Principles of Clinical Medicine for Space Flight

Principles of Clinical Medicine for Space Flight

Principles of Clinical Medicine for Space Flight

Michael R. Barratt, MD, MS Astronaut and Physician, NASA Johnson Space Center, Houston, TX, USA

Sam L. Pool, MD Chief, Medical Sciences Division, NASA Johnson Space Center (retired), Houston, TX, USA

Editors

Michael R. Barratt, MD, MS Astronaut and Physician NASA Johnson Space Center Houston, TX USA

Sam L. Pool, MD Chief, Medical Sciences Division NASA Johnson Space Center (retired) Houston, TX USA

ISBN: 978-0-387-98842-9 e-ISBN: 978-0-387-68164-1 DOI: 10.1007/978-0-387-68164-1 Library of Congress Control Number: 2007939575 © 2008 Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY-10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com

Dr. Patricia Hilliard Robertson (Photo courtesy of NASA) To our cherished friend and colleague Patricia Hilliard Robertson—pilot and flight instructor, physician and flight surgeon, adventurer and astronaut. She is greatly missed by the aerospace community and all who knew her.

Foreword

The space environment does strange things, both to the workings of the human body and to the behavior of ordinary medical equipment. Space medicine describes the “normal person in an abnormal environment” and is an outgrowth of aviation medicine. Aviation medicine didn’t exist when my father was born in 1884. By the time he served in the Army during World War I, it did, but its medical standards were still under construction. The Air Service Medical Manual issued by the War Department in 1918 discussed the public’s impression that the medical examination of an aviator was “a form of refined torture.” One story was that of the needle test. This mythical examination supposedly involved placing a needle between the candidate’s forefinger and thumb, blindfolding him, then shooting off a pistol behind his ear. The examiner would then note whether, owing to a supposed lack of nerve, the applicant had pushed the needle through his finger. The test sounded plausible then. Aviation medicine as a specialty grew quickly during World War II and the onset of the jet age in the 1950s. However, when the space age dawned suddenly with Sputnik in 1957, medicine was not ready. The pages of the Journal of Aviation Medicine for the years 1959 through 1961 were filled with forecasts of the effects of “zero G” on the human body—most of them dire. For example, doubt was expressed whether the gastrointestinal system would function when weightless; nourishment, it was reasoned, might have to be given intravenously. The altitude and solitude, it was opined, would cause “break off phenomenon,” a sort of psychosis of loneliness. My favorite of these predictions was that space travelers weren’t going to be able to urinate. This was “proven” in an experiment wherein a rookie medical technician was strapped into the back seat of a jet fightertrainer, helmeted, masked, and instrumented, flown to 35,000 ft, then pulled up into a zero-G parabola. At the peak of the maneuver, the pilot cried “Go!” and the poor fellow couldn’t do it. Catheters were solemnly recommended for astronauts.

It sure was fun knowing so little about the physiology of weightlessness. Skylab was a prototype space station in which three crews spent 1, 2, and 3 months learning how to homestead in space and to care for ourselves up there. A demand that a physician be on each crew was rejected, but a small medical kit was in place, and two members of each crew— most of whom were test pilots—were trained to sew up cuts, extract teeth, and examine and report on their fellow crewmen. Fortunately, the practice was slow; we never had a serious medical problem to treat. The U.S. Space Shuttle program, and later the joint NASA– Mir and International Space Station programs, have given the physician-authors of this book experience with hundreds of person-trips into space. The dreaded space motion sickness has been conquered, end-of-mission problems with vertigo and fluid loss have been brought under control, and confidence in human capabilities has been engendered. But true longduration weightlessness is still a frontier. A Mars mission is still a substantial challenge. Another critical perspective on space medicine is the recognition of its inherently interdisciplinary nature. Weightless humanity exists only in a special world, a “space craft” crafted by engineers, a closed-loop system with a man-made atmosphere and its own rules of up and down. This pulls doctors into the world of engineers and vice versa. We must help each other solve problems that arise not only from weightlessness but also from where we are and what we’re in—a vessel where, to get to Mars, we will have to recycle the very air we breathe and the water we consume. Engineering equipment— medical and otherwise—is a challenge when everything floats and nothing settles. The details are all in this book. The nature of interplanetary space, its effect on our bodies (and minds), the treatments and countermeasures we currently prescribe, and the mysteries that remain, are graphically described and illustrated. If you are a researcher needing a fact or reference, an engineer who wants to know how your design affects its users, or a curious student drawn to medicine or biology but also to the adventure

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of space flight—fill your mind here, and let your imagination carry you to Mars. Exploration of the heavens still has a value independent of the commercial and military arguments we use in its defense. The hunger to know and to see is one of our defining

Foreword

characteristics as human beings. The future does not exist. We get to help write its story. Joseph P. Kerwin, MD Houston, Texas

Preface There is no land uninhabitable, nor sea innavigable. —Robert Thorne, 1527

In 1768, Captain James Cook was preparing his vessel, the Whitby collier Endeavour, and her crew for an extended sea voyage. At that time, mortality rates of 50% or more were not uncommon for trade voyages. Scurvy, resulting from lack of dietary ascorbic acid (vitamin C), was the great enemy. Cook developed and, with the help of ship’s surgeon William Munkhouse, administered to his crew a preventive regimen that included required consumption of “antiscorbutics”—food supplements consisting of such items as onions, sauerkraut, fruit, and occasionally native grasses found on islands en route. Not a single life was lost from scurvy. Subsequent voyages by Cook and countless others were spared from the curse of scurvy, and many lives were thus saved. A new expectation arose: that crews could safely remain at sea for the prolonged periods required to make their voyages. We now stand near where Cook stood more than 200 years ago. Many bold steps have been taken into space over the past four decades, and we now contemplate still more ambitious missions of exploration and science. The mortality and morbidity rates associated with these preliminary efforts have been relatively low, though certainly not negligible. In taking these early steps, we have gained invaluable knowledge of how humans live in the space environment, particularly with regard to weightlessness. Key adverse influences and effects have been identified, including radiation exposure and acquired dose, bone and muscle atrophy, and cardiovascular deconditioning. Thus far these effects have been tolerable during the course of low-Earth orbit and preliminary lunar explorations. However, future missions will involve greater distances and times and will demand that these effects be countered and other capabilities provided to sustain the human presence and to support optimal work. Our current charge is to expand human exploration while maintaining the safety and health of the exploring crewmembers. As Endeavour’s surgeon Munkhouse did, we too have a standard of medical care and safety that must be “taken to sea” with us. To the extent possible and practical, current standards of medicine are expected to accompany space crews on their

missions. Along with these standards, a more complete understanding of how the space environment affects the human body is required. The application of standard medical practice in this unique and challenging context defines space medicine as a distinct discipline. In 1968, after the first few years of human space flight, Dr. Douglas Busby wrote Space Clinical Medicine, a well-referenced and highly prospective and insightful work. Since that time, a tremendous amount of information has accrued regarding the physiologic effects of weightlessness as well as medical and environmental events occurring during flight that influence crew health. In many ways, this text is a successor to Dr. Busby’s fine work. Principles of Clinical Medicine for Space Flight was written by practitioners of space medicine for practitioners of space medicine and for others who may benefit from this knowledge in their own unique circumstances. Neither an overall basic medical text nor a comprehensive review of space physiology, this book focuses on aspects of medicine that arise uniquely and are dealt with uniquely in human space flight, and how the effects of space flight—whether adverse or simply anomalous—are addressed to provide the best care for space crewmembers. Principles of Clinical Medicine for Space Flight draws heavily on the experience of the U.S. Skylab and Space Shuttle programs as well as the Russian experience with longduration missions aboard the Salyut and Mir space stations and, most recently, from our joint work on the first several missions aboard the International Space Station (ISS). Contributors have a rich and practical experience base of direct space mission support and human life sciences research, and this is reflected in the detailed information presented. Readers will find background information on the relevant physical forces and mechanical aspects of spaceflight necessary for complete understanding of the environment and its influence on the human space traveler. This is followed by a comprehensive review of the human response to every aspect of spaceflight, the most likely medical problems encountered, their diagnosis, management, and prevention. Special emphasis is given to those areas most limiting to long duration flights,

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such as radiation, bone and muscle loss, cardiovascular and neurovestibular deconditioning, nutrition and metabolism, and psychological reactions. Flight crew medical selection and retention standards are addressed, with discussion on rationale and application. In addition, cutting-edge technical issues particularly associated with provision of medical care in space are discussed, including selection and use of medical systems, telemedicine, medical imaging, surgical care, and medical transport. When warranted, reasonable speculations are offered regarding principles of medical support and practice for future exploration missions involving a return to the Moon and interplanetary flight. There is an expanding niche of medical practitioners who may utilize this book as a standard of care for supporting human space missions. This cadre is international, both civil and military, and is now extending into the commercial sector. This knowledge base should also greatly benefit the many groups and academic institutions involved in space life sciences or other environmental human research. Those participating in aerospace program and mission support and planning which involves or overlaps with medical decision making should also find useful information in this book. In addition, those involved with similar responsibilities of medical support in environments which are analogous to spaceflight, including submarine and surface ships, polar research stations, and other extreme or remote settings may benefit from our findings, as we have often benefited from such venues and exchange of experience. Finally, for the medically curious, we offer a comprehensive reference on one of the very latest medical specialties; none is more fascinating.

Preface

The size and scope of this book attests to the technical support and logistical efforts that were required to bring it into being. Our thanks go to technical editors Sharon Hecht and Luanne Jorevich and graphics wizards Sid Jones and Terry Johnson, who went extra miles during extra hours translating space medical jargon into plain English and clear figures; to space life sciences librarians Janine Bolton and Kim So for helping us to mine the world’s literature on space medicine; and to Brooke Heathman and Ellen Prejean, who helped organize and mold the chapters into a coherent work. Special thanks go to Chris Wogan, world expert on space life sciences technical literature, for bringing her talents to bear on this project, and to Merry Post and her exemplary skill and patience for guiding the transformation of our knowledge base into a userfriendly text. Of course our deepest gratitude goes to our families, and especially to our spouses Michelle Barratt and Jane Pool, who have weathered our fascinations and obsession with space flight these many long years; we can never adequately repay you for your dedication and support. Finally, to all of the world’s space travelers of all flags and professions who have undergone examination, monitoring, and sampling for medical certification and science for over four decades, we offer heartfelt thanks. A rising space-faring civilization owes you a debt of gratitude for your patience, endurance, and your great contribution to human space flight. Michael R. Barratt, MD, MS Sam L. Pool, MD

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part 1.

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Unique Attributes of Space Medicine

Chapter 1 Physical and Bioenvironmental Aspects of Human Space Flight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael R. Barratt

3

Chapter 2 Human Response to Space Flight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ellen S. Baker, Michael R. Barratt, and Mary L. Wear

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Chapter 3 Medical Evaluations and Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gary Gray and Smith L. Johnston

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Chapter 4 Spaceflight Medical Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Terrance A. Taddeo and Cheryl W. Armstrong

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Chapter 5 Acute Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas H. Marshburn

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Chapter 6 Surgical Capabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark R. Campbell and Roger D. Billica

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Chapter 7 Medical Evacuation and Vehicles for Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smith L. Johnston, Brian A. Arenare, and Kieran T. Smart

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Chapter 8 Telemedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scott C. Simmons, Douglas R. Hamilton, and P. Vernon McDonald

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Chapter 9 Medical Imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ashot E. Sargsyan

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Part 2.

Spaceflight Clinical Medicine

Chapter 10 Space and Entry Motion Sickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hernando J. Ortega Jr. and Deborah L. Harm Chapter 11 Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William T. Norfleet

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Chapter 12

Contents

Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan B. Clark

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Chapter 13 Renal and Genitourinary Concerns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey A. Jones, Robert A. Pietrzyk, and Peggy A. Whitson

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Chapter 14

Musculoskeletal Response to Space Flight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linda C. Shackelford

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Chapter 15

Immunologic Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clarence F. Sams and Duane L. Pierson

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Chapter 16

Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Douglas R. Hamilton

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Chapter 17

Neurologic Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan B. Clark and Kira Bacal

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Chapter 18

Gynecologic and Reproductive Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard T. Jennings and Ellen S. Baker

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Chapter 19

Behavioral Health and Performance Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christopher F. Flynn

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Chapter 20

Fatigue, Sleep, and Chronotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lakshmi Putcha and Thomas H. Marshburn

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Chapter 21

Health Effects of Atmospheric Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John T. James

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Chapter 22

Hypoxia, Hypercarbia, and Atmospheric Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kira Bacal, George Beck, and Michael R. Barratt

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Chapter 23

Radiation Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey A. Jones and Fathi Karouia

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Chapter 24

Acoustics Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan B. Clark and Christopher S. Allen

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Chapter 25

Ophthalmologic Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Keith Manuel and Thomas H. Mader

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Chapter 26

Dental Concerns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael H. Hodapp

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Chapter 27

Spaceflight Metabolism and Nutritional Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scott M. Smith and Helen W. Lane

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contributors

Christopher S. Allen, MS, BS Lead, Johnson Space Center Acoustics Office, ISS Acoustics Sub System Manager, NASA Johnson Space Center, Houston, TX, USA

Christopher F. Flynn, MD Clinical Associate Professor, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA

Brian A. Arenare, MD, MPH, MBA Director, Cardiopulmonary Lab, Kelsey-Seybold Clinic, NASA Johnson Space Center, Houston, TX, USA

Gary W. Gray, MD, PhD Senior Consultant Flight Surgeon, Canadian Space Agency, Toronto, Ontario, Canada

Cheryl W. Armstrong, BS Biomedical Engineer, Wyle Laboratories, Houston, TX, USA

Douglas R. Hamilton, MD, PhD, MSc, E Eng, PE, P Eng, FRCPC, ABIM Flight Surgeon, Electrical Engineer, Wyle Laboratories, Houston, TX, USA

Kira Bacal, MD, PhD, MPH, FACEP Research and Developmental Branch Director, Mauri Ora Associates, Auckland, New Zealand Ellen S. Baker, MD, MPH Astronaut, NASA Johnson Space Center, Houston, TX, USA Michael R. Barratt, MD, MS Astronaut and Physician, NASA Johnson Space Center, Houston, TX, USA George Beck, BA, RRT, FAARC Director, Engineering and Research, Impact Instrumentation, Inc., West Caldwell, NJ, USA Roger D. Billica, MD, FAAFP President, Tri-Life Health, Center for Integrative Medicine, Fort Collins, CO, USA Mark R. Campbell, BS, MD General Surgeon, Paris Regional Medical Center, Paris, TX, USA Jonathan B. Clark, MD, MPH Space Medicine Liaison, Baylor College of Medicine, National Space Biomedical Research Institute, Houston, TX, USA

Deborah L. Harm, PhD Senior Scientist, Human Adaptation and Countermeasures Division, Neurosciences Laboratory, NASA Johnson Space Center, Houston, TX, USA Michael H. Hodapp, DDS University of Texas Dental Branch, Houston, TX, USA John T. James, PhD Chief Toxicologist, NASA Johnson Space Center, Houston, TX, USA Richard T. Jennings, MD, MS Associate Professor, Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA Smith L. Johnston, MD, MS Medical Officer, Flight Surgeon, University of Texas Medical Branch, Preventive, Occupational, and Environmental Medicine, NASA Johnson Space Center, Houston, TX, USA Jeffrey A. Jones, MD, MS, FACS, FACPM Exploration Medical Operations Lead Flight Surgeon, NASA Johnson Space Center, Houston, TX, USA xiii

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Contributors

Fathi Karouia, MS, ASD, MSS Research Associate, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

Sam Lee Pool, MD Chief, Medical Sciences Division, NASA Johnson Space Center (retired), Houston, TX, USA

Joseph P. Kerwin, BA, MD Captain, Medical Corps, United States Navy (retired), Houston, TX, USA

Lakshmi Putcha, PhD, FCP Chief Pharmacologist, NASA Johnson Space Center, Houston, TX, USA

Helen W. Lane, PhD, RD NASA Chief Nutritionist, NASA Johnson Space Center, Houston, TX, USA

Clarence F. Sams, PhD Medical Project Scientist, International Space Station, SK/Human Adaptation and Countermeasure Division, NASA Johnson Space Center, Houston, TX, USA

Thomas H. Mader, MD Alaska Native Medical Center, Department of Ophthalmology, Anchorage, AK, USA F. Keith Manuel, OD Former Sr. Vision Consultant, Flight Medicine, NASA Johnson Space Center, Houston, TX, USA Thomas H. Marshburn, MD, MS Astronaut, NASA Johnson Space Center, Houston, TX, USA P. Vernon McDonald, PhD Director, Commercial Human Space Flight, Wyle Laboratories, Houston, TX, USA William T. Norfleet, MD Assistant Professor, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA Hernando J. Ortega, MD, MPH Colonel, Chief Flight Surgeon, United States Air Force, San Antonio, TX, USA Duane L. Pierson, PhD Senior Microbiologist, NASA Space Life Sciences Directorate, Houston, TX, USA Robert Pietrzyk, MS Project Scientist, Human Adaptation and Countermeasures Division, Wyle Laboratories Life Sciences Group, Houston, TX, USA

Ashot E. Sargsyan, MD Scientist, Wyle Laboratories Life Sciences Group, Houston, TX, USA Linda C. Shackelford, MD Manager, Bone and Muscle Lab, NASA Johnson Space Center, Houston, TX, USA Scott C. Simmons, MS Assistant Director, The Telemedicine Center, Brody School of Medicine, East Carolina University, Greenville, NC, USA Kieran T. Smart, MBChB, MSc, MPH, MRCGP Flight Surgeon, Wyle Laboratories, Houston, TX, USA Scott A. Smith, PhD Manager for Nutritional Biochemistry, NASA Johnson Space Center, Houston, TX, USA Terrance A. Taddeo, MD, MS Medical Officer, Deputy Manager of Medical Operations, NASA Johnson Space Center, Houston, TX, USA Mary L. Wear, PhD Health Care Services Manager, NASA Johnson Space Center, Houston, TX, USA Peggy A. Whitson, PhD Astronaut and Research Scientist, NASA Johnson Space Center, Houston, TX, USA

Part 1 Unique Attributes of Space Medicine

1 Physical and Bioenvironmental Aspects of Human Space Flight Michael R. Barratt

Life on Earth has developed and flourished under a wide range of diverse circumstances. These include familiar conditions at Earth’s surface and in upper layers of the seas, as well as the more exotic subterranean and deep ocean aphotic zones, where oxidative and anaerobic life processes can flourish at extreme limits of temperature, pressure, and exposure to what are classically considered toxic substances. A static gravitational field of 9.81 m/s2 and a protective and physiologically supportive atmospheric gas layer comprise the major factors that have profoundly influenced Earth as a place of human life. We are designed to function optimally in this environment—and within a fairly narrow envelope at that. Without protective methods and devices, human beings are effectively confined to a vertical gradient beginning at the surface of the sea to perhaps 5,000 m in altitude, the rough practical limit of human adaptation for prolonged acclimation. Simply put, human performance and survivability seem optimized to near sea level. Nevertheless, humans have now ventured to more than 10 km beneath the surface of the ocean, into near-Earth space, and to the surface of the Moon. Advances in technology and political organizations have enabled large-scale cooperative projects that have led to the expectation that humans will travel and live well beyond our narrow envelope. We have adapted to a larger environment and expanded our original sphere of existence. This expansion is a dynamic process that by all indications will continue and probably accelerate as more nations obtain the technology and industrial wherewithal to join this effort. As humans continue to explore and survive in environments that are beyond standard physiologic limits, an understanding of human reactions to these new environments and development of protective systems and processes becomes more critical. Over the past century, such disciplines as aviation medicine and diving medicine have arisen and matured, playing key roles in expanding human performance and endurance in new environments. These disciplines have successfully fostered the necessary interfaces between physical systems required to support the human aviator or diver and the knowledge of physiology and practice of medicine. To this same end, keeping pace with

current efforts in space exploration, the field of space medicine is emerging as a distinct discipline. Aviation medicine, diving medicine, and space medicine all involve pressure excursions, operational changes in body attitude and position, controlled breathing sources, and critical dependence on supportive mechanisms and protective equipment. Many of the basic problems of space medicine—hypoxia, dysbarism, thermal support, moderate levels of acceleration, response to unusual altitudes—had been studied over the course of decades of aviation and high-altitude balloon flight and were fairly well understood before the first human space flight ever took place. A basic working knowledge of aviation medicine and physiology remains required of the space medicine specialist. A review of these basics or of atmospheric science is beyond the scope of this chapter; the interested reader is referred to the sources in the Suggested Readings section at the end of this chapter. This book focuses on the unique medical circumstances and clinical problems associated with excursions outside of Earth’s atmosphere. These circumstances include a wide range of acceleration forces, adaptive processes and problems associated with weightlessness and partial gravity fields, radiation, excursions to other planetary bodies, and biotechnical problems associated with life support systems in enclosed environments. This chapter provides an overview of the basic physics of space flight and physical conditions faced by human space travelers that influence their physiologic responses and adaptation.

