Wilderness Medicine: Expert Consult Premium Edition, 6th Edition

WILDERNESS MEDICINE

WILDERNESS MEDICINE Sixth Edition Paul S. Auerbach, MD, MS, FACEP, FAWM Redlich Family Professor of Surgery Division of Emergency Medicine Department of Surgery Stanford University School of Medicine Stanford, California

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

WILDERNESS MEDICINE

ISBN: 978-1-4377-1678-8

Copyright © 2012, 2007, 2001, 1995, 1989, 1983 by Mosby, an imprint of Elsevier Inc. Chapter 83 © 2012 by Michael E. Jacobs and Charles G. Hawley Chapter 3 all figures, tables, and photographs © Dr. Mary Ann Cooper Chapter 29 photographs © Dr. Grant S. Lipman, Elsevier granted non-exclusive license to publish Chapter 20 © Swaminatha Mahadevan No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of product liability, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Wilderness medicine / [edited by] Paul S. Auerbach.—6th ed.     p. ; cm.   Includes bibliographical references and index.   ISBN 978-1-4377-1678-8 (hardcover : alk. paper)   I.  Auerbach, Paul S.   [DNLM:  1.  Wilderness Medicine.  2.  Emergency Treatment—methods.  3.  Environmental Exposure.  4.  Recreation.  5.  Rescue Work.  6.  Survival.  WB 107]   LC classification  not assigned   616.9′8—dc23                      2011032078 Acquisitions Editors: Dolores Meloni and Stefanie Jewell-Thomas Developmental Editor: Lucia Gunzel Publishing Services Manager: Anne Altepeter Associate Project Manager: Jessica Becher Design Direction: Steve Stave Printed in China Last digit is the print number:  9  8  7  6  5  4  3  2  1 

Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org

Contributors Javier A. Adachi, MD, FIDSA, FACP

Associate Professor, Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center; Adjunct Professor, The University of Texas Health Science Center at Houston, Medical School and School of Public Health; Adjunct Professor, Baylor College of Medicine, Houston, Texas; Visiting Professor, Universidad Peruana Cayetano Heredia, Lima, Peru

Martin E. Alexander, BScF, MSc, PhD, RPF

Adjunct Professor, Wildland Fire Science and Management, Department of Renewable Resources, Alberta School of Forest Science and Management, University of Alberta; Honorary Research Associate, Faculty of Forestry and Environmental Management, University of New Brunswick, Fredericton, New Brunswick, Canada; Senior Fire Behavior Research Officer (Retired), Canadian Forest Service, Northern Forestry Centre, Edmonton, Alberta, Canada

Robert C. Allen, DO, FACEP

Colonel, United States Air Force MC CFS (Retired), Contingency Operations Division, United States Air Force School of Aerospace Medicine, Brooks City, Texas

Susan Anderson, MD, MS

Clinical Associate Professor, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California; Travel, Tropical, and Wilderness Medicine Consultant, Travel Medicine and Emergency/Urgent Care, Palo Alto Medical Foundation, Palo Alto, California

Aaron L. Baggish

Associate Director, Cardiovascular Performance Program, Division of Cardiology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts

Jennifer G. Baine, MD

Clinical Instructor, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California

Buddha Basnyat, MD, MSc, FACP, FRCP(E)

Medical Director, Nepal International Clinic, Himalayan Rescue Association; Principal Investigator, Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal

Ryan P. Bayley, MD

Resident Physician, Emergency Medicine, New York-Presbyterian Weill Cornell Medical Center and Columbia University Medical Center, New York, New York

Greta J. Binford, PhD

Associate Professor of Biology, Lewis and Clark College, Portland, Oregon

Nicholas H. Bird, BA, MD, DABFM, DABPM

CEO and Chief Medical Officer, Divers Alert Network, Durham, North Carolina

Christopher J. Andrews, BE, MBBS, MEngSc, PhD, JD, EDIC, DipCSc, GDLP

Ryan Blumenthal, MBChB (Pret), MMed (Med Forens) Pret, FC for Path (SA), Dip For Med (SA)

E. Wayne Askew, PhD

Jolie Bookspan, MEd, PhD, FAWM

Mt Ommaney Family Clinic, Australia

Colonel, United States Army MSC (Retired), Professor and Chair, Division of Nutrition, University of Utah, Salt Lake City, Utah

Dale Atkins, BA

Forensic Pathologist, Department of Forensic Medicine, University of Pretoria, Pretoria, Gauteng, South Africa

Medical Director, Neck and Back Pain Sports Medicine, Academy of Functional Exercise Medicine, Temple University, Philadelphia, Pennsylvania

President, American Avalanche Association; Vice President, Avalanche Rescue Commission; International Commission for Alpine Rescue, North America Training and Education Manager, RECCO, AB, Boulder, Colorado

Ralph S. Bovard, MD, MPH, FACSM

Paul S. Auerbach, MD, MS, FACEP, FAWM

Warren D. Bowman, MD, FACP

Redlich Family Professor of Surgery, Division of Emergency Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California

Kira Bacal, MD, PhD, MPH, FACEP

Phase 2 Director, Medical Programme Directorate, University of Auckland, Auckland, New Zealand

Howard D. Backer, MD, MPH

Director, California Emergency Medical Services Authority

Department of Occupational and Environmental Medicine, HealthPartners, St. Paul, Minnesota

Clinical Associate Professor Emeritus, Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington; Staff Physician (Retired), Department of Internal Medicine, Division of Hematology-Oncology, The Billings Clinic, Billings, Montana

Leslie V. Boyer, MD

Director, Venom Immunochemistry, Pharmacology, and Emergency Response Institute; Associate Professor of Pathology, University of Arizona, Tucson, Arizona

v

CONTRIBUTORS

John E. Bradford, RN, MPAS, PA-C

Charles Clarke, MA, MBBCh, FRCP

Mark A. Brandenburg, MD

Kenneth S. Cohen, MA, MSTh

Peace Corps Medical Officer, United States Peace Corps, Malawi, Lilongwe, Malawi, Africa; Clinical Adjunct Professor, University of Utah Physician Assistant Program, Salt Lake City, Utah

Medical Director, Emergency Department, Bristow Medical Center, Bristow, Oklahoma; Medical Director, Emergency Medical Services, Tulsa Technology Center, Tulsa, Oklahoma

Beau Briese, MD

Resident Physician, Division of Emergency Medicine, Stanford/ Kaiser Emergency Medicine Residency Program, Stanford University, Stanford, California

Colin M. Bucks, MD

Clinical Instructor, Division of Emergency Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California

George H. Burgess

Florida Program for Shark Research, Florida Museum of Natural History, University of Florida, Gainesville, Florida

Sean P. Bush, MD, FACEP

Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom

Independent Scholar, Traditional Healer, Nederland, Colorado

Stephen D. Coleman, MD

Clinical Assistant Professor, Department of Anesthesia, Pain Management Division, Stanford University School of Medicine, Stanford, California

Bryan R. Collier, DO, FACS, CNSP

Assistant Professor of Surgery, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee

Shon Compton, MPAS, PA-C

Major, Specialty Corps (Retired), Chief Instructor, Center for Predeployment Medicine, United States Army Medical Department Center and School, Fort Sam Houston, Texas

Benjamin B. Constance, MD

Professor of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, California

Chief Resident Physician, Division of Emergency Medicine, Stanford/Kaiser Emergency Medicine Residency Program, Stanford University, Stanford, California

Frank K. Butler Jr., BS, MD

Donald C. Cooper, PhD, MBA, EMT-P

Dale J. Butterwick, ATC(C), BA, MSc

Jimmy L. Cooper, MD, FACEP

Chairman, Committee on Tactical Combat Casualty Care, Defense Health Board, Pensacola, Florida

Associate Professor, Faculty of Kinesiology, University of Calgary; Former President, Canadian Pro Rodeo Sport Medicine Team, Calgary, Alberta, Canada

Steven C. Carleton, MD, PhD

Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio

Betty Carlisle, MD

Adjunct Assistant Professor, Department of Public Health and Preventive Medicine, State University of New York Upstate Medical University; Staff Physician, Emergency Department, St. Joseph’s Hospital, Syracuse, New York

Scott P. Carroll, PhD

Department of Entomology, University of California, Davis, California

John W. Castellani, PhD

Research Physiologist, Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts

Samuel N. Cheuvront, PhD

Research Physiologist, Division of Thermal and Mountain Medicine, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts

Richard F. Clark, MD

Professor of Clinical Medicine, Director, Division of Medical Toxicology, University of California, San Diego, San Diego, California

vi

State Fire Marshal, Department of Commerce, State of Ohio, Columbus, Ohio

Staff Physician, Department of Emergency Medicine, Director, Center for Predeployment Medicine, San Antonio, Texas

Mary Ann Cooper, MD, FAMS, FAAEM

Emerita Professor, Department of Emergency Medicine, University of Illinois College of Medicine, Chicago, Illinois

Kevin Coppock, BSc, MSc

Head of Mission, Northern Sudan, Médecins Sans Frontières, Khartoum, Sudan

Larry I. Crawshaw, PhD

Professor Emeritus, Department of Biology, Portland State University, Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon

Joy E. Crook, MD, MPH

Instructor, Department of Emergency Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Gregory A. Cummins, DO, MS

Assistant Clinical Instructor, Department of Internal Medicine, Kansas University of Medicine and Biosciences; Hospitalist, Department of Medicine, North Kansas City Hospital, Kansas City, Missouri

Tracy A. Cushing, MD, MPH, FACEP, FAWM

Assistant Professor, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado; Attending Physician, Fellowship Director, Denver Health Wilderness Medicine Fellowship, Department of Emergency Medicine, Denver Health Medical Center, Denver, Colorado

Specialty Doctor, Emergency Department, Bristol Royal Infirmary, Bristol, United Kingdom

Daniel F. Danzl, MD

Professor and Chair, Department of Emergency Medicine, University of Louisville School of Medicine, Louisville, Kentucky

Ian Davis, MBBCH, BSc (Hons)

Herbert L. DuPont, MD

Professor and Director, Center for Infectious Diseases, University of Texas School of Public Health and Medical School; Chief of Internal Medicine, St. Luke’s Episcopal Hospital; Vice Chairman, Department of Medicine, Baylor College of Medicine, Houston, Texas

Blair Dillard Erb, BS, MD, FACP, FACC

Past President, Wilderness Medical Society, The Study Center, Townsend, Tennessee

Resident Medical Officer, Department of Accident and Emergency, Cirencester Hospital, Gloucestershire; Polar Medicine, Medical Cell, Royal Geographical Society, London; Chief Medical Officer, Polar Challenge, Venture Group, Cirencester, England, United Kingdom

Timothy B. Erickson, MD

Kathleen Mary Davis, BScF, MSc

Charles D. Ericsson, MD

Kevin Davison, ND, Lac

Peter J. Fagenholz, MD

Superintendent, Montezuma Castle and Tuzigoot National Monument, National Park Service, Camp Verde, Arizona

Director, Maui Prolotherapy Clinic, Hamakuapoko, Peahi, Haiku, Maui, Hawaii

Chad P. Dawson, BS, MPS, PhD

Professor, Forest and Natural Resources Management, State University of New York College of Environmental Science and Forestry, Syracuse, New York

Janice A. Degan, RN, MS

Senior Research Nurse, Venom Immunochemistry, Pharmacology, and Emergency Response Institute, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona

Thomas G. DeLoughery, MD, FACP

Professor, Department of Emergency Medicine, Division of Medical Toxicology; Director, Center for Global Health, University of Illinois College of Medicine, Chicago, Illinois

Professor of Medicine, Head, Clinical Infectious Disease, Division of Infectious Disease, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas

Department of Surgery, Division of Trauma, Emergency Surgery, and Critical Care, Massachusetts General Hospital; Instructor in Surgery, Harvard Medical School, Boston, Massachusetts

Joanne N. Feldman, MD, MS

Clinical Faculty, Division of Emergency Medicine, University of California, Los Angeles, Los Angeles, California

D. Nelun Fernando, BA, MA, PhD

Department of Geography, Rutgers University, New Brunswick, New Jersey

Murray E. Fowler, BS, DVM

Professor of Medicine, Pathology, and Pediatrics, Head, Benign Hematology Section, Oregon Health and Science University, Portland, Oregon

Professor Emeritus, Veterinary Medicine and Epidemiology, University of California, Davis, California

Arlene E. Dent, MD, PhD

Assistant Professor, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio

Clinical Associate Professor, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Thomas F. Ditzler, PhD, MA, FRSPH, FRAI

Michael E. Franco, Major, MSM, MPAS, PA-C

Director of Research, Department of Psychiatry, Tripler Army Medical Center, Honolulu, Hawaii

Mark Donnelly, MD

Salem Emergency Department, Salem, Oregon

Howard J. Donner, MD

Wilderness Medicine Instructor, Mountain Medical Seminars, Bozeman, Montana; Adventure Training Coordinator, The Finer Points of Flying, San Francisco, California

Mark S. Fradin, MD

Chief, Plans and Operations, United States Army Environmental Management Systems Programs Office, United States Army Medical Department Center and School, Fort Sam Houston, Texas

Luanne Freer, MD, FACEP, FAWM

Medical Director, Medcor, Yellowstone National Park, Wyoming; Founder and Director, Everest Base Camp Medical Clinic, Himalayan Rescue Association, Kathmandu, Nepal

Eric Douglas, BA, EMT, DMT

Steven P. French, MD, BS, MS, IUCN, ASNE, SFW

Jennifer Dow, MD, FACEP, FAWM

Nathan K. Friedline, MD

Director, Education, Divers Alert Network, Durham, North Carolina

Medical Director, Denali National Park and Preserve; Medical Director, National Park Service, Alaska Region, Department of Emergency Medicine, Alaska Regional Hospital, Anchorage, Alaska

Co-founder and Research Director, Yellowstone Grizzly Foundation, Jackson Hole, Wyoming

Resident, Division of Emergency Medicine, University of Utah, Salt Lake City, Utah; Captain, United States Army, 32nd Medical Brigade, Fort Sam Houston, Texas

vii

CONTRIBUTORS

Jon Dallimore, MB, BS, MSc, MRCGP, MCEM, FFTM RCPS (Glasg), DCH, DRCOG

CONTRIBUTORS

Raymond R. Gaeta, MD

Charles G. Hawley, BS

Tom Garrison, BS, MA, PhD

David M. Heimbach, MD

Associate Professor, Department of Anesthesiology, Medical Director, Pain Management Service, Stanford University School of Medicine, Stanford, California

Professor, Department of Oceanography, Orange Coast College, Costa Mesa, California; Adjunct Professor, Higher Education, University of Southern California, Los Angeles, California

Daniel Garza, MD

Assistant Professor, Department of Orthopaedic Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California

Alan Gianotti, MS, MD

Clinical Assistant Professor, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California

Gordon G. Giesbrecht, BPE, BTh, MPE, PhD

Professor of Thermophysiology, Health Leisure and Human Performance Research Institute, University of Manitoba; Professor, Department of Anesthesia, University of Manitoba, Winnipeg, Manitoba, Canada

Kimberlie A. Graeme, BS, MD

Division of Emergency Medicine, Naval Medical Center San Diego, San Diego, California

Colin K. Grissom, MD

Associate Professor of Medicine, University of Utah School of Medicine; Associate Medical Director, Shock Trauma Intensive Care Unit, Intermountain Medical Center, Murray, Utah

Kirby R. Gross, MD, FACS

Trauma Services, United States Army Medical Department, Walter Reed Army Medical Center, Washington, DC

Peter H. Hackett, MD

Clinical Professor of Surgery, Department of Emergency Medicine, Altitude Research Center, University of Colorado Denver School of Medicine, Denver, Colorado; Director, Institute for Altitude Medicine, Telluride, Colorado

N. Stuart Harris, MD

Chief, Division of Wilderness Medicine, Director, Wilderness Medicine Fellowship, Department of Emergency Medicine, Massachusetts General Hospital; Assistant Professor of Surgery, Harvard Medical School, Boston, Massachusetts

Patricia R. Hastings, DO, MPH, FACEP, RN, NREMT

Colonel, Medical Corps, United States Army; MEDCOM Liaison, Department of Homeland Security, Washington, DC, Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, Texas

Seth C. Hawkins, MD, FACEP, FAWM

Director, Mountain Emergency Physicians; Medical Director, Burke Emergency Medical Services Special Operations Team; Executive Director, Appalachian Center for Wilderness Medicine, Morganton, North Carolina; Assistant Professor, Emergency Medical Care Program, Western Carolina University, Cullowhee, North Carolina

viii

Vice President, West Marine, Safety at Sea Moderator, United States Sailing Technical Board Member, American Boat and Yacht Council, Santa Cruz, California

Professor of Surgery, University of Washington School of Medicine, Seattle, Washington

Carlton E. Heine, MD, PhD, FACEP, FAWM

Clinical Instructor, University of Washington School of Medicine, Seattle, Washington; Attending Physician, Emergency Department, Bartlett Regional Hospital, Juneau, Alaska

Lawrence E. Heiskell, MD, FACEP, FAAFP

International School of Tactical Medicine, Palm Springs, California

John C. Hendee, PhD

Emeritus Professor and Dean (Retired), University of Idaho, College of Natural Resources, Moscow, Idaho

Henry J. Herrmann, DMD, FAGD Dentist, Falls Church, Virginia

Ronald L. Holle, BS, MS

Meteorologist, Holle Meteorology and Photography, Oro Valley, Arizona

Renee Y. Hsia, MD, MSc

Assistant Professor, Department of Emergency Medicine, University of California, San Francisco; Attending Physician, Department of Emergency Services, San Francisco General Hospital, San Francisco, California

Franklin R. Hubbell, DO

Physician and Director, Urgent Care and Spine Center, Saco River Medical Group; Physician, Director of Education, Stonehearth Open Learning Opportunities Schools; Author, Wilderness Medicine Newsletter, TMC Books, Conway, New Hampshire

Stephen E. Hudson, CEO, NTC

National Training Coordinator, National Cave Rescue Commission, National Speleological Society, Huntsville, Alabama; President, Pigeon Mountain Industries, Lafayette, Georgia

Cynthia L. Idzik-Starr, DDS

Assistant Professor, Director of Urgent Care, Department of Oral and Maxillofacial Surgery, University of Maryland Dental School, Baltimore, Maryland

Christopher H.E. Imray, PhD, MB, BS, DiMM, Clin Med Sci, FRCS, FRCP

Professor of Surgery, Warwick Medical School, Department of Vascular Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom

Kenneth V. Iserson, MD, MBA, FACEP, FAAEM, FIFEM

Professor Emeritus, Department of Emergency Medicine, The University of Arizona, Tucson, Arizona

United States Coast Guard Licensed Captain; Founder and Program Director, MedSail (Medicine for Mariners and Safety at Sea); Medical Director, Vineyard Medical Services, Martha’s Vineyard, Massachusetts

Ramin Jamshidi, MD

Fellow, Department of Pediatric Surgery, Children’s Hospital of Wisconsin; Clinical Instructor, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; Adjunct Professor, Physics Department, University of California, San Francisco, San Francisco, California

James M. Jeffers, BA, LLB, LLM, MPhil

PhD Candidate, Department of Geography, Rutgers University, New Brunswick, New Jersey

Jamie G. Jenkins, MD

Brian J. Krabak, MD, MBA

Clinical Associate Professor, Department of Rehabilitation, Orthopedics, and Sports Medicine; Team Physician, Seattle Children’s Sports Medicine, Seattle University Athletics, University of Washington; Team Physician, USA Swimming; Medical Director, RacingThePlanet: 4 Deserts Ultra Marathon Series, Seattle, Washington

Andrew C. Krakowski, MD

Pediatrician and Dermatologist, Rady Children’s Hospital of San Diego, University of California, San Diego, San Diego, California; Founder and Director, boonDOCS Wilderness and Travel Medicine, La Jolla, California

Peter Kummerfeldt, AD

President, OutdoorSafe, Former Survival Training Director, United States Air Force Academy, Colorado Springs, Colorado

Ultrasound Fellow, Department of Emergency Medicine, Washington Hospital Center, Georgetown University Hospital, Union Memorial Hospital, Washington, DC

Ashley R. Laird, MD

Kirsten Johnson, MD, MPH, CCFP-EM

Carolyn S. Langer, MD, JD, MPH

Assistant Professor, Department of Family Medicine; Director, University Humanitarian Studies Initiative; Affiliated Faculty, Institute for Health and Social Policy, McGill University, Montreal, Canada; Affiliated Faculty, Harvard Humanitarian Initiative, Harvard University, Cambridge, Massachusetts

Hemal K. Kanzaria, MD

Resident Physician, Department of Emergency Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, California

Emergency Physician, Sonora Regional Medical Center, Sonora, California

Instructor, Harvard Massachusetts

School

of

Public

Health,

Boston,

Patrick H. LaValla

CEO, ERI International; Operations Chief, All Hands Consulting; Former President, National Association for Search and Rescue, Olympia, Washington

Jay Lemery, MD, FACEP, FAWM

Lee A. Kaplan, MD

Clinical Professor, Department of Dermatology, University of California, San Diego Health System, La Jolla, California

Assistant Professor, Weill Cornell Medical College; Attending Physician, New York Presbyterian Hospital; President-Elect, Wilderness Medical Society; Visiting Scientist, François-Xavier Bagnoud Center for Health and Human Rights, Harvard School of Public Health, Boston, Massachusetts

Misha R. Kassel, MD

Lisa R. Leon, PhD

Stephanie Kayden, MD, MPH

Benjamin D. Levine, MD, FACC, FACSM

Clinical Instructor, Departments of Emergency Medicine and Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California

Director, Harvard International Emergency Medicine Fellowship; Attending Physician, Brigham and Women’s Hospital; Instructor, Harvard Medical School; Faculty, Harvard Humanitarian Initiative, Boston, Massachusetts

James W. Kazura, MD

Professor of International Health and Medicine, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio

Robert W. Kenefick, PhD

Research Physiologist, Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts

Alexa B. Kimball, MD, MPH

Vice Chair, Department of Dermatology, Massachusetts General Hospital; Associate Professor, Harvard Medical School, Boston, Massachusetts

Judith R. Klein, MD, FACEP

Research Physiologist, Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts

Director, Institute for Exercise and Environmental Medicine; S. Finley Ewing Jr., Chair for Wellness, Texas Health Presbyterian Dallas; Harry S. Moss Heart Chair for Cardiovascular Research; Professor of Medicine and Cardiology, Distinguished Professorship in Exercise Science, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Matthew R. Lewin, MD, PhD, FACEP

Director, Center for Exploration and Travel Heath, California Academy of Sciences, San Francisco, California

James R. Liffrig, MD, MPH, FAAFP

Chair, Department of Family Medicine, Womack Army Medical Center, Fort Bragg, North Carolina; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Grant S. Lipman, MD, FACEP

Clinical Assistant Professor, Division of Emergency Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California

Assistant Professor, Department of Emergency Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, California ix

CONTRIBUTORS

Michael Jacobs, MD, FAWM

CONTRIBUTORS

Joanne Liu, MDCM, FRCPC

Board of Directors, Médecins Sans Frontières-Switzerland, Assistant Professor, Sainte-Justine Hospital, Montreal, Canada

Vicki Mazzorana, MD, FACEP, FAAEM, FAWM

Andrew M. Luks, MD

Assistant Professor, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington

Associate Clinical Professor, Department of Emergency Medicine, University of Nevada School of Medicine; Codirector, Wilderness Medicine Clerkship; Co-medical Director, Death Valley, Joshua Tree National Park, Mojave National Reserve; Ringside Physician, Nevada Athletic Commission, Las Vegas, Nevada

Binh T. Ly, MD, FACMT

Loui H. McCurley, RAT, TRS

Professor, Director, Medical Toxicology Fellowship, Division of Medical Toxicology; Director, Emergency Medicine Residency, Department of Emergency Medicine, University of California San Diego, California Poison Control System, San Diego, California

Edgar Maeyens Jr., MD

Board of Visitors, Nicholas School of the Environment, Duke University, Durham, North Carolina; Private Practice Dermatology, Dermatopathology and Mohs Surgery, Coos Bay, Oregon

Swaminatha V. Mahadevan, MD, FACEP, FAAEM

Associate Professor of Surgery and Associate Chief, Division of Emergency Medicine, Stanford University School of Medicine; Emergency Department Medical Director, Stanford University Medical Center, Stanford, California

Rick Marinelli, ND, MAcOM

Clinical Professor, National College of Natural Medicine, Doctoral Faculty, Division of Biomedicine, Oregon College of Oriental Medicine, Portland, Oregon

David S. Markenson, MD, FAAP, FACEP

Medical Director, Disaster Medicine and Regional Emergency Services, Westchester Medical Center, Maria Fareri Children’s Hospital; Professor of Pediatrics, New York Medical College; Director, Center for Disaster Medicine and Professor of Clinical Public Health, New York Medical College School of Health Sciences and Practice, Valhalla, New York

Millicent Marmer, BA, MS

Graduate Student, Alden March Bioethics Institute, Albany Medical College, Albany, New York

Armando Márquez Jr., MD, FACEP

Assistant Clinical Professor, Director, Emergency Medical Services, Department of Emergency Medicine, University of Illinois College of Medicine, Chicago, Illinois

Denise Martinez, MS, RD

Adjunct Faculty, Division of Nutrition, University of Utah, Salt Lake City, Utah

Nicholas P. Mason, MB, ChB, FRCA

Consultant in Intensive Care Medicine, Royal Gwent Hospital, Newport, United Kingdom

Michael J. Matteucci, MD, FAAEM

Assistant Professor, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Director, Emergency Medicine Residency Program, Emergency Medicine Department, Naval Medical Center San Diego, San Diego, California

x

Technical Rescue Specialist, Alpine Rescue Team, Evergreen, Colorado; Technical Director, Vertical Rescue Solutions; Vice President, Pigeon Mountain Industries, Denver, Colorado

Marion C. McDevitt, DO, MPH

Associate Director, Wilderness Medicine Emergency Medical Services Fellowship; Associate Director, Global Health Fellowship; Assistant Professor, Division of Emergency Medicine, University of Utah, Salt Lake City, Utah

Marilyn McHarg, MSc (A), LLD (Hon)

Executive Director, Médecins Sans Frontières-Canada, Toronto, Ontario, Canada

Scott E. McIntosh, MD, MPH

Assistant Professor, Division of Emergency Medicine, University of Utah, Salt Lake City, Utah

Christopher M. McStay, MD, FACEP, FAWM

Assistant Professor of Emergency Medicine, Chief of Service, Bellevue Hospital Center Emergency Department, Department of Emergency Medicine, New York University School of Medicine, New York, New York

Timothy P. Mier, BA, EMT-P

Deputy Fire Marshal, Cuyahoga Falls Fire Department, Cuyahoga Falls, Ohio

Alicia B. Minns, MD

Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, University of California, San Diego, San Diego, California

John Mioduszewski, BA, MA

Department of Geography, Rutgers University, New Brunswick, New Jersey

James K. Mitchell, PhD

Professor of Geography, Rutgers University, New Brunswick, New Jersey

James Moore, RN, BSc (Hons), Dip TravMed, MFTM, RCPS (Glasg), FRGS

Director, Travel Health Consultancy, Exeter, Devon, United Kingdom

Larry A. Moore, MD

Department of Emergency Medicine, Penrose-St. Francis Hospital, Wilderness Medicine Instructor, WildernessWise, Colorado Springs, Colorado

Barry Morenz, MD

Associate Professor of Psychiatry, Department of Psychiatry, College of Medicine, University of Arizona, Tucson, Arizona

Professor of Surgery and Biomedical Informatics, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee

Roger B. Mortimer, MD

Health Sciences Associate Clinical Professor, Department of Family and Community Medicine, University of California, San Francisco; Fresno Medical Education Program, Western Region Coordinator, National Cave Rescue Commission, Fresno, California

Michael J. Mosier, MD

Assistant Professor of Surgery, Loyola University Medical Center, Maywood, Illinois

Parveen K. Parmar, MD, MPH

Associate Director, International Emergency Medicine Fellowship, Brigham and Women’s Hospital; Associate Faculty, Harvard Humanitarian Initiative, Harvard Medical School, Boston, Massachusetts

Naresh J. Patel, DO

Private Practice, Fort Wayne Allergy and Asthma Consultants, Fort Wayne, Indiana

Sheral S. Patel, MD, FAAP

Consultant, Pediatrics and Pediatric Infectious Diseases, Hartford, Connecticut

Martin I. Radwin, MD

Robert W. Mutch, BA, MScF, DF (Honorary) Consultant, Fire Management Applications, Darby, Montana

Department of Medicine, Granger Medical Clinic, Chief of Gastrointestinal Endoscopy, Department of Medicine, Pioneer Valley Hospital, Salt Lake City, Utah

Kei Nagashima, MBSS, DMSci

Sheila B. Reed, MS

Professor, Laboratory of Integrative Physiology (Body Temperature and Fluid Laboratory), School of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan

Mayumi Nakamura, PhD

Consultant, Disaster Risk Reduction and Development, Middleton, Wisconsin

William P. Riordan Jr., MD, MS†

Visiting Researcher, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan

Assistant Professor of Surgery, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee

