pregnancy. Trichloroacetic Acid (Tri-Chlor)[1]

Trichloroacetic acid ([TCA] Tri-Chlor)[1] chemically coagulates warts and adjacent skin. Use for small, few, moist warts. TCA [1] can be used during pregnancy. Although 30% to 70% solutions are employed, the optimal concentration is undetermined. Use extreme caution with the higher concentrations, which can be highly caustic. Apply sparingly to lesions, being careful not to let the solution run onto normal skin. Treatment can be repeated weekly, or every other week, as needed. TCA[1] can be neutralized, if needed, with soap and sodium bicarbonate. Surgery

Surgery renders the patient wart free with a single visit. It is a good choice for limited or large treatment areas. There is no clearly superior surgical modality. Selection of a surgical approach depends on clinician experience and availability of equipment. Good results can be achieved with superficial tangential scissors, electrodesiccation, hot cautery, curettage, or CO2 laser. PATIENT-APPLIED THERAPIES Podofilox

The major active lignin in podophyllin resin is podofilox, available as a 0.5% solution or gel (Condylox). Apply to warts twice daily for 3 days followed by a treatment-free period of 4 days. Repeat this cycle four to six times to achieve wart clearance. A maximum of 10 cm2 should be treated, and podofilox should be avoided in pregnancy.

Imiquimod

Imiquimod (Aldara) is a 5% cream, applied three times weekly at bedtime to moist wart areas. Dry and nonintertriginous areas may respond better to daily application. It can be used for up to 16 weeks. As imiquimod stimulates an inflammatory response, however, local irritation, burning, and ulceration are expected side effects and are similar to those seen with other modalities. 5-Fluorouracil

5-Fluorouracil creams (Carac, Effudex),[1] used previously for genital warts, are no longer recommended because of side effects, uproven efficacy, and the availability of other treatments. Transmission and Prevention HPV is a sexually transmitted disease (STD). Educate patients to tell sexual partners that they have this infection. Condoms may decrease transmission but do not completely prevent infection. Asymptomatic partners can harbor a subclinical infection, and examination for genital warts is appropriate if lesions are suspected. It is unknown whether treatment of genital wart lesions eliminates infectivity. Discuss the oncogenic potential of HPV types associated with bowenoid papulosis. Women with external genital warts or whose male partners have lesions should have a Pap smear and remain in the system for monitoring for cervical cancer. Investigations for other STDs should be done if suspected. Acquiring an STD carries a negative social stigma and emotional trauma. Patients often fear discovery and rejection and feel guilty and victimized. They view themselves as less sexually desirable, enjoy sex less, and have concerns about transmission. Teaching and educational materials are available from the American Social Health Association (1-919-361-8422).



REFERENCES Beutner et al., 1998. Beutner KR, Richwald GA, Wiley DJ, et al: External genital warts: Report of the American Medical Association consensus conference. Clin Infect Dis 1998; 27:796-806. Beutner et al., 1999. Beutner KR, Wiley DJ, Douglas JM, et al: Genital warts and their treatment. Clin Infect Dis 1999; 28(Suppl 1):S37-S56. Habif, 2004. Habif TP: Sexually transmitted viral infections. In: Hodgson S, Cook L, ed. Clinial Dermatology, A Color Guide to Diagnosis and Therapy, 4th ed.. Philadelphia: Mosby; 2004:336-342. Odom et al., 2000. Odom RB, James WD, Berger TG: Viral diseases. In: Fathman EM, Geisel EB, Salmo A, ed. Andrews' Diseases of the Skin, Clinical Dermatology, 9th ed.. Philadelphia: WB Saunders; 2000:541-591.



Chapter 205 – Nevi

Method of: Raymond L. Barnhill, MD Seth I. Felder, BA Brandon D. Einstein, BA A nevus (plural, nevi), also known as a melanocytic nevus, nevocellular nevus, or mole, is a benign neoplasm composed of melanocytes. Melanocytic nevi originate from melanoblasts that migrate from the neural crest to the epidermis. Nevi are believed to be either developmental malformations (hamartomas) or benign clonal proliferations that have a growth advantage over surrounding basilar melanocytes. This article discusses the most common acquired and congenital benign melanocytic lesions. Epidemiology Acquired melanocytic nevi most commonly appear in childhood and adolescence, but they can also develop later in life. In contrast, congenital melanocytic nevi are usually presumed to be present at birth, possibly resulting from a developmental error in neuroectodermal melanocyte migration. This classification of melanocytic nevi as acquired or congenital, however, has limitations. Relatively small melanocytic nevi that fulfill clinical and histopathologic criteria for congenital nevi might not be present at birth. Such lesions can develop later as congenital nevus–like nevi or tardive congenital nevi. Few nevi are present in early childhood, and prevalence increases until the third decade of life. Over time, melanocytic nevi commonly become less pigmented and therefore less noticeable, and some nevi actually disappear. The incidence of nevi is related to age, race, and genetic and environmental factors. Gender is not a factor in the proclivity for developing nevi. Generally, white persons have more nevi than persons from darkerskinned ethnic groups, such as persons of Asian or sub-Saharan African ancestry. Additionally, persons with fair complexions, such as Fitzpatrick types I and II—especially those with a history of sun exposure—are most likely to acquire nevi. The notion that benign melanocytic nevi are potentially precursors to malignancy is often misinterpreted, because most melanomas arise de novo from normal skin. Regardless of origin, a greater number of melanocytic nevi, with or without atypical features, is associated with an increased risk of developing melanoma.

CURRENT DIAGNOSIS The diagnosis of a nevus is based on clinical appearance When a nevus is suspicious for melanoma, it must be biopsied for histopathologic examination Total body skin examination is recommended and should be accomplished in light of the individual patient's personal and familial histories Suspicious nevi are generally asymmetric, have irregular borders, show color variegation, and are often greater than 6 mm in diameter Appropriate documentation should include the lesion's location, pattern, color, and size Evaluation of nevi consists of unaided visual inspection along with advanced diagnostic tools such as dermoscopy and computer-aided image analysis, which are increasingly available and supplement clinical diagnostic accuracy. Broad-spectrum sun protection and skin self-examination using the ABCD criteria should be discussed and encouraged. Baseline photography is often useful in the surveillance of high-risk patients, particularly those with multiple nevi, and allows evaluation of comparative changes over time. Clinical Presentations Melanocytic nevi can manifest as macules, papules, plaques, or nodules with variable contours, patterns, and pigmentations. Despite variability of nevi morphology, distinctive attributes allow classification with high specificity using clinical, dermoscopic, and histopathologic examination. Melanocytic nevi are biologically benign lesions. That is, they arise, grow to a certain size, and then cease developing. The common denominator of all melanocytic nevi is an increased number of melanocytes within the epidermis, dermis, subcutaneous fat, or any combination of these sites. Common acquired nevi are well-circumscribed round or ovoid lesions, generally from 2 to 6 mm in diameter. They appear orderly and symmetric, with regular, well-defined borders. Junctional nevi are uniform light to dark brown macules with regular borders. These lesions are characterized histologically by nests of melanocytes at the dermoepidermal junction. Nests of melanocytes confined to the dermis are referred to as dermal nevi. These pigmented papules or nodules are light to dark brown dome-shaped lesions. Compound nevi are slightly raised papules or plaques, light to dark brown, and composed of nests of melanocytes at the dermoepidermal junction and papillary dermis. There is clinical and histologic overlap among the three types of nevi ( Table 1 ). In general, benign nevi differ from melanoma by their smaller size, overall symmetry, homogenous coloration, and well-defined borders ( Box 1 ).

TABLE 1 -- Clinical and Histologic Features of Common Acquired Melanocytic Nevi Feature

Junctional

Compound

Dermal

Size

20 vesicles outside the primarily involved dermatome) is most frequently observed in the immunosuppressed population. Atypical clinical manifestations such as crusted, verrucous papules and plaques may also be noted. DIAGNOSIS Herpes Simplex Virus

Viral culture, serology, direct immunofluorescence, and molecular techniques are available laboratory tests for the diagnosis of HSV infection. Viral culture is a useful method of diagnosis in first-time genital outbreaks or few mucocutaneous lesions. The cell culture technique is most reliable at the onset of symptoms, before healing or crusting of the vesicular lesions. False negative results may occur, especially in lesions that are already healing. Direct fluorescent antibody staining of vesicle base scrapings is 95% diagnostic and can be used to distinguish VZV from HSV. In one study direct immunofluorescence and culture were shown to be equally sensitive at 88% in detection of HSV, whereas direct immunofluorescence was four times more sensitive (100% versus 18%) than culture in the case of VZV. The gold standard of serologic diagnosis is the Western blot test, which is 99% sensitive and 99% specific for HSV antibodies. To distinguish between HSV-1 and HSV-2, type-specific serologic assays based on type-specific glycoproteins from HSV-1 and HSV-2 are available and approved by the Food and Drug Administration (FDA). The Tzanck smear offers a rapid and useful bedside test of HSV infection and relies on the identification of multinucleated giant cells in vesicular scrapings. However, this test does not differentiate among HSV-1, HSV-2, or VZV.

CURRENT DIAGNOSIS Grouped or clustered vesicles and erosions on an erythematous base should prompt consideration of herpetic etiology The presence of painful crusted, eroded, or vesicular lesions on the nose should prompt immediate ophthalmologic evaluation and empiric antiviral therapy (the so-called Hutchinson's sign, a diagnostic urgency implicating possible herpes keratitis) A high suspicion for herpetic etiology in an immunosuppressed patient is critical Laboratory tests: Viral culture is useful in first-time outbreaks, however time sensitive Serology Western blot Type-specific serologic assays based on glycoproteins Direct immunofluorescence: rapid and specific Tzanck smear:[*] rapid, but nonspecific Polymerase chain reaction of cerebrospinal fluid Abbreviations: HSV-1 = herpes simplex virus type 1; HSV-2 = herpes simplex virus type 2; VZV = varicella-zoster virus. * This test does not differentiate between HSV-1, HSV-2, or VZV.

On histopathologic examination, characteristic ballooning degeneration of keratinocytes, spongiosis or frank vesiculation, and nuclear molding may be observed. Intranuclear inclusion bodies may also be present. Polymerase chain reaction (PCR) of the cerebrospinal fluid is the test of choice for HSV infections of the central nervous system. Varicella-Zoster Virus

A thorough history and physical examination are critical in diagnosis and often prompt initial antiviral therapy. The Tzanck smear (see previous mention) may aid in prompt diagnosis but will not distinguish between HSV and VZV. Similar limited information may be provided by histopathologic specimens of lesional skin. Direct fluorescent antibody, viral culture, serology, and PCR may all distinguish between HSV and VZV. Viral culture is the most specific, albeit a less-sensitive test.

CURRENT THERAPY Both topical and systemic antiviral treatments may be used to manage orolabial herpes in immunocompetent people Systemic agents offer the best treatment for primary and recurrent genital herpes Immunosuppressed individuals need more aggressive management with oral or IV antivirals Early treatment and empirical therapy are critical for herpes zoster Prompt ophthalmologic evaluation and empirical therapy is critical for nasal herpetic presentations. Abbreviation: IV = intravenous.

Polymerase chain reaction is the test of choice for detection of VZV in the cerebrospinal fluid. Serologic tests have limited utility, because most of the population is seropositive. TREATMENT Both topical and systemic antiviral treatments are useful in the management of orolabial herpes in immunocompetent people. Oral valacyclovir (Valtrex), 2 grams orally taken twice in one 24-hour period,[3] and topical 1% penciclovir result in decreased duration of pain, clinical lesions, and duration of viral shedding. Systemic antiviral agents are the agents of choice for the treatment of primary and recurrent genital herpes (see Table 1 ). Three highly effective and well-tolerated antivirals are acyclovir (Zovirax), valacyclovir (Valtrex), and famciclovir (Famvir). All have been shown to shorten the duration, severity, pain, and period of viral shedding for initial and recurrent genital herpes infections. Because they inhibit only actively replicating viral DNA, these medications are not useful for the treatment of latent infection.

TABLE 1 -- Systemic Antiviral Therapy for Herpes Simplex Virus and Varicella Zoster Virus Herpes Simplex Virus Infection First episode of genital herpes Acyclovir (Zovirax)

400 mg PO tid for 7–10 d

Acyclovir

200 mg PO 5 times/d for 7–10 d

Famciclovir (Famvir)

250 mg PO tid for 7–10 d

Valacyclovir (Valtrex)

1 g PO bid for 7–10 d

Recurrent episode of genital herpes Acyclovir

400 mg PO tid for 5 d

Acyclovir

200 mg PO 5 times/d for 5 d

Acyclovir

800 mg PO bid for 5 d

Famciclovir

125 mg PO bid for 5 d

Valacyclovir

500 mg PO bid for 3–5 d

Valacyclovir

1.0 g PO bid for 5 d

Valacyclovir

2.0 g PO bid for 1 d[3]

Chronic suppressive therapy Acyclovir

400 mg PO bid

Famciclovir

250 mg PO bid

Valacyclovir

500 mg PO qd (90% BSA) Involvement of multiple mucosal surfaces usual High morbidity; mortality rate: 25% to 40% Abbreviations: BSA = body surface area; EM = erythema multiforme; HSV = herpes simplex virus 1 Not FDA approved for this indication.

Supportive Care

Because of the extensive epidermal and mucosal necrosis and detachment that can occur in SJS and TEN, careful monitoring is critical and hospitalization is often required. Early referral of severe cases to an intensive care or burn unit decreases mortality. Poor outcome can be predicted by a TEN-specific severity of illness score and correlates with the number of specific independent risk factors for mortality present within the first 24 hours after admission to an intensive care unit ( Box 2 ). BOX 2

SCORTEN: A Severity-of-Illness Score Predictive of Mortality in Toxic Epidermal Necrolysis •

Age =40 y

•

Presence of malignancy

•

Initial epidermal detachment =10% BSA

•

BUN =28 mg/dL

•

Glucose =252 mg/dL

•

HCO3 slightly 15 to 20 minutes), they should not be allowed to return to play on that day or even not for 1 to 2 weeks following the complete resolution of all symptoms. It should also be stressed that an individual may have a concussion without loss of consciousness and that concussion is defined as any transient change in mental status. To this end many organizations including the National Football League have developed a sideline neuropsychological screening test that can often help illustrate these deficits even when the athlete appears normal. Restorative Therapies Patients suffering any type of TBI can have long-lasting cognitive, psychological, and emotional dysfunction in addition to their functional and neurologic deficits. Although most people assume that the resolution of decreased alertness and consciousness symbolizes resolution of the overall neurologic injury, this is not the case in most patients. In our series of patients with moderate TBI, we found that almost 50% of patients at median follow-up of 27 months complained of persistent emotional or cognitive problems that interfered with their lifestyle despite the fact that they all were discharged from the hospital with a GCS score of 14 to 15. Long-term speech and cognitive therapies as well as individual, group, and family counseling will be helpful for many of these patients. In the late hospital and early rehabilitative stages, numerous pharmacologic agents may be helpful to overcome some of the neurologic side effects following TBI. Patients with autonomic storms (intermittent episodes of diaphoresis, tachycardia, fever, agitation) may respond to adrenergic antagonists such as clonidine (Catapres)[1] or propanolol (Inderal), [1] in addition to volume resuscitation, morphine (Lioresal),[1] baclofen,[1] and bromocriptine (Parlodel).[1] Patients with hypoarousal are treated with amantadine[1] (Symmetrel), 100 mg at 8 am and 12 pm, and bromocriptine,[1] 5 to 15 mg every day. Trazodone (Desyrel), 50 to 100 mg at bedtime, may be helpful in restoring sleep-wake cycles, whereas risperidone (Risperdal),[1] olanzapine (Zyprexa),[1] and quetiapine (Seroquel)[1] may be helpful to control agitation and combativeness during the subacute recovery phases. Future Considerations

The previously mentioned treatment strategies include what is considered common practice at the University of Louisville; however, newer, more aggressive treatments and monitoring capabilities are always being developed. Some of the newer monitoring systems under development include cerebral oximetry measurements (frequently through invasive indwelling catheters) or cerebral microdialysis systems, in which continuous assessments are performed to determine the concentrations of critical markers such as lactate in the brain or CSF. Both of these methods provide physiologic feedback for the metabolic environment of the brain, are sensitive enough to predict changes in regional oxygenation, and have been found to be correlated with outcomes in small nonrandomized studies.



REFERENCES Brain Trauma Foundation, 2000. Brain Trauma Foundation : Management and Prognosis of Severe Traumatic Brain Injury, New York, Brain Trauma Foundation, 2000. Mcilvoy et al., 2001. Mcilvoy L, Spain DA, Raque G, et al: Successful incorporation of the Severe Head Injury Guidelines into a phased-outcome clinical pathway. J Neurosci Nurs 2001; 33(2):72-78.82 Miller et al., 2001. Miller PR, Fabian TC, Bee TK, et al: Blunt cerebrovascular injuries: Diagnosis and treatment. J Trauma 2001; 51(2):279-286. Temkin et al., 1990. Temkin NR, Dikmen SS, Wilensky AJ, et al: A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990; 323:497-502. Vitaz et al., 2001. Vitaz TW, McIlvoy L, Raque GH, et al: Development and implementation of a clinical pathway for severe traumatic brain injury. J Trauma 2001; 51(2):369-375. Vitaz et al., 2001. Vitaz TW, McIlvoy L, Raque GH, et al: Development and implementation of a clinical pathway for spinal cord injuries. J Spinal Disord 2001; 14(3):271-276. Vitaz et al., 2003. Vitaz TW, Jenks J, Raque GH, Shields CB: Outcome following moderate traumatic brain injury. Surg Neurol 2003; 60(4):285-291.



Chapter 241 – Traumatic Brain Injury in Children

Method of: Stephen R. Deputy, MD Traumatic brain injury (TBI) is one of the leading causes of death and disability among children, adolescents, and young adults. An estimated 185 per 100,000 children (ages 0 to 14 years) and 550 per 100,000 adolescents (ages 15 to 19 years) are hospitalized each year for TBI. The etiology of TBI varies depending on the age of the patient, with younger children more likely to be injured from falls and pedestrian injuries, and adolescents more often injured in motor vehicle accidents and assaults. Inflicted TBI (shakingimpact syndrome of infancy) is the leading cause of injury-related deaths in children younger than 4 years of age and accounts for 80% of deaths from head trauma in children younger than 2 years of age. Types and Severity of Head Injury Closed head injury is the most common type of TBI seen in children. Forces from rapid deceleration are applied diffusely throughout the brain and consciousness is frequently impaired. Open head injuries, in which the dura is breached, are caused by focal penetrating forces, and the risk of post-traumatic epilepsy is relatively high. Primary brain injury is caused by the mechanical forces of the trauma itself. Diffuse axonal injury is an example of primary brain injury. During rapid deceleration, angular forces applied to the head cause the brain to rotate about its center of gravity. Shifting regions of differing densities within the brain itself result in shearing along planes such as the gray-white junction, corpus callosum, and brainstem. The shearing of axons effectively serves to “disconnect” the cortex from the brainstem and consciousness becomes impaired. Translational (straight-line) forces applied to the head produce impact-loading contact phenomena, resulting in focal injuries to the scalp, skull, and brain, such as lacerations, skull fractures, cerebral contusions, and epidural hematomas. Subdural hematomas may occur because of tearing of fragile dural bridging veins during rapid decelerations. Secondary brain injury follows and is the consequence of primary injury. Examples include hypoxic-ischemic injury (secondary to low cerebral perfusion pressure or anoxia), disrupted cerebral autoregulation, seizures or status epilepticus, diffuse cerebral edema, hydrocephalus, and raised intracranial pressure. The goal of treatment for TBI is to reduce or prevent secondary brain injury from occurring because the primary brain injury has already happened at the time of trauma and cannot be altered. The severity of TBI can be broken down into mild, moderate, and severe. Mild TBI is defined as head trauma with an initial Glasgow Coma Scale (GCS) score of 13 to 15. Moderate TBI occurs with an initial GCS score of 9 to 12. Severe TBI occurs with an initial GCS score of 8 or less. The GCS is modified for use in infants under the age of 36 months ( Table 1 ).

TABLE 1 -- Glasgow Coma Scale for Children Score Eyes Open

Best Verbal Response

Best Verbal Response

Best Motor Response (6.0 mg/dL).

Serum transaminase levels

Rising serum transaminase values suggest severe preeclampsia with hepatic involvement.

Serum albumin, lactic acid dehydrogenase, blood smear, and coagulation profile

For women with severe disease, these values indicate the extent of endothelial leak (hypoalbuminemia), presence of hemolysis (lactic aciddehydrogenase level increase, schizocytosis, spherocytosis), and possible coagulopathy, including thrombocytopenia.

Prevention of Preeclampsia Preventing preeclampsia is a challenge because of the limited knowledge of its etiology. During the past two decades, numerous clinical reports and randomized trials described the use of various methods to reduce the rate and/or severity of preeclampsia. Table 4 summarizes current opinion and data on the prevention of preeclampsia. Prevention focuses on identifying women at higher risk and conducting close clinical and laboratory monitoring, to recognize the disease process in its early stages. Although these measures do not prevent preeclampsia, they may be helpful for preventing some adverse maternal and fetal sequelae.

TABLE 4 -- Effectiveness of Agents in Prevention of Preeclampsia Agent

Prevention

Low-dose aspirin prophylaxis

Minimal to no reduction in the incidence of preeclampsia. The prevailing opinion is that women without risk factors do not benefit from treatment. Overall, administration of low-dose aspirin to women at risk leads to a 19% reduction in the risk of developing preeclampsia. On average, for every 69 women treated, 1 case is prevented. Starting aspirin before 12 weeks and/or using higher doses cannot be recommended for clinical practice until more information is available about safety. As the reductions in risk are small to moderate, relatively large numbers of women need to be treated to prevent a single adverse outcome.

Calcium supplementation

No data indicate that dietary supplementation with calcium prevents preeclampsia in lowrisk women in the United States. Randomized trials of calcium supplementation in women considered at high risk of gestational hypertension (teenagers, previous preeclampsia, women with increased sensitivity to angiotensin II, preexisting hypertension) and in communities with low dietary calcium intake (mean intake equals 900 mg per day) demonstrate significant reductions in incidence of preeclampsia.

Magnesium supplementation

Prophylactic magnesium is not beneficial in preventing preeclampsia.

Zinc supplementation

No benefit in preventing preeclampsia.

Agent

Prevention

Fish oil supplementation

No reduction in the incidence of preeclampsia.

Antioxidant therapy (vitamin C[1] and vitamin E [1])

Limited data show some promise in preventing preeclampsia.

Salt restriction


Diuretic therapy[1]


1 Not FDA approved for the indication.

Management of Hypertensive Disorders of Pregnancy Three factors underlie any management scheme in hypertension and pregnancy. First, delivery is always appropriate therapy for the mother but may not be for the fetus. Second, the pathophysiologic changes of severe preeclampsia indicate that poor perfusion is the major factor leading to maternal physiologic derangement and increased perinatal morbidity and mortality. Third, the pathogenic changes of preeclampsia are present long before clinical diagnostic criteria are manifest. For maternal health, the goal of therapy is to prevent eclampsia as well as other severe complications of preeclampsia. If there is a rationale for management other than delivery, it is to palliate the maternal condition to allow fetal maturation and cervical ripening. ANTICONVULSIVE THERAPY Anticonvulsive therapy is usually indicated either to prevent recurrent convulsions in women with eclampsia or to prevent convulsions in women with preeclampsia. There is universal consensus that women with eclampsia should receive anticonvulsive therapy. Several randomized studies indicate that parenteral magnesium sulfate reduces the frequency of eclampsia more effectively than phenytoin (Dilantin). Parenteral magnesium sulfate is given during labor and delivery and for variable durations postpartum. There is no clear agreement concerning the use of prophylactic magnesium for women with preeclampsia. Although parenteral magnesium sulfate should be given peripartum to women with severe preeclampsia, its benefits with mild gestational hypertension or preeclampsia remain unclear. Women with eclampsia require prompt intervention. When an eclamptic seizure occurs, the woman should be medically stabilized. First, it is important to control convulsions and prevent their recurrence with intravenous or intramuscular magnesium sulfate. One protocol is a 4- to 6-g loading dose diluted in 100 mL fluid and administered intravenously for 15 to 20 minutes, followed by 2 g per hour as a continuous intravenous infusion. ANTIHYPERTENSIVE THERAPY Therapy in Acute Hypertension

Antihypertensive therapy is indicated when blood pressure is dangerously high or rises suddenly in women with preeclampsia, especially intrapartum. Pharmacologic treatment with antihypertensives can be withheld as long as maternal pressure is only mildly elevated. Some experts treat persistent diastolic blood pressure of 105 mm Hg or above. Others withhold treatment until the diastolic blood pressure reaches 110 mm Hg. Table 5 summarizes the medications used to treat acute elevations in blood pressure. The goal of blood pressure reduction in emergency situations should be a gradual reduction to the normal range.

TABLE 5 -- Medications to Treat Acute Severe Hypertensive Crises in Pregnancy Route of Dose Pharmacologic Agent Administration Notes Arterial vasodilator (hydralazine: e.g., Apresoline)

IV or IM 5 mg over 1-2 min

After 20 min, subsequent doses are dictated by initial response; once desired response, repeat as necessary (usually 3 h)

ß-Blockers (labetalol: e.g., Normodyne or Trandate)

IV

20-40 mg bolus or 1 mg/kg infusion (max 220 mg)

If effect is suboptimal to initial 20 mg IV, give 40 mg 10 min later and 80 mg every 10 min for additional two doses. Avoid in women with asthma and in those with congestive heart failure (CHF).

Calcium antagonists (nifedipine: e.g., Adalat, Procardia)

PO

10 mg PO and repeat The JNC VII recommends rapidly acting nifedipine in 30 min, if necessary not be used for treating hypertension or hypertensive emergencies.

Sodium nitroprusside (Nipride)

IV

0.25 µ g/kg/min to a maximum of 5 µ g/kg/min

After failure of hydralazine, nifedipine, and labetalol. Fetal cyanide poisoning may occur if used more than 4 h.

Abbreviations: IM = intramuscularly; IV = intravenously; JNC VII = Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; PO = by mouth.

Therapy in Chronic Hypertension

The role of antihypertensive therapy for pregnant women with mild to moderate chronic hypertension (stage 1 or 2 hypertension, defined as systolic blood pressure of 140 to 179 mm Hg or diastolic blood pressure of 90 to 109) is unclear. Among women with stage l to 2 preexisting essential hypertension and normal renal function, most pregnancies have good maternal and neonatal outcomes. Because there is no immediate need to lower blood pressure, the rationale for treatment is that it will prevent or delay progression to more severe disease, thereby benefiting the woman and/or her infant and reducing consumption of health service resources. In addition to reducing blood pressure, these drugs are believed to reduce the risk of preterm delivery and placental abruption and improve fetal growth. A wide variety of drugs are advocated, and each group has different potential side affects and adverse effects ( Table 6 ). More importantly, these women are candidates for nonpharmacologic therapy because to date no evidence indicates that pharmacologic treatment results in improved neonatal outcomes. Because blood pressure usually falls during the first half of pregnancy, hypertension may be easier to control with less or no medication.

TABLE 6 -- Antihypertensive Drug Selection Usual Dose Range in mg/day (Daily Drug Example Notes Frequency Central a2agonists

Methyldopa (e.g., Aldomet)

250-1000 (2)

First-line therapy on the basis of reports of stable uteroplacental blood flow and fetal hemodynamics.

ß-Blockers

Labetalol (e.g., Normodyne, Trandate)

200-800 (2)

There is a suggestion that ß-blockers prescribed early in pregnancy, specifically atenolol (Tenormin), may be associated with growth restriction. None of these agents are associated to date with any consistent ill effect.

Calcium antagonists

Nifedipine long-acting (e.g., Adalat CC, Procardia XL)

30-60 (1)

Experience is limited, with most reported uses late in pregnancy.

Diuretic

Hydrochlorothiazide (e.g., HydroDIURIL)

12.5-50 mg (1)

Use is controversial; however, if their use is indicated, they are safe and efficacious agents; they can markedly potentiate the response to other antihypertensive agents, and they are not contraindicated, except in settings where uteroplacental perfusion is already reduced (preeclampsia and IUGR).

Contraindicated

Contraindicated because of association with fetal growth restriction, oligohydramnios, neonatal renal failure, and neonatal death. Fetal risks with ACE inhibitors depend on timing and dose.

Angiotensin II Losartan (e.g., Cozaar) Contraindicated receptor antagonists

Data are limited. Adverse effects likely to be similar to those reported with ACE inhibitors, and these agents should be avoided.

ACE inhibitors Captopril (e.g., Capoten)

Abbreviations: ACE = angiotensin-converting enzyme; IUGR = intrauterine growth retardation.

The value of continued administration of antihypertensive medications to pregnant women with chronic hypertension continues to be debatable. Although it may be beneficial for the mother with hypertension to reduce her blood pressure, lower pressure may impair uteroplacental perfusion and thereby interfere with fetal development. On the basis of available data, some centers currently manage women with chronic hypertension by stopping antihypertensive medications under close observation. In patients who have had hypertension for several years, show evidence of target organ damage, or take multiple antihypertensive agents, medications may be tapered on the basis of blood pressure readings, but medications should be continued if they are needed to control blood pressure. The end point for reinstituting treatment includes exceeding threshold blood pressure levels of 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic or the presence of target organ damage. Methyldopa (Aldomet) is preferred by most practitioners. Women who are well controlled on antihypertensive therapy before pregnancy may be kept on the same agents during

pregnancy, with the exception of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. For women with severe hypertension (stage 3 hypertension, usually defined as 160 to 170 mm Hg or more systolic blood pressure or 110 mm Hg or more diastolic blood pressure), there is a risk of direct arterial damage, so antihypertensive medications are indicated to lower blood pressure (see Table 6 ). The most effective antihypertensive drug is unclear. Fetal Assessment FETAL ASSESSMENT IN PREECLAMPSIA Nonstress testing (NST), ultrasound assessment of fetal activity and amniotic fluid volume (biophysical profile [BPP]), and fetal movement counts constitute the most common fetal surveillance techniques. Although weekly to biweekly assessment usually suffices, daily testing is appropriate for women with severe preeclampsia who are being managed expectantly. If fetal surveillance (nonreactive NST, oligohydramnios, nonreassuring BPP) indicates possible fetal compromise, the decision to deliver must be significantly weighted by fetal age ( Box 3 ). BOX 3 Fetal Monitoring in Hypertensive Disorders •

•

•

Gestational hypertension—Hypertension only without proteinuria, with normal laboratory test results, and without symptoms. 1.

Perform estimation of fetal growth and amniotic fluid status at diagnosis. If results are normal, repeat testing only if a significant change occurs in maternal condition.

2.

Perform NST at diagnosis. If NST is nonreactive, perform BPP. If BPP value is 8 or if NST is reactive, repeat testing only if a significant change occurs in maternal condition.

Mild preeclampsia—Mild hypertension plus proteinuria (300 mg or more per 24-hour period), normal platelet count, normal liver enzymes values, and no maternal symptoms. 1.

Perform estimation of fetal growth and amniotic fluid status at diagnosis. If results are normal, repeat testing every 3 weeks.

2.

Perform NST, BPP, or both at diagnosis. If NST is reactive or if BPP value is 8, repeat weekly. Repeat testing immediately if abrupt change in maternal condition occurs.

3.

If estimated fetal weight by ultrasound is less than 10th percentile for gestational age, or if there is oligohydramnios (amniotic fluid index equals or is less than 5 cm), perform testing at least twice weekly.

Severe preeclampsia—Severe hypertension in association with abnormal proteinuria; hypertension in association with severe proteinuria (at least 5 g per 24-hour period); presence of multiorgan involvement such as pulmonary edema, seizures, oliguria (less than 500 mL per 24-hour period), thrombocytopenia (platelet count less than 100,000/mm3), abnormal liver enzymes in association with persistent epigastric or right upper quadrant pain; persistent severe central nervous system symptoms (altered mental status, headaches, blurred vision, or blindness).

1.

Term Hospitalize, prevent seizures, control hypertension, and proceed with delivery.

2.

Remote from term Provide care in a tertiary-care setting. Perform laboratory evaluation and fetal surveillance (as outlined for mild preeclampsia earlier) daily depending on the severity and progression of the disorder.[1]

•

Chronic hypertension—Mild hypertension (BP more than 140/90 mm Hg) or severe hypertension (BP equal or more than 180/110 mm Hg) present before the 20th week of pregnancy or hypertension present before pregnancy. 1.

Perform baseline ultrasonography at 18 to 20 weeks and repeat at 28 to 32 weeks of gestation and monthly thereafter until delivery, to monitor fetal growth.

2.

If growth restriction is detected or suspected, monitor fetal status frequently with NST or BPP.[1]

3.

If growth restriction is not present and superimposed preeclampsia is excluded, these tests are not indicated.[1]

Abbreviations: BPP = biophysical profile; NST = nonstress test. 1 Not FDA approved for this indication.

FETAL ASSESSMENT IN CHRONIC HYPERTENSION Much of the increased perinatal morbidity and mortality associated with chronic hypertension can be attributed to superimposed preeclampsia and/or fetal growth restriction. A plan of antepartum fetal assessment is directed by these findings. Thus efforts should be directed toward the early detection of superimposed preeclampsia and fetal growth restriction. If these conditions are excluded, extensive fetal antepartum testing is less essential. Most authorities recommend an initial sonographic assessment of fetal size and dating at week 18 to 20 of gestation. Fetal growth should be carefully assessed thereafter. If this assessment is not possible with usual clinical estimation of fundal height, sonographic assessment should be performed at 28 to 32 weeks and every 4 weeks until term. If growth restriction is evident, fetal well-being should be assessed by nonstress tests or biophysical profiles as usual for the growth-restricted fetus. Similarly, if preeclampsia cannot be excluded, fetal assessment as appropriate for the fetus of a woman with preeclampsia is mandatory. If the infant is normally grown and preeclampsia can be excluded, however, these studies are not indicated. Maternal Assessment MATERNAL ASSESSMENT IN PREECLAMPSIA Antepartum monitoring has two goals. The first goal is to recognize preeclampsia early; the second is to

observe progression of the condition, both to prevent maternal complications by delivery and to determine whether fetal well-being can be safely monitored with the usual intermittent observations. Current clinical management of preeclampsia is directed by overt clinical signs and symptoms. Although rapid weight increase and facial edema may indicate the fluid and sodium retention of preeclampsia, they are neither universally present nor uniquely characteristic of preeclampsia. These signs are, at best, a reason to monitor blood pressure and urinary protein more closely. Early recognition of impending preeclampsia is based primarily on blood pressure increases in the late second and third trimesters. Once blood pressure starts to rise, a repeat examination within 1 to 3 days is recommended. The woman should be evaluated for symptoms suggestive of preeclampsia and undergo laboratory testing for platelet count, renal function, and liver enzymes. Quantification of a 12- to 24-hour urine sample for proteinuria is recommended. The frequency of subsequent observations is determined by the initial observations and the ensuing clinical progression. If the condition appears stable, weekly observations may be appropriate. MATERNAL ASSESSMENT IN CHRONIC HYPERTENSION No consensus exists as to the most appropriate fetal surveillance test(s) or interval and timing of testing in women with chronic hypertension. Testing should be individualized, based on clinical judgment and on the severity of disease. There are no conclusive data to address either the benefits or the harms of various monitoring strategies for pregnant women with chronic hypertension. Box 3 lists the current proposed recommendations for antepartum monitoring. When chronic hypertension is complicated by intrauterine growth retardation (IUGR) or preeclampsia, fetal surveillance is warranted. Indications for Delivery INDICATIONS FOR DELIVERY IN PREECLAMPSIA-ECLAMPSIA Delivery is the only definitive treatment for preeclampsia; Box 4 lists some suggested indications for delivery. All women with the diagnosis of preeclampsia should be considered for delivery at 40 weeks' gestation. Delivery may be indicated for women with mild disease and a favorable cervix at 38 weeks' gestation and should be considered in women who have severe preeclampsia beyond 32 to 34 weeks' gestation. Prolonged antepartum management with severe preeclampsia is possible in a select group of women with fetal gestational age between 23 and 32 weeks but should be attempted only at centers equipped to provide close maternal and fetal surveillance. Vaginal delivery is preferable to cesarean delivery, thus avoiding the added stress of surgery to multiple physiologic aberrations. Labor induction should be carried out aggressively once the decision for delivery is made. In a gestation that is remote from term in which delivery is indicated and fetal and maternal conditions are stable enough to permit pregnancy to be prolonged 48 hours, glucocorticoids can be safely administered to accelerate fetal pulmonary maturity. BOX 4

Indications for Delivery in Preeclampsia Maternal

•

Gestational age =38 wk

•

Platelet count 35 y or 24 h)

Rh isoimmunization

Prolonged rupture of membranes (>12 h)

Prematurity (< 37 wk gestation)

Meconium-stained amniotic fluid

Postmaturity (>42 wk gestation)

Placental abruption

Premature rupture of the membranes

Prolapsed cord

Malnutrition or poor weight gain

Fetal distress (fetal heart rate abnormalities, fetal acidosis)

Lack of prenatal care Substance abuse (including alcohol)

Emergent operative delivery

Antepartum hemorrhage Multiple gestation Chronic disease (cardiovascular, rheumatologic, neurologic, etc.)

Perinatal Asphyxia Perinatal asphyxia occurs when oxygen delivery is insufficient to meet metabolic demands, resulting in hypoxia, hypercarbia, and metabolic acidosis. Initial compensatory mechanisms, including tachycardia and vasoconstriction, may allow adequate oxygen delivery to the vital organs for a time. However, without resolution or treatment, these compensatory mechanisms will eventually fail, leading to a fall in heart rate and blood pressure (BP) with eventual cardiopulmonary arrest. World Health Organization (WHO) estimates from 1995 conclude that birth asphyxia is responsible for 19% of the 5 million neonatal deaths that occur annually. Intrauterine asphyxia manifests as alterations in fetal heart rate (late decelerations, bradycardia), passage of meconium (see text following), fetal gasping, and eventual apnea, termed primary apnea. This initial period of apnea is followed by further gasping, which gradually weakens in intensity, eventually terminating in what is termed secondary apnea. In the delivery room, spontaneous respirations can be elicited in newborns with primary apnea by stimulation (vigorous warming and drying) or a brief trial of positive-pressure ventilation (PPV). Newborns with secondary apnea, on the other hand, have suffered a prolonged period of inadequate oxygen delivery and require aggressive resuscitation to prevent further decompensation, cardiac arrest, and death. The longer the delay in initiating resuscitation for primary apnea, the longer the time required to establish spontaneous respirations following PPV. Because there is no definitive method of differentiating between primary and secondary apnea following delivery, the neonatal resuscitation team must promptly recognize and institute proper treatment for all newborn infants with apnea and suspected perinatal asphyxia. Neonatal Resuscitation

Neonatal resuscitation is directed toward assuring a smooth transition to extrauterine life by achieving the following goals: 1.

Maintaining or restoring normal body temperature

2.

Maintaining or establishing effective ventilation and oxygenation

3.

Maintaining or restoring adequate cardiac output and tissue perfusion

4.

Avoiding hypoglycemia

Neonatal resuscitation follows an orderly sequence known as the “ABCs” (airway, breathing, circulation) of resuscitation. Concurrently, the overall physiologic status of the newborn is continuously monitored via a cycle of repeated assessment and intervention (“assess-intervene-assess”). Unique to newborn infants is an increased ratio of body surface area to volume; and they are at risk for significant heat loss and temperature instability. Temperature instability and cold stress will increase oxygen consumption and may impede an effective resuscitation. Therefore, initial efforts should be directed toward minimizing heat loss. On delivery the infant should be placed on a radiant warmer. Other heat sources, such as a heating lamp may be used if a radiant warmer is not available. Heated bags of intravenous (IV) fluid should be avoided because they may cause burns. The infant is then dried vigorously with a warm, sterile towel. To minimize conductive heat losses, wet linens should be removed as soon as possible. Use of a polyethylene bag may help reduce heat loss and maintain body temperature during resuscitation of very-lowbirth weight (VLBW) infants. If the newborn is otherwise stable, he or she may be placed naked against the mother's skin and covered with a clean blanket or towel. Initial resuscitative efforts are directed toward maintaining the airway (“A = AIRWAY”). Properly positioning the infant on his or her back, with the head and neck in a neutral, midline position will assist in opening the airway. A towel roll may be placed beneath the shoulders to assist in opening the airway. Hyperextension, may lead to airway obstruction and should be avoided. The mouth and nose should be suctioned with a bulb syringe in order to remove any secretions that may contribute to airway compromise. Drying, positioning, and suctioning will usually provide sufficient stimulation to help the newborn initiate effective breathing. If respirations are adequate and cyanosis is present, supplemental oxygen should be administered, using an appropriately sized facemask. Preclinical studies suggest that administration of 100% oxygen adversely affects the developing lung and brain, although at present there is insufficient evidence to advocate resuscitation with room-air (21% oxygen) versus 100% oxygen. Current guidelines, however, recommend administering supplemental oxygen at a sufficient concentration (Fio2 0.21-1.00) to maintain peripheral oxygen saturations at approximately 90% in neonates less than 32 weeks gestational age. The oxygen concentration should be decreased for oxygen saturations greater than 95%. Acrocyanosis (bluish discoloration of the hands and feet), on the other hand, is a normal physical finding that is often present in the first few minutes of life and does not require oxygen supplementation. Using a bag-valvemask, positive pressure ventilation is indicated for those infants with either absent (apnea) or slow, gasping respiratory movements (“B = BREATHING”). In addition, because one of the most common causes of bradycardia is lack of sufficient oxygen, positive pressure ventilation is indicated when the heart rate is below 100 beats per minute (bpm).

Both neonatal-sized self-inflating bags and anesthesia bags ( Figure 1 ) are acceptable for administering positive pressure ventilation in the delivery room. The main advantages to using an anesthesia bag are that these devices are capable of delivering 100% blow-by oxygen or continuous positive airway pressure (CPAP). Inspiratory pressures can be controlled and titrated with the use of an in-line manometer when using an anesthesia bag. The use of an anesthesia bag requires practice, and some centers preferentially use a self-inflating bag due to its ease of use. The main disadvantages to the self-inflating bag are that these devices require an additional oxygen reservoir attachment and inspiratory pressures cannot be closely titrated. Both devices are acceptable for use in neonatal resuscitation provided that staff is familiar with the requirements of each device.

FIGURE 1 Anesthesia bag preparation. Setting the initial flow rate to 8 to 10 L/minute and the end-respiratory pressure to 8 to 10 cm H2O allows for effective bag filling while providing positive-pressure ventilation. Copied with permission from Golden SM. Resuscitation of the Neonate. Rakel RE, Bope ET (eds): Conn's Current Therapy, 2004. W.B. Saunders Co., 2003, p. 1082 (Figure 1).

Proper placement and sizing of the face mask are required to produce an effective seal around the mouth and nose ( Figure 2 ). Adequate ventilation is assured using a rate of 40 to 60 breaths per minute, with a tidal volume sufficient enough to produce adequate, symmetric expansion of the chest. Initially, inspiratory pressures as high as 30 cm H2O or more may be required for adequate lung inflation. Smaller pressures (generally 20 cm H2O or less) are generally sufficient for subsequent breaths. An 8 or 10 F orogastric tube may be placed to decompress the stomach and improve ventilation. Ventilation via the bag-valve-mask is relatively simple to perform and can be lifesaving. An increase in heart rate is the primary sign of effective PPV during resuscitation. Additional signs of effective PPV include improving color, spontaneous breathing, or improving muscle tone. Endotracheal intubation should be considered if bag-valve-mask ventilation is ineffective after attempts to optimize, if it appears that prolonged ventilation will be required, or if an intravascular route for epinephrine administration is unattainable. However, intubation should only be attempted by providers experienced with the management of the neonatal airway. Intubation of a newborn requires careful assessment to determine that the tube has been properly placed. Use of a disposable CO2 indicator should be considered to confirm proper endotracheal tube placement initially and during the course of the resuscitation. The laryngeal mask airway (LMA) is an effective alternative for providing PPV when either bag-valve-mask ventilation fails or attempts at endotracheal intubation are unsuccessful.

FIGURE 2 Proper placement and seal of face mask. The thumb and third finger (which is on the mandible or ramus of the mandible) are being squeezed toward each other in a C hold. Copied with permission from Golden SM. Resuscitation of the Neonate. Rakel RE, Bope ET (eds): Conn's Current Therapy, 2004. W.B. Saunders Co., 2004, p. 1082 (Figure 2).

Once adequate ventilation and oxygenation are assured, attention is directed toward the circulatory system (“C = CIRCULATION”). Heart rate is assessed by palpating the brachial pulse, palpating the pulse at the base of the umbilical cord, or by auscultation of cardiac sounds with a stethoscope. The heart rate in a newborn normally ranges from 100 to 170 beats per minute. As mentioned previously, PPV should be initiated for infants whose heart rates are less than 100 bpm. However, chest compressions should be performed immediately if the heart rate is less than 60 bpm after 30 seconds of effective PPV with supplemental oxygen ( Box 2 ). Chest compressions are performed using either the two-thumb technique ( Figure 3 ) or two-finger technique ( Figure 4 ), but the two-thumb technique is thought to provide a more controlled depth of compression and better cardiac output. Team members should coordinate ventilations with chest compressions. After three compressions, a positive pressure breath with supplemental oxygen should be administered (for a compression to breath ratio of 3:1). Chest compressions should be continued until the heart rate is greater than 60 bpm. BOX 2 Newborn Resuscitation Equipment for the Emergency Department Airway

•

Bulb syringe

•

DeLee suction catheter

•

Meconium aspirator

•

Laryngoscope and straight blades (sizes 0, 1)

•

Endotracheal tubes, uncuffed (sizes 2.5, 3.0, 3.5, and 4.0 mm)

•

Stylet

•

Suction catheters (5 F, 8 F, 10 F)

•

Suction source with manometer

•

Nasogastric tube

•

Feeding tubes (8 F, 10 F)

Breathing

•

Face masks (premature, newborn, and infant sizes)

•

Self-inflating ventilation bag (450 to 750 mL), with oxygen reservoir and manometer

•

Oxygen source

•

Chest tubes (8 F and 10 F)

Circulation

•

Sterile umbilical vessel catheterization tray

•

Umbilical catheters (3.5 F, 5.0 F)

•

Three-way stopcocks

•

Syringes (tuberculin, 1, 3, 10, and 20 mL)

•

Medications and fluids: •

Epinephrine 1:10,000 concentration

•

Naloxone hydrochloride

•

Sodium bicarbonate (0.5 mEq/mL or 4.2% solution)

•

Normal saline

•

Lactated Ringer's

•

10% Dextrose

•

5% Albumin

Miscellaneous Equipment

•

Radiant warmer or heat lamps

•

Sterile towels

•

Pulse oximeter

•

Cardiorespiratory monitor with small electrocardiographic leads

•

Sterile gowns, gloves

•

Resuscitation chart

FIGURE 3 Two-thumb chest-encircling external cardiac massage technique. This is the preferred technique. Note that the thumbs are above the xyphoid process in the midsternum region. Copied with permission from Golden SM. Resuscitation of the Neonate. Rakel RE, Bope ET (eds): Conn's Current Therapy, 2004. W.B. Saunders Co., 2003, p. 1083 (Figure 4).

FIGURE 4 Two-finger external cardiac massage technique. Fingers are above xyphoid process; approximately one finger width beneath the nipple line. Copied with permission from Golden SM. Resuscitation of the Neonate. Rakel RE, Bope ET (eds): Conn's Current Therapy, 2004. W.B. Saunders Co., 2003, p. 1083 (Figure 5).

Resuscitation medications ( Table 1 ) should be administered if the heart rate remains less than 60 bpm despite 30 seconds of chest compressions and adequate PPV. Vascular access should be established at this time, as drug (e.g., epinephrine), fluid, and dextrose administration may be necessary, but endotracheal administration of drugs may be the most accessible route. The medication is either flushed through the endotracheal tube with 0.5 to 1 mL normal saline or pushed through a 5 F feeding tube passed to the tip of the endotracheal tube. Both methods of drug administration should be followed by several positive-pressure breaths.

TABLE 1 -- Drugs for Resuscitation/Stabilization Medication Concentration Dosage/Route Indications Epinephrine

1:10,000

0.1-0.3 mL/kg IV

Asystole

Comment No studies for ETT route

Medication

Volume expanders

Concentration

Dosage/Route Indications

Comment

0.3-1 mL/kg ETT

Bradycardia that is unresponsive to PPV and chest compressions

Repeat dose Q 3-5 min

Hypovolemia

Cross-match to mother if possible

Lactated Ringer's10 mL/kg IV 0.9% normal saline O-negative blood

Shock Glucose

10% (D10W)

2 mL/kg IV

Hypoglycemia

May need to repeat

Sodium bicarbonate

0.5 mEq/mL

2 mL/kg IV

Documented severe metabolic acidosis or prolonged resuscitation with no response to other interventions

Administer slowly (approx. 2 mL/min)

0.1 mg/kg IV

Continued respiratory depression AFTER PPV has restored a normal heart rate and color

May precipitate, acute, life-threatening withdrawal in neonates born to drug-abusing mothers

Naloxone

AND History of maternal narcotic administration in past 4 hours Abbreviations: ETT = endotracheal tube; IM, intramuscularly; IV = intravenously; PPV = positive pressure ventilation; q = every.

Vascular access may be achieved most readily via umbilical vein cannulation. The umbilical vein is easily identified and cannulated and is therefore the preferred site of vascular access in the newborn. The umbilical vein is identified as a single, thin-walled, larger vessel compared to the small, thick-walled pair of umbilical arteries ( Figure 5 ). A 3.5 or 5.0 F catheter is inserted until the tip of the catheter is below the skin or until blood can readily be aspirated. This should be done sterilely if possible. If not placed sterilely, however, after stabilization the catheter must be replaced to avoid potential complications. A peripheral intravenous (IV) line is also perfectly acceptable but may be difficult to establish by inexperienced providers.

FIGURE 5 Umbilical vein catheterization. The umbilical vein is the preferred route for immediate venous access for drug medication and volume administration. Copied with permission from Golden SM. Resuscitation of the Neonate. Rakel RE, Bope ET (eds): Conn's Current Therapy, 2004. W.B. Saunders Co., 2003, p. 1084 (Figure 6).

Epinephrine is the drug used most frequently during resuscitation of the newborn. It may be administered via the IV or endotracheal routes for either asystole or heart rate less than 60 bpm despite effective ventilations and chest compressions. Generally, the dose is 0.01 to 0.03 mg/kg (0.1 to 0.3 mL/kg of the 1:10,000 solution) administered as needed every 3 to 5 minutes. If the endotracheal route is used, a higher dose (up to 0.1 mg/kg) is preferred. Volume expanders are also used frequently and are indicated for the treatment of hypovolemia. Generally, 10 mL/kg of either normal saline or lactated Ringer's are administered through an IV catheter over 5 to 10 minutes. If there is concern for significant anemia in the fetus or newborn, Onegative blood, crossmatched with the mother if possible, should be considered as a volume expander. If time does not allow, emergent-release O-negative blood should be used to initially resuscitate the severely anemic infant. Naloxone (Narcan) is no longer recommended during the primary steps of resuscitation with the current guidelines. Narcan is indicated when continued respiratory depression is present after PPV has restored a normal heart rate and color, AND, when there is a history of maternal narcotic administration within the past 4 hours. The IV route is the preferred route of administration. Intravenous glucose (2 mL/kg D10W) is administered for suspected or documented hypoglycemia. Sodium bicarbonate should only be given in cases of documented severe acidosis or in prolonged resuscitations with no response to other

described interventions. Finally, surfactant preparations (e.g., Survanta, Infasurf) may be administered in the delivery room to preterm newborns with respiratory distress. It should be emphasized that resuscitation proceeds according to the above protocols, and not according to the result of the Apgar score. The Apgar score is based on five objective signs ( Table 2 ) and was designed to provide an easily reproducible measure of the status of a newborn shortly after birth. Scores are usually determined at 1 and 5 minutes of life. Resuscitation should not be delayed while awaiting the results of the 1-minute Apgar score.