General Physics of Human Space Flight Leaving Earth A singular definition of space is elusive and somewhat arbitrary in terms of a specific border and limit relative to the surface of Earth; the definition varies with the particular parameter being assessed. For example, the pressure limit for maintaining body fluids in a liquid state (the physiologic limit) occurs at a specific altitude (about 19 km), whereas the limit 3

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at which forces between aircraft or spacecraft surfaces and the atmosphere support effective aerodynamic control (the physical limit) is quite different (about 80 km). The common factor for most biophysical parameters in defining a limit is a threshold degree of removal from nominal atmospheric gas composition and pressure, and for mechanical parameters a threshold reduction in density leading to, for instance, absence of aerodynamic lift and drag. Fifty years ago Hubertus Strughold, in a classic and insightful treatise on the interface between Earth and space [1], described three major atmospheric functions that serve as base points for understanding these limits: (1) the function of supplying breathing air and climate; (2) the function of supplying a filter against cosmic factors (e.g., ionizing radiation, ultraviolet light, meteoroids); and (3) the function of supplying mechanical support to the craft. Each of these functions can be further stratified into specific limits and borders. Table 1.1 lists several of these limits and physiologic milestones as one ascends vertically through the atmosphere. For astronauts flying to low Earth orbit (LEO), all of these limits and zones are traversed in a relatively short time, on the order of several minutes. The flight crew is of course enclosed in a highly protective and controlled environment; however, knowledge of these limits remains important with regard to mishaps that might occur at any altitude during ascent or descent, and knowledge of these limits also defines the capabilities of protective and emergency systems.

In the process of launching to a sustainable orbit, a lofting force must be applied that exceeds the gravitational force on the mass to be delivered. In the history of space flight thus far, this force has been provided by chemical rockets, which typically combine a fuel and oxidizer at high temperatures and pressures to create a reactive force through rapid combustion. The hazardous aspects of these systems, with highly explosive mixtures flowing through conduits at extremes of material and hardware performance limits, are obvious. Engine performance is described in terms of two basic parameters—thrust and specific impulse [2]. Thrust (F), is the amount of force applied to a rocket based on expulsion of exhaust gases. In simplified form: & e F = mV

(1.1)

. where F = force in Newtons (in N or m/kg/s2), m = mass flow rate of propellant (in kg/s), and Ve is exit velocity of the propellant (in m/s). Thrust increases with the product of combustion chamber temperature and the ratio of combustion-chamber pressure to nozzle-exit pressure. Thrust is usually expressed in Newtons (N) or pounds (lbs). The five large kerosene and liquid oxygen F1 first-stage engines of the Apollo Saturn V vehicle each supplied 6.7 million N (1.5 million lbs) of thrust. Each of the three Space Shuttle main engines, fueled by liquid hydrogen and liquid oxygen, generates 1.67 million N (375,000 lbs) of thrust at sea level.

Table 1.1. Physical and physiological milestones during the transition from the earth surface to space. Altitude

Event or Limit

1,525–2,440 m (5,000– 8,000 ft) 3,048 m (10,000 ft)

Cabin pressure of commercial air carriers; PAO2 = 81–69 mmHg

4,570 m (15,000 ft)

Approximate upper limit of human acclimation; PAO2 = 45 mmHg breathing ambient air. Supplemental oxygen is required if not in pressurized cabin. Practical limit for breathing 100% O2 in an unpressurized cabin. Above this altitude, positive pressure breathing is required to maintain normoxia. Ambient pressure = 187 mmHg; PAO2 on 100% O2 = 100 mmHg. Respiratory exchange limit; ambient pressure = 87 mmHg, equivalent to sum total of alveolar water vapor tension (47 mmHg) and CO2 tension (40 mmHg). No respiratory exchange is possible. Pressure suit or pressurized cabin is required. Practical limit of atmospheric weather processes and phenomena at equator (the altitude is lower near the poles). “Armstrong’s line”; Ambient pressure = 47 mmHg, equivalent to tension of water vapor at body temperature. Above this altitude, body fluids vaporize. Practical limit of ram pressurized cabin; above this altitude, fully enclosed pressurized cabins are required. Atmosphere ceases to protect objects from high-energy radiation particles. Little protective ozone. “Van Karman Line”; threshold of effectiveness of aerodynamic surfaces. Astronaut wings awarded. Minimal atmospheric light scattering, “blackness of space” The so-called “atmospheric entry interface” for returning spacecraft; initial onset of perceptible acceleration forces, control surface resistance. Dysacoustic zone; insufficient atmospheric density to facilitate the effective transmission of sound. Meteor safe zone limit; insufficient atmospheric density to effectively stop entry of micrometeorites. Aerothermodynamic border; minimal aerodynamic resistance or structural heating. Essentially no aerodynamic support; sustainable orbital altitude. Border of atmosphere; collisions between atmospheric gas molecules become undetectable. Particle density gradually diminishes over thousands of km to free space density of 1–10 per cc, mostly atomic hydrogen.

10,400 m (34,000 ft) 15,240 m (50,000 ft) 16 km (10 mi) 19,200 m (63,000 ft) 25–30 km (15.5–18.6 mi) 40 km (24.9 mi) 45 km (28 mi) 80 km (50 mi) 100 km (62 mi) 120 km (75 mi) 140 km (87 mi) 150 km (96 mi) 200 km (124 mi) 700 km (440 mi)

U.S. Air Force requires that pilots breathe supplemental oxygen. PAO2 = 60 mmHg if breathing ambient air.

Note: PAO2 = alveolar oxygen tension

1. Physical and Bioenvironmental Aspects of Human Space Flight

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For initial launch to orbit, the velocity component of Earth’s rotation can provide a significant boost in ∆v. Such a boost is best afforded by launching directly into the rotational velocity vector, or straight eastward (Figure 1.1). Practically, launch & I sp = F / mg (1.2) from the equator eastward would provide an additional 1,600 kilometers per hour (1,000 mph) in ‘free’ ∆v, or nearly 6% Substituting for F in (1.1) above, of final ∆v required to achieve LEO, which would translate I sp = Ve / g (1.3) into enhanced system performance and increased payload. Thus launching from higher latitude sites, or for any given site . where Isp = specific impulse (in seconds), F = thrust in N, m launching to azimuth angles higher than the latitude, trans= propellant mass flow rate (in kg/s), Ve is the exit velocity of lates into degraded performance and diminished payload-tothe propellant (in m/s), and g = gravitational acceleration at orbit capability. To date, all crewed launches have involved Earth’s surface, 9.81 m/s2. Isp is thus a measure of the exhaust eastward or posigrade launches. The U.S. Space Shuttle, velocity. Isp is proportional to the square root of combustion- launching from the Kennedy Space Center at about 28 degrees chamber temperature divided by the average molecular north latitude, attains its maximum performance by launching weight of combustion products and provides a measure of the directly eastward over the Atlantic Ocean. In doing so, the energy content and thrust conversion efficiency of the pro- shuttle attains an orbit of 28 degrees of inclination, defined pellant. Using a propellant with low molecular mass such as as the angle between Earth’s equatorial plane and the plane hydrogen or increasing the temperature of the propellant will of the spacecraft’s orbit (Figure 1.2). For a given launch site, serve to increase Isp. Isp can also be defined as the time (in launching straight eastward attains an orbital inclination equal seconds) required to burn one kg of propellant in an engine to the launch site’s latitude. A vehicle can launch to a higher producing one N of force. As a point of reference, the Space inclination while losing some of Earth’s rotational velocity Shuttle main engines are among the most efficient chemical advantage. To date, Space Shuttle missions have ranged from rockets yet developed, with a vacuum-rated Isp of 452.5 s. minimum inclinations of 28.35 degrees to a maximum of 62 The shuttle’s solid rocket boosters have a vacuum-rated Isp degrees, the latter extreme during STS-36, a Department of Defense Space Shuttle mission. of 267.3 s [3]. The inclination of the desired orbit cannot be lower than the Limitations of engine performance are the most important factor currently influencing space exploration. These limita- launch site latitude without a significant performance penalty; tions affect the amount of payload that can be delivered to in such a case, the ground site never rotates through the orbital orbit and the payload mass and velocity that can be directed to plane, and no practical launch windows exist. Posigrade a distant site out of LEO. For a given spacecraft, the ultimate measure of overall performance is its capability to provide the change in velocity, or ∆v, required for a certain orbital maneuver. This includes launch to orbit, in which the required ∆v is the difference between the velocity component of Earth’s rotation in the desired orbital plane and the final orbital velocity. It also includes losses from drag and gravity while traversing the atmosphere en route to orbit, as well as subsequent changes in orbital altitude and plane and potentially escaping from Earth orbit. For launching to orbit, provision of sufficient ∆v for a given payload depends greatly on the engine efficiency and the amount of propellant. To gain an appreciation of the relationship between payload, spacecraft structure, and propellant, it is instructive to examine the mass fractions of a standard Earth-to-orbit spacecraft. Typical values for propellant, structural, and payload mass fractions are 0.85, 0.14, and 0.01, respectively [4]. The Saturn V Apollo Lunar vehicle had a total launch weight of 2,621,000 kg. Of this, 129,250 kg (4.9%) was delivered to LEO, but only 45,350 kg or about 1.7% was accelerated to escape velocity away from Earth toward the Moon [5]. After the lunar mission was completed, including crew descent to the surface and subsequent shedding of the lunar module, the final reentry weight of the command module carrying the crew was only about 5,670 kg—roughly Figure 1.1. Velocity assist from Earth’s rotation for eastward (posigrade) launch 0.2% of the original launch weight. Specific impulse (Isp), the other parameter of engine performance, is the ratio of the thrust F to the weight flow rate of propellant:

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Figure 1.2. Orbital inclination, the angle between the orbital plane and earth’s equatorial plane. For any launch site, the minimum achievable inclination is equal to the launch site’s latitude. Higher inclination orbits are mechanically achievable but obtain less advantage from Earth’s rotation

launches from NASA’s Kennedy Space Center site in Florida are constrained to orbital inclinations 28 degrees and above, whereas launches from the Russian launch site in Baikonur, Kazakhstan are restricted to inclinations at or above the site latitude of about 46 degrees. Geopolitical constraints prohibit straight-east launches from Baikonur (to avoid dropping spent stages on Chinese territory), further limiting the effective inclination. A practical implication of this fact is that target orbits for large-scale projects involving multiple launch facilities are limited by the facility located at the highest latitude. For this reason, the orbital inclination of 51.6 degrees for the International Space Station (ISS) is defined by the Russian launch, range, and tracking capabilities and must be accommodated by the lower-latitude U.S. and European Space Agency sites (located in Khorou, French Guyana at 6 degrees latitude). The most flexible launch site in terms of access to the widest range of orbital inclinations would be located near the Equator; also, for a given orbital altitude, higher inclination orbits, although deriving minimal launch benefits from Earth rotation, cover more of Earth’s surface in their ground track, a situation that influences Earth observation and access to ground communication facilities. The desired orbit to which a spacecraft is lofted is said to be fixed in inertial space rather than relative to the ground, although the central point of reference is the center of the Earth. In other words, the motion of the orbiting spacecraft becomes indifferent to the ground surface features rotating beneath it. A reference system independent of Earth-surface features is

M.R. Barratt

Figure 1.3. The J2000 Inertial Reference Frame. With Earth at the center (geocentric), the Z axis points through the rotational North Pole, the X axis lies in the plane of the equator and points toward the vernal equinox (first point of Ares) for the year 2000, and the Y axis passes through the equatorial plane to complete a right-handed coordinate system. The inclination of a spacecraft’s orbit is the angle between the orbital plane of the spacecraft and the earth’s equatorial plane

needed to describe orbital motion; as such, an inertial coordinate system has been adopted that characterizes the basic elements of an object’s orbit. This system is based on a geocentric model, which places the gravitational center of Earth at the origin of a three-axis system (Figure 1.3). The plane of Earth’s equator contains two perpendicular axes, X and Y. The Z-axis extends through the axis of rotation, and X points toward a fixed position in space, the vernal equinox or first point of Ares defined for the year 2000. The Y-axis completes a right-handed coordinate system. This so-called J2000 reference system recently replaced the M50 coordinates, for which X was defined as the vernal equinox for the year 1950. The most efficient insertion into a desired orbit comes about by lofting from the launch site, which is fixed relative to the ground, directly into the desired orbit. Missions involving rendezvous and docking with another orbiting spacecraft require synchrony between launch time and the target object’s motion. This requirement gives rise to launch windows, spans of time during which the launch site rotates through the target orbital plane. Thus the time of the launch depends on the latitude and longitude of the launch site and the desired orbital plane and inclination. Launch opportunities may exist for both ascending (northbound) and descending (southbound) legs of the orbit. Higher inclination orbits imply steeper intersect angles between the launch site velocity vector from Earth rotation and launch azimuth as well as shorter launch windows. For a Space Shuttle launching straight out from the Kennedy Space Center at a latitude of 28 degrees with no rendezvous requirements, a launch window is not constrained by orbital mechanics and may last several hours. By contrast, launching from

1. Physical and Bioenvironmental Aspects of Human Space Flight

that site to a high-inclination rendezvous orbit, such as to the 51.6-degree ISS, the launch window, given the current performance limitations, effectively becomes 5–10 min long. Little margin exists for steering sideways to intercept an orbital plane if the optimal launch time is missed. Adverse weather conditions or hardware anomalies during the period immediately before launch that require assessment and timely action by the ground team thus can have a more profound effect on the success of launches that attempt to reach higher inclination rendezvous targets. Other launch-window determinants include constraints of lighting from the angle of the Sun, the flight path over ground sites during critical activities, the planetary geometry for transplanetary flights, and crew factors such as time spent in the launch position in full launch suit and rescue gear and crew duty day. For flights that do not involve rendezvous, lighting and crew physical and duty limits become the primary factors determining the duration of the launch window. For a given orbit, the launch window changes from day to day as Earth rotates eastward independent of the inertial orbital plane. The node of an orbit, the point where it crosses the equator, can be seen to track westward for a given clock time relative to the day before. This phenomenon, known as nodal regression, is due primarily to the oblate nature of Earth induced by the equatorial bulge. On successive days, the launch site rotates through the orbital plane earlier than on the previous day. For a planned launch from Kennedy Space Center to the 51.6-degree ISS orbit, for example, missing a launch opportunity because of weather or mechanical factors results in the next day’s opportunity being approximately 20 min earlier than on the planned day. This time accumulates over a delay of several days, and thus such a delay may require shifting the crew’s sleep period if the crew is adapted to a certain operational time schedule.

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Even at these altitudes, over a period of months atmospheric drag is sufficient to cause eventual orbital decay. Solar magnetic activity also is dynamic along short-term spikes and in long-term cycles, and it may increase to cause effective thermal expansion of the atmosphere and increase its resulting drag influence on an orbiting spacecraft. A large orbiting platform thus requires periodic reboosting to remain in orbit. As an example, in its final configuration, the Russian space station Mir, with a mass of about 90 metric tons and a large cross-sectional area, required several hundred kg of propellant per year to perform altitude reboosts. A typical reboost might loft the station from the lower levels of the operating envelope (350 km) to the maximum levels (440 km) limited by the performance of docking vehicles. Decreasing the cross-sectional area of the craft relative to the velocity vector, which can be done by feathering solar arrays or changing the structure’s attitude, serves to decease drag and maintain orbital altitude for longer periods. The orbital shape of an object gravitationally held by Earth is typically elliptical, with two major landmarks: the perigee, the point along the elliptical path closest to Earth’s center, and the apogee, the corresponding point farthest from the center. The complete characteristics of a spacecraft’s orbit can be defined by six primary factors, or orbital elements. Also known as the classic Keplerian elements, these elements are based on a three-axis reference system using Earth’s center as an inertial origin point. Figure 1.4 describes the basic elements of a body in orbit. The Z-axis is the earth’s axis of rotation and goes through the north (+Z) and south poles. The X and Y-axes are in the equatorial plane, with +X pointing to the vernal equinox and +Y offset 90 degrees in a right-handed system. The following elements are required to completely describe an orbit for a two-body system [6]: a: semi-major axis: describes the size of the ellipse (Figure 1.4A)

Earth Orbit In attaining orbit, the influence of aerodynamics on a spacecraft and its crew becomes negligible and the influence of the basic laws of Newtonian mechanics increases. Weightlessness (or free fall) is sustained when the inward force of gravity is exactly counterbalanced by the outward centrifugal force of the spacecraft, with sufficient velocity forward to result in a flight path tangential to the surface of Earth. For a circular orbit, the flight path becomes a constant altitude; for an elliptical orbit, the altitude will vary depending on relative position on the orbital track. To be sustainable, the altitude must be sufficient to escape drag-inducing atmospheric interaction, and forward (tangential) velocity must be high enough to keep the spacecraft falling around Earth rather than to Earth; this is the state of free fall, which is perceived as weightlessness. The standard orbital velocity in LEO is 8 km/s (5 mi/s). A typical Space Shuttle mission is flown at an altitude of 320 km (200 mi) with a forward velocity of 28,160 km/h (17,500 mph).

e: eccentricity: describes the shape of the ellipse (Figure 1.4A) i: inclination: the angle between the angular momentum vector and the unit vector in the Z-direction. (Figure 1.4B) W : right ascension of the ascending node: angle from the vernal equinox to the ascending node. The ascending node is the point where the satellite passes through the equatorial plane moving south to north. Right ascension is measured as a right-handed rotation about the pole, Z. (Figure 1.4B) w : argument of perigee: the angle from the ascending node to the eccentricity vector measured in the direction of the spacecraft’s motion. The eccentricity vector points from the center of the earth to perigee with a magnitude equal to the eccentricity of the orbit. (Figure 1.4B) n : true anomaly: the angle from the eccentricity vector to the satellite position vector, measured in the direction of satellite motion. This is a time component; alternatively, time since perigee passage could be used.