Eric K. Noji, MD, MPH

Robert C. Roach, PhD

Chairman and CEO, Noji Global Health and Security LLC, Director (Retired), International Emergency and Refugee Health Program, Centers for Disease Control and Prevention, Washington, DC

Robert L. Norris Jr., MD

Professor of Surgery, Stanford University School of Medicine; Chief, Division of Emergency Medicine, Stanford University Medical Center, Stanford, California

Director, Altitude Research Center; Co-Chair, International Hypoxia Symposia, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado

David A. Robinson, PhD

Professor and New Jersey State Climatologist, Department of Geography, Rutgers University, New Brunswick, New Jersey

Eloy Rodriguez, PhD

Command Surgeon, United States Army Training and Doctrine Command, Fort Monroe, Virginia

James A. Perkins Endowed Professor of Environmental and Toxicology Studies, Institute of Comparative Environmental Toxicology, Department of Plant Biology, Cornell University, Ithaca, New York

Lesley J. Ogden, MD, MBA, FACEP

Nancy V. Rodway, MD, MPH, MS

Karen K. O’Brien, MD

Staff Physician and Assistant Emergency Room Director, Department of Emergency Medicine, Samaritan North Lincoln Hos­ pital, Lincoln City, Oregon; Clinical Faculty, Department of Emergency Medicine, Western University of Health Sciences, Pomona, California; Affiliate Assistant Professor, School of Medicine, Oregon Health and Science University, Portland, Oregon

Bohdan T. Olesnicky, MD

Medical Director of Occupational Medicine and Ambulatory Care, Lake Health Hospital System, Painesville, Ohio; Adjunct Faculty, Department of Occupational Medicine, Ohio State University College of Medicine, Columbus, Ohio

Richard S. Salkowe, DPM, FACFAS, FAWM

PhD Candidate, Department of Geography, Environmental Science, and Policy, University of South Florida, Tampa, Florida

SWAT Team Physician, Palm Springs Police Department, Palm Springs, California; Partner, Global Protection Medical Group, Indian Wells, California; Director of EMS, Eisenhower Medical Center, Rancho Mirage, California

Sandra M. Schneider, MD

Sheryl Olson, BSN, RN, FAWM, CCRN

Robert B. Schoene, MD, FACP

Outdoor Survival and Navigation Instructor, Flight Nurse, Wilderness Safety Instructor, Colorado Springs, Colorado

Edward J. Otten, MD

Professor of Emergency Medicine and Pediatrics, Director, Division of Toxicology, University of Cincinnati, Cincinnati, Ohio

Professor and Chair Emeritus, Department of Emergency Medicine, University of Rochester, Rochester, New York

Clinical Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, Washington, Bozeman Deaconess Hospital, Bozeman, Montana

Justin Sempsrott, MD, EMT

Emergency Medicine Resident, University of Nevada School of Medicine, Las Vegas, Nevada †

Deceased.

xi

CONTRIBUTORS

John A. Morris Jr., MD, FACS

CONTRIBUTORS

Jamie R. Shandro, MD, MPH

Assistant Professor, Division of Emergency Medicine, University of Washington School of Medicine, Seattle, Washington

Charley Shimanski

Education Director and Past President, Mountain Rescue Association; Senior Vice President, Disaster Services, American Red Cross, Washington, DC

Uta S. Shimizu, MD

Clinical Instructor, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California

David R. Shlim, MD

Jackson Hole Travel and Tropical Medicine, Jackson, Wyoming

Joshua D. Shofner, MD

Resident, Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts

Julie A. Switzer, MD

Assistant Professor, Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota; Director, Geriatric Orthopaedic Trauma Program, Regions Hospital, St. Paul, Minnesota

Robert I. Tilling, BA, MS, PhD

Senior Research Volcanologist, Volcano Science Center, U.S. Geological Survey, Menlo Park, California

Ken Tokizawa, PhD

Assistant Professor, Faculty of Sport Sciences, Waseda University, Tokorozawa, Saitama, Japan

Joseph E. Tonna, MD

Division of Emergency Medicine, Stanford/Kaiser Emergency Medicine Residency Program, Stanford University School of Medicine, Stanford, California

David A. Townes, MD, MPH, DTM&H

Eunice Singletary, MD, FACEP

Clinical Associate Professor, Department of Emergency Medicine, University of Virginia, Charlottesville, Virginia

Associate Professor of Medicine, Division of Emergency Medicine; Adjunct Associate Professor of Global Health, Department of Global Health, University of Washington School of Medicine, Seattle, Washington

Kieran Smart, MBChB, MSc, MPH, MRCGP

Stephen J. Traub, MD

Physician, Florida FL-3 Disaster Medical Assistance Team, Florida State Medical Response Team Region 4; Advisor, Space Medicine Associates; Adjunct Clinical Assistant Professor, Department of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville, Florida

Jennifer Cohen Smith, MD

Medical Toxicologist, Banner Good Samaritan Medical Center, Phoenix, Arizona

Will Smith, MD, EMT-P

Clinical Faculty, Division of Emergency Medicine, WWAMI, University of Washington School of Medicine, Seattle, Washington; Medical Director, Teton County Search and Rescue, Jackson Hole Fire/EMS, Grand Teton National Park; President and Medical Director, Wilderness and Emergency Medicine Consulting, LLC; Faculty, Student/Resident Rotation Coordinator, Department of Emergency Medicine, St. John’s Medical Center, Jackson, Wyoming

Matthew C. Spitzer, MD, DTMH

Chairman, Department of Emergency Medicine, Mayo Clinic Arizona, Phoenix, Arizona; Assistant Professor of Emergency Medicine, Mayo Medical School, Rochester, Minnesota

Yuki Uchida, MS

PhD Student, Laboratory of Integrative Physiology (Body Temperature and Fluid Lab), Graduate School of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan

Sydney J. Vail, MD, FACS

Director of Trauma Surgery, Medical Director, Tactical Medicine Program, Trauma Center, Maricopa Medical Center, Phoenix, Arizona

Karen B. Van Hoesen, MD

Clinical Professor, Department of Emergency Medicine, University of California, San Diego; Director, University of California San Diego Diving Medicine Center; Director, Undersea and Hyperbaric Medicine Fellowship, University of California San Diego, San Diego, California

President, Doctors Without Borders/Médecins Sans Frontières, Member, International Council and International Council Board, Médecins Sans Frontières; Assistant Clinical Professor of Medicine, Director, Predoctoral Education, Center for Family and Community Medicine, College of Physicians and Surgeons of Columbia University, New York, New York

Michael VanRooyen, MD, MPH, FACEP

Alan M. Steinman, MD, MPH, FACPM

Raghu Venugopal, MD, MPH, FRCPC

Rear Admiral (Retired), United States Public Health Service, Director of Health and Safety, United States Coast Guard, Olympia, Washington

Robert C. Stoffel

CEO, Emergency Response International; Prime Survival Training Contractor, Department of Homeland Security; Customs and Border Protection, United States Coast Guard Aviation Survival Technician Program, Cashmere, Washington

Jeffrey Suchard, MD

Professor of Clinical Emergency Medicine, Director of Medical Toxicology, Department of Emergency Medicine, University of California, Irvine Medical Center, Orange, California xii

Chief, International Division, Department of Emergency Medicine, Brigham and Women’s Hospital; Director, Harvard Humanitarian Initiative, Harvard University; Associate Professor, Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts

Assistant Professor of Medicine, University of Toronto; Attending Physician, Department of Emergency Medicine, University Health Network, Toronto, Ontario, Canada

Brandee L. Waite, MD

Medical Director, Racing The Planet: 100, Ultra Marathon Series; Assistant Professor, Physical Medicine and Rehabilitation, Sports Medicine, University of California, Davis Medical Center, Sacramento, California

John Walden, MD, DTM&H

Professor and Chairman, Department of Family and Community Health, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia

Emeritus Professor of Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

Eric A. Weiss, MD, FACEP

Associate Professor of Surgery, Director, Wilderness Medicine Fellowship, Division of Emergency Medicine, Stanford University School of Medicine; Medical Director, Office of Emergency Management, Stanford University Medical Center, Lucile Packard Children’s Hospital, Stanford, California

Jan West, PhD

Visiting Professor of Biology, Soka University of America, Aliso Viejo, California

James A. Wilkerson III, MD

Merced Pathology Medical Group (Retired), Merced, California

Tamae Yoda, PhD

Associate Professor, Department of Interdisciplinary Studies, Faculty of International Liberal Arts, Dokkyo University, Soka, Saitama, Japan

Lynn E. Yonge, MD, FAAFP, FAWM

Chairman, Environmental Council, Wilderness Medical Society, Director, Wilderness Medicine Training, Outward Bound, Assistant Clinical Professor, The University of South Alabama College of Medicine, Mobile, Alabama

Ken Zafren, MD, FAAEM, FACEP, FAWM

Clinical Associate Professor of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California; Staff Emergency Physician, Alaska Native Medical Center, Alaska Mountain Rescue Group, Anchorage, Alaska; Vice President, International Commission for Mountain Emergency Medicine; Associate Medical Director, Himalayan Rescue Association, Kathmandu, Nepal.

xiii

CONTRIBUTORS

David A. Warrell, MA, DM, DSc, FRCP, FRCPE, FMedSci, HonFZS, FRGS

Foreword Two hours into my first trans-Pacific flight to Hong Kong (on my way to Nepal), a flight attendant put out a call to see if there was a physician on board. I raised my hand and was taken to see a 22-year-old American soldier who was suffering a moderately severe allergic reaction to peanuts. The young man was flushed, had a diffuse urticarial rash, and felt some swelling in his throat. He was so itchy he could not sit still. The reaction had been going on for 45 minutes. As I looked him over, the captain of the plane came down the aisle to talk to me. “We’re as close as we’re going to be to Anchorage,” he said. “We can dump the entire trans-Pacific load of fuel and land there, if you say so.” I greeted this with disbelief. A few hours into my first trip to Asia, and suddenly I was in charge of the plane. I did not want to land in Anchorage if we did not have to (apart from not wanting to dump 40,000 gallons of fuel into the ocean). I asked the flight attendants to bring me the first-aid kit from the plane. I would give the soldier a shot of epinephrine and an antihistamine tablet, and we could keep going. “We don’t carry a first-aid kit,” came the reply. “We have a few bandages, that’s it.” I looked at the soldier. I did not think he was in danger of dying, but it would be a long flight for him with itchy skin and a swollen face. On the other hand, hundreds of people would be delayed a day or more, at a cost of hundreds of thousands of dollars, if we diverted to Anchorage. It occurred to me that someone on a Boeing 747 with 400 passengers might be carrying a bee sting kit. I asked the flight attendant to make an announcement, and three people raised their hands. I accepted one of the kits, injected the soldier, gave him some diphenhydramine, and watched him quickly improve. I told the captain that we could continue flying to Hong Kong. Solving problems with what you have at hand is one of the main themes of wilderness medicine, a discipline that had yet to evolve in 1979 when I was on that flight. Ten days later, I was trekking on my way to the Himalayan Rescue Association Aid Post at Pheriche, a yak-herding village at 14,000 feet, near the base of Mt Everest. Eating dinner at a teahouse next to the Thyangboche monastery, I was asked if I could help an 84-yearold Sherpa man just up the valley in Pangboche. He had fallen down his stairs and sustained a scalp laceration the day before. I was not carrying suture supplies, but I had just visited the Kunde Hospital and was familiar with the staff, so I wrote a note to request instruments and suture material. A Sherpa runner carried the note and would return with the supplies the next morning. In the morning, I walked a couple of hours to Pangboche, where I was led to the house of the man who had fallen down. He lay inside, moaning, and his hair was densely matted with blood. We carried him outside into the sun, where it was warm enough to work and there was good light. I put the instruments in a pot of water and boiled them on the hearth inside. I had no gloves and no sterile field. I poured povidone-iodine into the bowl that held the instruments and used the bowl as my sterile field, reaching into the disinfectant each time I needed to use an instrument. This kept both my hands and the instruments relatively sterile as I worked. The laceration was truly major. It split the old man’s right eyebrow and extended across his forehead and over the crown of his head to the back of his neck. A huge skin flap had been created, so I lifted it up and irrigated underneath it with copious quantities of water I had boiled earlier. I began to sew. The man moaned and muttered as I worked. I asked one of the Sherpas what he was saying. “He’s saying, ‘Leave me alone. I just want to die.’ ”

I finished the repair and placed a padded dressing on his head. I gave instructions to his son and continued my journey to the Pheriche aid post. Three days later in Pheriche, the defining case in my wilderness medicine education arrived on the back of a yak. The patient being carried down the valley was a young New Zealand nurse named Barbara. She had not been feeling well for 2 days at 16,000 feet and was no longer able to descend under her own power. Barbara was alert and oriented, although she appeared very tired. She denied having a headache, nausea, or shortness of breath over the past 2 days, and she had just descended 2000 feet. I gave her a cup of tea. She drank half the cup and then lay down and fell asleep. I sat in a chair across the room and watched her. I half-convinced myself that she looked a little blue, then talked myself out of it. She had just descended a considerable distance, with only mild symptoms of possible altitude illness. She could not have high-altitude cerebral edema (HACE). I continued this internal debate for about an hour, until I felt like I needed to know if she was okay. I touched her shoulder and spoke her name. She did not respond. I shook her gently, and she shifted slightly and made unintelligible sounds. I shook her more vigorously, but she was unable to wake up. She was no longer just sleeping—she was unconscious. There was no radio at the aid post. I sent a written note to the park ranger in Namche, requesting a helicopter rescue for early the next morning. I gave her intravenous dexamethasone and put an oxygen mask over her mouth and nose running at 2 liters per minute, trying to conserve the only two small bottles of oxygen that we had on hand. A little while later, she suddenly stirred and vomited all over her sleeping bag. Over the course of the night, she deteriorated steadily. I observed the effects of every additional drop of fluid that leaked into her brain. She became decerebrate, then flaccid, then unresponsive to deep pain. She was clearly dying. It was now just a matter of whether the helicopter would arrive in time. I felt very alone, wondering if there was anything more that I could do. The night had been completely clear when I had stepped outside before taking a short nap. When I awoke at 6:00 A.M., it was snowing. I did not think a helicopter could fly through the mountains in a snowstorm. I had kept up my hope for rescue all night long, but at that moment I began to feel that she might not make it. When that thought hit me, I found myself emotionally unprepared to watch her die. Alone in a remote aid post, with one Sherpa helper and the patient’s best friend, the circumstances were too intimate, the patient too like myself. I realized what it meant to do medicine in a wilderness setting. You are on your own. There is no one to call, no one to help. You just have to do the best you can with whatever limited resources you have. At 10:00 A.M., a Sherpa arrived carrying a portable radio. This enabled me to tell the park ranger how desperate the situation had become. His response was not encouraging. He informed me that he had been unable to reach Kathmandu by radio to request a helicopter. Later in the day, he was finally able to contact Kathmandu, but the trekking company refused to guarantee payment for a helicopter evacuation. The park ranger offered to guarantee the money himself. It got worse from there. A helicopter was ready at the airport, but the pilot had gone home for the day. When they tried to telephone him, they found that the phone lines had just gone dead. By this point, Barbara was completely unresponsive to deep pain and barely breathing at a rate of 4 times per minute. She had even lost her corneal reflexes. xv

FOREWORD

At least it had stopped snowing. I sat near the radio, waiting. The park ranger called again. “Maybe we should just try to organize the helicopter for tomorrow,” he told me. “She’s going to die this afternoon if we don’t rescue her,” I replied. “If you can’t get a helicopter this afternoon, there won’t be any point in sending one tomorrow.” “Got that,” said the ranger. Another hour went by. Finally, I heard the ranger’s voice. “Pheriche, Pheriche, Pheriche. This is Namche. The pilot has landed here and set off fuel. He’s on his way up the valley, but the weather is bad and he wants the patient ready to go.” I pulled out the intravenous line, and we secured Barbara in her sleeping bag. Her friend would fly out with her. I stepped outside the clinic and looked down the valley. Clouds whipped past the peaks. I spotted the Alouette III helicopter emerging from the clouds. I had never before been involved in a helicopter rescue, and the miraculous appearance of the aircraft seemed like an angel descending from heaven. The helicopter flew past the clinic, made an abrupt turn, and landed. The pilot shut down the rotors, but left the engine running. He waved impatiently for us to bring the patient. We carried her outside with the help of some trekkers and slid her onto the floor in the back of the helicopter, which immediately took off. We turned our faces away from the dust as the chopper disappeared down the valley, back into the clouds. It was 3 days before we got word about Barbara. She had arrived in the emergency room at Patan Hospital in Kathmandu an hour and a half after leaving us, having descended 10,000 feet. On arrival at the hospital, she was breathing 18 times per minute and was already responding to pain. Twenty-four hours later, she was sitting up in bed and eating. Thirty years later, I recognize that the key things I have learned about wilderness medicine were introduced during my experience of caring for Barbara. I was on my own, with no expert to whom I could turn for advice. I had to care for a patient in ways that I had never done in a hospital setting. I had to clean her up, turn her, catheterize her—all by candlelight, in addition to trying to figure out how to medically treat and evacuate her. Although her presentation of HACE remains the most atypical I have ever encountered, I still had to make a diagnosis and act on it, with no further tests or opinions to rely on. As I reflect back on these events, I still recall the depth of my fear that she would die despite my efforts. I have since witnessed on a number of occasions that this is a not-uncommon feeling among rescuers, who often feel devastated when the person they have tried to rescue ends up dying. Barbara’s illness taught me the value of personal experience. After this episode, the lectures I gave every day that season at the aid post on the prevention of altitude illness carried a sense of personal authority that I could not otherwise have evoked. Symptoms can be subtle. Altitude illness really can be fatal. Descent really is lifesaving. My career in medicine ran parallel to the development of the field of wilderness medicine. In the mid-1970s, physicians and mountain guides began to meet to discuss what was then called “mountain medicine.” The topics included altitude illness, first aid, frostbite, hypothermia, and evacuation. Lectures and handson workshops were included. Gradually the gatherings expanded to include topics of hiking and rafting and the skills that supported those activities, such as water disinfection, treatment of traveler’s diarrhea, and heat and cold injury. Because we were no longer talking only about the mountains, this new field was dubbed wilderness medicine. Lecturers shared their anecdotal experiences and opinions, but soon they mined the research literature and carried out investigations of their own. In 1983, the first edition of Wilderness Medicine was published. It was also in 1983 that I moved to Kathmandu to begin a 15-year stint working at the CIWEC Clinic Travel Medicine Center and started carrying out my own research into the diseases and injuries that affect travelers in Nepal. Wilderness Medicine now appears in its sixth edition. Rather than wilderness medicine defining what should be in the textbook, the textbook has helped define what is in the field of wilderness medicine. Instead of focusing solely on traditional xvi

areas, the editor has opted for inclusiveness, covering topics that include such stalwarts as lightning and frostbite, but also volcanic eruptions, combat casualty care, alligator and crocodile attacks, global humanitarian medicine, and space travel. Despite this wide range of knowledge, the specialty of wilderness medicine still has a common denominator: when something bad happens in the field, immediacy and bonding lead to an increased emotional requirement from the rescuers. In addition to diagnosis and treatment of the patient, one is confronted with limited resources and the compounding factors of weather, terrain, and isolation. Not infrequently, rescuers have to place themselves in harm’s way. At the very least, they may have to endure their own discomfort and exhaustion. Although these factors create a different dynamic of medical care, ultimately the goal is the same—to ease or prevent suffering in the patient. The quest for adventure may take travelers to countries with little or no available medical care. Many adventurers think only of their personal medical situation or of the risks that they are taking in a remote environment. They may give little or no thought to the thousands of people along their routes who can live entire lives without access to even basic medical care. The plight of the world’s poorest people may only briefly come to light at those times when a major disaster strikes. Wilderness medicine aficionados have frequently been rescuers in these extreme situations. Their experiences have sometimes taught the physicians what it really means to try to practice medicine on behalf of people who have no resources. They often return with a newly discovered desire to share medical knowledge and skills around the planet on an ongoing basis. They have come to recognize that all human beings are the same in wanting to be happy and free from suffering. Seen in this light, there is no difference between a mountaineer with altitude illness, the traveler with diarrhea, a Tibetan refugee with frostbite, the woman in an African village in the midst of a difficult birth, or a child shivering with the fever of malaria. My initial attraction to high-altitude medicine had far-reaching consequences in my personal life that I could never have foreseen. After three trekking seasons in the mountains, I moved to Kathmandu, and within a year I had volunteered to be the doctor for a Tibetan Buddhist monastery. The head of the monastery, Chokyi Nyima Rinpoche, became my teacher and close personal friend. By applying his teachings on Buddhist philosophy to my medical practice, I became more the physician I wanted to be— calmer, kinder, clear thinking, and willing to help. Our friendship led to collaboration on a book about how to train in compassion. I strongly believe that there is a way to connect wilderness medicine to conventional medicine, and even further, to our personal lives. This advice can be condensed into three key principles. First, there is competence. We should be advocates of learning and apprenticeship in the backcountry and not be satisfied with merely attaining just enough fitness to be guided on an adventure. Although one can take pleasure from achieving a distinct goal, one’s satisfaction is greatly enhanced by the cultivation of skills gained through lectures, practice in the field, and extensive personal experience. When one starts to plan a journey or an adventure, one needs to do research and fully understand the limitations imposed by that activity. Are there hazards of weather and terrain that could result in being stranded for long periods? Is there the possibility of rescue? Where is the closest medical care? To what degree are we prepared to accept the situation? Commitment means accepting the risks and limitations of a given adventure before facing the challenge, so that one can deal with it realistically. Ideally one would like to avoid having to say, “If I had known it was going to be like this, I would never have gone.” Finally, no matter what happens, one should always make decisions with full consideration of compassion. This could involve abandoning one’s own goals to help someone else or modifying the trip so that everyone can succeed. There is a famous Tibetan Buddhist saying that is true in all aspects of our lives, including our wilderness adventures:

Adventures in the wilderness, by occasionally taking us close to our limits, can teach us a great deal about our true nature. A well-known mountaineer, after living through a major rescue drama on Mt Everest, once said, “The person I wanted to be met the person I actually was.” In such defining moments, I have observed that those who abandoned their own ambitions in order to help others have always ended up happier than those who pursued only their own goals.

The wilderness is a proving ground that draws us in with its physical splendor, then tests us with hardship. We are often changed by these encounters. Whether we perceive these changes as positive or not may depend less on whether we have succeeded in our adventurous goals and more on how we learned to conduct ourselves in pursuit of those goals. The elderly Sherpa with the head laceration healed without infection and lived for 3 more years, before dying of old age. David R. Shlim, MD Author, Medicine and Compassion: A Tibetan Lama’s Guidance for Caregivers Jackson Hole, Wyoming

xvii

FOREWORD

All the joy the world contains Has come through wishing happiness for others. All the misery the world contains Has come through wanting pleasure for oneself.

Preface The sixth edition of Wilderness Medicine arrives at an exciting juncture for the field and its practitioners. Except at the time of the origin of the practice of medicine, when one might argue that perhaps all of medicine was “wilderness medicine,” there has never been greater need for people to heal in austere settings. With each natural disaster, adventure into uncharted territory, and global humanitarian relief effort, medical professionals and amateurs alike must make diagnoses with their eyes, ears, fingertips, and noses; better understand the unique physiology and pathophysiology of extreme environments; and recognize the limitations of technology in the deepest jungles and on the most remote mountaintops. More than any other specialty of medicine, wilderness medicine engages humans with Planet Earth, as it constantly calls the question, “What can we do to help?” We should help our fellow humans, while we always seek to preserve the planet. On the eve of the sixth edition, it is fair for an editor to reminisce. I suspect that many readers of this book were not born when the first edition of Wilderness Medicine (then titled Management of Wilderness and Environmental Emergencies) was published. I owe so much to the contributors to each and every edition, who in the beginning ranged from savvy clinicians and hardy explorers to youthful (and upstart) innovators. Without the collaboration of my best friend, Edward Geehr, and inspiration from the legendary professors Charlie Houston and Dave Sabiston, this book would have never exited my typewriter. In the beginning, it was no more complicated than the fact that Ed and I loved the outdoors. We had been medical students together at Duke, where we camped and hit the beach, and then enjoyed what little free time we had as interns at Dartmouth hiking and cross-country skiing. During medical school, I had been an extern on the prairie for the Indian Health Service at Fort Belknap in Montana and Ed an instructor in the mountains of New Hampshire for Outward Bound. When we were emergency medicine residents at the University of California, Los Angeles, we attended one particular mountain medicine symposium at the Yosemite Institute and listened to Charlie Houston, Herb Hultgren, John Dill, and other experts spin tales of intertwined adventure and medicine. There was no book for physicians that covered what we had heard and what more we wished to learn, so we proposed the first edition of what became Wilderness Medicine. After more than a few turndowns, the book was published as a title in the Nursing Division at Macmillan, because even though we were young and unknown, an acquisitions editor believed in us. We endured a tempestuous relationship with our senior editor, so we eagerly moved to Mosby for the second edition. The book has remained here through a series of mergers with Saunders and Elsevier. It has been a blessing to have a publisher with a vision for the vitality and relevance of wilderness medicine, and the imagination to understand that this field crosses into uncharted territory. In this edition, Dolores Meloni, Lucia Gunzel, and Jessica Becher have put forth their wonderful Elsevier spirit. My lifelong wilderness medicine buddies are too numerous to count, sustaining me for more than three decades. Each generation has raised the bar. With every edition, we used the book to push the envelope. As the content of Wilderness Medicine expanded, so did the training, practice, research, and education. It was not my intention to define the specialty, but it happened. Somewhere around the third edition, numerous aspects of a thriving specialty emerged, eminently capable leaders arose, and I could put the cart behind the horse. Now, we run to catch up, and I suspect that it will be that way forever. As change abounds, we daily appreciate novel interrelationships that are integral to a complete understanding of wilderness

medicine. High altitude is not just about hypoxia. It is about exercise physiology, genetics, ventilatory response during sleep, and much more. Understanding frostbite requires superb knowledge of anatomy, cell membrane function, reperfusion injury, and much more. To comprehend the field management of trauma, one must integrate all of the complexities related to hemorrhage, shock, hypoxia, and pain. The entire field of wilderness medicine does much more than overlap with military medicine, disaster medicine, sports medicine, environmental medicine, and travel medicine—it defines many of their most important features. Wilderness medicine is much more holistic than I would ever have imagined. Yet as robust as it has become, it will continue to expand, because we have only scratched the surface and our need is so great to know more. In recognition of venues in which wilderness medicine has been applied, to support a continuing effort to deliver credible information about the wilderness environment, and based upon requests from readers, much has been added to this sixth edition. Some of the chapters, such as Expedition Medicine, Global Humanitarian Medicine and Disaster Relief, and Ultrasound and Telemedicine in the Wilderness, are completely new, whereas others are refinements derived from wanting to leave no stone unturned. Because wilderness medicine volunteers are so capable under difficult circumstances, such as while providing disaster or global humanitarian relief, I have invited experts to broaden the coverage and better meet the information needs of the readers. Wilderness Medicine is affected by an accelerating sea change in the publishing world. Electronic publishing—words, images, and multimedia presentations—will one day render paper pages obsolete, except for collectors. Information is available instantly and disseminates at light speed, so the obligations of authors and editors have multiplied and deepened. This edition of Wilderness Medicine occurs at a watershed, when the contributors have provided much more material than can be economically offered in printed volumes. As a result, the traditional book contains the information one must be able to retrieve even when the power fails (… and if you are willing to carry 20 pounds of textbook with you); the entire electronic offering with its additional features will be there when your Internet connection is good or the power for your tablet or e-reader is plentiful. For authors, all of this takes a bit of acclimation. For readers, I suspect the transition will be welcome. There is much discussion these days about the future of medicine and in particular, if it is headed in a good direction. The camaraderie of the wilderness medicine community negates any doubts about whether or not medicine is still a desirable career path. In the days immediately after the January 2010 earthquake in Haiti, I stood side by side in Port-au-Prince with wilderness medicine colleagues from around the globe—pediatric surgeons from Switzerland, logistics experts from Norway, mountaineers from the United States, ocean divers from Spain— to put our collective skills to the most difficult challenge of our careers. Time and time again, military medical personnel make essential use of research and practice advances generated by wilderness medicine specialists that decrease morbidity and improve survival in extreme environmental settings. During global humanitarian relief efforts, when there are scarce resources, physicians, nurses, and other health care professionals who have learned how to make do with what is at hand through wilderness medicine education programs are vital to their adopted communities. The doctor who accompanies climbers to the base camp at Mt Everest also builds clinics in rural Nepal, and a nurse who leads adventure treks is moved to staff a refugee camp in the Sudan. Wilderness medicine resides at the core of what it means to be a healer. xix

PREFACE

Wilderness is at the center of wilderness medicine. To a certain degree and appropriately so, wilderness will always remain enigmatic and mysterious. Its verdant landscapes and abundant wildlife should be approached with the explicit understanding that human intrusion on its current scale is a recent phenomenon. The best that our collective environmental efforts have been able to do for wilderness is limit its destruction. We speak and write of managing wilderness, but that activity really means that we are trying to protect it from humansponsored consumption and devastation. Humans are a force of nature, so if wilderness is to cease shrinking and unimpeded fulfill its destiny, without wholesale alteration of patterns and disruption of natural cycles, then our behaviors must change. Today wilderness is considered austere because it is remote and not defined by modern technology. Our appreciation for it grows greater because breathtaking scenery is becoming more elusive. If we are not proactive, then tomorrow’s wilderness will be desolate because it has become used up and bleak. For heaven’s sake, we cannot let that happen. For the rest of my career, I am going to try to give something back. My wife, Sherry, and I began doing that with three wonderful children—Brian, Lauren, and Danny. By helping to establish a specialty, a research tradition, the Wilderness Medical Society, a peer-reviewed journal, education programs, affinity groups, clubs, and an ethos of service and multiple goals to which wilderness medicine enthusiasts can aspire, this book has accomplished its mission. Wilderness medicine in the modern

xx

age has passed its infancy and is now into childhood. There is still so much to be done. Let us together go forward with integrity and optimism.