TABLE 2 -- The Apgar Score[*] Sign

0

1

2

Heart rate

Absent

Slow (less than 100 bpm) Greater than 100 bpm

Respirations

Absent

Slow, irregular

Good, crying

Muscle tone

Limp

Some flexion

Active motion

Reflex irritability (catheter in nares) No response Grimace

Cough or sneeze

Color

Pink

Blue or pale Acrocyanosis

Abbreviations: bpm beats per minute.

* A score of 0, 1, or 2 is assigned in each category at 1 and 5 minutes of life.

Meconium Staining of the Amniotic Fluid Meconium is a viscous, greenish-black substance consisting of gastrointestinal (GI) secretions, blood, bile acids, amniotic fluid, and cellular debris present in the fetal GI tract. In the majority of cases, meconium is cleared from the GI tract with the first few bowel movements. However, in approximately 10% to 15% of all deliveries, meconium is passed prior to birth, leading to meconium staining of the amniotic fluid, which increases an infant's risk of developing the meconium aspiration syndrome (MAS), a disease with serious morbidity and mortality. Historically, routine intrapartum oropharyngeal and nasopharyngeal suctioning with a DeLee suction catheter was universally recommended. Recent evidence suggests that this is no longer necessary, and routine intrapartum suctioning is no longer recommended in the current guidelines. After the infant is delivered, if the amniotic fluid contains meconium and the infant has absent or depressed respirations, decreased muscle tone, or heart rate 40 mg/dL in the first 48-72 h and > 45 mg/dL after 72 h. When hypoglycemic, a bolus of D10W at 200 mg/kg (2 mL/kg) is given. Glucose level is obtained in 30 min, frequent monitoring is continued every 1-3 h, and further boluses are given as needed. Maintenance fluid provides 4-6 mg/kg/min of glucose infusion. This rate of infusion should be increased by 2 mg/kg/min with every need for D10W bolus. Refer to specific text for detailed management.

Calcium. The stores of calcium are limited and the reserves are rapidly depleted after birth.

Higher intake of calcium with adequate phosphorus intake is required for bone formation and growth.

Jaundice. These infants are at increased risk for brain toxicity from high bilirubin levels. High bilirubin level develops due to hepatic immaturity, shorter RBC life span, extravasation of blood, and increased enterohepatic circulation, coupled with lower serum albumin level.

The level that causes toxicity is lower in these infants. A crude method to determine the need for phototherapy at 50% the weight in kg: A 0.9 Kg infant is placed under phototherapy for a bilirubin level of 4.5 mg/dL. Exchange level is determined by the weight, in this case 9 mg/dL. The risk for toxicity increases in the unstable infant, the reason why lower levels should be used when managing. Fluid intake should be increased 15%-20% in infants under phototherapy.

Abbreviations: ABC = airway, breathing, and circulation; BP = blood pressure; CLD = chronic lung disease; CMV = cytomegalovirus; CVC = central venous catheter; ELBW = extremely low birth weight infant; ETT = endotracheal tube; GFR = glomerular filtration rate; HMD = hyaline membrane disease; I&O = intake and output; ICH = intracranial hemorrhage; IV = intravenous; IVH = intraventricular hemorrhage; NCPAP = nasal continuous positive airway pressure; NICU = neonatal intensive care unit; PDA = patent ductus arteriosus; PIP = peak inspiratory pressure; PRBC = packed red blood cells; RBC = red blood cell; US = ultrasound.

Special Therapy Although there are continued attempts to provide care for the ELBW infant, there are infants outside the scope of viability— infants with complex congenital malformations, including those labeled as incompatible with life, and those whose condition is irreversible and ultimately will lead to death. For such infants, we see the need for comfort care or palliative care. In these situations both the health care professional and parents find themselves in an awkward position. The family remains hopeful based on the perceived information that the health care professional gives, or the family goes through turmoil when interventions seem endless in a situation that they perceive as hopeless.

CURRENT DIAGNOSIS Review of risk factors: antenatal, perinatal, and postnatal Assessment of infants in the delivery room: airway, breathing and circulation—respiration, heart rate, and color Continued assessment in the nursery: respirations, heart rate, color, temperature, and CNS Common problems: pulmonary, circulatory, gastrointestinal, metabolic, surgical, and temperature instability Abbreviation: CNS = central nervous system.

The decision for palliative care is made through collaboration between the health care team and the parents. The two factual considerations in making the decision for palliative care are pertinent medical facts (diagnosis, response to treatment given, potential response to other treatments, and prognosis) and the human value (what the parents anticipate, expect, and desire for their infant) and what motivates these values in the parents. The values of the health care team involved in the care of the infant are also considered. Palliative care, as defined by the World Health Organization (WHO), is care for patients for whom cure is no longer a reasonable expectation or possibility. It is an active and comprehensive management of the entire patient, and not abandonment of care.

Practical considerations that need to be taken into account, and specific components of the palliative care that are appropriate for each individual high-risk neonate, are considered before a specific plan can be put in place. The application of palliative care in the NICU is not only possible, but necessary.

CURRENT THERAPY Use functioning equipment and qualified personnel in the delivery room: initial steps and ABCs of neonatal resuscitation. Provide neutral thermal environment. Respiratory and cardiovascular support: oxygen, mechanical ventilation, vasopressor agent (dopamine). Infuse bolus of D10W and glucose at 6-8 mg/kg per minute or higher if needed. Use phototherapy for early jaundice and the bruised ELBW infant. Transfer to appropriate level of care when indicated. Monitor closely fluid and electrolytes and decreased IWL. Provide good nutritional support beginning in the first 24 hours and closely monitor for complications and tolerance. Provide family-centered care and appropriate environment to promote growth and development. Benefit special cases, especially those deemed futile, with a multidisciplinary approach. Abbreviations: ABC = airway, breathing, and circulation; ELBW = extremely low birth weight; IWL = insensible water loss.



REFERENCES Aly, 2004. Aly H: Respiratory disorders in the newborn: Identification and diagnosis. Pediatr Rev 2004; 25:201-208. Avery et al., 1999. In: Avery GB, Fletcher MA, Macdonald MG, ed. Neonatology: Pathophysiology and Management of the Newborn, 5th ed.. Philadelphia: Lippincott Williams & Wilkins; 1999:143-173. Blackburn, 2003. Blackburn ST: Maternal, Fetal, and Neonatal Physiology: A Clinical Perspective, 2nd ed.. Philadelphia: WB Saunders; 2003:707-730. Carter, 2004. Carter BS: Comfort care principles for the high-risk newborn. NeoReviews 2004;e484-e490. Chescheir and Harsen, 1999. Chescheir NC, Harsen WF: What's new in perinatology. Pediatr Rev 1999; 20:57-63. Downard and Wilson, 2003. Downard CD, Wilson JM: Current therapy of infants with congenital diaphragmatic hernia. Semin Neonatol 2003; 8:215-221. Field, 2003. Field TM: Stimulation of preterm infants. Pediatr Rev 2003; 24:4-10. Heird, 2001. Heird WC: Determination of nutritional requirements in preterm infants, with special reference to “catch-up” growth. Semin Neonatol 2001; 6:365-375. Klaus and Fanaroff, 2001. Klaus MH, Fanaroff MB: Care of the High-Risk Neonate, 5th ed.. Philadelphia: WB Saunders; 2001:195-215. Kattwinkel. Kattwinkel J (ed): Neonatal Resuscitation Textbok, 5th ed. American Heart Association, American Academy of Pediatrics, Elk Grove Village, Ill. Kleinman, 2004. In: Kleinman RE, ed. Pediatric Nutrition Handbook, 5th ed.. Elk Grove Village, Ill: American Academy of Pediatrics; 2004:23-55. Thureen et al., 1999. Thureen PJ, Deacon J, O'Neill P, Hernandez JA: Assessment and care of the well newborn, Philadelphia: WB Saunders; 1999:83-113. Welch and Malone, 2002. Welch KK, Malone FD: Advances in prenatal screening: Nuchal translucency ultrasonography in the first trimester. NeoReviews 2002; 3:e202-e208. Welch and Malone, 2002. Welch KK, Malone FD: Advances in prenatal screening: Maternal serum screening for Down syndrome. Neoreviews 2002; 3:e209-e213.



Chapter 259 – Normal Infant Feeding

Method of: Meg Begany, RD, CSP, LDN Maria Mascarenhas, MBBS Adequate and appropriate nutrition is especially critical during infancy. Infancy, defined as birth to 1 year of age, is characterized by the period of most rapid growth and development during the life cycle. In addition, recent research shows that nutrition during infancy can influence risk factors for disease at other stages of the life cycle. Infant Feeding For the healthy term infant, the suck-swallow and rooting reflexes are present at birth, and thus liquid feedings can be initiated almost immediately following delivery. BREAST-FEEDING The American Academy of Pediatrics (AAP) recommends human milk as the feeding of choice for nearly all infants whenever possible and mutually desirable for the mother and infant. Successful lactation and breastfeeding requires a supportive environment for the mother provided by the medical practitioner, including instruction and counseling. The World Health Organization (WHO) Expert Consultation on the Optimal Duration of Exclusive Breastfeeding, which considered the results of a systematic review of the evidence, concluded that human milk is recommended as the exclusive source of nutrition for the first 6 months and continuing human milk in combination with complementary foods until at least 12 months of age. The nutrient needs of the full-term normal birth weight infant can be met by human milk alone, with few exceptions, for the first 6 months if the mother is well nourished. The benefits of breast-feeding over formula feeding are well established and include enhanced maturity and motility of the gastrointestinal tract; maternal–infant bonding; monetary savings; facilitated fat, protein, and carbohydrate digestion and absorption; passive immunity; improved cognitive development; and decreased incidence of otitis media and respiratory and gastrointestinal disease. Further potential benefits, such as lower risk of overweight in children and adults, as well as decreased risk of cardiovascular disease in adulthood, were demonstrated in recent research. Breast-feeding should be offered as early as possible after birth and then every 2 to 3 hours until satiety for approximately 10 to 15 minutes per breast during the first few weeks. Less frequent feedings may occur once breast-feeding is established. Intervals of more than 5 hours in between breast-feeding should be avoided during the first few weeks, including at night. Adequacy of breast-feeding is demonstrated when the infant has feedings 8 to 12 times per day, at least 6 to 8 wet diapers per day, regular stooling pattern, and is growing along established growth curves. The composition of breast milk varies from individual to individual, as well as within the same individual, with

composition changes occurring with stage of lactation, time of day, maternal diet, and time elapsed since feeding began. Milk production tends to be higher during the daytime, and fat content is increased toward the end of a feeding. On average, breast milk provides approximately 20 calories per ounce. Contraindications to breast-feeding include maternal infections by organisms known to be transmitted to the infant via breast milk (e.g., HIV); maternal exposure to drugs, foods, or environmental agents that are excreted in human milk and harmful to the infant; and inborn errors of metabolism that are exacerbated by components present in human milk (e.g., galactosemia). INFANT FORMULA When a mother chooses not to breast-feed or human milk is not an option, infant formula is an appropriate substitute. Although the composition of infant formula does not exactly duplicate that of breast milk, the composition of infant formulas continues to evolve in an effort to do so. The addition of docosahexaenoic acid (DHA) and arachidonic acid (ARA) is a recent modification to infant formula. Unlike breast milk, infant formulas prior to 2002 contained only the precursor essential fatty acids, linoleic and a-linolenic acids, from which DHA and ARA had to be synthesized. Multiple studies in both preterm and term infants have demonstrated significantly lower levels of DHA and ARA in the erythrocytes of formula-fed infants compared to their breast-fed counterparts. This suggested that infant formula containing only the precursors, a-linolenic acid and linoleic acid, could be ineffective in allowing adequate synthesis of DHA and ARA. Thus multiple studies have been published comparing visual acuity, developmental outcomes, and growth of infants fed DHA and ARA supplemented and unsupplemented formula or breast milk. Some of these studies, but not all, found short-term improvements in visual and cognitive functions in both preterm and term infants. However, no long-term benefits were demonstrated. Although the single supplementation of DHA alone resulted in ARA deficiency status and poor growth in premature infants, the balanced supplementation of both DHA and ARA consistently do not show any adverse effect on growth. Both iron-fortified and low-iron formulas are commercially available. The AAP has stated that there is no role for the use of low-iron formulas in infant feeding and recommends that all formulas fed to infants be fortified with iron. Well-controlled studies failed to show a benefit, in terms of feeding tolerance, related to the use of low-iron formula. The amount of iron present in iron-fortified formulas meets the iron requirements through the entire first year. Infant formula should be prepared and stored with careful attention to the manufacturer's guidelines to prevent the risk of bacterial growth. VITAMIN AND MINERAL SUPPLEMENTATION The majority of vitamin and mineral requirements for infants are met in full by breast milk or infant formula. Guidelines for supplementation of vitamin K, vitamin D, iron, and fluoride are established. A single dose of vitamin K is typically given to all infants intramuscularly at birth to prevent hemorrhagic disease of the newborn. For the breast-fed infant, the AAP recommends a supplement of 200 IU of vitamin D by 2 months of age. A multivitamin or tri-vitamin preparation can be used; solitary vitamin D supplements are not practical because

of cost and dosing. The iron requirements for formula-fed infants are met through iron-fortified formula. Although the iron content of human milk is minimal, its bioavailability is high. However, the iron body stores of the breast-fed infant diminish by 4 to 6 months of age, and thus an additional iron source is recommended at this age. Iron needs of the breast-fed infant can be met with the introduction of complementary foods when foods with good sources of iron are included (e.g., meat, fish, iron-fortified cereal, whole grains, and dark leafy green vegetables). Fluoride supplementation is recommended at 6 months of age for both breast-fed infants and formula-fed infants who receive exclusively ready-to-feed formulas or whose water supply contains less than 0.3 ppm of fluoride. INTRODUCTION OF COMPLEMENTARY FOODS At approximately 6 months of age, human milk or infant formula can no longer supply all of an infant's nutrition requirements, and complementary foods are needed to ensure adequate nutrition and growth. It is the micronutrients, rather than energy and protein, which are likely to become lacking. The ability to digest and absorb carbohydrates, proteins, and fats is mature by 6 months of age. Trypsin and chymotrypsin activities increase during the first 4 months of life. Age should not be the only factor in determining the timing of introduction of complementary feeding, but rather the timing should be determined by individual physical and psychological readiness of the infant, as well as rate of maturation of the nervous system, intestinal tract, and kidneys. Before spoon feedings are introduced, the infant should exhibit trunk stability, head control, and disappearance of the extrusion reflex. At approximately 5 to 6 months, an infant is able to indicate a desire for food by leaning forward and opening his or her mouth to indicate hunger and leaning back and turning away to show disinterest or satiety. Muraro et al. state that introduction of complementary feedings prior to 4 months of age is associated with an increased risk of atopic eczema and cow's milk protein allergy. There are presently no controlled studies showing an allergy preventative effect of restrictive diets after 6 months of age. Studies suggest that introducing complementary foods prior to 6 months does not result in increased caloric intake and has no growth advantage because the infant will displace breast milk to maintain the same level of caloric intake. Although it is possible to meet the nutrition needs of the infant solely from infant formula through the entire first year, delay of introduction of solids can lead to feeding aversions and food refusal. All infants need exposure to a variety of tastes, textures, and foods to develop appropriate feeding practices and a wider acceptance of new foods. In addition to adequate nutrition, the feeding relationship between the infant and caregiver is vital for normal growth and development. To observe for symptoms of intolerance, only one new food should be introduced every 3 days. Because of its hypoallergenicity, infant rice cereal is often introduced as the first feeding. However, if spoon feeding is initiated at 6 months of age, gastrointestinal and renal development is mature enough to allow feedings from multiple food groups. Despite enhanced bioavailability, breast milk is relatively low in iron and zinc. Because low liver reserves of zinc at birth may predispose some infants to zinc deficiency, similar to the situation for iron, meat may be the ideal first food to provide these nutrients at the levels needed. Dr. Samuel Fomon states that unless there is a strong family history of allergy, introduction of soft-cooked red meats is desirable by 5 to 6 months of age. Furthermore, the proportion of Dietary Reference Intakes that needs to be supplied by complementary foods is highest for iron, zinc, phosphorus, and magnesium. Regardless of the food

choice for the first feeding, the consistency should be thin and liquid/pureed. Thinning foods with breast milk or infant formula can enhance acceptability of the food by the infant. Repeated exposure to a new food may be necessary before it is accepted.

CURRENT THERAPY

Infant Formula Composition and Indications FORMULA Milk based

EXAMPLES Enfamil LIPIL

INDICATIONS Breast milk substitute for term infants

Similac Advance Enfamil LactoFree LIPIL

CHARACTERISTICS Ready to feed, powder, or liquid concentrate Variable whey: casein

Similac Lactose Free

20 kcal/oz Contain DHA/ARA

Enfamil AR LIPIL (prethickened) Good Start Supreme Soy based

ProSobee Isomil

Breast milk substitute for infants with lactose intolerance or milk protein allergy[*]

Lactose free; some sucrose free Ready to feed, powder, or liquid concentrate

Good Start Supreme Soy Isomil DF

20 kcal/oz Contain DHA/ARA May contain fiber

Premature (hospital grade)

Enfamil Premature LIPIL Similac Special CareAdvance

Breast milk substitute for low birth weight hospitalized preterm infants

Low lactose 60:40 whey-tocasein ratio High calcium and phosphorus Contain MCT 20 and 24 cal/oz Contain DHA/ARA Ready to feed only

Infant Formula Composition and Indications FORMULA Human milk fortifiers

EXAMPLES Similac HMF Enfamil HMF

INDICATIONS Fortification of human milk for low birth weight preterm infants

CHARACTERISTICS Increase calorie, protein, and vitamin/mineral content of breast milk Contain MCT

Premature transitional

NeoSure Advance EnfaCare LIPIL

Hypoallergenic/protein Nutramigen hydrolysate

Breast milk substitute for preterm infants >2.5 kg or discharge formula for preterm infants (used until 6-12 mo corrected age or until catch-up growth is completed)

22 kcal/oz

Milk or soy protein allergy

Hydrolyzed protein

Ready to feed or powder Contain DHA/ARA Vitamin and mineral content between that of term and premature formulas

Ready to feed, powder, or liquid concentrate Sucrose free Lactose free No MCT Protein hydrolysate with MCT

Alimentum

Malabsorption

Lactose free

Pregestimil

Short bowel syndrome

Hydrolyzed protein

Allergy

Contain MCT Ready to feed or powder

Amino acid based

Neocate

Malabsorption

Lactose free

EleCare

Short bowel syndrome

Free amino acids

Allergy

Powder only

Infant Formula Composition and Indications FORMULA Fat modified

EXAMPLES Portagen (no longer recommended for infants)

INDICATIONS Defects in digestion, absorption, or transport of fat

CHARACTERISTICS Contain increased % of kcal as MCT

Simple sugar intolerance

Requires addition of complex carbohydrate to be complete

Alimentum Pregestimil Carbohydrate modified

RCF Product 3232 A

Amino acid modified

Multiple products (e.g., Inborn errors of metabolism Cyclinex, MSUD Analog, Phenyl-Free)

Electrolyte modified

Similac PM 60/40

Renal or other disease state requiring low renal solute load

Low or devoid of specific amino acids that cannot be metabolized Decreased potassium content Decreased calcium and phosphorus content

Abbreviations: ARA=arachidonic acid; DHA =docosahexaenoic acid; HMF = human milk fortifier; MCT =medium chain triglycerides; MSUD = maple syrup urine disease.

* Children allergic to milk protein may also be allergic to soy protein.

By 9 months of age, finely chopped foods and finger foods can be added to the infant's diet. At 12 months of age, rotary chewing is well controlled, and many infants can progress to table foods. Choking hazards that are round and hard, such as grapes, nuts, popcorn, hot dogs, and hard candy, should be avoided. For the average healthy infant, meals of complementary foods should be provided two to three times per day from 6 to 8 months of age and three to four times per day from 9 to 12 months of age, with addition of nutritious snacks once or twice per day as desired. Vegetarian diets cannot meet nutrient needs at this age unless fortified products or nutrient supplements are provided. Estimates of the energy gap that must be filled by complementary food in industrialized countries is approximately 130 kcal/day at 6 to 8 months, 310 kcal/day at 9 to 11 months and 580 kcal/day at 12 to 23 months of age. Juice is not a necessary component of the diet and may displace the intake of nutrient-dense breast milk or formula. In addition, offering juice by bottle can contribute to dental caries. If juice is provided, it should be limited to 4 to 8 ounces per day and should not be given prior to 6 months of age.

Whole cow's milk should not be introduced before 12 months of age because of its low iron content, high renal solute load, potential for causing gastrointestinal bleeding, and increased risk of cow's milk protein allergy. Furthermore, cow's milk is a poor source of vitamin C, vitamin E, and essential fatty acids. Breastfed infants weaned before 12 months of age should receive an iron-fortified infant formula rather than cow's milk. Nutritional Requirements Because of the rapid rate of growth and development during infancy, nutrient needs per unit of body weight are very high in comparison to that of the older child or adult. Energy needs for the healthy term infant are 108 kcal/kg from birth to 6 months of age. From 6 to 12 months of age, caloric needs are 98 kcal/kg. The Recommended Daily Allowance (RDA) for protein is 2.2 g/kg from birth to 6 months of age and 1.6 g/kg from 6 to 12 months of age. Caloric distribution during infancy is recommended to be 40% to 50% fat, 7% to 11% protein, and 40% to 55% carbohydrate. The water-to-energy ratio should be 1.5 mL/kcal. Both human milk and infant formulas are models of this distribution. Hydration requirements are met by breast milk or infant formula without further addition of water to the diet, except potentially during periods of illness with fever, diarrhea, or emesis.

CURRENT DIAGNOSIS

Expected Growth Velocity during Infancy AGE

WEIGHT GAIN (g/d) LENGTH (cm/mo) HEAD CIRCUMFERENCE (cm/wk)

0–3 mo

25–35

2.5–3.5

0.3–0.6

3–6 mo

15–21

1.6–2.5

0.2–0.5

6–12 mo 10–13

1.2–1.7

0.1–0.4

Growth Weight, length, and head circumference should be monitored serially during infancy and plotted on the gender-specific 2000 CDC (Centers for Disease Control and Prevention) Growth Charts. Breast-fed infants tend to gain less weight and usually are leaner than formula-fed infants in the second half of infancy. This difference does not seem to be the result of nutritional deficits but rather infant self-regulation of energy intake. Obesity is increasing among children in the United States. High rates of weight gain during the first few months of life are associated with obesity in childhood and early adulthood. Optimal nutrition and growth during infancy should be promoted by encouraging healthy eating patterns in the infant to prepare for a healthy lifestyle later in life. Early identification and intervention may be a key component for establishing appropriate weight gain patterns. Although no consensus exists on universal criteria to define failure to thrive, careful evaluation should occur

when weight is less than the 5th percentile or falls more than two major percentiles from a previously established growth channel. In addition, relationship of weight to height must be considered. Prompt intervention with nutritional rehabilitation is essential to prevent illness, growth stunting, cognitive delay, and social and behavioral problems. For the treatment of either over- or undernutrition, a multidisciplinary team approach involving the physician, dietitian, psychologist, and social worker, along with community services, can often be beneficial and necessary. In conclusion, infant feeding during the first year of life is a complex process, and guidelines are based on developmental, nutritional, and social factors. Human milk is superior to infant formula and should be the feeding of choice for all infants. Although infant formulas do not exactly duplicate breast milk, the composition of infant formulas continues to evolve in an effort to do so. Complementary foods should be introduced at 6 months of age. Cow's milk should not be introduced until 1 year of age. Careful attention should be paid to growth and nutritional status throughout infancy, with prompt attention to any deviation from expected growth patterns.



REFERENCES American Academy of Pediatrics and Committee on Nutrition, 1999. American Academy of Pediatrics , Committee on Nutrition : Iron fortification of infant formulas. Pediatrics 1999; 104:119-123. American Academy of Pediatrics and Section on Breastfeeding, 2005. American Academy of Pediatrics , Section on Breastfeeding : Breastfeeding and the use of human milk. Pediatrics 2005; 115:496-506. Dewey, 2001. Dewey KG: Nutrition, growth and complementary feeding of the breastfed infant. Pediatr Clin North Am 2001; 48:87-104. Foman, 2001. Foman SJ: Feeding normal infants: Rationale for recommendations. J Am Diet Assoc 2001; 101:1002-1005. http//www.cdc.gov/growthcharts. http//www.cdc.gov/growthcharts Kleinman, 2003. In: Kleinman RE, ed. Pediatric Nutrition Handbook, 5th ed.. Elk Grove Village, Ill: American Academy of Pediatrics, Committee on Nutrition; 2003. Michaelsen, 2000. Michaelsen KF: Cows' milk in complementary feeding. Pediatrics 2000; 106:1302-1303. Muraro et al., 2004. Muraro A, Dreborg S, Halken S, et al: Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol 2004; 15:291-307. PAHO and WHO, 2003. PAHO , WHO : Guiding Principles for Complementary Feeding of the Breastfed Child, Washington, DC, Pan American Health Organization and World Health Organization, 2003. Samour and King, 2005. In: Samour PQ, King K, ed. Handbook of Pediatric Nutrition, 3rd ed.. Sudbury, Mass: Jones and Bartlett; 2005. Slaughter and Bryant, 2004. Slaughter CW, Bryant AH: Hungry for love: The feeding relationship in the psychological development of young children. Permanente J 2004; 8:23-29. WHO Working Group on the Growth Reference Protocol and the WHO Task Force on Methods for the Natural Regulation of Fertility, 2002. WHO Working Group on the Growth Reference Protocol and the WHO Task Force on Methods for the Natural Regulation of Fertility : Growth of healthy infants and the timing, type, and frequency of complementary foods. Am J Clin Nutr 2002; 76:620-627.



Chapter 260 – Diseases of the Breast

Method of: Paniti Sukumvanich, MD Patrick Borgen, MD Benign Diseases of the Breast Benign diseases of the breast historically are subdivided into proliferative and nonproliferative lesions ( Table 1 ). In a study by Dupont and Page, patients with breast biopsies yielding nonproliferative lesions had no increased risk of subsequent breast cancer. In contrast, proliferative lesions were associated with a minimal to a fivefold increased risk of breast cancer. In clinical practice, of the proliferative lesions, only atypical epithelial lesions increase breast cancer risk significantly. Appropriate treatment and counseling of patients depends on the risk of breast cancer associated with these benign breast diseases.

TABLE 1 -- Benign Diseases of the Breast Increase in Breast Cancer Risk Nonproliferative Lesions Mild hyperplasia without atypia

None

Squamous or apocrine metaplasia None Duct ectasia

None

Mastitis

None

Cysts

None

Proliferative Lesions Fibroadenoma

None

Moderate or florid hyperplasia

Minimal

Microglandular adenosis

Minimal

Sclerosing adenosis

Minimal

Papilloma

Minimal

Atypical ductal hyperplasia

4- to 5-fold

Atypical lobular hyperplasia

5.8-fold

Copyright © 1985 Massachusetts Medical Society. All rights reserved.

Nonproliferative Lesions

Nonproliferative lesions comprise mild hyperplasia without atypia, squamous or apocrine metaplasia, duct ectasia, mastitis, and cysts. In the study of 3303 patients by Dupont and Page, only 2.2% of patients with nonproliferative lesions had breast cancer following a benign breast biopsy with a mean follow-up time of 17 years ( Figure 1 ).

FIGURE 1 Nonproliferative lesions in breast cancer.

BREAST CYSTS AND FIBROCYSTIC BREAST DISEASE

Fibrocystic breast disease is a benign process in which generalized microcystic formation with stromal proliferation leads to increased breast nodularity. Cysts within the breast are most common in perimenopausal women 50 to 59 years of age as well as premenopausal women. Postmenopausal women not on hormone replacement therapy are unlikely to develop cysts in their breasts. Benign cysts are often tender and fluctuate in size with the menstrual cycle. Cysts may be detected either on physical examination as a palpable, smooth, mobile nodule or by breast ultrasound. They may appear as a solitary nodule or in a cluster. Ultrasonographic appearance of simple benign cysts is that of an anechoic, round or oval, wellcircumscribed mass with posterior enhancement. If the mass has all four criteria, the accuracy of ultrasound is close to 100% for the diagnosis of a simple benign cyst. Cysts that appear complex, with internal echoes, thick septations, and irregular walls, are suspicious for breast carcinoma and should be examined surgically or with an ultrasound-guided biopsy. Confirmation of the diagnosis can be made by fine-needle aspiration (FNA) of the cystic fluid. Bloody fluid may be an indication for a biopsy. In a study of 6782 cyst aspirates, Ciatto and colleagues found that cytologic examination identified atypical cells in 1677 specimens. Of these specimens, only 0.3% of these cases had clinically and radiologically negative intracystic papillomas. Cytologic examination was positive in only 0.1% of these cases. Thus fluid from cyst aspirations are not sent routinely for cytologic examination. Figure 2 describes the management of suspected cysts.

FIGURE 2 Algorithm for the management of suspected cysts.

MASTITIS AND DUCT ECTASIA Mastitis is divided into lactational or nonlactational. Lactational mastitis can occur from the reflux of bacteria into the breast during breast-feeding. The causative bacteria are usually gram-positive cocci. Patients should be treated with antibiotics with the appropriate coverage and can continue to nurse or pump the breast to prevent engorgement. Nursing mothers can continue to breast-feed because the infant is not at risk for infection. Nonlactational (periductal) mastitis can be caused by duct ectasia, which occurs when the milk ducts become congested with secretions and debris, resulting in a periductal inflammation. These patients may present with greenish nipple discharge, nipple retraction, and subareolar noncyclical pain. The

treatment of nonlactational mastitis includes broad-spectrum antibiotics to cover for gram-positive cocci and skin anaerobes. Total duct excision and eversion of the nipple may be necessary to treat recurrent periductal mastitis. Proliferative Benign Breast Diseases Proliferative breast diseases include moderate or florid hyperplasia, microglandular and sclerosing adenosis, papilloma, fibroadenoma, and atypical ductal and lobular hyperplasia. All proliferative lesions have an increased risk of subsequent breast cancer after biopsy except for fibroadenoma. Overall, with a median follow-up of 17 years, 5.3% of patients with proliferative lesions develop breast cancer. This percentage increases to 12.9% in the presence of atypia (see Figure 1 ). Patients with moderate or florid hyperplasia, sclerosing adenosis, and solitary papilloma without atypia carry a minimal increase in risk of developing breast cancer over the general population. These patients are not classified as high risk. But the risk of subsequent breast cancer is increased by four- to fivefold in the presence of atypia. Atypical lobular hyperplasia carries a higher risk than atypical ductal hyperplasia, with a relative risk as high as 5.8. This increased risk applies to the contralateral breast because subsequent breast carcinomas are evenly divided between both breasts. PROLIFERATIVE LESIONS WITH NO INCREASED RISK OF SUBSEQUENT CANCER: FIBROADENOMA Fibroadenomas are benign tumors commonly found in young women (less than 30 years of age with a peak incidence at 21 to 25 years of age). They are characteristically detected on physical examination as wellcircumscribed, rubbery, highly mobile, palpable masses. On mammograms, these lesions may appear as a well-circumscribed mass. Involution of fibroadenomas in the elderly can lead to hyalinization and dense popcorn-like calcification on mammograms. Fibroadenomas pose no increased risk of breast cancer and do not mandate surgical removal unless desired by the patient. Pregnancy can increase the size of these lesions; thus it may be reasonable to remove them prior to a planned pregnancy. Removal may facilitate follow-up, given the inability to follow breast masses adequately during pregnancy. Other types of fibroadenomas include juvenile and giant fibroadenomas. Juvenile fibroadenomas occur in adolescent women and can grow larger than 5 cm in diameter. These lesions are not malignant; given their large size, however, surgical excision may be needed to prevent asymmetry of the breasts. Giant fibroadenomas are large fibroadenomas found in the lactating breast or in the breasts of pregnant patients. These lesions may regress in size once hormonal stimulation subsides. Lesions that remain large can be excised surgically. Fibroadenomas and phyllodes tumors may be linked. Any rapidly enlarging fibroadenoma should be considered for surgical excision to rule out phyllodes tumor because it is difficult clinically to differentiate fibroadenoma from phyllodes tumor. PROLIFERATIVE LESIONS WITH MINIMAL INCREASED RISK OF SUBSEQUENT BREAST CANCER Multiple Peripheral Papillomas

Multiple peripheral papillomas are lesions that occur in the peripheral ducts. They most commonly present as a mass but may also present with nipple discharge. Complete excisional removal should be considered to rule out a papillary carcinoma of the breast. Approximately 10% to 33% of patients have subsequent breast cancer; thus close follow-up of these patients is warranted. Sclerosing and Microglandular Adenosis

Sclerosing adenosis occurs as result of the proliferation of stromal tissue along with small terminal ductules. Often these lesions are picked up incidentally, but they may also present as microcalcifications on mammogram or as a mass (termed adenosis tumor). Sclerosing adenosis may be confused with a tubular carcinoma. Staining with immunohistochemical (IHC) markers such as actin, smooth muscle myosin heavy chain p63, or calponin may be helpful in distinguishing between the two lesions because only sclerosing adenosis contains myoepithelial cells. Microglandular adenosis is an uncommon lesion that may be mistaken for tubular carcinoma on histologic examination, and it can increase the patient's subsequent breast cancer risk. Concomitant breast cancer has been reported, so complete surgical excision should be considered for these lesions. PROLIFERATIVE LESIONS WITH A FOUR- TO FIVEFOLD RISK OF SUBSEQUENT BREAST CANCER: ATYPICAL DUCTAL AND LOBULAR HYPERPLASIA Atypical ductal and lobular hyperplasia are very similar to their in situ counterparts. These lesions are termed atypical hyperplasia because they lack some of the microscopic features of in situ disease. The distinction between atypical hyperplasia and carcinoma in situ is sometimes hard to make. In a study by Rosai, five expert breast cancer pathologists reviewed 17 cases of ductal or lobular lesions. In no case did all five agree on a diagnosis. Four out of the five were able to agree on a diagnosis in three cases (18%). In one third of the patients, the diagnosis ran the gamut from hyperplasia without atypia to carcinoma in situ. Despite such difficulty, the diagnosis of atypical hyperplasia is on the rise as mammographic screening becomes more popular. Atypical hyperplasia, which is detected secondary to microcalcifications or by serendipity, carries the highest risk of subsequent breast carcinoma among all proliferative lesions of the breast, with a four- to fivefold increased risk over the general population. Atypical lobular hyperplasia carries a higher risk than atypical ductal hyperplasia, with a relative risk as high as 5.8. This risk applies to the contralateral breast as well as the ipsilateral breast. Surgical excision of atypical hyperplasia on a core biopsy is recommended because 20% of patients are found to have breast cancer at time of surgical excision for atypical hyperplasia. It is not necessary to achieve negative margins for these lesions. OTHER BENIGN BREAST LESIONS: FAT NECROSIS, HAMARTOMA, MONDOR'S DISEASE, RADIAL SCARS, AND PSEUDOANGIOMATOUS STROMAL HYPERPLASIA Other benign lesions of the breast include fat necrosis, hamartoma, Mondor's disease, radial scars, and pseudoangiomatous stromal hyperplasia (PASH). Trauma to the breast may lead to fat necrosis and can be mistaken for carcinomas on clinical examination. Fat necrosis lesions present clinically as painless, irregular masses with or without associated skin changes such as skin thickening. These lesions can be normal or may have rim calcifications on mammograms. No further treatment is needed when a core biopsy definitively makes the diagnosis of fat necrosis. Hamartomas are benign lesions that are often picked up on a mammogram. The fatty composition of the mass makes these lesions clinically occult. They can be mistaken for fibroadenomas on mammograms. Hamartomas can be left alone without histologic confirmation if diagnosed definitively on a mammogram. Mondor's disease is a thrombophlebitis of the superficial breast veins that presents as a palpable tender cord leading to the axilla. In a study of 63 cases, 8 patients (25%) had an underlying malignancy; thus a mammogram should be done to rule out the presence of breast carcinoma.

Radial scars are benign lesions whose etiology is unknown. They are often mistaken for breast carcinoma on mammograms because of their stellate appearance. Radial scars may also mimic breast carcinoma histologically. Staining for myoepithelial cells can help distinguish between invasive carcinoma and a radial scar. Radial scars carry a 1.5-fold increase in risk of subsequent breast carcinoma, so these lesions should be considered markers of future disease. First described in 1986, PASH is a benign proliferative lesion that may present as an incidental finding or a mobile breast mass. It can occur in all ages and also in men. On a mammogram, PASH appears as a round noncalcified mass. Histologically, PASH may be mistaken for low-grade angiosarcoma. Unlike angiosarcoma, however, there should be no evidence of mitosis or cytologic atypia in PASH specimens. The role of hormones in the pathogenesis of PASH is controversial. Although these lesions tend to occur in young patients or in elderly patients on hormone therapy, most cases tend to be negative for estrogen receptors. The treatment for PASH is complete surgical excision. Approximately 7% of cases recur despite adequate treatment. Risk Factors for Breast Cancer An estimated 80% of women in whom breast cancer develops have no documented risk factors or determinants. Risk factors cannot be changed, whereas risk determinants can be altered to decrease a person's risk of subsequent breast cancer. Common risk factors include a familial history of breast cancer, personal breast biopsy history, menarche before 12 years of age, menopause after 55 years of age, increasing age, geographical location, and mutations of the BRCA1 or BRCA2 genes. Women known to have the BRCA1 or BRCA2 genetic mutation have an 85% lifetime risk of breast cancer as well as an increased risk of ovarian cancer. BRCA1 carriers are at a higher risk for developing ovarian cancer than BRCA2 (60% versus 20%, respectively). The risk determinants for breast cancer include reproductive factors such as nulliparity and first pregnancy after the age of 30 years and previous radiation exposure. Previous therapy for lymphoma, especially during adolescence, elevates a woman's risk of subsequent breast cancer. Screening Techniques Screening for breast cancer includes mammography, ultrasound, breast self-examination (BSE), and physical examination by a physician. Multiple studies such as the Göthenborg and Malmö trials show a reduction in breast cancer mortality from 30% to 40% in patients 40 to 49 years of age who undergo screening mammograms. A meta-analysis of six randomized trials indicates a 30% reduction in breast cancer mortality in patients 50 to 69 years of age. The sensitivity of mammograms depends on the patient's age and ranges from 53% to 81% in women 40 to 49 years of age to 73% to 81% in patients 50 years of age or older. An estimated 10% to 15% of breast cancer cases are not detectable on screening mammography, thus emphasizing the importance of physical breast examination by a physician and BSE that include both visual inspection and manual examination of the breast. On inspection, signs of breast malignancy include skin or nipple retraction or discoloration, nipple discharge/crusting, or peau d'orange edema of the breast. On palpation, any asymmetric mass of the breast or axilla may be regarded as a potential malignancy that deserves further evaluation. Current recommendations are for a woman to start performing BSE at 18 years of age, have a yearly physical exam, and initiate annual mammography at 40 years of age. Little data exist on what should be the

upper age limit of mammogram screening. Given that breast density decreases with age and breast cancer increases with age, mammograms should be even more sensitive and specific in the older age group. For these reasons, mammograms may be continued in very elderly patients as long as the patient is not suffering from any major co-morbidities. In patients who have a very high risk of breast cancer, such as BRCA carriers, screening should start 10 years earlier than the age of onset of an affected relative or at the age of 35. Kriege screened 1909 patients (including 358 BRCA mutation carriers) who had more than a 15% lifetime risk of developing breast cancer. These patients had a biannual breast exam as well as annual mammogram and breast magnetic resonance imaging (MRI). In this population, mammograms had a sensitivity of 33% with a specificity of 95%. Breast MRI had significantly higher rates of sensitivity and specificity at 80% and 90%, respectively. Given these findings, breast MRI should be a part of the screening exam for these high-risk patients. MRI is recommended as a standard screening test in BRCA heterozygotes. Routine surveillance in high-risk patients includes a 6-month interval alternating between breast MRI and mammograms. Patients with a history of mantle radiation for lymphoma should start annual screening at 25 years of age and biannual screening 10 years after receiving radiation therapy. Workup of a Breast Mass DOMINANT PALPABLE MASS The workup of a dominant palpable breast mass depends on the patient's menopausal status and the degree of suspicion. It is not unreasonable to follow a premenopausal patient with a nonsuspicious mass over one menstrual cycle and then reexamine her. Suspicious lesions present as a hard, nontender, irregular mass or as a mass in a high-risk patient. Palpable masses in postmenopausal patients may also warrant a workup. FNA should not be performed prior to diagnostic imaging because it may result in a hematoma that could obscure the image of the mass. Certain benign lesions on core biopsy should be excised, including lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH), radial scars, sclerosing papillary lesions, columnar cell hyperplasia with atypia, and PASH ( Figure 3 ). Twenty percent of surgeries performed for atypical ductal hyperplasia have concurrent carcinoma in the specimen. Patients with a high-risk proliferative lesion should have close follow-up after surgery including physical examinations. Negative findings on a mammogram do not preclude the diagnosis of cancer because 10% of cancers are occult mammographically. This number drops to 3% when a lesion is occult both mammographically and ultrasonographically. An alternative to core biopsies in younger women is the use of the triple test: a physical exam in conjunction with breast imaging (mammogram or ultrasound) and FNA. When all three components indicate the mass is benign, the negative predictive value is 100%. In a study by Morris, a triple test score assigns points to each component of the test. One point is given for benign findings, 2 points for suspicious findings, and 3 points for malignant findings. When added together, masses with scores of 4 or less are found to be benign. The triple test should only be used in women 40 years of age or younger because the incidence of breast cancer increases dramatically after that cutoff.

FIGURE 3 Algorithm for workup of a breast mass. ADH = atypical ductal hyperplasia; LCIS = lobular cancer in situ; U/S = ultrasound.

MASSES REVEALED ON SCREENING MAMMOGRAMS The American College of Radiology's classification lexicon, the Breast Imaging Reporting and Data System (BI-RADS), is used in breast imaging ( Table 2 ). BI-RADS 0 means the assessment is incomplete and more workup is needed. BI-RADS 1 indicates a normal mammogram. Mammograms with BI-RADS 2 signify benign findings. Patients with BI-RADS 3 have a 1% to 2% risk of malignancy and should have short-term follow-up with another mammogram in 6 months. BI-RADS 4 indicates the presence of suspicious lesions with a 20% to 40% probability of a malignant lesion. BI-RADS 5 is highly suggestive of cancer with a greater than 95% chance of harboring an underlying malignant lesion. BI-RADS 6, recently added as a category, indicates known malignant disease. BI-RADS 4 and 5 both indicate a biopsy.

TABLE 2 -- BI-RADS Mammography Classification

BI-RADS Category

Definition

Risk of Malignancy

Recommended Follow-Up

0

Incomplete assessment

N/A

Further workup

1

Negative study

N/A

Repeat mammogram in 1 y

2

Benign

N/A

Repeat mammogram in 1 y

3

Probably benign

African American White = African American

Differentiation

Well differentiated

Poorly differentiated

Histology

Endometrioid

PS, CC, Grade 3

Stage

Early

Advanced

Prognosis

Favorable

Poorer

Ploidy

Diploid

Aneuploid

k-ras over expression

Yes

Yes

Molecular Features

Factor

Type I

Type II

her-2/neu over expression No

Yes

p53 mutation

No

Yes

PTEN mutation

Yes

No

Microsatellite instability

Yes

No

Abbreviations: CC = clear cell; PS = papillary serous.

The etiology is unclear. Despite the broad generalizations of the two categories, molecular and genetic changes differentiate these two groups as well. For example, mutations of p53 are common in papillary serous tumors and are rare in type I tumors. PTEN mutations are common in type I tumors but are rare in papillary serous tumors. Global gene expression profiles also differ between type I and type II tumors. Increased exposure to endogenous or exogenous estrogen increases the risk of developing type I cancers. Since the 1970s, unopposed estrogen use has been a known risk factor, prompting the routine addition of a progestin in combination with hormone replacement therapy regimens. Endogenous exposure to estrogens associated with obesity or chronic anovulation (polycystic ovary syndrome) are believed to be more common etiologies. Other factors associated with an increased risk of developing endometrial cancer include late menopause (older than 52 years), nulliparity, diabetes, hypertension, or a diagnosis of complex atypical hyperplasia. In contrast, normal weight, oral contraceptives, progestin use, cigarette smoking, and multiparity have been associated with a decreased incidence of endometrial cancer. Type II tumors account for a small percentage of endometrial cancers, occur in an older population, and account for nearly one half of all relapses. Papillary serous, clear cell, and perhaps, grade 3 tumors fit into the type II category. Tamoxifen (Nolvadex) used in the prophylaxis of, or treatment for, breast cancer is an established risk factor for developing either type I or type II tumors. Presentation and Diagnosis Patients with endometrial cancer most commonly present with abnormal bleeding. Papanicolaou (Pap) smears detect only 30% to 50% of endometrial cancers and are not useful for diagnosing endometrial cancer. The diagnosis of endometrial cancer is most commonly made by biopsy. An endometrial biopsy can usually be performed in the office and has greater than 90% diagnostic accuracy. The histologic classification of endometrial cancers is listed in Box 1 . Ultrasound has also been used to evaluate abnormal bleeding. Studies show that endometrial cancers are exceedingly uncommon if the endometrial thickness is less than 5 mm on ultrasound in postmenopausal women. Symptomatic patients with a thickened endometrium or patients with persistent bleeding despite a thin lining should have a histologic evaluation. BOX 1

Histologic Classification of Endometrial Cancers •

Endometrioid adenocarcinoma (includes adenosquamous carcinoma)

•

Mucinous carcinoma

•

Serous carcinoma

•

Clear cell carcinoma

•

Squamous carcinoma

•

Undifferentiated carcinoma

•

Mixed carcinoma

CURRENT DIAGNOSIS Patients with postmenopausal bleeding warrant endometrial biopsy. Patients at risk include those with abnormal bleeding and obesity, chronic anovulation, and unopposed estrogen or tamoxifen (Nolvadex) exposure. Office biopsy should be performed when possible, and D&C should be performed if office biopsy is not available or biopsy results are equivocal. Malignancy is unlikely if the endometrial stripe/thickness is less than 5 mm on ultrasound. Abbreviation: D&C = dilation and curettage.

Currently there is no good screening test for endometrial cancer, and thus there are no screening recommendations. A high degree of suspicion should be maintained for women who have received unopposed estrogens and for patients with vaginal bleeding who are postmenopausal, obese, or taking tamoxifen. Hereditary syndromes (Lynch's) account for 3% to 5% of endometrial cancers and are seen in patients with strong familial histories of hereditary nonpolyposis colorectal, ovarian, and pancreatic cancers. Staging Endometrial cancer is surgically staged according to the 1988 criteria established by the International Federation of Gynecology and Obstetrics (FIGO) ( Table 2 ). Staging includes collection of pelvic washings for cytology, a hysterectomy with removal of bilateral fallopian tubes and ovaries, and pelvic and para-aortic lymph node dissection. Controversies currently exist as to who should undergo lymph node dissection (all, some, or few patients), the type of nodal dissection (sampling or complete lymphadenectomy), and when to use adjuvant therapies.

TABLE 2 -- FIGO (1988) Surgical Staging System for Endometrial Cancer Stage Description

Stage Description IA

Tumor is confined to the endometrium

IB

Tumor is confined to less than one half of the myometrium

IC

Tumor is confined to more than one half of the myometrium

IIA

Cervical involvement is limited to the endocervical glands

IIB

Cervical involvement includes cervical stroma

IIIA

Tumor involves uterine serosa or adnexa or positive peritoneal cytology

IIIB

Vaginal metastases

IIIC

Tumor involves pelvic or para-aortic lymph nodes

IVA

Tumor involves bladder or bowel mucosa

IV B

Distant metastases including intra-abdominal and inguinal lymph node involvement

Abbreviation: FIGO = International Federation of Gynecology and Obstetrics.

The most important pathologic prognostic indicators include histologic grade, depth of invasion and lymph node status. The Gynecologic Oncology Group (GOG) performed a surgical pathologic study evaluating 621 patients with endometrial cancer and demonstrated important associations between grade, depth of myometrial invasion, and nodal involvement. For example, patients with deeply invasive (extending into the outer two thirds of the myometrium) tumors had pelvic nodal metastases between 11% and 34%, depending on tumor grade. Fortunately, most women with endometrial cancer have stage I disease and have a favorable prognosis ( Table 3 ). The 5-year survival for stage I disease approaches 90%, but the 5-year survival for women with stage IV (abdominal or distant spread) disease is only about 10%.

TABLE 3 -- Estimates of Distribution and Survival of Endometrial Cancer by Stage Stage Distribution of Cases (%) 5-year Survival (%) Stage IA 22

92

Stage IB 37

88

Stage IC 13

78

Stage II

72

9

Stage III 15

53

Stage IV 4

10

Treatment

SURGICAL MANAGEMENT Surgical management continues to evolve. The GOG has recently completed a large prospective trial evaluating the role of laparoscopic hysterectomy and nodal dissection compared with an abdominal approach. The study, evaluating more than 2500 patients, found that laparoscopic management was feasible, and 76% of the time patients randomized to laparoscopy could have the procedure performed without conversion to laparotomy. The numbers of nodes removed and the frequency of finding positive lymph nodes were similar in the two treatment arms. Despite an increased operative time, results showed that laparoscopic surgery resulted in a shorter hospital stay.

CURRENT THERAPY Surgical therapy is the mainstay of endometrial cancer treatment. Laparoscopic surgery is increasingly being used. Surgical staging, including pelvic and para-aortic lymph node dissection, is recommended. The best way to define risk is to identify patients with nodal disease. Staging typically requires referral to a gynecologic oncologist. Unstaged patients may be considered for a restaging operation. Most patients have stage I (uterine-confined) disease. Low-risk patients—stages IA and IB, grades 1 or 2—require no additional therapy. Intermediate-risk patients—stage IB grade 3 and stage IC grades 1 or 2—require no additional therapy or vaginal cuff brachytherapy. High-intermediate-risk patients are those 50 years old with two risk factors or older than 70 years with one risk factor. Risk factors are: Grade 2 or 3 tumor Lymphovascular space involvement Outer one third myometrial invasion Stage I plus papillary serous or clear cell histology Treatment of these patients is controversial. There is no clear consensus regarding performing no additional therapy, performing vaginal cuff brachytherapy with or without chemotherapy, or performing pelvic radiation therapy. The benefits of routine nodal dissection include better stratification of patients into high-, intermediate-, or low risk-categories, reduced use of postoperative therapies for most node-negative patients, and improved identification of a subset of patients with nodal metastases who might benefit from adjuvant therapies. Information from a lymph node dissection is prognostic, but a lymphadenectomy is potentially therapeutic. Today, the more frequent use of nodal dissection has resulted in the less-frequent use of postoperative pelvic irradiation therapy.