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M.R. Barratt

Figure 1.5. Ground track of a spacecraft in low Earth orbit, in this case the International Space Station with an orbital inclination of 51.6

Figure 1.4. A and B. The six primary elements describing a spacecraft orbit. These are known as the classic Keplerian elements and define the size, shape, and orientation of the orbit, as well as the position of the spacecraft on the orbit

The precise orbit of a spacecraft may not be fully described with these classical elements because of various perturbation forces such as third-body effects (e.g. lunar gravitational influence), solar radiation, atmospheric drag, and the influence of a nonspherical Earth. Although the effects of these perturbation factors are smaller than those of the basic elements for a spacecraft in LEP, the perturbation factors must nevertheless be accounted for in mission operations. Detailed descriptions of the classical elements and other factors is beyond the scope of this text; however, a basic understanding of these factors is useful for the space medicine specialist’s situational understanding of crewed space flight. After launch and ascent, which typically lasts 7–9 min, a crewed spacecraft such as the Soyuz or Space Shuttle quickly crosses the atmosphere and realm of aerodynamics into LEO. The path of a spacecraft over the ground (its ground track) can be envisioned by flattening out Earth’s spherical shape, thus producing the familiar sine-wave track over the Mercator projection maps used in mission control centers (Figure 1.5). The

22.5-degree westward precession of the ground track for each 90-min orbit can be seen as Earth continues to rotate eastward independent of the inertial orbital plane. Spacecraft can be placed into a wide variety of orbits, including those involving retrograde launches (opposite the direction of Earth rotation) and geostationary positions, which maintain a constant position relative to a fixed ground point. However, the human presence introduces limitations that are based on environmental hazards. For human space flight, LEO is for practical purposes bounded at the lower altitude by the physical constraint of atmospheric interaction and at the upper altitude by the physiologic constraint of increasing radiation exposure from the geomagnetically held Van Allen radiation belts. These constraints result in the standard LEO work envelope for long-duration flight being between 200 km (124 mi), below which atmospheric drag would cause rapid decay of the spacecraft orbit, and approximately 500 km (312 mi), where depending on orbital inclination the daily radiation dose might exceed 5 × 10−4 sieverts (Sv) (50 millirem [mrem]). The relationship of orbital characteristics and radiation exposure is described further in Chap. 23.

Orbital Debris Early seafarers had to contend with uncharted reefs and occasional floating debris; space vehicles in LEO are faced with an analogous collision potential. Operations in Earth orbit can bring spacecraft near other similarly held objects, primarily originating from artificial sources. Given the standard orbital velocities of such objects and assuming unlimited radical orbital paths, the collision velocities can be formidable, with an average relative velocity between two objects of 10 kilometers per

1. Physical and Bioenvironmental Aspects of Human Space Flight

second (kps); with this relative velocity, a 100-gram fragment possesses kinetic energy equivalent to 1 kg of TNT [7]. Most of the material in LEO is artificial, consisting of active spacecraft, spent and inactive satellites, booster components, and fragmentation products resulting from pyrotechnic separation devices. More than 95% of tracked objects are considered unusable debris. The more heavily used orbits tend to be the most cluttered with debris. In contrast, the flux of natural material, consisting mostly of fragmentation and disintegration products of comets and asteroids, is much lower than that of artificial material. Natural material flux is primarily confined to particles smaller than 1 mm with velocity on the order of 16 kps. Such particles continually rain down on Earth and rarely slow enough to become trapped in LEO. Approximately 40 million kg of such matter is thought to reach Earth’s surface annually, with the peak in the size distribution at about 200 µm in diameter. This mass amount is thought to be comparable over very long time scales to the contribution from bodies of much larger size (in the 1-cm to 10-km range) [8]. Orbiting objects are tracked by the U.S. Space Surveillance Network; objects larger than 10 cm (4 in.) can be detected and tracked with Earth-bound radar. Currently about 8,000 such objects are being actively tracked [9]. Figure 1.6 depicts the rise over time in the number of tracked objects in LEO, where most spacecraft operate, showing a nearly linear and parallel relationship with the history of spaceflight activities. These tracking data occasionally allow avoidance maneuvers to be made when imminent collisions or proximity are calculated, as has been done for the Space Shuttle, Mir, and ISS. However, most of the material, in terms of both number and total mass, consists of small objects below the size threshold for tracking by radar. Shielding can be reasonably afforded against hypervelocity collision forces with objects up to 1 cm in size; shielding for larger objects becomes unduly heavy and carries substantial costs in terms of performance and structure. As such, the greatest danger for large crewed space platforms stems from objects 1–10 cm in size, which are large enough

Figure 1.6. Population over time of orbital debris larger than 10 cm in low Earth orbit, as cataloged by the Space Surveillance Network

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to inflict substantial damage on spacecraft but are essentially invisible and therefore unavoidable. Risk parameters for collision of orbital debris with crewed platforms and EVA systems are discussed further in Chap. 12, which deals specifically with the issue of decompression of habitable cabin atmospheres. International efforts are currently being made to minimize the further generation of orbital debris by limiting the use of frangible bolts and actively deorbiting spent stages.

Beyond Earth Orbit Pulling away from Earth requires an escape velocity that depends on the radius of the orbit, according to the equation Vesc = 2µ / r

(1.4)

where Vesc is escape velocity (in km/s), µ is Earth’s gravitational constant (equal to Earth’s mass multiplied by G, the universal gravitational constant, or 398,600.5 km3/s2), and r is the distance from Earth’s center (the radius of the orbit). The farther the distance from Earth’s center, the smaller the ∆V required. At the surface of Earth, where the distance from Earth’s center to the equator is 6,378 km, a theoretical ∆V of 11.2 km/s is needed to escape gravitational pull; an additional ∆V would be needed to make up for atmospheric losses. For example, from the typical LEO altitude of the ISS (386 km with an orbital radius of 6,764 km), the escape velocity is 10.8 km/s; for a spacecraft already established in this orbit with a velocity of about 7.8 km/s, only a small additional ∆V is required. For travel beyond near-Earth space, the factor of greatest influence becomes sheer distance and its effect on travel time and subsequent radiation exposure. Near-Earth destinations outside of LEO such as the Moon and Lagrangian points (points of Earth-Sun or Earth-Moon gravitational equilibrium) can be reached relatively easily with currently available chemical rockets, although the payload mass that can be delivered to these sites remains limited. However, with conventional chemical rocket technology, travel beyond near-Earth space becomes much more daunting. Most Mars flight scenarios have involved mission durations on the order of 450 to more than 1,000 days [10–12] and mission profiles at the extremes of chemical rocket capabilities. These missions might also involve some gravitational assist maneuver such as a planetary (Venus or Earth) flyby. The bulk of the total mission time could be taken up by interplanetary transit in weightless conditions. Aside from the limitations on the vehicles involved, such mission scenarios also are well outside the current experience with human space flight. The longest space flight to date was the laudable 438-day mission of the Russian physician-cosmonaut Dr. Valery Polyakov aboard Mir between January 1994 and March 1995. Although this mission was highly successful, the longer limit of flight duration must be extended significantly to entertain thoughts of very long mis-

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sions using current propulsive technology. Provision of some degree of artificial gravity en route, although fraught with medical, performance, and engineering challenges, may mitigate the adverse effects of prolonged exposure to microgravity (described later in this chapter under Microgravity and Partial Gravity). However, to consider distances to Mars and other more distant potential targets of crewed missions such as the larger asteroids, the development of advanced propulsion and power systems must be a high priority to enable human exploration of the solar system in earnest. Scenarios involving the exposure of humans for many months to interplanetary transit, with its harsh radiation environments, should be avoided by applying technology to travel faster. Although the desirability of faster interplanetary transit times may seem obvious, specific operational factors may be identified that bolster this requirement. Prominent among these factors is the absolute radiation dose to which a human can be exposed and still meet the annual and career limits of radiation exposure. Maintenance of bone and muscle mass and cardiovascular conditioning in microgravity also becomes critically dependent on the use of countermeasures, and to date no countermeasure regimen has proven completely effective. Unlike crewmembers who return to Earth after a long-duration mission, crewmembers landing on the surface of Mars, with its gravitational field of 0.38 G (where G is a multiple or fraction of g = unit gravity on Earth, or 9.8 m/s2), will be alone in managing their postflight medical treatment and rehabilitation program, with only remote guidance from ground specialists and onboard medical references to augment their preflight medical training. The author and others, in observing several crewmembers freshly returned from long-duration flight, have noted a considerable degree of individual variability in postflight condition and performance despite similarities in flight experience and use of countermeasures. It would be highly advisable that those crewmembers embarking on inaugural remote exploration missions with planned surface excursions have previous experience with long-duration space flight and well documented postflight performance and readaptation to a gravity field. The psychological tolerance and mission performance of such crewmembers should also be known. A problem becomes immediately apparent in making previous long-duration flight a requirement. Such experience on a LEO station, for instance, coupled with 14- to 36-month interplanetary transit times would probably result in radiation exposure that exceeds established career radiation limits. With a few notable exceptions, standard LEO duty tours onboard the Mir and ISS have been on the order of 120–180 days; this constitutes a reasonable period for performing effective work without incurring unacceptable cumulative radiation exposure and bone mineral loss. Perhaps the only reason to perform longer missions would be to expand the long-duration flight envelope for characterization of human response and development of more effective countermeasures. A clear near-term goal, then, is to provide transit times well within this experience base. This would ensure that radiation limits

M.R. Barratt

can be met, experienced long-duration space crewmembers with known in-flight and postflight performance can be sent, and reasonable microgravity countermeasures can be used. Provision of artificial gravity may prove to be an effective countermeasure if prolonged exposures to weightlessness are inevitable. However, providing a constant rotational artificialgravity field confers substantial mechanical and engineering problems in addition to human tolerance challenges. From a life sciences standpoint, the most efficacious solution to ensure mission success is to keep transit times short. Critical space medical research objectives would thus focus on optimizing human performance within a familiar time envelope and on developing true clinical autonomy during space flight. Many new propulsion technologies are currently being examined to use propellants much more efficiently and reduce transit times to destinations such as Mars. Figure 1.7 compares the relative performance characteristics of several propulsion concepts. Although expounding on the details of propulsion is beyond the scope of this text, it is readily evident that conventional chemical rocket technology is at the low end of the scale with regard to enabling crewed solar system exploration. Technical comparisons of new propulsion technologies are factored into exploration mission planning [2,13]. Some of these advanced technologies, such as nuclear thermal rocket engines, are relatively mature and offer performance well beyond that of chemical systems, although crews will need to be shielded from artificial ionizing radiation. Other technologies, such as magnetoplasmadynamic engines, are more exotic and require much forward work but offer tremendous

Figure 1.7. Relative performance of various propulsion concepts. Although chemical rockets have served well for near-Earth space exploration, exploration class missions must utilize advanced technologies to become practical

1. Physical and Bioenvironmental Aspects of Human Space Flight

advantages in planetary transit scenarios. Given that Mars is at an extreme limit of chemical rocket technology for round-trip flights, it is logical to use a new technology on an evolutionary step toward these advanced propulsion concepts, then apply and enhance the same technology to go further and to increase the feasibility and practicality of maintaining a presence on the surface of Mars. One such concept, the variable specific-impulse magnetoplasma rocket (VASIMR), consists of a plasma engine that can be throttled. The relative balance of thrust F and specific impulse Isp is varied under constant power, enabling the optimal use of propellant. Greater F is used for orbital boost and deceleration phases, whereas lower F and higher Isp are used for efficient transplanetary flight [14]. Plans for Mars missions involve multiple launches for vehicle assembly and unmanned cargo missions, with transit times shorter than those that can be achieved with chemical rockets. One representative piloted scenario uses a 12-MW nuclear-electric VASIMR rocket to deliver a payload mass of 61 metric tons to Mars [15]. The cryogenic hydrogen propellant can also be positioned around the crew cabin, providing an optimal barrier against high-energy galactic cosmic rays. Along with enabling the near-term exploration of Mars, this basic technology could represent an evolutionary step over a greater time scale, most likely on the order of several decades. Incorporation of advanced power systems, such as nuclear fusion, as they become available will afford a further drastic improvement in performance. With 10–100 gigawatts available, for example, accelerations involving potentially protective fractions of linear unit-gravity, on the order of 0.3–0.5 G, become available. Such technology could fully open up the solar system to human exploration and exploitation. A similar need for advanced technologies exists for onboard power generation. Systems such as environmental control and life support, avionics, communication, and laboratory and investigational facilities require electrical power in abundance. Solar energy is readily available in LEO, and solar arrays have proven effective in supplying satellites and crewed stations. At “assembly-complete,” the solar arrays of the ISS will supply the 75 kW needed for systems and laboratory operations. However, these arrays typically provide little reserve power in standard operations and, because of their large surface area, are vulnerable to damage by orbital debris. Venturing further outward in the solar system also means that diminished solar energy flux will be available to generate power. Fuel cells, such as those used on the Space Shuttle, function well for short-duration missions and provide the added by-product of potable and hygiene-grade water after reacting liquid hydrogen and oxygen. Power requirements on the Space Shuttle average 14 kW, and thus water is in fact produced in surplus, necessitating periodic overboard dumps. However, coupled with the relatively short operational life of fuel cells, a typical Space Shuttle mission involves the consumption of 1,590 kg (3,500 lbs) of cryogenically stored hydrogen and oxygen to generate the onboard electrical power needed.

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To venture confidently and frequently beyond near-Earth space, high-yield and reliable power systems are required to ensure autonomy and mission success and to enhance crew safety and comfort. A transplanetary craft carrying four to six crewmembers might be expected to require 20–60 kW for systems operations, and the same would be true for a modest surface habitat. These power requirements must be met over periods of at least several months and must be absolutely assured. As such, a forward step beyond solar and fuel cells is necessary. Submarines provide a historical analog: the transition from fossil-fuel burning engines to nuclear-powered steam turbines has afforded electrical power generally in excess of standard propulsion requirements. Power for life support system functions, desalinization of seawater and processing it into potable and hygienic water, electrolytic production of breathing oxygen from seawater, and various other support systems has become relatively abundant. For space flight, access to abundant power with sufficient margins is critical for crew safety as well as for mission success. Nuclear fission reactors—if they can be safely launched and managed—offer an attractive and currently available option for generating electrical power for long-duration space flights. This approach would change the current situation of resource and power limitation to one of resource limitation only; resources could then be better managed, such as by advanced but power-intensive regenerative life support systems. Using nuclear reactors as a power source for an advanced propulsion system might afford this electrical power as a by-product and drastically increase the margin for mission success and safety. Obviously, many safety and engineering issues are associated with nuclear systems; aside from the potential problems of further exposing the crews to ionizing radiation, such systems may require large radiators to dissipate heat, which would be vulnerable to debris and micrometeoroid impact while the craft is in LEO. However, with no other equivalent available power source in the immediate future, barring a breakthrough in fusion technology, the safe and careful use of nuclear reactors for spaceflight propulsion and planetary surface use should be vigorously explored. Whether any sustainable crewed exploration beyond near-Earth space can be undertaken without nuclear power is doubtful.

Acceleration Forces Acceleration Basics With the advent of powered vehicles, notably aircraft and spacecraft, the possibility first arose for prolonged human exposures to significant sustained acceleration forces. As stated earlier, ascending the gravity ladder to leave Earth implies a climb to above the atmosphere and a ∆v of 8 kps to attain a sustainable LEO. The time during which the spacecraft must accelerate to this new velocity determines the forces acting on the human occupant. In theory, this acceleration could be slow enough to produce minimal effects; in practice, however, the time span is

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bounded by vehicle performance—a slow ascent to final velocity and sustainable orbit involves more time fighting against gravity and hence greater propellant consumption, whereas an overly rapid ascent incurs greater aerodynamic and structural loads. The acceleration of ascent is not linear, but rather shows peaks and troughs based on engine staging and structural limits. At the end of a mission, after a deorbit engine burn, the spacecraft must reenter the atmosphere and slow to its original velocity in a reciprocal negative acceleration (deceleration) profile, with aerodynamic drag as the prevailing force. Returning from the Moon, the Apollo capsules carried more velocity than a spacecraft returning from LEO and thus were subject to even higher acceleration loads for entry. Earth launch and landing loads will probably be the greatest acceleration forces experienced by human beings as more remote exploration missions are considered, and these forces have shown to be tolerable. In any case, physiologically significant acceleration loads are a fundamental consequence of transition between gravity fields of planetary bodies. Extensive reviews of acceleration forces and their effects on the human are available in the aviation medical literature; this section focuses instead on the genesis of acceleration forces in the spaceflight environment and highlights the differences between aviation and space crewmembers. A review of Sir Isaac Newton’s three basic laws of motion is both useful and relevant in clarifying acceleration: 1 A body at rest (in motion) will remain at rest (in motion) unless acted upon by an outside force. 2 F = ma, where F = force in Newtons (kg/m/s2), m = mass in kg, and a = acceleration in m/s2. 3 For every action, there is an equal and opposite reaction. The constant acceleration caused by Earth’s gravity at sea level is taken as 9.81 m/s2, and is denoted as ‘g’. Using this value as a reference, the notation ‘G’ is used to denote fractions or multiples of g; G is thus a dimensionless quantity. The unit G is not to be confused with ‘G’, the universal gravitational constant, as discussed later.

Acceleration Forces in Space Flight In many aerospace operations, components of basic accelerations can be mixed. However, the loads typically involved in spacecraft launch and entry involve linear acceleration, with the spacecraft maintaining a more or less constant relation to the acceleration vector. This situation allows crewmembers and payloads to be placed in optimal positions relative to the acceleration vector so as to best withstand those forces. An exception is the U.S. Space Shuttle, which effectively becomes an airplane with standard upright seating as it reenters Earth’s atmosphere during landing. For any activity involving sustained acceleration loads, the orientation of the human crewmember to the vector of G loading, along with the absolute G load incurred, can profoundly influence crew activity and performance. In terms of aviation,

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the pilot of a high-performance aircraft is seated upright, which is necessary for optimal control in a dominantly horizontal reference plane. However, during tight turns, that position subjects the pilot to G loads in the most physiologically vulnerable axis (head to foot or +Gz). The major determinant and limiting factor of performance under sustained +Gz acceleration is the cardiovascular system; the hydrostatic pressure acting on the vertical blood column between the heart and brain in particular renders cerebral perfusion vulnerable. In the early days of human space flight, control during ascent and descent was highly automated; the human inputs that were required were largely independent of the familiar horizontal vision reference required and maintained by the aviator. Thus for the first 20 years of space flight, the space flyer did not require upright orientation, thus avoiding this physiologically vulnerable position and allowing positions with the most favorable orientation to the G vector, +Gx (chest to back), to be assumed for launch and landing. Moreover, as spacecraft have become less of a crewed ballistic missile and more of the multiperson, payload-carrying, and cross-range-capable spaceships of today, launch and landing loads have eased. The basic types of acceleration are linear, radial, angular, and Coriolis, all of which can occur alone or in combination, and each of which contributes a vector component to a resultant sum. Accelerations are characterized by the vector direction (axis), rate of onset, magnitude, and duration of application to the human occupant. The accelerations described also involve reactive forces (linear and torque) determined by the mass of the object. From the three basic laws of motion, it is understood that mass provides inertial resistance to acceleration. These inertial forces, resulting from changes in linear and angular velocity, are what actually lead to the physiologic effects. In addition to considering the basic accelerations encountered in space flight, one must also consider the forces resulting from those accelerations; Coriolis accelerations in particular will be considered in a subsequent discussion of artificial rotational gravity. Linear acceleration. For linear acceleration, the direction of movement is constant, and only the velocity changes. The equation for linear acceleration is: a = ∆v/t

(1.5)

where a = acceleration (expressed in m/s2), ∆v = change in velocity (in m/s), and t = time (in s). The resultant force on a human undergoing linear acceleration, which acts opposite the perceived acceleration, is described by Newton’s second law: F = ma

(1.6)

where F is the force acting on a body (in N [m/kg/s 2]), m = the mass of an object (in kg), and a = acceleration (in m/s2). The gravitational force that holds us to Earth’s surface implies a reactive force based on our mass and a linear acceleration of 9.81 m/s2, denoted as g or 1 G. Significant, sustained linear accelerations involving multiple Gs are a phenomenon of spacecraft, associated thus far with launch and landing activities. (For a hypothetical spacecraft capable of prolonged

1. Physical and Bioenvironmental Aspects of Human Space Flight

acceleration at 9.8 m/s2, the force acting “downward” on the body would be perceived as natural unit gravity.) The well-known effects of multiple-G forces on the human body depend greatly on orientation, and thus require a coordinate system to depict direction. The accepted body coordinate system, along with resulting inertial forces and circumstances of these linear acceleration components in space flight, is shown in Table 1.2.