Paul S. Auerbach, MD, MS, FACEP, FAWM

Photo credits for cover images and part openers Cover: Photographs on the cover are provided courtesy of fine art landscape photographer Elizabeth Carmel from Truckee, California. Her wonderful images may be viewed at www.ElizabethCarmel.com and www.TheCarmelGallery.com. (All images copyright ElizabethCarmel.com.) Back Cover: For cover photos and other outdoor images, visit www.TheCarmelGallery.com. Part 1: Upper: Courtesy Paul S. Auerbach, MD; Middle and Lower: Courtesy Mathias Schar, MD Part 2: Upper: Courtesy Mathias Schar, MD; Lower: Courtesy Paul S. Auerbach, MD Part 3: Upper: Courtesy R.W. Halsey, California Chaparral Field Institute; Middle: Courtesy NASA; Lower: Courtesy Michael Poland, U.S. Geological Survey Part 4: Upper: Courtesy Paul S. Auerbach, MD; Middle: Courtesy Sheri Trbovich and Weber County Sheriff’s Department; Lower: Courtesy Jack Putnam, Maridocs Part 5: Upper: Courtesy Will Smith; Middle: Courtesy Kris H. Green; Lower: Courtesy Mathias Schar, MD Part 6: Upper: Courtesy Timothy Floyd; Middle: Courtesy Jan Ove Rein; Lower: Courtesy Michael Cardwell Part 7: Upper: Provided by K. Davison and R. Marinelli; Middle: Courtesy asimulator via flickr.com; Lower: Courtesy Daniel Ryan Part 8: Upper: Courtesy Brenda Tiernan, RN; Middle and Lower: Courtesy Paul S. Auerbach, MD Part 9: Upper and Lower: Courtesy Carl Roessler; Middle: Courtesy Marty Snyderman Part 10: Upper: Courtesy Paul S. Auerbach, MD; Middle: Courtesy Francesco Zizola, Médecins Sans Frontiéres; Lower: Courtesy N. Stuart Harris, MD Part 11: Upper: Courtesy N. Stuart Harris, MD; Middle: Courtesy Mathias Schar, MD; Lower: Courtesy Mingmar Sherpa, Peak Promotion Pvt. Ltd., Kathmandu, Nepal Part 12: Upper: Courtesy Corbis; Middle: Courtesy Craig Gray; Lower: Courtesy Paul S. Auerbach, MD Part 13: Upper: Courtesy Arius Hopman; Middle: Courtesy Mingmar Sherpa, Peak Promotion Pvt. Ltd., Kathmandu, Nepal; Lower: Courtesy Paul S. Auerbach, MD Index: Courtesy Mingmar Sherpa, Peak Promotion Pvt. Ltd., Kathmandu, Nepal Preface: Courtesy Chuck Liddy, The News & Observer, 2010

xxv

CHAPTER 1 

High-Altitude Medicine and Physiology PETER H. HACKETT AND ROBERT C. ROACH

The Population More than 40 million tourists visit recreation areas above 2400 m (7874 feet) in the American West each year. Hundreds of thousands visit central and south Asia, Africa, and South America, many traveling to altitudes above 4000 m (13,123 feet). In addition, millions live in large cities above 3000 m (9843 feet) in South America and Asia. The population in the Rocky Mountains of North America has doubled in the past decade; 700,000 live above 2500 m (8202 feet) in Colorado alone. Increasingly, physicians and other health care providers are confronted with questions of prevention and treatment of high-altitude medical problems (Box 1-1), as well as the effects of altitude on preexisting medical conditions. Despite advances in high-altitude medicine, significant morbidity and mortality persist (Table 1-1). Clearly, better education of the population at risk and those advising them is essential. Altitude illness should be considered a public health problem. In this chapter, we emphasize clinical issues likely to be encountered in lowlanders visiting high-altitude locations by reviewing basic phy­siology of ascent and the pathophysiology, recognition, and management of medical problems for both visitors and residents of high altitudes (see Box 1-1).

Definitions HIGH ALTITUDE (1500 to 3500 M [4921 to 11,483 FEET]) The onset of physiologic effects of diminished partial pressure of inspired oxygen (PIO2) includes decreased exercise performance and increased ventilation (lower PaCO2) (Box 1-2). Minor impairment exists in arterial oxygen transport (arterial oxygen saturation [SaO2] at least 90%), but PaO2 is significantly diminished. Because of the large number of people who ascend rapidly to 2500 to 3500 m (8202 to 11,483 feet), high-altitude illness is common in this range (Table 1-2; see Table 1-1).

VERY HIGH ALTITUDE (3500 to 5500 M [11,483 to 18,045 FEET]) Maximum arterial oxygen saturation falls below 90% as PaO2 falls below 50 mm Hg (Figure 1-1; see Table 1-2). Extreme hypoxemia may occur during exercise, sleep, and high-altitude pulmonary edema or other acute lung conditions. Severe altitude illness occurs most commonly in this range.

EXTREME ALTITUDE (HIGHER THAN 5500 M [18,045 FEET]) Marked hypoxemia, hypocapnia, and alkalosis characterize extreme altitude. Progressive deterioration of physiologic function eventually outstrips acclimatization. As a result, no permanent human habitation is above 5500 m (18,045 feet). A period of acclimatization is necessary when ascending to extreme altitude; abrupt ascent without supplemental oxygen for other than brief exposures invites severe altitude illness.

The Environment of High Altitude Barometric pressure falls with increasing altitude in a logarithmic fashion (Table 1-3). Therefore the partial pressure of oxygen 2

(21% of barometric pressure) also decreases, resulting in the primary insult of high altitude: hypoxia. At approximately 5800 m (19,029 feet), barometric pressure is one-half that at sea level, and on the summit of Mt Everest (8848 m [29,029 feet]) the inspired pressure of oxygen is approximately 28% that at sea level (see Figure 1-1 and Table 1-3). The relationship of barometric pressure to altitude changes with distance from the equator. Thus, polar regions afford greater hypoxia at high altitude in addition to extreme cold. West565 has calculated that barometric pressure on the summit of Mt Everest (27 degrees N latitude) would be about 222 mm Hg instead of 253 mm Hg if Mt Everest were located at the latitude of Mt McKinley (62 degrees N). Such a difference, he claims, would be sufficient to render impossible an ascent without supplemental oxygen. In addition to the role of latitude, fluctuations related to season, weather, and temperature affect the pressure-altitude relationship. Pressure is lower in winter than in summer. A lowpressure trough can reduce pressure 10 mm Hg in one night on Mt McKinley, making climbers awaken “physiologically higher” by 200 m (656 feet). The degree of hypoxia is thus directly related to barometric pressure, not solely to geographic altitude.565 Temperature decreases with altitude (average of 6.5° C [11.7° F] per 1000 m [3281 feet]), and the effects of cold and hypoxia are generally additive in provoking both cold injuries and highaltitude pulmonary edema.419,559 Ultraviolet light penetration increases approximately 4% per 300-m (984-foot) gain in altitude, increasing the risks for sunburn, skin cancer, and snowblindness. Reflection of sunlight in glacial cirques and on flat glaciers can cause intense radiation of heat in the absence of wind. We have observed temperatures of 40° to 42° C (104° to 107.6° F) in tents on both Mt Everest and Mt McKinley. Heat problems, primarily heat exhaustion, are often unrecognized in this usually cold environment. Physiologists have not yet examined the consequences of heat stress or rapid, extreme changes in environmental temperature combined with the hypoxia of high altitude. Above the snow line is the “high-altitude desert,” where water can be obtained only by melting snow or ice. This factor, combined with increased water loss through the lungs from increased respiration and through the skin, commonly results in dehydration that may be debilitating. Thus, the high-altitude environment imposes multiple stresses, some of which may contribute to or be confused with the effects of hypoxia.

Acclimatization to High Altitude Although rapid exposure from sea level to the altitude at the summit of Mt Everest (8848 m [29,029 feet]) causes loss of consciousness in a few minutes and death shortly thereafter, climbers can ascend Mt Everest over a period of weeks, without supplemental oxygen, because of a process termed acclimatization. A complex series of physiologic adjustments increases oxygen delivery to cells and also improves their hypoxic tolerance. The severity of hypoxic stress, rate of onset, and individual physiology determine whether the body successfully acclimatizes or is overwhelmed. Recently, a revolution has taken place in our understanding of the molecular mechanisms of human responses to hypoxia. At the center of this rapidly changing field is hypoxia-inducible factor (HIF), a transcription factor that modulates the expression

BOX 1-2  Glossary of Physiologic Terms

Lowlanders on Ascent to Altitude • Acute hypoxia • High-altitude headache • Acute mountain sickness • High-altitude cerebral edema • Cerebrovascular syndromes • High-altitude pulmonary edema • Symptomatic pulmonary hypertension • High-altitude deterioration • Organic brain syndrome (extreme altitude) • Peripheral edema • Retinopathy • Disordered sleep • Sleep periodic breathing • High-altitude pharyngitis, bronchitis, and cough • Ultraviolet keratitis (snowblindness) • Exacerbation of preexisting conditions

PB P O2 PIO2 PAO2 PACO2 PaO2 PaCO2 SaO2 RQ Alveolar gas equation

Barometric pressure* Partial pressure of oxygen Inspired PO2 (0.21 × [PB − 47 mm Hg] (47 mm Hg = vapor pressure of H2O at 37° C [98.6° F]) PO2 in alveolus PCO2 in alveolus PO2 in arterial blood PCO2 in arterial blood Arterial oxygen saturation (HbO2 ÷ total Hb × 100) Respiratory quotient (CO2 produced ÷ O2 consumed) PAO2 = PIO2 − (PACO2/RQ)

*Pressures are expressed as mm Hg (1 mm Hg = 1 Torr).

on repeated exposure if rate of ascent and altitude gained are similar, supporting the notion of important genetic factors. Successful initial acclimatization protects against altitude illness and improves sleep. Longer-term acclimatization (weeks) primarily improves aerobic exercise ability. These adjustments disappear at a similar rate on descent to low altitude. A few days at low altitude may be sufficient to render a person susceptible to altitude illness, especially high-altitude pulmonary edema (HAPE), on reascent. The improved ability to do physical work at high altitude, however, persists for weeks.317 Persons who live at high altitude during growth and development appear to realize the maximum benefit of acclimatization changes; for example, their exercise performance matches that of persons at sea level.365

Life or Long-Term Residents of Altitude • Chronic mountain sickness (chronic mountain polycythemia) • Symptomatic high-altitude pulmonary hypertension with or without right heart failure • Problems of pregnancy: preeclampsia, hypertension, and low-birth-weight infants • Exacerbation of lung disease and congenital heart disease

of hundreds of genes, including those involved in apoptosis, angiogenesis, metabolism, cell proliferation, and permeability processes.90,423,484-487,503,504 In chronic hypoxia, HIF activation by hypoxia has the positive effect of elevating oxygen delivery by boosting hemoglobin mass. But HIF also plays a role in carotid body sensitivity to hypoxia, which in turn largely determines the ventilatory response to hypoxia. As a master regulator of the hypoxia response in humans, HIF has some beneficial and harmful effects at different stages in the time course of human exposure to hypoxia, and in different cells in the body. See Figure 1-2 for an overview of some of the hundreds of processes in which the response to hypoxia is modulated by HIF. Individuals vary in their ability to acclimatize, no doubt reflecting certain genetic polymorphisms, including HIF. Some adjust quickly, without discomfort, whereas acute mountain sickness (AMS) develops in others, who go on to recover. A small percentage fails to acclimatize even with gradual exposure over weeks. The tendency to acclimatize well or to become ill is consistent

VENTILATION By reducing alveolar carbon dioxide, increased ventilation raises alveolar oxygen, improving oxygen delivery (Figure 1-3; see Figure 1-1). This response starts as low as 1500 m (4921 feet) (PIO2 = 124.3 mm Hg; see Table 1-3) and within the first few minutes to hours of high-altitude exposure. The carotid body, sensing a decrease in PaO2, through a HIF-mediated process, signals the central respiratory center in the medulla to increase ventilation.153,281 This carotid body function (hypoxic ventilatory response [HVR]) is genetically determined562 but influenced by a number of extrinsic factors. Respiratory depressants such as alcohol and soporifics, as well as fragmented sleep, depress HVR. Agents that increase general metabolism, such as caffeine and coca, as well as specific respiratory stimulants, such as progesterone277 and almitrine,192 increase HVR. (Acetazolamide, a respiratory stimulant, acts on the central respiratory center rather than

TABLE 1-1  Incidence of Altitude Illness in Various Groups

Study Group

Number at Risk per Year

Western state visitors

30 million

Mt Everest trekkers

12,000

Mt McKinley climbers Mt Rainier climbers Mt Rosa, Swiss Alps

1200 10,000 †

Indian soldiers Aconcagua climbers Kilimanjaro hikers

Unknown 4200 2500

Maximum Altitude Reached (m [ft])

Average Rate of Ascent*

~2000 (6562) ~2500 (8202) ~≥3000 (9843) 3000-5200 (9843-17,060)

3500 (11,483)

1-2

5500(18,045)

3000-5300 (9843-17,388) 3000 (9843) 2850 (9350) 4559 (14,957) 3000-5500 (9843-18,045) 3300-5800 (10,827-19,029) 2700-4700 (8858-15,420)

6194 4392 2850 4559 5500 6962 5895

1-2 (fly in) 10-13 (walk in) 3-7 1-2 1-2 2-3 1-2 2-8 2-6

Sleeping Altitude (m [ft])

(20,322) (14,409) (9350) (14,957) (18,045) (22,841) (19,341)

Percent With AMS 18-20 22 27-42 47 23 30-50 30 67 7 27 † 39 (LLS >4) 50-83

Percent With HAPE and/or HACE

Reference

0.01

214

1.6 0.05 2-3 — — 5 2.3-15.5 2.2 †

376 181 286 323 99, 323, 475 499, 500 405 106, 242

AMS, Acute mountain sickness; HAPE, high-altitude pulmonary edema; HACE, high-altitude cerebral edema; LLS, Lake Louise score. *Days to sleeping altitude from low altitude. †Reliable estimate unavailable.

3

CHAPTER 1  High-Altitude Medicine and Physiology

BOX 1-1  Medical Problems of High Altitude

PART 1  MOUNTAIN MEDICINE

TABLE 1-2  Arterial Blood Gases and Altitude* Population

Altitude Meters †

Altitude residents Acute exposure

Subacute exposure

1646 2810‡ 3660‡ 4700‡ 5340‡ 6140‡ 6500§ 7000§ 8000§ 8400|| 8848§ 8848¶

Feet

PB (mm Hg)

5400 9219 12,008 15,420 17,520 20,144 21,325 22,966 26,247 27,559 29,029 29,029

630 543 489 429 401 356 346 324 284 272 253 253

PaO2 (mm Hg)

SaO2 (%)

PaCO2 (mm Hg)

73.0 60.0 47.6 44.6 43.1 35.0 41.1

(65.0-83.0) (47.4-73.6) (42.2-53.0) (36.4-47.5) (37.6-50.4) (26.9-40.1) ± 3.3

95.1 91.0 84.5 78.0 76.2 65.6 75.2

35.6 (30.7-41.8) 33.9 (31.3-36.5) 29.5 (23.5-34.3) 27.1 (22.9-34.0) 25.7 (21.7-29.7) 22.0 (19.2-24.8) 20 ± 2.8

36.6 24.6 30.3 30.6

± ± ± ±

67.8 ± 5 54 58 ± 4.5

2.2 5.3 2.1 1.4

(93.0-97.0) (86.6-95.2) (80.5-89.0) (70.8-85.0) (65.4-81.6) (55.5-73.0) ±6

12.5 ± 1.1 13.3 11.2 ± 1.7 11.9 ± 1.4

PB, Barometric pressure; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; SaO2, arterial oxygen saturation. *Data are mean values and (range) or ± SD, where available. All values are for subjects age 20 to 40 years who were acclimatizing well. † Data from reference 302. ‡ Data from reference 343. § Data for chronic exposure during Operation Everest II from reference 526. || Data from near the summit of Mt Everest from reference 172. ¶ Data from the simulated summit of Mt Everest from reference 430.

SaO2

160

100

140

90

PIO2

120

80

100 80

70

PaO2

60

SaO2 (%)

Partial pressure oxygen (mm Hg)

on the carotid body.) Physical conditioning apparently has no effect on HVR. Numerous studies have shown that a good ventilatory response enhances acclimatization and performance and that a very low HVR may contribute to illness433 (see Acute Mountain Sickness and High-Altitude Pulmonary Edema, later). However, over a normal range of values, HVR is not a reliable predictor of susceptibility to altitude illness. Other factors influence ventilation on ascent to high altitude. As ventilation increases, hypocapnia produces alkalosis, which acts as a braking mechanism on the central respiratory center and limits a further increase in ventilation. To compensate for the alkalosis, within 24 to 48 hours of ascent the kidneys excrete bicarbonate, decreasing the pH toward normal; ventilation increases as the braking effect of the alkalosis is removed. Ventilation continues to increase slowly, reaching a maximum only after 4 to 7 days at the same altitude (see Figure 1-3). The plasma bicarbonate concentration continues to drop and ventilation to increase with each successive increase in altitude. Persons with

60

40 20 0

2000

4000

6000

50 8000 10,000

Altitude (m) FIGURE 1-1  Increasing altitude results in decreasing inspired PO2 (PIO2), arterial PO2 (PaO2), and arterial oxygen saturation (SaO2). Note that the difference between PIO2 and PaO2 narrows at high altitude because of increased ventilation and that SaO2 is well maintained while awake until over 3000 m (9843 feet). (Data from Morris A: Clinical pulmonary function tests: A manual of uniform lab procedures, Salt Lake City, 1984, Intermountain Thoracic Society; and Sutton JR, Reeves JT, Wagner PD, et al: Operation Everest II: Oxygen transport during exercise at extreme simulated altitude, J Appl Physiol 64:1309, 1988.)

4

lower oxygen saturation at altitude have higher serum bicarbonate values; whether the kidneys might be limiting acclimatization or whether this reflects poor respiratory drive is not clear.102 This process is greatly facilitated by acetazolamide (see Acetazolamide Prophylaxis, later). The paramount importance of hyperventilation is readily apparent from the following calculation: the alveolar PO2 on the summit of Mt Everest (about 33 mm Hg) would be reached at only 5000 m (16,404 feet) if alveolar PCO2 stayed at 40 mm Hg, limiting an ascent without supplemental oxygen to near this altitude. Table 1-2 gives the measured arterial blood gas levels resulting from acclimatization to various altitudes.

CIRCULATION The circulatory pump is the next step in the transfer of oxygen, moving oxygenated blood from the lungs to the tissues. Systemic Circulation Increased sympathetic activity on ascent causes an initial mild increase in blood pressure, moderate increases in heart rate and cardiac output, and increase in venous tone. Stroke volume is low because of decreased plasma volume, which drops as much as 12% over the first 24 hours577 as a result of the bicarbonate diuresis, a fluid shift from the intravascular space, and suppression of aldosterone.35 Resting heart rate returns to near sea level values with acclimatization, except at extremely high altitude. Maximum heart rate follows the decline in maximal oxygen uptake with increasing altitude. As the limits of hypoxic acclimatization are approached, maximum and resting heart rates converge. During Operation Everest II (OEII), cardiac function was appropriate for the level of work performed and cardiac output was not a limiting factor for performance.417,518 Interestingly, myocardial ischemia at high altitude has not been reported in healthy persons, despite extreme hypoxemia. This is partly because of reduction in myocardial oxygen demand from reduced maximal heart rate and cardiac output. Pulmonary capillary wedge pressure is low, and catheter studies have shown no evidence of left ventricular dysfunction or abnormal filling pressures in humans at rest.174,236 On echocardiography, the left ventricle is smaller than normal because of decreased stroke volume, whereas the right ventricle may become enlarged.518 The abrupt increase in pulmonary artery pressure can cause a change in left ventricular diastolic function, but because of compensatory increased atrial contraction, no overt diastolic dysfunction results.7 In trained athletes doing an ultramarathon, the strenuous exercise at high altitude did not result in left ventricular damage; however, wheezing, reversible pulmonary hypertension, and right ventricular dysfunction occurred in one-third of those completing the race and resolved within 24 hours.107

Pressure, Estimated Partial Pressure of Inspired Oxygen, and the Equivalent Oxygen Fraction at Sea Level*

m

ft

PB

PIO2

FIO2 at SL

Sea level 1000 1219 1500 1524 1829 2000 2134 2438 2500 2743 3000 3048 3353 3500 3658 3962 4000 4267 4500 4572 4877 5000 5182 5486 5500 5791 6000 6096 6401 6500 6706 7000 7010 7315 7500 7620 7925 8000 8230 8500 8534 8839 8848 9000 9144 9500 10,000

Sea level 3281 4000 4921 5000 6000 6562 7000 8000 8202 9000 9843 10,000 11,000 11,483 12,000 13,000 13,123 14,000 14,764 15,000 16,000 16,404 17,000 18,000 18,045 19,000 19,685 20,000 21,000 21,325 22,000 22,966 23,000 24,000 24,606 25,000 26,000 26,247 27,000 27,887 28,000 29,000 29,029 29,528 30,000 31,168 32,808

759.6 678.7 661.8 640.8 639.0 616.7 604.5 595.1 574.1 569.9 553.7 536.9 533.8 514.5 505.4 495.8 477.6 475.4 460.0 446.9 442.9 426.3 419.7 410.2 394.6 393.9 379.5 369.4 364.9 350.7 346.2 337.0 324.2 323.8 310.9 303.4 298.6 286.6 283.7 275.0 265.1 263.8 253.0 252.7 247.5 242.6 230.9 215.2

149.1 132.2 128.7 124.3 123.9 119.2 116.7 114.7 110.3 109.4 106.0 102.5 101.9 97.9 95.9 93.9 90.1 89.7 86.4 83.7 82.9 79.4 78.0 76.0 72.8 72.6 69.6 67.5 66.5 63.6 62.6 60.7 58.0 57.9 55.2 53.7 52.6 50.1 49.5 47.7 45.6 45.4 43.1 43.1 42.0 40.9 38.5 35.2

0.209 0.185 0.180 0.174 0.174 0.167 0.164 0.161 0.155 0.154 0.149 0.144 0.143 0.137 0.135 0.132 0.126 0.126 0.121 0.117 0.116 0.111 0.109 0.107 0.102 0.102 0.098 0.095 0.093 0.089 0.088 0.085 0.081 0.081 0.077 0.075 0.074 0.070 0.069 0.067 0.064 0.064 0.060 0.060 0.059 0.057 0.054 0.049

Exp, Exponent; FIO2, fraction of inspired oxygen; PB, barometric pressure; PIO2, partial pressure of inspired oxygen; SL, sea level. *Barometric pressure is approximated by the equation PB = Exp (6.6328 − {0.1112 × altitude − [0.00149 × (altitude2)]}), where altitude = terrestrial altitude in meters/1000 or km. PIO2 is calculated as the PB − 47 (where 47 = water vapor pressure at body temperature) × fraction of O2 in inspired air. The equivalent FIO2 at sea level for a given altitude is calculated as PIO2 ÷ (760 − 47). Substituting ambient PB for 760 in the equation allows similar calculations for FIO2 at different altitudes.

Pulmonary Circulation On ascent to high altitude, a prompt but variable increase in pulmonary vascular resistance from hypoxic pulmonary vasoconstriction increases pulmonary artery pressure. Mild pulmonary hypertension is greatly augmented by exercise, with pulmonary pressure reaching near-systemic values,174 especially in persons with a previous history of high-altitude pulmonary edema.32,110 During OEII, Groves and colleagues174 demonstrated that even with a mean pulmonary artery pressure of 60 mm Hg, cardiac output remained appropriate and right atrial pressure did not rise above sea level values. Thus, right ventricular function was intact

in spite of extreme hypoxemia and pulmonary hypertension in these well-acclimatized subjects. Administration of oxygen does not completely restore pulmonary artery pressure to sea level values,324 likely because of vascular remodeling with medial hypertrophy. See Stenmark and associates509 for an excellent review of molecular and cellular mechanisms of the pulmonary vascular response to hypoxia, including remodeling. Pulmonary vascular resistance returns to normal within a few weeks after descent to low altitude. Cerebral Circulation Cerebral oxygen delivery, the product of arterial oxygen content and cerebral blood flow (CBF), depends on the net balance between hypoxic vasodilation and hypocapnia-induced vasoconstriction. CBF increases, despite hypocapnia, when PaO2 is less than 60 mm Hg (altitude greater than 2800 m [9186 feet]). In a classic study, CBF increased 24% on abrupt ascent to 3810 m (12,500 feet) and returned to normal over 3 to 5 days.491 These findings have been confirmed by positron emission tomography and brain magnetic resonance imaging (MRI) studies showing both elevations in CBF in hypoxia in humans and striking heterogeneity of the CBF, with CBF rising up to 33% in the hypothalamus and 20% in the thalamus, with other areas without significant changes.66,396 Cerebral autoregulation, the process by which cerebral perfusion is maintained as blood pressure varies, is impaired in hypoxia. Interestingly, this occurs both in newcomers, with acute246,296,521,547 and prolonged hypoxia,522 and in natives to high altitude.246 This observation raises questions about the importance of this process in AMS and acclimatization, because it appears to be a uniform response in all humans made hypoxemic. Overall, global cerebral metabolism seems well maintained with moderate hypoxia.103,356

BLOOD Hematopoietic Responses to Altitude Ever since the observation in 1890 by Viault550 that hemoglobin concentration was higher than normal in animals living in the Andes, scientists have regarded the hematopoietic response to increasing altitude as an important component of the acclimatization process. On the other hand, hemoglobin values apparently have no relationship to susceptibility to high-altitude illness. In response to hypoxemia, erythropoietin is secreted by the kidneys and stimulates bone marrow production of red blood cells.483 The hormone is detectable within 2 hours of ascent, nucleated immature red blood cells can be found on a peripheral blood smear within days, and new red blood cells are in circulation within 4 to 5 days. Over a period of weeks to months, red blood cell mass increases in proportion to the degree of hypoxemia. Iron supplementation can be important; women who take supplemental iron at high altitude approach the hematocrit values of men at altitude202 (Figure 1-4). The increase in hemoglobin seen 1 to 2 days after ascent is due to hemoconcentration secondary to decreased plasma volume, rather than a true increase in red blood cell mass. This results in a higher hemoglobin concentration at the cost of decreased blood volume, a trade-off that might impair exercise performance. Longer-term acclimatization leads to an increase in plasma volume as well as in red blood cell mass, thereby increasing total blood volume. Overshoot of the hematopoietic response causes excessive polycythemia, which may impair oxygen transport because of increased blood viscosity. Although the “ideal” hematocrit at high altitude is not established, phlebotomy is often recommended when hematocrit values exceed 60% to 65%. During the American Medical Research Expedition to Mt Everest (AMREE), hematocrit was reduced by hemodilution from 58% ± 1.3% to 50.5% ± 1.5% at 5400 m (17,717 feet) with no decrement in maximum oxygen uptake and increased cerebral functioning.465 Oxyhemoglobin Dissociation Curve The oxygen dissociation curve (ODC) plays a crucial role in oxygen transport. The sigmoidal shape of the curve allows wellmaintained SaO2 up to 3000 m (9843 feet), despite significant 5

CHAPTER 1  High-Altitude Medicine and Physiology

TABLE 1-3  Altitude Conversion: Barometric

PART 1  MOUNTAIN MEDICINE

Ub Ub

A Normoxia

PHD2

HIF-1α

Fe2+ 2-OG Ascorbate

PHD1 O2

Ub

PHD3

HIF-1α

HIF-1α

OH OH OAc

OH OH OAc

VHL

VHL

B Hypoxia HIF-1α HIF-1α

Ub Ub

Ub

26s Proteasome

Proteolytic degradation

HIF-1α HIF-1α p300/CBP HIF-1α

Nucleus

HIF-1β

HIF-1β HRE

Angiogenesis Erythropoiesis Apoptosis

Cell proliferation and survival

HIF-1 target genes

Proteolysis pH regulation Glucose metabolism

FIGURE 1-2  Regulation of oxygen sensing by hypoxia-inducible factor (HIF). The HIF is produced constitutively, but in normoxia the α subunit is degraded by the proteasome in an oxygen-dependent manner. Hypoxic conditions prevent hydroxylation of the α subunit, enabling the active HIF transcription complex to form at the hypoxia-response element (HRE) associated with HIF-regulated genes. A range of cell functions are regulated by the target genes, as indicated. CBP, CREB binding protein; OAc, acetylation of HIF-1α; 2-OG, 2-oxoglutarate; PHD, prolyl hydroxylase; Ub, ubiquitin; VHL, von Hippel–Lindau tumor suppressor. (Reprinted from Carroll VA, Ashcroft M: Targeting the molecular basis for tumour hypoxia, Expert Rev Mol Med 7:1, 2005.)

decreases in PaO2 (see Figure 1-1). Above 3000 m (9843 feet), small changes in PaO2 cause large changes in SaO2 (Figure 1-5). Because PaO2 determines diffusion of oxygen from capillary to cell, small changes in PaO2 can have clinically significant effects. This is often confusing for clinicians because SaO2 appears relatively well preserved. At high altitude, small changes in PaO2 lead to lower O2 uptake that can have a large effect on systemic hypoxemia, and thus on clinical status, while the SaO2 may appear relatively unchanged. In 1936, Ansel Keys and colleagues266 demonstrated an in vitro right shift in position of the ODC at high altitude, favoring release of oxygen from blood to tissues. This change, due to increased 2,3-diphosphoglycerate, is proportional to the severity of hypoxemia. In vivo, however, the alkalosis at moderate altitude offsets this, and no net change occurs. In contrast, the marked alkalosis of extreme hyperventilation, as measured on the summit and simulated summit of Mt Everest (PaCO2 8 to 10 mm Hg, pH greater than 7.5), shifts the ODC to the left, facilitating oxygen-hemoglobin binding in the lung that raises SaO2 and is advantageous.462 Persons with a very left-shifted ODC, caused by an abnormal hemoglobin (Andrew-Minneapolis), when taken to moderate (3100 m [10,171 feet]) altitude, had less tachycardia and dyspnea and remarkably had no decrease in exercise performance.208 Highaltitude adapted animals also have a left-shifted ODC.