Without information on nodal status, physicians and patients must decide whether or not to use postoperative therapies based on perceived risk determined from the hysterectomy findings. Because of this, many have recommended that a second surgery to complete the surgical staging be performed when only a hysterectomy was performed. Laparoscopic restaging is often a feasible approach. The risk of nodal dissection must be balanced by the information provided. Serious complications related to nodal dissection include bleeding and visceral injury, and complications have been reported to occur in less than 2% of surgeries. Lower extremity lymphedema appears to be more common but is rarely severe. ADJUVANT THERAPY Early Stage Disease

Two large trials have evaluated the role of post-operative pelvic radiation in patients with early stage (stage I to occult stage II) endometrial cancer. In the PORTEC trial, 715 patients were randomized to pelvic radiation or surveillance. Lymph node dissection was not performed. Most patients had low-grade tumors (90% grade 1-2), and about 50% had superficial myometrial invasion (2 cm T3 Adjacent spread to urethra, vagina, perineum, or anus (any size) T4 Infiltration of upper urethral mucosa, bladder, rectum, or bone N

Regional lymph nodes

N0 No lymph node metastases N1 Unilateral regional lymph node metastasis N2 Bilateral regional lymph node metastasis M

Distant metastases

M0 No clinical metastases M1 Distant metastasis (including pelvic lymph node metastasis)

Abbreviations: TNM = tumor, node, metastasis.

BOX 2

FIGO Classification (With Corresponding TNM Classification) for Vulvar Carcinoma

Stage I (T1N0M0)

Tumor confined to vulva and/or perineum, £2 cm in greatest dimension; nodes are negative

Stage IA

Stromal invasion no greater than 1 mm

Stage IB

Stromal invasion >1 mm

Stage II (T2N0M0)

Tumor confined to the vulva and/or perineum, >2 cm in greatest dimension; nodes are negative

Stage III T3N0M0

Tumor of any size with adjacent spread to the lower urethra and/or the vagina or the anus

T3N1M0

Unilateral regional lymph node metastasis

T2N1M0 Stage IVA T1N2M0

Tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa, pelvic bone, and/or bilateral regional node metastasis

T2N2M0 T3N2M0 T4 any N M0 Stage IVB Any T any N M1

Any distant metastasis including pelvic lymph nodes

Abbreviations: FIGO = International Federation of Gynecology and Obstetrics; TNM = tumor, node, metastasis.

SQUAMOUS CELL CARCINOMAS AND ADENOCARCINOMAS Surgical management of squamous cell carcinomas and adenocarcinomas depends on the size, depth of invasion, and location of the lesion. The vulvar lesion is managed with a radical excision. Management of the groins is based on depth of invasion. Lesions with invasion of 150, diastolic blood pressure >100, or heart rate >100). Consider adding anticonvulsants.

* All treatment must be individualized to meet specific patient needs and adjusted based on response to treatment.

Phencyclidine (PCP) intoxication can have a frightening presentation. The patient may become agitated and unpredictable, requiring physical and chemical restraints to ensure the safety of the patient and those around him or her. Medication may not be necessary if the patient is placed in a quiet, supportive setting. If medications are used, benzodiazepines are typically chosen first. If antipsychotics are required, agents with low anticholinergic activity are preferred. Toxic doses of PCP can produce a life-threatening condition with severe autonomic instability in which hypertension, hyperthermia, convulsions, and coma may become serious medical management problems. Treatment While medication management is increasingly important in the treatment of alcohol and drug dependence, nonpharmacologic approaches are the mainstay of substance abuse treatment. Alcoholics Anonymous (AA) helped many alcoholics recover before physicians had treatment techniques to offer. AA remains a proven resource, and other self-help groups are modeled after it. Narcotics Anonymous (NA) and Cocaine Anonymous (CA), similar to AA, are pivotal in the recovery of some drug abusers. The caveat is that one group may be very different from another. There are significant problems in some self-help groups. Patients may have concerns about heavy cigarettesmoking in meetings, about attendees who actively use or sell drugs, and about criticism of prescribed psychotropic medications. Therefore, when a patient finds one group unsatisfactory for some reason, the clinician can suggest he or she try another group. Some patients object to the religious tone of traditional 12step groups. For these individuals alternative groups such as Women for Sobriety and Rational Recovery may be more acceptable. In addition, self-help groups are free of charge, which is a factor for some patients. Most professional addiction treatment occurs in an outpatient setting. However, higher levels of care are available in hospital, residential, or partial hospital programs if there are chaotic living situations, or pressing

psychiatric or other medical needs. Social interventions are crucial for patients faced with unemployment, legal consequences, and housing dilemmas. Psychiatric disorders occur with a high frequency in drugabusing populations, and both disorders should be treated to optimize the patient's chances for recovery. Therefore, a multidisciplinary approach to treatment often works best. Psychiatric symptoms in patients who abuse drugs are easy to recognize. Mood lability, depression, and anxiety are common. The challenge lies in sorting out whether these symptoms are caused by the use of a mood-altering substance or represent a separate mood or anxiety disorder. Psychiatric expertise may be needed to assist in sorting out this diagnostic dilemma. Patients with schizophrenic and bipolar disorders are also at high risk for drug abuse, which can exacerbate psychoses. The cognitive aspects of professional treatment often include educational, motivational, cognitive–behavioral, relapse prevention, and 12-step strategies. Most treatment programs try to get the patient to more fully recognize the problems associated with his or her drug use, identify reasons to change, acknowledge obstacles to sobriety, become aware of triggers to relapse, and consider ways to build a sober support network. Patients with addictive disorders do get better, and treatment of patients with drug abuse can be highly rewarding. It is important to recognize this problem as one of many chronic, relapsing conditions seen in medicine today.



Chapter 278 – Anxiety Disorders

Method of: Jacqueline Carinhas McGregor, MD Anxiety disorders are the most common psychiatric disorders in the world among both children and adults. In the United States, 30 million people or approximately one of every four meet the criteria for an anxiety disorder in their lifetimes. It is estimated that the annual cost of anxiety disorders in 1998 dollars was more than $63 billion. More than half of these costs were due to nonpsychiatric direct medical costs, which include undiagnosed, misdiagnosed, or inadequately treated anxiety disorders. It is clear that much of the emotional and economic burden caused by these disorders could be alleviated by improving diagnosis and treatment. Genetics, temperament, and life stressors can all be contributors to anxiety disorders. Norepinephrine and serotonin are thought to be the major neurotransmitters involved in mediating anxiety symptoms whereas the sympathetic nervous system also plays an important role. The onset of anxiety disorders can usually be traced to childhood, adolescence, or young adulthood. With the exception of obsessive-compulsive disorder, women are more likely than men to suffer from anxiety disorders. Anxiety disorders occur across racial groups without distinction. Anxiety is characterized by subjective feelings of worry, dread, or anticipation and can include hypervigilance, excessive negativity, and a myriad of somatic symptoms. These symptoms can include diaphoresis, palpitations, shortness of breath, dizziness, chest pain, tremulousness, gastrointestinal complaints, fatigue, dry mouth, sleep problems, hot flashes, polyuria, and restlessness. Because of the wide variety of physical complaints, underlying organic causes and disorders secondary to substances use must first be ruled out ( Box 1 ). A detailed history of present illness, past medical history, substance history, and review of symptoms is essential. If a patient initially presents with anxiety symptoms in middle or late adulthood, has no family history of anxiety disorders, has no temporally related stressors, and does not respond to psychiatric intervention, a closer investigation of organic causes of anxiety should be undertaken. In patients describing chest pain, cardiovascular causes such as angina, mitral valve prolapse, arrhythmias, and pulmonary embolism should be ruled out. Pulmonary ailments such as asthma, chronic obstructive pulmonary disorder, and pneumonia should be considered in patients describing shortness of breath. Hyperthyroidism, pheochromocytoma, and Cushing's syndrome are examples of endocrine disorders that can mimic anxiety disorders. Other disorders to consider include anemia, delirium, menopause, and gastroesophageal reflux. Medications such as stimulants (including herbal supplements and caffeine), decongestants, antipsychotics, theophylline, steroids, calcium channel blockers, and anticholinergics should all be considered. Alcohol and illicit drug use or withdrawal are other possible causes of anxiety symptoms. The most common diagnoses of anxiety disorders include generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and specific phobias. Those suffering from anxiety disorders are likely to have another co-morbid psychiatric disorder such as a mood disorder or substance dependence. These patients also have a higher

risk for suicidal behaviors. It is important to distinguish anxiety disorders from each other, as well as from other psychiatric disorders because the specific diagnosis may have significant impact on treatment decisions. Simple phobias, for example, are not responsive to medication and require cognitive behavioral intervention. OCD requires significantly higher doses of antidepressants than other disorders. Patients with GAD and panic disorder need lower starting doses of antidepressants to avoid iatrogenically exacerbating their symptoms. In the case of patient with comorbid bipolar disorder, special care should be used with antidepressants to prevent the induction of a manic episode. Psychotherapeutic interventions are often considered the first line of intervention in anxiety disorders, particularly for patients with mild symptoms, those who prefer nonpharmacologic treatment, and for children. Cognitive behavior therapy (CBT) is a specific type of psychotherapy that combines behavioral therapy with cognitive therapy and has the best evidence-based research supporting its use in anxiety disorders. The behavioral component of CBT includes exposure and ritual prevention whereas the cognitive aspect includes identifying false, irrational thoughts and the automatic responses to them. It is important to find skilled therapists with specialized training in these modalities in order to facilitate helpful referrals. The pharmacologic treatment of most anxiety disorders usually includes selective serotonin reuptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or benzodiazepines. The SSRIs fluoxetine (Prozac) and paroxetine (Paxil) are both potent inhibitors of cytochrome P450 2D6, and significant interactions can occur with other drugs that a patient may be taking. Escitalopram (Lexapro) has the most favorable SSRI side effect profile with the least protein-binding and cytochrome-P450 interactions. The most common side effects of SSRIs are nervousness, insomnia, restlessness, nausea, and diarrhea. Venlafaxine (Effexor) has a lower risk of significant drug interactions compared to the SSRIs; however, patients prescribed venlafaxine (Effexor) should have their blood pressure monitored as it can cause or worsen existing hypertension. Benzodiazepines should be used carefully because of their addictive potential and should be avoided in patients with a history of substance abuse. As with any drug, it is important to discuss the risk and benefits of medication options with patients before coming to a treatment decision. The dosage of a medication should be carefully titrated to minimize side effects while providing adequate symptom response. The Food and Drug Administration (FDA) issued a labeling change request in October 2004 for a black box warning on antidepressant medications about the possible association of SSRIs with suicidality in the treatment of major depressive disorder. The antidepressant side effect of agitation has been known to trigger suicidal behavior in those with or without premorbid depression. A physician should exercise special care in using SSRI medications, especially with those younger than 18 years of age. Frequent follow-up visits are recommended to monitor side effects and treatment response. Three of the most prevalent and burdensome anxiety disorders are GAD, OCD, and panic disorder. The remainder of this article will focus on the diagnosis and treatment of GAD and OCD disorders. Panic disorder is discussed in another article. BOX 1

Organic Causes of Anxiety Symptoms

Cardiopulmonary Angina, mitral valve prolapse, pulmonary embolism, COPD, asthma Endocrine

Hyperthyroidism, pheochromocytoma, Cushing's syndrome, menopause

Gastrointestinal

Gastroesophageal reflux, irritable bowel syndrome, gastritis

Neurologic

Dementia, substance intoxication or withdrawal, seizure disorder, migraine

Medications

Stimulants, herbal supplements, decongestants, steroids, antipsychotics, theophylline, calcium channel blockers, anticholinergics

Abbreviation: COPD = chronic obstructive pulmonary disease. Generalized Anxiety Disorder DIAGNOSIS According to the Diagnostic and Statistical Manual of Mental Disorders IV-TR, individuals with GAD suffer from uncontrollable, excessive anxiety and worry involving several areas of functioning on most days in a 6 month period. It must be associated with three or more of the following symptoms: restlessness, fatigue concentration difficulties, irritability, muscle tension, or sleep problems. The anxiety cannot be the result of another Axis I disorder; it must cause a significant impairment in functioning, and it cannot be due to substance abuse, a medical disorder, or occur exclusively in the context of a mood disorder, psychotic disorder, or pervasive developmental disorder. The 12-month prevalence for GAD is 3.1%, and the lifetime prevalence is close to 5%. Women are twice as likely as men to suffer from GAD. GAD usually develops sometime during late adolescence or early adulthood, its symptoms tend to have a chronic duration, and there is a high incidence of comorbid psychiatric disorders (especially depression) associated with it. GAD can be difficult for the physician to diagnose because patients can be reluctant to discuss their anxiety or be unable to identify it as the source of their concerns. Patient complaints of fatigue, insomnia, somatic symptoms, or chronic pain should be a signal for the physician to ask more about anxiety symptoms. TREATMENT Psychotherapy, pharmacotherapy, and their combination can be successfully used to treat GAD. Psychotherapy, particularly cognitive-behavior therapy and applied relaxation, are effective treatment strategies for GAD. Psychotherapy can be used concomitantly with pharmacotherapy, often with better result than if either were used alone. There are a variety of psychopharmacologic interventions that can be used for patients with GAD ( Table 1 ). An antidepressant or the 5-HT 1A partial agonist, buspirone (BusPar), is considered the first line of drug

treatment. Paroxetine (Paxil), escitalopram (Lexapro), and venlafaxine (Effexor) are the only antidepressants that have an FDA indication for GAD, although there is evidence that both imipramine (Tofranil)[1] and sertraline (Zoloft)[1] are effective drugs in the treatment of GAD. SSRIs are usually considered the antidepressant of choice because of their safety and relatively modest side effects. Use tricyclic antidepressants such as imipramine (Tofranil) with care because of their more troublesome side-effect profile, proarrhythmic properties, and potential lethality in overdose. The most commonly noted side effects of buspirone (BusPar) are dizziness, nausea, headache, nervousness, and insomnia. Benzodiazepines can play an important role in the treatment of GAD. It is important to keep in mind the addictive potential of these medications before using them. In the first weeks of treatment with SSRIs, it can be helpful to use benzodiazepines to address acute anxiety symptoms while allowing sufficient time for the SSRI to achieve its effect. As symptoms begin to respond, the physician should consider tapering and discontinuing the benzodiazepine.

TABLE 1 -- Pharmacotherapy in the Treatment of Generalized Anxiety Disorder Drug Starting Dose Target Dose SSRIs Paroxetine (Paxil CR)[*]

10 mg qd

10–60 mg qd

Escitalopram (Lexapro)[*]

5–10 mg qd

10–20 mg qd

Sertraline (Zoloft)

12.5–25 mg qd 50–200 mg qd

Fluoxetine (Prozac)

10 mg qd

20–40 mg qd

SNRIs Venlafazine (Effexor XR)[*] 37.5 mg qam

150-300 mg qam

OTHER Buspirone (BusPar)

5 mg bid-tid

10 mg bid to tid

Abbreviations: bid = twice daily; qam = every morning; qd = every day;tid = three times daily. SNRIs = serotonin-norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors.

* FDA indication for generalized anxiety disorder (GAD).

After an 8- to 10-week course of treatment with an antidepressant, if there has been an insufficient response at an adequate dose, the clinician should consider switching to or augmenting with another drug (e.g., another antidepressant, buspirone [BusPar] or a benzodiazepine). Patients need significant support and encouragement from their physician to be compliant with daily medication regimes and to continue their medication once they begin to experience symptom relief. There is little data on the length of treatment or whether pharmacologic intervention can prevent future relapse. It is common practice to continue treatment for at least 6 to 12 months after resolution of symptoms before stopping medications. At that time a gradual tapering of the medication dose can be considered.


Obsessive Compulsive Disorder DIAGNOSIS The Diagnostic and Statistical Manual of Mental Disorders IV-TR outlines the criteria for OCD as having obsessions and/or compulsions. Obsessions are defined as recurrent, persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate and cause significant distress. They cannot be excessive worries about realistic or reasonable concerns. The individual attempts to ignore the obsessions or counteract them with another thought or action and understands that the obsessions are a product of his or her own mind. Compulsions are defined as repetitive behaviors or mental acts that the individual feels compelled to perform in response to an obsession. The compulsion is aimed at reducing distress or preventing some dreaded event, but is not clearly connected to the distress or event or is clearly excessive. Except in the case of children, at some point in the course of the disorder the individual recognizes that the obsessions or compulsions are unreasonable. This last point is important in distinguishing OCD from obsessive compulsive personality disorder. The obsessions or compulsions must cause significant impairment and, if another Axis I disorder coexists, the obsessions and/or compulsions cannot be restricted only to the content of that disorder (e.g., preoccupations with food in the case of an eating disorder, hair pulling in the case of trichotillomania). As in the case of GAD, the symptoms cannot occur because of the effects of a substance or secondary to a general medical disorder.

CURRENT THERAPY

First Intervention GAD CBT

Second Intervention

Third Intervention

SSRI OR venlafaxine (Effexor) OR buspirone (BusPar) OR

Change to different antidepressant or buspirone (BusPar) OR Augment with a different antidepressant class, buspirone (BusPar), or benzodiazepine

OCD CBT

High dose SSRI (push to maximum dose in 4 to 8 weeks)

Change to another SSRI or clomipramine (anafranil) OR Augment with atypical antipsychotic

Abbreviations: CBT = cognitive behavior therapy; GAD = generalized anxiety disorder; OCD = obsessivecompulsive disorder; SSRI = selective serotonin reup-take inhibitor. It is not uncommon for OCD to occur with other psychiatric disorders including major depressive disorder, other anxiety disorders, eating disorders, and tic disorders. In children, streptococcal infections are associated with the development of obsessions and compulsions. Psychotic disorders can have obsessive or compulsive behaviors, but these are typically much more bizarre, and the individual has little insight into

his or her behavior. It is also important to consider illnesses that can have OCD-like symptoms such as basal ganglia disorders (e.g., Huntington's disease) or tic disorders. OCD usually appears in late adolescence or early adulthood and has a waxing and waning course. Unlike other anxiety disorders there is an equal occurrence in males and females. The lifetime prevalence rate of OCD is 2% to 3% of the population. Neuroimaging studies of OCD suggest that there are structural and functional problems in the orbitofrontal-subcortical circuitry. People with OCD often avoid seeking treatment for their illness. Diagnosis often requires explicit questioning regarding specific behaviors such as perfectionism, rituals, washing, counting, checking, or hoarding. The physicians should also be on the lookout for excessively red or raw hands, recurring request for reassurance about medical illnesses, frequent emergency room visits, or usual repetitive behaviors observed in the examining room such as tic-like motions or tapping. TREATMENT There are a variety of treatment approaches that can be used for OCD. As with GAD, psychotherapy can be utilized effectively. There is significant research that supporting cognitive behavioral therapy that incorporates exposure-response prevention is a successful treatment for obsessions and compulsions. In more severe cases of OCD, optimal treatment uses a combination of cognitive behavioral therapy and medication. Several studies demonstrated the efficacy of SSRIs in OCD. A reasonable trial of SSRIs in OCD can be longer and requires higher doses than what would be expected in GAD or major depressive disorder. Setraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and fluvoxamine (Luvox) are SSRIs with FDA indications for OCD. For those with an inadequate response to treatment with SSRIs, the clinician should consider changing SSRIs, switching to the tricyclic antidepressant, clomipramine (Anafranil), or to the SNRI, venlafaxine (Effexor). [1] The most common side effects of clomipramine (Anafranil) include dry mouth, sedation, dizziness, and weight gain, however, more serious, less common side effects include hypertension and cardiac arrhythmias. Augmentation with a dopamine agonist such as risperidone (Risperdal)[1] or olanzapine (Zyprexa) has been shown to be an effective treatment approach as has the addition of buspirone (BusPar)[1] or benzodiazepines ( Table 2 ).

TABLE 2 -- Pharmacotherapy in the Treatment of Obsessive-Compulsive Disorder Drug

Starting Dose Target Daily Dose

SSRI Sertraline (Zoloft)[*]

25-50 mg qd

100-300 mg[3]

Paroxetine (Paxil CR)[*]

12.5 mg qd

25-50 mg

Fluoxetine (Prozac)[*]

10 mg qd

20-60 mg

Fluvoxamine (Luvox)[*]

25-50 mg qd

100-300 mg

Drug

Starting Dose Target Daily Dose

SNRI Venlafaxine (Effexor XR) 37.5 mg qam

150-300 mg

TCA Clomipramine[*]

25 mg qhs

100-300 mg

(Anafranil) Abbreviations: qam = every morning; qd = every day; qhs = at bed time.

* FDA indication for obsessive-compulsive disorder (OCD). 3 Exceeds dosage recommended by the manufacturer.

There is some evidence to support the use of monoamine oxidase inhibitors (MAOIs) in treatment-resistant OCD, but because of the significant side effects, potential drug and food interactions, and toxicity, they are considered an option only when other medication options have proven unsuccessful. For those who fail psychotherapy and psychopharmacology and continue to have significant functional impairment, transcranial magnetic stimulation and neurosurgery are considered treatments of last resort. Treatment of OCD can usually be accomplished on an outpatient basis; however, in severe refractory cases, inpatient treatment at a facility that specializes in OCD may be necessary. Whatever treatment strategy is employed, the physician should be mindful of the fact that the patient's family often needs to be involved in the treatment. Families often unknowingly reinforce a patient's OCD behaviors by going along with their rituals or participating in excessive reassurance. Anxiety disorders are quite common and cause a significant burden to individuals as well as to society. The differential diagnosis of anxiety disorders is quite extensive given that anxiety symptoms are often nonspecific. Anxiety disorders often go undiagnosed or are inadequately treated and are likely to occur together with other psychiatric disorders. Primary care physicians are more likely to have the opportunity to detect anxiety disorders and, in fact treat more of these disorders than mental health care practitioners. Effective treatments for anxiety including psychotherapeutic as well as psychopharmacologic interventions are shown in Box 2 . BOX 2

Helpful Resources for Anxiety Disorders

National Alliance for the Mentally Ill

www.nami.org

National Institute of Mental Health

www.nimh.org

Anxiety Disorders Association of America www.adaa.org Obsessive-Compulsive Foundation

www.ocfoundation.org



REFERENCES American Psychiatric Association, 2000. American Psychiatric Association : Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev, Washington, DC, American Psychiatric Association, 2000. Baer et al., 1995. Baer L, Rauch SK, Ballantine T, et al: Cingulotomy for intractable obsessive-compulsive disorder. Arch Gen Psych 1995; 52:384-392. Borkovec and Costello, 1993. Borkovec T, Costello E: Efficacy of applied relaxation and cognitive-behavioral therapy in the treatment of generalized anxiety disorder. Journal of Consulting and Clinical Psychology 1993; 61(4):611-619. Food and Drug Administration, 2004. Food and Drug Administration: FDA labeling change request letter for antidepressant medications, 2004. Greenberg et al., 1997. Greenberg BD, George MS, Martin DJ, et al: Effect of prefrontal repetitive transcranial stimulation in obsessive-compulsive disorder: A preliminary study. Am J Psychiatry 1997; 154:867-869. Greenberg et al., 1990. Greenberg PE, Sisitsky T, Kessler RC, et al: The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 1990; 60:427-435. Jenike et al., 1998. In: Jenike MA, Baer L, Minichiello WE, ed. Obsessive-compulsive disorders: practical management, 3rd ed.. St Louis: Mosby; 1998. Karno et al., 1988. Karno M, Golding JM, Sorenson SB, et al: The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry 1988; 45(12):1094-1099. Kessler et al., 1994. Kessler RC, McGonagle KA, Zhao S: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry 1994; 51(1):8-19. Kobak et al., 1998. Kobak KA, Griest JH, Jefferson JW, et al: Behavioral versus pharmacologic treatment of obsessive compulsive disorder: A meta-analysis. Psychopharmacology (Berl) 1998; 136:205-216. Koran et al., 2000. Koran LM, Rinhold AL, Elliot MA: Olanzapine augmentation in obsessive compulsive disorder refractory to selective serotonin reuptake inhibitors: An open label case series. J Clin Psychiatry 2000; 61:514-517. Ladouceur et al., 2000. Ladouceur R, Dugas MJ, Freeston MH, et al: Efficacy of a cognitive behavioral treatment for generalized anxiety disorder evaluation in controlled clinical trial. J Consult Clin Psychol 2000; 68(6):957-964. Liebowitz et al., 2003. Liebowitz MR, DeMartinis NA, Weihs K, et al: Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study. J Clin Psychiatry 2003; 64(7):785-792. McDougle et al., 2000. McDougle CJ, Epperson CN, Pelton GH, et al: A double blind placebo controlled study of risperidone addition in serotin reuptake inhibitor-refractory obsessive compulsive disorder. Arch Gen Psych 2000; 57:794-801.

Rickels et al., 1993. Rickels K, Downing R, Schweizer E, et al: Antidepressant for the treatment of generalized anxiety disorder: a placebo controlled comparison of imipramine, trrazodone, and diazepam. Arch Gen Psychiatry 1993; 50:884-895. Rickels and Schweizer, 1998. Rickels K, Schweizer E: The spectrum of generalized anxiety in clinical practice: The role of short term intermittent treatment. Br J Psychiatry 1998; 173(Suppl 34):49-54. Saxena et al., 2001. Saxena S, Bota RG, Brody AL: Brain-behavior relationships in obsessive-compulsive disorder. Semin Clin Neuropsychiatry 2001; 6(2):82-101.



Chapter 279 – Bulimia Nervosa

Method of: David B. Herzog, MD Kamryn T. Eddy, PhD Bulimia nervosa is a prevalent eating disorder most commonly observed in late adolescent and young adult women and often associated with psychiatric co-morbidity and medical sequelae. The course of the disorder may be chronic and relapsing, and patients may demonstrate early ambivalence regarding treatment. There is often a considerable delay between onset of symptoms and presentation for treatment that may reflect shame, control issues, and fear of change (e.g., weight gain). Currently, psychosocial treatments—particularly cognitive behavioral therapy—are considered the first-line of treatment for the disorder, having demonstrated the most successful outcomes, but psychopharmacologic interventions are also promising. Diagnosis and Clinical Features DIAGNOSIS Bulimia nervosa was first recognized formally as a clinical diagnosis in 1979 by Gerald Russell. The disorder is currently defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) on the basis of recurrent binge eating and compensatory behaviors and related cognitions. Binge eating is defined as the consumption of a large amount of food (typically 2000 to 4000 calories) within a discrete period of time accompanied by loss of control overeating. Loss of control overeating involves the subjective experience of being unable to control what or how much one is eating and may be characterized by eating more rapidly than usual and consuming calorie-dense foods that are typically avoided outside of binge episodes. Compensatory behaviors are designed to counteract the effects of binge eating and can be classified as purging (self-induced vomiting, misuse of laxatives, diuretics, and enemas) and nonpurging (excessive exercise, fasting). The DSM-IV specifies that the binge eating and compensatory behaviors occur on average at least twice weekly during a 3-month period. In addition to the behavioral components, the DSM-IV indicates a cognitive component of overevaluation of the importance of weight and shape on sense of self. Weight is not part of the bulimia nervosa criteria; although most patients with bulimia nervosa are within an average weight range, patients may be overweight, obese, or even underweight. Patients with bulimia nervosa can be grouped into purging and nonpurging types based on the compensatory behaviors used. Notably, purging type appears to be predominant; less research exists on the nonpurging type. According to the DSM-IV hierarchy rules, a diagnosis of bulimia nervosa is not made if the binge and compensatory behaviors occur exclusively during a period of anorexia nervosa. Similarly, a diagnosis of binge eating disorder (currently recognized in the DSM-IV as an eating disorder not otherwise specified) can be appropriate if recurrent binge eating is present in the absence of any compensatory behaviors.

Although the current diagnostic system is useful, limitations exist. For example, there appears to be heterogeneity within the diagnostic category of bulimia nervosa on the basis of psychosocial functioning, personality style, and co-morbidity, which may have treatment implications. Furthermore, a large subset of patients present for treatment in clinical settings with symptom profiles that closely resemble that of a patient with bulimia nervosa but do not meet all of the diagnostic criteria. For example, although a formal diagnosis of bulimia nervosa stipulates a twice-weekly binge/compensatory behaviors frequency criterion, patients often present to eating disorder clinics for the treatment of bingeing and/or purging that occurs less frequently. Thus, this treatment review derives from the literature on bulimia nervosa but can be considered applicable across patients with a spectrum of bulimic symptoms. DIFFERENTIAL DIAGNOSIS Consideration of a range of conditions that may be characterized by features similar to bulimia nervosa is necessary in the initial assessment. Neurologic disorders impacting appetite regulation and eating behaviors (e.g., pituitary or hypothalamic brain tumors, Kleine-Levin or Klüver-Bucy syndromes), hormonal disorders relating to malnutrition and hypometabolism (e.g., adrenal disease, diabetes mellitus, pituitary dysfunction, hyperthyroidism), and gastrointestinal (GI) disorders (e.g., malabsorption, enteritis) should be considered. Psychiatric disorders including major depression and borderline personality disorder should be considered because they may be associated with binge eating even though compensatory behaviors and cognitive features of bulimia nervosa are absent. MEDICAL COMPLICATIONS Patients with bulimia nervosa are generally within the normal weight range, but they may show signs of malnutrition. Medical complications secondary to bingeing and purging behaviors and malnutrition are common. Patients often present with transient facial swelling, peripheral edema, weakness and fatigue, dental problems, and abrasions on the dorsal surface of the hand (Russell's sign). Medical assessment should be based on current symptom presentation and should include complete blood count, serum electrolytes, serum blood urea nitrogen (BUN)/creatinine levels, urinalysis, and an electrocardiogram (ECG). Electrolyte and acid-based complications secondary to purging are common and may include hypochloremia, hyponatremia, and hypokalemia. Hypokalemia is related to significant cardiac problems including arrhythmias. Long-term ipecac use may lead to cardiomyopathy. Edema may be present and related to laxative and diuretic abuse. Dental complications related to chronic regurgitation of gastric contents can include enamel erosion and caries. Swelling of the parotid glands is also common. GI difficulties ranging from constipation and bloating to esophageal disorders may also be present. Many of these symptom-related complications remit when the purging is discontinued, but additional treatment and monitoring can be warranted for some patients. CO-MORBIDITY Bulimia nervosa is often associated with psychiatric co-morbidity including mood, anxiety, and substance use disorders. Approximately half of patients with bulimia nervosa report a lifetime history of depression. Similarly, anxiety disorders including social phobia and obsessive-compulsive disorder are commonly reported. Although depression may precede the onset, have simultaneous onset, or follow the eating disorder onset, anxiety disorders most often precede the onset of the eating disorder. A substantial minority of patients with bulimia nervosa also reports a lifetime history of substance use disorders, with alcohol abuse being the most common.

Personality styles have received considerable attention in patients with bulimia nervosa. Research indicates that a subset of patients with bulimia can be characterized as multi-impulsive or dysregulated across multiple domains including eating, affect, interpersonal functioning, and sexuality, for example. Bulimic patients with dysregulated personality styles are more likely to present with co-morbid substance use disorders, cluster B axis II disorders, self-destructive and self-injurious behaviors, and kleptomania. Epidemiology Population surveys indicate a 1% to 4% lifetime prevalence rate for bulimia nervosa. However, subthreshold binge/purge symptoms and overvaluation of weight and shape are more common. Further, rates of bulimia nervosa are generally higher within given population subsets including college females, for example. Typical age of onset is in late adolescence or early adulthood and may occur during a time of transition (e.g., high school to college) or psychosocial stress. Approximately 90% of patients presenting for treatment of bulimia nervosa are female. Current research indicates that bulimia nervosa is prevalent across ethnicity and socioeconomic status. Notably, however, eating disorders are more commonly seen in industrialized nations where a thin female appearance is valued. Etiology A large body of research has considered the etiology of bulimia nervosa, implicating psychological, biological, and social factors. Psychological factors include general personality traits such as perfectionism and difficulty with emotion regulation, difficulty dealing with conflict, and pervasive low self-esteem. It is hypothesized that these variables represent vulnerability factors that are triggered by biological and environmental variables (e.g., transition, parent eating disorder, family conflict). The biological model of bulimia nervosa is supported by the higher concordance of monozygotic than dizygotic twins, which suggests genetic factors are implicated. Further, the biological model suggests that patient-induced dietary restraint leads to binge eating. The implication of social factors is supported by the increased prevalence of bulimia nervosa in industrialized nations. The images of ideal beauty portrayed by the media are inundating in Western society, and yet they are unrealistically thin for most women; women with a childhood history of overweight and obesity may be at particular risk. This leads to internalization of a thin body ideal and associated body dissatisfaction, both of which predict bulimic symptoms. It is likely that the confluence of multiple psychological, biological, and sociocultural factors predicts the development of bulimia nervosa. Early warning signs that may be observed by family members or primary care physicians are changes in eating behaviors and weight-related concerns (e.g., not eating with the family, nighttime eating, increased body concerns in normal or underweight females), physical changes (e.g., weight loss, amenorrhea), changes in social behaviors (e.g., avoidance of activities, isolation), and mood-related changes (e.g., loss of self-esteem, depressed mood, irritability). Treatment Options Treatment for bulimia nervosa often involves multiple components, the most common of which are psychosocial and pharmacologic. The primary aims of treatment for bulimia nervosa are to reduce and eliminate binge/purge behaviors, modify unhealthy attitudes toward weight and shape, and encourage healthier coping styles. Most patients with bulimia nervosa can be treated on an outpatient basis; however, hospitalization may be necessary for patients who are medically unstable (e.g., because of complications secondary to bulimia nervosa or medical morbidity such as diabetes), severely depressed, or treatment-

refractory. ASSESSMENT A comprehensive assessment is needed to determine an appropriate and individualized treatment course. Assessment should provide detailed information regarding:

•

Eating disorder symptom severity (i.e., frequency, type, history)

•

Medical issues and bulimia-related complications

•

Developmental history

•

Psychiatric history

•

Treatment history

•

Family history

For a subset of patients bulimia nervosa may be complicated by a concomitant medical condition; in these cases prioritizing the severity of various medical problems is necessary as a piece of the assessment. Patients with bulimia nervosa tend to manifest shame and embarrassment about their binge/purge symptoms. There is often considerable ambivalence in these patients who, on the one hand, describe feeling out of control with their eating behaviors and perhaps wish for immediate relief and therefore may be interested in beginning a treatment that will help them regain stability over their eating. Yet, they may be hesitant to implement recommendations, demonstrating significant fears that discontinuing the binge/purge cycle will result in weight gain, which they believe would be unbearable. Determining motivation and readiness to change is an important phase of the assessment process. Psychosocial

Several psychosocial interventions have received empirical support for the treatment of bulimia nervosa, and currently psychotherapy is regarded as the first-line of treatment for the disorder. Cognitive behavioral therapy (CBT) is one such approach that has received the strongest empirical support. CBT has been widely studied: in clinical trials it achieves 80% reductions in bingeing and purging behavior in patients and leads to full recovery in approximately 50% of patients. CBT for bulimia nervosa works on a model in which dietary restraint leads to binge eating and subsequent compensatory behaviors; both reinforce concern about eating, weight, and shape and in turn drive the bulimic cycle. CBT aims to intervene in this cycle by targeting dietary restraint to reduce and eliminate binge eating and purging and simultaneously address dysfunctional eating, weight, and shape cognitions. Core treatment components include psychoeducation around healthy eating and the implications of disordered eating behaviors, the prescription of regular eating, self-monitoring (in the form of daily food logs), and cognitive restructuring around eating, weight, and shape concerns. CBT is typically short-term focused treatment comprising 15 to 20 sessions held during a 4 to 5 month period. CBT can be delivered in an individual, group, or self-help manual format. Meta-analytic review indicates that individual treatment confers an advantage over group treatment. Additionally CBT-focused self-help and guided self-help approaches have also demonstrated

efficacy. Although response rates with self-help are not as high as individual CBT, advantages include the wide availability and low cost. Interpersonal psychotherapy (IPT) has also demonstrated efficacy in the treatment of bulimia nervosa, achieving rates of improvement and recovery comparable to those of CBT but somewhat less quickly. In the treatment of bulimia nervosa, IPT was first tested as a viable control treatment in clinical trials of CBT for bulimia nervosa. In contrast to CBT, which directly addresses the maladaptive eating disordered behaviors and cognitions, IPT focuses on interpersonal functioning. The IPT model of bulimia nervosa hypothesizes that interpersonal difficulties lead to low self-esteem and dysphoria and that bingeing and purging are used as coping mechanisms to regulate affect. The treatment focuses on addressing interpersonal difficulties in a short-term structured treatment, which leads to improvements in bulimic symptoms that often accrue even post-treatment. In spite of the efficacy of CBT and IPT treatments, approximately 50% of patients in clinical trials do not achieve full recovery post-treatment. Presently treatment trials are aiming to deconstruct CBT and IPT approaches to identify mechanisms of change as well as understand why treatment does not work for all patients. Integrated therapies, which incorporate elements of different treatment modalities, are often used in clinical practice and attempts to study them in controlled treatment trials are underway. One such example is an enhanced version of CBT (CBT-E), which incorporates cognitive behavioral principles, interpersonal aspects, regulation strategies taken from dialectical behavior therapy, and other techniques all in an individualized approach as they apply to the patient. Preliminary findings suggest high rates of improvement and recovery for difficult-to-treat patients. A limitation of these clinical trials for bulimia nervosa is that patient samples are most often adults; the generalizability of these findings to adolescents with the disorder is unclear. Two randomized controlled clinical trials for adolescents with bulimia nervosa have recently been completed. Both studies supported the use of family-based therapy, using the Maudsley model, in the treatment of adolescents with bulimia nervosa, and one indicated that CBT focused guided self-help was also effective and available at a lower cost. These empirically supported treatments are described in detail in treatment manuals available for use by treating clinicians. Pharmacotherapy

Psychotropic medication can be helpful for patients with bulimia nervosa in reducing bingeing and purging symptoms. Controlled trials have indicated that a range of antidepressants demonstrate efficacy in reducing bulimic symptoms, with the research finding post-treatment reductions in bingeing and purging symptoms for approximately 50% of patients and post-treatment abstinence rates of 30%. Currently, the only medication that has received FDA approval in the treatment of bulimia nervosa is fluoxetine (Prozac) at a recommended dose of 60 mg every day. Studies have suggested other selective serotonin reuptake inhibitors (SSRIs) may be equally effective but controlled clinical trials and long-term follow-up data are unavailable. In particular, patients with co-morbid anxiety disorders may benefit from paroxetine (Paxil)[1] or sertraline (Zoloft).[1] Additionally, earlier studies suggested tricyclic antidepressants, particularly desipramine (Norpramin), [1] were useful in reducing bulimic symptoms, but research indicates the SSRIs may be better tolerated. Monoamine oxidase inhibitors (MAOIs) are typically avoided because they may be dangerous in patients with erratic

eating patterns and nutritional instability because of bingeing and purging. Similarly, bupropion (Wellbutrin) is contraindicated in patients with bulimia nervosa because of an increased risk of seizures. Notably, the mechanism of action in the utility of antidepressant medication in reducing bulimic behaviors is unclear. Antidepressants seem to be equally effective in patients without depressive co-morbidity, arguing against an antidepressant effect. Given the role of serotonin in appetite regulation, it has been hypothesized that certain antidepressants may act on serotonin to reduce bingeing behaviors. Additionally, several other medications have been examined in patients with bulimia nervosa demonstrating moderate efficacy, including the opiate antagonist naltrexone (ReVia),[1] and the anticonvulsant Topiramate (Topamax).[1] There is also some indication that anxiolytic and sleep medications may also be useful for patients with bulimia nervosa. Thus psychotropic medications, particularly antidepressants, can be helpful for patients with bulimia nervosa, but they are typically less effective than cognitive behavioral therapy. Further, there is some indication that medication in combination with psychotherapy confers an advantage, but this finding is not consistent. Similar to the psychotherapy literature, however, clinical trials including adolescent patients are limited and the applicability of these findings to younger patients is unclear. 1 Not FDA approved for this indication.

Adjunctive Treatments

A medical assessment is indicated in patients with bulimia nervosa, and ongoing medical management may be useful particularly to treat patients with complications or those discontinuing laxative and/or diuretic abuse. Nutritional counseling may also be helpful to provide additional structure, support, and education for patients who have difficulty meal planning and regulating their eating. Nutritional psychoeducation is often a component of psychotherapy (e.g., CBT), but additional support may be needed for some patients. Additionally, supportive group therapy can be useful for some patients, particularly in helping them feel less isolated by interacting with that others who experience similar feelings and symptoms. Impact of Co-Morbidity on Treatment

The role of psychiatric co-morbidity in the treatment of bulimia nervosa is unclear. Generally, improvement of bulimic symptoms is associated with an improvement in mood and anxiety, but further treatment to target comorbidity is often warranted. Pharmacologic intervention studies indicate that antidepressants improve mood in patients with bulimia who are depressed in addition to targeting bulimic symptoms. Course and Outcome

The longitudinal course of bulimia nervosa is variable but can be chronic and relapsing. Long-term follow-up studies suggest that 50% to 75% of patients with bulimia nervosa will achieve full recovery from their eating disorder, but approximately 33% of them will go on to relapse. A small minority of patients seem to present with chronic bulimia nervosa. It appears that a longer duration of illness, history of unsuccessful treatment attempts, co-morbid substance abuse, and cluster B personality disorders are predictive of a worse outcome for patients with bulimia nervosa.

CURRENT DIGNOSIS DSM-IV defines bulimia nervosa on the basis of binge/compensatory behaviors and associated maladaptive cognitions. Binge eating is defined as the consumption of an objectively large amount of food within a discrete period of time accompanied by uncontrolled overeating. Compensatory behaviors include purging (self-induced vomiting, misuse of laxatives, diuretics, enemas) and nonpurging (excessive exercise, fasting). Binge/compensatory behaviors must occur on average twice weekly over a 3-month period. Cognitive component of overvaluation of weight and shape on sense of self. Differential diagnosis must consider medical and psychiatric conditions. Abbreviations: DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

CURRENT THERAPY Goals of treatment for bulimia nervosa are to reduce and eliminate binge/compensatory behaviors, modify maladaptive eating- and body-related cognitions, and improve coping skills. Psychotherapy is considered first-line treatment. Psychotherapies receiving empirical support for thetreatment of bulimia nervosa include CBT and IPT. Additional promising treatments include integrative psychotherapy approaches and family psychotherapy. Pharmacotherapy can also be helpful in targeting bulimic symptoms. Antidepressants have received the most empirical support. Fluoxetine (Prozac) at 60 mg qd is the only medication currently approved by the FDA in the treatment. CBT and IPT are effective in achieving reductions in binge/compensatory behaviors for the majority of patients and recovery in approximately 50% of patients. Antidepressant therapy leads to reductions in binge/compensatory behaviors for half of patients and recovery in approximately 30% of patients. Additional treatment research is warranted to address bulimic symptoms in the considerable subset of patients who remain ill following treatment. Abbreviations: CBT = cognitive behavioral therapy; FDA = Food and Drug Administration; IPT = interpersonal psychotherapy. Currently, viable psychosocial and pharmacologic treatments exist for the treatment of bulimia nervosa. Psychosocial approaches, particularly cognitive behavioral therapy, lead to substantial improvement in the majority of patients. Antidepressant therapy may also be useful for a subset of patients, but alone it does not seem to be as effective as psychotherapy. Self-help and guided self-help approaches with a cognitive behavioral focus may also be helpful for patients who have difficulty accessing care. Although these psychosocial and psychopharmacologic treatments are promising and helpful for most patients, approximately 50% of patients do not achieve full recovery even following treatment. Additional treatment

research with adolescent and adults patients is needed.



REFERENCES Agras et al., 2000. Agras WS, Walsh T, Fairburn CG, et al: A multicenter comparison of cognitive-behavioral therapy and interpersonal psychotherapy for bulimia nervosa. Arch Gen Psychiatry 2000; 57(5):459-466. Apple, 1999. Apple RF: Interpersonal therapy for bulimia nervosa. J Clin Psychol 1999; 55:715-725. Casper, 2002. Casper RC: How useful are pharmacological treatments in eating disorders?. Psychopharmacol Bull 2002; 36(2):88-104. Fairburn et al., 2003. Fairburn CG, Cooper Z, Shafran R: Cognitive behaviour therapy for eating disorders: A “transdiagnostic” theory and treatment. Behav Res Ther 2003; 41(5):509-528. Fairburn et al., 1993. Fairburn CG, Marcus MD, Wilson GT: Cognitive-behavioral therapy for binge eating and bulimia nervosa: A comprehensive treatment manual. In: Fairburn CG, Wilson GT, ed. Binge Eating: Nature, Assessment, and Treatment, New York: Guilford; 1993. Fairburn and Wilson, 1993. In: Fairburn CG, Wilson GT, ed. Binge eating: Nature, assessment and treatment, New York: Guilford Press; 1993:361-404. Kotler and Walsh, 2000. Kotler LA, Walsh BT: Eating disorders in children and adolescents: Pharmacological therapies. Eur Child Adolesc Psychiatry 2000; 9(Suppl 1):I108-I1016. Le Grange et al., 2007. Le Grange D, Crosby RD, Rathouz PJ, et al: A randomized controlled comparison of family-based treatment and supportive psychotherapy for adolescent bulimia nervosa. Arch Gen Psychiatry 2007; 64(9):1049-1056. Le Grange and Lock, 2007. Le Grange D, Lock J: Treating bulimia in adolescents, New York, Guilford Press, 2007. Mitchell et al., 2003. Mitchell JE, de Zwaan M, Roerig JL: Drug therapy for patients with eating disorders. Curr Drug Targets CNS Neurol Disord 2003; 2(1):17-29. Peterson and Mitchell, 1999. Peterson CB, Mitchell JE: Psychosocial and pharmacological treatment of eating disorders: A review of research findings. J Clin Psychol 1999; 55:685-697. Schmidt et al., 2007. Schmidt U, Lee S, Beecham J, et al: A randomized controlled trial of family therapy and cognitive behavior therapy guided self-care for adolescents with bulimia nervosa and related disorders. Am J Psychiatry 2007; 164:591-598. Shapiro et al., 2007. Shapiro JR, Berkman ND, Brownley KA, et al: Bulimia nervosa treatment: A systematic review of randomized controlled trials. Intl J Eat Disord 2007; 40:321-336. Steffen et al., 2006. Steffen KJ, Roerig JL, Mitchell JE, et al: Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs 2006; 11:315-336. Thompson-Brenner et al., 2003. Thompson-Brenner H, Westen D, Glass S: A multidimensional metaanalysis of psychotherapy for bulimia nervosa. Clin Psychol Rev 2003; 10:269-287.

Wilson et al., 2002. Wilson GT, Fairburn CC, Agras WS, et al: Cognitive-behavioral therapy for bulimia nervosa: Time course and mechanisms of change. J Consult Clin Psychol 2002; 70:267-274.



Chapter 280 – Delirium

Method of: Soenke Boettger, MD Delirium is a neuropsychiatric syndrome characterized by the abrupt onset of changes in consciousness, attention, cognition, and perception, which tend to fluctuate throughout the day and have an underlying physiologic etiology. Delirium is recognized as a medical condition where psychiatrists have a prominent role in treatment given their expertise in using antipsychotic medications and their familiarity with other conditions that resemble delirium. Subtypes of delirium specified by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) (DSM-IV TR) include delirium resulting from a general medical condition, substance intoxication, substance withdrawal, and multifactorial etiologies ( Box 1 ). Delirium can be further classified as hyperactive (or hyperdynamic) and hypoactive (or hypodynamic.) Other terms used for delirium are acute confusional state, encephalopathy, and organic brain syndrome. Although delirium is a transient state and may be self-resolving, its recognition and management are of utmost importance to minimize patient distress, reduce caregiver burden, and mitigate complications, including hospitalization. BOX 1 DSM-IV Criteria for Delirium (Modified) •

Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention

•

Change in cognition (e.g., memory deficit, disorientation, language disturbance, or perceptual disturbance) that is not better accounted for by a preexisting, established, or evolving dementia

•

The disturbance develops over a short time (usually hours to days) and tends to fluctuate during the course of the day

•

Delirium due to general medical condition

•

Delirium due to substance intoxication

•

Delirium due to substance withdrawal

•

Delirium due to multiple etiologies

Abbreviation: DSM-IV TR = Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision). Epidemiology and Etiology Due to its diverse etiology, the incidence and prevalence of delirium vary from 1% in the community to as much as 80% in the severely ill population. Predisposing factors are those that increase a patient's risk of developing delirium; precipitating factors are those that trigger delirium.

Advanced age and premorbid brain function may be the most important predisposing factors for developing delirium (see Box 2 for predisposing factors of delirium). Particularly in the elderly population, the treatment of delirium should be pursued aggressively due to prolonged hospitalization, increased morbidity and mortality, and risk of cognitive decline. Precipitating factors for developing delirium include acute and chronic illness, medications (especially polypharmacy, which is common in the elderly or severely ill), and drugs of abuse whether the patient is in a state of intoxication or withdrawal. BOX 2 Predisposing Factors in Delirium General

•

Alcoholism

•

Male sex

•

Older age

•

Severity of physical illness

Cardiopulmonary

•

Anemia

•

Arrhythmia

•

Myocardial infarction

•

Respiratory failure

Central Nervous System

•

Cerebrovascular disease and stroke

•

Head trauma

•

Presence and severity of dementia and degenerative disease

•

Primary brain tumor or metastatic spread to CNS

Metabolic

•

Dehydration

•

Hepatic and renal impairment

•

Hypoalbuminemia

•

Metabolic abnormalities

•

Nutritional deficiencies

Systemic

•

Hematologic abnormalities

•

Infection

•

Neoplasm

Other

•

Functional dependence and immobility

•

Hip fracture

•

Visual impairment


Boxes 3 and 4 [3] [4], respectively, list medical conditions and medications known to trigger delirium. Table 1 lists select medications in managing delirium. BOX 3 Precipitating Factors in Delirium General

•

High number of hospital procedures

•

Intensive care unit admission

•

Severe, acute illness

Cardiopulmonary

•

Cardiac surgery

•

Hypoxia

•

Myocardial infarction

•

Pneumonia

•

Shock

Central Nervous System

•

Bleeding

•

Narcotics

•

Seizures

•

Stroke

Metabolic

•

Acid-base disturbances

•

Dehydration

•

Endocrinopathies

•

Hyponatremia, hypercalcemia, and other electrolyte imbalances

Systemic

•

Urinary tract infection

•

Other infections

Other

•

Drugs of abuse

•

Medications

•

Noncardiac surgery

•

Orthopedic surgery

•

Pain

•

Physical restraint

BOX 4 Medications that Can Cause Delirium Medications with High Anticholinergic Activity Analgesics

•

Codeine, Dipyridamole (Persantine)

•

Prednisone (Deltasone)

•

Theophylline (Uniphyl)

H2 -Receptor Antagonists

•

Cimetidine (Tagamet)

•

Ranitidine (Zantac)

Heart Disease Medications

•

Captopril (Capoten)

•

Digoxin (Lanoxin)

•

Furosemide (Lasix)

•

Isosorbide dinitrate (Isordil)

•

Nifedipine (Adalat)

•

Triamterene with thiazide (Dyazide)

•

Warfarin (Coumadin)

Psychotropic Medications

•

Antipsychotics (e.g., chlorpromazine [Thorazine])

•

Benztropine (Cogentin)

•

Biperiden (akineton)

•


•

Trihexyphenidyl (Artane)

Other Medications Associated with Delirium

•

Antibiotics

•

Antiparkinsonian agents (e.g., l-dopa)

•

Benzodiazepines

•

Laxatives

•

Narcotics

•

Nonsteroidal anti-inflammatory drugs

Over-the-Counter Medications

•

Antidiarrheal agents (containing belladonna)

•

Chlorpheniramine (e.g., Piriton)

•

Diphenhydramine (e.g., Benadryl)

•

Irritable bowel syndrome treatments with hyoscine (e.g., Buscopan)

•


TABLE 1 -- Select Medications In Managing Delirium Drug

Approximate Daily Dosage Range Route

Neuroleptics Chlorpromazine (Thorazine)[1] 12.5-50 mg eq4-12h

PO, IV, IM

Drug

Approximate Daily Dosage Range Route

Haloperidol (Haldol)[1]

0.5-5 mg q2-12h

PO, IV, SC, IM

Aripiprazole (Abilify)[1]

5-30 mg q24h

PO

Olanzapine (Zyprexa)[1]

2.5-20 mg q12-24h

PO

Quetiapine (Seroquel)[1]

12.5-200 mg q6-24h

PO

Risperidone (Risperdal)[1]

0.5-3 mg q12-24h

PO

Ziprasidone (Geodon)[1]

10-80 mg q12-24h

PO, IM

Diazepam (Valium)[1]

2–10 mg q4-6h

PO, IV, IM

Lorazepam (Ativan)[1]

0.5–2.0 mg q1-4h

PO, IV, IM

Atypical Neuroleptics

Benzodiazepines

Barbiturates (for alcohol withdrawal only) Phenobarbital[1]

30-60 mg q4-6h

PO

* Maximum IM dose is 40 mg/d.