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In all piloted launch vehicles leaving Earth, crewmembers are positioned such that the major G loads incurred by the body during ascent are taken along the body +Gx axis. Representative G profiles of various piloted launch vehicles during nominal ascent are shown in Figure 1.8; Figure 1.9 shows entry G loads for the same vehicles. The vector sum of the resultant loads on the human occupant depends on seat positioning and orientation with respect to the vehicle and acceleration vector.

Table 1.2. Standard three-axis coordinate system describing linear accelerations and resulting inertial forces on the human body for space flight. Axis/Direction

Acceleration

Resultant Inertial Force

+Gz

Headward

Head to Foot

−Gz +Gx

Footward Forward

Foot to Head Chest to Back

−Gx +Gy

Backward To Right

Back to Chest Right to Left

−Gy

To Left

Left to Right

Primary Spaceflight Circumstances (Most involve mixed acceleration vector components) Space Shuttle entry (1.2 G sustained) Shuttle landing turn (1.2–1.98 G) Apollo Lunar Ascent Module Launch (3–8 G all vehicles) Entry (1.2 G recumbent in Shuttle to 8 G in Mercurytype capsules) Launch abort scenarios (17–20 G) Aerocapture maneuvers (future transplanetary flight) Parachute opening (Apollo, Soyuz, etc.) Landing impact (transient, 4–20 G) Shuttle runway deceleration from brakes, drogue chute Impact (land or water) on capsule from horizontal velocity component (wind) Same

Note: Spacecraft orbital maneuvering can be applied to all axes, typically involving very low G forces.

Figure 1.8. Representative acceleration profiles and resultant G loading for launch of the Gemini, Apollo, and Space Shuttle (Space Transportation System) spacecraft. Most of the loading is received along the crewmembers’ +Gx axis

Figure 1.9. Representative acceleration profiles and resultant G loads on occupants of the Gemini, Apollo, and Space Shuttle (Space Transportation System) spacecraft during atmospheric reentry. Gemini and Apollo crew capsules allowed most of the load to be taken in the crewmembers’ +Gx axis. Space Shuttle crewmembers land in an upright, seated position, exposing deconditioned crewmembers to much smaller loads but in the +Gz axis for much longer periods

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Such positioning is also related to vehicle structure, center of gravity, and flight characteristics. Crewmembers returning from a U.S. Space Shuttle mission assume an upright position, the position of greatest vulnerability in the transition from being adapted to weightlessness to being relatively deconditioned aviators. Crewmembers maintain a standard aircraft seating arrangement during landing, with the entry vector in the +Gz orientation for vehicle and occupants. Shuttle landing forces are fairly gentle and gradual, with a constant acceleration of about 1.2 G over 17 min during actual atmospheric entry, culminating in a turn to final approach resulting in a maximum of 2.0 +Gz, with 1.4–1.5 +Gz being typical. Mishaps during ascent and entry can lead to much higher loads, primarily in the +Gx axis. Escape tower systems, such as those currently used for the Russian Soyuz booster and those formerly used for the U.S. Apollo and Mercury spacecraft, are designed to remove the crewmember from the launch pad or from an early launch explosion as rapidly as possible. This design incurs very high (10–20 G) acceleration loads in the +Gx orientation. This system has been used operationally on one occasion—a fire on the launch pad during the Soyuz T10A launch. During that event, the escape rockets pulled the capsule containing cosmonauts V. Titov and G. Strekalov up and away from the fire, briefly subjecting them to about 17 +Gx while a safe altitude was attained for parachute deploy followed by a soft landing about 4 km away from the launch pad [16,17]. Launch abort scenarios are also possible, such as that experienced by cosmonauts V. Lazarev and O. Makarov in the Soyuz 18A flight bound for the Salyut 4 orbital station. Failure of third-stage separation on ascent subjected the crewmembers to a high-load suborbital flight lasting approximately 21 min before the chute deployed and the craft landed. Maximal forces were said to be 20–21 +Gx. Although some minor injuries were sustained during the hillside landing, no persistent effects from the high G loads sustained were reported—a remarkable testament to G-load tolerance in this axis [18,19]. In both of these extreme cases, crewmembers were not already deconditioned from weightlessness. A more rapid ballistic entry after a LEO mission might result from an overly long deorbit burn time, with higher transient G loads than normal. Loads such as these typically would not be as high as those in a launch abort scenario, but because they would be applied to deconditioned individuals, they may have more significant physiologic effects. Radial acceleration. Radial acceleration involves a change in direction without a change in speed. In particular, for an object traveling in a circular course, radial acceleration describes the inward or centripetal acceleration towards the center of the circle: 2

a = v /r

(1.7)

where a = radial acceleration (in m/s2), v = velocity about the circular course, and r = radius of the circle. The force that produces the radial acceleration is balanced by a pseudoforce

acting on the body in the opposite direction of angular acceleration (outward), the centrifugal force: Fc = mv2/r

(1.8)

where Fc = centrifugal force (in N), v = velocity about the circular course, m = the mass of an object in kg, and r = radius of the circle. From the standpoint of human exposures, significant, multiple-G radial accelerations are experienced in human-rated centrifuges, in which a rigid moment arm holds a crew fixed to the center of rotation, and high-performance aircraft, in which engine thrust applied in a constant direction and aerodynamic lift forces circularize the path. Loads of 1–12 G can be incurred by piloted aircraft, with the centrifugal force applied to the pilot in the +Gz body orientation causing the well-known adverse effects on the hydrostatic blood column. For a spacecraft that is free of the atmosphere, such radial motion and forces are fairly untenable because of the huge expense in propellant necessary to apply thrust to support constant directional change. The one caveat, however, is the Space Shuttle, which effectively becomes an aircraft upon landing. A turn around an imaginary heading alignment circle aligns the Shuttle for final approach to land, incurring a force of between 1.0 and 1.8 sustained +Gz on its upright-seated occupants. Although this force is small compared with that on occupants of high-performance aircraft, the cardiovascular deconditioning and relative plasma-volume depletion characteristic of returning space flyers renders them physiologically equivalent to terrestrial pilots experiencing several Gs. The major implications of radial acceleration for human space flight relate to the provision of artificial gravity, as discussed in the next section. Angular acceleration. Angular acceleration involves change in rotation rate about an axis passing through the body, as might be incurred in a rotating chair or rolling an aircraft. Angular motion may be expressed in degrees of rotation, revolutions, or radians, where one radian is one revolution (360 degrees) divided by 2π, or about 57.3 degrees. Angular velocity and acceleration are given by: w = (θ2–θ1)/t or dθ/dt

(1.9)

a = (w2–w1)/t or dw/dt

(1.10)

where ω = angular velocity (in radians/s), θ = angular motion, α = angular acceleration (in radians/s2), and t = time (in s). In general, angular acceleration is caused by torque, caused by a force applied at a specific distance (the moment arm) from the center of rotation: M = Ja

(1.11)

where M = torque applied to a rotating body (in N-m), J = rotational inertia (in kg-m2/radian, where the radius of the rotation is expressed in meters), and α = the angular acceleration (in radians/s2). In space flight, angular accelerations can be incurred by human occupants of a spacecraft undergoing orbital maneuvers

1. Physical and Bioenvironmental Aspects of Human Space Flight

or ballistic reentry vehicles undergoing spin stabilization (e.g., the early space capsules). These maneuvers involve some offset from the spin axis, so that components of both radial and angular acceleration are involved (although the angular accelerations involved would be fairly small). Mishaps can provide large and adverse components of angular accelerations; one such event occurred on Gemini VIII as a result of a rotational thruster that was stuck in the “on” position. In addition, crewmembers can themselves induce angular accelerations, both inside and outside the spacecraft, to levels that can produce motion sickness in the first few days of flight. Unlike linear and radial accelerations, where the resultant forces mechanically affect organs and blood columns, the angular motion itself is provocative to the neurovestibular system at thresholds greatly below those for mechanical organ effects. Angular accelerations exert these influences through their effects on the graviceptors and the visual system, both components of body motion perception and control (discussed further in Chap. 17).

Acceleration Forces and Spaceflight Deconditioning The human response to sustained acceleration in the +Gx orientation has been known for several decades. However, these responses have been characterized and documented primarily in healthy subjects in centrifuges and thus apply to normally conditioned individuals during launch. The hypokinetic states of bed rest [20,21] and actual space flight [22] and its attendant physiologic deconditioning are known to adversely influence the response to sustained accelerations. In terms of spacecraft operations, concerns focus on the pilot’s ability to make manual inputs to spacecraft control during the entry phase as well as the crew’s ability to perform physical tasks immediately after landing, when the G load incurred in the vulnerable Gz axis is fully dictated by the body’s postural positioning. As such, more conservative limits are needed for space flight than those in the aviation environment. The current NASA limit for sustained linear acceleration in the +Gz axis during landing after prolonged space flight is 0.5. This limit would also apply to other linear acceleration loads that may be encountered, including engine burns and aerobraking after transplanetary flight. The Space Shuttle returns from space unpowered and humanpiloted, placing unique performance demands on the deconditioned flight crew. Protective measures such as fluid loading, anti-G garments, active cooling, and anti-G straining maneuvers are used if needed (described further in Chap. 16). These measures have been relatively effective for Space Shuttle flights lasting up to 18 days. However, missions that last 30 days or more (considered long-duration flights in the current system, based on best available information and risk thresholds) engender other considerations with regard to crew duty rotations and the need for mission-specific hardware. For example, crewmembers returning on the Space Shuttle from a long-duration

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flight assignment, such as from an ISS or Mir station tour, do so in a recumbent seat on the Shuttle middeck that positions them on their backs with their feet forward to meet the +Gz limit noted above. (Such crewmembers are not involved in piloting the Space Shuttle during entry and landing.)

Landing Loads Landing loads associated with impact refer primarily to transient acceleration events that last 500 ms or less. Before the advent of the Space Shuttle, which lands on a runway like a conventional aircraft, U.S. spacecraft used parachutes to slow themselves as they passed through the atmosphere and landed in water. Landing loads were somewhat variable, depending in part on wind and waves, which might induce horizontal and angular components to the impact forces. A typical Apollo capsule landing with an initial vertical velocity of 9 m/s (30 ft/s) during the final parachute descent in 5-knot (2.6 m/s) winds might experience a sharp 17-G spike, peaking in the first few ms, in the vehicle’s +Gx axis. Such spikes were also incurred in the body +Gx axis and were found to be tolerable by crewmembers returning from Apollo lunar and Skylab missions. (The water impact was then followed by the real possibility of seasickness.) Soviet and Russian spacecraft have used landbased landing systems that involve a combination of parachutes, braking rockets, and form-fitting seat liners in couches with independent compression struts. A typical Soyuz landing profile induces a +Gx impact load on the crewmember of a 400-ms square-wave pulse at about 4 G in the vehicle’s vertical axis, with the possibility of an added horizontal component from wind velocity. Should the soft-landing engines fail, the parachute-and-compression-strut combination affords a +Gx transient spike of more than 20, which has been experienced on two occasions without undue injuries. These impact profiles have shown to be well within the tolerance of crewmembers returning from long-duration missions, provided that the seats and equipment are secured. During the landing of Apollo 12, a camera broke loose from its mounting and struck the pilot in the head, inflicting a minor laceration [23].

Microgravity and Partial Gravity Microgravity Probably the most pervasive physical factor associated with orbital operations, and certainly the one most associated with human space flight, is the absence of perceptible gravity, also known as weightlessness. Gravitational force is described by Newton’s Law of Universal Gravitation: F = GM1m2/r2

(1.12)

where F is the magnitude of force, G is the universal gravitational constant common to all bodies and planetary surfaces, M1 and m2 are the two masses being described, and r is the effective radius between gravitational centers. For

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LEO operations, M1 is Earth and m2 represents the orbiting spacecraft. The term “zero G” is often used when referring to LEO, although from a physical standpoint this is somewhat of a misnomer; as the above equation shows, the gravitational force is nowhere near zero. With an equatorial Earth radius of 6,378 km (3,963 mi), a spacecraft orbiting over the equator at a typical altitude of 370 km (230 mi) still experiences a relative force of gravity of (6,378)2/(6,748)2, or about 90% of what would be felt at the surface. The practical influence of gravity on an object persists until the object is removed from a dominant mass to such a distance that the force is negligible, or until forces of gravity and inertia are in balance and the object attains a state of free-fall. This is the dominant condition for orbiting spacecraft. This weightless state affects all aspects of physical activities, from liquid fuel transfer to any of a number of standard processes relying on air-fluid separation (buoyancy), such as delivering intravenous infusions free of bubbles and handling body fluids and liquid laboratory reagents. The presence of any remaining or unbalanced gravitational force will influence mechanical and fluid systems. For most scientific and investigational purposes, microgravity is determined as 10−6 G. However, below a certain arbitrary threshold, which probably resides near a few hundredths of a G (where fluid shifts and body pressure on surfaces would be imperceptible), the space flyer for all practical purposes resides in a weightless state. Although humans thrive in a 1-G environment and may be said to physiologically maintain a 1-G set point, this terrestrial set point itself actually implies a dynamic condition. Humans possess adaptive mechanisms to account for changes in body orientation with respect to the standard G vector. For example, lying down (i.e., shifting position from standing to recumbent) changes the effective G load on the hydrostatic blood column between the heart and brain from one or unit gravity to near zero. From the standpoint of cardiovascular (as well as musculoskeletal) regulation, the weightless state induces a much more constant loading condition that closely resembles the recumbent state. Entering weightlessness thus does not imply entering a completely foreign physiologic condition, and of course space flyers can endure very long periods in weightlessness. Human response to microgravity can be adequately studied only in space. Parabolic flight provides brief periods of freefall, on the order of 20–25 s, and has become a useful tool for evaluating hardware and human factors and for studying physical processes that react quickly to the absence of gravity. However, these brief periods of “zero G” alternate with periods of increased G load as the aircraft pulls out of its powered dives. The resultant oscillating G field, between zero and 1.8 G, does not invite the same possibilities for human adaptation and is provocative to the neurovestibular system in a manner different from prolonged weightlessness (see Chap. 10). Water immersion provides a suitable analog for some task-evaluation and training activities, notably EVA practice. Neutral buoyancy affords simulation of body motion

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and mass handling such that end-to-end tasks are timelined with reasonable accuracy as compared with their in-flight execution. However, rapid limb movements are limited by hydrostatic drag in neutral buoyancy, which increases in proportion to the square of velocity [24]. In addition, effects such as sinus pooling persist, a reminder that gravity is still at work on the body, and thus ‘hanging upside down’ for prolonged periods in a water-immersed suit is uncomfortable. The human response to microgravity is described in more detail in Chap. 2. Among the more quickly perceived aspects are the novel (e.g., “flying” from one place to another) and the annoying (e.g., constantly losing items that float away upon being laid aside). Along with human factors and ergonomics issues, microgravity’s influences on some of the more fundamental physical forces—including buoyancy, sedimentation, hydrostatic pressure, and convection—are relevant to life and medical sciences and are noted below. Buoyancy, the separation of substances, especially liquids and gases, by gravity owing to differences in their densities, is absent in weightlessness, leading to a more homogeneous mixing of fluids and gases than on Earth. The implications of loss of buoyancy range from difficulty in handling fluids to loss of standard air-fluid levels in diagnostic imagery. As an example, one cannot expect to see the familiar gastric bubble on chest or abdominal radiography. Sedimentation, the downward force, or physical separation of liquids and solutes caused by the linear acceleration of gravity, is typically opposed by buoyancy and frictional forces and is described by the expression: Fs = mg – Fb – Ff

(1.13)

where Fs is the sedimentation force, m is the mass of a solute, g is the linear acceleration of gravity, Fb is the buoyancy force, and Ff is the frictional force. Sedimentation is also absent in weightlessness, with the corresponding implications again including homogeneous mixing, this time between liquids and solutes or suspended particles. For example, a urine sample centrifuged for microscopic analysis must be spun and read before the physical separation induced by the centrifugal force is undone by the lack of gravitational force. Also, contaminants are not easily separated and must be filtered rather than eluted away from a supernatant unless centrifugally separated. On a more macroscopic level, atmospheric particles do not settle out from spacecraft cabin air and as such may be inspired or inadvertently ingested by crewmembers. Hydrostatic pressure is the force F of a liquid caused by its weight standing above a certain surface area A, expressed by: Ph = F/A

(1.14)

and Ph is linearly proportional to g. The total pressure acting on a fluid column consists of hydrostatic plus atmospheric pressure. In weightlessness, hydrostatic pressure is reduced to atmospheric pressure and any other induced forces, such as centrifugal or pump forces. The physiologic implications are that no changes in pressure in the hydrostatic blood column

1. Physical and Bioenvironmental Aspects of Human Space Flight

accompany changes in position, and blood pressure above the heart is dominated more by intrinsic cardiovascular dynamics such as pumping forces and vascular constriction and dilation. This pressure can be added back in weightlessness by using centrifugal forces. Convection is the dynamic movement of fluids and gases that facilitates heat transfer and affects mixing as well. Convection can be based on density variations and thus be driven by buoyancy, or it can result from forced or induced flow. Standard terrestrial buoyancy-driven convection is the force that facilitates candle burning, involving movement of oxygen to replenish the oxygen that is locally consumed and circulation of volatilized fuel and combustion products. Without convection, a flame in weightlessness will consume the oxygen in close proximity and if forced airflow from an outside source or the means to propagate along a fuel source to an oxygenated area is not provided, the flame will extinguish itself. In microgravity, forced convection is important to make up for the absence of buoyancy-driven convection for such processes as dispersion of metabolically produced CO2 and body cooling. The basic equation for convective heat transfer is: C = hc(t1 – t2)

(1.15)

where C is the rate of heat transfer (typically watts/m2 of surface area), t1 and t2 are the temperatures of the body and fluid medium, and hc is the convection coefficient, which includes consideration of fluid movement. Other forces and processes are not altered in weightlessness. Heat transfer may still occur via conduction, radiation, and evaporation, and gases and liquids may still be mixed by diffusion. Terrestrially, diffusion exerts a lesser influence on mixing and particulate dispersion than buoyancy, convection and sedimentation, but this is one of the more prominent mixing forces in zero G. In a pressurized LEO module lacking any artificial physical agitation, diffusion alone will drive the dispersion of an atmospheric contaminant from a point source throughout the remainder of the volume. This process is slow enough relative to physiologic CO2 production that local areas of increased concentration will build around a crewmember, who may then manifest signs of CO2 toxicity in an unventilated module. Similarly, for a crewmember breathing supplemental oxygen in the same circumstance, the oxygen-enriched exhalation may produce a local flammability risk. Induced air movement is a fundamental requirement for human occupants of a weightless habitat. The human body is a highly active and dynamic machine, endowed with countless processes to facilitate mixing and transport. Circulation of blood and other fluids, active transport and diffusion across membranes, nerve conduction, and chemotactic mechanisms are basically left to function intact in weightlessness. It is mainly on the macro level that weightlessness exerts its primary effects. These effects, such as unloading of the hydrostatic blood column, thoracic fluid shifts, and unloading of otoconia and other gravitational sensors, give rise to corresponding secondary effects such as desensitization

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of cardiovascular regulatory mechanisms, endocrine changes associated with volume changes, and neurovestibular disturbances. It should not come as a particular surprise that humans function as well as has been observed in weightlessness. However, an awareness of the above forces and how they influence human physiology is necessary for filling in the substantial gaps remaining in our understanding of zero G physiology. A basic understanding of this physiology enables a practical approach to various medical problems involving fluid handling, heat transfer, gaseous dispersion, and biomechanics.