TISSUE CHANGES The next link in the oxygen transport chain is tissue oxygen transfer, which depends on capillary perfusion, diffusion distance, and driving pressure of oxygen from the capillary to the cell. Banchero20 has shown that capillary density in dog skeletal muscle doubled in 3 weeks at a barometric pressure of 435 mm Hg. A recent study in humans noted no change in 6

capillary density or in gene expression thought to enhance muscle vascularity.316 Ou and Tenney395 revealed a 40% increase in mitochondrial number but no change in mitochondrial size, whereas the study of Oelz and colleagues392 showed that highaltitude climbers had normal mitochondrial density. A significant drop in muscle size is often noted after high-altitude expeditions because of net energy deficit,316,319 resulting in increased capillary density and ratio of mitochondrial volume to contractile protein fraction as a result of the atrophy. Although there is no de novo synthesis of capillaries or mitochondria, the net result is a shortening of diffusion distance for oxygen.316,319

SLEEP AT HIGH ALTITUDE Disturbed sleep is common at high altitude. There are multiple causes. Reflecting the great interest in sleep, more than 160 papers in the last 10 years have addressed sleep at altitude. The interested reader is referred to recent reviews.67,308,551,561,569 Nearly all subjects complain of disturbed sleep at high altitude, with severity increasing with the altitude. At moderate altitude, sleep architecture is changed, with a reduction in stages 3 and 4 sleep, stage 1 time increased, and little change in stage 2. Overall, there is a shift from deeper sleep to lighter sleep. In addition, more time is spent awake, with significantly increased arousals. Clinicians have reported either slightly less rapid eye movement (REM) time or no change in REM compared with what occurs at low altitude. REM sleep may improve over time at altitude.268 The subjective complaints of poor sleep are out of proportion to the small reduction (if any) in total sleep time and appear to be due to sleep fragmentation. With more extreme hypoxia, sleep time was dramatically shortened and arousals increased, without a change in ratio of sleep stages but with a reduction in REM sleep.10 The mechanisms of this change in sleep architecture and

~10% decrease

80 10 8 40

PACO2 (mm Hg)

~ No change

12

SaO2 (%)

· VE (L/min, BTPS)

100

CHAPTER 1  High-Altitude Medicine and Physiology

14

60

40

35

B

20

30 25

A

0 0

100

20

40

60

80

100

120

SaO2 (%)

PaO2 (mm Hg) FIGURE 1-5  Oxygen-hemoglobin dissociation curve showing effect of 10-mm Hg decrement in arterial partial pressure of oxygen (PaO2) on arterial oxygen saturation (SaO2) at sea level (A) and near 4400 m (14,436 feet) (B). Note the much larger drop in SaO2 at high altitude. (Modified from Severinghaus JW, Chiodi H, Eger EI, et al: Cerebral blood flow in man at high altitude: Role of cerebrospinal fluid pH in normalization of flow in chronic hypoxia, Circ Res 19:274, 1966.)

90

80 0 1 Denver

2

3

4

5 Placebo

Days at 4300 m FIGURE 1-3  Change in minute ventilation ( V E ), end-tidal carbon dioxide (PACO2), and arterial oxygen saturation (SaO2) during 5 days’ acclimatization to 4300 m (14,108 feet). BTPS, Body temperature pressure saturated. (Modified from Huang SY, Alexander JK, Grover RF, et al: Hypocapnia and sustained hypoxia blunt ventilation on arrival at high altitude, J Appl Physiol 56:602, 1984.)

50

Hematocrit (%)

100 80 SaO2 (%) 60 40

Acetazolamide

Men Women (+Fe)

48 46

Women (−Fe) 44 42 40

Respiratory pattern

Sea level 1

20

40

60

Days at 4300 m

FIGURE 1-4  Hematocrit changes on ascent to altitude in men and in women with and without supplemental iron. (Modified from Hannon JP, Chinn KS, Shields JL: Effects of acute high altitude exposure on body fluids, Fed Proc 28:1178, 1969.)

fragmentation are poorly understood. Periodic breathing appears to play only a minor role in altering sleep architecture at high altitude.461 The arousals have been linked to periodic breathing in some studies but not in others. Other factors might include change in circadian rhythm and perhaps body temperature.98 Obesity may explain susceptibility to both deranged sleep and sleep-disordered breathing in some individuals.155 Recent studies

Respiratory pattern 100 80 60 40

SaO2 (%)

FIGURE 1-6  Respiratory patterns and arterial oxygen saturation (SaO2) with placebo and acetazolamide in two sleep studies of a subject at 4200 m (13,780 feet). Note pattern of hyperpnea followed by apnea during placebo treatment, which is changed with acetazolamide. (Modified from Hackett PH, Roach RC, Harrison GL, et al: Respiratory stimulants and sleep periodic breathing at high altitude: Almitrine versus acetazolamide, Am Rev Respir Dis 135:896, 1987.)

of infants and children590 and athletes in simulated altitude devices used for training also revealed deranged sleep quality in these groups.269,270,401 Although deranged sleep is a frequent complaint in high-altitude visitors, it seems to have little relation to susceptibility to altitude illness or other serious problems. Symptomatic treatment that avoids respiratory depression is safe (see Treatment under Acute Mountain Sickness, later). Periodic Breathing Periodic breathing is most common in early and light sleep, may occur during wakefulness when drowsy, and does not occur in REM sleep. The pattern is characterized by hyperpnea followed by apnea (Figure 1-6) and is caused by a battle for control of 7

100

SaO2 (%)

80 60 40 Arrival Acclimatized

20

0

50

100 150 200 250 300 350 400 450 500 Time asleep (min)

FIGURE 1-7  Sleep oxygenation improves with acclimatization to same altitude. Top line is maximum, and bottom line is minimum arterial oxygen saturation (SaO2) in an acclimatized person. Shaded area is maximum and minimum SaO2 values for new arrival at 5360 m (17,585 feet). (Modified from Sutton JR, Gray GW, Houston CS, et al: Effects of acclimatization on sleep hypoxemia at altitude. In West JB, Lahiri S, editors: High altitude man, Bethesda, Md, 1984, American Physiological Society, pp 141-146.)

breathing between peripheral chemoreceptors (carotid body) and the central respiratory center. Respiratory alkalosis during hyperpnea acts on the central respiratory center, causing apnea. During apnea, SaO2 decreases, carbon dioxide increases, and the carotid body is stimulated, causing a recurrent hyperpnea and apnea cycle. The apnea is central, not associated with snoring, and occurs with absence of rib cage movement. Persons with high hypoxic ventilatory response have more periodic breathing,55 with mild oscillations in SaO2,282 whereas persons with low hypoxic ventilatory response have more regular breathing overall but may suffer periods of apnea with extreme hypoxemia distinct from periodic breathing.192 As acclimatization progresses, periodic breathing lessens but does not disappear, especially over 5000 m (16,404 feet), and sleep SaO2 increases (Figure 1-7; see Figure 1-6).10,55,524 Periodic breathing has not been implicated in the etiology of highaltitude illness, but nocturnal oxygen desaturation has been implicated.55,133,150 Eichenberger and colleagues130 have also reported greater periodic breathing in persons with HAPE, secondary to lower SaO2. As with fragmented sleep, intensity of periodic breathing is quite variable. Total sleep time with periodic breathing can vary from 1% to over 90%.598 Most studies report no association between periodic breathing and AMS.55 This may relate to the fact that persons with periodic breathing tend to have higher HVR and greater average ventilation and oxygenation.561 Pharmaceutical Aids Acetazolamide, 125 mg at bedtime, diminishes periodic breathing and awakenings, improves oxygenation and sleep quality, and is a safe and superior agent to use as a sleeping aid (see Figure 1-6). It has the added benefit of diminishing symptoms of AMS. Other agents include diphenhydramine (Benadryl, 50 to 75 mg) or the short-acting benzodiazepines such as triazolam (Halcion, 0.125 to 0.25 mg) and temazepam (Restoril, 15 mg).308 Although caution is warranted for any agent that might reduce ventilation at high altitude, some studies have suggested that benzodiazepines in low doses are generally safe in this situation.124,164,384 Another option is to use both acetazolamide and a benzodiazepine. Bradwell and colleagues63 showed that acetazolamide (500 mg slow-release orally) given with temazepam (10 mg orally) improved sleep and maintained SaO2, counteracting a 20% decrease in SaO2 when temazepam was given alone. The nonbenzodiazepine hypnotic zolpidem (Ambien, 10 mg) was shown to improve sleep at 4000 m (13,123 feet) without adversely affecting ventilation.45

EXERCISE Maximal oxygen consumption drops dramatically on ascent to  2 max ) falls from high altitude.151,434 Maximal oxygen uptake ( VO 8

sea level by approximately 10% for each 1000 m (3281 feet) of altitude gained above 1500 m (4921 feet). Persons with the  2 max values have the largest decrement in highest sea level VO  2 max at high altitude, but overall performance at high altitude VO  2 max .392,428,566 In fact, is not consistently related to sea level VO many of the world’s elite mountaineers have quite average  2 max values, in contrast with other endurance athletes.392 VO Acclimatization at moderate altitudes enhances submaximal  2 max (Figure 1-8).151 endurance time but does not enhance VO Oxygen transport during exercise at high altitude becomes increasingly dependent on the ventilatory pump. The marked rise in ventilation produces a sensation of breathlessness, even at low work levels. The following quotation is from a high-altitude mountaineer: After every few steps, we huddle over our ice axes, mouths agape, struggling for sufficient breath to keep our muscles going. I have the feeling I am about to burst apart. As we get higher, it becomes necessary to lie down to recover our breath.347 In contrast to the increase in ventilation with exercise, at increasing altitudes in OEII, cardiac function and cardiac output were maintained at or near sea level values for a given oxygen consumption (workload).417 Recent work has attributed the  2 max to the lower PIO2, impairment altitude-induced drop in VO of pulmonary gas exchange, and reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third  2 max .76 However, mechanisms to explain the of the loss in VO impairment of gas exchange and the lower blood flow remain elusive. Wagner556 proposes that the pressure gradient for diffusion of oxygen from capillaries to the working muscle cells may be inadequate. Another concept is that increased cerebral hypoxia from exercise-induced desaturation is the limiting factor.91,241,356,519,520 Mountaineers, for example, become lightheaded and their vision dims when they move too quickly at extreme altitude (Figure 1-9).564 Training at High Altitude Optimal training for increased performance at high altitude depends on the altitude of residence and the athletic event. For aerobic activities (events lasting more than 3 or 4 minutes) at altitudes above 2000 m (6562 feet), acclimatization for 10 to 20 days is necessary to maximize performance.104 For events

180 Endurance time · VO2max

160 Sea level performance (%)

PART 1  MOUNTAIN MEDICINE

SLEEP SATURATION AT 5360 m

140 120 100 80 60 40 0

2

4

6

8

10

12

Days at altitude FIGURE 1-8  On ascent to altitude, maximum oxygen consumption  2max ) decreases and remains suppressed. In contrast, endurance ( VO  2max ) time (minutes to exhaustion at 75% of altitude-specific VO increases with acclimatization. (Modified from Maher JT, Jones LG, Hartley LH: Effects of high altitude exposure on submaximal endurance capacity of men, J Appl Physiol 37:895, 1974.)

Alveolar

Arterial

PO2 (torr)

30

20

Mixed venous

Assumed critical PO2

NEUROLOGIC SYNDROMES

Loss of consciousness · VO2max

10 Man on summit PB 253 torr DMO2 100 mL/min/torr 0 0

200

400

600

800

1000

1200

Oxygen uptake (mL O2/min) FIGURE 1-9  Calculated changes in the PO2 of alveolar gas and arterial and mixed venous blood as oxygen uptake is increased for a climber on the summit of Mt Everest. Unconsciousness develops at a mixed venous PO2 of 15 mm Hg. PB, Barometric pressure; DMO2, muscle dif 2max , maximum oxygen consumption. (Modified fusing capacity; VO from West JB: Climbing Mt. Everest without oxygen: An analysis of maximal exercise during extreme hypoxia, Respir Physiol 52:265, 1983.)

occurring above 4000 m (13,123 feet), acclimatization at an intermediate altitude is recommended. Highly anaerobic events at intermediate altitudes require only arrival at the time of the event, although mountain sickness may become a problem. The benefits of training at high altitude for subsequent performance at or near sea level depend on choosing the training altitude that maximizes the benefits and minimizes the “detraining” inevitable when maximal oxygen uptake is limited (altitude greater than 1500 to 2000 m [4921 to 6562 feet]). Hence, data from training above 2400 m (7874 feet) have shown no increase in subsequent sea level performance. Also, intermittent exposures to hypoxia seem to have no benefit.251,540 Runners returning to sea level after 10 days’ training at 2000 m (6562 feet) had faster running times and an increase in aerobic power, plasma volume, and hemoglobin concentration.19 Today the “live high–train low” approach pioneered by Levine and Stray-Gundersen294,513 has been adopted by many endurance athletes. The optimal dose for specific sports is still being worked out,570 but overall, endurance athletes believe and the science supports a small, but significant improvement in sea level performance after participating in a live high–train low training camp.514 The benefit appears to be due to enhanced erythropoietin production and increased red cell mass, which requires adequate iron stores and thus usually iron supplementation.328,443,512 Some individuals do not respond to live high–train low, perhaps related to genetic polymorphisms and the inability to increase erythropoietin levels sufficiently to raise red cell mass and thus increase oxygen-carrying capacity.79,247

High-Altitude Syndromes High-altitude syndromes are illnesses attributed directly to hypobaric hypoxia, even if exact mechanisms are unclear. Clinically and pathophysiologically these syndromes overlap. Rapidity of onset of hypoxia is crucial; for example, sudden exposure to extreme altitude may result in death from acute hypoxia (asphyxia), whereas more gradual ascent to the same altitude may result in AMS or no illness at all. Where symptoms of acute hypoxia end and AMS begins is vague, as reflected in the classic

Neurologic syndromes reflect both nervous system sensitivity to hypoxia and effects of compensatory mechanisms. Although brain adenosine triphosphate (ATP) production and overall metabolism remain intact during moderate hypoxia, impaired synthesis of neurotransmitters can produce cerebral symptoms such as lassitude, malaise, and cognitive defects. Compensatory cerebral vasodilation at altitude appears to be the trigger for altitude headache and contributes to development of AMS and HACE. However, much of the pathophysiology of AMS and HACE remains a mystery. Focal neurologic deficits without cerebral edema are also difficult to explain; cerebral artery spasm and watershed hypoxia have both been invoked. Understanding the exact etiology of these neurologic syndromes will parallel advances in neuroscience; the emphasis in altitude illness is finally and appropriately on the brain.438

ACUTE CEREBRAL HYPOXIA Acute, profound hypoxia, although of greatest interest in aviation medicine, may also occur on terra firma when ascent is too rapid or when hypoxia abruptly worsens. Carbon monoxide poisoning, pulmonary edema, sudden overexertion, sleep apnea, or a failed oxygen delivery system may rapidly exaggerate hypoxemia. Unacclimatized persons will lose consciousness from acute hypoxia at SaO2 of 40% to 60% or a PaO2 of less than about 30 mm Hg or mixed venous PO2 of 15 mm Hg. Tissandier, the sole survivor of the flight of the balloon Zenith in 1875, gave a graphic description of the effects of acute hypoxia: But soon I was keeping absolutely motionless, without suspecting that perhaps I had already lost use of my movements. Towards 7500 m [24,606 feet], the numbness one experiences is extraordinary. The body and the mind weaken little by little, gradually, unconsciously, without one’s knowledge. One does not suffer at all; on the contrary. One experiences inner joy, as if it were an effect of the inundating flood of light. One becomes indifferent; one no longer thinks of the perilous situation or of the danger; one rises and is happy to rise. Vertigo of the lofty regions is not a vain word. But as far as I can judge by my personal impression, this vertigo appears at the last moment; it immediately precedes annihilation—sudden, unexpected, irresistible. I wanted to seize the oxygen tube, but could not raise my arm. My mind, however, was still very lucid. I was still looking at the barometer; my eyes were fixed on the needle which soon reached the pressure number of 280, beyond which it passed. I wanted to cry out “We are at 8,000 meters.” But my tongue was paralyzed. Suddenly I closed my eyes and fell inert, completely losing consciousness.54 The ascent to over 8000 m (26,247 feet) took 3 hours, and the descent less than 1 hour. When the balloon landed, Tissandier’s two companions were dead. The prodigious work that Paul Bert conducted in an altitude chamber during the 1870s showed that lack of oxygen, rather than an effect of isolated hypobaria, explained the symptoms experienced during rapid ascent to extreme altitude. There exists a parallelism to the smallest details between two animals, one of which is subjected in normal air to a 9

CHAPTER 1  High-Altitude Medicine and Physiology

experiments of Bert.54 In terms of altitude illness, the general concept of a spectrum of illness with a common underlying pathogenesis is well accepted and provides a useful framework for discussion. For the neurologic syndromes, the spectrum progresses from high-altitude headache to AMS to high-altitude cerebral edema (HACE). In the lungs, the spectrum includes pulmonary hypertension, interstitial edema, and HAPE. These problems all occur within the first few days of ascent to a higher altitude, have many common features, and respond to descent and/or oxygen. Longer-term problems of altitude exposure include high-altitude deterioration in sojourners and chronic mountain sickness in high-altitude residents.

40

PART 1  MOUNTAIN MEDICINE

progressive diminution of pressure to the point of death, while the other breathes, also to the point of death, under normal pressure, an air that grows weaker and weaker in oxygen. Both will die after having presented the same symptoms.54 Bert goes on to describe the symptoms of acute exposure to hypoxia: It is the nervous system which reacts first. The sensation of fatigue, the weakening of the sense perceptions, the cerebral symptoms, vertigo, sleepiness, hallucinations, buzzing in the ears, dizziness, pricklings … are the signs of insufficient oxygenation of central and peripheral nervous organs. … The symptoms … disappear very quickly when the balloon descends from the higher altitudes, very quickly also … the normal proportion of oxygen reappears in the blood. There is an unfailing connection here.54 Bert was also able to both prevent and immediately resolve symptoms by breathing oxygen. Modern studies of acute hypoxic exposure use the measurement of time of useful consciousness; that is, the time until a subject can no longer take corrective measures, such as putting on an oxygen mask. With exposure to 8500 m (27,887 feet), that time is 60 seconds during moderate activity and 90 seconds at rest. Acute hypoxia can be quickly reversed by immediate administration of oxygen, rapid pressurization or descent, or correction of an underlying cause, such as relief of apnea, removal of a carbon monoxide source, repair of an oxygen delivery system, or cessation of overexertion. Hyperventilation increases time of useful consciousness during severe hypoxia.

HIGH-ALTITUDE HEADACHE The term high-altitude headache (HAH) has been used in the literature for decades, and studies directed toward the pathophysiology and treatment of HAH have been reported. Obviously these are to an extent also studies of AMS. Headache lends itself to investigation better than do some other symptoms, because headache scores have been well validated.244 Headache is generally the first unpleasant symptom consequent to altitude exposure and is sometimes the only symptom.214 It may or may not be the harbinger of AMS, which is defined as the presence of headache plus at least one of four other symptoms, in the setting of an acute altitude gain.435 One could even argue that it is the headache itself that causes other symptoms such as anorexia, nausea, lassitude, and insomnia, as is commonly seen in migraine or tension headaches, and that mild AMS is essentially due to headache. The International Headache Society206 has defined high-altitude headache as headache with at least two of the following characteristics: (1) bilateral; (2) frontal or frontotemporal; (3) dull or pressing quality; (4) mild or moderate intensity; and (5) aggravated by exertion, movement, straining, coughing, or bending. In addition, the headache must occur with an ascent to altitude greater than 2500 m (8202 feet), develop within 24 hours after ascent, and resolve within 8 hours after descent. Recent studies have attempted to characterize the clinical features and incidence of headache at altitude (Table 1-4). Silber and co-workers496 found that 50 of 60 trekkers (83%) in Nepal up to 5100 m (16,732 feet) developed at least one headache when over 3000 m (9843 feet). Older persons were less susceptible; women and those with headaches in daily life had more severe headaches, but no more headaches than others. Of those with headache, 52% did not have AMS by the Lake Louise criteria. The clinical features were widely variable. In general, the headaches were bilateral, generalized, dull, exacerbated by exertion or movement, often occurring at night, and resolved within 24 hours. Thus the headaches had some features of increased intracranial pressure (ICP). Persons with history of migraine did not have a higher incidence of headache. Various medications alleviated the headaches, especially mild ones, 70% of the time. Serrano-Duenas489 also described in detail HAH in 98 climbers in the Andes. Persons with history of primary headache were excluded. He found the following characteristics: holocranial, 65.6%; pulsatile-burst type quality, 75.3%; oscillating evolution, 10

TABLE 1-4  Clinical Characteristics of Headache Characteristic Location Global Frontal Hemi-cranial Occipital Change side Quality Pulsatile-burst Pressing/tightening Burning Dull Evolution Oscillate Disappear Diminish Increase Equal Break out in Elements Worsening Exercise Sudden movements Valsalva maneuver Light Elements Relieving Rest Analgesics Darkness Activity Concurrent Symptoms Anorexia Irritability Nausea Vomiting Apathy Gastric Malaise Somnolence Dysphasia Feelings Pessimism Anxiety Fear Isolation Strangeness

Percent Reporting 65.6 18.9 8.7 3.6 3.2 75.3 14.8 5.1 4.8 36.7 18.1 17.8 10.4 10.4 6.6 49.5 30.2 13.8 6.5 41.8 39 10.2 9 26.8 26.5 16.3 9.7 7.1 6.1 5.7 1.8 33.2 29.5 23.4 11.2 2.7

Modified from Serrano-Duenas M: High-altitude headache: A prospective study of its clinical characteristics, Cephalalgia 25:1110, 2005.

36.7%; increasing with exercise, 49.5%; relieved by rest, 41.8%; concurrent symptoms referred to: anorexia, 26.8%, irritability, 26.5%, and finally pessimism and anxiety feelings, 33.2% and 29.5%, respectively. Headaches were worse after a night’s sleep, more common in men, were of moderate intensity, and responded to analgesics. In general, the literature suggests that HAH can be prevented by the use of nonsteroidal antiinflammatory drugs65,72,157 and acetaminophen204 as well as the drugs commonly used for prophylaxis of AMS, acetazolamide and dexamethasone. Some agents appear more effective than do others, with ibuprofen and aspirin apparently superior to naproxen.65,70,73 A serotonin agonist (sumatriptan, a 5-HT1 [serotonin type 1] receptor agonist) was reported to be effective for HAH prevention and/or treatment in some studies,69,243,544 but not in others.28 Flunarizine, a specific calcium antagonist used for treatment of migraine, was not effective in one study.44 Interestingly, oxygen is often immediately effective for HAH (within 20 minutes) in subjects with and without AMS, indicating a rapidly reversible mechanism of the headache.26,191 The response to many different agents might reflect multiple components of the pathophysiology, or merely the nonspecific nature of analgesics. As Sanchez del Rio and Moskowitz463 have

Hypothalamus Brainstem

Autonomic response

CNS processing

High-altitude headache

Lower threshold for pain Trigeminovascular system activation

Hypoxia

eNOS upregulation

ACUTE MOUNTAIN SICKNESS Epidemiology and Risk Factors Although the syndrome of AMS has been recognized for centuries, modern rapid transport and proliferation of participants in mountain sports have increased the number of victims and therefore public awareness (see Table 1-1). The incidence and severity of AMS depend on the rate of ascent and the altitude attained (especially the sleeping altitude), duration of altitude exposure, level of exertion, recent altitude exposure, and inherent physiologic (genetic) susceptibility.440,475 For example, AMS is more common on Mt Rainier because of the rapid ascent, whereas high-altitude pulmonary or cerebral edema is uncommon because of the short stay (less than 36 hours). Persons with a demonstrated susceptibility to AMS had twice the incidence of AMS compared with nonsusceptibles, and this was independent of rate of ascent.475 The basis for inherent susceptibility is still unknown, but obviously depends on genetic factors. Acclimatization induced by recent altitude exposure can be protective; 4 days or more in the previous 2 months above 3000 m (9843 feet) reduced susceptibility to AMS on ascent to 4559 m (14,957 feet) by one-half, which was as effective as slow ascent475 (Figure 1-11). It also appears that protective effects of acclimatization persist after descent to low altitude. AMS was essentially absent in those who acclimatized to high altitude, returned to low altitude for 7 days, and were then reexposed to 4300 m (14,108 feet) in a hypobaric chamber.317 In addition, ventilation, SaO2, and exercise performance at altitude were maintained for at least 7 days,46,317,377 with some enhanced physical performance retained for several weeks.59,60,141,273,274 Recent epidemiologic studies suggest that protection from AMS may persist for months.475,586 Retention of the HVR might explain these results;305,433 yet studies showed that HVR returned to preascent values 7 days after descent.377 Compared with persons living at a lower altitude, residents at 900 m (2953 feet) or above reduced the incidence of AMS from 27% to 8% when ascending to between 2000 and 3000 m (6562 and 9843 feet) in Colorado.214 Age has an influence on incidence, with those over 50 years old somewhat less vulnerable.439,496 In a large study in Colorado, those over 60 had one-half the

incidence of AMS as those under 60 years of age. In contrast, a study of 827 mountaineers in Europe showed no influence of age on susceptibility.475 Perhaps different populations and physical activity explain the differing results. No study has ever shown older people to be more susceptible. Children from 3 months to puberty studied in Colorado had the same incidence as did young adults.534,592 A small study of tourists in Chile, however, found lower oxygen saturation and higher AMS in the 6- to 48-month age-group at 4440 m (14,567 feet).369 The largest study of children to date, of Han Chinese after ascent to Tibet, showed essentially the same incidence of AMS in 464 children as in 5335 adults, 34% and 38%, respectively.580 Women apparently have the same442,464,475 or a slightly greater incidence of AMS,214,546 but may be less susceptible to pulmonary edema.99,506 There appears to be no relation between AMS and the menstrual cycle.424 Most studies show no relation between physical fitness and susceptibility to AMS. However, obesity seems to increase the odds of developing AMS.154,214 Neither smoking nor the use of oral contraceptives increases risk for AMS.214,259,391 In summary, the most important variables related to AMS susceptibly are genetic predisposition, altitude of residence, altitude reached, rate of ascent, and prior recent altitude exposure. 70% 60%

Prevalence of AMS

pointed out, different inciting factors for headache may result in a final common pathway, such that the response to different therapies is not necessarily related to the initial cause of the headache. They have provided a useful multifactorial concept of the pathogenesis of HAH, based on current understanding of headaches in general.463 They suggest that the trigeminovascular system is activated at altitude by both mechanical and chemical stimuli (vasodilation, nitric oxide [NO] and other noxious agents), and in addition, the threshold for pain is likely altered at high altitude (Figure 1-10).463 If AMS and especially HACE ensue, then altered intracranial dynamics may also play a role, via compression or distension of pain-sensitive structures. A recent study provided evidence against sustained trigeminovascular activity,14 but more study will hopefully bring better understanding of the pathophysiology of these often debilitating headaches, and new treatments as well.