Pathophysiology The current pathophysiologic model for delirium developed by Trzepacz implies an imbalance in the neurotransmitters acetylcholine and dopamine. The acetylcholine level is reduced, as seen in the prototypic anticholinergic delirium, but dopamine levels may be elevated (seen in delirium with stimulating agents) or reduced (seen in hypoactive delirium, which can improve through the use of dopaminergic agents alone.) The deficit in anticholinergic transmission explains why the elderly are predisposed to develop delirium because these patients have reduced acetylcholine function at baseline. Through brain imaging and lesion studies, areas in the right hemisphere have been implicated in a common final pathway of delirium. Delirium caused by alcohol withdrawal has as its pathophysiology an imbalance in -aminobutyric acid (GABA)-ergic and glutamatergic transmission; treatment (essential to reduce mortality associated with delirium tremens) differs accordingly ( Figure 1 ).

FIGURE 1 Treatment algorithm for delirium. Abbreviation: GMC = general medical condition.

Diagnosis The diagnosis of delirium is made by evaluating a patient in light of DSM-IV TR criteria. Delirium represents an acute change in mental status, specifically level of consciousness and cognitive ability. The patient presents with disturbances in arousal and awareness, abrupt cognitive changes such as decreased attention, concentration, and memory, as well as hallucinations and delusions, sleep-wake cycle disturbances, psychomotor changes like apathy or agitation, and mood changes resembling anxiety and depression. Hallucinations are more often visual rather than auditory. Tactile hallucinations are often associated with substance intoxication and withdrawal. Screening for abrupt, unexpected changes in mental status, cooperation, and behavior is the first step toward an accurate diagnosis of delirium. Differential Diagnosis The differential diagnosis of delirium includes dementia, depression, anxiety, mania, intoxication, and psychosis, given the overlap in symptoms delirium shares with these maladies. Most challenging is distinguishing delirium from dementia as both disorders present with cognitive changes. In both disorders anticholinergic transmission is reduced. Both disorders have a high degree of comorbidity. Whereas dementia develops slowly in a relatively stable (or stepwise) process, delirium is characterized by an abrupt onset, often within 24 hours, and fluctuations within its course. Delirium involves a disturbance of

consciousness, something generally not seen in dementia. It is, of course, possible for delirium to be superimposed on dementia. Anxiety, depression, mania, and psychosis may resemble delirium as the latter may involve changes in affect and behavior and the presence of hallucinations and delusions. The former may be distinguished by the absence of disturbances in consciousness, the lack of impaired cognition, and the nature of symptom onset. Delirium caused by substance intoxication and withdrawal should be also differentiated as a different course of treatment is indicated. Delirium due to substance intoxication and withdrawal involves vital sign changes such as tachycardia and hypertension. Thorough history taking, good clinical observation, and the search for precipitating factors are the keys to the accurate diagnosis of delirium. Unfortunately, delirium continues to be underdiagnosed and undertreated. Treatment The delirious patient may harm him/herself or others through agitation or combativeness. Such harm may arise through pulling out lines, falls from bed, and interruption of medical treatment. Patient safety is ensured by treatment of delirium through both pharmacologic and nonpharmacologic approaches. The most important step in treatment is to identify and eliminate, where possible, precipitating factors. Interventions include a thorough physical examination and comprehensive analysis of blood (including ammonia), urine, perhaps CSF, to rule out infection (UTI, pneumonia) and electrolyte and metabolic abnormalities. Infections must be treated and other abnormalities corrected. EEG and brain imaging may be needed if no causes are found by the preceding. In some cases, the etiology of delirium may not be clearly identified; in others, the cause may be apparent but not correctable; in still others, there may be several causes working at once. In any event, active treatment is needed to protect the patient and caregivers. Nonpharmacologic approaches include providing a safe, consistent environment with frequent reorientation by caregivers, if necessary the use of a companion. A low threshold should be maintained with regard to the use of pharmacologic approaches, which include mostly neuroleptics, occasionally benzodiazepines, and rarely cholinergics, depending on the nature of delirium. The prototypic anticholinergic delirium should be treated primarily with cholinergics such as physostigmine and acetylcholinesterase inhibitors; neuroleptics may be indicated in treatment-refractory cases or where there is a significant behavioral disturbance. Delirium due to medical conditions is generally best treated with neuroleptics with or without adjunctive benzodiazepines. Benzodiazepines alone are usually contraindicated due to their hypnotic and amnestic properties; their use may worsen delirium. Delirium associated with substance intoxication should be treated by discontinuing (often tapering) the substance and controlling symptoms with neuroleptics and benzodiazepines. It is essential to monitor for and treat withdrawal in a chemically dependent patient. Delirium due to substance withdrawal usually requires substitution of the used substance with a cross-tolerant medication. Frequent monitoring of vital signs provides information as to the state of withdrawal. Alcohol withdrawal, which has a risk of mortality if it proceeds to delirium tremens, requires generous use of GABA-ergic agents such as benzodiazepines and barbiturates. The use of neuroleptics adjunctively may be helpful, but treatment with neuroleptics alone increases mortality in cases of DT. Multifactorial delirium or delirium with unclear etiology should be treated with neuroleptics and adjunctive benzodiazepines similarly to the delirium due to general medical condition. The “gold standard” neuroleptic for the treatment of delirium is haloperidol (Haldol),[1] even in light of the risk of acute dystonia, pseudo parkinsonism, akathisia, and tardive dyskinesia associated with all first-generation neuroleptics, regardless of dose or duration. So called “atypical” neuroleptics have been broadly used in the treatment of delirium with good results and a lower incidence of side effects. Risperidone (Risperdal) [1] and olanzapine (Zyprexa)[1] are examples of newer agents for which studies exist demonstrating efficacy. Such use is “off label” however, and there is remote controversy over a possible increased risk of cerebrovascular events, which should not prevent their use. Other agents in this class include quetiapine (Seroquel)[1],

ziprasidone (Geodon), [1] and aripiprazole (Abilify)[1]. Both olanzapine and quetiapine are more sedating than risperidone, ziprasidone, and aripiprazole; this favorable side effect profile may be advantageous in the agitated delirious patient. None of the atypical neuroleptics currently comes in an intravenous application, thus making the use of haloperidol[1] (or chlorpromazine[1] when haloperidol fails) necessary. All neuroleptics (and many other agents) can prolong QTc interval and a baseline and repeat EKG are recommended. Other less studied adjunctive interventions in the treatment of hypoactive delirium due to general medical condition or multifactorial delirium are the use of dopaminergic agents (such as methylphenidate (Ritalin)[1]) and cholinergic agents (acetylcholinesterase inhibitors). 1 Not FDA approved for this indication.

Course and Prognosis Delirium is often a transient self-resolving state, thus symptoms may clear with monitoring only and no further intervention. The elimination of underlying etiologic factors may be sufficient to promote resolution; at times, however, this is impossible and pharmacologic treatment should be initiated. Once pharmacologic treatment has been started, symptoms often resolve in the first 48 to 72 hours; treatment should be continued for up to one week to prevent recurrence of symptoms. In the younger population, delirium is usually a transient state with no residual effects. In the older population, delirium can contribute to unnecessary suffering, increased morbidity and mortality, and yield persistent cognitive deficits, which may interfere with independent living. In alcohol withdrawal, the mortality associated with delirium tremens represents the greatest threat to the patient's life; alcohol withdrawal must be treated appropriately. Following a case of DT, there may be minor brain damage in the form of excitotoxicity. Additionally, the risk of subsequent DT is increased. If correctly recognized, diagnosed, and treated, delirium is a manageable, reversible condition with no or few long-term effects. In many settings however, delirium remains underdiagnosed and under-treated, inflicting unnecessary suffering and complications on the individual patient. Thus, improving the recognition and treatment of delirium will contribute to better medical care for the patient, care-givers, and medical staff.



REFERENCES American Psychiatric Association, 1994. American Psychiatric Association : Diagnostic and Statistical Manual of Mental Disorders, 4th ed.. Washington, DC: American Psychiatric Association; 1994:124-127. Boettger and Breitbart, 2005. Boettger S, Breitbart W: Atypical antipsychotics in the management of delirium: A review of the empirical literature. Palliat Support Care 2005; 3(3):227-237. Boettger et al., 2006. Boettger S, Friedlander M, Breitbart W: Delirium. In: Blumenfeld M, Strain J, ed. Textbook of Psychosomatic Medicine, Philadelphia: Lippincott Williams & Wilkins; 2006:493-512. Breitbart et al., 1996. Breitbart W, Marotta R, Platt MM, et al: A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153(2):231-237. Bucht et al., 1999. Bucht G, Gustafson Y, Sandberg O: Epidemiology of delirium. Dement Geriatr Cogn Disord 1999; 10(5):315-318. Inouye, 1998. Inouye SK: Delirium in hospitalized older patients: Recognition and risk factors. J Geriatr Psychiatry Neurol 1998; 11(3):118-125. Inouye et al., 1999. Inouye SK, Bogardus Jr ST, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340(9):669-676. Inouye and Charpentier, 1996. Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons: Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 20(11):852857.275 Karlsson, 1999. Karlsson I: Drugs that induce delirium. Dement Geriatr Cogn Disord 1999; 10(5):412-415. Lipowski, 1987. Lipowski ZJ: Delirium (acute confusional states). JAMA 1987; 258(13):1789-1792. Rockwood et al., 1999. Rockwood K, Cosway S, Carver D, et al: The risk of dementia and death after delirium. Age Ageing 1999; 28(6):551-556. Trzepacz, 1999. Trzepacz PT: Update on the neuropathogenesis of delirium. Dement Geriatr Cogn Disord 1999; 10(5):330-334. Trzepacz et al., 1999. Trzepacz PT, Breitbart W, Franklin J, et al: Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry 1999; 156(5 Suppl):1-20. Tune, 2000. Tune LE: Serum anticholinergic activity levels and delirium in the elderly. Semin Clin Neuropsychiatry 2000; 5(2):149-153.



Chapter 281 – Mood Disorders

Method of: Melanie W. Conway, MD Merry N. Miller, MD Mood disorders are common. Depressed mood is the fourth most common presenting complaint in a primary care setting. Approximately 1 of 10 patients seen by a primary care physician has a major depressive disorder (MDD), with a 10% to 25% lifetime prevalence for women and a 5% to 12% lifetime prevalence for men. Prevalence for bipolar disorder ranges from 1% to 5%. Mood disorders worsen the morbidity and mortality rates of other medical disorders, and in fact, 68% of so-called service overutilizers of medical care have had a major depression diagnosis. Moreover, up to 15% of people with untreated depression kill themselves. Because nonpsychiatrists prescribe 80% of antidepressants, it is essential that the primary care physician be acquainted with the diagnosis and treatment of mood disorders. Diagnosing Mood Disorders As stated previously, mood disorders are very common, have high morbidity and mortality rates, and are highly treatable, but studies show that only a third to a half of those with major depressive episodes are properly recognized by practitioners, and fewer than a third of patients with bipolar disorder are in treatment. One reason might be that although mood disorders are not transitory reactions to external stressors, 70% of those who have a major depression could cite a stressor that preceded their depressive episode. A common occurrence is that both the patient and the physician focus on the stressor. This focus on the stressor generally elicits an internalized reaction from the physician, for example, “That is not bad enough to get depressed about,” or conversely, “If that were happening, I would be depressed, too”; both of these reactions decrease the probability that the physician will elicit depressive symptomatology and treat a possible mood disorder. Also, many patients do not tell the physician that they are “depressed.” In fact, a lot of men use the words “stressed out.” Children and adolescents may commonly present with behavioral disturbances, and the elderly (65 years and older) with somatic complaints. So key words that might clue the physician into a mood disorder are “irritated,” “short fused,” “stressed,” “not acting right,” “not myself,” “don't care,” “no energy,” “can't think, focus, or concentrate,” or a plethora of vague physical complaints. Table 1 summarizes the diagnostic criteria, and a decision-making algorithm can be followed as presented in Figure 1 . First, the physician suspecting depression should ask about depressed mood and/or decreased interests and SIGECAPS (Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicide [*]). Primary care physicians should routinely ask about sleep and appetite and consider depression when these are altered: With depression these may change in either direction, although it is more common for depressed patients to report decreased sleep and appetite. In addition, depressed patients report decreased

interests (ability to enjoy usual activities, changes in energy (usually decreased), and difficulty concentrating. The latter symptom may cause the patient to develop problems with short-term memory, and it is not unusual for depressed patients to fear they are losing their mind or becoming demented owing to difficulty concentrating and remembering. They may show psychomotor slowing or alternatively, they may become agitated. Most seriously, patients with depression may develop suicidal ideation. They also may experience feelings of guilt about real or imagined sins, and may become preoccupied with feelings of worthlessness.

TABLE 1 -- Diagnostic Criteria for Depressive and Manic Episodes Major Depressive Episode Manic Episode Five or more of the following symptoms present most of the time for 2 weeks:

At least 3 (or 4 if mood is only irritable) of the following symptoms for at least a 1-wk period or any duration if hospitalization required:

Depressed or irritable mood[*]

Elevated, expansive, or irritable mood[*]

Diminished interest or pleasure (anhedonia)[*]

Inflated self-esteem or grandiosity

Disturbance of appetite Insomnia or hypersomia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or guilt Diminished ability to concentrate

Decreased need for sleep Hyperverbal Racing thoughts/flight of ideas Distractibility Increased activity or psychomotor agitation Excessive involvement with pleasurable activities with risk for painful consequences

Recurrent thoughts of death/suicidal ideation/suicide attempt * For a major depressive episode diagnosis, the symptom for either depressed mood or anhedonia must be present. For a manic episode diagnosis, the altered mood symptom must be present.

FIGURE 1 Basic algorithm for diagnosis and treatment of mood disorders. Abbreviations: CBC = complete blood count; DIGFAST = Distractibility, Insomnia, Grandiosity, Flight of ideas, Activities, Speech, Thoughtfulness; F/U = follow up; SIGECAPS = Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicide; TSH = thyroid-stimulating hormone.

The physician must first address the management of any potential suicidal risk (see later discussion of suicide). Then the physician answers this question: “Does this patient have depressed mood or loss of interests or pleasure in usual activities with four other neurovegetative symptoms most of the day, nearly every day, for at least 2 weeks or not?” If the answer is yes, the patient has a major depression regardless of the presence or absence of stressors.

CURRENT DIGNOSIS Look for symptoms (SIGECAPS) in patients with suspected depression regardless of the presence of stressors. Always screen for a history of mania in patients who present for depression. Always ask about suicidality, including the presence of thoughts, specific plans, intent, and a history of attempts. Be prepared to hospitalize, including involuntarily, if patients are actively suicidal. Look for medical conditions and medications that may precipitate or worsen depression. Check T4, TSH, and CBC in all patients with mood symptoms if not recently done. Always ask about use of alcohol and illicit drugs in patients presenting with depression. Abbreviations: CBC = complete blood count; SIGECAPS = Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicide; T4 = thyroxine; TSH = thyroid-stimulating hormone. If instead a patient reports a recent stressor but does not meet the full criteria for a major depression, the patient has an adjustment disorder. This distinction is important because first-line treatment recommendations differ between an adjustment disorder and MDD. If a person is determined to have a major depressive episode, it is incumbent on the physician to ask about manic symptoms as well because the prevalence of bipolar disorder is now thought to be higher than previously documented. Antidepressants alone in a depressed patient with bipolar disorder can switch them into a mania even if they were never manic before. Useful screening questions include, “Have you ever felt the opposite of what you do now, like on top of the world?” or “Have you ever had a period in which you felt you did not need sleep, or very little sleep, and still had plenty of energy?” If they answer yes, then the rest of the mania answers can be elicited with the useful mnemonic DIGFAST (Distractibility, Insomnia, Grandiosity, Flight of ideas, Activities, Speech, Thoughtfulness[*]). However, a word of caution: mania is very difficult to diagnose accurately retrospectively. It would not be difficult to get affirmative answers to such questions as “Have you ever spent more money than usual?” or “Have you ever had more energy than usual?” from most people asked the questions in the mania criteria. By definition (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSMIV]), a mania has to be a distinctly different period than normal where “the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others” that must last at least 1 week (less if hospitalized) or with a hypomanic episode last at least 4 days and be “an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic.” The symptoms should occur together in the same 1-week period. Sometimes a severely depressed person answers yes to mania symptomatology when describing not a mania, but rather a baseline level of functioning as compared to the depression. The distinction is important because of its implications about treatment (see treatment discussion). Other depressive disorders that should be screened for are dysthymic disorder and premenstrual dysphoric disorder (PMDD). In dysthymic disorder, patients have a chronic low-grade level of depression (not enough to qualify for MDD) that exists for more than 2 years. Women with PMDD experience depressive symptoms

that occur exclusively during the premenstrual portion of the menstrual cycle and then resolve after the onset of menses. Another variation of depression is premenstrual exacerbation of depression in which women with MDD experience worsening of the mood premenstrually that does not fully resolve with the onset of menses. These variations of depressive disorder may be treated with antidepressants, and PMDD responds to intermittent dosing (i.e., only during the premenstrual phase). A diagnostic and treatment review of other types of mood disorders is beyond the scope of this chapter. * Carey Gross, MD, originally developed this mnemonic for depression. * William Falk, MD, originally developed this mnemonic for mania.

SUICIDE If you are considering a diagnosis of a mood disorder, and especially if you prescribe medications for a mood disorder, you must always ask about suicide because two thirds of all depressed patients contemplate suicide at some point. Studies show that 50% of all people who commit suicide see their primary care physician within 1 month of the suicide and 40% within 1 week of the suicide. Suicidal ideation, just like radiating chest pain, is a medical emergency and should be treated as such, especially when being presented to the physician the first time. Critical considerations that increase the level of risk are these: (1) Does the patient have a plan and means? How lethal is the plan? (Gunshots and hanging are the most lethal and most concerning plans.) Has the patient considered acting on the plan? (2) History of suicide attempts: Were high-risk methods used in the past, and how likely was the patient to be rescued? (3) Lack of social supports or recent losses (e.g., job, relationships); (4) Chronic medical illnesses; (5) Substances abuse, especially in the intoxicated or withdrawal state. Consulting with a family member, with the patient's consent, is a very good way not only to elicit information but also to garner needed social support should the decision be made to treat the patient on an outpatient basis or to support an inpatient recommendation. If the physician does not consider the patient's risk to be imminent and the decision is made to continue treatment on an outpatient basis, a psychiatric referral should be made and the physician should see the patient often; at least until the patient is seen by the psychiatrist. Contracting for safety with the patient has some psychological value, although doing so grants no legal protection to the physician. In every area of the United States there is the equivalent of a mobile response team with a psychiatric backup that can be called in case no psychiatrist is available for consultation or if the patient or the patient's family is against an inpatient recommendation and you are very concerned about suicide risk. These telephone numbers should be readily available to the physician so during a time of crisis valuable time does not have to be spent searching for them. Although there is some variation among the states, if the patient (and/or family) is unwilling for the patient to wait for the mobile crisis evaluation or go to the emergency department and the patient shows evidence of being dangerous to himself or others, he or she can be involuntarily committed. Every physician should know the commitment criteria for one's own state. If the patient's current symptoms meet these criteria, the

police/security should be called to detain or apprehend the patient if necessary, and the patient should be held against his or her will until further evaluation by mobile crisis or an emergency department physician can be done. Although ideally rare, this set of events often garners extreme emotions and occasionally litigious threats. Most patients later are able to appreciate the concern that led to their hospitalization. Legal precedent tends to fall in favor of the physician who acted with due diligence rather than the physician whose patient was let go who went on to kill themselves. Regardless of the in/outpatient status of the patient, careful documentation of the symptoms, decision-making process, and plan is essential.

CURRENT THERAPY Choose an antidepressant based on how the side-effect profile fits with the symptoms of depression (e.g., a sedating medication for insomnia). Make sure to use an adequate dose for an adequate duration (at least 4-6 wk) before judging the effectiveness of an antidepressant. Watch for signs of antidepressant-induced switching to mania. If ineffective after an adequate trial, consider another antidepressant, possibly from another class. If still ineffective, consider augmentation of antidepressant with another class of medication; for example, lithium or thyroid hormone. For bipolar patients, start a mood stabilizer first. If the patient remains depressed, consider a possible antidepressant after the mood stabilizer dosage is therapeutic. When withdrawing antidepressants, taper the dose gradually to avoid the discontinuation syndrome. For patients with depression that does not respond to medication, consider electroconvulsive therapy (ECT). Always assess for suicidality throughout treatment for depression. MEDICAL CONDITIONS AND DRUGS ASSOCIATED WITH MOOD DISORDERS Fifty percent of those with psychiatric illness also have substance abuse problems. Substance use alone could cause mood disorders such as depression in chronic ethanol, benzodiazepine, barbiturate, and opiate use, cocaine withdrawal, or mania in methamphetamine or cocaine intoxication. However, many times it is difficult to separate which came first, the substance abuse or the mood disorder. Useful questions are these: (1) When did the mood disorder symptoms start? When did the substance abuse start? (2) What has been your longest period of nonuse of any alcohol or illicit substances (drugs)? During that time (especially if it was more than 1 year), how was your mood? Many prescribed substances can also evoke mood symptoms such as anesthetics, analgesics, anticholinergics, anticonvulsants, antihypertensives, antiparkinsonian medications, antiulcer medications, cardiac medications (especially ß-adrenergic antagonists), isotretinoin (Accutane), oral contraceptives, muscle relaxants, anabolic steroids, corticosteroids, and sulfonamides. Heavy metals and toxins also can cause mood symptoms. This list is not exhaustive, and the patient's medication list always should be examined in search of temporal associations between newly prescribed agents and the onset or exacerbation of mood complaints.

Also, a long list of medical conditions can be associated with depression or mania, or a mood disorder can be the presenting symptom. The list is huge, but two deserve special mention. One medical condition is poststroke depression. At both 15-month and 10-year follow-ups, patients with poststroke major or minor depression are between four and eight times more likely to die than are nondepressed stroke patients. The second medical condition is cardiovascular disease. Even when one controls for smoking (depressed patients are more likely to smoke) and other factors, a large study showed that at 6 months, 17% of depressed patients had died versus 3% of the nondepressed patients. There was a 42% reduction in combined endpoint of death or recurrent myocardial infarction with antidepressant use. LABORATORY TESTS Again, although the list of medical illnesses that can cause or exacerbate a depression is extensive, two of the most common illnesses etiologically related to mood disorders are thyroid disease and anemia. Either hypothyroidism or hyperthyroidism can be associated with depressive symptoms. Therefore, obtaining a thyroxine/thyroid-stimulating hormone (T4/TSH) and a complete blood count (CBC) are standard in a mood disorder workup. Other laboratory tests may be indicated based on the medication chosen (see Treatment section). Treatment First, a physician must address any etiologic or contributing factors such as medical conditions or substance use. If substances are used, treatment for such must be addressed first because mood disorder symptoms may be related to their use alone, and even if mood disorder symptoms are primary (many substance abusers state they are “self-medicating”), the benefit of antidepressant or mood stabilizer pharmacotherapy will be reduced by continuing use. The standard used to be that clinicians waited to medicate until the patient had been sober many months, but recent studies show that pharmacotherapy does have a modest effect on abstinence rates. For adjustment disorders, the recommended treatment is psychotherapy, and as with the other mood disorders, the patient is advised to return to see the physician within 2 weeks. At the later appointment, SIGECAPS should be reevaluated for progressing to a major depressive episode, and the recommendation for psychotherapy is repeated if necessary. The majority of patients with major depressive episodes, whether of the unipolar or bipolar type, are best treated with a combination of psychotherapy and medication. Cognitive-behavioral therapy and interpersonal therapy is as effective as medication in mild to moderate depression. In addition to individual psychotherapy, group and marital and family therapy may be useful depending on the patient's circumstances. It may be best to delay the use of marital or family therapy in a depressed patient until some improvement begins to occur. Psychotherapy produces longer lasting benefits than medication. Many patients have an individual preference for either psychotherapy or medication or may have logistical difficulty in participating in therapy, so the treatment plan should be developed in conjunction with the patient with mindfulness of patient preference. If the patient should initially choose medication management alone and does not garner the full benefits he or she expected from an adequate trial of medication(s), psychotherapy should definitely be reconsidered. ANTIDEPRESSANTS

No particular antidepressant or class of antidepressants is more efficacious than the rest. However, effectiveness does differ because the older agents, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), are less tolerable owing to side effects and lifestyle restrictions. Their use should not be ruled out because TCAs are generally inexpensive and are used to treat a variety of other medical conditions and MAOIs tend to work when other drugs have not. Many factors need to be considered in picking an antidepressant, but there are three initial factors to consider in a treatment-naive patient. First, sleep-mood disorders do not get better if sleep does not improve, so, in treating someone who is not sleeping enough, one may consider a sedating antidepressant or a nonsedating one with a sleep agent. In treating someone who is sleeping too much or is anergic, the physician may consider a stimulating antidepressant. Second, side effects are one of the most common reasons for treatment failure because of lack of compliance. Two of the most common side effect concerns tend to be gender linked. Women are more likely to stop a drug if they feel it is making them gain weight. Therefore, in general, it is best to avoid antidepressants with higher rates of weight gain in the weightconscious patient. Men may be more likely to stop a drug secondary to sexual side effects. Although they initially may not care about this possible side effect secondary to their depressive state, 2 or 3 months later they tend to change their mind, putting the clinician in the precarious position of either changing the antidepressant and risking relapse of the depressed state or adding agents such as yohimbine (Yocon) or sildenafil (Viagra) to help counter the sexual side effects. The third factor is cost because a minimum recommended duration of antidepressant treatment is approximately 1 year (see Patient Education section), and patients will not take or continue to take what they cannot afford to buy. That is why the TCAs are still useful to consider in some populations because of reduced cost. It is important to know your patient's resources and your sample closet. Also, many pharmaceutical companies have programs for those in need. In the recurrent mood disorder patient, it is essential to obtain a more detailed history of what antidepressants the patient has tried, the length of treatment, the maximum dose, and the patient's view of the helpfulness of the agent. Many times antidepressant trials are not successful because of an inadequate length of treatment (generally 1 month or less) or inadequate dose. A partial response may have occurred in which the medication was not increased to a full therapeutic dose, or over time the effectiveness of the medication may have dwindled, which is common in selective serotonin reuptake inhibitors (SSRIs), and the dose not subsequently increased. In general, if it has worked before, it will probably work again with adjustments to dose. Another useful piece of information (in the treatment-naive patient as well) is family history of response to medication. A general rule of thumb is that if one family member has responded to a particular antidepressant agent, the patient seeking treatment may also respond to that agent. All that being said, with the wide selection of antidepressants available, there is no reason to fight the uphill battle of trying to get patients to take a medication they do not want to take regardless of their reasons. Convincing them in the short term will probably only lead to noncompliance later. Tables 2 through 5 [2] [3] [4] [5] summarize the currently available antidepressants.

TABLE 2 -- Selective Serotonin Reuptake Inhibitors (SSRIs) Drug

Effective Dose

Comments

Fluoxetine (Prozac, Prozac weekly, Sarafem)

20–80 mg/d; weekly capsule 90 mg

Longest half-life, good for noncompliant patients, many drug interactions

Drug

Effective Dose

Comments

Sertraline (Zoloft)

50–200 mg/d

Least potential for cytochrome-related drug interactions of SSRIs

Paroxetine (Paxil) (Paxil CR)

20–50 mg/d 25–62.5 mg/d

Benefit for anxious depression; discontinue slowly

Citalopram (Celexa)

20–60 mg/d

Least highly protein bound so fewer drug interactions

Escitalopram (Lexapro)

10–20 mg/d

S-enantiomer of citalopram

Fluvoxamine (Luvox)

50–250 mg/d

Potentiates caffeine and theophyllines

TABLE 3 -- Other Antidepressants (non-SSRIs) Drug

Effective Dose

Comments

Bupropion (Wellbutrin, Zyban)

225–450 mg in 3 divided doses; do not give after 5 PM

Maximum single dose: 150 mg; seizure risk if dose excessive; contraindicated in bulimia and anorexia

Bupropion SR (Wellbutrin SR)

200–450 mg in 2 divided doses; do not give after 5 PM

Maximum single dose: 200 mg

Bupropion XL (Wellbutrin XL)

150–450 mg once daily

Less risk of sexual dysfunction than other antidepressants

Mirtazapine (Remeron)

15–45 mg at bedtime

Sedating, causes weight gain; low rates of sexual dysfunction

Venlafaxine (Effexor, Effexor XR)

75–225 mg/d once daily (extended release) or 2–3 doses (immediate release)

Monitor blood pressure; low protein binding so less drug interactions

Duloxetine (Cymbalta)

40–60 mg/d in 1–2 doses

Benefit for co-morbid pain

Abbreviations: SSRI = selective serotonin reuptake inhibitor.

TABLE 4 -- Tricyclic Antidepressants Drug Dosage Range (mg/d) Amitriptyline

25–300

Clomipramine

50–250

Desipramine

25–300

Doxepin

25–300

Drug

Dosage Range (mg/d)

Imipramine

25–300

Maprotiline

50–225

Nortriptyline

25–150

Protriptyline

20–60

Trimipramine

75–300

TABLE 5 -- Mood Stabilizers Drug

Effective Dose

Lithium (Lithobid, Eskalith)

Start 300 mg bid–tid; maintain 900–1200 mg/d See text.

Divalproex (Depakote, Depakote ER)

Titrate up to 20 mg/kg/d, usually 500 mg bid–tid or 1000 to 1500 mg extended release

Carbamazepine (Tegretol, Tegretol XR)

Start 200 mg bid up to maximum of 1600 mg/d See text.

Lamotrigine (Lamictal)

25 mg qd × 2 wk, 50 mg qd × 2 wk, 50-mg increases weekly thereafter

Effective in depression. 1/2 dose for combination with Depakote (see text).

Aripiprazole (Abilify)

5–30 mg qd

Little sedation.

Olanzapine (Zyprexa, IM 5–20 mg/d (tab and Zydis) and Zydis forms)

Comments

See text.

More likely to cause weight gain, metabolic syndrome.

IM: 10 mg up to tid Quetiapine fumarate (Seroquel)

100–800 mg/d

Low rate of EPS, more effective at > 300 mg/d.

Risperidone (Risperdal, Risperdal Consta)

2–3 mg qd initially, maximum 6 mg/d, Constainjection 25 mg IM q2 wk in combination with oral for 2–3 mo

Slightly more likely to cause EPS, prolactinemia, especially at doses > 6 mg/d.

Ziprasidone (Geodon)

20 mg bid with food; maximum dose: 160 mg

Discontinue if QTc > 500 msec, less weight gain. Take with food.

Abbreviations: EPS = extrapyramidal side effect; IM = intramuscular.

Selective Serotonin Reuptake Inhibitors

The SSRIs ( Table 2 ) are currently considered first-choice antidepressants for many patients with depression. These medications share the mechanism of blocking serotonin reuptake. As a group, they have the advantages of being relatively low in side effects, safer than the tricyclics (nonlethal in overdose), easy to

administer, and efficacious. The most common side effects of the SSRIs are nausea and diarrhea during early treatment, and if these occur, they usually resolve within a week or two. Some patients experience increased energy or jitteriness soon after SSRIs begin, which can be desirable for patients with fatigue or can be uncomfortable but usually diminishes within a few weeks. Sexual dysfunction is another side effect sometimes seen with SSRIs and may include decreased libido, impotence, delayed ejaculation, or anorgasmia. Medication interactions are seen with certain SSRIs that inhibit the cytochrome P-450 liver enzyme systems, especially fluoxetine (Prozac) and paroxetine (Paxil), so caution should be used in patients taking other medications. A discontinuation syndrome is described that is most likely to occur with paroxetine and includes flulike symptoms such as nausea, vomiting, fatigue, headache, and myalgia. Slow tapering at discontinuation may prevent this syndrome. Other Newer Antidepressants and Novel Agents

A number of other antidepressants ( Table 3 ) have been developed that differ in mechanism from the SSRIs. Trazodone (Desyrel) and nefazodone (Serzone) block serotonin reuptake and also block 5hydroxytryptamine 2 (5-HT2) receptors. Trazodone is often used for its sedative effect. The use of nefazodone has declined dramatically after being found to be the etiologic agent in some deaths secondary to hepatic failure. Bupropion (Wellbutrin) is an effective antidepressant that acts to boost the neurotransmitters norepinephrine and dopamine. It has the potential benefits of being less likely to induce mania and less likely to cause sexual dysfunction than the SSRIs. It should be avoided in patients with a history of eating disorders because it can induce seizures in those patients. Antidepressants with dual noradrenergic and serotonergic mechanisms include venlafaxine (Effexor) and duloxetine (Cymbalta). Venlafaxine actually has a mechanism that varies with its dose: At lower doses it blocks serotonin reuptake, whereas when the dose exceeds 150 mg/day, it blocks increasingly higher amounts of norepinephrine. Venlafaxine may increase blood pressure, especially at high doses, and should be monitored. Duloxetine is effective for major depression and also for pain that may coexist with depression. Mirtazapine (Remeron) blocks a-2 and serotonin receptors. It has a low rate of sexual dysfunction, is sedating, and causes weight gain. It has the unusual feature of a decrease in side effects associated with increasing dose. It may be especially helpful for patients with melancholic depression who have poor sleep and appetite. A transdermal selegiline patch (Ensam) has been approved by the FDA for depression and consists of a selective MAO-B inhibitor that is believed at high doses to inhibit both MAO-A and MAO-B in the brain, while at the same time preserving the gastrointestinal MAO-A barrier that breaks down ingested tyramine. Vagus nerve stimulation (VNS), also FDA approved, requires a surgical procedure to wrap an electrode around the vagus nerve and implant a stimulator, which on average delivers 30 seconds of current to the vagus nerve every 5 minutes. Theoretically, the stimuli, carried via afferent fibers in the vagus nerve to mood-regulating centers in the brain, alleviate some cases of previously refractory depression. Repetitive transcranial magnetic stimulation, whereby non-seizure-inducing magnetic pulses stimulate the cerebral cortex, is being investigated for the treatment of depression.

Tricyclic Antidepressants

TCAs ( Table 4 ) are as efficacious as the newer agents but less effective because of side effects. These side effects include antihistaminic effects (sedation and weight gain), anticholinergic effects (dry mouth, dry eyes, constipation), and antiadrenergic effects (orthostatic hypotension, which is a significant problem in the elderly (65 years and older) owing to increased fall risk). Cardiac conduction problems are of concern because the TCAs can provoke bradyarrhythmias, lengthen the QT interval, and induce symptomatic conduction delays in patients with conduction delays and bundle-branch block. The most serious problem with TCA therapy is lethality in overdose. As little as a 10-day supply can cause cardiac arrhythmias, seizures, and death. Other agents should also be considered in patients with narrow-angle glaucoma because of the TCA's anticholinergic properties. TCAs are also thought to switch depressed patients into mania at a higher rate than the other antidepressants. All of this being said, TCAs have been used for decades for treatment of depression. Patients should receive a pretreatment electrocardiogram (ECG), and subsequent ECGs should be ordered, particularly with dosage increases. TCAs also have several other indications, including pain disorders, and sometimes simply increasing the TCA dose helps with pain and depression instead of adding a second antidepressant. This recommendation is especially important to keep in mind because TCA levels can increase two- to threefold with some SSRIs, especially fluoxetine (Prozac) and paroxetine (Paxil). Many TCAs also have the distinct advantage of the physician being able to obtain clinically relevant serum drug levels. Most TCAs show an onset of clinical effects occurring at serum levels between 150 and 200 µg/mL with little therapeutic benefit and increased side effects above these ranges. The exception is nortriptyline (Pamelor), which appears to have a therapeutic window of between 50 and 150 µg/mL. Monoamine Oxidase Inhibitors

Although very effective, especially in cases of refractory or atypical depression, MAOIs are used very rarely, even in the hands of a specialist, owing to their medication interactions and dietary restrictions. However, physicians should be aware of this class, and drug interaction profiles should be run on any patient who is on a MAOI before another medication is prescribed. Patient Education

The physician must spend a few minutes educating the patient for an antidepressant trial to be successful. As stated earlier, one of the major reasons for antidepressant trial failure is noncompliance. People stop taking antidepressants for a number of reasons including a so-called antibiotic view of medications: “Once I feel better I can stop.” Anxious people, scared of initial side effects, may abruptly stop a medication. To address these, the physician needs to spend approximately 2 to 3 minutes saying something like this (tempered by the education and sophistication of the patient): “I am recommending that you take an antidepressant called _______. All antidepressants take 4 to 8 weeks to get a full effect, and you will not really know if this will work for you until you have been on it that long, although you may get a partial response sooner. Unfortunately, you may get side effects in the first few weeks before you get most of the good effects. Although there can be different side effects for different people, the most common ones for _______ are _______. I expect you to have at least one or two of these. If you have not had at least one side effect by 2 weeks, you need to call me. You can expect the side effects to be at their worst initially, then to decrease. The therapeutic benefit may not occur until a full month or more has passed, so it is important to keep taking it. If you respond to this medication, you will need to be on it at least a year to reduce your risk

of a relapse.” This short statement addresses two of the biggest obstacles to compliance: anxiety over side effects and duration of treatment. It must be added, to the suicidal patient especially, that any emergence or worsening of suicidal ideation should be reported to the physician immediately because energy and concentration generally improve before mood, which would make the still depressed patient more capable of carrying out a plan. This explanation has been the historical reasoning for the tie between suicide and antidepressant treatment, and susceptible patients should be closely monitored, especially during the first month of treatment. In fact, the Food and Drug Administration (FDA) has now issued a black box warning for children and adolescents about the potential for emerging suicidal ideation with antidepressants and is considering extending this warning to all populations. Although this should not keep the clinician from prescribing needed treatment, it might lower the bar for specialist referral. MOOD STABILIZERS Lithium, lamotrigine, olanzapine, quetiapine, and fluoxetine-olanzapine combination have shown reasonable evidence they work for bipolar depression. Antidepressants are receiving mixed to negative views in the treatment of bipolar depression and, in particular, tricyclics and venlafaxine seem to cause more switching from depression into mania than other antidepressants. If used, antidepressants should only be used in combination with an antimanic agent and in contrast with unipolar depression, the antidepressant should be withdrawn when the depressive episode is over while the antimanic agent is continued. Lithium, divalproex, carbamazapine, haloperidol, aripiprazole, olanzapine, quetiapine, ziprasidone and risperdal have shown reasonable evidence they work in acute mania. The newer anticonvulsants gabapentin (Neurontin), lamotrigine, and topiramate (Topamax) have not shown evidence they work in acute mania. Lamotrigine, as mentioned, is indicated for bipolar depression, whereas gabapentin is used as an adjunct for anxiety and pain and topiramate for help with weight gain for antimanic agents. The only FDA-approved medication for pediatrics is lithium, although there are some data to suggest that the other above agents have efficacy in children as well. Lithium is generally started at 300 mg two to three times per day in the nonrenally impaired patient. An initial trough level can be obtained 4 to 5 days from initiation with a target blood level between 0.8 and 1.0 mEq/L. The effectiveness of lithium is decreased by its side effects, which include the following:

1.

Tremor: Best evidenced when the patient's hands and fingers are outstretched; may benefit from mild dosage reduction or ß-blockers.

2.

Renal: Lithium is metabolized in the kidney, and interactions with the kidney can cause polyuria with secondary polydipsia in 25% of cases. Anything that affects the kidney can affect lithium metabolism. Although the list is extensive, certain nonsteroidal medications and diuretics, particularly thiazide diuretics, decrease the clearance of lithium and could cause lithium toxicity.

3.

Thyroid: 5% of patients (more often women) develop hypothyroidism during chronic lithium treatment.

4.

Cardiac: Lithium can cause T-wave flattening or inversion owing to displacement of intracellular potassium.

5.

Weight gain.

6.

Cognitive: Mental slowing, memory problems, and apathy.

7.

Hematologic: Benign leukocytosis that does not require intervention.

8.

Birth defects: Not recommended in pregnancy, but only in the second or third trimester by a specialist if no other option is available.

9.

Gastrointestinal: Initial nausea, vomiting, and diarrhea common.

10. Toxicity: Small therapeutic window; levels above 1.5 mEq/L are toxic. Overdose, drug interactions, and dehydration can cause toxicity. Symptoms of toxicity include nausea, vomiting, tremor, diarrhea, confusion, and ataxia; at higher levels, toxicity can lead to seizures, coma, or death. Pretreatment, it is recommended that an ECG, blood urea nitrogen (BUN), creatinine, CBC, electrolytes, pregnancy test, and thyroid studies be done as well as an evaluation of the patient's medication list. Thyroid tests, renal tests, and trough (10 to 13 hours after the evening dose and before the morning dose) levels should be obtained every 2 to 3 months during the first 6 months of maintenance therapy and then every 6 months thereafter or when clinically indicated. A common practitioner mistake is to obtain random and not trough levels. Because this is relevant to lithium, divalproex (Depakote), and carbamazepine (Tegretol), it is important to understand that all therapeutic values are based on trough levels, so obtaining a random level is virtually useless. Divalproex (Depakote) is generally started at 500 mg twice daily, but a loading dose of approximately 20 mg/kg can be given in acutely manic patients with an initial trough level obtained after 4 to 5 days with a target blood level between 50 and 125 µg/mL. Divalproex is generally thought to be better tolerated than lithium, but common dose-related side effects include sedation, nausea, vomiting, and diarrhea, especially upon initiation. Divalproex can cause thrombocytopenia and rarely can cause fatal hepatotoxicity, hemorrhagic pancreatitis, and agranulocytosis. Also, because divalproex is highly protein bound and only the free portion reaches the central nervous system (CNS), in cases of hypoalbuminemia or in combination with other highly protein-bound drugs, it is recommended that clinicians obtain free plasma levels. Divalproex can cause neural tube defects in pregnancy. Therefore, it is recommended that liver function tests (LFTs), pregnancy tests, CBC, electrolytes, and prothrombin time be obtained pretreatment. Drug trough levels should also be done 5 days after initial therapy or after dosage change, CBC and LFTs monthly for 6 months, then CBC, LFTs, and prothrombin times quarterly for the next 6 months. Androgen and amylase need to be checked if symptoms arise. Carbamazepine (Tegretol) is generally started at 200 mg twice daily, with an initial trough level to be

obtained after 4 to 5 days with a target blood level between 4 and 12 µg/mL. Most common dose-related side effects include gastrointestinal effects (nausea, vomiting, cramps, and diarrhea) and CNS effects (confusion, drowsiness, ataxia, hyperreflexia/clonus, and tremor). Uncommon, but potentially lethal, side effects include transient leukopenia and mild thrombocytopenia, which in rare cases can progress to aplastic anemia and agranulocytosis. From 10% to 30% of people develop an elevation of liver enzymes from chemical hepatitis, elevation of bilirubin and alkaline phosphatase, and hyponatremia and hypo-osmolality from an antidiuretic hormone-like effect. Therefore, patients should be warned to call their physician if they experience any symptoms of hepatitis such as malaise, anorexia, nausea/vomiting, edema, or abdominal pain. Of great importance is carbamazepine's propensity to speed up its own metabolism and that of a number of other drugs through induction of hepatic enzymes. This induction results in lowering of the serum drug levels and can cause it and particularly oral contraceptives not to work. Because carbamazepine can also cause neural tube defects, this interaction is of particular importance. Therefore, pretreatment hepatic functioning, a pregnancy test, and a CBC should be obtained with trough level and CBC every 2 to 3 months and hepatic enzymes when clinically indicated. Lamotrigine (Lamictal) is started at 25 mg every day and increased to 50 mg after 2 weeks with 50-mg increment increases weekly up to 500 mg.[1] If combined with Depakote, the initial dosing is 25 mg every other day with 25-mg increments to a maximum dosage of 200 mg.[1] The slow dosage titration is related to the risk of Stevens-Johnson syndrome, especially when Lamictal is titrated up too quickly and/or combined with Depakote. The atypical antipsychotics, including aripiprazole, olanzapine, quetiapine, risperdal, and ziprasidone all have indications for acute mania and in combination with lithium or divalproex showed an efficacy rate of approximately 62% for the combined treatment versus a 42% response rate for lithium or divalproex alone. The major side effects surrounding the atypicals center on the increased risk for inducing the metabolic syndrome, which increases the cardiovascular risks and mortality rates, although ziprasidone seems to have the least risk among these agents. Because of these risks, laboratory work should be done as indicated in Table 6 .

TABLE 6 -- SECOND-GENERATION ANTIPSYCHOTICS (except Clozapine)—Aripiprazole (Abilify), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Ziprasidone (Geodon) 4 8 12 If sx Every 5 Baseline wk wk wk Quarterly Yearly arise y Pregnancy test[*]

X

Weight/BMI

X

Waist circumference

X

Blood pressure (BP)[**]

X

X

X

Fasting glucose/Glycosylated hemoglobin (HbA1c)[***]

X

X

X

Fasting lipid profile[***]

X

X

Prolactin ECG[****]

X X

X

X

X X

X X

X

X

From Biological Therapies in Psychiatry, Sept. 2006, Vol 29: 9, on Second-Generation Antipsychotics.

*

In women of childbearing age.

**

Orthostatic in elderly.

***

More frequent assessment in the event of marked weight gain.

**** In patients taking ziprasidone, which may cause QT prolongation (may also consider checking potassium and magnesium, as hypokalemia and hypomagnesemia can increase risk of QT prolongation).


Patient Education

Compliance is a major factor in treatment success. There are more suicides secondary to bipolar depressive episodes than unipolar depressive episodes. A major study found the prophylactic effects of lithium to be so great it added 7 years to the life expectancy. However, nonadherence rates range from 33% to 64% within 1 month from initiation of treatment, primarily because of denial of illness and need for treatment, especially in the substance-abusing population. With education, bipolar patients can learn to recognize the symptoms of an impending episode and avoid hospitalizations by working closely with their physician. ELECTROCONVULSIVE THERAPY Electroconvulsive therapy (ECT) is the most effective available treatment for mood disorders. It surpasses treatment efficacy of all the other modalities and is used in fragile populations such as pregnant women and the elderly (65 years and older). There are no absolute contraindications to ECT, and it is the treatment of choice when a patient is refractory to all other therapies.



REFERENCES Bauer, 2003. Bauer MS: Mood disorders: bipolar (manic-depressive) disorders. In: Tasman A, Kay J, Lieberman JA, ed. Psychiatry, 2nd ed.. Chichester, England: Wiley & Sons; 2003:1237-1270. Blazer, 1993. Blazer G: Depression in Late Life, St. Louis, Mosby-Year Book, 1993. Cohen, 2003. Cohen BJ: Theory and Practice of Psychiatry, New York, Oxford University Press, 2003. Dubovsky et al., 2003. Dubovsky SL, Davies R, Dubovsky AN: Mood disorders. In: Hales RE, Yudofsky SC, ed. Textbook of Clinical Psychiatry, 4th ed.. Washington, DCx: American Psychiatric Association; 2003:439-542. Gelenberg, September 2006. Gelenberg AJ: A concise guide to psychotropic medications: Laboratory testing, patient warnings, and drug interactions, Part I of II. Biological Therapies in Psychiatry newsletter September 2006; 29(9):39. Ghaemi, 2003. Ghaemi SN: Mood Disorders, Philadelphia, Lippincott Williams & Wilkins, 2003. Greist and Jefferson, 1992. Greist JH, Jefferson JW: Depression and Its Treatment, Washington, DC, American Psychiatric Association, 1992. Gruenberg and Goldstein, 2003. Gruenberg AM, Goldstein RD: Mood disorders: Depression. In: Tasman A, Kay J, Lieberman JA, ed. Psychiatry, 2nd ed.. Chichester, England: Wiley & Sons; 2003:1207-1236. Mondimore, 1993. Mondimore FM: Depression: The Mood Disease, Baltimore, Md, Johns Hopkins University Press, 1993. Pies, 2005. Pies RW: Handbook of Essential Psychopharmacology, 2nd ed.. Washington, DC, American Psychiatric Association, 2005. Sadock and Sadock, 2003. Sadock BJ, Sadock VA: Mood disorders. In: Sadock BJ, Sadock VA, ed. Kaplan & Sadock's Synopsis of Psychiatry, 9th ed.. Philadelphia: Lippincott Williams & Wilkins; 2003:534-590. Stahl, 2005. Stahl SM: Essential Psychopharmacology: The Prescriber's Guide, Cambridge, England, Cambridge University Press, 2005. U. S. Department of Health and Human Services, 1993. U. S. Department of Health and Human Services : Depression in Primary Care. Vol 1: Detection and Diagnosis, Rockville, Md, Agency for Health Care Policy and Research, 1993.