Fractional G Partial gravitational fields, that is, fractional relative to Earthnormal, must be thought of on a graded scale with several practical threshold values. From the human standpoint, threshold of detection stands at the far end, where in a spacecraft the crewmember will notice objects (including himself) resting on a surface oriented opposite to the acceleration vector. This probably occurs with a few hundredths of G. Other potentially relevant thresholds include effective air-fluid separation, a force sufficient to support an active gait, and passive loads sufficient to influence bone and muscle mass. Sustained partial G is of interest for the human space flyer in two main areas: planetary surfaces and provision of artificial G as a countermeasure to the deleterious effects of prolonged exposure to weightlessness. Planetary surface forces most relevant to us currently are lunar (1/6 G) and Mars gravity (about 1/3 G), and possibly smaller fields such as may be encountered during short-term flights to asteroids (or other planetary satellites). People have worked successfully on the lunar surface despite the changes noted in biomechanics and energetics [25], although none have stayed long enough to effect detectable changes in physiologic parameters, particularly bone and muscle mass losses. Given the demonstrated feasibility of lunar surface exploration, Mars should not be problematic for exploration efforts from the practical human standpoint; the major issue is that it will most likely follow prolonged exposure to weightlessness. This implies neurovestibular deconditioning, orthostatic intolerance, and bone and muscle atrophy commensurate with the amount of time spent in microgravity during the voyage. Provision of artificial G as a countermeasure to deleterious effects of weightlessness has been considered for many decades. Shipov has written an excellent review of these considerations [26]. Artificial G may be afforded by rotating a spacecraft or a structure, which may be contained within a non-rotating spacecraft, to provide continuous centrifugal force. This could be employed for a stable platform, such as an orbiting station, or an interplanetary spacecraft. Expressed in terms of angular velocity ω, the pseudoforce known as centrifugal force conveniently describes rotational artificial G and is expressed by: Fc = mw2r

(1.16)

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It is apparent that altering the rotational velocity and radius components influence two extreme ends of a practicality continuum. At the structural end, very large formations and masses well beyond anything built in space thus far would be required to maintain a relatively low rotational rate while providing Earth-equivalent artificial G. For example, a structure with a rotation radius of 900 m with an angular velocity ω of one revolution per minute (about 0.1 rad/s) would be required to provide Earth-normal gravity [27]. Various approaches have been elaborated, from very large structures to distinct capsules joined by a tether and spinning about a central axis. Problems include limitations in structural mass, tether performance and reliability, abort capabilities for interplanetary spacecraft because of a limited number of spin/de-spin cycles, mishaps that might require EVA repair, and interference with astronomical observations. It is much more feasible to increase rotational velocity for short-radius structures to obtain a desired force. However, this is bounded by the biomechanical end associated with human tolerance of rotation. A significant implication of rotation to a human occupant is unwanted Coriolis acceleration effects, induced with linear motion in a rotating reference frame. Coriolis acceleration Ac and force Fc can be expressed by: Ac = 2(v × ω)

(1.17)

Fc = 2m(v × ω)

(1.18)

where v is the linear velocity of a moving object in m/s, ω is the angular velocity of a rotating system in rad/s, and m is the mass of an object in kg. Coriolis forces will affect the motion of any object or occupant, complicating motion sensation, motor control, and mass handling. Humans are equipped with sensitive multiaxial acceleration sensors in the form of semicircular canals and otoliths, designed to work optimally to sense motions and changes in body orientation in a static 1-G background field. In a rotating structure, head movement will change the orientation of these sensors to the direction of rotation and induce an unwanted transient input suggesting whole body rotation. These are so-called cross-coupled responses to angular motions in two planes. Cross-coupled Coriolis responses are known to be annoying and potentially provocative to humans. Effects and symptoms are greatest when moving in a plane perpendicular to the axis of rotation, and include neurovestibular instability, vertigo, nausea, emesis, and disorientation. Preliminary U.S [28–30]. and Russian [31,32] studies in the early 1960s with human subjects have proven the capacity for sustained tolerance to angular acceleration in rotating rooms, but this tolerance was limited by neurovestibular disturbances and motion disorders at rotation rates well below what might be required to produce a significant fractional G level (when the pervasive Earth G component was subtracted). It was generally thought that rotational rates must be limited to 4–5 rpm to avoid incapacitating vestibular and motor effects. Subsequently, it was demonstrated that gradually increasing the

rotation rates will allow tolerance of these sustained rates [33] up to 10 rpm [34]. With stepwise increases in rotational forces, it may be possible for crewmembers to adapt to rates whereby structures a few tens of meters in diameter could provide useful and protective levels of G. For example, a structure with a 10-m (33-ft) rotational radius at 10 rpm would provide 1.1 G at the rim; a 15-m (49-ft) radius at 7 rpm would provide 0.82 G. Aside from potentially inducing cross-coupling effects and neurovestibular dysfunction, a rotating structure implies a gravity gradient extending from the rotational hub to the rim. The perception of this gradient would be most pronounced with shorter radii, of which a human subject’s height is a significant fraction. Considering a rotating crew module with a diameter of 7.2 m (23 ft) and a rotational radius of 3.6 m (11.8 ft), a 1.8-m (71-inch) crewmember would assume half of this height when standing. The force at the head will be half of the force at the level of the feet, introducing a gradient of 50% over the crewmember’s standing height. This gradient induces significant motor control and mass handling challenges as the crewmember bends and transitions between standing and seated or horizontal postures. A rotational radius longer than 12.2 m (40 ft) would be required to produce gravity gradients below a recommended 15% for a rotating spacecraft or centrifuge [35]. In addition, an overall additive velocity effect serves to increase weight while ambulating in the direction of rotation and to decrease weight in the opposite direction. These anomalies, along with mass handling and motor control challenges, suggest that comprehensive adaptation to such rates may be difficult. However ground studies have suggested that humans can gradually adapt to these higher rotational rates with regard to head and arm control along with tolerance of cross-coupling effects [36]. An alternative to sustained rotation of a habitation module is provision of short periods of artificial G more intense than one G. Various schemes involving human-rated centrifuges, some human-powered to couple cardiovascular countermeasures with this loading, have been proposed [37–39]. Combinations of time and multiples of G could be determined to lead to a “gravitational acquired dose” curve [40] specifically oriented toward maintenance of bone and muscle mass. The most elegant solution for interplanetary flight, most likely relegated to the far future, is provision of a linear G field in some significant fraction of Earth gravity. This implies constant linear acceleration, which might be provided by a highly advanced propulsion system. Such advanced systems would be needed to reach and practically sustain operations on desirable targets of interest beyond Mars, such as asteroids. Linear G would enable a constant vertical reference with passive exposure to the acceleration load, broken only at some midcourse point when the ship’s engine is powered down to turn and begin the deceleration burn. Ironically, the ensuing sudden exposure to microgravity might imply a mid-mission risk of space motion sickness, albeit a transient one. Assuming that large stationary platforms may someday be built at departure and destination points that can be spun and are large

1. Physical and Bioenvironmental Aspects of Human Space Flight

enough to avoid undesirable Coriolis effects, a propulsion concept affording linear G offers the best solution for long transit times. For rotational and linear G, it must be determined what fraction of unit gravity would be required to maintain bone and muscle. One G may be considered the gold standard, but a lesser fraction is more in keeping with attainable structures, future propulsion, and energy cost. During in-flight artificial gravity studies with centrifuged rats, Yuganov et al. observed a threshold level of 0.15 G for bioelectric activity, which steadily increased in parallel with transverse G forces up to a level of 0.28 G. Between 0.28 and 0.31 G, the bioelectric activity was equivalent to what was seen in ground controls, and no further increase was seen up to 0.7 G [41]. In an investigation to determine the minimum fractional G load that would sustain bone in hindlimb-suspended rats, Schultheis and colleagues determined that 0.25 G may be equivalent to 0.75 G in preserving bone formation [42]. From the standpoint of human factors, studies in parabolic flight of progressive G levels have demonstrated that for walking, mass handling, and mechanical tasks such as bolt tightening, very little gain is seen beyond 0.2 G [43]. Although much research remains to be done, provision of a constant force of perhaps 0.3 G may enable fairly normal biomechanical activity, and in combination with modest physical countermeasures augmented with heavy resistive exercise, may well maintain bone and muscle mass at near Earth-normal levels. It is hoped that this critical focus of investigation will be addressed with the laboratory facilities on board the ISS.

Radiation Sources For what has been found to be such a pervasive entity in the universe and among the more important factors limiting human exploration beyond Earth, radioactivity was discovered relatively recently. In 1895, Konrad Wilhelm Roentgen discovered that invisible, penetrating rays (x rays) could be produced by electrically exciting a low-pressure gas. Radioactivity was discovered and first described a year later in 1896 by Antoine-Henry Becquerel while he was experimenting with uranium salts. Becquerel observed that these salts could blacken a photographic plate in the absence of light, and he later determined that this was caused by the emission of energetic particles from the element uranium. Over the ensuing years, many other emitting substances were identified and their radioactivity characterized. As sensitive detectors were developed, a background flux of radioactivity was noted to persist in the absence of known emitters. Some of this radioactivity was eventually attributed to naturally occurring substances in the ground. However, balloon experiments conducted between 1911 and 1913 by V.F. Hess in which these detectors were flown to altitudes of 9,000 m showed a tenfold increase in this background flux over surface values, suggesting an extraterrestrial source [44]. These observations

19

were bolstered by further balloon experiments to 15,000 m in 1925, and prompted R.A. Millikan to term this background flux cosmic radiation. The term radiation can be broadly defined as the emission and propagation of waves transmitting energy through space or a medium and includes electromagnetic energy (X rays, gamma rays, visible light, radio waves, etc.) as well as charged particles (protons, electrons, alpha particles, etc.) and uncharged particles (neutrons). Radioactivity refers to a certain type of radiation emitted by a specific substance, typically from decay of unstable nuclei. These particles and waves carry a wide spectrum of energies and may interact with a medium they traverse. If this interaction involves collisions with atoms or molecules such that imparted energy expels electrons and creates new charged ion species, it is termed ionizing radiation. Radiation may induce damage directly, as by a high-energy particle imparting energy to a cellular molecule, or indirectly, by inducing the formation of secondary ion species through collision events. These secondary particles may then go on to interact with biological material. High-energy electrons traversing a dense medium, such as metal structures, may interact with the material, and, in the process of slowing and imparting their kinetic energy to the material they induce the formation of X rays. This phenomenon is termed bremsstrahlung (German for “braking radiation”) and has obvious implications for shielding considerations. Non-ionizing radiation, such as from ultraviolet light and radiofrequency energy, may also cause tissue damage from burns and local heating effects. Throughout the early experiments mentioned above, adverse health effects from radiation were observed, including local effects such as eye irritation, skin burns, and dermal necrosis. Over time, more sinister effects such as blood and lymphoid malignancies and solid tumors were noted. Many of these effects were directly related to the overzealous use of X rays, in both diagnostic and therapeutic applications. Despite the significant energies involved, human senses cannot detect, and thus cannot avoid, radioactivity and most forms of electromagnetic radiation. Rather, the damaging secondary effects consisting of physical, chemical, and biological changes are what are eventually perceived. As such, dose-response relationships were slow to be identified, especially with regard to malignancies arising after a prolonged latency period. The establishment of the International Council for Radiological Protection, along with international acceptance of common monitoring units in 1928, led to a more systematic understanding of this relationship and the means for monitoring and mitigating radiation-induced health problems [45]. We have learned that space is a radiation environment, or more properly that Earth, thanks to its protective atmosphere and magnetic field, is a radiation haven, a shelter from the effects of products of the most fundamental processes in the universe. These processes include the formation, life, and death of stars, solar system accretion, and stellar and planetary magnetism. Radiation exposures for humans in space flight stem from three main natural sources: galactic cosmic

20

rays, solar particles and electromagnetic radiation, and geomagnetically bound charged particles. In addition, secondary particles (e.g. neutrons) are known to be produced from the interaction of primary particles with spacecraft structures. Future artificial sources (power sources, detonation of nuclear weapons) may also be considered. The character of radiation sources, their biological effects, and risk mitigation strategies are discussed in detail in Chap. 23. The present discussion will be limited to the physical distribution of the major ionizing radiation sources pertaining to human space flight.

Galactic Cosmic Radiation A background flux of high-energy-particle radiation is present in interstellar space. This galactic cosmic radiation, or GCR, most likely originates in supernova explosions, in which massive quantities of nuclei from hydrogen (H) and helium (He) and a smaller proportion of heavier nuclei are ejected in the stellar debris. Kinetic energy is imparted in the initial explosion, and these charged particles may be further accelerated by interstellar magnetic fields to near light speed (3 × 108 m/s). Although supernova explosions are point events, the distribution of GCR seems to be isotropic because of galactic magnetic field lines that prevent travel along straight paths. It is estimated that supernovae can maintain the observed flux of GCR if such explosions occur, on average, every 50 years in our galaxy [46]. GCR consists primarily of protons or H nuclei (about 90%), and alpha particles or He nuclei (about 9%), with the remaining species being heavier elements in ionized states. Compared with terrestrial radiation sources, which might generate detectable counts of many millions of particles per cm2 per second, the flux from GCR is relatively low, at a few species per cm2 per second. However, GCR species contain massively higher amounts of energy. These energies are typically denoted in electron volts, or eV, which is a convenient unit of measure for particle physics. One eV is defined as the energy gained by an electron accelerating between two plates, 1 m apart, with a potential difference of 1.0 volts; one eV = 1.6021 × 10−19 joules (J). Whereas radium may emit energies on the order of several mega eV (MeV, where mega = 106), GCR particles must often be measured in the giga eV range (GeV, where giga = 109). The most abundant GCR species are protons with energy of about 2 GeV, and the remainder consists of an exponentially diminishing flux of progressively higher energy species, up to 1011 GeV (1020 eV). To put this energy into perspective, a single cosmic ray particle at the very high end of the energy spectrum, with 1.5 × 1020 eV, carries 25 joules, sufficient to raise 1 kg a height of 2.5 m on Earth [47]. GCR is effectively attenuated by Earth’s atmosphere, which has a thickness equivalent of 1,000 grams/cm2, and by powerful geomagnetic fields to a relatively low flux at the surface. Local solar system effects also modulate GCR. The solar wind and interplanetary magnetic field lines distort the paths of charged GCR particles with energies less than 1 GeV

M.R. Barratt

[46], causing them to lose significant energy and some to be deflected away. This modulation varies with the biphasic 22-year solar cycle so that at solar maximum, the GCR bathing Earth is about half of the flux at solar minimum [48]. Particles with energies exceeding 10 GeV are minimally susceptible to the influence of the solar wind and magnetic fields and continue unimpeded.

Solar Radiation and Solar Cosmic Particles The Sun, with a radius of 6.95 × 105 km, is a generator of massive energies. Fueled by the fusion of H into He and heavier nuclei at its core, the Sun radiates energy at a rate of 3.86 × 1026 W, virtually all in the visible light spectrum. Along with electromagnetic radiation, which among other things affords our planet light and warmth, a continual emission of electrically neutral plasma known as the solar wind streams outward. Free electrons are electrically balanced primarily by protons, as well as alpha particles and some heavier ionic species, moving in magnetic field lines that spiral outward because of the Sun’s rotation. These particles carry the Sun’s magnetic field into the solar system and are thus distributed in an anisotropic fashion. Irregularities in the solar corona alter plasma velocity and density. The velocity of these particles as measured near Earth ranges 300–700 km/s, with particle densities of 1–20/ cm3 [49]. Solar wind particles are of low energy, typically about 1,000 eV (1 keV). In contrast to the relatively gentle flux of the solar wind are solar cosmic rays (SCR), particles similar to those of the solar wind but of much higher energy. These stem from solar flares, which are associated with large magnetic disturbances on the surface, and carry energies typically in the MeV range and possibly up to 20 GeV. These flares also radiate in the electromagnetic spectrum, with such radiation ranging from gamma rays and X rays through ultraviolet and long-wavelength radio waves. Along with electromagnetic emission and accelerating atomic particles, solar flares induce a blast wave that propagates through the solar wind at 1,500 km/s. The relative energy distribution is such that about half is invested in the electromagnetic emission, half in the blast wave, and only about 1% in the actual SCR. Most of the particles detected near Earth are protons, and a smaller fraction consists of He nuclei. A large electron flux is stemmed by loss of energy in exciting radiofrequency bursts in the corona, the Sun’s outer atmosphere. SCR particles at the high end of the energy range reach Earth vicinity 20–30 min after the first optical evidence of the flare can be seen, with periods of maximal SCR flux lasting a few hours. Clouds of lower energy particles and solar wind disturbance reach Earth in 6–24 h. A diminishing flux of high-energy particles followed by lower-energy particles can be detectable for several days after a large flare. The vast majority of SCR particles is effectively stopped by the geomagnetic field and poses little threat to crewmembers in LEO in typical orbital inclinations. The main hazard with regard

1. Physical and Bioenvironmental Aspects of Human Space Flight

to human space flight arises for activities outside of the geomagnetosphere, such as interplanetary transit, occupation of a Lagrangian point station, or lunar surface activities, where radiation flux could increase by a thousand-fold to a millionfold. A minimally shielded crewmember, such as one engaging in EVA operations, could receive a lethal dose of ionizing radiation in a few hours during a major solar flare. Solar flares correlate with the 22-year biphasic solar cycle, the most frequent and intense being at or near the solar maximum. The resulting periods of increasing probability of solar flare occurrence can drive some operational considerations for long-term human space flight activities. However, although a buildup may be detected early enough to warn a crew to take shelter in a radiation-hardened structure, buildups cannot be reliably forecasted. As for solar wind emissions, SCR emissions are anisotropically projected into the solar system, in part because of the regionality of their sources on the solar surface. Most flares producing high-energy particles seem to originate in the Sun’s western hemisphere [44]; this coupled with the Sun’s rotational rate of 25 days at the equator (slower at higher latitudes) means that not all flares are visible from Earth. For a spacecraft not in Earth’s vicinity, e.g., one en route to Mars, a major flare detected on Earth may not be problematic for or even detected by the spacecraft; however the opposite is also true. Transplanetary spacecraft should be equipped with the means to detect sentinel electromagnetic and particle emissions preceding high particle flux and guide appropriate crew responses. Strategically placed solar-orbiting spacecraft with electromagnetic and particle detection capability could also relay such information to spacecraft and Earth, analogous to ocean weather buoys.