↑ NO

Nonsusceptible Susceptible

50% 40% 30% 20% 10% 0% Either ascent Ascent <4 days >3 days or and preexposure preexposure <5 days ≥5 days Rate of ascent and pre-exposure

Ascent >3 days and preexposure ≥5 days

FIGURE 1-11  The prevalence of acute mountain sickness (AMS) and 95% confidence intervals in nonsusceptible (blue bars) and susceptible (red bars) mountaineers in relation to the state of acclimatization defined as slow ascent (more than 3 days), fast ascent (3 days or less), preexposed (5 days or more above 3000 m [9843 feet] in the preceding 2 months), and not preexposed (4 days or less above 3000 m [9843 feet] in the preceding 2 months). (Reprinted from Schneider M, Bernasch D, Weymann J, et al: Acute mountain sickness: Influence of susceptibility, preexposure, and ascent rate, Med Sci Sports Exerc 34:1886, 2002.)

11

CHAPTER 1  High-Altitude Medicine and Physiology

FIGURE 1-10  Proposed pathophysiology of high-altitude headache. CNS, Central nervous system; eNOS, endothelial nitric oxide synthase; NO, nitric oxide. (Modified from Sanchez del Rio M, Moskowitz MA: High altitude headache. In Roach RC, Wagner PD, Hackett PH, editors: Hypoxia: Into the next millennium, New York, 1999, Plenum/Kluwer Academic Publishing, pp 145-153.)

PART 1  MOUNTAIN MEDICINE

TABLE 1-5  Clinical Characteristics of High-Altitude Illnesses Clinical Classification HAH

Mild AMS

Moderate to Severe AMS

HACE

Symptoms

Headache only

Headache plus one or more symptoms (nausea/vomiting, fatigue/lassitude, dizziness or difficulty sleeping) Symptoms of moderate to severe intensity

±Headache Worsening of symptoms seen in moderate to severe AMS

LL-AMS score* Physical signs

1-3, headache only None

Headache plus one more symptom (nausea/ vomiting, fatigue/ lassitude, dizziness or difficulty sleeping) All symptoms of mild severity 2-4 None

Findings

None

None

Pathophysiology

Unknown; cerebral vasodilation, trigeminovascular system?†

Unknown; same as HAH?

Antidiuresis Slightly increased body temperature Slight desaturation Widened A-a gradient Elevated ICP White matter edema (CT, MRI) Vasogenic edema; cytotoxic edema?

5-15 None

Ataxia Altered mental status HAPE common: positive chest radiograph, rales, dyspnea at rest Elevated ICP White matter edema (CT, MRI) Advanced vasogenic cerebral edema; cytotoxic edema?

AMS, Acute mountain sickness; CT, computed tomography; HACE, high-altitude cerebral edema; HAH, high-altitude headache; HAPE, high-altitude pulmonary edema; ICP, intracranial pressure; MRI, magnetic resonance imaging. *The self-reported Lake Louise AMS score. † See Figures 1-10 and 1-12.

Diagnosis Diagnosis of AMS is based on the setting, symptoms, physical findings, and exclusion of other illnesses. The setting is generally rapid ascent of unacclimatized persons to 2500 m (8202 feet) or higher from altitudes below 1000 m (3281 feet). For partially acclimatized persons, abrupt ascent to a higher altitude, overexertion, use of respiratory depressants, and perhaps onset of infectious illness376 are common contributing factors. The cardinal symptom of early AMS is headache, followed in incidence by fatigue, dizziness, and anorexia.214,500 The headache is usually throbbing, bitemporal, typically worse during the night and on awakening, and made worse by the Valsalva maneuver or stooping over (see High Altitude Headache, earlier). A good appetite is unusual, and nausea is common. These initial symptoms are strikingly similar to an alcohol hangover. Frequent awakening may fragment sleep, and periodic breathing often produces a feeling of suffocation. Although sleep disorder is nearly universal at high altitude, also affecting those without AMS, these symptoms may be exaggerated during AMS. Affected persons commonly complain of a deep inner chill, unlike mere exposure to cold temperature, accompanied by facial pallor. Other symptoms may include vomiting, dyspnea on exertion, and irritability. Lassitude can be disabling, with the victim too apathetic to contribute to his or her own basic needs. Pulmonary symptoms vary considerably. Everyone experiences dyspnea on exertion at high altitude; dyspnea at rest is distinctly abnormal, however, and presages HAPE rather than AMS. Cough is also extremely common at high altitude and not associated with AMS. Recent work suggests that altitude hypoxia actually lowers the cough threshold, as measured with an inhaled citric acid stimulus.333 However, any pulmonary symptom mandates careful examination for pulmonary edema. Specific physical findings are lacking in mild AMS. A higher heart rate has been noted in those with AMS,34,391 but Singh and associates500 noted bradycardia (heart rate less than 66 beats/min) in two-thirds of 1975 soldiers with AMS. Blood pressure is normal, but postural hypotension may be present. Occasionally, localized rales may be present,323 but this has also been observed in those without AMS.187 A slight increased body temperature with AMS may be present but is not diagnostic.321 Peripheral oxygen saturation as measured by pulse oximetry correlated poorly with presence of AMS during rapid ascent391,439,450 but was related to AMS during trekking.39 SaO2 at altitude on Denali was predictive of developing AMS on further ascent.436 Overall, pulse oximetry is 12

of limited usefulness in diagnosing AMS. Funduscopic examination reveals venous tortuosity and dilation; retinal hemorrhages may or may not be present and are not diagnostic. They are more common in AMS than non-AMS subjects at 4243 m (13,921 feet).187 Absence of the normal altitude diuresis, evidenced by lack of increased urine output and retention of fluid, is an early finding in AMS, although not always present.35,188,442,500,528 More obvious physical findings develop if AMS progresses to HACE. AMS displays no neurologic findings, whereas HACE is an encephalopathy (see High-Altitude Cerebral Edema, later). It is clinically useful to classify AMS as mild or moderate to severe on the basis of symptoms (Table 1-5). Importantly, AMS can herald the beginning of life-threatening cerebral edema. Differential Diagnosis Given the nonspecific nature of the symptoms, AMS is commonly confused with other conditions (Box 1-3). AMS is most commonly misdiagnosed as a viral flulike illness, hangover, exhaustion, dehydration, or medication or drug effect. Unlike an infectious illness, uncomplicated AMS is not associated with fever and myalgias. Hangover is excluded by the history. Exhaustion may cause lassitude, weakness, irritability, and headache and may therefore be difficult to distinguish from AMS. Dehydration, which causes weakness, decreased urine output, headache, and nausea, is commonly confused with AMS. Response to fluids BOX 1-3  Differential Diagnosis of High-Altitude

Illnesses

Acute mountain sickness and high-altitude cerebral edema

High-altitude pulmonary   edema

Dehydration, exhaustion, viral or bacterial infection, alcohol hangover, hypothermia, carbon monoxide poisoning, migraine, hyponatremia, hypoglycemia, diabetic ketoacidosis, CNS infection, transient ischemic attack, arteriovenous malformation, stroke, seizures, brain tumors, ingestion of toxins or drugs, acute psychosis Asthma, bronchitis, pneumonia, mucus plugging (secondary to previous), hyperventilation syndrome, pulmonary embolus, heart failure, myocardial infarction

CNS, Central nervous system.

↓O2 vasodilation

Acute hypoxic ventilatory ↓CO2 response vasoconstriction ←→

Ca2+

sensitivity NO→impaired →relaxation/vasodilation

↑Ca2+ No release

Endothelium Elastic lamina Smooth muscle

Other molecules that may be involved: Acetylcholine Substance P Prostaglandins

Microhemorrhage

↑K+

Raised hydrostatic pressure

Venous

Capillary and blood-brain barrier

Arteriole

CHAPTER 1  High-Altitude Medicine and Physiology

Artery

NO

HIF-1α not broken down

Hypoxemia

Raised venous pressure

Free radical formation

Basement membrane damage Na+/K+ Upregulation ATPase failure of VEGF →intracellular Edema→↑ICP edema Adenosine →hypoxic vasodilation

Headache

Capillary basement membrane damage and angiogenesis Mechanical mediator PO2/PCO2 mediator Chemical mediator

Vasodilation→pain Pain fibers of trigeminal nerve→trigeminovascular system

FIGURE 1-12  Proposed pathophysiology of acute mountain sickness. HIF, Hypoxia-inducible factor; ICP, intracranial pressure; NO, nitric oxide; VEGF, vascular endothelial growth factor. (Modified from Wilson MH, Newman S, Imray CH: The cerebral effects of ascent to high altitudes, Lancet Neurol 8:175, 2009.)

helps to differentiate the two. AMS is not improved by fluid administration alone, and body hydration does not influence susceptibility to AMS (contrary to conventional wisdom).11 Hypothermia may manifest as ataxia and mental changes. Sleeping medication can cause ataxia and mental changes, but soporifics may also precipitate high-altitude illness because of increased hypoxemia during sleep. Migraine may be very difficult to distinguish from AMS. A trial of oxygen breathing or descent can be helpful to discriminate these other conditions from AMS. Pathophysiology The basic cause of AMS is hypoxemia, but the syndrome is different from acute hypoxia. Because symptoms are somewhat worse with hypobaric hypoxia than with normobaric hypoxia, hypobaria apparently also plays a minor role, most likely through its effect on fluid retention.240,261,303,304,441 Because of a time lag in onset of symptoms after ascent and lack of immediate or complete reversal of all symptoms with oxygen, AMS is thought to be secondary to the body’s responses to modest hypoxia. In addition, even though an altitude of 2500 to 2700 m (8202 to 8858 feet) presents only a minor decrement in arterial oxygen transport (SaO2 is still above 90%), AMS is common and some individuals may become desperately ill. Some aspects of AMS pathophysiology are clear. Findings documented in mild to moderate AMS include relative hypoventilation,336,366 impaired gas exchange (interstitial edema),171,286 fluid retention and redistribution,35,442,528 and increased sympathetic

drive.31,34 In mild to moderate AMS, limited data show that ICP or cerebrospinal fluid (CSF) pressure is not elevated at rest.17,205,579 In contrast, increased ICP and cerebral edema are documented in severe AMS, reflecting the continuum from advanced AMS to HACE.220,276,337,500,573 The known, well-established findings in AMS are reviewed extensively elsewhere.179,233,240 The remainder of this section focuses on remaining questions and new work in the quest to find the cause of AMS. We proposed more than a decade ago that moderate to severe AMS was caused by brain swelling leading to elevated ICP via a compromised buffering capacity. This hypothesis has not yet been directly tested. We now examine the data on brain swelling, ICP, and cranial buffering capacity in AMS. Brain Swelling in AMS.  For decades, clinicians have postulated that AMS is a mild form of cerebral edema. Although this appears true for moderate to severe AMS, it now seems unlikely that mild AMS, or the headache alone, is due to edema (see High-Altitude Headache, earlier). Persons with moderate to severe AMS or HACE display elevated ICP and white matter edema on brain imaging in most but not all studies,144 whereas those with mild AMS do not.* Recent MRI studies have demonstrated that brain swelling occurs in all subjects ascending rapidly to moderate altitude, regardless

*References 197, 220, 276, 295, 337, 500.

13

PART 1  MOUNTAIN MEDICINE

of the presence of AMS, and is due to both vasodilation and minor vasogenic edema. In addition, there may be an intracellular fluid shift as evidenced by low apparent diffusion coefficient. Although this was greater in those with AMS, the volumetric changes were minor and unlikely to result in increased ICP without contributing factors.144,239,252,372,481 In summary, no gross elevation in brain volume has been found yet in mild AMS or headache alone, but elevated brain volume is almost universally observed in moderate to severe AMS and HACE. Intracranial Pressure and AMS.  A fascinating story was recently reported in which a neurosurgeon measured ICP changes from a self-implanted ICP monitoring bolt in himself and in two others.572 They demonstrated that ICP remained normal at rest at all altitudes (studied from sea level to 5030 m [16,503 feet]); however, in the single subject with AMS, there was a dramatic increase in ICP even on minimal exertion. This study is consistent with recent indirect assessment of elevated ICP in AMS based on optic nerve sheath diameter.138,523 In addition, a study that measured opening lumbar pressure revealed significant elevations in AMS subjects compared with control or after AMS resolved.500 In contrast, one recent study in normobaric hypoxia reported no elevation of ICP in AMS when measured indirectly by repeat lumbar puncture.252 The evidence that ICP is elevated in mild AMS is limited and not compelling. Stronger evidence suggests that perhaps intracranial compliance is altered,275 and that although ICP might not be elevated at rest, it rises abruptly with isometric maneuvers such as lifting a pack, with Valsalva, or even with turning the head, which slightly elevates venous pressure.205,572 Altered compliance is consistent with the tight-fit hypothesis (see below). The Tight-Fit Hypothesis and AMS.  Ross457 hypothesized in 1985 that persons with smaller intracranial and intraspinal CSF capacity would be disposed to develop AMS, because they would not tolerate brain swelling as well as those with more “room” in the craniospinal axis. It is displacement of CSF through the foramen magnum into the spinal canal that is the first compensatory response to increased brain volume, followed by increased CSF absorption and decreased CSF formation. Studies have shown that the increase in ICP for a given increase in brain volume is directly related to the “tightness” of the brain in the cranium (the brain volume: intracranial volume ratio) and to the volume of the spinal canal.492 Thus, the greater the initial CSF volume, the more accommodation that can take place in response to brain edema. Increases in volume are “buffered” by CSF dynamics. In light of our present understanding of increased brain volume on ascent to altitude, his hypothesis is still very attractive. Preliminary data that showed a relationship of preascent ventricular size or brain volume: cranial vault ratios and susceptibility to AMS support this hypothesis,182,252,572,593 as do the studies showing elevated ICP in moderate to severe AMS.220,276,337,500,573 The idea deserves further study. New Concepts.  New, potentially important work is under way to understand the potential role of inflammatory mediators, free radicals, and even HIF-modulated reactions in the pathophysiology of AMS.14,16 Progress is hampered by the technical difficulty of some of these approaches, by lack of an animal model, and by the unresolved status of the basic pathophysiology. A potentially unifying hypothesis, with several novel ideas, is presented in Figure 1-12. In this schema, mechanical factors increase intravascular pressure and hence can cause vasogenic edema and vessel wall damage. This pressure can act in the artery (increased hydrostatic pressure associated with increased flow) or vein (if there is venous outflow obstruction, as in benign intracranial hypertension, for example). The partial pressures of oxygen and carbon dioxide are thought to have direct vasoactive properties, with hypoxemia causing vasodilation and hypocarbia causing vasoconstriction. A balance between these is mediated by the hypoxic and CO2 ventilatory responses. Cytotoxic edema is attributed to direct hypoxia-induced Na+/K+ ATPase failure. Many chemical mediators have been implicated. Free radical formation could directly damage the blood–brain barrier, causing vasogenic edema. Accumulation of HIF-1α and subsequent upregulation of 14

vascular endothelial growth factor (VEGF) could contribute to further blood–brain barrier damage and edema. Neuronally mediated adenosine release also causes vasodilation. Vessel dilation has been implicated in activating the trigeminovascular system, causing headache. An important element of HACE is microhemorrhage formation, caused by vessel damage from chemical mediators or cytokines or by damage through increased hydrostatic pressure.253 Natural Course of Acute Mountain Sickness The natural history of AMS varies with initial altitude, rate of ascent, and clinical severity. Symptoms can start within 2 hours after arrival and rarely if ever start after 36 hours at a given altitude. AMS usually resolves over the next 24 to 48 hours. The more rapid the ascent, and the higher the altitude, the more likely that symptoms will appear sooner and be worse. Singh and associates500 followed the illness in soldiers airlifted to altitudes of 3300 to 5500 m (10,827 to 18,045 feet). Incapacitating illness lasted 2 to 5 days, but 40% still had symptoms after 1 week and 13% after 1 month. Nine soldiers failed to acclimatize in 6 months and were considered unfit for duty at high altitude.500 Chinese investigators report that a percentage of lowland Han Chinese stationed on the Tibet Plateau cannot tolerate the altitude because of persistent symptoms and must be relocated to the plains.583 Persistent anorexia, nausea, and headache may afflict climbers at extreme altitude for weeks and can be considered a form of persistent AMS. The natural history of AMS in tourists who sleep at more moderate altitudes is much more benign. Duration of symptoms at 2700 m was 15 hours, with a range of 6 to 94 hours.361 Most individuals treat or tolerate their symptoms as the illness resolves over 1 to 3 days while acclimatization improves, but some persons with AMS seek medical treatment or are forced to descend if symptoms persist. A small percentage of those with AMS (3.4% at 4243 m [13,921 feet]) go on to develop cerebral edema, especially if ascent continues in spite of illness. Although 50% of persons with HAPE have AMS, no study has documented how many with AMS develop HAPE. Treatment Management of AMS is based on severity of illness at presentation, logistics, terrain, and experience of the caregiver. Early diagnosis is key, because treatment in the early stages of illness is easier and more successful (Box 1-4). Proceeding to a higher sleeping altitude in the presence of symptoms is contraindicated. The victim must be carefully monitored for progression of illness. If symptoms worsen despite 24 hours of acclimatization or treatment, descent is indicated. The two indications for immediate descent are neurologic findings (ataxia or change in consciousness) and pulmonary edema. Mild AMS can be treated by halting the ascent and waiting for acclimatization to improve, which can take from 12 hours to 3 or 4 days. Acetazolamide (250 mg twice a day orally, or as a single dose) speeds acclimatization and thus terminates the illness if given early.171,326 Symptomatic therapy includes analgesics such as aspirin (500 or 650 mg), acetaminophen (650 to 1000 mg), ibuprofen65 or other nonsteroidal antiinflammatory drugs, or codeine (30 mg) for headache. Ondansetron 4 mg orally disintegrating tablets every 4 hours as necessary is useful for nausea and vomiting. Persons with AMS should avoid alcohol and other respiratory depressants because of possible exaggerated hypoxemia during sleep. Descent to an altitude lower than where symptoms began effectively reverses AMS. Although descent should be as far as necessary for improvement, 500 to 1000 m (1640 to 3281 feet) is usually sufficient. Exertion should be minimized. Oxygen, if available, is particularly effective (and supply is conserved) if given in low flow (0.5 to 1 L/min by mask or cannula) during the night. Hyperbaric chambers, which simulate descent, have been used to treat AMS and aid acclimatization. They are effective and require no supplemental oxygen. Lightweight (less than 7 kg) fabric pressure bags inflated by manual air pumps are now being used on mountaineering expeditions and in mountain clinics (Figure 1-13). An inflation of 2 psi is roughly equivalent to a drop in altitude of 1600 m (5249 feet); the exact equivalent depends on initial altitude.257,437 A few hours of pressurization

High-Altitude Headache and Mild Acute Mountain Sickness • Stop ascent, rest, acclimatize at same altitude • Symptomatic treatment as necessary with analgesics and antiemetics • Consider acetazolamide, 125 to 250 mg bid, to speed acclimatization • OR descend 500 m (1640 feet) or more Moderate to Severe Acute Mountain Sickness • Low-flow oxygen, if available • Acetazolamide, 125 to 250 mg bid, with or without dexamethasone, 4 mg PO, IM, or IV q6h • Hyperbaric therapy • OR immediate descent High-Altitude Cerebral Edema • Immediate descent or evacuation • Oxygen, 2 to 4 L/min • Dexamethasone, 8 mg PO, IM, or IV, then 4 mg q6h • Hyperbaric therapy High-Altitude Pulmonary Edema • Minimize exertion and keep warm • Immediate descent or hyperbaric therapy • Oxygen, 4 to 6 L/min until improving, then 2 to 4 L/min • If above unavailable, one of the following: • Nifedipine, 30 mg extended release q12h • Sildenafil 50 mg q8h • Tadalafil 10 mg q12h • Consider inhaled β-agonist Periodic Breathing • Acetazolamide, 62.5 to 125 mg at bedtime as needed

hydrochlorothiazide, and other diuretics have not yet been evaluated for treatment (see Prevention, later). The steroid betamethasone was initially reported by Singh and co-workers500 to improve symptoms of soldiers with severe AMS. Subsequent studies have found dexamethasone to be effective for treatment of all degrees of AMS.140,196,262 Hackett and colleagues196 used 4 mg orally or intramuscularly every 6 hours, and Ferrazinni and associates140 gave 8 mg initially, followed by 4 mg every 6 hours. Both studies reported marked improvement within 12 hours, which was the first postdrug assessment, but clinical experience suggests improvement of AMS within 4 hours. There were no significant side effects. Symptoms increased when dexamethasone was discontinued after 24 hours.196 Clinicians debate whether the use of dexamethasone should also mandate descent. Is it safe to continue to ascend after treatment with dexamethasone or while taking the medication? In reality, people do, and problems seem to be few. In our opinion, dexamethasone use should be limited to less than 72 hours to minimize side effects. This generally is sufficient time to descend, or to better acclimatize, with or without acetazolamide. The mechanism of action of dexamethasone is unknown; it does not affect oxygen saturation, fluid balance, or periodic breathing.295 The drug blocks the action of VEGF,476 diminishes the interaction of endothelium and leukocytes (thus reducing inflammation),167 and may also reduce cerebral blood flow.250 Dexamethasone seems to not improve acclimatization, because some symptoms recur when the drug is withdrawn. Therefore an argument could be made for using dexamethasone to relieve symptoms and acetazolamide to speed acclimatization.52 Prevention Prevention strategy is based on risk assessment311 (Table 1-6). Graded ascent is the surest and safest method of prevention, although particularly susceptible individuals may still become ill. TABLE 1-6  Risk Categories for Acute Mountain

Sickness

IM, Intramuscularly; IV, intravenously; PO, orally.

result in symptomatic improvement and can be an effective temporizing measure while awaiting descent or the benefit of medical therapy.257,375,398,444,532 Long-term (12 hours or more) use of these portable devices is necessary to resolve AMS completely. Acetazolamide is of unquestionable prophylactic value and is now commonly and successfully used to treat AMS as well, although data supporting this are minimal.171,326 Singh and colleagues500 successfully used furosemide (80 mg twice a day for 2 days) to treat 446 soldiers with all degrees of AMS; it has not since been studied for treatment. Furosemide induced a brisk diuresis, relieved pulmonary congestion, and improved headache and other neurologic symptoms.500 Spironolactone,

Risk Category Low

Moderate

High

FIGURE 1-13  A fabric hyperbaric pressure bag being used on Mt Everest for treatment of severe altitude illness. Two psi pressure is equivalent to a drop of approximately 1600 m (5249 feet) in altitude.

Description Individuals with no prior history of altitude illness and ascending to <2800 m (9186 feet) Individuals taking >2 days to arrive at 2500-3000 m (8202-9843 feet) with subsequent increases in sleeping elevation <500 m (1640 ft)/day and an extra day for acclimatization every 1000 m (3281 feet) Individuals with prior history of AMS and ascending to 2500-2800 m (8202-9186 feet) in 1 day No history of AMS and ascending to >2800 m (9186 feet) in 1 day All individuals ascending >500 m (1640 ft)/day (increase in sleeping elevation) at altitudes above 3000 m (9843 feet) but with an extra day for acclimatization every 1000 m (3281 feet) History of AMS and ascending to >2800 m (3281 feet) in 1 day All individuals with a prior history of HAPE or HACE All individuals ascending to >3500 m (11,483 feet) in 1 day All individuals ascending >500 m (1640 ft)/day (increase in sleeping elevation) above >3000 m (9843 feet) without extra days for acclimatization Very rapid ascents (e.g., <7-day ascents of Mt Kilimanjaro)

Modified from Luks AM, McIntosh SE, Grissom CK, et al: Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness, Wilderness Environ Med 21:146, 2010. AMS, Acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema. Notes: Altitudes listed in the table refer to the altitude at which the person sleeps. Ascent is assumed to start from elevations <1200 m (3937 feet). The risk categories described above pertain to unacclimatized individuals.

15

CHAPTER 1  High-Altitude Medicine and Physiology

BOX 1-4  Field Treatment of High-Altitude Illness

PART 1  MOUNTAIN MEDICINE

Carbonic anhydrase

CO2 + H2O <==> H2CO3 <==> H+ + HCO3 FIGURE 1-14  Action of acetazolamide to block carbonic anhydrase (shown in a molecular ribbon diagram) and thus slow the hydration of carbon dioxide.

Current recommendations are to avoid abrupt ascent from low altitude to sleeping altitudes greater than 2800 m (9186 feet) in 1 day, to spend 2 to 3 nights at 2500 to 3000 m (8202 to 9843 feet) before going higher, to not advance sleeping altitude more than 500 m (1640 ft)/day, and to take an extra night for acclimatization every 1000 m if continuing ascent.311 However, a recent study on Aconcagua reinforced the notion that individual susceptibility is a key factor, and that persons who are resistant to AMS can proceed much more quickly on the mountain safely.405 Day trips to higher altitude, with a return to lower altitude for sleep, aid acclimatization. Alcohol and sedative-hypnotics are best avoided on the first 2 nights at high altitude. Whether a diet high in carbohydrates reduces AMS symptoms is controversial.96,203,530 Exertion early in altitude exposure contributes to altitude illness,440 whereas limited exercise seems to aid acclimatization. Because altitude exposure in the previous weeks is protective, a faster rate of ascent may then be possible.475,586 Acetazolamide Prophylaxis.  Acetazolamide is the drug of choice for prophylaxis of AMS. A carbonic anhydrase inhibitor, acetazolamide slows the hydration of carbon dioxide (Figure 1-14).

The effects are protean, involving particularly red blood cells, the brain, lungs, and kidneys. By inhibiting renal carbonic anhydrase, acetazolamide reduces reabsorption of bicarbonate and sodium and thus causes a bicarbonate diuresis and metabolic acidosis, beginning within 1 hour after ingestion. This rapidly enhances ventilatory acclimatization, increasing oxygenation. Importantly, the drug maintains oxygenation during sleep and prevents periods of extreme hypoxemia (see Figure 1-6).192,525,529 Because of acetazolamide’s diuretic action, it counteracts the fluid retention of AMS. It also diminishes nocturnal antidiuretic hormone secretion86 and decreases CSF production and volume and possibly CSF pressure.488 Acetazolamide also impacts brain aquaporin channels, possibly preventing water transport into the brain.533 Which of these effects is most important in preventing AMS is unclear. Numerous studies taken together indicate that acetazolamide is approximately 75% effective in preventing AMS in persons rapidly transported to altitudes of 3000 to 4500 m (9843 to 14,764 feet).132 Acetazolamide prophylaxis should be considered for persons with moderate to severe risk, as indicated in Tables 1-6 and 1-7. The ideal dose of acetazolamide for prevention is debated. Many studies have shown that 250 mg twice a day or 3 times a day was effective, as well as 500 mg in sustained action capsule taken every 24 hours.* To reduce the side effects, especially paresthesias, clinicians have more recently been using smaller doses (125 mg twice a day),348 and a number of studies now support this.37,77,548 Renal carbonic anhydrase is blocked with 5 mg/kg/ day, and this may be the maximum dose required, both in children and adults. Duration of medication use varies; the standard advice is to start 24 hours before ascent. Most clinicians recommend continuing for at least the first 2 days at high altitude, and longer if there is continuing gain in altitude. Acetazolamide can also be taken episodically, to speed acclimatization at any point while gaining altitude or to treat mild AMS. There is no rebound when discontinued. Although the danger of altitude illness passes after a few days of acclimatization, acetazolamide may still be useful to promote more effective sleep. Acetazolamide has side effects, most notably peripheral paresthesias and polyuria, and less commonly nausea, drowsiness, impotence, and myopia. Because it inhibits the instant hydration of carbon dioxide on the tongue, acetazolamide allows carbon dioxide to be tasted and can ruin the flavor of carbonated beverages, including beer. The issue of sulfonamide allergy and acetazolamide was recently reviewed.263 As a nonantibiotic sulfonamide drug, acetazolamide is usually tolerated well by persons with a history of sulfa antibiotic allergy; approximately 10% may have an allergic reaction.517 In persons without a history *References 83, 156, 170, 186, 286, 421, 575.

TABLE 1-7  Recommended Dosages for Medications Used in the Prevention and Treatment of Altitude Illness Medication

Indication

Route

Dosage

Acetazolamide

AMS, HACE prevention

Oral

AMS treatment*

Oral

AMS, HACE prevention

Oral

AMS, HACE treatment

Oral, IV, IM

HAPE HAPE HAPE HAPE HAPE

Oral Oral Oral Oral Inhaled

125 mg twice per day Pediatric dose: 2.5 mg/kg q12h 250 mg twice per day Pediatric dose: 2.5 mg/kg q12h 2 mg q6h or 4 mg q12h Pediatrics: should not be used for prophylaxis AMS: 4 mg q6h HACE: 8 mg once then 4 mg q6h Pediatric dose: 0.15 mg/kg/dose q6h up to 4 mg 30 mg SR version q12h 30 mg SR version q12h 10 mg twice per day 50 mg q8h 125 mcg twice per day*

Dexamethasone

Nifedipine Tadalafil Sildenafil Salmeterol

prevention treatment prevention prevention prevention

Modified from Luks AM, McIntosh SE, Grissom CK, et al: Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness, Wilderness Environ Med 21:146, 2010. AMS, Acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema; IM, intramuscular; IV, intravenous; SR, sustained release. *Should not be used as monotherapy and should only be used in conjunction with oral medications.