Chapter 282 – Schizophrenia

Method of: Adriana Foster, MD Peter Buckley, MD Schizophrenia is a chronic debilitating illness, affecting 1% of the population, with an economic burden of $32.5 billion per year in the United States. Its implications include lost human potential because of inability to function personally, socially, and professionally, disability, risk of suicide, and impact on families. The etiology of schizophrenia is still elusive. The neurodevelopmental hypothesis prevails and postulates that illness starts in utero with abnormal neuronal development. The knowledge about potential genetic loci for schizophrenia is yet limited but it is known that dizygotic twins have a 12% chance of developing schizophrenia if one twin is affected, whereas for monozygotic twins the risk increases to 50%. Genetic predisposition is thus a major risk factor—but by no means the only risk factor—for schizophrenia. It is currently thought that individuals with genetic predisposition to schizophrenia are especially vulnerable to in utero factors like hypoxia, rubella, maternal influenza, birth during late winter and spring, and maternal malnutrition. The pathologic brain abnormalities thought to be resulting from this interaction (smaller prefrontal cortex and hippocampus, enlarged ventricles) appear to be static in nature and occur without evidence of gliosis, commonly found in neurodegenerative disorders. At the molecular level, it is thought that genetic factors converge, leading to abnormal neuronal connectivity and synaptic signaling, and they may alter the dopaminergic and the glutamatergic pathways of the brain. There is early evidence of altered gene expression profiles for a variety of neurotrophic factors involved in brain development and regulation. A causal relationship and a mechanism by which susceptibility genes can predispose to schizophrenia are still to be identified.

CURRENT DIGNOSIS Impairment in reality testing: delusions and hallucinations Negative symptoms: anhedonia, alogia, avolition, affective flattening Disorganized thought and behavior Cognitive and executive dysfunction Symptoms lasting >6 mo Significant impairment in professional, social function, and personal relationships Onset in early 20s in men and early 30s in women Psychosis because of drugs, general medical condition, or major mood disorder ruled out. The neurodegenerative hypothesis of schizophrenia is based on longitudinal studies showing that

morphologic brain changes progress, especially early, during the first 5 years of illness, even before the clinical manifestations of schizophrenia are apparent. A recent trend in schizophrenia research is the study of the prodromal period and family members of probands with schizophrenia, in an effort to understand the effect of brain changes thought to be induced by untreated illness. In parallel, we are trying to treat the illness as early as possible to avoid the potential for neuronal damage, which some claim may result from episodes of florid psychosis. However, this approach is contentious because it proposes treatment of a population in their early twenties with antipsychotic medications, associated with noxious side effects of abnormal movements or metabolic disturbances. A summary of the recent knowledge about neurotransmitter changes in schizophrenia ( Table 1 ) is necessary to understand the postulated mechanism of action for antipsychotic drugs. Some patients may have a prodromal period, with peculiarities of thought and behavior, followed by onset of full-blown psychosis. The illness has a relapsing course. During acute episodes patients lose contact with reality and often attend and respond to internal stimuli (hallucinations). Behavior may be motivated by commands from voices or delusional beliefs. The patients' thought processes can be loose and disorganized leading to like behavior, with disregard to self-care, isolation and social withdrawal, sometimes aggression, and hostility. The course may become less acute as patients advance in age (residual type schizophrenia). However, deficits of attention and working memory, executive dysfunction with decrease in goal-directed behavior, planning, flexibility and self-monitoring, as well as poor insight and judgment, persist. Significant suicide risk is present, associated with delusions, command hallucinations, or superimposed depression. Co-morbidity with alcohol and drug abuse is significant. Noncompliance with medication is common and requires extensive psychosocial intervention. The patients have major difficulty accessing medical care, following recommendations, and complying with treatment for their psychiatric and medical conditions, as illustrated next.

TABLE 1 -- Neurotransmitter Abnormalities in Schizophrenia Neurotransmitter Dysfunction

Localization

Normal Function

Antipsychotic Effect

Dopamine (DA)

Nigrostriatal tract

Extrapyramidal system, controlling movement.

Movement disorders.

Mesolimbic tract

Memory, stimulus Reduce processing, motivation psychosis. (internal and external stimuli are postulated to have exaggerated motivational and emotional relevance in psychosis).

Mesocortical tract

Cognition, executive function.

Hyperactivity

Reduce psychosis. Can induce akathisia.

Neurotransmitter Dysfunction

Antipsychotic Effect

Localization

Normal Function

Tuberoinfundibular tract

Controls prolactin release.

Increased prolactin, galactorrhea, sexual dysfunction.

Serotonin (5-HT)

Same distribution with dopaminergic neurons

Serotonergic stimulation in the striatum decreases DA release.

5-HT2 antagonism reduces psychosis and decreases DArelated movement disorders.

Glutamate (excitatory neurotransmitter)

Corticostriatal Widespread in the glutamate brain hypoactivity leads to DA hyperactivity (e.g., psychosis related to phencyclidine, an antagonist of the NMDA glutamate receptor)

Synaptic plasticity, learning, memory. Under traumatic or ischemic conditions, glutamate concentrations rise to excitotoxic levels (it is postulated that obstetric complications generate a toxic glutamatergic release and thus the brain development becomes abnormal in-utero).

Not a primary mechanism of action for any current antipsychotic.

Case 1 A man with schizophrenia was admitted after being forcefully evicted from his apartment. He maintained that he owned the place and referred to his relationship with God. He complained of difficulty urinating and squatted on the unit at times. As part of his routine laboratory tests, his prostate-specific antigen (PSA) value returned in the thousands. He invoked delusional beliefs when he refused a prostate biopsy. His family, after numerous attempts to care for him, was not available to do so any longer. An emergency guardianship was obtained, and a prostate biopsy was performed in the operating room under general anesthesia. The results showed cancer of the prostate, and the urologist offered treatment with hormone injections. The patient passively accepted the treatment but never agreed that he had cancer. Case 2 A smoker with hypertension (HTN), chronic obstructive pulmonary disease (COPD), and paranoid schizophrenia requested to change doctors because he felt that his psychiatrist was part of a plot against him, along with people at his supported housing facility. He came in stating he felt “depressed” and demanded that his new psychiatrist be paged. He appeared somnolent and short of breath. The records showed visits to the emergency department (ED) twice in the past week, with vague complaints of fatigue; he was offered treatment for respiratory symptoms and left before any treatment was administered. At arrival

in the ED, the patient's oxygen saturation was 79% and at a psychiatrist's insistence, he eventually agreed to be examined by the ED physician. He was admitted to the intensive care unit, intubated, and underwent treatment for community-acquired pneumonia. Upon discharge from the hospital he thanked the psychiatrist for “saving my life” but continued to refuse his antipsychotic medication. Many patients with schizophrenia, after brief hospitalizations, become clients of state-sponsored and federal outpatient mental health systems, where case management, day treatment, substance rehabilitation, vocational and incentive therapy, employment, and housing programs are accessible. The most refractory and noncompliant patients may respond to assertive community treatment, an intensive outreach approach by multidisciplinary teams available around the clock. Often the relationships with their families are under strain because of the burden on caretakers or the patient's delusional mistrust. Counseling and peer support for families of patients with schizophrenia at illness onset is key and helps them maintain involvement for the patient's lifetime. The National Alliance for Mentally Ill (NAMI) is a remarkable resource for self-help, support, and advocacy for patients and families of people with severe mental illnesses. NAMI provides education, combats stigma, promotes increased funding for research, and advocates tirelessly at the local and national level for health insurance, housing, rehabilitation, and jobs for people with mental illnesses ). It is a challenge to integrate the broad range of outpatient services needed to fulfill the (www.nami.org needs of the patients with schizophrenia. An innovative approach is to include peer support specialists (trained individuals who are themselves in recovery from mental illness) to act as a support (analogous to the Alcoholics Anonymous [AA] sponsorship approach) and to help the patient focus on meaningful goals for his or her recovery. Table 2 presents the two classes of antipsychotics currently in clinical use.

TABLE 2 -- Summary of Antipsychotics in Clinical Use First Generation

Mechanism of Action

Chlorpromazine Dopamine D2 (Thorazine), receptor thioridazine (Mellaril), blockade perphenazine (Trilafon), trifluoperazine (Stelazine), haloperidol (Haldol), fluphenazine (Prolixin), pimozide (Orap)

Side Effects Extrapyramidal side effects (dystonia, parkinsonism treated with anticholinergics) Akathisia (treated with ß-blocker or benzodiazepine), neuroleptic malignant syndrome (rare but life threatening), tardive dyskinesia (involuntary movements potentially irreversible) Hyperprolactinemia manifested as sexual dysfunction, menstrual irregularities, gynecomastia, galactorrhea, weight gain, and increased risk for diabetes; dyslipidemia and decreased bone mineral density; QTc prolongation with thioridazine; anticholinergic effects for thioridazine and chlorpromazine

Administration Forms Oral for all; injectable forms available for haloperidol (can be given IM and IV) and fluphenazine. Haloperidol and fluphenazine available in long-acting injection form.

Second generation Risperidone (Risperdal)

D2 antagonism and 5-HT2 antagonism

Dose dependent EPS and Oral (including rapid Hyperprolactinemia; risk of CVA in elderly with dissolving tablet dementia treated for behavioral symptoms Risperdal Soltab) and long acting injection (Risperdal Consta)

First Generation

Mechanism of Action

Side Effects

Administration Forms

Olanzapine (Zyprexa)


Weight gain, abnormal glucose and lipid metabolism

Oral (including rapid dissolving tablet Zydis) and IM

Quetiapine (Seroquel)

Lowest D2 antagonism

Sedation and orthostatic hypotension at therapeutic dose

Oral

Ziprasidone (Geodon)

D2 QT prolongation, discontinue in patients with antagonism QTc > 500 ms and 5-HT2 antagonism, 5-HT1 agonist

Oral and IM

Aripiprazole (Abilify)

Partial D2 agonist and antagonist

Warnings common to all atypical

Oral (including rapid dissolving tablet Abilify Discmelt) and IM

Clozapine (Clozaril)

Low D2 antagonist and high 5HT2 antagonist

Agranulocytosis, weight gain, seizures; fatalities due to myocarditis have been reported; highest risk in the first month of therapy

Oral (including rapid dissolving tablet FazaClo)

Paliperidone (Invega)


Risk of CVA in elderly with dementia treated for behavioral symptoms

Oral

Abbreviations: IM = intramuscular; IV = intravenous.

Co-morbidity of schizophrenia with substance use disorders is common (estimated prevalence of 47%), nearly three times higher than in the general population, and can lead to frequent rate of relapse and hospitalization, treatment noncompliance, and poor overall response to treatment. Alcohol has a prevalence rate of 33.7% and other substance use a rate of 27.5%, with cannabis and cocaine the most common. Patients with co-morbid substance abuse have an increased risk of violence and suicide and contribute to the increased overall economic burden of schizophrenia by extensive use of the social, institutional services, and EDs. Preliminary data exist about the possible role of second-generation antipsychotic drugs (clozapine [Clozaril], quetiapine [Seroquel], and olanzapine [Zyprexa]) in reducing the substance use in patients with schizophrenia. An estimated 58% to 90% of patients with schizophrenia smoke in comparison with the general population (28% to 30%). Medical Co-morbidity Patients with schizophrenia are at high risk for cardiovascular disease because of high rates of cigarette

smoking, obesity, diabetes, and hypertriglyceridemia. Thioridazine, an older drug, has now only limited use because of its QTc prolongation effect, which is associated with the development of torsades de pointes and sudden death. Dose-related QTc prolongation with ziprasidone (Geodon) is reported, but it is not clinically relevant unless other risk factors occur, like hypokalemia, hypomagnesemia, or concomitant use of quinolone antibiotics (sparfloxacin [Zagam], moxifloxacin [Avelox], and gatifloxacin [Tequin]). Myocarditis can be associated with clozapine, especially in the first month of therapy. Diabetes and obesity are 1.5 to 2 times more common in patients with schizophrenia than in the general population. Obesity (body mass index [BMI] =30 kg/m) is common in patients with schizophrenia, especially women. Histamine-1 and serotonin-2C receptor antagonists and increased leptin levels may underlie the antipsychotic-induced weight gain. In addition to the common risks associated with obesity, coronary heart disease, and stroke, the patients with weight gain are more likely to face stigma and increased cost of health care. Treatment should include education of the patient and family or caregiver about nutrition, exercise, symptoms of diabetes, and results of neglecting one's medical care. Presently clinicians opt to switch antipsychotic if the weight gain is 5% over initial weight or if there is worsening of dyslipidemia or hyperglycemia, rather than adding antiobesity or lipid-lowering agents. Medications with additive weight gain effect should be avoided.

CURRENT THERAPY Lifelong approach Families involved as support system Complex psychosocial intervention Availability of crisis intervention and inpatient care Medication management customized for patient's co-morbid status and compliance level Ongoing monitoring of compliance and side effects in collaboration with primary care provider Patients with schizophrenia have an increased risk of abnormal glucose regulation with increased insulin resistance even without treatment with antipsychotics, which can further induce weight gain, reduce sensitivity to insulin, affect glucose transporters, and damage pancreatic islet cells. Lipid abnormalities in schizophrenia occur as a result of antipsychotic treatment, with elevations in triglycerides and total cholesterol. Phenothiazine (chlorpromazine) and dibenzodiazepine (clozapine, olanzapine) derivatives increase serum triglycerides and total cholesterol. There is an intermediate effect from quetiapine. Risperidone (Risperdal) and ziprasidone lowered the baseline values of cholesterol and triglycerides in a landmark 18-month study comparing effectiveness of older agents with second-generation antipsychotics. The metabolic syndrome is highly prevalent in patients with schizophrenia and increases their cardiovascular risk, especially in women. The American Diabetes Association, American Psychiatric Association, and American Association of Clinical Endocrinologists developed monitoring guidelines for obesity, diabetes, and lipid abnormalities for patients on antipsychotic drugs. The patient's personal and family history should be taken before the treatment starts and annually; weight should be monitored monthly for the first 3 months and then quarterly; waist circumference, blood pressure, and fasting plasma glucose should be obtained at baseline, 3 months, then annually; and fasting lipid profile at baseline, 3 months, and

then every 5 years. Co morbidity with HIV affects 3.1% of patients with schizophrenia (eight times the prevalence in the general population). Hepatitis C affects 8.5% of psychiatric inpatients versus 1.8% of the general population. Some of the medications administered as part of the highly active antiretroviral treatment (HAART) may exacerbate psychosis. Interferon and ribavirin may induce or exacerbate depression. Cytochrome P450 2D6 and 3A4 interactions occur between antipsychotics and HAART (e.g., increased exposure to given doses of olanzapine and risperidone). Clozapine should be used with caution in patients with HIV because of possible agranulocytosis and seizures. Cognitive-behavioral therapy leads to lifestyle modifications in patients with schizophrenia; however, it has to be ongoing. Risk factors for noncompliance with treatment are poor insight, substance abuse, lack of social support, and poor therapeutic alliance. The coordination of care between medical and psychiatric staff is essential. In using antipsychotics, psychiatrists have to bear in mind the characteristics of individual patients, appreciate the side-effect profile, and monitor carefully during the maintenance therapy. Their collaboration with primary care providers is vital in addressing the side effects when they occur. Algorithms were developed to guide the choice of antipsychotic and other somatic therapies (like electroconvulsive therapy [ECT]) at various stages of treatment. Noncompliance is managed with long acting injectable and rapid dissolving forms of medication ( Table 2 ) and through the psychiatrist's collaboration with the patient's family and caretakers. For refractory patients whose noncompliance exposes them at risk of hurting themselves or others, assertive community treatment and even involuntary treatment can be employed.



REFERENCES American Diabetes Association et al., 2004. American Diabetes Association , American Psychiatric Association , American Association of Clinical Endocrinologists , North American Association for Studies on Obesity : Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry 2004; 65(2):267-272. Buckley et al., 2007. Buckley PF, Fenley G, Mabe A, et al: Recovery and schizophrenia. Schizophrenia and Related Psychoses 2007; 11:96-100. Cournos et al., 2005. Cournos F, McKinnon K, Sullivan G: Schizophrenia and comorbid human immunodeficiency virus or hepatitis C virus. J Clin Psychiatry 2005; 66(Suppl 6):27-33. Glassman, 2005. Glassman A: Schizophrenia, antipsychotic drugs and cardiovascular disease. J Clin Psychiatry 2005; 66(Suppl 6):5-10. Green, 2005. Green A: Schizophrenia and comorbid substance use disorder: Effects of antipsychotics. J Clin Psychiatry 2005; 66(Suppl 6):21-26. Harrison and Weinberger, 2005. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Mol Psychiatry 2005; 10(1):40-68. Lieberman et al., 2005. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353(12):1209-1223. McEvoy et al., 2005. McEvoy JP, Meyer JP, Goff DC, et al: Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the clinical antipsychotic trials of intervention effectiveness (CATIE). Schizophrenia Research 2005; 80:19-32. Miller et al., 2004. Miller A, Hall CS, Buchanan RW, et al: The Texas Medication Algorithm Project Antipsychotic Algorithm for Schizophrenia, 2003 Update. J Clin Psychiatry 2004; 65(4):500-508. Practice Guideline for the Treatment, 2004. Practice Guideline for the Treatment of Patients with Schizophrenia, 2nd ed. Am J Psychiatry 2004; 161(2):Suppl Sadock and Sadock, 2005. Sadock BJ, Sadock VA: Schizophrenia and other psychotic disorders. In: Sadock BJ, Sadock VA, ed. Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 8th ed.. Philadelphia: Lippincott Williams and Wilkins; 2005. Velakoulis et al., 2006. Velakoulis D, Wood SJ, Wong MTH, et al: A magnetic resonance imaging study of chronic schizophrenia, first episode psychosis and ultra-high-risk individuals. Arch Gen Psychiatry 2006; 63(2):139-149.



Chapter 283 – Panic Disorder

Method of: Alexander Bystritsky, MD, PhD Kira Williams, MD Diagnosis Panic disorder (PD) and related agoraphobia (AG) are very prevalent and disabling conditions affecting 3% to 8% of the world population. Panic disorder is character ized by sudden episodes of acute apprehension or intense fear that occur out of the blue without any apparent cause-panic attacks. Intense panic usually lasts no more than a few minutes, but, in rare instances, can return in waves for a period of up to 2 hours. During the panic itself, any of the symptoms listed in Box 1 may occur. BOX 1 Symptoms of Panic Attack •

Dizziness, unsteadiness, or faintness

•

Fear of dying

•

Fear of going crazy or losing control

•

Feeling of choking

•

Feeling of unreality—as if you're not all there

•

Heart palpitations—pounding heart or accelerated heart rate

•

Hot and cold flashes

•

Nausea or abdominal distress

•

Numbness, pain, or tingling in hands, feet, arms, legs, fingers, toes, lips, face

•

Pain or discomfort in chest, upper back, shoulder blades

•

Shortness of breath or a feeling of being smothered

•

Sweating

•

Trembling or shaking

The attack is spontaneous, unexpected, and occurs for no apparent reason. The word agoraphobia means fear of open spaces; however, under many instances agoraphobia is a fear of panic attacks. Patients suffering from agoraphobia are afraid of being in situations from which escape might be difficult, or in which help might be unavailable if they suddenly had a panic attack. Many agoraphobics not only fear having panic attacks but also fear embarrassment should they be seen having a panic attack. It is common for the agoraphobic to avoid a variety of situations ( Box 2 ). The fear usually results in travel restrictions, or a need

to be accompanied by others when leaving home. They may avoid certain situations such as waiting in a line, being in crowded places (malls, theaters) and even using transportation, including driving a car. In the end, agoraphobic patients often end up completely housebound. BOX 2 Some of the More Common Situations Feared by Agoraphobics •

Being at home alone

•

Crowded public places such as grocery stores, department stores, restaurants

•

Enclosed or confined places such as tunnels, bridges, or the hairdresser's chair

•

Public transportation such as trains, buses, subways, planes

Impact and Cost Panic attacks are very common events. Some studies show that lifetime prevalence of panic or panic-like episodes is somewhere from 15% to 45%. PD characterized by frequent, disturbing panic attacks accompanied by at least 1 month of persistent fear of having another attack is less frequent. Epidemiologic studies throughout the world indicate the lifetime prevalence of PD (with or without AG) ranges between 1.5% and 3.5%. Twice as many women as men suffer from panic disorder. Studies have suggested high comorbidity, showing that 63% to 73% of PD patients have had at least one other mental health condition, including major depressive disorder, obsessive–compulsive disorder, or another anxiety disorder during their lifetime. Panic patients also tend to seek relief from their anxiety by self-medicating with alcohol and drugs (prescription and/or illicit). The professional life of a PD patient is also likely to suffer. The majority of these patients admit that the quality of their work diminished as a result of their anxiety. Those who are financially dependent and those who receive either welfare or disability benefits constitute a considerable 27% of all PD patients. Furthermore, there seems to be a lower life expectancy among PD patients because of an increased risk of developing some cardiovascular disease or because of suicidal behavior, although the evidence for this is not consistent. The actual costs of PD are difficult to evaluate because they are indirect and hidden, but it is estimated that they are quite extensive. Because of the physical nature of panic attack symptoms, most PD patients repeatedly consult their family physicians, internists or other health professionals. Current estimates of cost of these conditions in U.S. society are more than $44 billion per year, a figure comparable to the cost of cardiovascular disorders. Differential Diagnoses Box 3 summarizes the differential diagnoses for PD. The relationship between panic disorder and the other disorders listed in the table can be very complex, for example: BOX 3 Differential Diagnosis and Co-morbidity of Panic Disorder

1.

2.

Cardiac conditions a.

Arrhythmias[a],[c],[d]

b.

Supraventricular tachycardia[a],[c],[d]

c.

Mitral valve prolapse[b],[c],[d]

Endocrine disorders a.

Thyroid abnormality[a],[b],[c],[d]

b.

Hyperparathyroidism[b],[c],[d]

c.

Pheochromocytoma[d]

d.

Hypoglycemia[a],[c],[d]

3.

Vestibular dysfunctions[a],[b],[c],[d]

4.

Seizure disorders (temporal lobe epilepsy)[a],[b],[c],[d]

5.

Other psychiatric conditions a.

Affective disorders (1) Major depression[d],[e],[f] (2) Bipolar disorder[b],[d],[e],[f]

b.

Other anxiety disorders (1) Acute stress disorder[a],[b],[c],[d],[e],[f] (2) Obsessive–compulsive disorder[a],[b],[c],[d],[e],[f] (3) Post-traumatic stress disorder[a],[b],[c],[d],[e],[f] (4) Social phobia[a],[c],[d],[e],[f] (5) Specific phobia[a],[c],[d],[e],[f]

c.

Psychotic disorders[a],[d],[e],[f]

d.

Substance abuse and dependence (1) Withdrawal from central nervous system depressants[a],[b],[c],[d],[e],[f] (a) Alcohol abuse (present in 40% of panic disorder patients) (b) Barbiturates (2) Stimulants[a],[b],[c],[d],[e],[f] (a) Cocaine (b) Amphetamines (c) Caffeine (3) Cannabis[a],[b],[c],[d],[e],[f] (4) Hallucinogens[a],[b],[c],[d],[e],[f]

a The disorder can mimic panic disorder (PD). c The disorder's symptoms could serve as triggers of panic attacks. d The disorder could coexist with PD as an independent disorder. b The disorder can cause or worsen PD through a variety of physiologic mechanisms. e The disorder could be a co-morbid disorder with symptoms that intermingle with PD. f The disorder could lead to PD or be a sequela of PD.

•

Another disorder can mimic PD.

•

Another disorder can cause or worsen PD through a variety of physiologic mechanisms.

•

Another disorder's symptoms could serve as triggers of panic attacks.

•

Another disorder could coexist with PD as an independent disorder.

•

Another disorder could be a co-morbid disorder with symptoms that intermingle with PD.

•

Another disorder could lead to PD or be a sequela of PD.

One such example of this interaction is cardiac arrhythmias. Although it is uncommon, an arrhythmia can coexist with panic disorder as an independent condition, and a sudden increase of heart rate could potentially provoke panic in a patient with PD. However, arrhythmia accompanied by fear could mimic a panic attack, and patients with potentially dangerous arrhythmias may receive inappropriate treatment as the result of misdiagnosis. Another possible association is mitral valve prolapse (MVP) in patients with PD, which is a frequent finding thought to be of doubtful clinical significance. However, recent research suggested that it is possible that these two disorders in some patients are linked genetically (via chromosome 13) in a syndrome characterized by ß-adrenergic hyperactivity, MVP, panic, and kidney problems. Careful initial medical and psychiatric evaluation is recommended in panic patients. However, prolonged and repetitive testing should be discouraged. Theoretical Framework D ifferent theories, including cognitive-behavioral and biomedical, have been used in an attempt to describe the biologic mechanisms of panic. A brief synthesis of these theories reveals that PD is likely a combination of:

•

An increase in alarm reaction

•

An error in information processing (catastrophic thinking)

•

Abnormal coping strategies to relieve anxiety and provide a sense of security (safety rituals and avoidance)

The disorder represents a sequential process where the symptoms start with the physical symptoms of panic and progress through the stages of abnormal thinking, rituals, and, finally, avoidance ( Table 1 ). These symptom clusters may be wired through different neuronal circuits and respond preferentially to different treatments. However, this theoretical frame work is incomplete, as the intricacy of the neuronal circuits and neurotransmitters is not fully understood.

TABLE 1 -- Theory of Panic Stages of Panic Disorder

Neuronal Circuits

Possible Treatments

Panic attacks (alarm reactions)

Periaqueductal gray amygdala, SSRI, SNRI, benzodiazepines, hippocampus interoceptive exposure

Catastrophic thoughts (abnormal information processing)

Orbital frontal cortex, cingulum, SSRI, SNRI, cognitive restructuring, hippocampus neuroleptics

Precaution rituals and avoidances

Prefrontal and temporal cortex

SSRI, SNRI, neuroleptics Exposure and response prevention

Abbreviations: SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

Treatment Algorithm The treatment of PD is a stepwise process that starts with treatments of proven efficacy that are capable of ameliorating symptoms and decreasing avoidance behaviors. Figure 1 provides an algorithm of the treatment steps.

FIGURE 1 Treatment of panic disorder. AD =antidepressant; CBT =cognitive behavior therapy; MED =medication;PTSD=posttraumatic stress disorder; SSRI =selective serotonin reuptake inhibitor.

Step 1 starts with a first-line medication of a selective serotonin reuptake inhibitor (SSRI) or a therapeutic approach with cognitive behavior therapy (CBT). Both treatments have demonstrated efficacy between 70% and 90% in multiple studies. The treatment choice is based on the initial patient session with the physician, in which patients usually express their preference for either medication or psychotherapy. When availability and cost of the therapy is an issue, medication is the simplest way of treating PD. If, after two trials, the SSRI is deemed unsuccessful, step 2 begins.

Step 2 should start with a discussion with the patient about his/her preference for adding another medication or switching to another treatment modality (e.g., psychotherapy). Step 3 involves treatment with more intensive CBT or with medications or combinations of treatments that have not yet been tried. Unusual and alternative treatments may be considered at that point (an expert consultation is usually recommended). BEHAVIORAL THERAPY Behavior therapy can be effective in as few as four sessions and can significantly reduce a patient's distress. Box 4 gives the stages of CBT. The treatment is based on desensitizing patients to their internal sensations and external phobic situations via exposure, reduction of catastrophic thinking, and improvement in coping strategies. However, patients who have very severe anxiety accompanied by depression are frequently unable to follow the therapist's instructions and may need to be started on antidepressants early. BOX 4 Cognitive Behavioral Therapy •

Assessment

•

Cognitive restructuring (de-catastrophizing thinking)

•

Coping enhancement

•

Education

•

Exposure and response prevention (to phobic situations)

•

Interceptive exposure (exposure to internal sensation)

•

Relapse prevention

•

Self-monitoring

MEDICATION Selection of medication depends on whether patients have received prior pharmacotherapy for the treatment of a mood or anxiety disorder, on their previous reaction to medication, and on the severity and acuity of their panic state. An SSRI is the treatment of choice for patients who have never received pharmacotherapy and have at least moderate severity of illness. In addition to treating anxiety, SSRIs will treat a co-morbid major depressive episode (MDE) and lower the risk of future MDEs. All of the SSRIs are thought to be effective in the treatment of the four major anxiety disorders (including PD, obsessive–compulsive disorder, generalized anxiety disorder, and social anxiety disorder) and have little differences except for subtle differences in sideeffect profiles and differences in their effects on the cytochrome P450 liver enzyme system ( Table 2 ). In general, selection among antidepressants should be based on the patient's anxiety symptom profile (one should avoid medications with side effects that mimic panic symptoms) and a history the side effects of medications previously taken. Table 3 can be used as a guide. For example, in the patient with severe insomnia, one might select a sedating tricyclic, such as nortriptyline (Pamelor),[1] or perhaps mirtazapine (Remeron).[1] Paroxetine (Paxil), fluvoxamine (Luvox),[1] or citalopram (Celexa)[1] would be the SSRI of choice for patients with prominent activation. For the patient with prominent gastrointestinal (GI) side effects,

one would avoid sertraline (Zoloft), and paroxetine would be the SSRI of choice. For patients with prominent palpitations and problems with weight gain, one would avoid tricyclics, paroxetine, and mirtazapine.

TABLE 2 -- Antidepressants Used in Treatment of Panic Antidepressant Anxiolytic Efficacy[*] Advantages Fluoxetine (Prozac)

Panic[†] and PTSD

Disadvantages

Generic form

Most stimulating

Long half-life (no withdrawal)

Longer half-life

Fluvoxamine (Luvox)[1]

Panic, GAD, and SAD

No P450 2D6 effects

Effects on P4501A2, 2C9, and 3A4

Paroxetine (Paxil)

Panic, GAD, SAD, PTSD[†]

Least stimulating

Most anticholinergic

No P4503A4 effects

Most sedating

Least P450-2D6 effects

Most diarrhea

Sertraline (Zoloft)

Panic, GAD, SAD, PTSD[†]

Minimal P4503A4 effects Intermediate halflife (less withdrawal) Citalopram (Celexa)[1]

Panic

No P450 effects

Least studied

Panic, GAD, SAD,[†] PTSD

No P450 effects

Short half-life

Escitalopram (Lexapro)[1] Venlafaxine ER (Effexor XR)[1]

Withdrawal with missed dose or sudden discontinuation—increased BP at >225 mg Nefazodone (Serzone)[1]

No controlled studies

Sedation, can take at bedtime

Open reports in panic, PTSD, SAD Mirtazapine (Remeron)[1]

No controlled studies Rare open reports

Prominent P450 3A4 effects Rare reports of fatal hepatotoxicity

Sedation

Oversedation Increased appetite and weight gain Rare agranulocytosis

Antidepressant

Anxiolytic Efficacy[*]

Advantages

Disadvantages

Nortriptyline (Pamelor)[1]

No controlled trials, but for other TCAs (imipramine), controlled evidence in panic, GAD, PTSD

Sedation, can take at bedtime

Too many SEs

Abbreviations: BP = blood pressure; GAD = generalized anxiety disorder; PTSD = post-traumatic stress disorder; SAD = social anxiety disorder; SEs = side effects; TCAs = tricyclic antidepressants.

1 Not FDA approved for this indication. * Data obtained from randomized clinical trials. † FDA approved for this indication.

TABLE 3 -- Adverse Effects of the Antidepressants[*] Citalopram (Celexa) or Fluoxetine Sertaline Paroxetine Fluvoxamine Escitalopram Nortriptyline Adverse Effect (Prozac) (Zoloft) (Paxil) (Luvox) (Lexapro) (Pamelor) Venlafaxine[†] Headache

–

Agitation/anxiety

–

–

–

–

Tremor

– –

–

Insomnia

–

–

Drowsiness Fatigue

–

–

Confusion

–

–

–

Dizziness

–

–

–

Anticholinergic[‡]

–

–

–

Sweating

–

–

–

–

–

–

–

Weight gain Gastrointestinal

–

–

Sexual *

indicates the drug increases the occurrence of the adverse effect; indicates that it decreases the occurrence.

† Can increase blood pressure; must be monitored. ‡ Anticholinergic side effects include dry mouth, constipation, urinary hesitancy or retention, blurred vision.

–

Benzodiazepines are not the first choice because of tolerance, dependency potential, and possible interference with CBT (especially with as-needed use). They should be reserved for emergency situations (initial panic attacks), for the reduction in extreme anxiety, or infrequent phobic situations (airplanes, elevators, etc.) before the beginning of the CBT. Finally, they can be used for maintenance of chronic patients with unremitting anxiety. If the benzodiazepines are used chronically, they should be prescribed using a pharmacokinetically appropriate schedule to minimize daily withdrawal or interdose anxiety. Asneeded use of benzodiazepines should be avoided and history of alcohol and drug abuse should be assessed before beginning treatment. 1 Not FDA approved for this indication.

TREATMENT RESISTANCE If the patient is nonresponsive or has side effects to two prior SSRI trials, the choice is then between:

•

A serotonin–norepinephrine reuptake inhibitor (SNRI)

•

A newer antidepressant (e.g., venlafaxine [Effexor],[1] nefazodone [Serzone],[1] mirtazapine [Remeron][1])

•

A tricyclic

•

A -aminobutyric acid (GABA) agent (e.g., gabapentin [Neurontin][1]) (step 2)

A final consideration (step 3) involves the management of anxiety and other symptoms with a concomitant medication that would not ordinarily be a first-line treatment choice for anxiety disorders. This involves the use of sedating atypical neuroleptics such as olanzapine (Zyprexa)[1] and quetiapine (Seroquel).[1] At this point one could consider the use of monoamine oxidase inhibitors (MAOIs), which boast very impressive data supporting their efficacy. These medications require dietary restrictions and stopping concomitant antidepressants. Combining intensive CBT (several times a week) with medication augmentation strategies may also bring a desired effect. Other strategies are under development for the treatment of this resistant population, but none of them have moved past an early experimental stage. Long-Term Management While in some patients panic attacks stop in the course of a few months, PD is usually a chronic, waxing and waning condition. Some patients may completely recover, while others may be left with symptoms of other disorders initially masked by the panic attacks. If CBT is initiated, it is important to coordinate the medication treatment with the therapy. Completely blocking anxiety may impair patients' learning in therapy and discourage them from developing new coping techniques. Gradual reduction and stopping medication can be attempted after 2 or 3 months of complete resolution of symptoms. Approximately 20% of patients will not respond to any treatment and need to be maintained in the most comfortable state with medication or therapy or a combination thereof.



SECTION 18 – Physical and Chemical Injuries

Chapter 284 – Burn Treatment Guidelines

Method of: Barbara A. Latenser, MD The initial management of the severely burned patient follows guidelines established by the American College of Surgeons (ACS). It is crucial that the patient be managed properly in the early hours after injury because the initial management of a seriously burned patient can significantly affect the long-term outcome. Optimal burn-care criteria have been established and refined by the American Burn Association (ABA) over the past 20 years. Because of regionalization, it is common for the initial care of the seriously burned patient to occur outside the burn center. Burns are a specialized form of trauma. Therefore, the ABCs (airway, breathing, circulation) are the same as for the trauma patient: airway with cervical spine immobilization if appropriate, breathing, circulation, disability, and exposure. Also, the burn patient could be a victim of associated trauma. It is easy to be sidetracked by the obvious thermal injury. Only after the primary and secondary surveys have been performed should you evaluate the severity of the burn injury. Obtain as much information as possible regarding the incident and about the patient. An easy way to remember the information is the mnemonic AMPLE: •

Allergies

•

Medications

•

Past medical history

•

Last meal

•

Events

Universal precautions appropriate for each burn patient must be implemented by every member of the health care team. The most commonly used guide for making an initial estimate of the second- and third-degree burns is the Rule of Nines ( Figure 1 ). Various anatomic regions are roughly 9% of the total body surface area (TBSA) or multiples thereof. To calculate scattered burn areas, the patient's palm, including fingers, represents approximately 1% of the TBSA. A much more precise estimate of TBSA burn is provided by the LundBrowder Classification ( Figure 2 ). By drawing in the areas that are burned, the TBSA burn necessary for calculating resuscitation requirements can be determined. The consensus formula for the first 24 hours postburn is:

4 mL lactated Ringer's × body weight in kg × percent BSA burn Half the calculated amount is given in the first 8 hours and the rest over the remaining 16 hours. Patients with burns on more than 20% TBSA are prone to gastric dilatation and should have a nasogastric (NG) tube. To determine hourly urine output, a urinary catheter is necessary. Intravenous (IV) morphine sulfate is indicated for control of pain associated with burns. Intramuscular (IM) or subcutaneous (SC) routes of drug administration should not be used as absorption is erratic. To calculate fluid needs, weigh the patient or estimate the preinjury weight. Reliable peripheral veins should be used to establish an IV line. Use vessels underlying burned skin if necessary. If it is impossible to establish peripheral IV access, a central line may be necessary. The burn wound should be covered with a clean, dry sheet to prevent air currents from causing pain in partial-thickness burns and to decrease fluid losses and hypothermia. Although there are many common topical antimicrobials in use, the optimal dressing prior to burn center transfer is plastic wrap such as Saran Wrap. Topical antimicrobials will just have to be washed off on arrival to the burn center, causing patient discomfort and mechanical trauma to the wound. Cold applications are appropriate only in small burns because they rapidly lead to hypothermia. Ice should never be applied because it will deepen the zone of ischemia in a thermal injury. Escharotomies and/or fasciotomies are rarely required prior to burn center transfer, unless transfer is delayed beyond 24 hours. Patients most at risk are those with large TBSA burns, circumferential fullthickness burns, and those with electrical injury. Circumferential chest/abdominal burns may restrict ventilatory excursion. A child has a more pliable rib cage and may need an escharotomy earlier than an adult burn. If you are considering performing an escharotomy, confer with the accepting burn physician before proceeding. So how do you know which patients should be referred to a burn center? To guide your decision making there are currently 10 burn unit referral criteria. You should have a written transfer agreement in place with a referral burn unit. The agreement should specify which patients will be referred, what stabilization is expected, who arranges transportation, and what the patient will need during transport.

FIGURE 1 Rule of Nines.

FIGURE 2 Lund-Browder Classification Burn Size and Diagram.

Partial-Thickness Burns on More Than 10% Total Body Surface Area Second-degree or partial-thickness burns involve a variable portion of dermis. The skin may be red, blistered, and edematous. Because sensory nerves are damaged and/or exposed, these wounds are typically extremely painful. Healing time is proportional to the depth of dermal injury. Scarring is minimal if healing occurs in 14 days or less. With closure time beyond 3 weeks, scarring will occur, the degree being greater in darker skinned individuals.

Proper fluid management is critical to the survival of patients with extensive burns. Fluid resuscitation is aimed at maintaining tissue perfusion and organ function while avoiding the complications of inadequate or excessive fluid therapy. Shock and organ failure, most commonly acute renal failure, may occur as a consequence of hypovolemia in a patient with an extensive burn who is inadequately resuscitated. The increase in capillary permeability caused by the burn is greatest in the immediate postburn period and diminution in effective blood volume is most rapid at that time. A marked increase in peripheral vascular resistance accompanied by a decrease in cardiac output occurs in the first 18 to 24 hours postinjury. In the presence of increased capillary permeability, colloid content of the resuscitation fluid exerts little influence on intravascular retention during the initial hours postburn. Crystalloid fluid is the initial resuscitation of burn patients. Always remember, estimates are inexact. Each patient reacts differently to burn injury and resuscitation. The actual volume of fluid infused should be varied from the calculated volume as indicated by physiologic monitoring. The patient's general condition reflects the adequacy of fluid resuscitation and should be assessed and reassessed. Mental status, anxiety, and restlessness may be signs of hypoxemia, hypovolemia, or pain. Although urine output does not guarantee tissue perfusion, it remains the most readily available and generally reliable guide to resuscitation. Adults should produce 0.5 mL/kg per hour of urine. Children should produce 1.0 mL/kg per hour of urine, and infants 12 months or younger should produce 2.0 mL/kg per hour of urine. Oliguria is most frequently the result of inadequate fluid administration. Diuretics are contraindicated; the rate of resuscitation should be increased. During the first 24 hours, neither the hemoglobin nor the hematocrit is a reliable guide to resuscitation, and using either leads to overresuscitation. Measuring blood pressure (BP) by a sphygmomanometer may be misleading in a burned limb with progressive edema formation. As the swelling increases, the signal becomes diminished. If fluid infusion is increased based on this finding, edema formation may be exaggerated. Even intra-arterial monitoring may be unreliable in patients with massive burns because of peripheral vasoconstriction secondary to marked elevation of catecholamines. Heart rate is also of limited usefulness in monitoring fluid therapy. The level of tachycardia depends on the normal heart rate in each child. Burns That Involve the Face, Hands, Feet, Genitalia, Perineum, or Major Joints Facial burns are considered a serious injury. The possibility of respiratory tract damage must be considered. Because of the rich blood supply and loose areolar tissue of the face, facial burns are associated with extensive edema formation. To minimize this edema, keep the head of the bed elevated at 30°. Cool saline compresses on the face may also help. Careful examination of the eyes should be completed as soon as possible because the rapid onset of eyelid swelling will make this difficult. Fluorescein should be used to identify corneal injury. Chemical burns to the eyes should be rinsed with copious amounts of saline. Burns of the ears require examination of the external auditory canal and ear drum before swelling occurs. Minor burns of the hands may result in only temporary disability and inconvenience. More extensive thermal injury may cause permanent loss of function. Monitoring the digital and palmar pulses with an ultrasonic flowmeter is the most accurate means of assessing perfusion of the tissues in the hand. The burned extremity should be elevated above the heart to minimize edema formation. Digital escharotomies are not

indicated prior to transfer to a burn center. Contact the accepting burn center physician if you are concerned about the extent of the digital injury. As with burns of the upper extremity, it is important to assess the circulation and neurologic function of the feet on an hourly basis. Third-Degree Burns in Any Age Group A full-thickness or third-degree burn occurs with destruction of the entire epidermis and dermis, leaving no dermal elements to repopulate. A characteristic initial appearance is a waxy white color. Full-thickness injuries require emergent management. In most cases, treatment of the wound requires surgical skin grafting. Deep partial-thickness and full-thickness burns heal with severe scarring if not treated by surgical excision and skin grafting for optimal recovery. Disfigurement is common, and long-term functional problems can persist for years. There is also a high risk of infection, because an unexcised full-thickness burn behaves like an undrained abscess. Electric Burns, Including Lightning Injury Electrical burns can be divided into flash (typical thermal injury) and high-tension injury. The latter, caused by more than 1000 volts, produces clinically characteristic entry and exit wounds. They are usually ischemic, painless, and dry; wounds of entry may appear charred and the exit explosive. Deep-muscle injury may be present even when skin appears normal. Findings that suggest electrical injury include loss of consciousness, paralysis or mummification of an extremity, loss of peripheral pulses, flexor surface burns, myoglobinuria, serum creatine kinase (CK) more than 1000, and cardiopulmonary arrest at the scene. Electrical injuries can produce vascular thrombosis, muscle tetany causing fractures, and internal organ damage. In addition to other interventions, obtain a 12-lead electrocardiogram (ECG), cardiac enzymes, and evaluate the urine for myoglobin. If there is evidence of myoglobin from muscle damage, the urine output should be maintained at 2 mL/kg per hour until the urine grossly clears to prevent acid hematin deposition in the kidney and irreversible renal damage. Compartment pressures must be monitored. If a compartment syndrome develops, contact your burn center physician because fasciotomy may be required. The most serious immediate problem associated with electrical injuries is ventricular fibrillation, asystole, or other dysrhythmias. Life-threatening arrhythmias are treated according to advanced cardiac life support (ACLS) protocols. Survival of contact with voltage greater than 70,000 volts is uncommon. The approximate electrical potential of a lightning bolt is 20 million volts. Lightning injury can produce an enormous spectrum of clinical symptoms and signs ranging from common (cardiac asystole, respiratory arrest, arborescent markings) to the rare (disseminated intravascular coagulation [DIC], intracerebral hemorrhage). Immediate neurologic manifestations include agitation, amnesia, loss of consciousness, or motor disturbances. The eyes are particularly vulnerable to injury from electrical current, and symptoms closely correlate with the extent of the central nervous system (CNS) injury. Vitreous hemorrhage, iridocyclitis, retinal tear, macular puncture, and retinal detachment have been reported. Lightning injuries are not usually associated with deep burns but most often with superficial injury to the skin and underlying soft tissue called ferning. The feathering type of burn appears as an arborescent, branching skin marking that disappears within a few hours. Pathognomonic of lightning injury, they may be of great diagnostic value in a comatose patient. Often the respiratory arrest lasts longer than the cardiac arrest. Severely injured victims often present in asystole or ventricular fibrillation. Cardiac resuscitation may occasionally be successful; but direct brain trauma as well as blunt trauma, skull fracture, and intracranial injuries, are common in these patients. The prognosis for recovery in this group is usually poor.

Chemical Burns Health care providers must wear protective clothing when caring for patients with potential chemical injury. The initial appearance of a chemical burn is usually deceptively benign. The severity of a chemical injury is related to the agent, concentration, volume, duration of contact, and mechanisms of action of the agent. Immediate irrigation decreases the concentration and duration of contact, reducing the severity of injury. If the agent is a powder, brush it off and irrigate with water. Irrigation should continue through emergency evaluation in the hospital and in general until evaluation in a burn center, especially for an alkali or if an unknown agent. Neutralizing agents are contraindicated because of the potential for heat generation, thereby giving the patient both a chemical and a thermal injury! Acid burns are less severe than alkali burns. They are found in many household products including bathroom cleansers, drain cleaners, and swimming pool acidifiers. Tissue is damaged by coagulation necrosis and protein precipitation. Once a layer of eschar is formed, the burning process is self-limiting. The exception to this rule is hydrofluoric acid (HA), which is used to etch glass, make Teflon, and to remove rust. The pathogenesis of tissue damage in HA burns is distinct from other acids. HA readily crosses lipid membranes and has a potent diffusing capacity into the tissues. The molecule releases the freely dissociable fluoride ion, which produces extensive liquefactive necrosis of the soft tissues. Fluoride rapidly binds free calcium in the blood, and death from hypocalcemia may occur. Treatment is intra-arterial calcium gluconate[1](or calcium chloride)[1] administered until the characteristic pain out of proportion to the burn has resolved. Even small areas of contact may result in profound hypocalcemia and death. Cardiac monitoring and frequent serum calcium determinations are indicated. Alkalis damage tissue by liquefaction necrosis and protein denaturation. Tissue pH abnormalities may persist for 12 hours postburn, allowing deeper spread of the chemical and more severe burns. Examples would include the hydroxides, caustic sodas, and ammonium compounds found in oven cleaners, fertilizer, and cement. Wet cement damages skin in three ways: allergic dermatitis as a reaction to chromate ions, abrasions caused by the gritty nature of the cement, and as an alkali with a pH of 12.5. The ability of cement to cause such injury is not well recognized, even by professional users. With the increased media interest in do-it-yourself projects, it is likely this problem will increase. Organic compounds such as creosote and petroleum products produce contact chemical burns as well as systemic toxicity. Gasoline and diesel fuel are petroleum products that may produce a full-thickness burn that initially appears as only partial thickness. Organic compounds cause cutaneous damage by delipidation because of their fat solvent action on cell membranes. After a motor vehicle crash involving petroleum products, always look for petroleum exposure in the lower extremities, back, and buttocks. Systemic effects include elevated liver enzymes and decreased urinary output. 1 Not FDA approved for this indication.

Inhalation Injury Smoke inhalation injuries are the leading cause of fatalities from burn injuries, accounting for some 80% of all fire-related deaths. The major forms of inhalation injuries are carbon monoxide (CO) toxicity, injury to the upper airway, and pulmonary parenchymal damage. Each has different symptoms and signs, treatment, and

prognosis. The compromised airway is protected by tracheal intubation, and respiratory failure is treated with assisted ventilation. Inhalation injury is manifested by the pathology and dysfunction that rapidly become evident in the airways, lungs, and respiratory system after inhaling the products of incomplete combustion. Patients receiving massive fluid resuscitation can develop upper airway edema with subsequent asphyxiation. Immediate medical attention and diagnosis depend on a high index of suspicion, an appropriate history, careful examination of the upper airway, the presence of clinical symptoms, and suggestive arterial blood gases. An inhalation injury is suspected in any patient with full-thickness facial burns or with any burns combined with a history of being confined within an enclosed space. Other classic signs are soot or carbonaceous sputum, stridor or hoarseness, or blistering of the pharynx or vocal cords. Late signs include grunting, nasal flaring, retractions, wheezes, and rales. Use of prophylactic antibiotics and steroids is discouraged. The effect of CO poisoning may be exhibited by respiratory symptoms and CNS findings such as altered level of consciousness, seizures, or coma. Cardiovascular effects include diminished cardiac output evidenced by decreased perfusion and hypotension. There is much controversy regarding hyperbaric oxygen therapy, but there are no objective data proving the efficacy of hyperbaric oxygen in CO poisoning. At this time, hyperbaric oxygen treatment for acute CO toxicity should be restricted to randomized prospective studies. The correct treatment is administering 100% oxygen, thereby decreasing the CO halflife from 4 hours to 45 minutes. Burn Injury in Patients with Preexisting Medical Disorders That Could Complicate Management, Prolong Recovery, or Affect Mortality Peripheral vascular disease can lead to a decrease in wound blood flow. Diabetes, through high glucose, will impede capillary flow. Optimum control of the blood glucose is needed to optimize blood flow. A local decrease in wound-tissue oxygen tension is recognized to be a major wound-healing impediment because all phases of healing are oxygen dependent, including local infection control. Most common causes are a decrease in systemic blood volume and oxygen delivery, decrease in hemoglobin saturation, eschar on the wound surface, or infection. Treatment modalities need to focus first on correction of systemic abnormalities: correct cardiovascular and lung function, correct large vessel obstructive disease impeding wound flow, aggressive wound debridement, and eliminate tissue exudates. Patients with preexisting cardiac disease are particularly sensitive to fluids and may tolerate the necessary fluid resuscitation poorly. Any Patient With Burns and Concomitant Trauma (Such as Fractures) in Which the Burn Injury Poses the Greatest Risk of Morbidity and Mortality In such cases, if the trauma poses the greater immediate risk, the patient may be initially stabilized in a trauma center before being transferred to a burn unit. Physician judgment will be necessary in such situations and should be in concert with the regional medical control plan and triage protocols. Most burn-trauma publications cite a 5% frequency of burn-trauma patient. Because burn trauma is rare outside of a major conflict or disaster, most centers see only a few patients annually. By definition, child abuse falls into the burn-trauma category. It may be the burn injury that prompts relatives or neighbors to bring the child to the hospital or report the family to authority. The visibility of the injury may instigate

corrective action. In a 44-month review we saw 120 cases of burns and trauma. Although motor vehicle crashes (MVCs) can result in fracture, soft tissue, and thermal injury, unique to this burn-trauma population was that the MVC injury was frequently a result of assault. With the graying of America, elder abuse may become a larger societal problem. Burned Children in Hospitals Without Qualified Personnel or Equipment for the Care of Children Each year more than 2500 children die and 10,000 more sustain permanent disability from thermal injury. Children are not just little adults! They respond differently than adults to severe trauma, maintaining normal vital signs longer but decompensating rapidly. Because of the smaller cross-sectional diameter of the pediatric airway, it takes much less edema to compromise a pediatric airway. If intubation is required, the most experienced pediatric airway manager should intubate the child because repeated attempts may create sufficient airway edema as to cause obstruction. Anatomical airway differences make intubation by the inexperienced even more difficult.