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Van Allen to study GCR flux above Earth’s atmosphere. Unexpectedly, this and subsequent Explorer and Pioneer space probes led to the discovery that the external field lines are heavily populated with highly energetic charged particles. Two main belts of intense trapped radiation, with fluxes many orders of magnitude over that of the background GCR, were identified [51]. These now bear the name of their discoverer, the Van Allen belts. The Van Allen belts are arranged as two concentric doughnuts centered on the geomagnetic equator (Figure 1.10). Two distinct concentration bands with a definitive gap between them have been mapped, although this gap is not totally devoid of particles. The inner belt begins at roughly 1,000 km in altitude and extends to 5,000 km; the outer belt extends from about 15,000 km to 25,000 km at the equator. The charged species populating the Van Allen belts are essentially captured particles from the solar wind and solar cosmic rays. Inner belt protons most likely originate from interaction of GCR with atmospheric species, inducing the formation of short-lived neutrons. Some of these neutrons decay into protons and electrons, which are then bound by the geomagnetic field. Eventually, they are removed by interaction with atmospheric molecules; the relative rates of removal and replenishment drive the concentrations observed. Outer belt particles originate from interaction of the solar wind with the magnetosphere, in which a small fraction of these particles leak into the field lines rather than being deflected away. The outer belt is more susceptible to the dynamic effects of the solar wind and SCR and so may vary considerably in

Geomagnetically Bound Radiation Magnetism and Earth’s magnetic field have been known and exploited for centuries by ocean navigators. More recent is the appreciation that Earth is endowed with a dipolar magnetic field, with field lines emerging at the North magnetic pole and re-entering at the South magnetic pole. This dipolar magnetic axis is offset by some 12 degrees from the rotational axis. Most of the geomagnetic field originates from Earth’s center, where conducting liquid iron of the outer core flows around the solid iron inner core, with the motion probably driven by convection resulting from heat flow from the core to cooler outer layers. Movement of the conducting fluid around the inner core’s preexisting magnetic field, most likely a remnant of core formation, induces an electric current, which in turn induces a secondary magnetic field much stronger than the original [50]. This is known as the geomagnetic dynamo model. Although much remains to be learned about the intrinsic properties of the geomagnetic field, the first landmark scientific discovery of the space age involved extraterrestrial implications of these field lines. In 1958, the first successful U.S. satellite, Explorer 1, lofted a Geiger counter in an experiment devised by James Alfred

Figure 1.10. The Van Allen radiation belts, showing relative distribution and shape of the inner and outer bands of geomagnetically bound charged particles. Darker shaded areas denote regions of greater particle density. The orbital track of a typical crewed spacecraft in low Earth orbit is seen to be well below the inner belt

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concentration. All bound particles travel along geomagnetic field lines, spiraling around these lines and bouncing back and forth between northern and southern mirror points with a period of 0.1–3 s. Inner belt particles typically carry high energies, with protons of 50 MeV and electrons of 30 MeV. The flux may be as large as 2 × 105 per cm2 per second, higher than the GCR flux by a factor of 104. These energies and quantities would constitute a grave radiation hazard to the occupants of spacecraft and their systems if sufficient time were spent in zones of high concentration. Most human platforms in LEO, such as the ISS at about 375 km altitude, operate well below the floor of the inner belt. However, the borders are not sharply defined, and a measurable increase in flux is observed with increasing altitude. In addition, an offset of the geomagnetic and rotational axes causes a defect in the basic shape of the inner belt in which it dips down to a lower altitude. This defect, known as the South Atlantic anomaly (SAA), consists of a region in which the radiation flux at a relatively low altitude is equivalent to that at a much higher altitude. The shape and boundaries of the SAA change with altitude. A spacecraft at 225 km altitude will experience a 100-fold increase in radiation flux while passing through the SAA, whereas a 1,000-fold increase would be experienced at 440 km altitude [52]. The greatest fraction of the radiation dose delivered to LEO crewmembers results from orbital crossings of the SAA. Although containing large quantities of charged particles, the geomagnetic field serves the vital role of shielding Earth from the brunt of the solar wind and SCR as well as from lower energy GCR. The shielding afforded depends on position relative to the dipole; with the shape of the magnetic fields shown in Figure 1.10, higher-inclination orbits become progressively less protected from GCR and SCR. A polar orbiting spacecraft is exposed to radiation flux similar to that in free space.

Planetary Surface Factors

M.R. Barratt

considerations for humans will likely be restricted to the moon and Mars. Table 1.3 [46,53] shows comparisons of physical attributes of Earth, the Moon, and Mars. Lunar exploration efforts, although brief, were highly successful, implying that more extensive and long-term efforts could be undertaken. However, particular medical considerations are associated with surface activities, some of which were suggested during our brief time on the moon. Two of the major factors underlying these considerations, partial gravity and surface dust, are discussed in the following sections. Radiation sources have been noted in a previous section, and Chap. 23 will cover aspects of surface dosimetry and shielding.

Partial Gravity Even a fraction of Earth gravity offers a tremendous convenience to human occupants. Locomotion in a familiar vertical reference frame is possible, and it is easier to adapt terrestrial tools and processes to this environment. Fluids and gases can separate, and items remain where they are placed. Some of the fundamental physiologic problems associated with prolonged weightlessness, such as bone demineralization and muscle atrophy, may be mitigated to some extent by even a partial gravitational field. Along with fractional Earth gravity, the activities inherent in exploration and exploitation of resources will likely favorably augment this force with regard to bone and muscle loading. Such activities will include use of heavy EVA suits, carrying heavy loads, and operating tools for construction and excavation. In addition, although partial gravity fields should not be considered benign environments, physical countermeasures are simplified by the existence of a gravitational vertical and the ease of increasing resistive force loads. However, the presence of partial gravity also restores, to some extent, a potential for injury that is largely absent in microgravity.

TABLE 1.3. Selected physical attributes of Earth, Earth’s Moon, and Mars. Earth

By far the greatest portion of human spaceflight activity has occurred in the weightlessness of LEO, with a small fraction of time spent on the lunar surface during the U.S. Apollo missions. However, activities such as these are a much-anticipated aspect of future endeavors, without which we are limited to microgravity investigations and Earth-observation studies. On planetary surfaces, we trade such problems as weightlessness, attitude control, and orbital thermal cycling for a stable base to support more familiar locomotion, allow construction, and provide raw materials for use. Inherent in this situation is a greater degree of isolation, both from the standpoint of distance from Earth and the additional “gravity ladder” that must be climbed to leave the new surface. Because of the extreme distances and inhospitable radiation environments associated with the moons of the giant planets, near-term surface

Moon

Mars

Solar distance, semi-major axis (×106 km) Radius, equatorial (km) Surface gravity (relative to Earth-normal) Escape velocity (km/s) Atmospheric pressure, surface

149.6

149.6

228

6,378 1.0

1,738 0.16

3,394 0.39

11.18 760 mmHg

2.38 Essentially 0

Atmospheric composition, major constituents Rotational period (sidereala) Rotational period (solar) Sidereala period (days)

N2 78%; O2 21% 23.93 h 24.00 h 365.26

–

5.03 4.8 mmHg global mean CO2 95.3%; N2 2.7% 24.62 h 24.65 days 686.98

27.3 days 29.53 days –

Source: Data from Lodders [53] and Zeilik [46]. a The term sidereal refers to time relative to the stars; solar is referenced to Earth’s Sun.

1. Physical and Bioenvironmental Aspects of Human Space Flight

Terrestrially, most major trauma is associated with forces in events such as motor vehicle accidents and falls. Surface vehicles were used on the Moon and will certainly be required for further lunar and Mars exploration. Falls were not uncommon during the lunar EVAs, although those falls were not associated with injuries [54]. Traversing more challenging terrain might easily lead to more serious falls, augmented by unfamiliar body mechanics. Carrying loads and obtaining samples may induce muscle strain injuries, as occurred during the core drilling operation on one lunar mission [23]. Construction activities could also lead to penetrating trauma whereby an EVA suit environment is compromised and injury is sustained. These are the primary factors that drive a medical capability involving the means to manage orthopedic and penetrating trauma, as well as decompression disorders, beyond what is required for LEO.

Surface Dust The surfaces of the Moon and Mars are largely covered with loose, unconsolidated rock material known as regolith. (This term may also be applied to terrestrial surface rock and soils, although the extraterrestrial implication is more common.) Lunar regolith is fairly well known from first-hand observations and sample analysis; it consists primarily of fragments less than 1 cm in size produced by shattering of material from meteorite impacts. Local lunar regolith formation begins with a nearby large impact that deposits large boulders and coarse material excavated from bedrock. Over geologic time, smaller impacts erode and fragment the coarse material, forming a fine component, and given enough time, the original coarse material disappears. Regolith can be 4–5 m thick in the lunar mare and as much as 10–15 m thick in the lunar highlands. In a mature regolith, the subcentimeter component is called lunar soil. The average grain size of analyzed soils is between 60 and 80 µm [55]. During the Apollo missions, lunar dust established itself early as a nuisance because of its physical properties and associated difficulties in its control and cleanup. With the lack of an atmosphere and in low-gravity conditions, lunar dust is easily dislodged from the surface by walking, by operating machinery, or by engine plumes. Lunar dust has a very low electrical conductivity and is prone to building up an electrostatic charge, with subsequent electrostatic deposition on surfaces. It is hard, abrasive, and easily embedded in looseweave fabrics. Although largely chemically inert, lunar dust did evoke symptoms of respiratory irritation in some crewmembers. Dust was introduced into the cabin atmosphere after ingress from a surface EVA, adhering to the suits and equipment. Scientist pilot Harrison Schmidt noted breathing irritation associated with dust upon returning to the Lunar Module cabin after the first EVA [56]. Some crewmembers used expectorants to facilitate clearance of the particles from the upper airways. Alan Bean, during the Apollo 12 mission, observed that “after lunar

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liftoff…a great quantity of dust floated free in the cabin. This dust made breathing without the helmet difficult, and enough particles were present in the cabin atmosphere to affect our vision” [57]. These effects seem to have been acute albeit mild reactions to airborne dust particles deposited in and cleared from the upper airways. No lasting respiratory effects were seen in returning Apollo crewmembers. However, the question arises regarding the propensity of lunar dust to cause chronic pulmonary diseases after prolonged exposures, similar to terrestrial occupational lung diseases. Pneumoconiosis—interstitial lung disease caused by dust exposure and the lung’s subsequent reaction to the dust—is caused by exposures to silica, coal dust, and asbestos (fibrous silicate) dusts. Classic silicosis results from moderate exposures to silica dust (SiO2) over many years, involving deposition of small particles into the alveoli and uptake by alveolar macrophages. Subsequent activation of alveolar macrophages causes them to release oxidants, cytokines, and other mediators that injure surrounding tissue and stimulate fibrosis. Typically, deposition occurs with particles in inspired air of 5 µm or smaller in size, with 1-µm particles having the best chance of deposition [58]; particles larger than 10 µm in diameter are effectively filtered by the upper and lower airways. Deposition may be enhanced for particles with electrostatic charges [59]. Several factors make pneumoconiosis from lunar dust unlikely. Silicate minerals, consisting of repeating crystalline structures of nonfibrous SiO4, are abundant and contribute 90% of the volume of most lunar rocks. By contrast, silica minerals, associated with terrestrial silicosis and characterized by the repeating formula SiO2, are fairly rare on the Moon [60]. In addition, the particles in the bulk of naturally occurring lunar dust are large enough to preclude their deposition in air exchange structures. More than 80% (by weight) of dust grains from most Apollo samples are larger than 20 µm, and most of the smaller particles are still larger than 10 µm [55]. Certainly in the near future, exposures for the periods associated with terrestrial pneumoconioses are not anticipated. The main health hazard associated with lunar dust will be probably be interference with environmental and life support systems and pressure seals as well as a greater chance of foreign bodies in the eye because of reduced gravity and possibly local skin irritation from direct contact with this abrasive material. However, bearing in mind that terrestrial occupational lung diseases were largely unanticipated, simple pulmonary monitoring for long-term lunar or Mars inhabitants may be prudent. Periodic pulmonary spirometry and chest x ray or an equivalent imaging modality could be performed on site. In any case, means of dust control to minimize levels in the habitable atmosphere will be necessary both for crew health and mitigating adverse affects on sensitive systems. Unlike the lunar regolith, which is formed by repeated impacts, Martian regolith is produced by physical weathering

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and chemical activity [61]. Mars surface dust, although only studied remotely, should be somewhat easier to control than lunar dust, given the presence of a low pressure atmosphere and a somewhat greater gravitational field. A particular hazard condition on Mars is the known ability of dust particles to become windborne. Wind speeds are seasonal, being lowest during the Martian summer, at 2–7 m/s, and highest in autumn and winter, at 5–10 m/s. Despite the rarefied atmosphere, sufficient dynamic pressure periodically builds to cause large and even global dust storms. During such storms, winds speeds can increase to 30 m/s. Such a dust storm could potentially halt surface activity for a period of several weeks to months and threaten sensitive systems. However, the observation that the solar-powered Viking Landers were able to function on the surface for several years during the late 1970s suggests this problem will not be insurmountable.

Conclusions This chapter was intended as an overview of the basic body of information required of the space medicine practitioner to understand the adaptive and operational environment of space flyers. An understanding of the physiologic and medical implications of this environment enables the practitioner to provide optimal medical support. This information should provide a foundation for discussions of physiologic and psychological processes associated with space flight and allow the response to medical events to be placed in proper context. Understanding this context also prepares the spaceflight surgeon to serve as a consultant in space program organizations, where human needs must fit into mission parameters and priorities.

Acknowledgments The author thanks Drs. Kevin Ford, Stanley Love, and Wendell Mendell for their thoughtful reviews and constructive comments while this chapter was being written.

References 1. Strughold H, Harber H, Buettner K, et al. Where does space begin? Functional concepts at the boundaries between atmosphere and space. J Aviat Med 1951; 22:342–349. 2. Humble RW, Henry GN, Larsen WJ. Introduction to space propulsion. In: Humble RW, Henry GN, Larsen WJ (eds.), Space Propulsion Analysis and Design. Reston, VA: American Institute of Aeronautics and Astronautics; 1995. 3. Isakowitz SJ, Hopkins JP, Hopkins JB. International Reference Guide to Space Launch Systems. 3rd edn. Reston, VA: American Institute of Aeronautics and Astronautics; 1999. 4. Loftus JP, Teixeira C. Launch systems. In: Larson WJ, Wertz JR (eds.), Space Mission Analysis and Design. 2nd edn. El Segundo, CA: Microcosm, Inc. and Kluwer Academic Publishers; 1992; Chapter 18.

M.R. Barratt 5. Enzell LN. NASA Historical Data Book, Volumes II and III. Washington, DC: Scientific and Technical Information Division, National Aeronautics and Space Administration; 1988. 6. Boden DG. Introduction to astrodynamics. In: Larson WJ, Wertz JR (eds.), Space Mission Analysis and Design. 2nd edn. El Segundo, CA: Microcosm, Inc. and Kluwer Academic Publishers; 1992; 129–156. 7. McKnight DS. Orbital debris—a man-made hazard. In: Larson WJ, Wertz JR (eds.), Space Mission Analysis and Design. 2nd edn. El Segundo, CA: Microcosm, Inc. and Kluwer Academic Publishers; 1992. 8. Love SG, Brownlee DE. A direct measurement of the terrestrial mass accretion rate of cosmic dust. Science 1993; 262:550– 553. 9. Spencer DB. Orbital debris and space operations. Aerospace America February 1997; 38–42. 10. Single-Stage Mars Mission. Proceedings of the NASA/USRA Advanced Design Program 7th Summer Conference; University of Minnesota; 1993:219–226. N93–29742. 11. Davis JR. Medical issues for a mission to Mars. Texas Med 1998; 94:47–55. 12. Balance JD, Dabbs JR, Dudley HJ, et al. Scientific Experiments for a Manned Mars Mission. Huntsville, AL: George C. Marshall Space Flight Center; March 1971. NASA TM X-2127. 13. Rauwolf G, Pelaccio D, Patel S, et al. Mission Performance of Emerging In-Space Propulsion Concepts for 1-Year Crewed Mars Missions. Proceedings of the 37th Joint Conference of the American Institute of Aeronautics and Astronauatics/American Society of Mechanical Engineers/Society of Automotive Engineers/American Society of Electrical Engineers on Propulsion; July 8–11, 2001; Salt Lake City, Utah. 14. Chang Diaz FR, Squire JP, Ilin AV, et al. The Development of the VASIMR Engine. Presented at the International Conference on Electromagnetics in Advanced Applications; September 13–17, 1999; Torino, Italy. 15. Chang Diaz FR. The VASIMR engine: Concept development, recent accomplishments, and future plans. Fusion Science and Technology 2003; 43:3–9. 16. Clark P. The Soviet Manned Space Programme. New York, NY: Orion; 1988. 17. Newkirk D. Almanac of Soviet Manned Space Flight. Houston, TX: Gulf Publishing Company; 1990:249–251. 18. Newkirk D. Almanac of Soviet Manned Space Flight. Houston, TX: Gulf Publishing Company; 1990:136–137. 19. Nicogossian AE, Pool SL, Uri JJ. Historical perspectives. In: Nicogossian AE, Leach-Huntoon C, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1994:3–49. 20. Kotovskaya AR. Human tolerance to acceleration after exposure to weightlessness. In: Proceedings of the Life Sciences and Space Research XIV. Berlin: Akademie-Verlag GmbH, 1976:129–135. 21. White WJ, Nyberg JW, Finney LM. Influence of Periodic Centrifugation on Cardiovascular Functions of Man During Bed Rest. Santa Monica, CA: Douglas Aircraft Co., 1966; Douglas Report DAC-59286. 22. Kotovskaya AR, Vil’-Vill’yams IF. +Gx tolerance in the final stage of space flights of various durations. Acta Astronautica 1991; 23:157–161. 23. Hawkins WR, Ziegleschmid JF. Clinical aspects of crew health. In: Johnson RS, Dietlein, LF, Berry, CA (eds.), Biomedical

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Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975:43–81. NASA SP-368. Barnby M, Griffin T, Lewis R. Neutral Buoyancy Methodology for Studying Satellite Servicing EVA Crewmember Interfaces. Presented at the 33rd Annual Meeting of the Human Factors Society; October 16–20, 1989; Denver, CO. Newman D, Barratt M. Life support and performance issues for extravehicular activity. In: Churchill SE (ed.), Fundamentals of Space Life Sciences. Malabar, FL: Krieger Publishing Co.; 1997:337–264. Shipov AA. Artificial gravity. In: Leach Huntoon CS, Antipov VV, Grigoriev AI (eds.), Humans in Space Flight. Vol. 3, Book 1. Reston, VA: American Institute of Aeronautics and Astronautics; 1996:349–363. Nicogossian AE, Mohler SR, Gazenko OG, Grigoriev AI (series eds.), Space Biology and Medicine. Kotovskaya AR, Galle RR, Shipov AA. Biomedical research on the problem of artificial gravity. Kosm Biol Aviakosm Med 1977; 11:12–19. Graybiel A, Kennedy R, Kneblock E, et al. The effects of exposure to a rotating environment (10 rpm) on four aviators for period of 12 days. Aerosp Med 1965; 36:733–754. Guedry FE, Kennedy RS, Harris CS, Graybiel A. Human performance during two weeks in a room rotating at three rpm. 1962 BuMed Project MR 005.13-6001 Subtask 1, report No. 74 and NASA Order R-47. Pensacola, FL: U.S. Naval School of Aviation Medicine. Kennedy RS, Graybiel A. Symptomatology during prolonged exposure in a constantly rotating environment at a velocity of one revolution per minute. Aerospace Med 1962; 33:817–825. Galle RR, Yemelyanov MD, Kitayev-Smyk LA, et al. Characteristics of adaptation to prolonged rotation. Kosm Biol Aviokosm Med 1974; 8:53–60. Kotovskaya AR, Galle RR, Shipov AA. Soviet research on artificial gravity. Kosm Biol Aviokosm Med 1981; 15:72–79. Reason JT, Graybiel A. Progressive adaptation to Coriolis accelerations associated with 1-rpm increments in the velocity of the slow rotation room. Aerospace Med 1970; 41:43–79. Graybiel A, Knepton J. Direction-specific adaptation effects acquired in a slow rotation room. Aerospace Med 1972; 43:1179– 1189. Roth EM. Compendium of Human Responses to the Aerospace Environment. Vol. II Washington, DC: National Aeronautics and Space Administration; 1969. NASA-CR-1205. Lackner JR, DiZio P. Artificial gravity as a countermeasure in long-duration space flight. J Neurosci Res 2000; 62:169–176. Antonutto G, Capelli C, di Prampero PE. Pedalling in space as a countermeasure to microgravity deconditioning. Microgravity Q 1991; 1:93–101. Burton RR, Meeker BS. Physiologic validation of a short-arm centrifuge for space application. Aviat Space Environ Med 1992; 63:476–481. Cardus D, McTaggart WG, Campbell S. Progress in the development of an artificial gravity sleeper. Physiologist 1991; 35 (Suppl 1):S224–S225. Barratt MR. Human-powered human-use centrifuges (letter to editor). Aviat Space Environ Med 1989; 60:85. Yuganov EM, Isakov PK, Kasyan II, et al. Vestibular analysis and artificial weight in animals. In: Parin VV, Kasyan II (eds.), Biomedical Studies in Weightlessness. Moscow: Meditsina; 1968:289–297.