16

Dexamethasone Prophylaxis.  Dexamethasone effectively prevents AMS. Two mg every 6 hours or 4 mg every 12 hours was sufficient for sedentary subjects,250 but for exercising subjects at or above 4000 m (13,123 feet), this was insufficient,51,196,446 and 4 mg every 6 hours was necessary to prevent AMS.447 The initial chamber study in 1984 was with sedentary subjects.250 The drug reduced the incidence of AMS from 78% to 20%, comparable with previous studies with acetazolamide. Dexamethasone was not as effective in exercising subjects on Pike’s Peak,446 but subsequent work has shown effectiveness comparable with acetazolamide.42,132,295,360,594 The combination of acetazolamide and dexamethasone proved superior to dexamethasone alone.594 Because of potential serious side effects and the rebound phenomenon, dexamethasone is best reserved for treatment rather than for prevention of AMS, or used for prophylaxis when necessary in persons intolerant of or allergic to acetazolamide. Other Agents for AMS Prevention.  Studies with Ginkgo biloba have had inconsistent results. Four studies had positive results, ranging from 100% to 50% reduction in AMS when given either 5 days or 1 day before ascent.158,318,368,451 Three studies were negative, two of which were follow-up studies by investigators with positive results previously.83,156,288 Conflicting results can possibly be explained by differences in dosing, duration of pretreatment, and varying rates of ascent, but most likely, they are due to differences in preparations of ginkgo.289 Ginkgo biloba is a complicated plant extract whose active ingredient in terms of preventing AMS is unknown. Even in the “standardized” preparations (24% flavonoids and 6% terpene ginkolides), the amounts of specific chemicals can vary considerably. Until the active ingredient is discovered and standardized, results with ginkgo will continue to be mixed. Meanwhile, because the product is very safe, nonprescription, inexpensive, and can be helpful, it is reasonable to consider its use. Acetazolamide, however, is likely the superior agent. Spironolactone,245,285 naproxen, calcium channel blockers, antacids, and medroxyprogesterone acetate have shown ineffectiveness for AMS prevention. Bailey and Davies15 tested an antioxidant “cocktail” for prevention of AMS. They reasoned that free-radicalmediated damage to the blood–brain barrier might play a role in the pathophysiology. They preloaded nine subjects with daily L-ascorbic acid, DL-α-tocopherol acetate and α-lipoic acid, and nine subjects with placebo for 3 weeks, and then during a 10-day trek to the Mt Everest base camp. Those on antioxidants had a slightly lower AMS score and higher arterial oxygen saturation and better appetite.15 A recent study failed to confirm any benefit of antioxidant therapy for preventing AMS.18 In spite of these marginal findings in field studies, some clinicians propose that regional changes in redox state in the brain can lead to focal blood–brain barrier disruption and vasogenic edema. See Bärtsch and associates25 for a detailed discussion of the antioxidant hypothesis.

HIGH-ALTITUDE CEREBRAL EDEMA HACE is an uncommon but deadly condition, usually occurring in those with AMS or HAPE. Although HACE is most common over 3000 m (9843 feet), it has been reported at altitudes as low as 2100 m (6890 feet).115 Reliable estimates of incidence range from 0.5% to 1% in unselect high-altitude visitors,33,186 but was 3.4% in those who had developed AMS.186 In Chinese railway workers at 4500 to 4900 m (14,764 to 16,076 feet), incidence was 0.5%. HACE occurs in 13% to 20% of persons with HAPE152,211,232 and in up to 50% of those who die from HAPE. In addition, HAPE is very common in those diagnosed with HACE; one series

from Colorado reported that 11 of 13 with a primary diagnosis of HACE also had HAPE. Pure cerebral edema, without pulmonary edema, appears to be uncommon at lower altitudes, but accounted for 54 of 66 HACE cases in Tibet.582 The mean altitude at onset was 4730 m (15,518 feet)in one survey, but was lower (3920 m [12,861 feet]) when associated with HAPE.233 Data are insufficient to draw any conclusions regarding effects of gender, age, preexisting illness, or genetics on susceptibility to HACE. Clinically and pathophysiologically, advanced AMS and HACE are similar, so that a distinction between them is inherently blurred. See our review190 and the recent series reported by Wu and associates582 for a more complete discussion. Clinical Presentation HACE is an encephalopathy, whereas AMS is not. The hallmarks of HACE are ataxic gait, severe lassitude, and altered consciousness, including confusion, impaired mentation, drowsiness, stupor, and coma. Headache, nausea, and vomiting are frequent, but not always present. Hallucinations, cranial nerve palsy, hemiparesis, hemiplegia, seizures, and focal neurologic signs have also been reported.118,199,220,500,582 Seizures are distinctly uncommon. Retinal hemorrhages are common but not diagnostic. The progression from mild AMS to unconsciousness may be as fast as 12 hours but usually requires 1 to 3 days; HACE can develop more quickly in persons with HAPE. Arterial blood gas study or pulse oximetry often reveals exaggerated hypoxemia. Clinical examination and chest radiography may reveal pulmonary edema. Laboratory studies and lumbar puncture are useful only to rule out other conditions. Computed tomography (CT) may show compression of sulci and flattening of gyri, and attenuation of signal more in the white matter than gray matter. MRI is more revealing, with a characteristic high T2 signal in the white matter, especially the splenium of the corpus callosum, and most evident on diffusion-weighted images.197,578,582 The following case report from Mt McKinley illustrates a typical clinical course of HACE in conjunction with HAPE. CLINICAL PRESENTATION H.E. was a 26-year-old German lumberjack with extensive mountaineering experience. He ascended to 5200 m (17,060 feet) from 2000 m (6562 feet) in 4 days and attempted the summit (6194 m [20,322 feet]) on the fifth day. At 5800 m (19,029 feet) he turned back because of severe fatigue, headache, and malaise. He returned alone to 5200 m (17,060 feet), stumbling on the way because of loss of coordination. He had no appetite and crawled into his sleeping bag too weak, tired, and disoriented to undress. He recalled no pulmonary symptoms. In the morning H.E. was unarousable, slightly cyanotic, and noted to have Cheyne-Stokes respirations. After 10 minutes on high-flow oxygen, H.E. began to regain consciousness, although he was completely disoriented and unable to move. A rescue team lowered him down a steep slope, and on arrival at 4400 m (14,436 feet) 4 hours later, he was conscious but still disoriented, able to move extremities but unable to stand. Respiratory rate was 60 breaths/min, and heart rate was 112 beats/min. Papilledema and a few rales were present. SaO2 was 54% on room air (normal is 85% to 90%). On a nonrebreather mask with 14 L/min oxygen, the SaO2 increased to 88% and the respiratory rate decreased to 40 breaths/min. Eight milligrams of dexamethasone were administered intramuscularly at 4:20 PM and continued orally, 4 mg every 6 hours. At 5:20 PM, H.E. began to respond to commands. The next morning H.E. was still ataxic but was able to stand, take fluids, and eat heartily. He was evacuated by air to Anchorage (sea level) at 12:00 PM. On admission to the hospital at 3:30 PM, roughly 36 hours after regaining consciousness, H.E. was somewhat confused and mildly ataxic. Arterial blood gas studies on room air showed a PO2 of 58 mm Hg, pH of 7.5, and PCO2 of 27 mm Hg. Bilateral pulmonary infiltrates were present on the chest radiograph. Magnetic resonance imaging of the brain revealed white matter edema, primarily of the corpus callosum (Figures 1-15 and 1-16). On discharge the next morning, H.E. was oriented, bright, and cheerful and had very minor ataxia and clear lung fields. 17

CHAPTER 1  High-Altitude Medicine and Physiology

of allergy to sulfa antibiotic, the incidence of hypersensitivity reaction to a sulfonamide nonantibiotic was 1.6%.517 The same analysis concluded that persons who are penicillin allergic are actually more likely to react to drugs like acetazolamide than those who are sulfa allergic. Nonetheless, it is wise to be cautious in persons with a history of allergy, especially anaphylaxis to either sulfa or penicillin. Many experts recommend a trial dose of the medication well before the altitude sojourn, to determine if the drug is tolerated well. Although the usual allergic reaction is a rash starting a few days after ingestion, anaphylaxis to acetazolamide does rarely happen.

PART 1  MOUNTAIN MEDICINE

Pathophysiology

FIGURE 1-15  Magnetic resonance image of a patient with highaltitude cerebral edema. Increased T2 signal in splenium of corpus callosum (arrow) indicates edema. (Reprinted from Hackett PH, Yarnell PR, Hill R, et al: High-altitude cerebral edema evaluated with magnetic resonance imaging: Clinical correlation and pathophysiology, JAMA 280:1920, 1998.)

The pathophysiology of HACE is a progression of the same mechanism as advanced AMS (see Acute Mountain Sickness, Pathophysiology, and Figure 1-12) and appears to be vasogenic edema. In cases similar to this, lumbar punctures have revealed elevated CSF pressures, often more than 300 mm H2O,220,573 evidence of cerebral edema on CT scan and MRI,197,272 and gross cerebral edema on necropsy.117,118 Small petechial hemorrhages were also consistently found on autopsy, and venous sinus thromboses were occasionally seen.117,118 Well-documented cases have often included pulmonary edema that was not clinically apparent. Whereas the brain edema of reversible HACE is most likely vasogenic, as the spectrum shifts to severe, end-stage HACE, then gray matter (presumably cytotoxic) edema develops as well, culminating in brain herniation and death. As Klatzo271 has pointed out, as vasogenic edema progresses, the distance between brain cells and their capillaries increases, so that nutrients and oxygen eventually fail to diffuse and the cells are rendered is­ chemic, leading to intracellular (cytotoxic) edema. Raised ICP produces many of its effects by decreasing cerebral blood flow, and brain tissue also becomes ischemic on this basis.344 Focal neurologic signs caused by brainstem distortion and by extraaxial compression, as in third and sixth cranial nerve palsies, may develop,452 making cerebral edema difficult to differentiate from primary cerebrovascular events. The most common clinical presentation, however, is change in consciousness associated with ataxia, without focal signs.582,589

1

2

3

4

5

6

FIGURE 1-16  Magnetic resonance imaging (MRI) scans of patient with high-altitude cerebral edema (HACE). A fluid-attenuated inversion recovery (FLAIR) (1) shows an areal lesion of the corpus callosum—confirmed by diffusion-weighted imaging (DWI) (2), with increased values in apparent diffusion coefficient (ADC) (3), indicating increased water diffusivity compatible with vasogenic edema; in combination, the characteristic MRI pattern consistent with HACE (1 to 3) that persists 6 weeks after the event. A novel finding relates to the multiple patchy hypointensities that correspond to multiple microhemorrhages (arrows) displayed on the T2* images (4 to 6). The right frontal meningioma (visible on FLAIR [1]; [arrowhead]) is an incidental finding. (Reprinted from Kallenberg K, Dehnert C, Dorfler A, et al: Microhemorrhages in nonfatal high-altitude cerebral edema, J Cereb Blood Flow Metab 28:1635, 2008.)

18

STROKE

Given the sporadic nature and generally remote location of this disorder, it is not surprising that there are no controlled trials regarding treatment of HACE. All experts agree that successful treatment requires early recognition. At the first sign of ataxia or change in consciousness, descent should be started, dexamethasone (4 to 8 mg intravenously, intramuscularly, or orally initially, followed by 4 mg every 6 hours) administered, and oxygen (2 to 4 L/min by vented mask or nasal cannula) applied if available (see Box 1-4). Oxygen can be titrated to maintain SaO2 at greater than 90% if oximetry is available. Comatose patients require additional airway management and bladder drainage. Attempting to decrease ICP by endotracheal intubation and hyperventilation is a reasonable approach, although these patients are already alkalotic and overhyperventilation could result in disastrous cerebral ischemia. Loop diuretics such as furosemide (40 to 80 mg) or bumetanide (1 to 2 mg) may reduce brain hydration, and have been used successfully,116,500 but an adequate intravascular volume to maintain perfusion pressure is critical. Hypertonic solutions of saline, mannitol, or oral glycerol have been suggested, but rarely used in the field. Controlled studies are lacking, but empirically the response to corticosteroids and oxygen seems excellent if they are given early in the course of the illness and disappointing if they are not started until the victim is unconscious. Coma may persist for days, even after evacuation to low altitude, but other causes of coma must be considered and ruled out by appropriate evaluation.220 The average duration of hospital stay in one series of patients with severe HACE was 5.6 days, and average time to full recovery was 2.4 weeks, with a range of 1 day to 6 weeks.197 Two patients of the 44 in the series by Dickinson118 remained in coma for 3 weeks. Sequelae lasting weeks are common;197,220 longer-term follow-up has been limited, but presumed permanent impairment has been reported.190,220 In the Chinese series of 66 patients, HACE was diagnosed early, and descent was uniformly successful. Ataxia resolved in all but one within 7 days, and only one patient had long-term sequelae, clonic convulsions affecting the left hand.582 Prevention of HACE is the same as for AMS and HAPE.

The occurrence of stroke in a young, fit person at high altitude is uncommon but tragic. A number of case reports have described climbers with resultant permanent dysfunction.85,219,505 Indian soldiers at extreme altitude have a high incidence of stroke.249 Cerebral venous thrombosis manifests more insidiously, and diagnosis is often delayed.* Factors contributing to stroke may include polycythemia, dehydration, increased ICP if AMS is present, increased cerebrovenous pressure, cerebrovascular spasm, and familial thrombophilia.38 Stroke may be confused with HACE. Neurologic symptoms, especially focal abnormalities without AMS or HAPE that persist despite treatment with oxygen, corticosteroids, and descent, suggest a cerebrovascular event and mandate careful evaluation with a complete neurologic workup.

FOCAL NEUROLOGIC CONDITIONS WITHOUT AMS OR CEREBRAL EDEMA Various localizing neurologic signs, transient in nature and not necessarily occurring in the setting of AMS, suggest migraine, cerebrovascular spasm, transient ischemic attack (TIA), local hypoxia without loss of perfusion (watershed effect), or focal edema.41 Cortical blindness is one such condition. Hackett and colleagues194 reported six cases of transient blindness in climbers or trekkers with intact pupillary reflexes, which indicated that the condition was due to a cortical process. Treatment with breathing of either carbon dioxide (a potent cerebral vasodilator) or oxygen resulted in prompt relief, suggesting that the blindness was due to inadequate regional circulation or oxygenation. Descent effected relief more slowly. Other conditions that could be attributed to spasm or “TIA” have included transient hemiplegia or hemiparesis, transient global amnesia, unilateral paresthesias, aphasia, and scotoma.* The true mechanism of these focal findings is unknown and may be multifactorial. Young, healthy altitude sojourners are unlikely to have TIA syndrome from cerebrovascular disease. Other neurologic complications at altitude include globus pallidum lesions, which were considered complications of AMS or HACE and reported to lead to Parkinson’s disease.248,355,495,527,543 Although these deficits were related to high altitude, whether altitude illness was truly the proximate cause of these lesions is unclear. The globus pallidum is sensitive to hypoxia, especially from carbon monoxide poisoning, and can also be damaged by ischemia.

*References 36, 41, 57, 78, 299, 576, 597.

CLINICAL PRESENTATION E.H., a 42-year-old male climber on a Mt Everest expedition, awoke at 8000 m (26,247 feet) with dense paralysis of the right arm and weakness of the right leg. On descent the paresis cleared, but at base camp (5000 m [16,404]) severe vertigo developed, along with extreme ataxia and weakness. Neurologic consultation on return to the United States resulted in a diagnosis of multiple small cerebral infarcts, but none was visible on CT scan of the brain. The hematocrit value 3 weeks after descent from the mountain was 70%. Over the next 4 years signs gradually improved, but mild ataxia, nystagmus, and dyslexia persist. The focal and persistent nature of the cerebral symptoms and signs, although multiple, indicates a cerebrovascular, rather than an intracranial, pressure etiology. The hematocrit value on the mountain was greater than 70%, high enough for increased viscosity and microcirculatory sludging to contribute to ischemia and infarction. No familial thrombophilia was detected. Treatment of stroke is supportive. Oxygen and corticosteroids may be worthwhile to treat any AMS or HACE component. Immediate evacuation to a hospital is indicated. Persons with TIAs at high altitude should probably be started on aspirin therapy and proceed to a lower altitude. Oxygen may quickly abort cerebrovascular spasms and will improve watershed hypoxic events. When oxygen is not available, rebreathing to raise alveolar PCO2 may be helpful by increasing cerebral blood flow.

COGNITIVE CHANGES AT HIGH ALTITUDE If cerebral oxygen consumption is constant, what causes the well-documented, albeit mild, cognitive changes at high altitude? The cognitive changes may be related to specific neurotransmitters. For example, tryptophan hydroxylase in the serotonin synthesis pathway has a high requirement for oxygen (Michaelis constant [Km] = 37 mm Hg).95,160 Tyrosine hydroxylase, in the dopamine pathway, is also oxygen sensitive. Gibson and Blass160 suggested that a decrease in acetylcholine activity during hypoxia might explain the lassitude. In a fascinating study, Banderet and Lieberman21 showed that increased dietary tyrosine reduced mood changes and symptoms of environmental stress in subjects at simulated altitude. Further work with neurotransmitter agonists and antagonists will help shed light on their role in cognitive dysfunction at altitude and could lead to new pharmacologic approaches to improve neurologic function.

HIGH-ALTITUDE PULMONARY EDEMA The most common cause of death related to high altitude, HAPE is completely and easily reversed if recognized early and treated properly. Undoubtedly HAPE was misdiagnosed for centuries, as evidenced by frequent reports of young, vigorous men suddenly dying of “pneumonia” within days of arriving at high altitude. The death of Dr. Jacottet, “a robust, broad-shouldered young man,” on Mt Blanc in 1891 (he refused descent so that he could *References 177, 256, 460, 505, 538, 597.

19

CHAPTER 1  High-Altitude Medicine and Physiology

Treatment

PART 1  MOUNTAIN MEDICINE

“observe the acclimatization process” in himself) may have provided the first autopsy of HAPE. Angelo Mosso wrote, From Dr. Wizard’s post-mortem examination . . . the more immediate cause of death was therefore probably a suffocative catarrh accompanied by acute edema of the lungs. . . . I have gone into the particulars of this sorrowful incident because a case of inflammation of the lungs also occurred during our expedition, on the summit of Monte Rosa, from which, however, the sufferer fortunately recovered.374 On an expedition to K2 (Karakorum Range, Pakistan) in 1902, Alistair Crowley101 described a climber “suffering from edema of both lungs and his mind was gone.” In the Andes, physicians were familiar with pulmonary edema peculiar to high altitude,238,301 but it was not until Hultgren and Spickard226 and Houston218 offered their observations that the English-speaking world became aware of high-altitude pulmonary edema (see Rennie422 for a review). Hultgren and colleagues237 then published hemodynamic measurements in persons with HAPE, demonstrating that it was a noncardiogenic edema. Since that time, many studies and reviews have been published, and HAPE is still the subject of intense investigation. The reader is referred to recent reviews.* Individual susceptibility, rate of ascent, altitude reached, degree of cold,419 physical exertion, and certain underlying medical conditions are all factors determining the prevalence of HAPE. The incidence varies from approximately 1 in 10,000 skiers at moderate altitude in Colorado to 1 in 50 climbers on Mt McKinley (6194 m [20,322 feet]) and up to 6% of mountaineers in the Alps ascending rapidly to 4559 m (14,957 feet).29 Hultgren and associates235 reported 150 cases of HAPE over 39 months at a Colorado ski resort at 2928 m (9606 feet). Some regiments in the Indian Army had a much higher incidence of HAPE (15%) because of very rapid deployment to the extreme altitude of 5500 m (18,045 feet)501 (see Table 1-1). Wu and colleagues582 reported HAPE in 0.5% of Chinese railway workers at 4000 to 4900 m (13,123 to 16,076 feet). Persons with previous HAPE had a 60% attack rate when they went to 4559 m (14,957 feet) in 36 hours, but with slower ascent, some of the same individuals climbed over 7000 m (22,966 feet) without illness.24,30 HAPE appears to be less common in women.99,232,506 Whether all persons are capable of developing HAPE (with a very rapid ascent to a sufficiently high altitude and with heavy exercise) is arguable.32 Likewise, some studies suggest that many persons contract subclinical extravascular lung water,100 whereas others contradict this.111 Even well-acclimatized individuals with a sudden push to a higher altitude can succumb to HAPE.100 Nonetheless, a population of HAPE-susceptible persons with unique physiologic characteristics has been described (see HAPE Susceptibility, later). These individuals represent the small percentage of people who develop HAPE when others in the same circumstances do not. HAPE in children is associated as well with antecedent viral infections, trisomy 21, and underlying congenital cardiovascular malformations, such as unilateral absence of the pulmonary artery.105 CLINICAL PRESENTATION D.L., a 34-year-old man, was in excellent physical condition and had been on numerous high-altitude backpacking trips, occasionally suffering mild symptoms of AMS. He drove from sea level to the trailhead and hiked to 3050 m (10,007 feet) sleeping altitude the first night of his trip in the Sierra Nevada. He proceeded to 3700 m (12,139 feet) the next day, noticing more dyspnea on exertion when walking uphill, a longer time than usual to recover when he rested, and a dry cough. He complained of headache, shivering, dyspnea, and insomnia the second night. The third day the group descended to 3500 m (11,483 feet) and rested, primarily for D.L.’s benefit. That night, D.L. was unable to eat, noted severe dyspnea, and suffered

*References 32, 109, 307, 320, 467, 472, 477, 515.

20

coughing spasms and headache. On the fourth morning D.L. was too exhausted and weak to get out of his sleeping bag. His companions noted that he was breathless, cyanotic, and ataxic but had clear mental status. A few hours later he was transported by helicopter to a hospital at 1200 m (3937 feet). On admission he was cyanotic, his oral temperature was 37.8° C (100° F), blood pressure 130/76 mm Hg, heart rate 96 beats/min, and respiratory frequency 20 breaths/min. Bilateral basilar rales to the scapulae were noted. Findings of cardiac examination were reported as normal. Romberg and finger-to-nose tests revealed 1+ ataxia. Arterial blood gas studies on room air revealed PO2 24 mm Hg, PCO2 28 mm Hg, and pH 7.45. The chest radiograph showed extensive bilateral patchy infiltrates (Figure 1-17, C ). D.L. was treated with bed rest and supplemental oxygen. On discharge to his sea level home 3 days later, the pulmonary infiltrates and rales had cleared, although blood gas values were still abnormal: PO2 76 mm Hg, PCO2 30 mm Hg, and pH 7.45. He had an uneventful, complete recovery at home. D.L. was advised to ascend more slowly in the future, staging his ascent with nights spent at 1500 m (4921 feet) and 2500 m (8202 feet). He was taught the early signs and symptoms of HAPE and advised on pharmacologic prophylaxis. This case illustrates typical aspects of HAPE. Victims are frequently young, fit males who ascend rapidly from sea level and may not have previously suffered HAPE even with repeated altitude exposures; the particular ascent may have been faster than previously. HAPE usually occurs within the first 2 to 4 days of ascent to higher altitudes (above 2500 m [8202 feet]), most commonly on the second night.180 Decreased exercise performance and increased recovery time from exercise are the earliest indications of HAPE. The victim suffers fatigue, weakness, and dyspnea on exertion, especially when walking uphill; he or she often ascribes these nonspecific symptoms to various other causes. Signs of AMS are present about 50% of the time.232 A persistent dry cough develops. Nail beds and lips become cyanotic. The condition typically worsens at night, and tachycardia and tachypnea develop at rest. Increasing respiratory distress heralds to the victim the development of a serious condition. In contrast to the usual 1- to 3-day gradual onset, HAPE may strike abruptly, especially in a sedentary person who may not notice the early stages.552 Orthopnea is uncommon (7%). Pink or blood-tinged, frothy sputum is a very late finding. Hemoptysis was present in 6% of victims in one series.235 Severe hypoxemia may produce cerebral edema with mental changes, ataxia, decreased level of consciousness, and coma. Hultgren and colleagues235 reported an incidence of HACE of 14% in those with HAPE at ski resorts. On admission to the hospital, the victim does not generally appear as ill as expected based on arterial blood gas and radiographic findings. Elevated temperature up to 38.5° C (101.3° F) is common. Tachycardia correlates with respiratory rate and severity of illness.237 Rales may be unilateral or bilateral and usually originate from the right middle lobe. Concomitant respiratory infection is sometimes present. Pulmonary edema may manifest with predominantly neurologic manifestations and minimal pulmonary symptoms and findings, most likely in persons with low HVR. Cerebral edema, especially with coma, may obscure the diagnosis of HAPE.189 Pulse oximetry or chest radiography confirms the diagnosis. Differential diagnosis includes pneumonia, bronchitis, mucus plugging, pulmonary embolism or infarct, heart failure, acute myocardial infarction, and sometimes asthma (see Box 1-3). Complications include infection, cerebral edema, pulmonary embolism or thrombosis, and such injuries as frostbite or trauma secondary to incapacitation.24,189,233 Hemodynamics Hemodynamic measurements by catheter show elevated pulmonary artery pressure and pulmonary vascular resistance, low to normal pulmonary wedge pressure, and low to normal cardiac output and systemic arterial blood pressure.234,403 Echocardiography demonstrates high pulmonary artery pressure, tricuspid regurgitation, normal left ventricular systolic function, somewhat

CHAPTER 1  High-Altitude Medicine and Physiology

A

B

C

D

FIGURE 1-17  A, Typical radiograph of high-altitude pulmonary edema (HAPE) in a 29-year-old female skier at 2450 m (8038 feet). B, The same patient 1 day after descent and oxygen administration, showing rapid clearing. C, Bilateral pulmonary infiltrates on radiograph of a patient with severe HAPE after descent (case presented in text). D, Ventilation and perfusion scans in a person with congenital absence of right pulmonary artery after recovery from HAPE.

abnormal diastolic function,7 and variable right-sided heart findings of increased atrial and ventricular size.193,393 The electrocardiogram (ECG) usually reveals sinus tachycardia. Changes consistent with acute pulmonary hypertension, such as right axis deviation, right bundle branch block, voltage for right ventricular hypertrophy, and P-wave abnormalities, have been described.24,232 Atrial flutter has been reported, but ventricular arrhythmias have not. Laboratory Studies Kobayashi and colleagues272 reported clinical laboratory values in 27 patients with HAPE that showed mild elevations of hematocrit and hemoglobin, probably secondary to intravascular volume depletion and perhaps plasma leakage into the lungs. Elevation of peripheral white blood cell count is common but is rarely above 14,000 cells/mL3. Serum concentration of creatine

phosphokinase (CPK) is increased, mostly due to skeletal muscle damage, although in two patients, CPK isoenzymes showed brain fraction levels of 1% of total, which may have indicated brain damage.272 An unpublished study in Colorado has found normal brain natriuretic peptide (BNP) values in patients with HAPE (S. Gallagher, personal communication). Arterial blood gases consistently reveal respiratory alkalosis and marked hypoxemia, more severe than expected for the patient’s clinical condition. Because respiratory or primary metabolic acidosis has not been reported, arterial blood gas studies are unnecessary if noninvasive pulse oximetry is available to measure arterial oxygenation. At 4200 m (13,780 feet) on Mt McKinley, the mean value of PaO2 in HAPE was 28±4 mm Hg. Values as low as 24 mm Hg in HAPE are not unusual. Arterial oxygen saturation values in HAPE subjects at 4300 m (14,108 feet) ranged from 40% to 70%, with a mean of 56% ± 8%.480 At 2928 m (9606 feet), mean 21

PART 1  MOUNTAIN MEDICINE

SaO2 was 74%.235 Arterial acid–base values may be misleading in patients taking acetazolamide, because this drug produces significant metabolic acidosis. Radiographic Findings The radiographic findings in HAPE have been described in original reports.237,330,554,555 Findings are consistent with noncardiogenic pulmonary edema, with generally normal heart size and left atrial size, and no evidence of pulmonary venous prominence, such as Kerley lines. The pulmonary arteries increase in diameter.555 Infiltrates are commonly described as fluffy and patchy with areas of aeration between infiltrates and in a peripheral rather than central location. Infiltrates may be unilateral or bilateral, with a predilection for the right middle lung field, which corresponds to the usual area of rales. Pleural effusion is rare. Radiographic findings generally correlate with illness severity and degree of hypoxemia. A small right hemithorax, absence of pulmonary vascular markings on the right, and edema confined to the left lung are criteria for diagnosis of unilateral absent pulmonary artery.185 Radiographic findings of HAPE are presented in Figure 1-17. Clearing of infiltrates is generally rapid once treatment is initiated. Depending on severity, complete clearing may take from 1 to several days. Infiltrates are likely to persist longer if the patient remains at high altitude, even if confined to bed and receiving oxygen therapy. Radiographs taken within 24 to 48 hours of return to low altitude may still be able to confirm diagnosis of HAPE. Recently, an ultrasound technique known as “comet-tail” scoring, previously validated in cardiogenic pulmonary edema, has been used to evaluate extravascular lung water at high altitude, which in the right setting might indicate clinical or subclinical pulmonary edema. The comet-tail artifacts are created by microreflections of the ultrasound beam within interlobular septa thickened by the presence of increased lymphatic fluid consistent with interstitial and/or alveolar edema. Eleven patients at 4240 m (13,911 feet) with a clinical diagnosis of HAPE underwent chest ultrasound examinations using this technique.137 Seven patients with no evidence of HAPE or other altitude illness served as control subjects. HAPE patients had much higher comet-tail scores and lower oxygen saturation than did control subjects, and scores decreased as HAPE cleared. The comet-tail technique seemed to be able to recognize and monitor the degree of pulmonary edema in HAPE. Although an ultrasound machine is rarely available in the wilderness, this technique might prove to be a valuable research tool, and it offers easy repeated measurements while avoiding radiation.313 Recently, investigators successfully used a satellite telemedical connection with a remote expert to guide thoracic ultrasound examinations at Advanced Base Camp on Mt Everest; high-quality images were obtained that verified increases in lung water.394 Another group, also in Nepal, used the technique while trekking up to 4700 m (15,420 feet) and found a high prevalence of extravascular lung water, but no association with estimated pulmonary artery pressure.409 This technique may lend itself well to answering the question of whether the oft-reported increase in extravascular lung water on ascent to high altitude and in AMS is actually a precursor to HAPE. Pathologic Findings More than 20 autopsy reports of persons who died of HAPE have been published.* Of those whose cranium was opened, more than one-half had cerebral edema. All lungs showed extensive and severe edema, with bloody, foamy fluid in the airways. Lung weights were two to four times normal. The left side of the heart was normal. The right atrium and main pulmonary artery were often distended. Proteinaceous exudate with hyaline membranes was characteristic. All lungs had areas of inflammation with neutrophil accumulation. The diagnosis of bronchopneumonia was common, although bacteria were not noted. Pulmonary veins, the left ventricle, and the left atrium were generally not dilated, in contrast to the right ventricle and atrium. Most reports mention *References 12, 117, 380, 500, 501, 573.