CURRENT DIAGNOSIS Maintain a high index of suspicion Remember the ABCs Rule out concomitant trauma Establish size and depth of burn Be wary of chemical and electrical burns, which may be misleading Establish resuscitation requirements Abbreviations: ABC = airway with cervical spine immobilization if appropriate, breathing, circulation, disability, and exposure.

The greater surface area per unit of body mass of children necessitates the administration of relatively greater amounts of resuscitation fluid. The surface area/body mass relationship of the child also defines a lesser intravascular volume per unit surface area burned. This makes the burned child more susceptible to fluid overload and hemodilution. Hypoglycemia may occur if the limited glycogen stores of the child are rapidly exhausted by the early postburn elevation of circulating levels of steroids and catecholamines. Infants should receive maintenance fluids with 5% dextrose in addition to the resuscitation fluids outlined in the consensus formula. Children younger than 2 years of age have disproportionally thin skin so that exposures that would produce only partial-thickness burns in older patients produce full-thickness injuries. Children have a relatively small muscle mass, hampering intrinsic heat generation. Children younger than 6 months of age are unable to shiver and thus are even more prone to develop hypothermia. Stress for the burned child not only includes the body surface area (BSA) burn and the pain that is involved but also the separation from parents and loved ones. This escalates especially if the parents were also burned in the fire. Emergency management of each pediatric burn patient requires an individual care plan. Early consultation with the burn center physician is advised.

Burn Injury in Patients Who Will Require Special Social, Emotional, and/or Long-Term Rehabilitative Intervention Failure to recognize the thermal manifestations of child abuse not only negates protection of the child but predicates potential lethal injury. Awareness of the patterns of abuse, the behavior patterns of the parents, and the physical manifestations will protect the child by early recognition and reporting. Physical child abuse victims frequently present with thermal injuries of varying degrees. The history of injury should correlate with the physical findings. The history also becomes important in identifying repetitious hospital visits for accidental injury. Not infrequently, the hospital visits will be made at different hospitals to avoid disclosure and identification. The events leading to an injury are extremely important in the initial evaluation of an infant or child. Always consider the potential for child abuse. The incidence of child abuse is approximately 10% of all children presenting to an emergency department (ED), with a mortality rate less than 1%. Abused children present with a higher median Injury Severity Score, more severe injuries of the head and integument, longer hospital lengths of stay, and a high mortality rate. A burn of any magnitude can be a serious injury. Health care providers must be able to assess the injuries rapidly and develop a priority-based plan of care. The plan of care is determined by the type, extent, and degree of burn as well as by available resources.

CURRENT THERAPY Communicate with your burn center early and often Remember the ABCs Cover the wound with Saran Wrap Prevent hypothermia Transport to the burn center Abbreviations: ABC = airway with cervical spine immobilization if appropriate, breathing, circulation, disability, and exposure.

Burn care is complex. It involves a multisystem assessment and appropriate intervention. The first 24 hours of management are perhaps the most critical for patient survival. Burn centers provide optimal care in a costeffective, multidisciplinary manner. Every health care provider must know how and when to contact the closest burn center. If the attending physician determines that the patient should be treated at the burn center, the extent of treatment provided at the referring hospital—and the method of transport to the burn center—should be decided in consultation with the burn center physician. A complete list of verified burn centers is available at http://ameriburn.org .



REFERENCES Advanced Burn Life, 2001. Advanced Burn Life Support Course, American Burn Association, 625 N. Michigan Ave., Suite 1530, Chicago, IL. 60611. 2001. American College of Surgeons Committee on Trauma, 1999. American College of Surgeons Committee on Trauma : Resources for optimal care of the injured patient: 1999, Chicago, American College of Surgeons, 1999. Andrews et al., 1992. In: Andrews CJ, Cooper MA, Darveniza M, Mackerras D, ed. Lightning injuries: Electrical, medical, and legal aspects, Boca Raton, Fla: CRC Press; 1992:62-63.82-85, 88-98, 101-110. Burd, 2004. Burd A: Hydrofluoric acid—revisited. Burns 2004; 30(7):720-722. Chang et al., 2004. Chang DC, Knight V, Ziegfeld S, et al: The tip of the iceberg for child abuse: The critical roles of the pediatric trauma service and its registry. J Trauma 2004; 57(6):1189-1198. Heimbach, 2003. Heimbach DM: Regionalization of burn care: A concept whose time has come. J Burn Care Rehabil 2003; 24(3):173-174. Latenser and Iteld, 2001. Latenser BA, Iteld L: Smoke inhalation injury. Seminars in Respiratory and Critical Care Medicine 2001; 22(1):13-22. Luce, 2000. In: Luce EA, ed. Clinics in Plastic Surgery. An International Quarterly. Burn Care and Management, Philadelphia: WB Saunders; 2000:133-143.27(1): Varghese et al., 2003. Varghese TK, Kim AW, Kowal-Vern A, Latenser BA: Frequency of burn-trauma patients in an urban setting. Arch Surg 2003; 138:1292-1296.



Chapter 285 – High-Altitude Illness

Method of: James A. Litch, MD, DTMH Decreased partial pressure of oxygen at high altitude results in pronounced physiologic responses that range from beneficial to pathologic. Slow ascent normally leads to acclimatization. High-altitude illness is a collective term for a cluster of acute clinical syndromes that are a direct consequence of rapid ascent to high altitude above 2500 m. The acute syndromes affecting the brain include acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). The acute syndrome affecting the lung is high-altitude pulmonary edema (HAPE). All unacclimatized sojourners to high altitude are potentially at risk. The characteristic cerebral and pulmonary abnormalities are not subtle, but when unrecognized or ignored, they may progress to death. Each year millions travel to high-altitude locations on every continent, resulting in morbidity and mortality with associated economic consequences. Normal Acclimatization It is not uncommon for normal acclimatization of novice healthy visitors to high altitude to cause concern that they are experiencing a health problem. Normal acclimatization includes immediate hyperventilation, shortness of breath with moderate excursion, and a decreased work capacity. These are followed by diuresis, disturbed sleep (including periodic breathing), and peripheral/facial edema. It is important to recognize the signs of normal acclimatization so reassurance and education may be appropriately provided. Incidence and Risk Factors Determinants of whether high-altitude illness will occur are individual susceptibility, rate of ascent, altitude reached, and sleep altitude. Incidence rates of AMS reported in literature are difficult to compare because of variability in methodology and rates of ascent. Reported incident figures for AMS following ascent by hiking, vehicle, or flying range from 10% to 40% at 2700 to 3000 m, and from 40% to 95% at 3800 to 4000 m. HACE and HAPE are both far less common than mild AMS, but actual incident rates are unavailable. HAPE can occur as low as 2500 m. HACE is rare below 3600 m. Most cases of HACE and HAPE are preceded by AMS. Risk factors for altitude illness include a history of previous high-altitude illness, residence at altitude below 1000 m, physical exertion, and preexisting cardiopulmonary conditions. Traveling in a large group presents a risk because a tight itinerary often does not allow time for acclimatization, and members are reluctant to declare symptoms for fear of being left behind. Children appear to carry the same risk for altitude illness as adults, but persons over 50 years of age seem less susceptible, possibly because of a more cautious ascent profile. There appears to be little or no gender difference for AMS, but women may be less susceptible to HAPE. Heavy physical exertion at exceedingly high altitude appears to be an important risk factor for HAPE. Rapid ascent, especially by flying or driving to altitude, places sojourners at risk for altitude illnesses. Prevention of Altitude Illnesses

Gradual ascent to altitude over several days to allow for acclimatization reduces the likelihood of acute mountain sickness. Ascent rates of less than 300 m per day at altitudes of more than 2500 m is a common recommendation; but individuals will still experience altitude illness when abiding to this recommendation. However, the critical understanding to prevent serious life-threatening altitude illness (HAPE and HACE) is to halt further ascent until symptoms resolve. Medications are available to help prevent the symptoms of AMS when rapid ascent (10 mEq/L), underlying medical conditions, intravascular thrombosis (fibrinogen 65 years of age), and 5% of ambulance calls. In one urban hospital, drug-related emergencies accounted for 38% of the emergency department visits. An evaluation of a medical intensive care unit and step-down unit over a 3-month period indicated that poisonings accounted for 19.7% of admissions. The largest number of fatalities resulting from poisoning reported to the TESS are caused by analgesics. The other principal toxicologic causes of fatalities are antidepressants, sedative hypnotics/antipsychotics, stimulants/street drugs, cardiovascular agents, and alcohols. Less than 1% of overdose cases reaching the hospitals result in fatality. However, patients presenting in deep coma to medical care facilities have a fatality rate of 13% to 35%. The largest single cause of coma of inapparent etiology is drug poisoning. Pharmaceutical preparations are involved in 50% of poisonings. The number one pharmaceutical agent involved in exposures is acetaminophen. The severity of the manifestations of acute poisoning exposures varies greatly depending on whether the poisoning was intentional or unintentional. Unintentional exposures make up 85% to 90% of all poisoning exposures. The majority of cases are acute, occurring in children younger than 5 years of age, in the home, and resulting in no or minor toxicity. Many are actually ingestions of relatively nontoxic substances that require minimal medical care. Intentional poisonings, such as suicides, constitute 10% to 15% of exposures and may require the highest standards of medical and nursing care and the use of sophisticated equipment for recovery. Intentional ingestions are often of multiple substances and frequently include ethanol, acetaminophen, and aspirin. Suicides make up 54% of the reported fatalities. About 25% of suicides are attempted with drugs. Sixty percent of patients who take a drug overdose use their own medication and 15% use drugs prescribed for close relatives. The majority of the drug-related suicide attempts involve a central nervous system (CNS) depressant, and coma management is vital to the treatment. Assessment and Maintenance of the Vital Functions The initial assessment of all patients in medical emergencies follows the principles of basic and advanced cardiac life support. The adequacy of the patient's airway, degree of ventilation, and circulatory status should be determined. The vital functions should be established and maintained. Vital signs should be measured frequently and should include body core temperature. The assessment of vital functions should include the rate numbers

(e.g., respiratory rate) and indications of effectiveness (e.g., depth of respirations and degree of gas exchange). Table 1 gives important measurements and vital signs.

TABLE 1 -- Important Measurements and Vital Signs Blood Pressure Hypertension Age

Body Surface Weight Area (m2) (kg)

Height (cm)

Pulse (bpm) Resting Hypotension Significant Severe

Respiratory Rate (rpm)

Newborn 0.19

3.5

50

70-190

96

>106

30-60

1 mo-6 mo

4-7

50-65

80-160

104

>110

30-50

6 mo-1 y 0.38

7-10

65-75

80-160

104

>110

20-40

1-2 y

0.50-0.55

10-12

75-85

80-140

112/74

>118/82

20-40

3-5 y

0.54-0.68

15-20

90-108

80-120

116/76

>124/84

20-40

6-9 y

0.68-0.85

20-28

122-133 75-115

122/82

>130/86

16-25

10-12 y

1.00-1.07

30-40

138-147 70-110

126/82

>134/90

16-25

13-15 y

1.07-1.22

42-50

152-160 60-100

136/86

>144/92

16-20

16-18 y

1.30-1.60

53-60

160-170 60-100

142/92

>150/98

12-16

Adult

1.40-1.70

60-70

160-170 60-100

140/90

>210/120 10-16

0.30

Data from Nadas A: Pediatric Cardiology, 3rded. Philadelphia, WB Saunders, 1976; Blumer JL (ed): A Practice Guide to Pediatric Intensive Care. St Louis, Mosby, 1990; AAP and ACEP: Respiratory Distress in APLS Pediatric Emergency Medicine Course, 1993; Second Task Force: Blood pressure control in children–1987, Pediatr 79:1, 1987; Linakis JG: Hypertension. In Fliesher GR, Ludwig S (eds); Textbook of Pediatric Emergency Medicine, 3rd ed. Baltimore, Williams & Wilkins, 1993.

Level of consciousness should be assessed by immediate AVPU (Alert, responds to Verbal stimuli, responds to Painful stimuli, and Unconscious). If the patient is unconscious, one must assess the severity of the unconsciousness by the Glasgow Coma Scale ( Table 2 ).

TABLE 2 -- Glasgow Coma Scale Scale

Adult Response

Eye opening

Spontaneous

4

Spontaneous

To verbal command

3

To shout

To pain

2

To pain

None

1

No response

Motor response

Score Pediatric, 0-1 Years

Scale

Adult Response

Score Pediatric, 0-1 Years

To verbal command

Obeys

6

To painful stimuli

Localized pain

5

Localized pain

Flexion withdrawal

4

Flexion withdrawal

Decorticate flexion

3

Decorticate flexion

Decerebrate extension

2

Decerebrate flexion

None

1

None

5

Cries, smiles, coos

Disoriented but converses

4

Cries or screams

Inappropriate words

3

Inappropriate sounds

Incomprehensible sounds

2

Grunts

None

1

Gives no response

Verbal response: adult Oriented and converses

Verbal response: child Oriented

5

Words or babbles

4

Vocal sounds

3

Cries or moans to stimuli

2

None

1

Data from Teasdale G, Jennett B: Assessment of coma impaired consciousness. Lancet 2:83, 1974; Simpson D, Reilly P: Pediatric coma scale. Lancet 2:450, 1982; Seidel J: Preparing for pediatric emergencies. Pediatr Rev 16:470, 1995.

If the patient is comatose, management requires administering 100% oxygen, establishing vascular access, and obtaining blood for pertinent laboratory studies. The administration of glucose, thiamine, and naloxone, as well as intubation to protect the airway, should be considered. Pertinent laboratory studies include arterial blood gases (ABG), electrocardiography (ECG), determination of blood glucose level, electrolytes, renal and liver tests, and acetaminophen plasma concentration in all cases of intentional ingestions. Radiography of the chest and abdomen may be useful. The severity of a stimulant's effects can also be assessed and should be documented to follow the trend. The examiner should completely expose the patient by removing clothes and other items that interfere with a full evaluation. One should look for clues to etiology in the clothes and include the hat and shoes. Prevention of Absorption and Reduction of Local Damage EXPOSURE Poisoning exposure routes include ingestion (76.8%), dermal (8%), ophthalmologic (5%), inhalation (6%), insect bites and stings (4%), and parenteral injections (0.5%). The effect of the toxin may be local, systemic, or both.

Local effects (skin, eyes, mucosa of respiratory or gastrointestinal tract) occur where contact is made with the poisonous substance. Local effects are nonspecific chemical reactions that depend on the chemical properties (e.g., pH), concentration, contact time, and type of exposed surface. Systemic effects occur when the poison is absorbed into the body and depend on the dose, the distribution, and the functional reserve of the organ systems. Shock and hypoxia are part of systemic toxicity. DELAYED TOXIC ACTION Therapeutic doses of most pharmaceuticals are absorbed within 90 minutes. However, the patient with exposure to a potential toxin may be asymptomatic at this time because a sufficient amount has not yet been absorbed or metabolized to produce toxicity at the time the patient presents for care. Absorption can be significantly delayed under the following circumstances: 1.

Drugs with anticholinergic properties (e.g., antihistamines, belladonna alkaloids, diphenoxylate with atropine [Lomotil], phenothiazines, and tricyclic antidepressants).

2.

Modified release preparations such as sustained-release, enteric-coated, and controlled-release formulations have delayed and prolonged absorption.

3.

Concretions may form (e.g., salicylates, iron, glutethimide, and meprobamate [Equanil]) that can delay absorption and prolong the toxic effects. Large quantities of drugs tend to be absorbed more slowly than small quantities.

Some substances must be metabolized into a toxic metabolite (acetaminophen, acetonitrile, ethylene glycol, methanol, methylene chloride, parathion, and paraquat). In some cases, time is required to produce a toxic effect on organ systems (Amanita phalloides mushrooms, carbon tetrachloride, colchicine, digoxin [Lanoxin], heavy metals, monoamine oxidase inhibitors, and oral hypoglycemic agents). Initial Management

1.

Stabilization of airway, breathing, and circulation and protection of same.

2.

Identification of specific toxin or toxic syndrome.

3.

Initial treatment: D50W; consider thiamine, naloxone (Narcan), oxygen, and antidotes if needed.

4.

Physical assessment.

5.

Decontamination: Gastrointestinal tract, skin, eyes.

DECONTAMINATION In the asymptomatic patient who has been exposed to a toxic substance, decontamination procedures should be considered if the patient has been exposed to potentially toxic substances in toxic amounts. Ocular exposure should be immediately treated with water irrigation for 15 to 20 minutes with the eyelids fully retracted. One should not use neutralizing chemicals. All caustic and corrosive injuries should be evaluated with

fluorescein dye and by an ophthalmologist. Dermal exposure is treated immediately with copious water irrigation for 30 minutes, not a forceful flushing. Shampooing the hair, cleansing the fingernails, navel, and perineum, and irrigating the eyes are necessary in the case of an extensive exposure. The clothes should be specially bagged and may have to be discarded. Leather goods can become irreversibly contaminated and must be abandoned. Caustic (alkali) exposures can require hours of irrigation. Dermal absorption can occur with pesticides, hydrocarbons, and cyanide. Injection exposures (e.g., snake envenomation) can be treated with venom extracts. Venom extractors can be used within minutes of envenomation, and proximal lymphatic constricting bands or elastic wraps can be used to delay lymphatic flow and immobilize the extremity. Cold packs and tourniquets should not be used and incision is generally not recommended. Substances of abuse may be injected intravenously or subcutaneously. In these cases, little decontamination can be done. Inhalation exposure to toxic substances is managed by immediate removal of the victim from the contaminated environment by protected rescuers. Gastrointestinal exposure is the most common route of poisoning. Gastrointestinal decontamination historically has been done by gastric emptying: induction of emesis, gastric lavage, administration of activated charcoal, and the use of cathartics or whole bowel irrigation. No procedure is routine; it should be individualized for each case. If no attempt is made to decontaminate the patient, the reason should be clearly documented on the medical record (e.g., time elapsed, past peak of action, ineffectiveness, or risk of procedure). Gastric Emptying Procedures

The gastric emptying procedure used is influenced by the age of the patient, the effectiveness of the procedure, the time of ingestion (gastric emptying is usually ineffective after 1 hour postingestion), the patient's clinical status (time of peak effect has passed or the patient's condition is too unstable), formulation of the substance ingested (regular release versus modified release), the amount ingested, and the rapidity of onset of CNS depression or stimulation (convulsions). Most studies show that only 30% (range, 19% to 62%) of the ingested toxin is removed by gastric emptying under optimal conditions. It has not been demonstrated that the choice of procedure improved the outcome. A mnemonic for gathering information is STATS: S—

substance

T—

type of formulation

A—

amount and age

T—

time of ingestion

S—

signs and symptoms

The examiner should attempt to obtain AMPLE information about the patient:

A—

age and allergies

M—

available medications

P—

past medical history including pregnancy, psychiatric illnesses, substance abuse, or intentional ingestions

L—

time of last meal, which may influence absorption and the onset and peak action

E—

events leading to present condition

The intent of the patient should also be determined. The Regional Poison Center should be consulted for the exact ingredients of the ingested substance and the latest management. The treatment information on the labels of products and in the Physician's Desk Reference are notoriously inaccurate. Ipecac Syrup

Syrup of ipecac–induced emesis has virtually no use in the emergency department. Although at one time it was considered most useful in young children with a recent witnessed ingestion, it is no longer advised in most cases. Current guidelines from the American Association of Poison Control Centers have significantly limited the indications for inducing emesis because the risk most often exceeds the benefit derived from this procedure. The Poison Control Center should be called if inducting emesis is being considered. Contraindications or situations in which induction of emesis is inappropriate include the following: •

Ingestion of caustic substance

•

Loss of airway protective reflexes because of ingestion of substances that can produce rapid onset of CNS depression (e.g., short-acting benzodiazepines, barbiturates, nonbarbiturate sedative-hypnotics, opioids, tricyclic antidepressants) or convulsions (e.g., camphor [Ponstel], chloroquine [Aralen], codeine, isoniazid [Nydrazid], mefenamic acid, nicotine, propoxyphene [Darvon], organophosphate insecticides, strychnine, and tricyclic antidepressants)

•

Ingestion of low-viscosity petroleum distillates (e.g., gasoline, lighter fluid, kerosene)

•

Significant vomiting prior to presentation or hematemesis

•

Age under 6 months (no established dose, safety, or efficacy data)

•

Ingestion of foreign bodies (emesis is ineffective and may lead to aspiration)

•

Clinical conditions including neurologic impairment, hemodynamic instability, increased intracranial pressure, and hypertension

•

Delay in presentation (more than 1 hour postingestion)

The dose of syrup of ipecac in the 6- to 9-month-old infant is 5 mL; in the 9- to 12-month-old, 10 mL; and in the 1to 12-year-old, 15 mL. In children older than 12 years and in adults, the dose is 30 mL. The dose can be repeated once if the child does not vomit in 15 to 20 minutes. The vomitus should be inspected for remnants of pills or toxic substances, and the appearance and odor should be documented. When ipecac is not available, 30 mL of mild dishwashing soap (not dishwasher detergent) can be used, although it is less effective.

Complications are very rare but include aspiration, protracted vomiting, rarely cardiac toxicity with long-term abuse, pneumothorax, gastric rupture, diaphragmatic hernia, intracranial hemorrhage, and Mallory-Weiss tears. Gastric Lavage

Gastric lavage should be considered only when life-threatening amounts of substances were involved, when the benefits outweigh the risks, when it can be performed within 1 hour of the ingestion, and when no contraindications exist. The contraindications are similar to those for ipecac-induced emesis. However, gastric lavage can be accomplished after the insertion of an endotracheal tube in cases of CNS depression or controlled convulsions. The patient should be placed with the head lower than the hips in a left-lateral decubitus position. The location of the tube should be confirmed by radiography, if necessary, and suctioning equipment should be available. Contraindications to gastric lavage include the following: •

Ingestion of caustic substances (risk of esophageal perforation)

•

Uncontrolled convulsions, because of the danger of aspiration and injury during the procedure

•

Ingestion of low-viscosity petroleum distillate products

•

CNS depression or absent protective airway reflexes, without endotracheal protection

•

Significant cardiac dysrhythmias

•

Significant emesis or hematemesis prior to presentation

•

Delay in presentation (more than 1 hour postingestion)

Size of Tube

The best results with gastric lavage are obtained with the largest possible orogastric tube that can be reasonably passed (nasogastric tubes are not large enough to remove solid material). In adults, a large-bore orogastric Lavacuator hose or a No. 42 French Ewald tube should be used; in young children, orogastric tubes are generally too small to remove solid material and gastric lavage is not recommended. The amount of fluid used varies with the patient's age and size. In general, aliquots of 50 to 100 mL per lavage are used in adults. Larger amounts of fluid may force the toxin past the pylorus. Lavage fluid is 0.9% saline. Complications are rare and may include respiratory depression, aspiration pneumonitis, cardiac dysrhythmias as a result of increased vagal tone, esophageal-gastric tears and perforation, laryngospasm, and mediastinitis. Activated Charcoal

Oral activated charcoal adsorbs the toxin onto its surface before absorption. According to recent guidelines set forth by the American Academy of Clinical Toxicology, activated charcoal should not be used routinely. Its use is indicated only if a toxic amount of substance has been ingested and is optimally effective within 1 hour of the ingestion. Because of the slow absorption of large quantities of toxin, activated charcoal may be beneficial after 1

hour postingestion. Activated charcoal does not effectively adsorb small molecules or molecules lacking carbon ( Table 3 ). Activated charcoal adsorption may be diminished by milk, cocoa powder, and ice cream.

TABLE 3 -- Substances Poorly Adsorbed by Activated Charcoal C Caustics and corrosives H Heavy metals (arsenic, iron, lead, mercury) A Alcohols (ethanol, methanol, isopropanol) and glycols (ethylene glycols) R Rapid onset of absorption (cyanide and strychnine) C Chlorine and iodine O Others insoluble in water (substances in tablet form) A Aliphatic hydrocarbons (petroleum distillates) L Laxatives (sodium, magnesium, potassium, and lithium)

There are a few relative contraindications to the use of activated charcoal: 1.

Ingestion of caustics and corrosives, which may produce vomiting or cling to the mucosa and falsely appear as a burn on endoscopy.

2.

Comatose patient, in whom the airway must be secured prior to activated charcoal administration.

3.

Patient without presence of bowel sounds.

Note: Activated charcoal was shown not to interfere with effectiveness of N-acetylcysteine in cases of acetaminophen overdose, so it is no longer contraindicated as was thought in the past. The usual initial adult dose is 60 to 100 g and the dose for children is 15 to 30 g. It is administered orally as a slurry mixed with water or by nasogastric or orogastric tube. Caution: Be sure the tube is in the stomach. Cathartics are not necessary. Although repeated dosing with activated charcoal may decrease the half-life and increases the clearance of phenobarbital, dapsone, quinidine, theophylline, and carbamazepine (Tegretol), recent guidelines indicate there is insufficient evidence to support the use of multiple-dose activated charcoal unless a life-threatening amount of one of the substances mentioned is involved. At present there are no controlled studies that demonstrate that multiple-dose activated charcoal or cathartics alter the clinical course of an intoxication. The dose varies from 0.25 to 0.50 g/kg every 1 to 4 hours, and continuous nasogastric tube infusion of 0.25 to 0.5 g/kg/h has been used to decrease vomiting. Gastrointestinal dialysis is the diffusion of the toxin from the higher concentration in the serum of the mesenteric vessels to the lower levels in the gastrointestinal tract mucosal cell and subsequently into the gastrointestinal lumen, where the concentration has been lowered by intraluminal adsorption of activated charcoal.

Complications of treatment with activated charcoal include vomiting in 50% of cases, desorption (especially with weak acids in intestine), and aspiration (at least a dozen cases of aspiration have been reported). There are many cases of unreported pulmonary aspirations and “charcoal lungs,” intestinal obstruction or pseudoobstruction (three case reports with multiple dosing, none with a single dose), empyema following esophageal perforation, and hypermagnesemia and hypernatremia, which have been associated with repeated concurrent doses of activated charcoal and saline cathartics. Catharsis was used to hasten the elimination of any remaining toxin in the gastrointestinal tract. There are no studies to demonstrate the effectiveness of cathartics, and they are no longer recommended as a form of gastrointestinal decontamination. Whole-Bowel Irrigation

With whole bowel irrigation, solutions of polyethylene glycol (PEG) with balanced electrolytes are used to cleanse the bowel without causing shifts in fluids and electrolytes. The procedure is not approved by the U.S. Food and Drug Administration for this purpose. Indications

The procedure has been studied and used successfully in cases of iron overdose when abdominal radiographs reveal incomplete emptying of excess iron. There are additional indications for other types of ingestions, such as with body-packing of illicit drugs (e.g., cocaine, heroin). The procedure is to administer the solution (GoLYTELY or Colyte), orally or by nasogastric tube, in a dose of 0.5 L per hour in children younger than 5 years of age and 2 L per hour in adolescents and adults for 5 hours. The end point is reached when the rectal effluent is clear or radiopaque materials can no longer be seen in the gastrointestinal tract on abdominal radiographs. Contraindications

These measures should not be used if there is extensive hematemesis, ileus, or signs of bowel obstruction, perforation, or peritonitis. Animal experiments in which PEG was added to activated charcoal indicated that activated charcoal-salicylates and activated charcoal-theophylline combinations resulted in decreased adsorption and desorption of salicylate and theophylline and no therapeutic benefit over activated charcoal alone. Polyethylene solutions are bound by activated charcoal in vitro, decreasing the efficacy of activated charcoal. Dilutional treatment is indicated for the immediate management of caustic and corrosive poisonings but is otherwise not useful. The administration of diluting fluid above 30 mL in children and 250 mL in adults may produce vomiting, reexposing the vital tissues to the effects of local damage and possible aspiration. Neutralization is not proven to be either safe or effective. Endoscopy and surgery have been required in the case of body-packer obstruction, intestinal ischemia produced by cocaine ingestion, and iron local caustic action. Differential Diagnosis of Poisons on the Basis of Central Nervous System Manifestations

Neurologic parameters help to classify and assess the need for supportive treatment as well as provide diagnostic clues to the etiology. Table 4 lists the effects of CNS depressants, CNS stimulants, hallucinogens, and autonomic nervous system anticholinergics and cholinergics.

TABLE 4 -- Agents with Central Nervous System (CNS) Effects Agents

General Manifestations

CNS Depressants Alcohols and glycols (S-H)

Bradycardia

Anticonvulsants (S-H)

Bradypnea

Antidysrhythmics (S-H)

Shallow respirations

Antihypertensives (S-H)

Hypotension

Barbiturates (S-H)

Hypothermia

Benzodiazepines (S-H)

Flaccid coma

Butyrophenones (Syly)

Miosis

ß-Adrenergic blockers (Syly)

Hypoactive bowel sounds

Calcium channel blockers (Syly) Digitalis (Syly) Opioids Lithium (mixed) Muscle relaxants Phenothiazines (Syly) Nonbarbiturate/benzodiazepine glutethimide, methaqualone, methyprylon, sedativehypnotics (chloral hydrate, ethchlorvynol, bromide) Tricyclic antidepressants (late Syly) CNS Stimulants Amphetamines (Sy)

Tachycardia

Anticholinergics[*]

Tachypnea and dysrhythmias

Cocaine (Sy)

Hypertension

Camphor (mixed)

Convulsions

Ergot alkaloids (Sy)

Toxic psychosis

Isoniazid (mixed)

Mydriasis (reactive)

Lithium (mixed)

Agitation and restlessness

Lysergic acid diethylamide (H)

Moist skin

Agents


Hallucinogens (H)

Tremors

Mescaline and synthetic analogs Metals (arsenic, lead, mercury) Methylphenidate (Ritalin) (Sy) Monoamine oxidase inhibitors (Sy) Pemoline (Cylert) (Sy) Phencyclidine (H)[†] Salicylates (mixed) Strychnine (mixed) Sympathomimetics (Sy) (phenylpropanolamine, theophylline, caffeine, thyroid) Withdrawal from ethanol, ß-adrenergic blockers, clonidine, opioids, sedative–hypnotics (W) Hallucinogens Amphetamines[‡]

Tachycardia and dysrhythmias

Anticholinergics

Tachypnea

Cardiac glycosides

Hypertension

Cocaine

Hallucinations, usually visual

Ethanol withdrawal

Disorientation

Hydrocarbon inhalation (abuse)

Panic reaction

Mescaline (peyote)

Toxic psychosis

Mushrooms (psilocybin)

Moist skin

Phencyclidine

Mydriasis (reactive) Hyperthermia Flashbacks

Anticholinergics Antihistamines

Tachycardia, dysrhythmias (rare)

Antispasmodic gastrointestinal preparations

Tachypnea

Antiparkinsonian preparations

Hypertension (mild)

Atropine

Hyperthermia

Cyclobenzaprine (Flexeril)

Hallucinations (“mad as a hatter”)

Agents


Mydriatic ophthalmologic agents

Mydriasis (unreactive)

Over-the-counter sleep agents

(“blind as a bat”)

Plants (Datura spp)/mushrooms

Flushed skin (“red as a beet”) Dry skin and mouth (“dry as a bone”)

Phenothiazines (early)

Hypoactive bowel sounds

Scopolamine

Urinary retention

Tricyclic/cyclic antidepressants (early)

Lilliputian hallucinations (“little people”)

Cholinergics Bethanechol (Urecholine)

Bradycardia (muscarinic)

Carbamate insecticides (Carbaryl)

Tachycardia (nicotinic effect)

Edrophonium

Miosis (muscarinic)

Organophosphate insecticides (Malathion, parathion)

Diarrhea (muscarinic)

Parasympathetic agents (physostigmine, pyridostigmine)

Hypertension (variable)

Toxic mushrooms (Clitocybe spp.)

Hyperactive bowel sounds Excess urination (muscarinic) Excess salivation (muscarinic) Lacrimation (muscarinic) Bronchospasm (muscarinic) Muscle fasciculations (nicotinic) Paralysis (nicotinic)

Abbreviations: H = hallucinogen; S-H = sedative–hypnotic; Sy = sympathomimetic; Syly = Sympatholytic; W = withdrawal.

* Anticholinergics produce dry skin and mucosa and decreased bowel sounds. † Phencyclidine may produce miosis. ‡ The amphetamine hybrids are methylene dioxymethamphetamine (MDMA, ecstasy,”ADAM”) and methylene dioxyamphetamine (MDA, “Eve”), which are associated with deaths.

Central nervous system depressants are cholinergics, opioids, sedative-hypnotics, and sympatholytic agents. The hallmarks are lethargy, sedation, stupor, and coma. In exception to the manifestations listed in Table 4 , (a) barbiturates may produce an initial tachycardia; (b) convulsions are produced by codeine, propoxyphene (Darvon), meperidine (Demerol), glutethimide, phenothiazines, methaqualone, and tricyclic and cyclic antidepressants; (c) benzodiazepines rarely produce coma that will interfere with cardiorespiratory functions; and (d) pulmonary edema is common with opioids and sedative-hypnotics. The CNS stimulants are anticholinergic, hallucinogenic, sympathomimetic, and withdrawal agents. The hallmarks of CNS stimulants are convulsions and hyperactivity. There is considerable overlapping of effects among the various hallucinogens, but the major hallmark manifestation is hallucinations. Guidelines for In-hospital Disposition Classification of patients as high risk depends on clinical judgment. Any patient who needs cardiorespiratory support or has a persistently altered mental status for 3 hours or more should be considered for intensive care. Guidelines for admitting patients older than 14 years of age to an intensive care unit, after 2 to 3 hours in the emergency department, include the following: 1.

Need for intubation

2.

Seizures

3.

Unresponsiveness to verbal stimuli

4.

Arterial carbon dioxide pressure greater than 45 mm Hg

5.

Cardiac conduction or rhythm disturbances (any rhythm except sinus arrhythmia)

6.

Close monitoring of vital signs during antidotal therapy or elimination procedures

7.

The need for continuous monitoring

8.

QRS interval greater than 0.10 second, in cases of tricyclic antidepressant poisoning

9.

Systolic blood pressure less than 80 mm Hg

10. Hypoxia, hypercarbia, acid–base imbalance, or metabolic abnormalities 11. Extremes of temperature 12. Progressive deterioration or significant underlying medical disorders Use of Antidotes Antidotes are available for only a relatively small number of poisons. An antidote is not a substitute for good supportive care. Table 5 summarizes the commonly used antidotes, their indications, and their methods of administration. The Regional Poison Control Center can give further information on these antidotes.

TABLE 5 -- Initial Doses of Antidotes for Common Poisonings Antidote Use Dose N-Acetyl Cysteine (NAC, Mucomyst): Stock level to treat 70 kg adult for 24 h: 25 vials, 20%, 30 mL Atropine: Stock level to treat 70 kg adult for 24 h: 1 g (1 mg/mL in 1, 10 mL)

Acetaminophen, carbon tetrachloride (experimental)

140/mg/kg loading, followed by 70 mg/kg every 4 h for 17 doses.

Organophosphate and carbamate pesticides: bradydysrhythmics, ßadrenergics, calcium channel blockers/nerve agents

Child: 0.02-0.05 mg/kg repeated q5-10 min to max of 2 mg as necessary until cessation of secretions Adult: 1-2 mg q5-10 min as necessary. Dilute in 1-2 mL of 0.9% saline for ET instillation. IV infusion dose: Place 8 mg of atropine in 100 mL D5W or saline. Conc. = 0.08 mg/mL; dose range = 0.02-0.08 mg/kg/h or 0.251 mL/kg/h. Severe poisoning may require supplemental doses of IV atropine intermittently in doses of 1-5 mg until drying of secretions

Route PO

Adverse Reactions/Comments Nausea, vomiting. Dilute to 5% with sweet juice or flat cola.

IV/ET

Tachycardia, dry mouth, blurred vision, and urinary retention. Ensure adequate ventilation before administration.

Antidote

Calcium Chloride (10%): Stock level to treat

Use

Dose secretions occurs.

Hypocalcemia, fluoride, calcium channel blockers, ß-blockers, oxalates, ethylene glycol, hypermagnesemia

0.1-0.2 mL/kg (10-20 IV mg/kg) slow push every 10 min up to max 10 mL (1 g). Since calcium response lasts 15 minutes, some may require continuous infusion 0.2 mL/kg/h up to maximum of 10 mL/h while monitoring for dysrhythmias and hypotension.

70 kg adult for 24 h: 10 vials 1 g (1.35 mEq/mL)

Route

Hypocalcemia, fluoride, calcium channel blockers, hydrofluoric acid; black widow envenomation

0.3-0.4 mL/kg (30-40 mg/kg) slow push; repeat as needed up to max dose 10-20 mL (1-2 g).

Infiltration of Calcium Gluconate

Hydrofluoric acid skin exposure

Dose: Infiltrate each Infiltrate square cm of affected dermis/subcutaneous tissue with about 0.5 mL of 10% calcium gluconate using a 30gauge needle. Repeat as needed to control pain.

Intra-arterial Calcium Gluconate


Infuse 20 mL of 10% calcium gluconate (not chloride) diluted in 250 mL D5W via the radial or brachial artery proximal to the injury over 3-4 hours.

Calcium Gluconate (10%): Stock level to treat

IV

Adverse Reactions/Comments

Administer slowly with BP and ECG monitoring and have magnesium available to reverse calcium effects. Tissue irritation, hypotension, dysrhythmias from rapid injection. Contraindications: digitalis glycoside intoxication. Same comments as calcium chloride.

70 kg adult for 24 h: 20 vials 1 g (0.45 mEq/mL)

Alternatively, dilute 10 mL of 10% calcium gluconate with 40-50 mL of D5W.

Antidote Calcium Gluconate Gel:

Use

Dose


2.5 g USP powder Dermal added to 100 mL water-soluble lubricating jelly, e.g., K-Y Jelly or Lubifax (or 3.5 mg into 150 mL). Some use 6 g of calcium carbonate in 100 g of lubricant. Place injured hand in surgical glove filled with gel. Apply q4h. If pain persists, calcium gluconate injection may be needed (above).

Stock level: 3.5 g

Cyanide Antidote Kit: Stock level to treat 70 kg adult for 24 h: 2 Lilly Cyanide Antidote kits

Cyanide Hydrogen sulfide (nitrites are given only) Do not use sodium thiosulfate for hydrogen sulfide Individual portions of the kit can be used in certain circumstances (consult PCC)

Amyl nitrite: 1 crushable ampule for 30 secs of every min. Use new amp q3 min.

Route

Adverse Reactions/Comments Powder is available from Spectrum Pharmaceutical Co. in California: 800772-8786. Commercial preparation of Ca gluconate gel is available from Pharmascience in Montreal, Quebec: 514340-1114.

Inhalation If methemoglobinemia occurs, do not use methylene blue to correct this because it releases cyanide.

May omit step if venous access is established.

Cyanide

Sodium nitrite: Child: IV 0.33 mL/kg of 3% Hydrogen sulfide (nitrites solution if hemoglobin are given only) level is not known, otherwise based on Do not use sodium tables with product. thiosulfate for hydrogen Adult: up to 300 mg sulfide (10 mL). Dilute nitrite in 100 mL 0.9% Individual portions of the saline, administer kit can be used in certain slowly at 5 mL/min. circumstances (consult Slow infusion if fall in PCC) BP.

If methemoglobinemia occurs, do not use methylene blue to correct this because it releases cyanide.

Do not use sodium thiosulfate for hydrogen

Nausea, dizziness, headache.

Sodium thiosulfate: Child: 1.6 mL/kg of

IV

Antidote

Use thiosulfate for hydrogen sulfide

Dose Route Child: 1.6 mL/kg of 25% solution, may be repeated every 30-60 Individual portions of the min to a maximum of Kit can be used in certain 12.5 g or 50 mL in circumstances (consult adult. Administer over PCC) 20 min.

Dantrolene Sodium (Dantrium):

Malignant hyperthermia

Stock level to treat 70 kg adult for 24 h: 700 mg, 35 vials (20 mg/vial)

Deferoxamine (Desferal): Stock level to treat 70 kg adult for 24 h: 17 vials (500 mg/amp).

Iron

2–3 mg/kg IV rapidly. IV/PO Repeat loading dose every 10 minutes, if necessary up to a maximum total dose of 10 mg/kg. When temperature and heart rate decrease, slow the infusion 1-2 mg/kg every 6 hours for 2428 h until all evidence of malignant hyperthermia syndrome has subsided. Follow with oral doses 1-2 mg/kg four times a day for 24 h as necessary.

Adverse Reactions/Comments headache. Tachycardia, muscle rigidity, and bronchospasm (rapid administration). Hepatotoxicity occurs with cumulative dose of 10 mg/kg. Thrombophlebitis (best given in central line). Available as 20 mg lyophilized dantrolene powder for reconstruction, which contains 3 g mannitol and sodium hydroxide in 70-mL vial. Mix with 60 mL sterile distilled water without a bacteriostatic agent and protect from light. Use within 6 hours after reconstituting.

IV infusion of 15 Preferred Hypotension (minimized mg/kg/h (3 mL/kg/h: IV: avoid by avoiding rapid infusion 500 mg in 100 mL D5 therapy rates) DFO challenge test W) max 6 g/d Rates 50 mg/kg is unreliable if of >45 µ g/kg/h >24 h negative. if cone >1000 µ g/dL.

Antidote

Use

Diazepam (Valium): Stock level to treat 70 kg adult for 24 h: 200 mg, 5 mg/mL; 2,10 mL

Dose Any intoxication that provokes seizures when specific therapy is not available, e.g., amphetamines, PCP, barbiturate and alcohol withdrawal. Chloroquine poisoning.

Digoxin-Specific Fab Antibodies (Digibind): Stock level to treat 70 kg adult for 24 h: 20 vials.

Digoxin, digitoxin, oleander tea with the following: (1) Imminent cardiac arrest or shock, (2) hyperkalemia >5.0 mEq/L. (3) serum digoxin >5 ng/mL (child) at 8–12 h post ingestion in adults, (4) digitalis delirium, (5) ingestion over 10 mg in adults or 4 mg in child, (6) bradycardia or second- or thirddegree heart block unresponsive to atropine, (7) life threatening digitoxin or oleander posioning.

Route

Adult, 5-10 mg IV (max 20 mg) at a rate of 5 mg/min until seizure is controlled. May be repeated 2 or 3 times.

IV

Child, 0.1-0.3 mg/kg up to 10 mg IV slowly over 2 min. IV (1) If amount ingested is known total dose × bioavailability (0.8) = body burden. The body burden + 0.6 (0.5 mg of digoxin is bound by 1 vial of 38 mg of FAB) = # vials needed. (2) If amount is unknown but the steady state serum concentration is known in ng/mL: Digoxin: ng/mL: (5.6 L/kg Vd) × (wt kg) = µ g body burden. Body burden + 100 = mg body burden/0.5 = # vials needed.

Adverse Reactions/Comments Confusion, somnolence, coma, hypotension. Intramuscular absorption is erratic Establish airway and administer 100% oxygen and glucose.

Allergic reactions (rare), return of condition being treated with digitalis glycoside. Administer by infusion over 30 min through a 0.22-µ filter. If cardiac arrest imminent, may administer by bolus. Consult PCC for more details.

Antidote

Use

Dose

Route

Adverse Reactions/Comments

Deep IM

Local infection site pain and sterile abscess, nausea, vomiting, fever, salivation, hypertension, and nephrotoxicity (alkalinize urine).

Digitoxin body burden = ng/mL × (0.56 L/kg Vd) × (wt kg) -

Body burden + 1000 = mg body burden/0.5 = # vials needed. (3) If the amount is not known, it is administered in lifethreatening situations as 10 vials (400 mg) IV in saline over 30 min in adults. If cardiac arrest is imminent, administer 20 vials (adult) as a bolus.

Dimercaprol (BAL in Peanut Oil): Stock level to treat 70 kg adult for 24 h: 1200 mg (4 amps—100 mg/mL 10% in oil in 3 mL amp)

Chelating agent for arsenic, mercury, and lead.

3-5 mg/kg q4th usually for 5-10 d

Antidote 2,3 Dimercaptosuccinic Acid (DMSA Succimer): 100 mg/capsule: 20 capsules

Diphenhydramine (Benadryl): Antiparkinsonian action. Stock level to treat a 70 kg adult for 24 h: 5 vials (10 mg/mL, 10 mL each)

Use

Dose

Used as a chelating agent for lead, especially blood lead levels >45 µg/dL. May also be used for symptomatic mercury exposure

10 mg/kg 3 × daily for PO 5 days followed by 10 mg/kg 2 × daily for 14 days.

Used to treat extrapyramidal symptoms and dystonia induced by phenothiazines, phencyclidine, and related drugs.

Route

IV Children: 1-2 mg/kg IV slowly over 5 minutes up to maximum 50 mg followed by 5 mg/kg/24 h orally divided every 6 hours up to 300 mg/24h

Adverse Reactions/Comments Precautions: monitor AST/ALT; use with caution in G6PD-deficient patients. Avoid concurrent iron therapy. Relatively safe antidote, rarely severe, uncommon minor skin rashes may occur. Fatal dose: 20-40 mg/kg. Dry mouth, drowsiness.

Adults: 50 mg IV followed by 50 mg orally four times daily for 57 days Note: Symptoms abate within 2-5 min after IV. Ethanol (Ethyl Alcohol): Stock level to treat 70 kg adult for 24 h: 3 bottles 10% (1 L each)

Methanol, ethylene glycol 10 mL/kg loading IV dose concurrently with 1.4 mL/kg (average) infusion of 10% ethanol (consult PCC for more details)

Nausea, vomiting, sedation. Use 0.22 m filter if preparing from bulk 100% ethanol.

Antidote Flumazenil (Romazicon): Stock level to treat 70 kg adult for 24 h: 4 vials (0.1 mg/mL, 10 mL)

Folic Acid (Folvite): Stock level to treat 70 kg adult for 24 h: 4 100mg vials

Use

Dose

Benzodiazepines (may also be beneficial in the treatment of hepatic encephalopathy)

Administer 0.2 mg (2 IV mL) IV over 30 sec (pediatric dose not established, 0.01 mg/kg), then wait 3 min for a response, then if desired consciousness is not achieved, administer 0.3 mg (3 mL) over 30 sec, then wait 3 min for response, then if desired consciousness is not achieved, administer 0.5 mg (5 mL) over 30 sec at 60-sec intervals up to a maximum cumulative dose of 3 mg (30 mL) (1 mg in children). Because effects last only 1-5 hours, if patient responds monitor carefully over next 6 hours for resedation. If multiple repeated doses, consider a continuous infusion of 0.2-1 mg/h.

Methanol/ethylene glycol 1 mg/kg up to 50 mg (investigational) q4h for 6 doses.

Route

IV

Adverse Reactions/Comments Nausea, vomiting, facial flushing, agitation, headache, dizziness, seizures, and death. It is not recommended to improve ventilation. Its role in CNS depression needs to be clarified. It should not be used routinely in comatose patients. It is contraindicated in cyclic antidepressant intoxications, stimulant overdose, long-term benzodiazepine use (may precipitate lifethreatening withdrawal), if benzodiazepines are used to control seizures, in head trauma.

Uncommon

Antidote

Use

Fomepizole (4-MP, Antizol):

Dose Ethylene glycol Methanol

Stock level to treat 70 kg adult: 4 1.5-mL vials (1 g/mL)

Glucagon: Stock level to treat 70 kg adult for 24 h: (10 vials, 10 units)

ß-Blocker, calcium channel blocker

Loading dose: 15 mg/kg (0.015 mL/kg) IV followed by maintenance dose of 10 mg/kg (0.01 mL/kg) every 12h for 4 doses, then 15 mg/kg every 12h until ethylene glycol levels are 7.55) and urine pH 7.5-8.0. Alkalinization recommended if salicylate conc. >40 mg/dL in acute poisoning and at lower levels if symptomatic in chronic intoxication. 2 mEq/kg will raise blood pH 0.1 unit

Ethylene glycol: 100 mg IV daily. 1-2 mEq/kg undiluted as a bolus. If no effect on cardiotoxicity, repeat twice a few minutes apart Adult with clear physical signs and laboratory findings of acute moderate or severe salicylism: Bolus 1-2 mEq/kg followed by infusion of 100150 mEq NaHCO3 added to 1 L of 5% dextrose at rate of 200-300 mL/h Child: Bolus same as adult followed by 1-2 mEq/kg in infusion of 20 mL/kg/h 5% dextrose in 0.45% saline. Add potassium when patient voids. Rate and amount of the initial infusion, if patient is volume depleted: 1 h to achieve urine output of 2

Route IV

Adverse Reactions/Comments Monitor sodium, potassium, and blood pH because fatal alkalemia and hyponatremia have been reported. Monitor both urine and blood pH. Do not use the urine pH alone to assess the need for alkalinization because of the paradoxical aciduria that may occur. Adjust the urine pH to 7.5-8 by NaHCO3 infusion. After urine output established, add potassium 40 mEq/L.

Antidote

Use

Dose output of 2 mL/kg/h and urine pH 7-8. In mild cases without acidosis and urine pH >6 administer 5% dextrose in 0.9% saline with 50 mEq/L or 1 mEq/kg NaHCO3 as maintenance to replace ongoing renal losses. If acidemia is present and pH HD

Phenobarbital

100 µg/dL

50

0.9

HP > HD

Salicylates

80-100 mg/dL

90

0.2

HD > HP

0

0.5

Theophylline Chronic

40-60 µg/mL

HP

Acute

80-100 µg/mL

HP

Trichlorethanol

250 µg/mL

70

0.6

HP

Data from Winchester JF: Active methods for detoxification. In Haddad LM, Winchester JF (eds). Clinical Management of Poisoning and Drug Overdose, 2nd ed. Philadelphia, WB Saunders, 1990; Balsam L, Cortitsidis GN, Fienfeld DA: Role of hemodialysis and hemoperfusion in the treatment of intoxications. Contemp Manage Crit Care 1:61, 1991. Abbreviations: HD = hemodialysis; HP = hemoperfusion; HP > HD hemoperfusion preferred over hemodialysis. Note: Cartridges for charcoal hemoperfusion are not readily available anymore in most locations, so hemodialysis may be substituted in these situations. In mixed or chronic drug overdoses, extracorporeal measures may be considered at lower drug concentrations.

The contraindications to hemodialysis include the following: (a) substances are not dialyzable; (b) effective antidotes are available; (c) patient is hemodynamically unstable (e.g., shock); and (d) presence of coagulopathy because heparinization is required.