25 42. Schultheis LW, Fallon M, Kiebzak G, Kaplan F, Benoit R. Physiological parameters of artificial gravity. In: Faughnan B, Maryniak G (eds.), Proceedings of the Ninth Princeton/AIAA/SSI Conference, “Space Manufacturing: 7 Space Resources to Improve Life on Earth,” May 10–13, 1989. Washington, DC: American Institute of Aeronautics and Astronautics; 1989:312–321. 43. Faget MA, Olling EH. Orbital space stations with artificial gravity. In: (eds.), Third Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: 1968:7–15. NASA SP-152. 44. Pomerantz MA, Duggal SP. The sun and cosmic rays. Rev Geophys Space Phys 1974; 12:343–361. 45. Dvorak V. Ionizing radiation. In: Last JM, Wallace RB (eds.), Public Health and Preventive Medicine. Norwalk, CT: Appleton and Lange; 1992:503–522. 46. Zeilik M, Smith E. The evolution of our galaxy. In: Introductory Astronomy and Astrophysics. 2nd edn. Philadelphia, PA: Saunders College Publishing; 1987:372. 47. Draganic IG, Adloff JP. Radiation and Radioactivity on Earth and Beyond. Boca Raton, FL: CRC Press Inc.; 1993:144. 48. Vaniman D, Reedy R, Heiken G, et al. The lunar environment. In: Heiken GH, Vaniman DT, French BM (eds.), The Lunar Sourcebook: A User’s Guide to the Moon. New York, NY: Cambridge University Press; 1991:27–60. 49. Feldman WC, Ashbridge JR, Bame SJ, Gosling JT. Plasma and Magnetic Fields from the Sun. In: White OR (ed.), The Solar Output and its Variation. Boulder, CO: Colorado Assoc. Univ.; 1977: pp. 351–382. 50. Bott MHP. The Earth’s magnetic field. In: The Interior of the Earth. 2nd edn. London, UK: Edward Arnold: Elsevier Science Publishing Co; 1982:256–263. 51. Van Allen JA. Remarks on observations of high intensity radiation by satellites 1958 Alpha and 1958 Gamma. In: IGY Satellite Report No. 13. Washington, DC: National Academy of Sciences; 1961:1–22. 52. Moore FD. Radiation burdens for humans on prolonged exomagnetospheric voyages. FASEB J 1992; 6:2338–2343. 53. Lodders K, Fegley B. The Planetary Scientist’s Companion. New York, NY: Oxford University Press; 1998:176, 185. 54. Hockey TA. The Book of the Moon. New York, NY: PrenticeHall, Inc.; 1986:138–172. 55. McKay DS. The lunar regolith. In: Heiken GH, Vaniman DT, French BM (eds.), The Lunar Sourcebook: A User’s Guide to the Moon. New York, NY: Cambridge University Press; 1991:285–356. 56. Apollo 17 Technical Crew Debriefing. Houston, TX: NASA Manned Spacecraft Center; 1971. MSC-07631. 57. Bean AL, Conrad CC, Gordon RF. Crew observations. In: Apollo 12 Preliminary Science Report. Washington, DC: NASA; 1970:29–38. NASA SP-235. 58. Levy SA. An overview of occupational pulmonary disorders. In: Zenz C (ed.), Occupational Medicine. 2nd edn. St. Louis, MO: Mosby-Year Book, Inc; 1988. 59. Melandri C, Prodi V, Tarroni G. et al. On the deposition of unipolarly charged particles in the human respiratory tract. In: Walton WH (ed.), Inhaled Particles IV. New York, NY: Pergamon Press; 1977:193–201. 60. Papike J, Taylow L, Simon S. Lunar minerals. In: Heiken GH, Vaniman DT, French BM (eds.), The Lunar Sourcebook. Cambridge, UK: Cambridge University Press; 1991:121–181. 61. Mendell W, Plesica J, Tribble A. Surface environments. In: Larson WJ, Pranke LK (eds.), Human Spaceflight: Mission Analysis and Design. Reston, VA: American Institute of Aeronautics and Astronautics; 1999:77–101.

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Suggested Readings DeHart RL, Davis JR (eds.), Fundamentals of Aerospace Medicine. 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.

M.R. Barratt Rainford DJ, Gradwell DP (eds.), Aviation Medicine. 4th edn. London, UK: Hodder Arnold; 2006. Zenz C, Dickerson OB, and Horvath EP (eds.), Occupational Medicine. 3rd edn. St. Louis, MO: Mosby-Year Book; 1994.

2 Human Response to Space Flight Ellen S. Baker, Michael R. Barratt, and Mary L. Wear

Over the past 45 years of piloted space flight, we have gained the knowledge, and indeed built the expectation, that humans can adapt to this environment and endure long and productive periods in space, up to and exceeding 1 year. Although the dominant condition associated with space flight that affects human physiology is weightlessness, other factors and phases of flight can influence the health and performance of crewmembers as well. Many of these factors have adverse consequences and require operational considerations, countermeasures, and protection. As such, an understanding of these factors and their influences is necessary for optimizing human performance. This chapter presents a comprehensive framework for understanding the experience and clinico-physiological response of human beings to space flight. This is purposely not an exhaustive physiology review, but rather an overview of consistent and predictable changes that are clinically relevant. These changes include outward symptoms and effects on health and performance as well as laboratory values and test results deemed important for understanding the clinical norms associated with space flight. Further physiological details are included in the subsequent system-oriented chapters; interested readers are also referred to the more detailed work in the Handbook of Physiology [1] and the recent text Space Physiology by Buckey [2]. By way of introduction, this chapter offers a brief history of human space flight to provide a context for the current state of knowledge of space medicine.

Historical Aspects of Space Medicine Many questions were raised in the early 1960s as the United States and Soviet Union were contemplating the first human flights. However, based on the existing knowledge of aviation and environmental medicine as well as educated speculation at the time, the risk was considered acceptable to proceed with the first few flights, and confidence was bolstered by the early experience demonstrating that humans could tolerate space flight reasonably well.

Medical and physiological data were collected from the beginning of human space flight, consisting primarily of preflight and postflight studies and passive inflight biomedical monitoring oriented toward high-level crew safety and verification that subsequent programmatic steps could be taken. Those steps included fundamental enabling technologies and practices such as extravehicular activity (EVA), piloted rendezvous and docking, and deployment of equipment. Early results along with crewmember reports and experience helped to quickly orient medical investigation and the provision of inflight medical care. As human space flight grew more routine, some missions specifically included assessments of physiological responses and the gathering of medical data, particularly with regard to systems most overtly affected. Scores of biomedical experiments have now been conducted during space flight, and a small number of missions dedicated to life sciences issues have provided considerable detail about some physiological systems. Although much has been learned about how humans respond to this new environment, that humans could tolerate or even survive space flight was hardly a foregone conclusion in the early days. The acceleration forces associated with launch into orbit and reentry into Earth’s atmosphere, as well as prolonged exposure to weightlessness, were seen by some to preclude human existence, let alone performance of useful work. The sentiments of the time preceding the first human launches were nicely summarized by Charles Berry: People who were concerned with the future of man in space quickly became aligned with one of two points of view. On the one side, there were the more cautious and conservative members of the medical and scientific community who genuinely believed man could never survive the rigors of the experience proposed for him. The spirit in the other camp ranged from sanguine to certain. Some physicians, particularly those with experience in aeronautical systems, were optimistic…. It became the task of the medical team to work toward bringing these divergent views toward a safe middle ground where unfounded fears did not impede the forward progress of the space program, and unbounded optimism did not cause us to proceed at a pace that might compromise the health or safety of the individuals who ventured into space. [3] 27

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FIGURE 2.1. Summary of human spaceflight experience as of December 2005, tabulated as person-flight experiences of orbital launches and depicting the relative flight durations. Suborbital flight experiences are not included. The time category of 1–20 days includes independent spacecraft and short-duration stays on orbiting stations; subsequent categories involve long-term residence on orbiting stations

We now have decades of accumulated information and flight experience from which to plan follow-on spaceflight activities. Figure 2.1 depicts the integrated experience of the Russian, U.S., and Chinese spaceflight activity to date, showing the relative distribution of person-flight experiences over the duration of flights. However, some of the sentiments echoed above still ring true as we contemplate taking steps beyond Earth orbit and subjecting crewmembers to additional challenges to health and performance, such as the increased remoteness and duration of missions, environmental exposures such as radiation and planetary surface dust, and the physical demands associated with lunar and Mars surface activities. In this regard, the role of the flight surgeon and medical support team remains much as it did in the formative years.

A Brief Chronology of Space Flight The pioneering human steps into space, beginning with Yuri Gagarin’s flight on April 12, 1961, were preceded by directed ground experimentation with humans and animals. This information was augmented with knowledge of human performance in other environments analogous in their isolation, crew composition, level of medical screening, and physical demands, such as polar stations, submarines, and surface ships. With regard to actual flight, the first terrestrial spacefarers in both the U.S. and Russian programs were animals. The Air Force “Man-High” and Navy “Strato-Lab” projects and other balloon studies gave an understanding of and experience with sealed cabin atmospheres in a near-spaceflight environment. The 1957 flight of Major David Simons, attaining an altitude of 31,100 m (102,000 ft) lasted more than 32 h, with

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44 h actually spent in the capsule [4]. By comparison, the first space flights were lasted several minutes to h. Life support and medical monitoring systems, scientific observations, and escape systems applicable to human space flight were fielded and verified during these balloon flights, and psychological and performance observations were made as well. The decade of the 1960s, the briskly paced formative years of human space flight, was begun with this information plus a fundamental understanding of human tolerance to acceleration forces from high-performance jet and rocket powered aircraft programs. Most of the more overt and clinically relevant physiological changes associated with space flight were identified early. At the conclusion of the Gemini program in 1966, more than 2,000 man-hours had been accrued by U.S. flight crews, and space flight was recognized to be associated with diminished red cell mass, body calcium loss, diminished postflight exercise capacity, and postflight orthostatic intolerance. By the conclusion of the Apollo program, many of the basic observations had been made that remain at the core of the human response to weightlessness (Table 2.1). Similar observations and conclusions were made in the Russian program. Given the effects of these findings on human performance, the goal of both programs became to further characterize these findings and to determine the mechanistic details underlying them, with the aim of developing protective countermeasures that would allow safe extension of human missions in space. To this end, more directed flight programs were developed involving wellequipped orbital laboratories and long-duration stays. The first U.S. long-duration experience was the three Skylab missions, flown in 1973 and 1974, each of which were crewed by three men; these missions lasted approximately 28, 59, and 84 days. The Skylab flights were dedicated to the systematic investigation of the physiological effects of space flight as well as the conduct of astronomical, geological, and other experiments and evaluation of equipment. Dietary issues, including long-term food storage and provision of palatable foods, physical countermeasures including aerobic and resistive exercise, and methods of medical and hygienic support were all tested

TABLE 2.1. Summary of significant biomedical observations in the Apollo program [5]. Observation Vestibular disturbances Flight diet adequate; food consumption suboptimal Postflight dehydration and weight loss Decreased postflight orthostatic tolerance Reduced postflight exercise tolerance Cardiac arrhythmiasa Decreased red cell mass and plasma volume Negative inflight balance of nitrogen, calcium, other electrolytes Increased inflight adrenal hormone secretion No inflight diuresisb a Sustained bigeminy during lunar orbit and surface EVA during Apollo 15 mission. b An expected consequence of the thoracic fluid shift.

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and refined during this program. The biomedical findings of these missions still stand as relevant contributions to space medicine; among the more significant outcomes were the development of procedures for efficiently operating a crewed space laboratory and the practical experience of long-duration flight. The Russian experience with the early Salyut stations was similar to that of Skylab. By the mid 1970s, both nations had concluded that humans could live and work effectively in weightlessness for periods up to 3 months and that nothing precluded longer missions if sufficient countermeasures were available [6,7]. Further Russian space activities involved a succession of orbital stations and longer duration missions; after a lag of several years, the United States began flying the Space Shuttle. The U.S. Space Shuttle science program has made great strides in working out details of human life sciences of short-duration space flight (i.e., up to 17 days). The ability to fly sophisticated laboratory facilities with interchangeable payloads and supporting sampling and analysis equipment, abundant power, additional crew members (including trained scientists), and high-bandwidth satellite communication have all been enabling aspects of this program. Along with human life sciences, the Space Shuttle program has benefited Earth observations, astronomy, materials and physical sciences, and fundamental biology. One of the more tangible benefits has been expansion of the basic medical and clinical knowledge base owing to the large volume of human flight experiences supported by this program. This knowledge base has guided the development of successful medical operational support to ensure that crew health and performance levels are sufficient to execute mission tasks. By the early 1980s, the Russian flight experiences had exceeded 6 months in duration, and the era of nearly continuous Russian presence in long-duration flight had begun. The Salyut series of space stations was succeeded by the venerable Mir station, which saw nearly continual crewed service from 1986 through 2000. Mir hosted scores of crewmembers in long-duration flights in addition to taxi and resupply flights by the Soyuz and Shuttle. Russian specialists learned how to maintain long-duration flyers for routine missions of 6 months and longer, also building a systematic operational support program emphasizing both physical and psychological countermeasures. In addition, the Mir station provided a venue for the United States to return to extended flight operations after a 20-year gap since the Skylab program. Seven U.S. crewmembers flew long-duration missions on Mir in combination with short-term Space Shuttle logistics flights. The International Space Station (ISS) has seen continual occupancy since 2000 and remains in assembly when this chapter was written. The ISS will accommodate science and technology development related to space flight and terrestrial applications. Mature and validated countermeasures to adverse effects of weightlessness and other practical products will be produced to contribute to further exploration efforts. Among the anticipated products will be an enhanced knowledge of practicing medicine in space with a greater evidence base.

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Preflight and Launch Factors Space crews launching to Earth orbit, either for a short-term mission or a long-duration stay aboard a station, have typically been in training for a few to several years. The demands of this preflight training are rigorous, and usually training requirements intensify in the few weeks to months preceding launch. Health monitoring and physical countermeasures are in place to ensure crew health, but accelerated training requirements, travel, and sleep shifting to the inflight schedule may lead to crew fatigue in the final days before launch. The pressure to succeed, along with impending separation from family and other social factors, can induce additional levels of stress. It is important to take these factors into account in developing prelaunch plans and schedules. Strict adherence to schedule limitations, methodical and effective circadian entrainment when sleep shifting is required, and limiting crew contact with unscreened visitors to curtail transmission of infectious disease are all part of the flight surgeon’s purview. Since the beginning of human space flight and for the foreseeable future, entry into space has involved a relatively short chemical rocket ride into low Earth orbit, either as a final destination or as a transitional phase for leaving Earth vicinity. A typical transatmospheric flight for the Space Shuttle or Soyuz lasts slightly more than 8 min, representing a best-fit balance between ballistic factors and limitations of hardware and crew—much faster, and the greater acceleration loads would exceed tolerance levels for crew and hardware; much slower, and the vehicle stack would spend too much time in the atmosphere, incurring excessive frictional heating and requiring excessive propellant. Launch and landing are understandably the most critical phases of space flight with regard to vehicle performance and crew safety, and history certainly bears this out with the losses of the U.S. Space Shuttles Challenger and Columbia and the loss of the Russian Soyuz 1 and Soyuz T11 crews. As such, large portions of program infrastructure and crew training are dedicated to the launch and landing phases of space missions. Without exception, crew positioning aboard spacecraft has been oriented such that the major acceleration loads associated with flight to Earth orbit are incurred in the most favorable physiologic axis for sustained acceleration, that is, in the +Gx (chest to back) direction. After donning pressure suits, crews are seated and launch restraints are applied, usually between 1.5 and 2.5 h before launch, with crewmembers positioned in a semi-recumbent, legs-elevated position. Launch loads in the Shuttle and Soyuz programs are variable and typically peak at about 3 G for the Shuttle and 3.7 for the Soyuz (see Chap. 1). Vibrational forces also accompany launch into orbit and, in combination with launch forces, may make throwing switches, reading displays, accessing checklists, and other activities requiring arm and head movements difficult. Background noise can also interfere with voice communications. These factors are accounted for in the design of hardware, displays, communication systems, and crew restraints, and such activities

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are routinely performed by flight crew members during ascent. Flight crewmembers are constantly monitoring launch parameters and vehicle performance, ready to execute abort procedures and possibly assume full manual control if needed. Ascent engines cut off abruptly, and the vehicle and crew must transition quickly to the orbital flight phase. This phase involves crew duties such as monitoring guidance and flight parameters, additional engine burns to adjust and finalize the orbit, loading new software into onboard computers, and securing engines and other systems associated with ascent. During this time, crewmembers may egress from restraints, doff launch suits, and begin stowing items no longer needed and deploying items needed during the orbital phase. The immediate post-ascent phase is fairly demanding in terms of crew activity, particularly as they are also adjusting to the acute effects of weightlessness.

Weightlessness Weightlessness is often misrepresented as a physiologically challenging condition but is more accurately described as an absence of the accustomed physiological challenges with respect to the gravity vector, to which the body is typically subjected daily in 1 G (one multiple of g, 9.8 m/s2, the gravitational load at the Earth’s surface). For normally active humans, “steady state” in 1 G is not steady at all with respect to forces, but instead involves the dynamic and frequent reorientation of organ systems to the gravity vector during lying, sitting, standing, and other activities. Many of these systems, including the cardiovascular, pulmonary, neurovestibular, and musculoskeletal systems, show specific or particular sensitivity to force loading; their structure, function, and regulation are all shaped by this gravitational dynamism. Stated simply, space flight “freezes” the natural outside physical forces acting on the body in a state of neutrality as compared with standard postural and loading changes. Any tissue, receptor, or organ system that depends on or is susceptible to hydrostatic pressure gradients and loading will demonstrate alterations of function and possibly morphology in weightlessness. A few of the assumptions and conditions that bound our understanding of microgravity physiology and human space flight are worth highlighting and noted below. The absolute effects of weightlessness on the human are not known. What has been learned about human beings in space has accumulated in the context of operational missions. We have not studied the absolute effects of weightlessness so much as the combined effects of weightlessness with a multitude of other factors, such as physical activity associated with mission operations, deliberate exercise countermeasures, psychological factors, environmental parameters, medical investigations, medical treatments and countermeasures, and other factors associated with space flight. It is doubtful that we will ever have true microgravity human control subjects.