22

capillary and arteriolar thrombi and alveolar fibrin deposits, as well as microvascular and gross pulmonary hemorrhage and infarcts. The autopsy findings thus suggest a protein-rich, permeability type of edema with thrombi or emboli. Confirmation of HAPE as a permeability edema was obtained by analysis of alveolar lavage fluid by Schoene and associates.478,480 These clinicians found a 100-fold increase in lavage fluid protein levels in patients with HAPE compared with well control subjects and patients with AMS.480 The lavage fluid also had a low percentage of neutrophils, in contrast to findings in adult respiratory distress syndrome. Further evidence for a permeability edema was a 1:1 ratio of aspirated edema fluid protein to plasma protein level found by Hackett and colleagues.184 In addition, the lavage fluid contained vasoactive eicosanoids and complement proteins, indicative of endothelium–leukocyte interactions. More recent research using repeated bronchoalveolar lavage as HAPE was developing found that inflammation was absent early on, suggesting that inflammation is a response to the alveolar damage, rather than an initiating event.531 Mechanisms of High-Altitude Pulmonary Edema An acceptable explanation for HAPE must take into account three well-established facts: excessive pulmonary hypertension, highprotein permeability leak, and normal function of the left side of the heart. A mechanism consistent with these facts is failure of capillaries secondary to overperfusion and capillary hypertension (Figure 1-18). Role of Pulmonary Hypertension.  Excessive pulmonary artery pressure (PAP) is the sine qua non of HAPE; no HAPE has been reported without pulmonary hypertension. All persons ascending to high altitude or otherwise enduring hypoxia, however, have some elevation of PAP. The hypoxic pulmonary vasoconstrictor response (HPVR) is thought to be useful in humans at sea level because it helps match perfusion with ventilation. When local areas of the lungs are poorly ventilated because of infection or atelectasis, for example, the HPVR Altitude hypoxia HVR, sleep, and exercise ↓ PaO2

Uneven HPV

↑ Sympathetic activity

Exercise PHTN

Pulmonary and peripheral venous constriction

Overperfusion

↑ Pcap

↑ Pulmonary blood volume

Capillary stress failure

Capillary leak

↓ Alveolar Na and H2O clearance

High-altitude pulmonary edema FIGURE 1-18  Proposed pathophysiology of high-altitude pulmonary edema. HPV, Hypoxic pulmonary vasoconstriction; HVR, hypoxic ventilatory response; PaO2, arterial partial pressure of oxygen; Pcap, capillary pressure; PHT, pulmonary hypertension.

Overperfusion and Capillary Leak.  To explain how pulmonary hypertension might lead to edema, Hultgren suggested that in those who develop HAPE, the hypoxic pulmonary vasoconstriction is uneven and the delicate microcirculation in an unconstricted (relatively dilated) area is subjected to high pressure and flow, leading to leakage (edema). The unevenness could be due to anatomic characteristics, such as distribution of muscularized arterioles, or to functional factors, such as loss of HPVR in severely hypoxic regions.227 Uneven perfusion is suggested clinically by the typical patchy radiographic appearance and is supported by lung scans and MRI imaging during acute hypoxia showing uneven perfusion in persons with a history of HAPE.215,553 Persons born without a right pulmonary artery are highly susceptible to HAPE (see Figure 1-17, D),185 supporting the concept of overperfusion of a restricted vascular bed as a cause of edema, because the entire cardiac output flows into one lung. Other causes of overperfusion of the pulmonary circulation that predispose to HAPE include left-to-right shunts such as atrial septal defect, ventricular septal defect, and patent ductus arteriosus. Rapid reversibility of the illness and response to vasodilators are also consistent with this mechanism. When hydrostatic pressure is reduced, alveolar fluid is quickly reabsorbed. Other factors contributing to increased hydrostatic pressure, such as exercise or high salt load with subsequent hypervolemia, also may play a role in HAPE. The authors have several times observed onset of HAPE after large salt intake. Some studies have also suggested roles for pulmonary venous constriction, which would contribute to increased capillary hydrostatic pressure.193,325 The end result of overperfusion and increased capillary pressure325 is distension, increased filtration of fluid, and even rupture of the capillary–alveolar membrane, termed “stress failure,”567,568 with subsequent leakage of cells and proteins. Alveolar Fluid Balance.  Fluid filtration into the interstitial and alveolar space, reabsorption back across the epithelial membrane, and clearance of interstitial fluid by lymph result in a dynamic balance that generally prevents alveolar flooding. On ascent to altitude, the hydrostatic pressure gradient for filtration is increased. As might be expected, multiple lines of evidence suggest that extravascular lung water is increased at altitude.100,169,409,557 Despite this, frank alveolar flooding is uncommon. This may well be due to differences in hydrostatic pressure in persons resistant and susceptible to HAPE. However, persons who contract HAPE appear to also have impaired ability to clear alveolar fluid. On a constitutive (genetic) basis, HAPE subjects have lower activity of the epithelial sodium channel and therefore reduced ability to transport sodium across the epithelium back into the interstitial space.329,466,468 (It is the sodium gradient across the epithelium that determines movement of water from alveoli.) In addition, epithelial sodium transport is diminished by hypoxia per se, so that those with already impaired function become more impaired at altitude. How large a role this mechanism plays in HAPE is uncertain216 (see Figure 1-18). Control of Ventilation.  As in AMS, persons with HAPE had a lower HVR than did persons who acclimatized well,195,336 but not

all persons with a low HVR become ill. Thus, low HVR appears to play a permissive, rather than causative, role in HAPE, whereas a brisk HVR appears to be protective. Persons who hypoventilate are more hypoxemic and presumably suffer greater pulmonary hypertension. Possibly more important, low HVR may permit episodes of extreme hypoxemia during sleep (see Figure 1-7).180,195 In addition, a low HVR may allow further ventilatory depression through central nervous system (CNS) suppression (hypoxic ventilatory depression). Such persons, when given oxygen, show a “paradoxical” increase in ventilation.195 Despite correlation of HAPE with low HVR, its value as a sea level predictor is poor.110 HAPE Susceptibility Persons susceptible to HAPE (HAPE-s) show at sea level abnormal rise of PAP and pulmonary vascular resistance during hypoxic challenge at rest and during exercise and even during exercise in normoxia, suggesting overreactivity of the pulmonary circulation to both hypoxia and exercise.131,175,258 Part of this reactivity may be related to greater alveolar hypoxemia secondary to lower HVR,195,212,338 but other factors have been uncovered. Microneurographic recordings from the peroneal nerve during hypoxia established a direct link in HAPE-s between the rise in PAP and greater sympathetic activation,126 indicating that sympathetic overactivation might contribute to HAPE. Smaller and less distensible lungs have been noted in HAPE-s, which might limit the ability to accommodate increased flow by vascular recruitment and thus result in a higher vascular resistance.131,212,508 Another characteristic of HAPE-s is abnormal endothelial function, as evidenced by reduced NO synthesis during hypoxia50,74,474 and during HAPE,125 and higher levels of endothelin, a potent pulmonary vasoconstrictor.470,509 The importance of reduced NO is reinforced by studies showing improvement in pulmonary hemodynamics when either NO or a phosphodiesterase (PDE)-5 inhibitor was given to HAPE subjects9,159,322,474 (Figure 1-19). As mentioned previously, HAPE-s also are characterized by impairment of respiratory transepithelial sodium and water transport, making it more difficult to reabsorb alveolar fluid.469,473 Patent foramen ovale (PFO) also has been observed to be more common among HAPE-susceptible than among HAPEresistant adult mountaineers.6,311 Since the initial report of Levine and co-workers,293 the association of PFO and HAPE has been confirmed, but cause and effect have not been established.6 Allemann and associates6 performed a case-control study of 16 HAPE-susceptible participants and 19 mountaineers resistant to HAPE. Presence of PFO was determined by transesophageal echocardiography and estimated pulmonary artery pressure by Doppler echocardiography at low (550 m [1804 feet]) and high altitude (4559 m [14,957 feet]). The frequency of PFO was more than four times higher in HAPE-susceptible than in HAPE-resistant participants, both at low altitude (56% versus 11%) and high altitude (69% versus 16%). At high altitude, SaO2 before the onset of pulmonary edema was significantly lower in HAPE-susceptible participants than in the control group (73% versus 83%). Also, in the HAPE-susceptible group, participants with a large PFO had more severe arterial hypoxemia (65% versus 77%) than did those with smaller or no PFO. The authors speculated that at high altitude a large PFO may contribute to exaggerated arterial

Nitric oxide—overview Hypoxia

eNOS

L-arginine

NO

cGMP

Vascular muscle relaxation

PDE-5 inhibitor

Degradation by PDE-5

FIGURE 1-19  The nitric oxide pathway and action of phosphodiesterase-5 inhibitors. In the presence of an inhibitor  c-GMP, the second messenger of nitric oxide is not degraded, and vasodilation is therefore enhanced. c-GMP, guanosine monophosphate; eNOS, endothelial nitric oxide synthase NO, nitric oxide; PDE, phosphodiesterase.

23

CHAPTER 1  High-Altitude Medicine and Physiology

directs blood away from those areas to well-ventilated regions. In the setting of global hypoxia, as occurs with ascent to high altitude, HPVR is presumably diffuse and all areas of the lung constrict, causing a restricted vascular bed and an increase in PAP, which is of little if any value for ventilation–perfusion matching at high altitude. The degree of HPVR varies widely among individuals (as well as among species), and is most likely an inherent trait. HAPE-susceptible persons have a greater increase in PAP than do persons who are not susceptible (see HAPE Susceptibility, later). Although other factors, such as the vigor of the ventilatory response and subsequent alveolar PO2, may help determine the ultimate degree of pulmonary hypertension, HPVR appears to be the dominant factor. Because all persons with HAPE have excessive pulmonary hypertension, but not all those with excessive pulmonary hypertension have HAPE, it appears that pulmonary hypertension is necessary but in and of itself is not the cause of HAPE.

PART 1  MOUNTAIN MEDICINE

hypoxemia and facilitate HAPE.6 Others pointed out, however, that the greater hypoxemia may have been due to subclinical pulmonary edema,139 or that a PFO was a marker of a reactive pulmonary vascular bed.108 HAPE-s are known to have exaggerated pulmonary pressure response to exercise at sea level, for example, which could maintain an open shunt. Because occurrence of PFO is so common in the general population, more compelling evidence is required before suggesting that PFO is a predisposing factor to HAPE, and that those with PFO should consider closure of the defect before significant altitude exposure, or as a result of an episode of HAPE, as some have recommended.82 Genetics of HAPE The first major genetic studies in lowlanders visiting high altitudes have focused on HAPE because it is the most fully understood pathophysiologic process occurring in lowlanders visiting high altitudes.* Although many characteristics of HAPE-susceptible persons are apparently genetically determined, actual genetic studies are conflicting and difficult to interpret. Good evidence for a genetic component to HAPE susceptibility comes from study of major human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE compared with HLA alleles in 100 healthy volunteers.201 The HLA-DR6 and HLA-DQ4 antigens were associated with HAPE, and HLA-DR6 with pulmonary hypertension. These findings suggest that immunogenetic susceptibility may underlie development of HAPE, at least in some cases. Given the importance of endothelial function in HAPE, investigators have looked at gene polymorphisms for endothelial nitric oxide synthase (eNOS). Two recent studies have established a link between HAPE-s and the Glu298Asp alleles of the eNOS gene in Japanese and Indian subjects.2,123 An additional study of NOS3-related gene polymorphisms that could explain decreased NO synthesis found no relation to HAPE-s.563 This may be explained by racial differences or by the specific processes encoded by the different gene fragments. The insertion–deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has also garnered attention, because the renin-aldosterone-angiotensin system is known to be activated in HAPE,34 and the ACE gene has also been linked to performance at altitude.362 The insertion–deletion polymorphism was not associated with HAPE susceptibility in populations of Indians, Japanese, and whites.112,217,280 However, one variant of the angiotensin receptor gene was correlated with HAPE susceptibility in Japanese.217 In summary, gene polymorphisms coding for the angiotensin receptor and endothelial NO distinguish HAPE-s from HAPEresistant subjects. In the near future, single nucleotide polymorphism scanning techniques as well as RNA gene expression techniques will be used to explore the genetic contributions to high-altitude physiology and pathophysiology. The search continues for a genetic basis for HAPE susceptibility.† Treatment Treatment choices for HAPE depend on severity of illness and logistics. As with all high-altitude illnesses, early recognition is key to successful outcome (see Box 1-4). In the wilderness, where oxygen and medical expertise may be unavailable, persons with HAPE need to be urgently evacuated to lower altitude. However, because of augmented pulmonary hypertension and greater hypoxemia with exercise, exertion must be minimized. Early HAPE responds rapidly to descent of only 500 to 1000 m (1640 to 3281 feet), and the victim may be able to reascend slowly 2 or 3 days later. In high-altitude locations with oxygen supplies, bed rest with supplemental oxygen may suffice, but severe HAPE may require high-flow oxygen (4 L/min or more) for more than 24 hours. Hyperbaric therapy with a fabric pressure bag (2 psi) is equivalent to low-flow oxygen and can help conserve oxygen supplies.437 Oxygen immediately increases arterial oxygenation and reduces pulmonary artery pressure, heart rate, respiratory rate, *References 3, 200, 306, 363, 412, 413, 458, 502, 510, 536, 558, 596. † References 3, 122, 200, 306, 363, 373, 412, 413, 458, 502, 510, 536, 558, 596.

24

and symptoms. When descent is not possible, oxygen (or a hyperbaric bag) can be lifesaving. Rescue groups should make delivery of oxygen to the victim, by airdrop if necessary, the highest priority if descent is slow or delayed. If oxygen is not available, immediate descent is lifesaving. Waiting for a helicopter or rescue team has too often proved fatal. Because cold stress elevates PAP, the victim should be kept warm.80 The use of a mask providing resistance on expiration (expiratory positive airway pressure [EPAP]) was shown to improve gas exchange in HAPE, and this or continuous positive airway pressure (CPAP) may be useful as a temporizing measure.479 The same is accomplished with pursed-lip breathing. An unusual case report suggested that a climber may have saved his partner’s life by postural drainage to expel airway fluid.56 Drugs are of limited necessity in HAPE, because oxygen and descent are so effective.311 Medications that reduce pulmonary blood volume, PAP, and pulmonary vascular resistance are physiologically rational to use when oxygen is not available or descent delayed. Singh and associates500 reported good results with furosemide (80 mg every 12 hours), and greater diuresis and clinical improvement occurred when 15 mg parenteral morphine was given with the first dose of furosemide. Their use, however, has been eclipsed by recent results with vasodilators. The calcium channel blocker nifedipine (30 mg slow release every 12 to 24 hours) was effective in reducing pulmonary vascular resistance and PAP during HAPE and slightly improved arterial oxygenation.30 Clinical improvement, however, was not dramatic. Nifedipine is well tolerated and unlikely to cause significant hypotension in healthy persons and avoids the danger of CNS depression from morphine and possible hypovolemia from diuretics. Clinical improvement is much better, however, with oxygen and descent than with any medication. NO, a potent pulmonary vasodilator, improves hemodynamics in HAPE but is rarely available, and in any event is usually given with oxygen. The PDE-5 inhibitors, which increase cyclic guanosine monophosphate (c-GMP) to produce pulmonary vasodilation during hypoxia159,425,427 (see Figure 1-19), have shown value for prevention of HAPE322 but have not yet been studied for treatment. Whether these agents will prove to be more effective than nifedipine for treatment is unknown. A theoretic advantage is that the PDE-5 inhibitors produce less systemic vasodilation. Nifedipine, and perhaps other vasodilators, might be useful adjunctive therapy but is not a substitute for definitive treatment (see Box 1-4 and Table 1-7).178,311 β-Agonists may also have an adjunctive role but should not be considered for monotherapy.311 After evacuation of the victim to a lower altitude, hospitalization may be warranted for severe cases. Treatment consists of bed rest and oxygen sufficient to maintain SaO2 greater than 90%; medications are rarely necessary. Rapid recovery is the rule.599 Antibiotics are indicated for infection when present. Occasionally pulmonary artery catheterization or Doppler echocardiography is necessary to differentiate cardiogenic from high-altitude pulmonary edema. Endotracheal intubation and mechanical ventilation are rarely needed. A HAPE victim demonstrating unusual susceptibility, such as onset of HAPE despite adequate acclimatization or onset below 2750 m (9022 feet), might require further investigation, such as echocardiography, to rule out an intracardiac shunt or preexisting pulmonary hypertension. In children, undiagnosed congenital heart disease is worth considering105 (Figure 1-20). Hospitalization until blood gas values are completely normal is not warranted; all persons returning from high altitude are at least partially acclimatized to hypoxemia, and hypocapnic alkalosis persists for days after descent. Distinct clinical improvement, radiographic improvement over 24 to 48 hours, and PaO2 of 60 mm Hg or SaO2 greater than 90% are adequate discharge criteria. Patients are advised to resume normal activities gradually and are warned that 1 to 2 weeks may be required to recover complete strength. Physicians should recommend preventive measures, including graded ascent with adequate time for acclimatization, and should provide instruction on use of acetazolamide, nifedipine, or PDE-5 inhibitors for future ascents. An episode of HAPE is not a contraindication to subsequent high-altitude exposure, but education to ensure proper preventive measures and recognition of early symptoms is critical.

FIGURE 1-20  Chest radiograph of severe high-altitude pulmonary edema (HAPE) in a 4-year-old girl with a small previously undiagnosed patent ductus arteriosus that predisposed her to HAPE.

Prevention The preventive measures previously described for AMS also apply to HAPE: graded ascent, time for acclimatization, low sleeping altitudes, and avoidance of alcohol and sleeping pills.311 Exertion may contribute to onset of HAPE, especially at moderate altitude. Reports from North America at 2500 to 3800 m (8202 to 12,467 feet) have included hikers, climbers, and skiers, all of whom were exercising vigorously. Menon and colleagues346 clearly showed that sedentary men taken abruptly to higher altitude were just as likely to become victims of HAPE. Prudence dictates not overexerting for the first 2 days at altitude. Considerable clinical experience suggests that acetazolamide prevents HAPE in persons with a history of recurrent episodes. Recent animal work showing that acetazolamide blocks hypoxic pulmonary hypertension supports this practice49,213 as does the fact that acetazolamide speeds acclimatization. Nifedipine (20 mg slow release every 8 hours) prevented HAPE in subjects with a history of repeated episodes.30 The drug should be carried by such individuals and started at the first signs of HAPE or, for an abrupt ascent, started when leaving low altitude. The PDE-5 inhibitors sildenafil and tadalafil effectively block hypoxic pulmonary hypertension and therefore will prevent HAPE.320 Tadalafil 10 mg every 12 hours prevented HAPE with rapid ascent in HAPEsusceptible subjects.322The optimal dose has not been established; regimens for sildenafil have varied from a single dose of 50 or 100 mg just before exposure for acute studies159,425 to 40 mg 3 times a day for 2 to 6 days at altitude,404,427 and for tadalafil 10 mg every 12 hours was effective.145,322 Most recently, and rather surprisingly, dexamethasone was also found effective in preventing HAPE in susceptible subjects. Maggiorini and co-workers322 gave 8 mg dexamethasone every 12 hours, starting 2 days before exposure, and found it as effective as tadalafil in reducing PAP and preventing HAPE. Dexamethasone has many actions in the lungs; which particular action(s) explains this observed effect is unknown.32 As these studies demonstrate, any agent that blocks hypoxic pulmonary hypertension will block onset of HAPE, reinforcing the concept of pulmonary hypertension as the sine qua non of high altitude pulmonary edema. Problems of Lifelong or Long-Term Residents of High Altitude Reentry Pulmonary Edema.  In some persons who have lived for years at high altitude, HAPE develops on reascent from a trip to low altitude.128 Clinicians have suggested that the incidence of HAPE on reascent of altitude residents may be higher than that during initial ascent by flatlanders,34,229 but data on true incidence are difficult to obtain. Children and adolescents are more susceptible than adults.128 Hultgren228 found HAPE prevalence in Peruvian natives of 6.4 per 100 exposures in the 1- to 20-year age-group, and 0.4 per 100 exposures in persons over 21 years.

Chronic Mountain Sickness.  In 1928 Carlos Monge359 described a syndrome in Andean high-altitude natives that was characterized by headaches, insomnia, lethargy, plethoric appearance, and polycythemia greater than expected for the altitude. Known variously as Monge’s disease, chronic mountain polycythemia, or chronic mountain sickness, the condition has now been recognized in all high-altitude areas of the world.279,358,402 Lowlanders who relocate to high altitude and native residents are susceptible. Chinese investigators reported that 13% of lowland Chinese males and 1.6% of females who had relocated to Tibet developed excessive polycythemia (hemoglobin level greater than 20 g/dL).588 The incidence in Leadville, Colorado, is also high in men over 40 years of age and distinctly low in women.278 The increased hematopoiesis is apparently related to greater hypoxic stress, which may be due to a number of causes, such as lung disease, sleep apnea syndromes, and idiopathic hypoventilation. A diagnosis of “pure” chronic mountain polycythemia excludes lung disease and is characterized by relative alveolar hypoventilation, excessive nocturnal hypoxemia, and respiratory insensitivity to hypoxia.292,358 Some studies suggest that even for the degree of hypoxemia, the red blood cell mass is excessive, implying excessive amounts or overactivity of erythropoietin.574 The new international guidelines propose a hemoglobin value greater than 21 g/dL for males and 19 g/dL for females as essential for the diagnosis, as well as residence above 2500 m (8202 feet) and absence of lung disease.292 The reader is referred to recent reviews for in-depth information.357,418,420,584 In addition, an international consensus group has recently published papers on the definition and scoring of chronic mountain sickness.291 Therapy of CMS is routinely successful. Descent to a lower altitude is the definitive treatment. The syndrome reappears after return to high altitude. Supplemental oxygen during sleep is valuable. Phlebotomy is a common practice and provides sub­ jective improvement, although without significant objective changes.574 The respiratory stimulants medroxyprogesterone acetate (20 to 60 mg/day)277 and acetazolamide (250 or 500 mg/ day)429 have also been shown to reduce hematocrit value by improving oxygenation. Acetazolamide (250 mg) increased nocturnal arterial O2 saturation by 5%, decreased mean nocturnal heart rate by 11%, the number of apnea/hypopnea episodes during sleep by 74%, and hematocrit by 7%.429 The response to acetazolamide emphasizes the contribution of hypoventilation and nocturnal desaturation to chronic mountain sickness. Another approach was based on the knowledge that ACE inhibitors blunt hypoxia-mediated erythropoietin release. Plata and associates406 showed that 5 mg/day of enalapril for 2 years reduced hemoglobin concentration, packed cell volume, proteinuria, and need for phlebotomy. Pulmonary hypertension and right heart failure may also occur in persons with CMS. Symptomatic High-Altitude Pulmonary Hypertension.  Children living at high altitude may be at risk for symptomatic highaltitude pulmonary hypertension (SHAPH).388 This problem has been identified in South America, North America, and Asia, with a predilection in populations not genetically adapted to altitude. Other names for this affliction previously have included “pediatric high-altitude heart disease” and “subacute infantile mountain sickness.” The underlying pathophysiology is pulmonary 25

CHAPTER 1  High-Altitude Medicine and Physiology

The phenomenon has been observed most often in Peru, where high-altitude residents can return from sea level to high altitude quite rapidly. Cases have also been reported throughout Colorado,482 but reports are conspicuously rare from Nepal and Tibet,581 perhaps because Himalayan highlanders are better adapted or because very rapid return back to high altitude has not been readily available,587 although that is changing. Wu581 reported a 37-year-old Tibetan man with chronic mountain sickness who developed reentry HAPE and suggested that similar cases may have been missed previously. Severinghaus490 has postulated that increased muscularization of pulmonary arterioles that develops with chronic high-altitude exposure generates an inordinately high PAP on reascent, causing the edema. Whether uneven pulmonary vasoconstriction is present has not been investigated. Changes in fluid balance with descent and reascent might also play a role.581

PART 1  MOUNTAIN MEDICINE

hypertension resulting in hypertrophy and dilation of the right ventricle with eventual right-sided congestive heart failure. Clinically these children have poor growth, fatigue, irritability, dyspnea, and cyanosis or pallor. On physical examination, as the illness advances, hepatomegaly and leg edema signal right-sided heart failure. Blood gases or pulse oximetry reveal exaggerated hypoxemia. Chest radiograph shows cardiomegaly and enlarged main pulmonary artery and sometimes infiltrates. Echocardiography usually confirms the diagnosis, although ECG and cardiac catheterization can also be useful. Right ventricular hypertrophy, right atrial dilation, and persistence of PFO and patent ductus arteriosus may also be noted. Definitive treatment is relocation to a lower altitude. Other but inferior therapies include supplemental oxygen, diuretics, and pulmonary vasodilators such as calcium channel blockers, PDE-5 inhibitors, and NO and prostaglandin inhibitors.292

CHILDREN AT HIGH ALTITUDE Children born at high altitude in North America appear to have a higher incidence of complications in the neonatal period than do their lower-altitude counterparts.386 In populations better adapted to high altitude over many generations, neonatal transition has not been as well scrutinized, but there does appear to be some morbidity.388,571 High-altitude residence does not clearly impact eventual stature, but growth and development are slowed. In the developing world, confounding factors such as nutrition and socioeconomic status make these issues difficult to assess. Children residing at high altitude are more likely to develop pulmonary edema on return to their homes from a low-altitude sojourn than are lowland children on induction to high altitude. Some of these children may have preexisting pulmonary hypertension of various etiologies.105 Lowland children traveling to high altitude are just as likely to suffer AMS as are adults.408 No data indicate that children are more susceptible to altitude illness, although diagnosis can be more difficult in preverbal children.591 Despite this somewhat reassuring fact, very conservative recommendations are made regarding taking children to high altitude; it should be made clear that these opinions are not based on science.40,407 Durmowicz and colleagues128 showed that children with respiratory infections were more susceptible to HAPE, as are children with Down syndrome, past repair of congenital shunts, following chemotherapy, and other problems. Children can be given acetazolamide or dexamethasone as necessary for AMS/HACE.129 The dosage of acetazolamide for prevention or treatment of AMS in children is 5 mg/kg/day in divided doses (see Table 1-7). See Pollard and associates408 for an excellent consensus document on children at altitude, and excellent recent reviews.129,388,591 Healthy newborn term infants born to lowland mothers should probably avoid sleeping altitudes greater than 2500 m (8202 feet) for the first 4 to 6 weeks of life because of concern regarding cardiopulmonary transition rather than for altitude illness.387 Infants with viral infections, neonatal intensive care unit stay, transient oxygen treatment, Down syndrome, or any pulmonary condition or cardiac defect should be carefully evaluated by a physician regarding altitude exposure. For all infants going to altitude, pulse oximetry monitoring should be considered. Parents need to be aware of potential problems at altitude, including symptoms of AMS unique to infants.387

Other Medical Concerns at High Altitude CARBON MONOXIDE Carbon monoxide poisoning is a danger at high altitude, where field shelters are designed to be small and windproof. Cooking inside closed tents and snow shelters during storms is a particular hazard.* The effects of carbon monoxide and high-altitude hypoxia are additive. A reduction in oxyhemoglobin caused by *References 146, 264, 290, 453, 535, 542.