Hemodialysis also has a role in correcting disturbances that are not amenable to appropriate medical management. These are easily remembered by the “vowel” mnemonic: A—

refractory acid–base disturbances

E—

refractory electrolyte disturbances

I—

intoxication with dialyzable substances (e.g., ethanol, ethylene glycol, isopropyl alcohol, methanol, lithium, and salicylates)

O—

overhydration

U—

uremia

Complications of dialysis include hemorrhage, thrombosis, air embolism, hypotension, infections, electrolyte imbalance, thrombocytopenia, and removal of therapeutic medications. HEMOPERFUSION Hemoperfusion is the parenteral form of oral activated charcoal. Heparinization is necessary. The patient's blood is routed extracorporeally through an outflow arterial catheter through a filter-adsorbing cartridge (charcoal or resin) and returned through a venous catheter. Cartridges must be changed every 4 hours. The blood glucose, electrolytes, calcium, and albumin levels; complete blood cell count; platelets; and serum and urine osmolarity must be carefully monitored. This procedure has extended extracorporeal removal to a large range of substances that were formerly either poorly dialyzable or nondialyzable. It is not limited by molecular weight, water solubility, or protein binding, but it is limited by a volume distribution greater than 400 L, plasma concentration, and rate of flow through the filter. Activated charcoal cartridges are the primary type of hemoperfusion that is currently available in the United States. The patient-related criteria for hemoperfusion are (a) anticipated prolonged coma and the likelihood of complications; (b) laboratory confirmation of lethal blood concentrations; (c) hepatic impairment when an agent is metabolized by the liver; and (d) clinical deterioration despite optimally supportive medical management. The contraindications are similar to those for hemodialysis. Limited data are available as to which toxins are best treated with hemoperfusion. Hemoperfusion has proved useful in treating glutethimide intoxication, phenobarbital overdose, and carbamazepine, phenytoin, and theophylline intoxication. Complications include hemorrhage, thrombocytopenia, hypotension, infection, leukopenia, depressed phagocytic activity of granulocytes, decreased immunoglobulin levels, hypoglycemia, hypothermia, hypocalcemia, pulmonary edema, and air and charcoal embolism. HEMOFILTRATION Continuous arteriovenous or venovenous hemodiafiltration (CAVHD or CVVHD, respectively) has been suggested as an alternative to conventional hemodialysis when the need for rapid removal of the drug is less urgent. These

procedures, like peritoneal dialysis, are minimally invasive, have no significant impact on hemodynamics, and can be carried out continuously for many hours. Their role in the management of acute poisoning remains uncertain, however. PLASMAPHERESIS Plasmapheresis consists of removal of a volume of blood. All the extracted components are returned to the blood except the plasma, which is replaced with a colloid protein solution. There are limited clinical data on guidelines and efficacy in toxicology. Centrifugal and membrane separators of cellular elements are used. It can be as effective as hemodialysis or hemoperfusion for removing toxins that have high protein binding, and it may be useful for toxins not filtered by hemodialysis and hemoperfusion. Plasmapheresis has been anecdotally used in treating intoxications with the following agents: paraquat (removed 10%), propranolol (removed 30%), quinine (removed 10%), l-thyroxine (removed 30%), and salicylate (removed 10%). It has been shown to remove less than 10% of digoxin, phenobarbital, prednisolone, and tobramycin. Complications include infection; allergic reactions including anaphylaxis; hemorrhagic disorders; thrombocytopenia; embolus and thrombus; hypervolemia and hypovolemia; dysrhythmias; syncope; tetany; paresthesia; pneumothorax; acute respiratory distress syndrome; and seizures. Supportive Care, Observation, and Therapy for Complications ALTERED MENTAL STATUS If airway protective reflexes are absent, endotracheal intubation is indicated for a comatose patient or a patient with altered mental status. If respirations are ineffective, ventilation should be instituted, and if hypoxemia persists, supplemental oxygen is indicated. If a cyanotic patient fails to respond to oxygen, the practitioner should consider methemoglobinemia. HYPOGLYCEMIA Hypoglycemia accompanies many poisonings, including with ethanol (especially in children), clonidine (Catapres), insulin, organophosphates, salicylates, sulfonylureas, and the unripe fruit or seed of a Jamaican plant called ackee. If hypoglycemia is present or suspected, glucose should be administered immediately as an intravenous bolus. Doses are as follows: in a neonate, 10% glucose (5 mL/kg); in a child, 25% glucose 0.25 g/kg (2 mL/kg); and in an adult, 50% glucose 0.5 g/kg (1 mL/kg). A bedside capillary test for blood glucose is performed to detect hypoglycemia, and the sample is sent to the laboratory for confirmation. If the glucose reagent strip visually reads less than 150 mg/dL, one administers glucose. Venous blood should be used rather than capillary blood for the bedside test if the patient is in shock or is hypotensive. Large amounts of glucose given rapidly to nondiabetic patients may cause a transient reactive hypoglycemia and hyperkalemia and may accentuate damage in ischemic cerebrovascular and cardiac tissue. If focal neurologic signs are present, it may be prudent to withhold glucose, because hypoglycemia causes focal signs in less than 10% of cases. THIAMINE DEFICIENCY ENCEPHALOPATHY

Thiamine is administered to avoid precipitating thiamine deficiency encephalopathy (Wernicke-Korsakoff syndrome) in alcohol abusers and in malnourished patients. The overall incidence of thiamine deficiency in ethanol abusers is 12%. Thiamine 100 mg intravenously should be administered around the time of the glucose administration but not necessarily before the glucose. The clinician should be prepared to manage the anaphylaxis that sometimes is caused by thiamine, although it is extremely rare. OPIOID REACTIONS Naloxone (Narcan) reverses CNS and respiratory depression, miosis, bradycardia, and decreased gastrointestinal peristalsis caused by opioids acting through µ, , and d receptors. It also affects endogenous opioid peptides (endorphins and enkephalins), which accounts for the variable responses reported in patients with intoxications from ethanol, benzodiazepines, clonidine (Catapres), captopril (Capoten), and valproic acid (Depakote) and in patients with spinal cord injuries. There is a high sensitivity for predicting a response if pinpoint pupils and circumstantial evidence of opioid abuse (e.g., track marks) are present. In cases of suspected overdose, naloxone 0.1 mg/kg is administered intravenously initially in a child younger than 5 years of age. The dose can be repeated in 2 minutes, if necessary up to a total dose of 2 mg. In older children and adults, the dose is 2 mg every 2 minutes for five doses up to a total of 10 mg. Naloxone can also be administered into an endotracheal tube if intravenous access is unavailable. If there is no response after 10 mg, a pure opioid intoxication is unlikely. If opioid abuse is suspected, restraints should be in place before the administration of naloxone, and it is recommended that the initial dose be 0.1 to 0.2 mg to avoid withdrawal and violent behavior. The initial dose is then doubled every minute progressively to a total of 10 mg. Naloxone may unmask concomitant sympathomimetic intoxication as well as withdrawal. Larger doses of naloxone may be required for more poorly antagonized synthetic opioid drugs: buprenorphine (Buprenex), codeine, dextromethorphan, fentanyl and its derivatives, pentazocine (Talwin), propoxyphene (Darvon), diphenoxylate, nalbuphine (Nubain), and long-acting opioids such as methadone (Dolophine). Indications for a continuous infusion include a second dose for recurrent respiratory depression, exposure to poorly antagonized opioids, a large overdose, and decreased opioid metabolism, as with impaired liver function. A continuous infusion has been advocated because many opioids outlast the short half-life of naloxone (30 to 60 minutes). The hourly rate of naloxone infusion is equal to the effective dose required to produce a response (improvement in ventilation and arousal). An additional dose may be required in 15 to 30 minutes as a bolus. The infusions are titrated to avoid respiratory depression and opioid withdrawal manifestations. Tapering of infusions can be attempted after 12 hours and when the patient's condition has been stabilized. Although naloxone is safe and effective, there are rare reports of complications (less than 1%) of pulmonary edema, seizures, hypertension, cardiac arrest, and sudden death. Agents Whose Roles Are Not Clarified Nalmefene (Revex), a long-acting parenteral opioid antagonist that the Food and Drug Administration has approved, is undergoing investigation, but its role in the treatment of comatose patients and patients with opioid overdose is not clear. It is 16 times more potent than naloxone, and its duration of action is up to 8 hours (half-life 10.8 hours, versus naloxone 1 hour).

Flumazenil (Romazicon) is a pure competitive benzodiazepine antagonist. It has been demonstrated to be safe and effective for reversing benzodiazepine-induced sedation. It is not recommended to improve ventilation. Its role in cases of CNS depression needs to be clarified. It should not be used routinely in comatose patients and is not an essential ingredient of the coma therapeutic regimen. It is contraindicated in cases of co-ingestion of cyclic antidepressant intoxication, stimulant overdose, and long-term benzodiazepine use (may precipitate lifethreatening withdrawal) if benzodiazepines are used to control seizures. There is a concern about the potential for seizures and cardiac dysrhythmias that may occur in these settings. Laboratory and Radiographic Studies An electrocardiogram (ECG) should be obtained to identify dysrhythmias or conduction delays from cardiotoxic medications. If aspiration pneumonia (history of loss of consciousness, unarousable state, vomiting) or noncardiac pulmonary edema is suspected, a chest radiograph is needed. Electrolyte and glucose concentrations in the blood, the anion gap, acid–base balance, the arterial blood gas (ABG) profile (if patient has respiratory distress or altered mental status), and serum osmolality should be measured if a toxic alcohol ingestion is suspected. Table 7 lists appropriate testing on the basis of clinical toxicologic presentation. All laboratory specimens should be carefully labeled, including time and date. For potential legal cases, a “chain of custody” must be established. Assessment of the laboratory studies may provide a clue to the etiologic agent.

TABLE 7 -- Patient Condition/Systemic Toxin and Appropriate Tests Condition Tests Comatose

Toxicologic tests (acetaminophen, sedative-hypnotic, ethanol, opioids, benzodiazepine), glucose.

Respiratory toxicity

Spirometry, FEV1, arterial blood gases, chest radiograph, monitor O2 saturation

Cardiac toxicity

ECG 12-lead and monitoring, echocardiogram, serial cardiac enzymes (if evidence or suspicion of a myocardial infarction), hemodynamic monitoring

Hepatic toxicity

Enzymes (AST, ALT, GGT), ammonia, albumin, bilirubin, glucose, PT, PTT, amylase

Nephrotoxicity

BUN, creatinine, electrolytes (Na, F, Mg, Ca, PO4), serum and urine osmolarity, 24-hour urine for heavy metals if suspected, creatine kinase, serum and urine myoglobin, urinalysis and urinary sodium

Bleeding

Platelets, PT, PTT, bleeding time, fibrin split products, fibrinogen, type and match

Abbreviations: ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; BUN = blood urea nitrogen; ECG = electrocardiogram; FEV1 = forced expiratory volume at 1 second; GGT = -glutamyltransferase; PT = prothrombin time; PTT = partial thromboplastin time.

ELECTROLYTE, ACID-BASE, AND OSMOLALITY DISTURBANCES Electrolyte and acid–base disturbances should be evaluated and corrected. Metabolic acidosis (usually low or normal pH with a low or normal/high Paco2 and low HCO3) with an increased anion gap is seen with many agents

in cases of overdose. The anion gap is an estimate of those anions other than chloride and HCO3 necessary to counterbalance the positive charge of sodium. It serves as a clue to causes, compensations, and complications. The anion gap (AG) is calculated from the standard serum electrolytes by subtracting the total CO2 (which reflects the actual measured bicarbonate) and chloride from the sodium: (Na - [Cl + HCO3]) = AG. The potassium is usually not used in the calculation because it may be hemolyzed and is an intracellular cation. The lack of anion gap does not exclude a toxic etiology. The normal gap is usually 7 to 11 mEq/L by flame photometer. However, there has been a “lowering” of the normal anion gap to 7 ± 4 mEq/L by the newer techniques (e.g., ion selective electrodes orcolorimetric titration). Some studies have found anion gaps to be relatively insensitive for determining the presence of toxins. It is important to recognize anion gap toxins, such as salicylates, methanol, and ethylene glycol, because they have specific antidotes, and hemodialysis is effective in management of cases of overdose with these agents. Table 8 lists the reasons for increased anion gap, decreased anion gap, or no gap. The most common cause of a decreased anion gap is laboratory error. Lactic acidosis produces the largest anion gap and can result from any poisoning that results in hypoxia, hypoglycemia, or convulsions.

TABLE 8 -- Etiologies of Metabolic Acidosis Normal Anion Gap Hyperchloremic Increased Anion Gap Normochloremic Decreased Anion Gap Acidifying agents

Methanol

Laboratory error

Adrenal insufficiency

Uremia[*]

Intoxication—bromine, lithium

Anhydrase inhibitors

Diabetic ketoacidosis[*]

Protein abnormal

Fistula

Paraldehyde,[*] phenformin

Sodium low

Osteotomies

Isoniazid

Obstructive uropathies

Iron

Renal tubular acidosis

Lactic acidosis[†]

Diarrhea, uncomplicated[*]

Ethanol,[*] ethylene glycol[*]

Dilutional

Salicylates, starvation solvents

Sulfamylon * Indicates hyperosmolar situation. Studies have found that the anion gap may be relatively insensitive for determining the presence of toxins. † Lactic acidosis can be produced by intoxications of the following: carbon monoxide, cyanide, hydrogen sulfide, hypoxia, ibuprofen, iron, isoniazid, phenformin, salicylates, seizures, theophylline.

Table 9 lists other blood chemistry derangements that suggest certain intoxications.

TABLE 9 -- Blood Chemistry Derangements in Toxicology Derangement Toxin Acetonemia without acidosis

Acetone or isopropyl alcohol

Hypomagnesemia

Ethanol, digitalis

Hypocalcemia

Ethylene glycol, oxalate, fluoride

Hyperkalemia

ß-Blockers, acute digitalis, renal failure

Hypokalemia

Diuretics, salicylism, sympathomimetics, theophylline, corticosteroids, chronic digitalis

Hyperglycemia

Diazoxide, glucagon, iron, isoniazid, organophosphate insecticides, phenylurea insecticides, phenytoin (Dilantin), salicylates, sympathomimetic agents, thyroid, vasopressors

Hypoglycemia

ß-Blockers, ethanol, insulin, isoniazid, oral hypoglycemic agents, salicylates

Rhabdomyolysis

Amphetamines, ethanol, cocaine, or phencyclidine, elevated creatine phosphokinase

Serum osmolality is a measure of the number of molecules of solute per kilogram of solvent, or mOsm/kg water. The osmolarity is molecules of solute per liter of solution, or mOsm/L water at a specified temperature. Osmolarity is usually the calculated value and osmolality is usually a measured value. They are considered interchangeable where 1 L equals 1 kg. The normal serum osmolality is 280 to 290 mOsm/kg. The freezing point serum osmolarity measurement specimen and the serum electrolyte specimens for calculation should be drawn simultaneously. The serum osmolal gap is defined as the difference between the measured osmolality determined by the freezing point method and the calculated osmolarity. It is determined by the following formula:

(where BUN is blood urea nitrogen). This gap estimate is normally within 10 mOsm of the simultaneously measured serum osmolality. Ethanol, if present, may be included in the equation to eliminate its influence on the osmolal gap (the ethanol concentration divided by 4.6; Table 10 ).

TABLE 10 -- Conversion Factors for Alcohols and Glycols Alcohols/Glycols 1 mg/dL in Blood Raises Osmolality mOsm/L Molecular Weight Conversion Factor Ethanol

0.228

40

4.6

Methanol

0.327

32

3.2

Ethylene glycol

0.190

62

6.2

Isopropanol

0.176

60

6.0

Alcohols/Glycols 1 mg/dL in Blood Raises Osmolality mOsm/L Molecular Weight Conversion Factor Acetone

0.182

58

5.8

Propylene glycol

not available

72

7.2

Example: Methanol osmolality. Subtract the calculated osmolality from the measured serum osmolarity (freezing point method) = osmolar gap × 3.2 (one-tenth molecular weight) = estimated serum methanol concentration. Note: This equation is often not considered very reliable in predicting the actual measured blood concentration of these alcohols or glycols.

The osmolal gap is not valid in cases of shock and postmortem state. Metabolic disorders such as hyperglycemia, uremia, and dehydration increase the osmolarity but usually do not cause gaps greater than 10 mOsm/kg. A gap greater than 10 mOsm/mL suggests that unidentified osmolal-acting substances are present: acetone, ethanol, ethylene glycol, glycerin, isopropyl alcohol, isoniazid, ethanol, mannitol, methanol, and trichloroethane. Alcohols and glycols should be sought when the degree of obtundation exceeds that expected from the blood ethanol concentration or when other clinical conditions exist: visual loss (methanol), metabolic acidosis (methanol and ethylene glycol), or renal failure (ethylene glycol). A falsely elevated osmolar gap can be produced by other low molecular weight un-ionized substances (dextran, diuretics, sorbitol, ketones), hyperlipidemia, and unmeasured electrolytes (e.g., magnesium). Note: A normal osmolal gap may be reported in the presence of toxic alcohol or glycol poisoning, if the parent compound is already metabolized. This situation can occur when the osmolar gap is measured after a significant time has elapsed since the ingestion. In cases of alcohol and glycol intoxication, an early osmolar gap is a result of the relatively nontoxic parent drug and delayed metabolic acidosis, and an anion gap is a result of the more toxic metabolites.

RADIOGRAPHIC STUDIES Chest and neck radiographs are useful for suspected pathologic conditions such as aspiration pneumonia, pulmonary edema, and foreign bodies and to determine the location of the endotracheal tube. Abdominal radiographs can be used to detect radiopaque substances. The mnemonic for radiopaque substances seen on abdominal radiographs is CHIPES:

C—

chlorides and chloral hydrate

H—

heavy metals (arsenic, barium, iron, lead, mercury, zinc)

I—

iodides

P—

PlayDoh, Pepto-Bismol, phenothiazine (inconsistent)

E—

enteric-coated tablets

S—

sodium, potassium, and other elements in tablet form (bismuth, calcium, potassium) and solvents containing chlorides (e.g., carbon tetrachloride)

TOXICOLOGIC STUDIES Routine blood and urine screening is of little practical value in the initial care of the poisoned patient. Specific toxicologic analyses and quantitative levels of certain drugs may be extremely helpful. One should always ask oneself the following questions: (a) How will the result of the test alter the management? and (b) Can the result of the test be returned in time to have a positive effect on therapy? Owing to long turnaround time, lack of availability, factors contributing to unreliability, and the risk of serious morbidity without supportive clinical management, toxicology screening is estimated to affect management in less than 15% of cases of drug overdoses or poisonings. Toxicology screening may look specifically for only 40 to 50 drugs out of more than 10,000 possible drugs or toxins and more than several million chemicals. To detect many different drugs, toxic screens usually include methods with broad specificity, and sensitivity may be poor for some drugs, resulting in false-negative or false-positive findings. On the other hand, some drugs present in therapeutic amounts may be detected on the screen, even though they are causing no clinical symptoms. Because many agents are not sought or detected during a toxicologic screening, a negative result does not always rule out poisonings. The specificity of toxicologic tests is dependent on the method and the laboratory. The presence of other drugs, drug metabolites, disease states, or incorrect sampling may cause erroneous results. For the average toxicologic laboratory, false-negative results occur at a rate of 10% to 30% and false-positives at a rate of 0% to 10%. The positive screen predictive value is approximately 90%. A negative toxicology screen does not exclude a poisoning. The negative predictive value of toxicologic screening is approximately 70%. For example, the following benzodiazepines may not be detected by some routine immunoassay benzodiazepine screening tests: alprazolam (Xanax), clonazepam (Klonopin), temazepam (Restoril), and triazolam (Halcion). The “toxic urine screen” is generally a qualitative urine test for several common drugs, usually substances of abuse (cocaine and metabolites, opioids, amphetamines, benzodiazepines, barbiturates, and phencyclidine). Results of these tests are usually available within 2 to 6 hours. Because these tests may vary with each hospital and community, the physician should determine exactly which substances are included in the toxic urine screen of his or her laboratory. Tests for ethylene glycol, red blood cell cholinesterase, and serum cyanide are not readily available. For cases of ingestion of certain substances, quantitative blood levels should be obtained at specific times after the ingestion to avoid spurious low values in the distribution phase, which result from incomplete absorption. The detection time for drugs is influenced by many variables, such as type of substance, formulation, amount, time since ingestion, duration of exposure, and half-life. For many drugs, the detection time is measured in days after the exposure.

Common Poisons ACETAMINOPHEN (PARACETAMOL, N—ACETYL-PARAAMINOPHENOL) Toxic Mechanism

At therapeutic doses of acetaminophen, less than 5% is metabolized by P450-2E1 to a toxic reactive oxidizing metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). In a case of overdose, there is insufficient glutathione available to reduce the excess NAPQI into nontoxic conjugate, so it forms covalent bonds with hepatic intracellular proteins to produce centrilobular necrosis. Renal damage is caused by a similar mechanism. Toxic Dose

The therapeutic dose of acetaminophen is 10 to 15 mg/kg, with a maximum of five doses in 24 hours for a maximum total daily dose of 4 g. An acute single toxic dose is greater than 140 mg/kg, possibly greater than 200 mg/kg in a child younger than age 5 years. Factors affecting the P450 enzymes include enzyme inducers such as barbiturates and phenytoin (Dilantin), ingestion of isoniazid, and alcoholism. Factors that decrease glutathione stores (alcoholism, malnutrition, and HIV infection) contribute to the toxicity of acetaminophen. Alcoholics ingesting 3 to 4 g/d of acetaminophen for a few days can have depleted glutathione stores and require Nacetylcysteine therapy at 50% below hepatotoxic blood acetaminophen levels on the nomogram. Kinetics

Peak plasma concentration is usually reached 2 to 4 hours after an overdose. Volume distribution is 0.9 L/kg, and protein binding is less than 50% (albumin). Route of elimination is by hepatic metabolism to an inactive nontoxic glucuronide conjugate and inactive nontoxic sulfate metabolite by two saturable pathways; less than 5% is metabolized into reactive metabolite NAPQI. In patients younger than 6 years of age, metabolic elimination occurs to a greater degree by conjugation via the sulfate pathway. The half-life of acetaminophen is 1 to 3 hours. Manifestations

The four phases of the intoxication's clinical course may overlap, and the absence of a phase does not exclude toxicity.

•

Phase I occurs within 0.5 to 24 hours after ingestion and may consist of a few hours of malaise, diaphoresis, nausea, and vomiting or produce no symptoms. CNS depression or coma is not a feature.

•

Phase II occurs 24 to 48 hours after ingestion and is a period of diminished symptoms. The liver enzymes, serum aspartate aminotransferase (AST) (earliest), and serum alanine aminotransferase (ALT) may increase as early as 4 hours or as late as 36 hours after ingestion.

•

Phase III occurs at 48 to 96 hours, with peak liver function abnormalities at 72 to 96 hours. The degree of elevation of the hepatic enzymes generally correlates with outcome, but not always. Recovery starts at about 4 days unless hepatic failure develops. Less than 1% of patients with a history of overdose develop fulminant hepatotoxicity.

•

Phase IV occurs at 4 to 14 days, with hepatic enzyme abnormalities resolving. If extensive liver damage has occurred, sepsis and disseminated intravascular coagulation may ensue.

Transient renal failure may develop at 5 to 7 days with or without evidence of hepatic damage. Rare cases of myocarditis and pancreatitis have been reported. Death can occur at 7 to 14 days. Laboratory Investigations

The therapeutic reference range is 10 to 20 µg/mL. For toxic levels, see the nomogram presented in Figure 1 .

FIGURE 1 Nomogram for acetaminophen intoxication. N-acetylcysteine therapy is started if levels and time coordinates are above the lower line on the nomogram. Continue and complete therapy even if subsequent values fall below the toxic zone. The nomogram is useful only in cases of acute single ingestion. Levels in serum drawn before 4 hours may not represent peak levels. (From Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 55:871, 1975.)

Appropriate and reliable methods for analysis are radioimmunoassay, high-pressure liquid chromatography, and gas chromatography. Spectroscopic assays often give falsely elevated values: bilirubin, salicylate, salicylamide, diflunisal (Dolobid), phenols, and methyldopa (Aldomet) increase the acetaminophen level. Each 1 mg/dL increase in creatinine increases the acetaminophen plasma level 30 µg/mL.

If a toxic acetaminophen level is reached, liver profile (including AST, ALT, bilirubin, and prothrombin time), serum amylase, and blood glucose must be monitored. A complete blood cell count (CBC); platelet count; phosphate, electrolytes, and bicarbonate level measurements; ECG; and urinalysis are indicated. Management Gastrointestinal Decontamination

Although ipecac-induced emesis may be useful within 30 minutes of ingestion of the toxic substance, we do not advise it because it could result in vomiting of the activated charcoal. Gastric lavage is not necessary. Studies have indicated that activated charcoal is useful within 1 hour after ingestion. Activated charcoal does adsorb Nacetylcysteine (NAC) if given together, but this is not clinically important. However, if activated charcoal needs to be given along with NAC, separate the administration of activated charcoal from the administration of NAC by 1 to 2 hours to avoid vomiting. N-Acetylcysteine (Mucomyst)

NAC ( Table 11 ), a derivative of the amino acid cysteine, acts as a sulfhydryl donor for glutathione synthesis, as surrogate glutathione, and may increase the nontoxic sulfation pathway resulting in conjugation of NAPQI. Oral NAC should be administered within the first 8 hours after a toxic amount of acetaminophen has been ingested. NAC can be started while one awaits the results of the blood test for acetaminophen plasma concentration, but there is no advantage to giving it before 8 hours. If the acetaminophen concentration result after 4 hours following ingestion is above the upper line on the modified Rumack-Matthew nomogram (see Figure 1 ), one should continue with a maintenance course. Repeat blood specimens should be obtained 4 hours after the initial level is measured if it is greater than 20 mg/mL, which is below the therapy line, because of unexpected delays in the peak by food and co-ingestants. Intravenous NAC (see Table 11 ) is approved in the United States.

TABLE 11 -- Protocol for N-Acetylcysteine Administration Route Loading Dose Maintenance Dose Oral

140 mg/kg

70 mg/kg every 4 h

Intravenous 150 mg/kg over 15 min 50 mg/kg over 4 h followed by 100 mg/kg over 16h

Course FDA Approval 72 h

Yes

20 h

Yes

There have been a few cases of anaphylactoid reaction and death by the intravenous route. Variations in Therapy

In patients with chronic alcoholism, it is recommended that NAC treatment be administered at 50% below the upper toxic line on the nomogram. If emesis occurs within 1 hour after NAC administration, the dose should be repeated. To avoid emesis, the proper dilution from 20% to 5% NAC must be used, and it should be served in a palatable vehicle, in a covered container through a straw. If this administration is unsuccessful, a slow drip over 30 to 60 minutes through a nasogastric tube or a fluoroscopically placed nasoduodenal tube can be used. Antiemetics can be used if

necessary: metoclopramide (Reglan) 10 mg per dose intravenously 30 minutes before administration of NAC (in children, 0.1 mg/kg; maximum, 0.5 mg/kg/d) or ondansetron (Zofran) 32 mg (0.15 mg/kg) by infusion over 15 minutes and repeated for three doses if necessary. The side effects of these antiemetics include anaphylaxis and increases in liver enzymes. Some investigators recommend variable durations of NAC therapy, stopping the therapy if serial acetaminophen blood concentrations become nondetectable and the liver enzyme levels (ALT and AST) remain normal after 24 to 36 hours. There is a loss of efficacy if NAC is initiated 8 or 10 hours postingestion, but the loss is not complete, and NAC may be initiated 36 hours or more after ingestion. Late treatment (after 24 hours) decreases the rates of morbidity and mortality in patients with fulminant liver failure caused by acetaminophen and other agents. Extended relief formulations (ER embossed on caplet) contain 325 mg of acetaminophen for immediate release and 325 mg for delayed release. A single 4-hour postingestion serum acetaminophen concentration can underestimate the level because ER formulations can have secondary delayed peaks. In cases of overdose of the ER formulation, it is recommended that additional acetaminophen levels be obtained at 4-hour intervals after the initial level is measured. If any level is in the toxic zone, therapy should be initiated. It is recommended that pregnant patients with toxic plasma concentrations of acetaminophen be treated with NAC to prevent hepatotoxicity in both fetus and mother. The available data suggest no teratogenicity to NAC or acetaminophen. Indications for NAC therapy in cases of chronic intoxication are a history of ingestion of 3 to 4 g for several days with elevated liver enzyme levels (AST and ALT). The acetaminophen blood concentration is often low in these cases because of the extended time lapse since ingestion and should not be plotted on the Rumack-Matthew nomogram. Patients with a history of chronic alcoholism or those on chronic enzyme inducers may also present with elevated liver enzyme levels and should be considered for NAC therapy if they have a history of taking acetaminophen on a chronic basis, because they are considered to be at a greater risk for hepatotoxicity despite a low acetaminophen blood concentration. Specific support care may be needed to treat liver failure, pancreatitis, transient renal failure, and myocarditis. Liver transplantation has a definite but limited role in patients with acute acetaminophen overdose. A retrospective analysis determined that a continuing rise in the prothrombin time (4-day peak, 180 seconds), a pH of less than 7.3 2 days after the overdose, a serum creatinine level of greater than 3.3 mg/dL, severe hepatic encephalopathy, and disturbed coagulation factor VII/V ratio greater than 30 suggest a poor prognosis and may be indicators for hepatology consultation for consideration of liver transplantation. Extracorporeal measures are not expected to be of benefit. Disposition

Adults who have ingested more than 140 mg/kg and children younger than 6 years of age who have ingested more than 200 mg/kg should receive therapy within 8 hours postingestion or until the results of the 4-hour postingestion acetaminophen plasma concentration are known. Amphetamines The amphetamines include illicit methamphetamine (“Ice”), diet pills, and formulations under various trade names. Analogues include MDMA (3,4 methylenedioxymethamphetamine, known as “ecstasy,” “XTC,” “Adam”) and MDA (3,4-methylenedioxyamphetamine, known as “Eve”). MDA is a common hallucinogen and euphoriant “club drug” used at “raves,” which are all-night dances. Use of methamphetamine and designer analogues is on the rise, especially among young people between the ages of 12 and 25 years. Other similar stimulants are phenylpropanolamine and cocaine. Toxic Mechanism

Amphetamines have a direct CNS stimulant effect and a sympathetic nervous system effect by releasing catecholamines from a- and ß-adrenergic nerve terminals but inhibiting their reuptake. Hallucinogenic MDMA has an additional hazard of serotonin effect (refer to serotonin syndrome in the SSRI section). MDMA also affects the dopamine system in the brain. Because of its effects on 5-hydroxytryptamine, dopamine, and norepinephrine, MDMA can lead to serotonin syndrome associated with malignant hyperthermia and rhabdomyolysis, which contributes to the potentially life-threatening hyperthermia observed in several patients who have used MDMA. Phenylpropanolamine stimulates only the ß-adrenergic receptors. Toxic Dose

In children, the toxic dose of dextroamphetamine is 1 mg/kg; in adults, the toxic dose is 5 mg/kg. The potentially fatal dose of dextroamphetamine is 12 mg/kg. Kinetics

Amphetamine is a weak base with pKa of 8 to 10. Onset of action is 30 to 60 minutes, and peak effects are 2 to 4 hours. The volume distribution is 2 to 3 L/kg. Through hepatic metabolism, 60% of the substance is metabolized into a hydroxylated metabolite that may be responsible for psychotic effects. The half-life of amphetamines is pH dependent—8 to 10 hours in acid urine (pH 7.5). Excretion is by the kidney—30% to 40% at alkaline urine pH and 50% to 70% at acid urine pH. Manifestations

Effects are seen within 30 to 60 minutes following ingestion. Neurologic manifestations include restlessness, irritation and agitation, tremors and hyperreflexia, and auditory and visual hallucinations. Hyperpyrexia may precede seizures, convulsions, paranoia, violence, intracranial hemorrhage, psychosis, and self-destructive behavior. Paranoid psychosis and cerebral vasculitis occur with chronic abuse. MDMA is often adulterated with cocaine, heroin, or ketamine, or a combination of these, to create a variety of mood alterations. This possibility must be taken into consideration when one manages patients with MDMA ingestions, as the symptom complex may reflect both CNS stimulation and CNS depression. Other manifestations include dilated but reactive pupils, cardiac dysrhythmias (supraventricular and ventricular), tachycardia, hypertension, rhabdomyolysis, and myoglobinuria. Laboratory Investigations

The clinician should monitor ECG and cardiac readings, ABG and oxygen saturation, electrolytes, blood glucose, BUN, creatinine, creatine kinase, cardiac fraction if there is chest pain, and liver profile. Also, one should evaluate for rhabdomyolysis and check urine for myoglobin, cocaine and metabolites, and other substances of abuse. The peak plasma concentration of amphetamines is 10 to 50 ng/mL 1 to 2 hours after ingestion of 10 to 25 mg. The toxic plasma concentration is 200 ng/mL. When the rapid immunoassays are used, cross-reactions can occur with amphetamine derivatives (e.g., MDA, “ecstasy”), brompheniramine (Dimetane), chlorpromazine (Thorazine), ephedrine, phenylpropanolamine, phentermine (Adipex-P), phenmetrazine, ranitidine (Zantac), and Vicks Inhaler (l-desoxyephedrine). False-positive results may occur. Management

Management is similar to management for cocaine intoxication. Supportive care includes blood pressure and temperature control, cardiac monitoring, and seizure precautions. Diazepam (Valium) can be administered. Gastrointestinal decontamination can be undertaken with activated charcoal administered up to 1 hour after ingestion. Anxiety, agitation, and convulsions are treated with diazepam. If diazepam fails to control seizures, neuromuscular blockers can be used and the electroencephalogram (EEG) monitored for nonmotor seizures. One should avoid neuroleptic phenothiazines and butyrophenone, which can lower the seizure threshold. Hypertension and tachycardia are usually transient and can be managed by titration of diazepam. Nitroprusside can be used for hypertensive crisis at a maximum infusion rate of 10 µg/kg/minute for 10 minutes followed with a lower infusion rate of 0.3 to 2 mg/kg/minute. Myocardial ischemia is managed by oxygen, vascular access, benzodiazepines, and nitroglycerin. Aspirin and thrombolytics are not routinely recommended because of the danger of intracranial hemorrhage. It is important to distinguish between angina and true ischemia. Delayed hypotension can be treated with fluids and vasopressors if needed. Life-threatening tachydysrhythmias may respond to an a-blocker such as phentolamine (Regitine) 5 mg IV for adults or 0.1 mg/kg IV for children and a short-acting ß-blocker such as esmolol (Brevibloc) 500 µg/kg IV over 1 minute for adults, or 300 to 500 µg/kg over

1 minute for children. Ventricular dysrhythmias may respond to lidocaine or, in a severely hemodynamically compromised patient, immediate synchronized electrical cardioversion. Rhabdomyolysis and myoglobinuria are treated with fluids, alkaline diuresis, and diuretics. Hyperthermia is treated with external cooling and cool 100% humidified oxygen. More extensive therapy may be needed in severe cases. If focal neurologic symptoms are present, the possibility of a cerebrovascular accident should be considered and a CT scan of the head should be obtained. Paranoid ideation and threatening behavior should be treated with rapid tranquilization using a benzodiazepine. One should observe for suicidal depression that may follow intoxication and may require suicide precautions. Extracorporeal measures are of no benefit. Disposition

Symptomatic patients should be observed on a monitored unit until the symptoms resolve and then observed for a short time after resolution for relapse. ANTICHOLINERGIC AGENTS Drugs with anticholinergic properties include antihistamines (H1 blockers), neuroleptics (phenothiazines), tricyclic antidepressants, antiparkinsonism drugs (trihexyphenidyl [Artane], benztropine [Cogentin]), ophthalmic products (atropine), and a number of common plants. The antihistamines are divided into the sedating anticholinergic types, and the nonsedating single daily dose types. The sedating types include ethanolamines (e.g., diphenhydramine [Benadryl], dimenhydrinate [Dramamine], and clemastine [Tavist]), ethylenediamines (e.g., tripelennamine [Pyribenzamine]), alkyl amines (e.g., chlorpheniramine [Chlor-Trimeton], brompheniramine [Dimetane]), piperazines (e.g., cyclizine [Marezine], hydroxyzine [Atarax], and meclizine [Antivert]), and phenothiazine (e.g., Phenergan). The nonsedating types include astemizole (Hismanal), terfenadine (Seldane), loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec). The anticholinergic plants include jimsonweed (Datura stramonium), deadly nightshade (Atropa belladonna), henbane (Hyoscyamus niger), and antispasmodic agents for the bowel (atropine derivatives). Toxic Mechanism

By competitive inhibition, anticholinergics block the action of acetylcholine on postsynaptic cholinergic receptor sites. The toxic mechanism primarily involves the peripheral and CNS muscarinic receptors. H1 sedating-type agents also depress or stimulate the CNS, and in large overdoses some have cardiac membrane–depressant effects (e.g., diphenhydramine [Benadryl]) and a-adrenergic receptor blockade effects (e.g., promethazine [Phenergan]). Nonsedating agents produce peripheral H1 blockade but do not possess anticholinergic or sedating actions. The original agents terfenadine (Seldane) and astemizole (Hismanal) were recently removed from the market because of the severe cardiac dysrhythmias associated with their use, especially when used in

combination with macrolide antibiotics and certain antifungal agents such as ketoconazole (Nizoral), which inhibit hepatic metabolism or excretion. The newer nonsedating agents, including loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec), have not been reported to cause the severe drug interactions associated with terfenadine and astemizole. Toxic Dose

The estimated toxic oral dose of atropine is 0.05 mg/kg in children and more than 2 mg in adults. The minimal estimated lethal dose of atropine is more than 10 mg in adults and more than 2 mg in children. Other synthetic anticholinergic agents are less toxic, and the fatal dose varies from 10 to 100 mg. The estimated toxic oral dose of diphenhydramine (Benadryl) in a child is 15 mg/kg, and the potential lethal amount is 25 mg/kg. In an adult, the potential lethal amount is 2.8 g. Ingestion of five times the single dose of an antihistamine is toxic. For the nonsedating agents, an overdose of 3360 mg of terfenadine was reported in an adult who developed ventricular tachycardia and fibrillation that responded to lidocaine and defibrillation. A 1500-mg overdose produced hypotension. Cases of delayed serious dysrhythmias (torsades de pointes) have been reported with doses of more than 200 mg of astemizole. The toxic doses of fexofenadine (Allegra), cetirizine, and loratadine (Claritin) need to be established. Kinetics

The onset of absorption of intravenous atropine is in 2 to 4 minutes. Peak effects on salivation after intravenous or intramuscular administration are at 30 to 60 minutes. Onset of absorption after oral ingestion is 30 to 60 minutes, peak action is 1 to 3 hours, and duration of action is 4 to 6 hours, but symptoms are prolonged in cases of overdose or with sustained-release preparations. The onset of absorption of diphenhydramine is in 15 minutes to 1 hour, with a peak of action in 1 to 4 hours. Volume distribution is 3.3 to 6.8 L/kg, and protein binding is 75% to 80%. Ninety-eight percent of diphenhydramine is metabolized via the liver by N-demethylation. Interactions with erythromycin, ketoconazole (Nizoral), and derivatives produce excessive blood levels of the antihistamine and ventricular dysrhythmias. The half-life of diphenhydramine is 3 to 10 hours. The chemical structure of nonsedating agents prevents their entry into the CNS. Absorption begins in 1 hour, with peak effects in 4 in 6 hours. The duration of action is greater than 24 hours. These agents are metabolized in the gastrointestinal tract and liver. Protein binding is greater than 90%. The plasma half-life is 3.5 hours. Only 1% is excreted unchanged; 60% of that is excreted in the feces and 40% in the urine.

Manifestations

Anticholinergic signs are hyperpyrexia (“hot as a hare”), mydriasis (“blind as a bat”), flushing of skin (“red as a beet”), dry mucosa and skin (“dry as a bone”), “Lilliputian type” hallucinations and delirium (“mad as a hatter”), coma, dysphagia, tachycardia, moderate hypertension, and rarely convulsions and urinary retention. Other effects include jaundice (cyproheptadine [Periactin]), dystonia (diphenhydramine [Benadryl]), rhabdomyolysis (doxylamine), and, in large doses, cardiotoxic effects (diphenhydramine). Overdose with nonsedating agents produces headache and confusion, nausea, and dysrhythmias (e.g., torsades de pointes). Laboratory Investigations

Monitoring of ABG (in cases of respiratory depression), electrolytes, glucose, and the ECG should be undertaken. Anticholinergic drugs and plants are not routinely included on screens for substances of abuse. Management

For patients in respiratory failure, intubation and assisted ventilation should be instituted. Gastrointestinal decontamination can be instituted. Caution must be taken with emesis in cases of diphenhydramine (Benadryl) overdose because of the drug's rapid onset of action and risk of seizures. If bowel sounds are present for up to 1 hour after ingestion, activated charcoal can be given. Seizures can be controlled with benzodiazepines (diazepam [Valium] or lorazepam [Ativan]). The administration of physostigmine (Antilirium) is not routine and is reserved for life-threatening anticholinergic effects that are refractory to conventional treatments. It should be administered with adequate monitoring and resuscitative equipment available. The use of physostigmine should be avoided if a tricyclic antidepressant is present because of increased toxicity. Urinary retention should be relieved by catheterization to avoid reabsorption of the drug and additional toxicity. Supraventricular tachycardia should be treated only if the patient is hemodynamically unstable. Ventricular dysrhythmias can be controlled with lidocaine or cardioversion. Sodium bicarbonate 1 to 2 mEq/kg IV may be useful for myocardial depression and QRS prolongation. Torsades de pointes, especially when associated with terfenadine and astemizole ingestion, has been treated with magnesium sulfate 4 g or 40 mL 10% solution intravenously over 10 to 20 minutes and countershock if the patient fails to respond. Hyperpyrexia is controlled by external cooling. Hemodialysis and hemoperfusion are not effective. Disposition Antihistamine H1 Antagonists

Symptomatic patients should be observed on a monitored unit until the symptoms resolve, then observed for a short time (3 to 4 hours) after resolution for relapse.

Nonsedating Agents

All asymptomatic children who acutely ingest more than the maximum adult dose and all symptomatic children should be referred to a health care facility for a minimum of 6 hours' observation as well as cardiac monitoring. Asymptomatic adults who acutely ingest more than twice the maximum adult daily dose should be monitored for a minimum of 6 hours. All symptomatic patients should be monitored for as long as there are symptoms present. Barbiturates Barbiturates have been used as sedatives, anesthetic agents, and anticonvulsants, but their use is declining as safer, more effective drugs become available. Toxic Mechanism

Barbiturates are -aminobutyric acid (GABA) agonists (increasing the chloride flow and inhibiting depolarization). They enhance the CNS depressant effect of GABA and depress the cardiovascular system. Toxic Dose

The shorter-acting barbiturates (including the intermediate-acting agents) and their hypnotic doses are as follows: amobarbital (Amytal), 100 to 200 mg; aprobarbital (Alurate), 50 to 100 mg; butabarbital (Butisol), 50 to 100 mg; butalbital, 100 to 200 mg; pentobarbital (Nembutal), 100 to 200 mg; secobarbital (Seconal), 100 to 200 mg. They cause toxicity at lower doses than long-acting barbiturates and have a minimum toxic dose of 6 mg/kg; the fatal adult dose is 3 to 6 g. The long-acting barbiturates and their doses include mephobarbital (Mebaral), 50 to 100 mg, and phenobarbital, 100 to 200 mg. Their minimum toxic dose is greater than 10 mg/kg, and the fatal adult dose is 6 to 10 g. A general rule is that an amount five times the hypnotic dose is toxic and an amount 10 times the hypnotic dose is potentially fatal. Methohexital and thiopental are ultrashort-acting parenteral preparations and are not discussed. Kinetics

The barbiturates are enzyme inducers. Short-acting barbiturates are highly lipid-soluble, penetrate the brain readily, and have shorter elimination times. Onset of action is in 10 to 30 minutes, with a peak at 1 to 2 hours. Duration of action is 3 to 8 hours. The volume distribution of short-acting barbiturate is 0.8 to 1.5 L/kg; pKa is about 8. Mean half-life varies from 8 to 48 hours. Long-acting agents have longer elimination times and can be used as anticonvulsants. Onset of action is in 20 to 60 minutes, with a peak at 1 to 6 hours. In cases of overdose, the peak can be at 10 hours. Usual duration of action is 8 to 12 hours. Volume distribution is 0.8 L/kg, and half-life is 11 to 120 hours. The pKa of phenobarbital is 7.2. Alkalinization of urine promotes its excretion. Manifestations

Mild intoxication resembles alcohol intoxication and includes ataxia, slurred speech, and depressed cognition. Severe intoxication causes slow respirations, coma, and loss of reflexes (except pupillary light reflex). Other manifestations include hypotension (vasodilation), hypothermia, hypoglycemia, and death by respiratory arrest. Laboratory Investigations

Most barbiturates are detected on routine drug screens and can be measured in most hospital laboratories. Investigation should include barbiturate level; ABG; toxicology screen, including acetaminophen; glucose, electrolyte, BUN, creatinine, and creatine kinase levels; and urine pH. The minimum toxic plasma levels are greater than 10 µg/mL for short-acting barbiturates and greater than 40 µg/dL for long-acting agents. Fatal levels are 30 µg/mL for short-acting barbiturates and 80 to 150 µg/mL for long-acting agents. Both short-acting and longacting agents can be detected in urine 24 to 72 hours after ingestion, and long-acting agents can be detected up to 7 days. Management

Vital functions must be established and maintained. Intensive supportive care including intubation and assisted ventilation should dominate the management. All stuporous and comatose patients should have glucose (for hypoglycemia), thiamine (if chronically alcoholic), and naloxone (Narcan) (in case of an opioid ingestion) intravenously and should be admitted to the intensive care unit. Emesis should be avoided especially in cases of ingestion of the shorter-acting barbiturates. Activated charcoal followed by MDAC (0.5 g/kg) every 2 to 4 hours has been shown to reduce the serum half-life of phenobarbital by 50%, but its effect on clinical course is undetermined. Fluids should be administered to correct dehydration and hypotension. Vasopressors may be necessary to correct severe hypotension, and hemodynamic monitoring may be needed. The patient must be observed carefully for fluid overload. Alkalinization (ion trapping) is used only for phenobarbital (pKa 7.2) but not for short-acting barbiturates. Sodium bicarbonate, 1 to 2 mEq/kg IV in 500 mL of 5% dextrose in adults or 10 to 15 mL/kg in children during the first hour, followed by sufficient bicarbonate to keep the urinary pH at 7.5 to 8.0, enhances excretion of phenobarbital and shortens the half-life by 50%. Diuresis is not advocated because of the danger of cerebral or pulmonary edema. Hemodialysis shortens the half-life to 8 to 14 hours, and charcoal hemoperfusion shortens the half-life to 6 to 8 hours for long-acting barbiturates such as phenobarbital. Both procedures may be effective in patients with both long-acting and short-acting barbiturate ingestion. If the patient does not respond to supportive measures or if the phenobarbital plasma concentration is greater than 150 µg/mL, both procedures may be tried to shorten the halflife. Bullae are treated as a local second-degree skin burn. Hypothermia should be treated. Disposition

All comatose patients should be admitted to the intensive care unit. Awake and oriented patients with an overdose

of short-acting agents should be observed for at least 6 asymptomatic hours; overdose of long-acting agents warrants observation for at least 12 asymptomatic hours because of the potential for delayed absorption. In the case of an intentional overdose, psychiatric clearance is needed before the patient can be discharged. Chronic use can lead to tolerance, physical dependency, and withdrawal and necessitates follow-up. BENZODIAZEPINES Benzodiazepines are used as anxiolytics, sedatives, and relaxants. Toxic Mechanism

The GABA agonists produce CNS depression and increase chloride flow, inhibiting depolarization. Flunitrazepam (Rohypnol; street name “roofies”) is a long-acting benzodiazepine agonist sold by prescription in more than 60 countries worldwide, but it is not legally available in the United States. Toxic Dose

The long-acting benzodiazepines (half-life >24 hours) and their maximum therapeutic doses are as follows: chlordiazepoxide (Librium), 50 mg; clorazepate (Tranxene), 30 mg; clonazepam (Klonopin), 20 mg; diazepam (Valium), 10 mg in adults or 0.2 mg/kg in children; flurazepam (Dalmane), 30 mg; and prazepam, 20 mg. The short-acting benzodiazepines (half-life 10 to 24 hours) and their doses include the following: alprazolam (Xanax), 0.5 mg, and lorazepam (Ativan), 4 mg in adults or 0.05 mg/kg in children, which act similar to the longacting benzodiazepines. The ultrashort-acting benzodiazepines (half-life 1500 mg diazepam or 2000 mg chlordiazepoxide) have been ingested with resulting mild coma but without respiratory depression. Fatalities are rare, and most patients recover within 24 to 36 hours after overdose. Asymptomatic unintentional overdoses of less than five times the therapeutic dose can be seen. Ultrashort-acting agents have produced respiratory arrest and coma within 1 hour after ingestion of 5 mg of triazolam (Halcion) and death with ingestion of as little as 10 mg. Midazolam (Versed) and diazepam (Valium) by rapid intravenous injection have produced respiratory arrest. Kinetics

Onset of CNS depression is usually in 30 to 120 minutes; peak action usually occurs within 1 to 3 hours when ingestion is by the oral route. The volume distribution varies from 0.26 to 6 L/kg (LA, 1.1 L/kg); protein binding is 70% to 99%. For flunitrazepam, the onset of action is in 0.5 to 2 hours, oral peak is in 2 hours, and duration 8 hours or more. The half-life of flunitrazepam is 20 to 30 hours, volume distribution is 3.3 to 5.5 L/kg, and 80% is protein bound. Flunitrazepam can be identified in urine 4 to 30 days after ingestion.

Manifestations

Neurologic manifestations include ataxia, slurred speech, and CNS depression. Deep coma leading to respiratory depression suggests the presence of short-acting benzodiazepines or other CNS depressants. In elderly persons, the therapeutic doses can produce toxicity and can have an additive effect with other CNS depressants. Chronic use can lead to tolerance, physical dependency, and withdrawal. Laboratory Investigations

Most benzodiazepines can be detected in urine drug screens. Quantitative blood levels are not useful. Some of the immunoassay urinary screens cannot detect all of the new benzodiazepines currently available. A consultation with the laboratory analyst is warranted if a specific case occurs in which the test result is negative but benzodiazepine use is suspected by the patient's history. Situations in which benzodiazepines may not be detected include ingestion of a low dose (e.g., 1000 mg/dL). The deferoxamine-iron complex is hemodialyzable if renal failure develops.