26

carbon monoxide increases hypoxic stress, rendering a person at a “physiologically higher” altitude, which may precipitate AMS. Because of preexisting hypoxemia, smaller amounts of carboxyhemoglobin produce symptoms of carbon monoxide poisoning. These two problems may coexist. Immediate removal of the victim from the source of carbon monoxide and forced hyperventilation, preferably with supplemental oxygen, rapidly reverse carbon monoxide poisoning.

HIGH-ALTITUDE DETERIORATION The world’s highest human habitation is at approximately 5500 m (18,045 feet). Above this altitude, deterioration outstrips the ability to acclimatize.265 The deterioration is more rapid the higher one goes above the maximum point of acclimatization. Above 8000 m (26,247 feet), deterioration is so rapid that without supplemental oxygen, death can occur in a matter of days. Life-preserving tasks such as melting snow for water may become too difficult, and death may result from dehydration, starvation, hypothermia, and especially neurologic and psychiatric dysfunction.142 Loss of body weight due to anorexia and malabsorption is a prominent feature during expeditions to extreme high altitude. Pugh410 reported 14 to 20 kg (30.9 to 44 lb) body-weight losses in climbers on the 1953 British Mt Everest Expedition. Nearly 30 years later, with improvement in food and cooking techniques, climbers on the American Medical Research Expedition to Mt Everest still lost an average of 6 kg (13.2 lb).61 This was due in part to 49% decrease in fat absorption and 24% decrease in carbohydrate absorption. During OEII, in which the “climbers” were allowed to eat foods of their choosing ad libitum, they still suffered large weight losses: 8 kg (17.6 lb) overall, including 3 kg (6.6 lb) of fat and 5 kg (11 lb) of lean body weight (muscle).221,455 At 4300 m (14,108 feet), weight loss was attenuated by adjusting caloric intake to match caloric expenditure.75 In fact, recent work supports hypoxic exposure as a treatment for obesity.298,381,414,593 Thus, significant weight loss with prolonged exposure to high altitude may be overcome with adequate caloric intake, but decreased appetite is a problem.260,541 At very high altitudes, an increase in caloric intake may not be sufficient to completely counteract the severe anorexia and weight loss because other mechanisms may come into play. At extreme altitude, Ryn459 reported an incidence of acute organic brain syndrome in 35% of climbers going above 7,000 m (22,966 feet), in association with high-altitude deterioration. This syndrome, which features impaired judgment or even psychosis, could directly threaten survival.

HIGH-ALTITUDE SYNCOPE Syncope within the first 24 hours of arrival occurs occasionally at moderate altitude382,383 but is not observed in mountaineers at higher altitudes; it is a problem of acute induction to altitude.370 The mechanism is an unstable cardiovascular control system, and it is considered a form of neurohumoral (or neurocardiogenic) syncope.149 An unstable state of cerebral autoregulation may also play a role.595 These events appear to be random and seldom occur a second time. Preexisting cardiovascular disease is not a factor in most cases. Postprandial state and alcohol ingestion seem to be contributing factors. Altitude syncope has no direct relation to high-altitude illness.41

ALCOHOL AT HIGH ALTITUDE Two questions regarding alcohol are frequently asked: (1) does alcohol affect acclimatization, and (2) does altitude potentiate the effects of alcohol? Epidemiologic research indicated that 64% of tourists ingested alcohol during the first few days at 2800 m (9186 feet).214 The effect of alcohol on altitude tolerance and acclimatization might therefore be of considerable relevance. Roeggla and co-workers449 determined arterial blood gases 1 hour after ingestion of 50 g of alcohol (equivalent to 1 L of beer) at 171 m (561 feet) and again after 4 hours at 3000 m (9843 feet). A placebo-controlled, double-blinded paired design was used. For the 10 subjects, alcohol had no effect on ventilation at the low altitude, but at high altitude it depressed ventilation, as gauged

THROMBOSIS: COAGULATION AND PLATELET CHANGES Autopsy findings in deaths due to altitude illness of widespread thrombi in the brain and lungs, as well as the impression that thrombosis is greater at altitude,249 have led to many investigations of the clotting mechanism at high altitude. For a review, see Grover and Bärtsch.173 Although changes in platelets and coagulation have been observed in rabbits, mice, rats, calves, and humans on ascent to high altitude,207 these are generally in vitro and with very rapid ascent. In vivo studies using more realistic ascent profiles up to 4500 m (14,764 feet) in the mountains, and higher in chambers, have generally not found changes in coagulation and fibrinolysis,173 but this is still an area of active study.62,549 Although the increased incidence of thrombosis in soldiers and others at extreme altitude can be attributed to dehydration, polycythemia, and forced inactivity, there is some

evidence of enhanced fibrin formation with stay of a few weeks over 5000 m (16,404 feet).449 In addition, unexplained thrombosis is reported at moderate altitude of 4000 to 5000 m (13,123 to 16,404 feet)81,136 and at extreme altitude.8,267 As for thrombosis in HAPE, Singh and colleagues498 reported increased fibrinogen levels and prolonged clot lysis times during HAPE, attributed to a breakdown of fibrinolysis. These authors also reported thrombotic, occlusive hypertensive pulmonary vascular disease in soldiers who had recently arrived at extreme altitude.497 A series of experiments by Bärtsch and colleagues,27,173 however, carefully examined this issue in well subjects and in those with AMS and HAPE. They concluded that HAPE is not preceded by a prothrombotic state and that only in “advanced HAPE” is there fibrin generation, which abates rapidly with oxygen treatment. They considered the coagulation and platelet activation as an epiphenomenon rather than as an inciting pathophysiologic factor and likely due to inflammation from structural damage to the capillaries or the extreme hypoxemia. A difficult clinical question is whether ascent to altitude might result in thrombosis in persons with familial thrombophilia, such as factor V Leiden, a common anomaly, or protein C deficiency, antiphospholipid syndrome, or others. Such cases have been reported,8,38,58,255,267,379 although cause and effect cannot be established with certainty. In addition, persons with a past history of deep vein thrombosis or pulmonary embolism wonder if they are at increased risk at high altitude, as do women on hormonal contraceptives. Unfortunately, the literature does not provide guidance for these individuals. Some experts empirically recommend daily aspirin during altitude exposure for such patients, and this seems to be a safe suggestion. Others have raised the possibility that aspirin therapy might cause or exacerbate retinal hemorrhages at high altitude. Although no study has investigated this at altitude, research from patients with diabetic retinopathy has shown no danger of increased hemorrhages from aspirin.22 In addition, a retinal hemorrhage in a climber was treated with aspirin, and the hemorrhage resolved.284

PERIPHERAL EDEMA Edema of the face, hands, and ankles at high altitude is common, especially in females. Incidence of edema in at least one area of the body in trekkers at 4200 m (13,780 feet) was 18% overall, 28% in females, 14% in males, 7% in asymptomatic trekkers, and 27% in those with AMS.187 Although not a serious clinical problem, edema can be bothersome. The presence of peripheral edema demands examination for pulmonary and cerebral edema. In the absence of AMS, peripheral edema is effectively treated with a diuretic. Treatment of accompanying AMS by descent or medical therapy also results in diuresis and resolution of peripheral edema. The mechanism is presumably similar to fluid retention in AMS but may also be merely due to exercise.350

IMMUNOSUPPRESSION Mountaineers have observed that infections are common at high altitude, slow to resolve, and often resistant to antibiotics.376 On the American Medical Research Expedition to Mt Everest in 1981, serious skin and soft tissue infections developed. “Nearly every accidental wound, no matter how small, suppurated for a period of time and subsequently healed slowly.”465 A suppurative hand wound and septic olecranon bursitis did not respond to antibiotics but did respond to descent to 4300 m (14,108 feet) from the 5300 m (17,388 feet) base camp. Nine of 21 persons had significant infections not related to the respiratory tract. Most highaltitude expeditions report similar problems. Data from OEII indicated that healthy individuals are more susceptible to infections at high altitude because of impaired T lymphocyte function; this is consistent with previous Russian studies in humans and animals.345 In contrast, B cells and active immunity are not impaired. Therefore resistance to viruses may not be impaired, whereas susceptibility to bacterial infection is increased. The degree of immunosuppression is similar to that seen with trauma, burns, emotional depression, and space flight. The mechanism may be related, at least in part, to release of 27

CHAPTER 1  High-Altitude Medicine and Physiology

by decreased PaO2 (from 69 to 64 mm Hg) and increased PCO2 (from 32.5 to 34 mm Hg). Whether this degree of ventilatory depression would contribute to acute mountain sickness and whether repeated doses would have greater effect was not tested. Nonetheless, the authors argue that alcohol might impede ventilatory acclimatization and should be used with caution at high altitude. Conventional wisdom proffers an additive effect of altitude and alcohol on brain function. McFarland,341 who was concerned about the interaction in aviators, wrote, “…the alcohol in two or three cocktails would have the physiologic action of four or five drinks at altitudes of approximately 10,000 to 12,000 feet.” Also, “Airmen should be informed that the effects of alcohol are similar to those of oxygen want and that the combined effects on the brain and the CNS are significant at altitudes even as low as 8,000 to 10,000 feet.”341 His original observations were made on two subjects in the Andes in 1936. He found that blood alcohol levels rose more rapidly and reached higher values at altitude but noted no interactive effect of alcohol and altitudes of 3810 and 5335 m (12,500 and 17,503 feet).342 Most subsequent studies refuted the increased blood alcohol concentration data except at the highest altitudes, over 5450 m (17,881 feet). Higgins and associates, 209,210 in a series of chamber studies, found blood alcohol levels were similar at 392 and 3660 m (1286 and 12,008 feet), and they noted no synergistic effects of alcohol and altitude. Lategola and colleagues287 found that blood alcohol uptake curves were the same at sea level and 3660 m (12,008 feet), and that performance on math tests showed no interaction between alcohol and altitude. In another study of 25 men, performance scores were similar at sea level and at a simulated 3810 m (12,500 feet) altitude, with blood alcohol level of 88 mg%.93 Performance was not affected by hypoxia, only by alcohol, and older subjects were more affected. When more demanding tasks were tested, Collins92 found that a blood alcohol level of 91 mg% affected performance, as did an altitude of 3660 m (12,008 feet) during night sessions when the subjects were sleep deprived, but there was no significant altitude–alcohol interaction. In the one study in which Collins and co-workers94 were able to discern some altitude effect, there was a simple additive interaction of altitude (hypoxic gas breathing) and alcohol. He concluded that performance decrements due to alcohol may be increased by altitudes of 3660 m (12,000 feet) if subjects are negatively affected by that altitude without alcohol. All of these aviation-oriented studies used acute hypoxia equivalent to no more than 3500 m (11,483 feet). Perhaps the highest altitude (without supplemental oxygen) at which alcohol was studied was 4350 m (14,272 feet), on the summit of Mt Evans in Colorado. Freedman and associates148 found that alcohol affected auditory evoked potentials the same as in Denver; that is, no influence of altitude was detectable. In summary, the limited data on blood gases at altitude after alcohol ingestion support the popular notion that alcohol could slow ventilatory acclimatization and therefore might contribute to AMS. Considerable data at least up to 3660 m (12,000 feet), however, refute the belief that altitude potentiates the effect of alcohol. How altitude and alcohol might interact during various stages of acclimatization in individuals at higher altitudes is still unknown.

PART 1  MOUNTAIN MEDICINE

adrenocorticotropic hormone, cortisone, and β-endorphins, all of which modulate the immune response.135,354 Intense ultraviolet exposure has also been shown to impair immunity. Persons with serious infections at high altitude may need oxygen or descent for effective treatment. Impaired immunity because of altitude should be anticipated in situations where infection could be a complication, such as trauma, burns, and surgical and invasive procedures.

HIGH-ALTITUDE PHARYNGITIS, BRONCHITIS, AND COUGH Sore throat, chronic cough, and bronchitis are nearly universal in persons who spend more than 2 weeks at an extreme altitude (over 5500 m [18,045 feet]).84,300,333,370 All 21 members of the 1981 American Medical Research Expedition to Mt Everest suffered these problems.465 Only two of eight subjects in OEII (where the temperature was greater than 21° C [69.8° F] and relative humidity was greater than 80%) developed cough, and only above 6500 m (21,325 feet). Only four had sore throat. Acute hypoxia directly lowers the cough threshold, thus exacerbating high-altitude cough.334 Other factors are at play.332 In the field, these problems usually appear without fever or chills, myalgia, lymphadenop­ athy, exudate, or other signs of infection. The increase in ventilation, especially with exercise, forces obligate mouth breathing at altitude, bypassing the warming and moisturizing action of the nasal mucous membranes and sinuses. Movement of large volumes of dry, cold air across the pharyngeal mucosa can cause marked dehydration, irritation, and pain, similar to pharyngitis. Vasomotor rhinitis, quite common in cold temperatures, aggravates this condition by necessitating mouth breathing during sleep. For this reason, decongestant nasal spray is one of the most coveted items in an expedition medical kit. Other countermeasures include forced hydration, hard candies, lozenges, and steam inhalation. High-altitude bronchitis can be disabling because of severe coughing spasms. Cough fractures of one or more ribs are not rare.300 Purulent sputum is common. Response to antibiotics is poor; most victims resign themselves to taking medications such as codeine and do not expect a cure until descent. Bronchitis developed in 13 of 19 climbers above 4300 m (14,108 feet) on Aconcagua.415 Mean sputum production was 6 teaspoons per day. All reported that onset was after a period of excessive hyperventilation associated with strenuous activity. Although an infectious etiology is possible, experimental evidence suggests that respiratory heat loss results in purulent sputum and sufficient airway irritation to cause persistent cough.340 This is supported by the beneficial effect of steam inhalation and lack of response to antibiotics. Many climbers find that a thin balaclava, porous enough for breathing, traps some moisture and heat and effectively prevents or ameliorates the problem. Many climbers with high-altitude cough use inhaled fluticasone and salmeterol or similar inhaled agents and report success; studies of these medications are underway. Differential diagnosis of persistent cough in these conditions can be difficult.162

HIGH-ALTITUDE RETINOPATHY AND ULTRAVIOLET KERATITIS See Chapter 28.

Common Medical Conditions and High Altitude Persons with certain preexisting illnesses might risk adverse effects on ascent to high altitude, due either to exacerbation of illnesses or to illnesses that impact acclimatization and susceptibility to altitude illness. Certain populations also require special consideration, such as the very young, the pregnant and older adults. This section presents an overview of current knowledge regarding these issues. Despite the importance of the interaction of altitude and common medical conditions, research has so far been limited. See the original review by Hackett183 and updated recent reviews for more detailed discussions.315,349,448,585 28

BOX 1-5  Advisability of Exposure to High and Very

High Altitude for Common Conditions (Without Supplemental Oxygen)

Probably No Extra Risk • Young and old • Fit and unfit • Mild obesity • Diabetes • After coronary artery bypass grafting (without angina) • Mild chronic obstructive pulmonary disease (COPD) • Asthma • Low-risk pregnancy • Controlled hypertension • Controlled seizure disorder • Psychiatric disorders • Neoplastic diseases • Inflammatory conditions Caution • Infants <6 weeks old • Moderate COPD • Asymptomatic pulmonary hypertension • Compensated congestive heart failure (CHF) • Morbid obesity • Sleep apnea syndromes • Troublesome arrhythmias • Stable angina/coronary artery disease • High-risk pregnancy • Sickle cell trait • Cerebrovascular diseases • Space-occupying brain lesions • Any cause for restricted pulmonary circulation • Seizure disorder (not on medication) • Radial keratotomy • Recent myocardial infarction or stroke Contraindicated • Sickle cell anemia (with history of crises) • Severe COPD • Symptomatic pulmonary hypertension • Uncompensated CHF • Unstable coronary or cerebrovascular disease

Conditions that can be aggravated by high-altitude exposure are listed in Box 1-5.

RESPIRATORY DISEASES Chronic Lung Disease Although oxygen saturation remains above 90% in a normally acclimatizing, healthy, and awake person until over 3000 m (9843 feet) (see Figure 1-1), persons with hypoxemic lung disease reach this threshold at a lower altitude that depends on the baseline blood oxygen values. As a result, these persons might have altitude-related problems at lower altitudes than would healthy individuals. Improved airflow will result from decreased air density at high altitude, but hypoxemia, pulmonary hypertension, disordered control of ventilation, and sleep-disordered breathing could all become worse. Unfortunately, few data are available to guide the clinician advising such a person undertaking a trip to altitude.89,314,516 Most literature addresses prediction of blood gas values at 2500 m (8202 feet), the maximum allowable cabin altitude in commercial aircraft. Ascent to terrestrial high altitude, of course, involves much longer time periods and often at higher altitudes. Thus, the clinical usefulness of these studies is limited. Hypoxic gas breathing at sea level, as in the High Altitude Simulation Test, can predict oxygenation at high altitude, but this does

Cystic Fibrosis Children with cystic fibrosis have been reported to do poorly at high altitude,507 and hypoxic testing has also tried to predict the need for supplemental oxygen upon ascent in this condition.143,254,390,454 As with COPD, such tests are not particularly useful and tend to underestimate the oxygen requirements, because they are done only during rest and while awake. Supplemental oxygen should be available for these children, and oxygen saturation monitoring might be desirable in certain circumstances. The physician should be liberal with the use of antibiotics and adjunctive therapy for exacerbations at high altitude, given the likely danger of greater hypoxemia and greater difficulty treating

infections at high altitude. Cystic fibrosis encompasses a wide range of pulmonary impairment; one patient with mild disease was able to hike to 5600 m (18,373 feet).89 Asthma The available literature suggests that asthmatics, both residents and sojourners, do well at moderate altitude, primarily because of decreased allergens and pollution.88,89,224,560,585 Indeed, high altitude as a treatment for asthma has been popular in Europe for many decades. The effect is comparable with high doses of inhaled corticosteroids.89 However, because altitude exposure often includes exercise (and cold), asthmatics with exerciseinduced bronchospasm (EIB), rather than allergic asthma, might have problems at altitude. Matsuda and colleagues335 investigated the effect of altitude on 20 asthmatic children with EIB in a hypobaric chamber simulating 1500 m (4921 feet), with the temperature and humidity held constant. Except for the increased respiratory rate during exercise, as expected, all other physiologic variables were unchanged compared with those at sea level. The authors concluded that the modest altitude of 1500 m (4921 feet) does not exacerbate exercise-induced asthma. Berntsen and coworkers53 reported similar results at 2500 m (8202 feet). Durand and associates, 127 however, found that 50% of highly trained ski mountaineers in the Alps developed EIB during racing, and that only one-fourth had been previously diagnosed with EIB. Whether this occurs with such frequency in nonelite athletes at lesser exercise intensities requires investigation. Given the frequency of exercise dyspnea at high altitude, EIB should always be considered by the clinician. Golan and colleagues163 screened travelers and found 147 asthmatics who trekked to high altitude. Risk factors for an asthma attack at altitude were use of inhaled bronchodilators more than 3 times a week before travel and intensive physical exertion during the trek. A small but careful study was done with 11 asthmatics who were in stable condition with normal respiratory function at sea level. Cogo and colleagues87 tested both methacholine challenge and hyperosmolar aerosol at sea level and multiple altitudes up to 5050 m (16,568 feet). At no altitude was there an increase in bronchial responsiveness, and at the highest altitude, there was a decrease. They concluded that the positive aspects of high altitude prevailed over potential negative factors for asthmatics and attributed the benefit to the increase in circulating catecholamines found in their subjects. In the presence of bronchoconstriction at high altitude, however, hypoxemia is likely to be greater than at low altitude, and for this reason there could be an association between asthma and HAPE or AMS. Reassuringly, no such relationship has yet been reported.224,511 Mirrakhlmov353 investigated the effect of acetazolamide in 16 asthmatic patients taken to 3200 m (10,499 feet). Acetazolamide showed the same benefits as in nonasthmatics, with higher oxygen saturation and fewer AMS symptoms compared with the placebo control group. Seven of the eight asthmatics in the control group developed symptoms of AMS, a rather high incidence, but without a nonasthmatic control group for comparison, it is not known whether this incidence was abnormal. Persons with asthma ascending to high altitude should be advised to be at maximum function before ascent, to continue on their usual medications, including corticosteroids, and to have corticosteroids and bronchodilators with them in the event of an exacerbation.88 Because airway heat loss can be a trigger for bronchospasm, the use of an airway warming mask might be helpful but is unproved.456 In summary, the available data, although limited, suggest that high altitude does not exacerbate asthma, and it actually improves allergic asthma. Further work needs to determine if asthma might have any influence on susceptibility to AMS and HAPE; anecdotally, this does not seem to be the case. Although it seems likely that a severe asthma attack at high altitude would be more dangerous than at low altitude, no data are available to answer this question. Although caution and adequate preparation are necessary, asthma is not a contraindication to high-altitude travel. Pulmonary Vascular Disorders Because of the danger of HAPE, pulmonary hypertension (PHT) of any etiology is at least a relative contraindication to 29

CHAPTER 1  High-Altitude Medicine and Physiology

not always correlate with symptoms and is inconvenient.121 Sea level PO2 values of 68 and 72 mm Hg successfully classified more than 90% of the subjects with a PaO2 greater than 55 mm Hg at simulated altitudes of 1525 m (5003 feet) and 2440 m (8005 feet), respectively.165,166 Such predictions have been further refined with the addition of spirometry.120 A PaO2 of 55 mm Hg results in saturation of 90% at high altitude, where there is slight alkalosis. These data suggested that persons with PaO2 values lower than these at sea level might require supplemental oxygen at modest altitudes. The British Thoracic Society states that patients with resting SaO2 less than 92% at sea level should use supplemental oxygen during airplane flight, and presumably on ascent to altitude. However, in the only clinical studies to date, patients with moderate chronic obstructive pulmonary disease (COPD) did quite well at altitude.168,339 Graham and Houston168 found that eight subjects with COPD taken to 1920 m (6299 feet) had only minor symptoms on ascent, despite the fact that mean PaO2 declined from 66 mm Hg at sea level to 51 mm Hg while at rest and from 63 to 47 mm Hg with exercise. The patients did acclimatize with a drop in PCO2 and a corresponding increase in PaO2 over 4 days, the same response as seen in healthy persons. Matthys and associates339 studied 10 patients at simulated altitude of 2500 m (8202 feet). Mean PAP increased from 21 to 25 mm Hg, PaO2 decreased from 68 to 51 mm Hg at rest, and the only symptom was an increase in fatigue. The authors concluded that travel to this moderate altitude is safe for such patients. They speculated that these persons might have been partially acclimatized because of their hypoxic lung disease and were therefore less likely to develop AMS. Unfortunately, no further investigations with sicker patients or at higher altitudes have yet been reported. Persons with COPD who become hypoxic and uncomfortable at altitude should be treated with oxygen therapy. Oxygen should also be considered for those predicted to become severely hypoxemic.47 See Luks310 for a helpful discussion on determining need for oxygen in these patients. To adjust oxygen therapy at altitude for persons already on supplemental oxygen, FIO2 is increased by the ratio of higher to lower barometric pressure (see Table 1-3). Oxygen also improved hemodynamics (lowered blood pressure) and decreased pulsus paradoxus and pulse pressure in COPD patients at a simulated altitude of 2438 m (8000 feet).48 With the advent of simple and inexpensive pulse oximetry, patients can be counseled to monitor their oxygen saturation, determine the need for oxygen, and titrate their own oxygen use. All patients with lung disease contemplating a trip to high altitude should be aware of oxygen availability at their destination, as well as medical services. Nearly all resorts worldwide, for example, have oxygen concentrators or compressed gas cylinders that can be obtained for use in hotels or other accommodations. In North America, home oxygen companies honor prescriptions from physicians in any state, and oxygen is quite easily obtained. Interestingly, reports of persons with COPD developing altitude illness are absent from the literature. On the other hand, the issue has not been specifically addressed. Any degree of pulmonary hypertension might be expected to increase the likelihood of HAPE, and although this has been clearly demonstrated in other conditions (see High-Altitude Pulmonary Edema, earlier), it has not yet been reported with pulmonary hypertension associated with COPD. No research has yet addressed the use of medications such as acetazolamide or medroxyprogesterone in these patients to determine if respiratory stimulants might improve altitude tolerance.

PART 1  MOUNTAIN MEDICINE

high-altitude exposure. In addition, hypoxic pulmonary vasoconstriction will most likely exaggerate preexisting pulmonary hypertension, leading to greater symptoms.183,309 Many patients with pulmonary hypertension may not be diagnosed as such, and the clinician must have an awareness of conditions associated with PHT, including trisomy 21, congenital heart disease, unilateral absent pulmonary artery, granulomatous mediastinitis, and restrictive lung diseases, all of which have been associated with high-altitude pulmonary edema.185,312,431,539 Other conditions warranting caution include bronchopulmonary dysplasia, recurrent pulmonary emboli, mitral stenosis, kyphoscoliosis, and scleroderma with CREST syndrome. As Hultgren has observed, however, some patients with PHT are able to tolerate high altitude,231 and hypoxic gas breathing can be used to identify an individual’s response to hypoxia if clinically indicated.309 Persons with PHT who must travel to high altitude might benefit from calcium channel blockers, isoproterenol, and especially low-flow oxygen.309 A report by Naeije and associates378 highlighted the increased susceptibility to HAPE in those with pulmonary hypertension; a lowland woman with pulmonary hypertension secondary to fenfluramine developed two episodes of HAPE. The first episode was at 2300 m (7546 feet) and the second one at only 1850 m (6070 feet), with skiing up to 2350 m (7710 feet). Whether pulmonary hypertension is primary or secondary, patients should be made aware of the potential hazards of high altitude, including right heart failure and HAPE. Despite lack of firm data to guide clinicians, a reasonable approach is that persons with mean PAP greater than 35 mm Hg or systolic PAP greater than 50 mm Hg at baseline should probably avoid travel to altitudes greater than 2500 m (8202 feet). If such travel is undertaken, supplemental oxygen during the sojourn should be recommended. Patients with milder degrees of pulmonary hypertension may travel to altitudes less than 3000 m (9843 feet) but should consider prophylactic measures, including pulmonary vasodilators or supplemental oxygen.309

(p <0.01 between altitudes) with ratios of central to obstructive events of 0.1, 0.8, 1.0, 1.9, and 1.9 (p <0.01 between altitudes), respectively. Tracking performance during simulated driving was significantly impaired at 2590 m (8497 feet) compared with 490 m (1608 feet). Systolic blood pressure and cardiac arrhythmias were increased at altitude. In a report linking obesity–hypoventilation syndrome, OSA, and reduced peripheral chemosensitivity to hypoxia, Richalet and co-workers426 studied a 24-year-old man with Down syndrome who developed HAPE at 2000 m (6562 feet); he did not have pulmonary hypertension. These studies were all in patients without treatment and suggest that a trade-off of OSA for CSA is not a benefit in terms of oxygenation or adverse events, and that patients with OSA or CSA must be cautious when traveling to high altitude. In contrast, patients with sleep apnea treated at altitude with CPAP, oxygen, or acetazolamide (for central events) apparently do well. Patz and associates400 showed that CPAP pressure did not vary significantly in seven patients traveling between 3048 m (10,000 feet) and sea level. Average CPAP 95th percentile absolute pressure and mean CPAP absolute pressure were stable, using a ResMed Autoset autotitrating CPAP unit. Others have suggested that the hypobaria of high altitude can decrease the delivered pressure of CPAP machines that do not have pressurecompensating features, but such machines are no longer in use. For those not being treated with CPAP, but who exhibit hypoxemia during sleep at low altitude, the physician should provide supplemental nocturnal oxygen during an altitude sojourn. Because central apnea events are easily treated with acetazolamide, patients with sleep apnea going to altitude should be considered for acetazolamide therapy, regardless of CPAP use.1,161 See Table 1-8 for recommendations regarding sleep apnea and other ventilatory disorders.

Sleep Apnea, Sleep-Disordered Breathing Persons with snoring, sleep apnea syndrome, and sleep-disordered breathing who become mildly hypoxemic at sea level may become severely hypoxemic at high altitude. This could contribute to high-altitude illness and aggravate attendant problems such as polycythemia, pulmonary hypertension, systemic hypertension, cardiac arrhythmia, or insomnia. On the other hand, changes in ventilatory control and breathing secondary to altitude hypoxia might conceivably improve certain apnea syndromes. In general, the limited research available has shown that obstructive sleep apnea (OSA) tends to improve at altitude, but that central sleep apnea (CSA) can either develop or become worse. Burgess and colleagues68 demonstrated a decrease in obstructive events but a “conversion” to severe central events in five men with moderate OSA studied without CPAP. The obstructive respiratory disturbance index fell from 25.5/hr at 60 m (197 feet) to 0.5/hr at 2750 m (9022 feet), while the central respiratory disturbance index rose from 0.4/hr at 60 m (197 feet) to 78.8/hr at 2750 m (9022 feet). Mean sleep SaO2 fell from 94% at 60 m (197 feet) to 85% at 2750 m (9022 feet) simulated altitude.68 They attributed the decrease in OSA to increased upper airway tone and increased respiratory rate, and the increased CSA to hypocapnia during non-REM sleep. Similarly, a small study in Colorado showed that the apnea–hypopnea index decreased in patients with OSA not on CPAP living at high altitude when they went to lower altitudes, due primarily to a decrease in central events, while OSA events persisted.399 These observations were confirmed in a detailed study of 34 patients with OSA with median apnea–hypopnea index of 47.5 events per hour, resi