Indications for chelation therapy are any of the following: •

Very large, symptomatic ingestions

•

Serious clinical intoxication (severe vomiting and diarrhea [often bloody], severe abdominal pain, metabolic acidosis, hypotension, or shock)

•

Symptoms that persist or progress to more serious toxicity

•

Serum iron level greater than 500 mg/dL

Chelation should be performed as early as possible within 12 to 18 hours to be effective. One should start the infusion slowly and gradually increase to avoid hypotension. Adult respiratory distress syndrome has developed in patients with high doses of deferoxamine for several days; infusions longer than 24 hours should be avoided. The endpoint of treatment is when the patient is asymptomatic and the urine clears if it was originally a positive “vin rosö” color. For supportive therapy, intravenous bicarbonate may be needed to correct the metabolic acidosis. Hypotension and shock treatment may require volume expansion, vasopressors, and blood transfusions. The physician should attempt to keep the urinary output at greater than 2 mL/kg/h. Coagulation abnormalities and overt bleeding require blood products or vitamin K. Pregnant patients are treated in a fashion similar to any other patient with iron poisoning. Hemodialysis and hemoperfusion are ineffective. Exchange transfusion has been used in single cases of massive poisonings in children. Disposition

The asymptomatic or minimally symptomatic patient should be observed for persistence and progression of symptoms or development of toxicity signs (gastrointestinal bleeding, acidosis, shock, altered mental state). Patients with mild self-limited gastrointestinal symptoms who become asymptomatic or have no signs of toxicity for 6 hours are unlikely to have a serious intoxication and can be discharged after psychiatric clearance, if needed. Patients with moderate or severe toxicity should be admitted to the intensive care unit. ISONIAZID

Isoniazid is a hydrazide derivative of vitamin B3 (nicotinamide) and is used as an antituberculosis drug. Toxic Mechanism

Isoniazid produces pyridoxine deficiency by increasing the excretion of pyridoxine (vitamin B6) and by inhibiting pyridoxal 5-phosphate (the active form of pyridoxine) from acting with l-glutamic acid decarboxylase to form -

aminobutyric acid (GABA), the major CNS neurotransmitter inhibitor, resulting in seizures. Isoniazid also blocks the conversion of lactate to pyruvate, resulting in profound and prolonged lactic acidosis. Toxic Dose

The therapeutic dose is 5 to 10 mg/kg (maximum 300 mg) daily. A single acute dose of 15 mg/kg lowers the seizure threshold; 35 to 40 mg/kg produces spontaneous convulsions; more than 80 mg/kg produces severe toxicity. A fatal dose in adults is 4.5 to 15 g. The malnourished patients, those with a previous seizure disorder, alcoholic patients, and slow acetylators are more susceptible to isoniazid toxicity. In cases of chronic intoxication, 10 mg/kg/d produces hepatitis in 10% to 20% of patients but less than 2% at doses of 3 to 5 mg/kg/d. Kinetics

Absorption from intestine occurs in 30 to 60 minutes, and onset is in 30 to 120 minutes, with peak levels of 5 to 8 µg/mL within 1 to 2 hours. Volume distribution is 0.6 L/kg, with minimal protein binding. Elimination is by liver acetylation to a hepatotoxic metabolite, acetyl-isoniazid, which is then hydrolyzed to isonicotinic acid. In slow acetylators, isoniazid has a half-life of 140 to 460 minutes (mean 5 hours), and 10% to 15% is eliminated unchanged in the urine. Most (45% to 75%) whites and 50% of African blacks are slow acetylators, and, with chronic use (without pyridoxine supplements), they may develop peripheral neuropathy. In fast acetylators, isoniazid has a half-life of 35 to 110 minutes (mean 80 minutes), and 25% to 30% is excreted unchanged in the urine. About 90% of Asians and patients with diabetes mellitus are fast acetylators and may develop hepatitis on chronic use. In patients with overdose and hepatic disease, the serum half-life may increase. Isoniazid inhibits the metabolism of phenytoin (Dilantin), diazepam, phenobarbital, carbamazepine (Tegretol), and prednisone. These drugs also interfere with the metabolism of isoniazid. Ethanol may decrease the half-life of isoniazid but increase its toxicity. Manifestations

Within 30 to 60 minutes, nausea, vomiting, slurred speech, dizziness, visual disturbances, and ataxia are present. Within 30 to 120 minutes, the major clinical triad of severe overdose includes refractory convulsions (90% of overdose patients have one or more seizures), coma, and resistant severe lactic acidosis (secondary to convulsions), often with a plasma pH of 6.8. Laboratory Investigations

Isoniazid produces anion gap metabolic acidosis. Therapeutic levels are 5 to 8 µg/mL and acute toxic levels are greater than 20 µg/mL. These levels are not readily available to assist in making decisions in acute overdose situations. One should monitor the blood glucose (often hyperglycemia), electrolytes (often hyperkalemia), bicarbonate, ABGs, liver function tests (elevations occur with chronic exposure), BUN, and creatinine. Management

Seizures must be controlled. Pyridoxine and diazepam should be administered concomitantly through different IV

sites. Pyridoxine (vitamin B6) is given in a dose of 1 g for each gram of isoniazid ingested. If the dose ingested is unknown, at least 5 g of pyridoxine should be given intravenously. Pyridoxine is administered in 50 mL D5W or 0.9% saline over 5 minutes intravenously. It must not be administered in the same bottle as sodium bicarbonate. Intravenous pyridoxine is repeated every 5 to 20 minutes until the seizures are controlled. Total doses of pyridoxine up to 52 g have been safely administered; however, patients given 132 and 183 g of pyridoxine have developed a persistent crippling sensory neuropathy. Diazepam is administered concomitantly with pyridoxine but at a different site. They work synergistically. Diazepam should be administered intravenously slowly, 0.3 mg/kg at a rate of 1 mg/min in children or 10 mg at a rate of 5 mg/min in adults. After the seizures are controlled, the remainder of the pyridoxine is administered (1 g/1 g isoniazid) or a total dose of 5 g. Phenobarbital or phenytoin is ineffective and should not be used. In asymptomatic patients or patients without seizures, pyridoxine has been advised by some toxicologists prophylactically in gram-for-gram doses in cases of large overdoses (100

Adult

Encephalopathic signs and symptoms

>80

Adult

Anemia

Child

Encephalopathy Chronic nephropathy (e.g., aminoaciduria)

>70

>60

Adult

Clinically evident peripheral neuropathy

Child

Colic and other gastrointestinal symptoms

Adult

Female reproductive effects CNS disturbance symptoms (i.e., sleep disturbances, mood changes, memory and concentration problems, headaches)

>50

Adult

Decreased hemoglobin production Decreased performance on neurobehavioral tests

Adult

Altered testicular function Gastrointestinal symptoms (i.e., abdominal pain, constipation, diarrhea, nausea, anorexia)

>40

Child

Peripheral neuropathy[*]

Adult

Decreased peripheral nerve conduction

Blood Lead Level (µ g/dL)

Age Group

Health Effect Hypertension, age 40–59 years Chronic neuropathy[*]

>25

Adult

Elevated erythrocyte protoporphyrin in males

15-25

Adult

Elevated erythrocyte protoporphyrin in females

>10

Child

Decreased intelligence and growth Impaired learning Reduced birth weight [*] Impaired mental ability

Fetus

Preterm delivery

From Anonymous: Implementation of the Lead Contamination Control Act of 1988. MMWR Morb Mortal Wkly Rep 41:288, 1992. * Controversial.

Hematologic

Lead inhibits -aminolevulinic acid dehydratase (early in the synthesis of heme) and ferrochelatase (transfers iron to ferritin for incorporation of iron into protoporphyrin to produce heme). Anemia is a late finding. Decreased heme synthesis starts at >40 µg/dL. Basophilic stippling occurs in 20% of severe lead poisoning. Neurologic

Segmental demyelination and peripheral neuropathy, usually of the motor type (wrist and ankle drop), occurs in workers. A venous blood level of lead greater than 70 µg/dL (usually >100 µg/dL), produces encephalopathy in children (symptom mnemonic “PAINT”: P, persistent forceful vomiting and papilledema; A, ataxia; I, intermittent stupor and lucidity; N, neurologic coma and refractory convulsions; T, tired and lethargic). Decreased cognitive abilities have been reported with a venous blood level of lead greater than 10 µg/dL, including behavioral problems, decreased attention span, and learning disabilities. IQ scores may begin to decrease at 15 µg/dL. Encephalopathy is rare in adults. Renal

Nephropathy as a result of damaged capillaries and glomerulus can occur at a venous blood level of lead greater than 80 µg/dL, but recent studies show renal damage and hypertension with low venous blood levels. A direct correlation between hypertension and venous blood level over 30 µg/dL has been reported. Lead reduces excretion of uric acid, and high-level exposure may be associated with hyperuricemia and “saturnine gout,” Fanconi's syndrome (aminoaciduria and renal tubular acidosis), and tubular fibrosis. Reproductive

Spontaneous abortion, transient delay in the child's development (catch up at age 5 to 6 years), decreased sperm count, and abnormal sperm morphology can occur with lead exposure. Lead crosses the placenta and fetal blood levels reach 75% to 100% of maternal blood levels. Lead is teratogenic. Metabolic

Decreased cytochrome P450 activity alters the metabolism of medication and endogenously produced substances. Decreased activation of cortisol and decreased growth is caused by interference in vitamin conversion (25-hydroxyvitamin D to 1,25 hydroxyvitamin D) at venous blood levels of 20 to 30 µg/dL. Other Manifestations

Abnormalities of thyroid, cardiac, and hepatic function occur in adults. Abdominal colic is seen in children at doses greater than 50 µg/dL. “Lead gum lines” at the dental border of the gingiva can occur in cases of chronic lead poisoning. Laboratory Investigations

Serial venous blood lead measurements are taken on days 3 and 5 during treatment and 7 days after chelation therapy, then every 1 to 2 weeks for 8 weeks, and then every month for 6 months. Intravenous infusion should be stopped at least 1 hour before blood lead levels are measured. Table 22 gives a classification of blood lead concentrations in children.

TABLE 22 -- Classification of Blood Lead Concentrations in Children Blood Lead (µ g/dL) Recommended Interventions 70

Hospitalization in intensive care unit Environmental inspection/abatement Pharmacologic therapy Dimercaprol (BAL in oil) IM initial alone Dimercaprol IM and CaNa2EDTA together Repeat every week

Abbreviations: BAL = British anti-Lewisite; CaNa2EDTA = Edetate calcium disodium; DMS = dimercaptosuccinic acid; IM = intramuscular.

One should evaluate CBC, serum ferritin, erythrocyte protoporphyrin (>35 µg/dL indicates lead poisoning as well as iron deficiency and other causes), electrolytes, serum calcium and phosphorus, urinalysis, BUN, and creatinine. Abdominal and long bone radiographs may be useful in certain circumstances to identify radiopaque material in bowel and “lead lines” in proximal tibia (which occur after prolonged exposure in association with venous blood lead levels greater than 50 µg/dL). Neuropsychological tests are difficult to perform in young children but should be considered at the end of treatment, especially to determine auditory dysfunction. Management

The basis of treatment is removal of the source of lead. Cases of poisoning in children should be reported to local health department and cases of occupational poisoning should be reported to OSHA. The source must be identified and abated, and dust controlled by wet mopping. Cold water should be let to run for 2 minutes before being used for drinking. Planting shrubbery (not vegetables) in contaminated soil will keep children away. Supportive care should be instituted, including measures to deal with refractory seizures (continued antidotal therapy, diazepam, and possibly neuromuscular blockers), with the hepatic and renal failure, and intravascular hemolysis in severe cases. Seizures are treated with diazepam followed by neuromuscular blockers if needed. Lead does not bind to activated charcoal. One must not delay chelation therapy for complete gastrointestinal decontamination in severe cases. Whole-bowel irrigation has been used prior to treatment. Some authorities recommend abdominal radiographs followed by gastrointestinal decontamination if necessary before switching to oral therapy. Chelation therapy can be used for patients in whom venous blood level of lead is greater than 45 µg/dL in children and greater than 80 µg/dL in adults or in adults with lower levels who are symptomatic or who have a “positive” lead mobilization test result (not routinely performed at most centers) ( Table 23 ).

TABLE 23 -- Pharmacologic Chelation Therapy of Lead Poisoning Drug Route Dose Duration Precautions Dimercaprol (BAL in oil)

IM

3-5 mg/kg q4-6h

3-5 days

G6PD deficiency Concurrent iron therapy

CaNa2 EDTA (calcium disodium. versenate)

D-Penicillamine (Cuprimine)

IM/IV 50 mg/kg per day

PO

10 mg/kg per day increase 30 mg/kg over 2 weeks

5 days

6-20 weeks

Monitor AST/ALT enzymes

Inadequate fluid intake

Urinalysis, BUN

Renal impairment

Creatinine

Penicillin allergy

Urinalysis, BUN

Concurrent iron therapy; lead exposure

Creatinine, CBC

Renal impairment 2,3-Dimercap-to-succinic acid (DMSA; succimer)

PO

10 mg/kg per dose 3 times daily 19 days 10 mg/kg per dose twice daily for 14 days

AST/ALT

AST/ALT

Concurrent iron therapy G6PD deficiency lead exposure

Abbreviations: ALT = alanine aminotransferase; AST = aspartate transaminase; BAL = British anti-Lewisite; bid = twice daily; BUN = blood urea nitrogen; CBC = complete blood count; G6PD = glucose-6-phosphate dehydrogenase; IM = intramuscular; IV = intravenous; PO = oral; tid = three times daily.

Succimer (dimercaptosuccinic acid, DMSA, Chemet), a derivative of British anti-Lewisite (BAL), is an oral agent for chelation in children with a venous blood level of greater than 45 µg/dL. The recommended dose is 10 mg/kg every 8 hours for 5 days, then every 12 hours for 14 days. DMSA is under investigation to determine its role in children with a venous blood level less than 45 µg/dL. Although not approved for adults, it has been used in the same dosage. Monitoring should be maintained by CBC, liver transaminases, and urinalysis for adverse effects. d-Penicillamine (Cuprimine) is another oral chelator that is given in doses of 20 to 40 mg/kg/d not to exceed 1 g/d. However, it is not FDA approved and has a 10% adverse reaction rate. Nevertheless, d-penicillamine has been used infrequently in adults and children with elevated venous blood lead levels. Edetate calcium disodium (ethylene diaminetetra-acetic acid or CaNa2EDTA Versenate) is a water-soluble chelator given intramuscularly (with 0.5% procaine) or intravenously. The calcium in the compound is displaced by divalent and trivalent heavy metals, forming a soluble complex, which is stable at physiologic pH (but not at acid pH) and enhances lead clearance in the urine. EDTA usually is administered intravenously, especially in severe

cases. It must not be administered until adequate urine flow is established. It may redistribute lead to the brain; therefore, BAL may be given first at a venous blood lead level of greater than 55 µg/dL in children and greater than 100 µg/dL in adults. Phlebitis occurs at a concentration greater than 0.5 mg/mL. Alkalinization of the urine may be helpful. CaNa2EDTA should not be confused with sodium EDTA (disodium edetate), which is used to treat hypercalcemia; inadvertent use may produce severe hypocalcemia. Dimercaprol (BAL) is a peanut oil–based dithiol (two sulfhydryl molecules) that combines with one atom of lead to form a heterocyclic stable ring complex. It is usually reserved for patients in whom venous blood lead is greater than 70 µg/dL, and it chelates red blood cell lead, enhancing its elimination through the urine and bile. It crosses the blood–brain barrier. Approximately 50% of patients have adverse reactions, including bad metallic taste in the mouth, pain at the injection site, sterile abscesses, and fever. A venous blood lead level greater than 70 µg/dL or the presence of clinical symptoms suggesting encephalopathy in children is a potentially life-threatening emergency. Management should be accomplished in a medical center with a pediatric intensive care unit by a multidisciplinary team including a critical care specialist, a toxicologist, a neurologist, and a neurosurgeon. Careful monitoring of neurologic status, fluid status, and intracranial pressure should be undertaken if necessary. These patients need close monitoring for hemodynamic instability. Hydration should be maintained to ensure renal excretion of lead. Fluids, renal and hepatic function, and electrolyte levels should be monitored. While waiting for adequate urine flow, therapy should be initiated with intramuscular dimercaprol (BAL) only (25 mg/kg/d divided into 6 doses). Four hours later, the second dose of BAL should be given intramuscularly, concurrently with CaNa2EDTA 50 mg/kg/d as a single dose infused over several hours or as a continuous infusion. The double therapy is continued until the venous blood level is less than 40 µg/dL. As long as the venous blood level is greater than 40 µg/dL, therapy is continued for 72 hours and followed by two alternatives: either parenteral therapy with two drugs (CaNa2EDTA and BAL) for 5 days or continuation of therapy with CaNa 2EDTA alone if a good response is achieved and the venous blood level of lead is less than 40 µg/dL. If one cannot get the venous blood lead report back, one should continue therapy with both BAL and EDTA for 5 days. In patients with lead encephalopathy, parenteral chelation should be continued with both drugs until the patient is clinically stable before changing therapy. Mannitol and dexa-methasone can reduce the cerebral edema, but their role in lead encephalopathy is not clear. Surgical decompression is not recommended to reduce cerebral edema in these cases. If BAL and CaNa2EDTA are used together, a minimum of 2 days with no treatment should elapse before another 5-day course of therapy is considered. The 5-day course is repeated with CaNa2EDTA alone if the blood lead level rebounds to greater than 40 µg/dL or in combination with BAL if the venous blood level is greater than 70 µg/dL. If a third course is required, unless there are compelling reasons, one should wait at least 5 to 7 days before administering the course. Following chelation therapy, a period of equilibration of 10 to 14 days should be allowed and a repeat venous blood lead concentration should be obtained. If the patient is stable enough for oral intake, oral succimer 30 mg/kg/d in three divided doses for 5 days followed by 20 mg/kg/d in two divided doses for 14 days has been suggested, but there are limited data to support this recommendation. Therapy should be continued until venous blood lead level is less than 20 µg/dL in children or less than 40 µg/dL in adults.

Chelators combined with lead are hemodialyzable in the event of renal failure. Disposition

All patients with a venous blood lead level of greater than 70 µg/dL or who are symptomatic should be admitted. If a child is hospitalized, all lead hazards must be removed from the home environment before allowing the child to return. The source must be eliminated by environmental and occupational investigations. The local health department should be involved in dealing with children who are lead poisoned, and OSHA should be involved with cases of occupational lead poisoning. Consultation with a poison control center or experienced toxicologist is necessary when chelating patients. Follow-up venous blood lead concentrations should be obtained within 1 to 2 weeks and followed every 2 weeks for 6 to 8 weeks, then monthly for 4 to 6 months if the patient required chelation therapy. All patients with venous blood level greater than 10 µg/dL should be followed at least every 3 months until two venous blood lead concentrations are 10 µg/dL or three are less than 15 µg/dL. Lithium (Eskalith, Lithane)

Lithium is an alkali metal used primarily in the treatment of bipolar psychiatric disorders. Most intoxications are cases of chronic overdose. One gram of lithium carbonate contains 189 mg (5.1 mEq) of lithium; a regular tablet contains 300 mg (8.12 mEq) and a sustained-release preparation contains 450 mg or 12.18 mEq. Toxic Mechanism

The brain is the primary target organ of toxicity, but the mechanism is unclear. Lithium may interfere with physiologic functions by acting as a substitute for cellular cations (sodium and potassium), depressing neural excitation and synaptic transmission. Toxic Dose

A dose of 1 mEq/kg (40 mg/kg) of lithium will give a peak serum lithium concentration about 1.2 mEq/L. The therapeutic serum lithium concentration in cases of acute mania is 0.6 to 1.2 mEq/L, and for maintenance it is 0.5 to 0.8 mEq/L. Serum lithium concentration levels are usually obtained 12 hours after the last dose. The toxic dose is determined by clinical manifestations and serum levels after the distribution phase. Acute ingestion of twenty 300-mg tablets (300 mg increases the serum lithium concentration by 0.2 to 0.4 mEq/L) in adults may produce serious intoxication. Chronic intoxication can be produced by conditions listed below that can decrease the elimination of lithium or increase lithium reabsorption in the kidney. The risk factors that predispose to chronic lithium toxicity are febrile illness, impaired renal function, hyponatremia, advanced age, lithium-induced diabetes insipidus, dehydration, vomiting and diarrhea, and concomitant use of other drugs, such as thiazide and spironolactone diuretics, nonsteroidal anti-inflammatory drugs, salicylates, angiotensin-converting enzyme inhibitors (e.g., captopril), serotonin reuptake inhibitors (e.g., fluoxetine [Prozac]), and phenothiazines. Kinetics

Gastrointestinal absorption of regular-release preparations is rapid; serum lithium concentration peaks in 2 to 4 hours and is complete by 6 to 8 hours. The onset of toxicity may occur at 1 to 4 hours after acute overdose but usually is delayed because lithium enters the brain slowly. Absorption of sustained-release preparations and the development of toxicity may be delayed 6 to 12 hours. Volume distribution is 0.5 to 0.9 L/kg. Lithium is not protein bound. The half-life after a single dose is 9 to 13 hours; at steady state, it may be 30 to 58 hours. The renal handling of lithium is similar to that of sodium: glomerular filtration and reabsorption (80%) by the proximal renal tubule. Adequate sodium must be present to prevent lithium reabsorption. More than 90% of lithium is excreted by the kidney, 30% to 60% within 6 to 12 hours. Manifestations

The examiner must distinguish between side effects, acute intoxication, acute or chronic toxicity, and chronic intoxications. Chronic is the most common and dangerous type of intoxication. Side effects include fine tremor, gastrointestinal upset, hypothyroidism, polyuria and frank diabetes insipidus, dermatologic manifestations, and cardiac conduction deficits. Lithium is teratogenic. Patients with acute poisoning may be asymptomatic, with an early high serum lithium concentration of 9 mEq/L, and deteriorate as the serum lithium concentration falls by 50% and the lithium distributes to the brain and the other tissues. Nausea and vomiting may occur within 1 to 4 hours, but the systemic manifestations are usually delayed several more hours. It may take as long as 3 to 5 days for serious symptoms to develop. Acute toxicity and acute on chronic toxicity are manifested by neurologic findings, including weakness, fasciculations, altered mental state, myoclonus, hyperreflexia, rigidity, coma, and convulsions with limbs in hypertension. Cardiovascular effects are nonspecific and occur at therapeutic doses, flat T or inverted T waves, atrioventricular block, and prolonged QT interval. Lithium is not a primary cardiotoxin. Cardiogenic shock occurs secondary to CNS toxicity. Chronic intoxication is associated with manifestations at lower serum lithium concentrations. There is some correlation with manifestations, especially at higher serum lithium concentrations. Although the levels do not always correlate with the manifestations, they are more predictive in cases of severe intoxication. A serum lithium concentration greater than 3.0 mEq/L with chronic intoxication and altered mental state indicates severe toxicity. Permanent neurologic sequelae can result from lithium intoxication. Laboratory Investigations

Monitoring should include CBC (lithium causes significant leukocytosis), renal function, thyroid function (chronic intoxication), ECG, and electrolytes. Serum lithium concentrations should be determined every 2 to 4 hours until levels are close to therapeutic range. Cross-reactions with green-top Vacutainer specimen tubes containing heparin will spuriously elevate serum lithium concentration 6 to 8 mEq/L. Management

Vital function must be established and maintained. Seizure precautions should be instituted and seizures, hypotension, and dysrhythmias treated. Evaluation should include examination for rigidity and hyperreflexia signs, hydration, renal function (BUN, creatinine), and electrolytes, especially sodium. The examiner should inquire about diuretic and other drug use that increase serum lithium concentration, and the patient must discontinue the

drugs. If the patient is on chronic therapy, the lithium should be discontinued. Serial serum lithium concentrations should be obtained every 4 hours until serum lithium concentration peaks and there is a downward trend toward almost therapeutic range, especially in sustained-release preparations. Vital signs should be monitored, including temperature, and ECG and serial neurologic examinations should be undertaken, including mental status and urinary output. Nephrology consultation is warranted in case of a chronic and elevated serum lithium concentration (>2.5 mEq/L), a large ingestion, or altered mental state. An intravenous line should be established and hydration and electrolyte balance restored. Serum sodium level should be determined before 0.9% saline fluid is administered in patients with chronic overdose because hypernatremia may be present from diabetes insipidus. Although current evidence supports an initial 0.9% saline infusion (200 mL/h) to enhance excretion of lithium, once hydration, urine output, and normonatremia are established, one should administer 0.45% saline and slow the infusion (100 mL/h) for all patients. Gastric lavage is often not recommended in cases of acute ingestion because of the large size of the tablets, and it is not necessary after chronic intoxication. Activated charcoal is ineffective. For sustained-release preparations, whole-bowel irrigation may be useful but is not proven. Sodium polystyrene sulfonate (Kayexalate), an ion exchange resin, is difficult to administer and has been used only in uncontrolled studies. Its use is not recommended. Hemodialysis is the most efficient method for removing lithium from the vascular compartment. It is the treatment of choice for patients with severe intoxication with an altered mental state, those with seizures, and anuric patients. Long runs are used until the serum lithium concentration is less than 1 mEq/L because of extensive reequilibration. Serum lithium concentration should be monitored every 4 hours after dialysis for rebound. Repeated and prolonged hemodialysis may be necessary. A lag in neurologic recovery can be expected. Disposition

An acute asymptomatic lithium overdose cannot be medically cleared on the basis of single lithium level. Patients should be admitted if they have any neurologic manifestations (altered mental status, hyperreflexia, stiffness, or tremor). Patients should be admitted to the intensive care unit if they are dehydrated, have renal impairment, or have a high or rising lithium level. Methanol (Wood Alcohol, Methyl Alcohol)

The concentration of methanol in Sterno fuel is 4% and it contains ethanol, in windshield washer fluid it is 30% to 60%, and in gas-line antifreeze it is 100%. Toxic Mechanism

Methanol is metabolized by alcohol dehydrogenase to formaldehyde, which is metabolized to formate. Formate inhibits cytochrome oxidase, producing tissue hypoxia, lactic acidosis, and optic nerve edema. Formate is converted by folate-dependent enzymes to carbon dioxide. Toxic Dose

The minimal toxic amount is approximately 100 mg/kg. Serious toxicity in a young child can be produced by the ingestion of 2.5 to 5.0 mL of 100% methanol. Ingestion of 5-mL 100% methanol by a 10-kg child produces estimated peak blood methanol of 80 mg/dL. Ingestion of 15 mL 40% methanol was lethal for a 2-year-old child in one report. A fatal adult oral dose is 30 to 240 mL 100% (20 to 150 g). Ingestion of 6 to 10 mL 100% causes blindness in adults. The toxic blood concentration is greater than 20 mg/dL; very serious toxicity and potential fatality occur at levels greater than 50 mg/dL. Kinetics

Onset of action can start within 1 hour but may be delayed up to 12 to 18 hours by metabolism to toxic metabolites. It may be delayed longer if ethanol is ingested concomitantly or in infants. Peak blood methanol concentration is 1 hour. Volume distribution is 0.6 L/kg (total body water). For metabolism, see Toxic Mechanism. Elimination is through metabolism. The half-life of methanol is 8 hours, with ethanol blocking it is 30 to 35 hours, and with hemodialysis 2.5 hours. Manifestations

Metabolism creates a delay in onset for 12 to 18 hours or longer if ethanol is ingested concomitantly. Initial findings are as follows: •

0 to 6 hours: Confusion, ataxia, inebriation, formaldehyde odor on breath, and abdominal pain can be present, but the patient may be asymptomatic. Note: Methanol produces an osmolal gap (early), and its metabolite formate produces the anion gap metabolic acidosis (see later). Absence of osmolar or anion gap does not always exclude methanol intoxication.

•

6 to 12 hours: Malaise, headache, abdominal pain, vomiting, visual symptoms, including hyperemia of optic disc, “snow vision,” and blindness can be seen.

•

More than 12 hours: Worsening acidosis, hyperglycemia, shock, and multiorgan failure develop, with death from complications of intractable acidosis and cerebral edema.

Laboratory Investigation

Methanol can be detected on some chromatography drug screens if specified. Methanol and ethanol levels, electrolytes, glucose, BUN, creatinine, amylase, and ABG should be monitored every 4 hours. Formate levels correlate more closely than blood methanol concentration with severity of intoxication and should be obtained if possible. Management

One should protect the airway by intubation to prevent aspiration and administer assisted ventilation as needed. If needed, 100% oxygen can be administered. A nephrologist should be consulted early regarding the need for hemodialysis.

Gastrointestinal decontamination procedures have no role. Metabolic acidosis should be treated vigorously with sodium bicarbonate 2 to 3 mEq/kg intravenously. Large amounts may be needed. Antidote therapy is initiated to inhibit metabolism if the patient has a history of ingesting more than 0.4 mL/kg of 100% with the following conditions: •

Blood methanol level is greater than 20 mg/dL

•

The patient has osmolar gap not accounted for by other factors

•

The patient is symptomatic or acidotic with increased anion gap and/or hyperemia of the optic disc.

The ethanol or fomepizole therapy outlined below can be used. Ethanol Therapy

Ethanol should be initiated immediately if fomepizole is unavailable (see Fomepizole Therapy). Alcohol dehydrogenase has a greater affinity for ethanol than ethylene glycol. Therefore, ethanol blocks the metabolism of ethylene glycol. Ethanol should be administered intravenously (oral administration is less reliable) to produce a blood ethanol concentration of 100 to 150 mg/dL. The loading dose is 10 mL/kg of 10% ethanol administered intravenously concomitantly with a maintenance dose of 10% ethanol at 1.0 mL/kg/h. This dose may need to be increased to 2 mL/kg/h in patients who are heavy drinkers. The blood ethanol concentration should be measured hourly and the infusion rate should be adjusted to maintain a concentration of 100 to 150 mg/dL. Fomepizole Therapy

Fomepizole (Antizol, 4-methylpyrazole) inhibits alcohol dehydrogenase more reliably than ethanol and it does not require constant monitoring of ethanol levels and adjustment of infusion rates. Fomepizole is available in 1 g/mL vials of 1.5 mL. The loading dose is 15 mg/kg (0.015 mL/kg) IV, maintenance dose is 10 mg/kg (0.01 mL/kg) every 12 hours for 4 doses, then 15 mg/kg every 12 hours until the ethylene glycol levels are less than 20 mg/dL. The solution is prepared by being mixed with 100 mL of 0.9% saline or D5W. Fomepizole can be given to patients requiring hemodialysis but should be dosed as follows: Dose at the beginning of hemodialysis: •

If less than 6 hours since last Antizol dose, do not administer dose

•

If more than 6 hours since last dose, administer next scheduled dose

Dosing during hemodialysis: •

Dose every 4 hours

Dosing at the time hemodialysis is completed:

•

If less than 1 hour between last dose and end dialysis, do not administer dose at end of dialysis

•

If 1 to 3 hours between last dose and end dialysis, administer one half of next scheduled dose

•

If more than 3 hours between last dose and end dialysis, administer next scheduled dose

Maintenance dosing off hemodialysis: •

Give the next scheduled dose 12 hours from the last dose administered

Hemodialysis increases the clearance of both methanol and formate 10-fold over renal clearance. A blood methanol concentration greater than 50 mg/dL has been used as an indication for hemodialysis, but recently some toxicologists from the New York City Poison Center recommended early hemodialysis in patients with blood methanol concentration greater than 25 mg/dL because it may be able to shorten the course of intoxication if started early. One should continue to monitor methanol levels and/or formate levels every 4 hours after the procedure for rebound. Other indications for early hemodialysis are significant metabolic acidosis and electrolyte abnormalities despite conventional therapy and if visual or neurologic signs or symptoms are present. A serum formate level greater than 20 mg/dL has also been used as a criterion for hemodialysis, although this is often not readily available through many laboratories. If hemodialysis is used, the infusion rate of 10% ethanol should be increased 2.0 to 3.5 mL/kg/h. The blood ethanol concentration and glucose level should be obtained every 2 hours. Therapy is continued with both ethanol and hemodialysis until the blood methanol level is undetectable, there is no acidosis, and the patient has no neurologic or visual disturbances. This may require several days. Hypoglycemia is treated with intravenous glucose. Doses of folinic acid (Leucovorin) and folic acid have been used successfully in animal investigations to enhance formate metabolism to carbon dioxide and water. Leucovorin 1 mg/kg up to 50 mg IV is administered every 4 hours for several days. An initial ophthalmologic consultation and follow-up are warranted. Disposition

All patients who have ingested significant amounts of methanol should be referred to the emergency department for evaluation and blood methanol concentration measurement. Ophthalmologic follow-up of all patients with methanol intoxications should be arranged. Monoamine Oxidase Inhibitors

Nonselective monoamine oxidase inhibitors (MAOIs) include the hydrazines phenelzine (Nardil) and isocarboxazid (Marplan), and the nonhydrazine tranylcypromine (Parnate). Furazolidone (Furoxone) and pargyline (Eutonyl)[2] are also considered nonselective MAOIs. Moclobemide,[2] which is available in many countries but not the United States, is a selective MAO-A inhibitor. MAO-B inhibitors include selegiline (Eldepryl), an antiparksonism agent, which does not have similar toxicity to MAO-A and is not discussed. Selectivity is lost in an overdose. MAOIs are

used to treat severe depression. Toxic Mechanism

Monoamine oxidase enzymes are responsible for the oxidative deamination of both endogenous and exogenous catecholamines such as norepinephrine. MAO-A in the intestinal wall also metabolizes tyramine in food. MAOIs permanently inhibit MAO enzymes until a new enzyme is synthesized after 14 days or longer. The toxicity results from the accumulation, potentiation, and prolongation of the catecholamine action followed by profound hypotension and cardiovascular collapse. Toxic Dose

Toxicity begins at 2 to 3 mg/kg and fatalities occur at 4 to 6 mg/kg. Death has occurred after a single dose of 170 mg of tranylcypromine in an adult. Kinetics

Structurally, MAOIs are related to amphetamines and catecholamines. The hydrazine peak levels are at 1 to 2 hours; metabolism is hepatic acetylation; and inactive metabolites are excreted in the urine. For the nonhydrazines, peak levels occur at 1 to 4 hours, and metabolism is via the liver to active amphetamine-like metabolites. The onset of symptoms in a case of overdose is delayed 6 to 24 hours after ingestion, peak activity is 8 to 12 hours, and duration is 72 hours or longer. The peak of MAO inhibition is in 5 to 10 days and lasts as long as 5 weeks. Manifestations

Manifestations of an acute ingestion overdose of MAO-A inhibitors are as follows: Phase I

An adrenergic crisis occurs, with delayed onset for 6 to 24 hours, and may not reach peak until 24 hours. The crisis starts as hyperthermia, tachycardia, tachypnea, dysarthria, transient hypertension, hyperreflexia, and CNS stimulation. Phase II

Neuromuscular excitation and sympathetic hyperactivity occur with increased temperature greater than 40°C (104°F), agitation, hyperactivity, confusion, fasciculations, twitching, tremor, masseter spasm, muscle rigidity, acidosis, and electrolyte abnormalities. Seizures and dystonic reactions may occur. The pupils are mydriatic, sometimes nonreactive with “ping-pong gaze.” Phase III

CNS depression and cardiovascular collapse occur in cases of severe overdose as the catecholamines are depleted. Symptoms usually resolve within 5 days but may last 2 weeks. Phase IV

Secondary complications occur, including rhabdomyolysis, cardiac dysrhythmias, multiorgan failure, and coagulopathies. Biogenic interactions usually occur while the patient is on therapeutic doses of MAOI or shortly after they are discontinued (30 to 60 minutes), before the new MAO enzyme is synthesized. The following substances have been implicated: indirect acting sympathomimetics such as amphetamines, serotonergic drugs, opioids (e.g., meperidine, dextromethorphan), tricyclic antidepressants, specific serotonin reuptake inhibitors (SSRI; e.g., fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil]), tyramine-containing foods (e.g., wine, beer, avocados, cheese, caviar, chocolate, chicken liver), and l-tryptophan. SSRIs should not be started for at least 5 weeks after MAOIs have been discontinued. In mild cases, usually caused by foods, headache and hypertension develop and last for several hours. In severe cases, malignant hypertension and severe hyperthermia syndromes consisting of hypertension or hyperthermia, altered mental state, skeletal muscle rigidity, shivering (often beginning in the masseter muscle), and seizures may occur. The serotonin syndrome, which may be a result of inhibition of serotonin metabolism, has similar clinical findings to those of malignant hyperthermia and may occur with or without hyperthermia or hypertension. Chronic toxicity clinical findings include tremors, hyperhidrosis, agitation, hallucinations, confusion, and seizures and may be confused with withdrawal syndromes. Laboratory Investigations

Monitoring of the ECG, cardiac monitoring, CPK, ABG, pulse oximeter, electrolytes, blood glucose, and acid–base balance should be maintained. Management

In the case of MAOI overdose, ipecac-induced emesis should not be used. Only activated charcoal alone should be used. If the patient is admitted to the hospital and is well enough to eat, a nontyramine diet should be ordered. Extreme agitation and seizures can be controlled with benzodiazepines and barbiturates. Phenytoin is ineffective. Nondepolarizing neuromuscular blockers (not depolarizing succinylcholine) may be needed in severe cases of hyperthermia and rigidity. If the patient has severe hypertension (catecholamine mediated), phentolamine (Regitine), a parenteral ß-blocking agent, 3 to 5 mg intravenously, or labetalol (Normodyne), a combination of an

a-blocking agent and a ß-blocker, 20-mg intravenous bolus, should be given. If malignant hypertension with rigidity is present, a short-acting nitroprusside and benzodiazepine can be used. Hypertension is often followed by severe hypotension, which should be managed by fluid and vasopressors. Caution: Vasopressor therapy should be administered at lower doses than usual because of exaggerated pharmacologic response. Norepinephrine is preferred to dopamine, which requires release of intracellular amines. Cardiac dysrhythmias are treated with standard therapy but are often refractory, and cardioversion and pacemakers may be needed. For malignant hyperthermia, dantrolene (Dantrium), a nonspecific peripheral skeletal relaxing agent, is administered, which inhibits the release of calcium from the sarcoplasm. Dantrolene is reconstituted with 60 mL sterile water without bacteriostatic agents. Glass equipment must not be used, and the drug must be protected from light and used within 6 hours. Loading dose is 2 to 3 mg/kg intravenously as a bolus, and the loading dose is repeated until the signs of malignant hyperthermia (tachycardia, rigidity, increased end-tidal CO2, and temperature) are controlled. Maximum total dose is 10 mg/kg to avoid hepatotoxicity. When malignant hyperthermia has subsided, 1 mg/kg IV is given every 6 hours for 24 to 48 hours, then orally 1 mg/kg every 6 hours for 24 hours to prevent recurrence. There is a danger of thrombophlebitis following peripheral dantrolene, and it should be administered through a central line if possible. In addition one should administer external cooling and correct metabolic acidosis and electrolyte disturbances. Benzodiazepine can be used for sedation. Dantrolene does not reverse central dopamine blockade; therefore, bromocriptine mesylate (Parlodel) 2.5 to 10 mg should be given orally or through a nasogastric tube three times a day. Rhabdomyolysis and myoglobinuria are treated with fluids. Urine alkalinization should also be treated. Hemodialysis and hemoperfusion are of no proven value. Biogenic amine interactions are managed symptomatically, similar to cases of overdose. For the serotonin syndrome cyproheptadine (Periactin), a serotonin blocker, 4 mg orally every hour for three doses, or methysergide (Sansert), 2 mg orally every 6 hours for three doses, should be considered. The effectiveness of these drugs has not been proven. Disposition

All patients who have ingested more than 2 mg/kg of an MAOI should be admitted to the hospital for 24 hours of observation and monitoring in the intensive care unit because the life-threatening manifestations may be delayed. Patients with drug or dietary interactions that are mild may not require admission if symptoms subside within 4 to 6 hours and the patients remain asymptomatic. Patients with symptoms that persist or require active intervention should be admitted to the intensive care unit. Opioids (Narcotic Opiates)

Opioids are used for analgesia, as antitussives, and as antidiarrheal agents and are illicit agents (heroin, opium) used in substance abuse. Tolerance, physical dependency, and withdrawal may develop.

Toxic Mechanism

At least four main opioid receptors have been identified. The µ receptor is considered the most important for central analgesia and CNS depression. The and d receptors predominate in spinal analgesia. The receptors may mediate dysphoria. Death is a consequence of dose-dependent CNS respiratory depression or secondary to pulmonary aspiration or noncardiac pulmonary edema. The mechanism of noncardiac pulmonary edema is unknown. Dextromethorphan can interact with MAOIs, causing severe hyperthermia, and may cause the serotonin syndrome (see Selective Serotonin Reuptake Inhibitors). Dextromethorphan inhibits the metabolism of norepinephrine and serotonin and blocks the reuptake of serotonin. It is found as a component of a large number of nonprescription cough and cold remedies. Toxic Dose

The toxic dose depends on the specific drug, route of administration, and degree of tolerance. For therapeutic and toxic doses, see Table 24 . In children, respiratory depression has been produced by 10 mg of morphine or methadone, 75 mg of meperidine, and 12.5 mg of diphenoxylate. Infants younger than 3 months of age are more susceptible to respiratory depression. The dose should be reduced by 50%.

TABLE 24 -- Doses and Onset and Duration of Action of Common Opioids Drug Adult Oral Child Oral Dose Onset of Dose Action

Duration of Action

Adult Fatal Dose

Camphored tincture of opium

25 mL

0.25-0.50 mL/kg (0.4 mg/mL)

15-30 min

4-5 h

NA

Codeine

30-180 mg

0.5-1 mg/kg

15-30 min

4-6 h

800 mg

>1 mg/kg is toxic in a child, above 200 mg in adult >5 mg/kg fatal in a child Dextromethorphan

15 mg

0.25 mg/kg

15-30 min

3-6 h

NA

10 mg/kg is toxic Diacetylmorphine; street heroin is less than 10% pure

60 mg

NA

15-30 min

3-4 h

100 mg

Diphenoxylate natiopine (Lomotil)

5-10 mg

NA

120-240 min

14 h

300 mg

7.5 mg is toxic in a child, 300 mg is toxic in adult Fentanyl (Duragesic)

0.1-0.2 mg

0.001-0.002 mg/kg

7-8 min

Intramuscular: ½-2h

1.0 mg

Hydrocodone with APAP (Lortab)

5-30 mg

0.15 mg/kg

30 min

3-4 h

100 mg

Drug

Adult Oral Dose

Child Oral Dose

Onset of Action

Duration of Action

Adult Fatal Dose

Hydromorphone (Dilaudid)

4 mg

0.1 mg/kg

15-30 min

3-4 h

100 mg

Meperidine (Demerol)

100 mg

1-1.5 mg/kg

10-45 min

3-4 h

350 mg

Methadone (Dolophine)

10 mg

0.1 mg/kg

30-60 min

4-12 h

120 mg

Morphine

10-60 mg

0.1-0.2 mg/kg

40 mg/dL) may be associated with clinical toxicity. Chronic intoxication occurs at ingestions greater than 100 mg/kg/d for more than 2 days because of accumulation kinetics. Methyl salicylate (oil of wintergreen) is the most toxic form of salicylate. A dose of 1 mL of 98% contains 1.4 g of salicylate. Fatalities have occurred with ingestion of 1 teaspoonful in children and 1 ounce in adults. It is found in topical ointments and liniments (18% to 30%). Kinetics

Acetylsalicylic acid and salicylic acid are weak acids with a pKa of 3.5 and 3.0, respectively. Acetylsalicylic acid is absorbed from the stomach, from the small bowel, and dermally. Onset of action is within 30 minutes. Methyl salicylate and effervescent tablets are absorbed more rapidly. Salicylate plasma concentration is detectable within 15 minutes after ingestion and peaks in 30 to 120 minutes. The peak may be delayed 6 to 12 hours in cases of large overdose, overdose with enteric-coated or sustained-release preparations, and development of concretions. The therapeutic duration of action is 3 to 4 hours but is markedly prolonged in cases of overdose. Volume distribution is 0.13 L/kg for salicylic acid but increases as the salicylate plasma concentration increases. Protein binding is greater than 90% for salicylic acid at pH 7.4 and a salicylate plasma concentration of 20 to 30 mg/dL, 75% at a salicylate plasma concentration greater than 40 mg/dL, 50% at a salicylate plasma concentration of 70 mg/dL, and 30% at a salicylate plasma concentration of 120 mg/dL. The half-life for salicylic acid is 3 hours after a 300 mg dose, 6 hours after a 1 g overdose, and greater than 10 hours after a 10-g overdose. Elimination includes Michaelis-Menten hepatic metabolism by three saturable pathways: (a) glycine conjugation to salicyluric acid (75%); (b) glucuronyl transferase to salicyl phenol glucuronide (10%); and (c) salicyl aryl glucuronide (4%). Nonsaturable pathways are hydrolysis to gentisic acid (>1%). Ten percent is excreted unchanged. Acidosis increases the severity of the intoxication by increasing the non-ionized salicylate that can cross membranes and enter the brain cells. In kidneys, the unionized salicylic acid undergoes glomerular filtration, and the ionized portion undergoes tubular secretion in proximal tubules and passive reabsorption in the distal tubules. Renal excretion of salicylate is enhanced by alkaline urine. Manifestations

The ingestion of concentrated topical salicylic acid preparations (e.g., wart remover) can cause mucosal caustic injury to the gastrointestinal tract. Occult salicylate overdose should be considered in any patient with unexplained acid–base disturbance. The manifestations of acute overdose of salicylates are as follows: Minimal Symptoms

Tinnitus, dizziness, and deafness may occur at high therapeutic salicylate plasma concentrations of 20 to 30 mg/dL. Nausea and vomiting may occur immediately because of local gastric irritation. Phase I.

Mild manifestations occur at 1 to 12 hours after ingestion with a 6-hour salicylate plasma concentration of 45 to 70 mg/dL. Nausea and vomiting followed by hyperventilation are usually present within 3 to 8 hours after acute overdose. Hyperventilation, an increase in both rate (tachypnea) and depth (hyperpnea), is present but it may be subtle. It results in a mild respiratory alkalosis with a serum pH greater than 7.4 and urine pH greater than 6.0. Some patients may have lethargy, vertigo, headache, and confusion. Diaphoresis may be noted. Phase II.

Moderate manifestations occur at 12 to 24 hours after ingestion with a 6-hour salicylate plasma concentration of 70 to 90 mg/dL. Serious metabolic disturbances, including a marked respiratory alkalosis with anion gap metabolic acidosis, dehydration, and urine pH less than 6.0, may occur. Other metabolic disturbances include hypoglycemia or hyperglycemia, hypokalemia, decreased ionized calcium, and increased BUN, creatinine, and lactate. Mental disturbances (confusion, disorientation, hallucinations) may occur. Hypotension and convulsions have been reported. Phase III.

Severe intoxication occurs more than 24 hours after ingestion with a 6-hour salicylate plasma concentration of 90 to 130 mg/dL. In addition to the above clinical findings, coma and seizures develop and indicate severe intoxication. Pulmonary edema may occur. Metabolic disturbances include metabolic acidemia (pH 7.4

>6.0

5% Dextrose, 0.45% saline

50 (adult) 1 mEq/kg (child)

20

Moderate

Respiratory alkalosis

>7.4 or 6 mo

Chamomile flower[7]

International case reports of liver dysfunction are suspected to be associated with its use Chamomile can cause an allergic reaction, especially in people with severe allergies to ragweed or other members of the daisy family (e.g., echinacea, feverfew, and milk thistle)

Used orally to calm nerves and treat GI spasms and inflammatory diseases of the GI tract Used topically to treat wounds, skin infections, and skin or mucous membrane inflammation

It can cause GI disturbances, headache, and hypotension

1 cup of freshly made tea 34 times daily (1 tbsp or 3 g dried flower in 150 mL boiling water for 5-10 min)

Should not be taken concurrently with other sedatives, such as alcohol or benzodiazepines

Herb/Nutritional Supplement

Common Uses

Reasonable Adult Oral Dosage [*]

Precautions and Drug Interactions Chaste tree berry can have uterus-stimulant properties and should be avoided in pregnancy Women with hormone-dependent conditions (e.g., breast, uterine, and ovarian cancers, endometriosis, and uterine fibroids) and men with prostate cancers should avoid chaste tree berry because it contains progestins

For normalizing irregular menstrual periods and relieving premenstrual complaints For relieving menopausal symptoms For restoring fertility in women For treating acne associated with menstrual cycles Chaste tree berry (Chasteberry, Vitex)[7]

For increasing breast milk production in lactating women

For menstrual irregularities and premenstrual complaints, 30-40 mg/d of the dried berries or an equivalent amount of aqueous-alcoholic extracts (50%-70% v/v) Dried fruit extract, standardized to 0.6% agnusides, is used in doses of 175-225 mg/d For other conditions, no established dosage is documented

Side effects include intramenstrual bleeding, dry mouth, headache, nausea, rash, alopecia, and tachycardia High doses (extract =480 mg/d) can paradoxically decrease lactation Chaste tree berry is believed to have dopaminergic effects and might interact with dopamine antagonists, such as antipsychotics and metoclopramide Chaste tree berry can also decrease the effects of oral contraceptives and hormone replacement therapy


Common Uses


Orally, often used in combination with glucosamine for osteoarthritis

Chondroitin[7]

Topically, used in combination with sodium hyaluronate, as a viscoelastic agent in cataract surgery

Precautions and Drug Interactions Occasional mild side effects include nausea, indigestion, and allergic reactions

Oral: 200-400 mg tid

Chondroitin derived from bovine cartilage carries a potential risk of contamination with diseased animals Adverse effects are rare, but they include headaches, insomnia, sleep disturbances, irritability, and mood changes. Some patients also experience cognitive, perceptual, and motor dysfunction Long-term use of high doses (600-2400 g/d) can cause anemia, thrombocytopenia, hemolysis, hepatic dysfunction, and renal failure

For diabetes, 100 µ g bid for =4 mo or 500 µ g bid for 2 mo

For diabetes For hypercholesterolemia Commonly found in weight-loss products Chromium [7]

Also promoted for body building

For hypercholesterolemia, 200 g tid or 500 µ g bid for 2-4 mo

Two case reports of interstitial nephritis A few studies suggest that chromium can cause DNA damage

For body building, 200-400 g/d

Chromium competes with iron for binding to transferrin and can cause iron deficiency

Chromium picolinate has been used in most studies, even though the chloride form is also available

Antacids, H2blockers, and PPIs can decrease the absorption of chromium


Common Uses


Precautions and Drug Interactions Mild adverse events include gastric distress, nausea, vomiting, and hypotension

As adjunctive treatment for congestive heart failure, angina, hypertension, and diabetes

Coenzyme Q10[7]

Also used for reducing cardiotoxicity associated with doxorubicin

Doses > 300 mg/d can cause elevated liver enzyme levels For heart failure, 100 mg/d in two or three divided doses For angina, 50 mg tid For hypertension, 60 mg bid For diabetes, 100-200 mg/d

Coenzyme Q10 can reduce the anticoagulation effects of warfarin Oral hypoglycemic agents and HMGCoA reductase inhibitors can reduce serum coenzyme Q10 levels Drinking excessive amounts of juice could cause GI upset or diarrhea

To prevent and treat UTIs or Helicobacter pylori infections that can lead to stomach ulcers To prevent dental plaque

Cranberry[7]

As an antioxidant to prevent cardiovascular disease and cancer

Prolonged use of cranberry juice in large doses can increase the risk of kidney stone formation due to its high oxalate content For UTIs, 150-600 mL of cranberry juice daily or 300-400 mg of standardized extract bid For other conditions, no dosage determined

Cranberry can interact with warfarin and cause an increase in INR The effectiveness of PPIs may be reduced by cranberry due to its acidity


Common Uses


Precautions and Drug Interactions Creatine can cause gastroenteritis, diarrhea, heat intolerance, muscle cramps, and elevated serum creatinine levels Creatine is contraindicated in patients taking diuretics

Creatine[7]

To enhance muscle performance, especially during short-duration, highintensity exercise

Loading dose of 20 g/d for 5-7 d followed by a maintenance dose of =2 g/d

Concurrent use with cimetidine, probenecid, or NSAIDs increases the risk of adverse renal effects

An alternative dosing of 3 g/d for 28 d has been suggested

Caffeine can decrease ergogenic effects Most common side effects are androgenic in nature and include acne, hair loss, hirsutism, and deepening of the voice Cases of hepatitis have been reported When used in high doses, DHEA can cause insomnia, manic symptoms, and palpitations DHEA at physiologic doses increases circulating androgens in women, but not in men; it also increases circulating estrogens in both men and women


Common Uses


Replace low-serum DHEA levels in adrenal insufficiency

No information on the safety of

Treat SLE

DHEA in persons

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