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The immediate effects of weightlessness on the human are not known. Relative to normal ambulatory conditions on the ground, launch into space involves positional challenges, acceleration forces, thermal loads, and psychological stress, which all occur over an interval preceding the first exposure to weightlessness. If the means were available to transition immediately and cleanly from a normally active 1-G posture into sustained weightlessness, certain physiologic details of early adaptation could be seen that are otherwise masked in the composite of forces and activities. Adaptation to weightlessness occurs at different rates in different systems. Multiple organ systems and tissue types may react and adjust to weightlessness at different rates, primarily based on the rapidity of response to loading in 1 G. Secondary effects such as reduction in blood cell mass lag behind primary effects such as reductions in plasma volume. Processes requiring hormonal responses (e.g., certain fluid regulation pathways) or cell turnover (e.g., skin desquamation) will reflect their own timelines in their manifestations. Longer-term processes are thought to include neuromotor adaptation, which depends in part on experience, as well as behavioral factors and exercise performance as the crewmember settles into a balance of mission activities, nutrition, physical countermeasures, and sleep schedule. Crewmembers by and large are functional immediately upon arrival into weightlessness, but several stages of adaptation occur over periods of days to weeks as their physiological systems adapt to weightlessness, individually and in combination with other systems. For the sake of convenience, this process can be considered in terms of specific systems or performance parameters, but from the standpoint of overall health and performance it represents a continuum. For some systems, such as fluid regulation, an endpoint in adaptation can be identified; for others, such as loss of bone density in the skeletal system, the endpoint is not known. Readaptation follows adaptation. Human space flight necessarily includes two phases of physiological response—that of inflight adaptation, in particular to weightlessness, and postflight readaptation after return to Earth. Both of these phases follow predictable time curves with distinct starting points, and both influence human performance and clinical findings. This process applies both globally (overall health and functionality) and on a systems level. Because certain inflight changes can only be assessed before and after flight, consideration must be given as to how these results could be influenced by the multisystem readaptation process at the time of assessment. Some flight activities will include intermediate adaptation phases, as crewmembers are exposed to fractional gravity fields of the moon or Mars, again followed by weightlessness and ultimately Earth return. Standard investigative and diagnostic methods are often not possible. Because of limitations in launch mass and volume, power, sampling and sample storage, interference with other activities, and the difficulties associated with fluid handling and other laboratory techniques in microgravity, inflight data

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may not be collected with the same level of control and scientific rigor as is possible during ground investigations. Investigators and support technicians are replaced by multipurpose crewmembers, who serve as subjects and operators in addition to performing their other flight-related duties. Life scientists often must settle for less than optimal means of deriving physiological and medical information during flight or simply settle for observations made after flight. The sample size remains small. As of the end of 2005, 971 human flight experiences (defined as reaching a sustainable orbit) have taken place with 435 separate individuals. Specific medical parameters have been measured in standardized fashions on only fractions of this group, and variability, both between and within individuals, remains a strong factor. Adaptation involves plasticity. Sustained weightlessness provides a state in which the “neutralization” of forces influencing physiological processes can be observed. Changes in heart mass, baroreceptor sensitivity, and pulmonary ventilation-perfusion distribution have been noted that suggest a greater degree of plasticity in mature organ systems than was previously thought. Overall, the human response to weightlessness involves adaptation without functional impairment, largely preserving human work capacity as required by the new environment. As noted throughout this book, the basic direction of adaptation seems less like optimizing to weightlessness and more like shedding physiological capabilities and functional control that help in the 1-G world but are no longer needed in space. Most of the impairment associated with space flight occurs when the body must transition back to a steady-state gravitational field. The exceptions to this are transient and occur in the period immediately after launch.

responses, each of which has multiple effects, are the thoracic fluid shift resulting from loss of hydrostatic gradients and neurovestibular disturbances, particularly in the form of space motion sickness. Because these responses are immediate and significant, they are described here separately from the system-oriented discussions that follow.

Short-Term Responses

From entry into microgravity until 3–4 days into flight, approximately two thirds of Space Shuttle crewmembers experience some degree of space motion sickness [9]. Space motion sickness among U.S. astronauts was first described during Apollo 9. The incidence was estimated to be 35% during the Apollo program and 60% during the Skylab program. Reports from the Russian program indicate an incidence of 40–50% among Salyut-6 and Soyuz crewmembers [10]. The syndrome varies in symptoms and intensity and includes increased sensitivity to motion, headache, diminished appetite, stomach awareness, nausea, and vomiting. Onset of motion sickness has occurred as early as 15 min and as late as 3 days after reaching orbit. Symptoms generally last 2–3 days, but may persist for up to 7–10 days in a small number of people. In the U.S. program, the treatment of choice has been promethazine, given by intramuscular injection. Promethazine has been effective in more than 90% of cases; it is normally administered late in the first day before sleep, and reported side effects have been few [11]. In particular, sedation is rarely reported as a side effect in space relative to ground use. Increased motor activity and head movements worsen the illusions and symptoms of motion sickness, whereas diminished

Given the requirement for rocket ascent into Earth orbit, it is understandable that the transition from normal terrestrial activity to weightlessness can be difficult. Crewmembers don protective pressure suits several hours before launch, which are uncomfortable and may involve a degree of heat stress. Ingress to the tight quarters of the Space Shuttle or Soyuz is followed by secure restraint into a launch and entry seat in a supine position with the waist and knees flexed. Inevitably, some of the fluid shifting from the lower extremities to the central circulation begins in the vehicle before launch while the crewmembers are seated in the required recumbent position. After ascent, the transition to weightlessness is abrupt as the engines switch off, and this transition is subjectively magnified by the greater-than-normal forces experienced during the preceding several minutes. Crewmembers experience subjective feelings of floating out of the launch seat, being held in place only by restraint straps. Whatever objects had been resting unrestrained on the spacecraft “floor” now float free. Some of the more prominent physiological effects of microgravity appear almost immediately. The two dominant short-term

Fluid Shift Upon reaching weightlessness, a thoracic body fluid shift beyond that induced by the launch position occurs in earnest, and it is this fluid shift that underlies many of the immediate effects of weightlessness. A sensation of fullness in the head is commonly reported, with onset in a few minutes to a few hours of becoming weightless, occasionally accompanied by nasal congestion. Some crewmembers equate this to the feeling of hanging upside down on Earth. Within minutes, objective facial edema and erythema may become apparent. The volume of the lower extremities begins to diminish, and the superficial vascular system of the upper body is seen to engorge. Subjectively, crewmembers may complain of discomfort associated with feelings of facial fullness, especially behind the eyes and in the maxillary and frontal sinus areas. The unpleasant sensation typically lasts from a few hours to a few days, and it usually resolves to a tolerable level as new set points for fluid regulation are established. Interestingly, Skylab crews reported relief from these symptoms with cycle exercise, presumably related to return of blood to the lower extremities [8]. Fluid shifting contributes to many of the findings noted later in this chapter regarding anthropometric changes and fluid regulation.

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Anthropometric Changes The basic structure of the human body is a result of long-term terrestrial development. However, certain aspects of body size and shape are more dynamic and may be influenced by force loading. Although variability exists between individuals, predictable trends are seen that influence the fit of highly customized garments and spacesuits as well as physical crew interfaces with the spacecraft such as work station restraint systems, medical and sleep station restraints, and landing vehicle couches. Internal motion and redistribution of organs may result secondarily from postural and musculoskeletal changes or independently from effects of fluid shifting and floating, all of which can influence findings on physical examination and medical imagery. Both internal and external findings may be influenced by the more long-term changes in physical activity, metabolism, and energetics associated with space flight. An understanding of these processes and findings is important to space medicine practitioners and hardware designers alike. Body weight is a fundamental clinical measure reflecting immediate fluid balance and, on a more long-term scale, metabolism. Generally some degree of weight loss has been noted after both short- and long-duration flights. Buckey et al reported an average loss of 1.1 kg in 14 subjects immediately after 10- to 14-day Space Shuttle flights [12]. Measurements obtained before and after flight can be compared but are subject to changes and fluid shifts during landing, and of course cannot guide inflight activity such as nutritional support and performance of countermeasures. The ability to assess body mass during flight was recognized early as a health monitoring requirement by the Russian and U.S. programs. Body mass has for years been determined in weightlessness by means of fixing the body to a linear spring-tension system and inducing oscillating motion. Knowing the mechanical characteristics and in particular the spring-constant of the system allows body mass to be assessed by the timing of the oscillation cycle. Currently on the ISS, body mass is measured every 2 weeks during long-duration missions. Losses in body mass of 4–5% are typical in long-duration flights and most likely result from negative dietary and energy balances [13,14] (see Chap. 27). A decline of a few kilograms below preflight baseline at the end of a 6-month mission is

common, although considerable variability has been noted. In describing a series of flight experiences on the Salyut 6 station lasting between 96 and 185 days, Kozerenko et al. reported losses up to 5.4 kg and, less often, gains in body mass, with a maximum gain of 4.7 kg [15]. Smith and colleagues reported a mean body weight loss of 5% for 11 astronauts aboard the ISS for 128- to 195-day missions [16]. Although inflight findings reflect individual variability and are subject to sporadic measurements, most of the mass loss seems to occur within the first 4–8 weeks of flight, followed by a slower decline or plateau for the duration of the mission. Limb volume, as determined by standardized circumference measurements, provides another more easily obtainable measure of tissue mass, reflecting body fluid shifting and muscular growth or atrophy. Typically calf circumference decreases rapidly within the first 48 h of flight in association with acute thoracic fluid shifting, which is not necessarily coupled to body mass loss. Buckey et al. reported a mean leg volume loss of 748 ml after Space Shuttle flights of up to 14 days [12]. In longer flights, this acute drop is followed by a more gradual decline associated with muscular atrophy, typically reaching a plateau depending on response to countermeasures and other individual factors. Measurements from two cosmonauts flying a year-long mission on the Mir station showed that calf circumference declined steadily to about 20% below preflight baseline, whereas arm and forearm circumference remained essentially unchanged [17]. Figure 2.2 shows calculated left upper and lower limb volume loss for three Skylab crewmembers during that 84-day flight. Changes in thoracic and abdominal anthropometry reflect axial unloading and perhaps represent the greatest threat to fitting highly customized garments and restraints. Observed increases in seated height in weightlessness presumably result from expansion of the unloaded intervertebral disks and loss of the thoracolumbar curvature [18]. Most of the increase occurs during the first 2 weeks and then stabilizes at approximately 3% above the preflight baseline [19]. A corresponding decrease in abdom inal girth is seen as the abdominal viscera float in a rostral direction and are pushed in by unopposed abdominal muscle tone, with a lesser decrease in chest girth. Figure 2.3 shows trunk measurements for two Skylab crewmembers during the 84-day flight. +0.3 Volume change, liters

activity reduces the symptoms. Crewmembers are educated before flight and also discover for themselves that slower movements are less provocative. Consciously maintaining a sense of a “vertical” in the environment also seems to be protective for many crewmembers during the early hours of flight. Purposely restraining the feet and “bending down” to retrieve an object rather than flipping upside down with the newfound freedom of movement, for example, is a wise choice early on. From a mission management perspective, EVA sorties are not scheduled within the first 72 h of launch to accommodate neurovestibular adaptation and to allow any symptoms of space motion sickness to clear.

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0 -0.3 -0.6 -0.9 -1.2 -1.5

0 4 Launch

Arm

8

31

37

57

59

82 0 2 Landing Mission Day

4

6

8

10

Leg

FIGURE 2.2. Changes in left limb volume for three crewmembers on the Skylab 4 mission. Combined/redrawn from [18]

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+6 +4 Change, cm

+2

0 -2 -4

Height Circumferences Chest (insp) Chest (exp) Waist

-6 -8 -10 0

10

20

30

40

50

60

70

80 R+10 +17

Mission Day

FIGURE 2.3. Changes in trunk measurements for two Skylab crewmembers during the 84-day flight. Combined/redrawn from [18]

Postural changes also follow predictable trends and are relevant to the design of inflight crew systems. The neutral body posture assumed in weightlessness (Figure 2.4) typically includes flexion of the musculature proximal to the limbs and thoracolumbar straightening with retention of the cervical curvature, resulting in neck flexion. This position should be accommodated by crew restraints at work and sleep stations; any other shape forces the body out of this position. Crewmembers testing a conventional medical restraint system during the STS-40 Space Shuttle mission noted significant discomfort with being restrained in an Earth-normal recumbent position [20].

Physical Examination Findings Physical examination is a time-honored means of obtaining vital information without the use of invasive techniques, electrical recording, or imaging. As is true on Earth, physical examina-

FIGURE 2.4. The neutral body posture assumed in weightlessness. Segment angles shown are means; values in parentheses are standard deviations. Data were developed in Skylab studies and based on measurements from three subjects [19]

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tion has a crucial role in space flight for making initial diagnoses and for monitoring health trends. Considered in light of medical history, findings from physical examination can hasten the diagnosis and treatment of an ill or injured crewmember and help to direct the use of other available investigative studies, which must be used strategically because of resource limitations. Most of the basic techniques and instruments used in terrestrial physical examination and diagnosis have been used during space flight. However, the known multisystemic physiological adaptation to weightlessness suggests that normal physical findings achieve new baselines, which must be considered for monitoring health and for interpreting new-onset possibly abnormal findings. Harris et al. developed a systematic method for performing physical examinations in weightlessness [21]. The techniques involved were verified during ground and parabolic flight sessions and then performed on seven subjects during the course of an 8-day Space Shuttle flight by a physician astronaut. Subjects underwent preflight and postflight examination and served as their own controls. Findings from longer flights are expected to reflect findings that may not have been captured by this investigation; however, the results of Harris’ study constitute the most complete systematic collection of space normal physical findings obtained by inflight physicians thus far. Major findings are presented below in the order of their performance during a standard physical examination, with corroboration and supplementation from other sources as available. Genitourinary and rectal systems were not examined. Eyes: Mild conjunctival erythema noted in some crewmembers, otherwise no changes. Normal funduscopic exam with no papilledema [21]. Increases in intraocular pressure of 92% during the first 16 min and then by 20–25% after 44 min of flight [22], suggesting a trend towards normal over time. Ears: No significant changes from preflight assessment [21]. Nose: Generally showed increased erythema and edema of nasal mucosa [21]. Throat: Slight hyperemia of mucosal membranes [21]. Neck: Jugular venous distension extending along entire length of neck [18,21]. Increase in jugular vein cross section via sonography [23]. Skin: Acutely edematous and hyperemic on face and upper body; prominent eyelid edema. Some subjects showed hyperemia and injection of conjunctivae and mucosal membranes [21]. Loss of calluses on feet and normal weight-bearing skin surfaces are noted after weeks in long-duration flight. Chest: “Barrel” appearance resulting from standard anthropometric changes [18,21]. Elevation of the diaphragm by one to two intercostal spaces, with corresponding decrease in basal lung sounds in some crewmembers. Heart: No discernible difference in intensity or rhythm. Substernal displacement of point of maximal impulse in four of seven subjects, not palpable in three [21]. Abdomen: Flattened abdominal contour [18,21]. Diminished bowel sounds in five of seven subjects, increasing over

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time but not returning to baseline. Rostral relocation of liver and spleen by palpation [21]. Musculoskeletal: All subjects assumed the neutral body posture. Noticeably diminished size and thinning of large muscle groups of lower extremities [21]. Neurological: Brisker tendon reflexes noted in five of seven subjects [21]. The following sections address more specifically the known clinical changes in specific physiological systems associated with weightlessness.

Cardiovascular System and Volume Regulation The cardiovascular system, which can be simplistically described as a closed hydraulic circuit oriented along the body’s longitudinal axis with a more or less centrally located pump, is one of the systems most influenced by hydrostatic gradients. In an effort to maintain end perfusion of body tissues and support oxidative metabolism in highly variable demand states, a complex system of interrelated subsystems and responses (neural, renal, endocrine) serves to compensate for dynamic changes in these hydrostatic forces as the body reorients itself relative to the gravity vector and responds to other physiologic perturbations. Volume-sensitive stretch receptors (baroreceptors) reside in the aorta and carotids in large numbers and normally help to mediate the rapid response to gravitational stresses to central circulation. Increasing pressure induces the firing of afferent nerves from baroreceptors to stimulate a centrally integrated and parasympathetically mediated vasodilatation and reduction in cardiac output in an effort to maintain normal arterial pressure. Conversely, a reduction in sensed pressure by the baroreceptors stimulates a centrally mediated sympathetic response, driving the opposite effect to maintain pressure during acute reductions. This baroreceptor reflex preserves pressure during postural changes, particularly in moving from recumbent to seated to standing positions [24]. In weightless environments, many of the non-gravitationally oriented factors that could influence demand and hence cardiac output (e.g., exercise, cold stress, volume loss, hypoxia) remain unchanged. However the hydrostatic gradients vanish, along with them the periodic stimulus for maintaining cardiac output under various orientations to gravitational loading. Venous pressure, normally under a significant gravitational influence, essentially equalizes throughout the body and directly reflects right atrial pressure. The changes of the cardiovascular and fluid regulatory system largely reflect the removal of these hydrostatic gradients and, to a lesser extent, the hypokinesia relative to terrestrial activity. Investigations of cardiovascular variables during space flight has been driven largely by the early recognition of postflight orthostatic intolerance and attempts to elucidate how adaptation leads to this maladaptive condition on return to Earth. Some of the major findings associated with the cardiovascular system in weightlessness observed during carefully controlled

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studies are summarized in Table 2.2. Unless otherwise noted, these findings are based on inflight measurements; the exceptions are for those variables less influenced by the immediate reverse fluid shifts and other dynamic effects of landing, such as cardiac mass and red blood cell (erythrocyte) mass. The major time division is artificial and tied to vehicle experience. Space shuttle flights have included sophisticated science payloads and allowed high-fidelity results, but of course are time-limited (up to 17 days in duration). Longer-duration flights from space station programs are better platforms for characterizing the long-term human response and changes over time. Generally speaking, the cardiovascular system undergoes predictable changes but adapts well to prolonged weightlessness, with a few significant findings.

Cardiovascular changes such as increased cardiac output due to increased cardiac filling and stroke volume begin very early during flight, accompanying the immediate central fluid shift. The observed maintenance of mean arterial pressure implies a corresponding decrease of peripheral vascular resistance. Unlike that in the terrestrial supine position, central venous pressure does not increase in response to this shift in weightlessness [26]. This may relate to the increased thoracic diameter consistent with the anthropometry changes noted above. Parabolic flight studies have corroborated the thoracic shape change [39] as well as the concomitant decrease of central venous pressure immediately upon entering weightlessness [40]. A lower thoracic pressure may result in lower central venous pressure and increased cardiac output, but would also

TABLE 2.2. Major cardiovascular findings associated with weightlessness. Variable

Short-term response (Max 17-day flight)

Long-term response Unchanged c/w preflight, measured FW 8, 16, and 24, n = 4 [29]; unchanged at 1,3, and 5 months, n = 6 [23]; ↑ 10–12 bpm n = 2, and ↓ to “moderate bradycardia” n = 1, measured periodically during 8-month flight [30]

Heart rate

Slightly decreased in comparative 24-h ambulatory studies, n = 12 [25]. No change early in flight c/w preflight seated (n = 3 [26]; n = 4 [27]) or minimally decreased c/w supine (n = 6 [28])

Heart rate variability Systolic blood pressure

Decreased in comparative 24-h ambulatory studies, n = 12 [25] Unchanged, comparative 24 h ambulatory studies, n = 12 [25] Unchanged while awake, slightly ↑during sleep c/w preflight, measured FW 8, 16, and 24, n = 4 [29]; unchanged at 1, 3, and 5 months, n = 6 [23] Decreased in comparative 24-h ambulatory studies, n = 12 [25]; ↓ slightly c/w preflight, measured FW 8, 16, and ↓ c/w preflight supine, n = 6 [28] 24, n = 4 [29]; unchanged at 1, 3, and 5 months, n = 6 [23] Unchanged c/w preflight seated, FD1 and FD 7/8, n = 4 [27]; Unchanged at 1, 3, and 5 months, n = 6 [23] ↓ c/w preflight supine, n = 6 [28] ↓ 8.4–2.5 cm H2O c/w seated preflight, FD1, n = 3 [26] Unchanged to slightly decreased c/w with preflight supine, n = 1 [31] No change early in flight c/w preflight seated, n = 3 [26]; ↓ 24% FD1 and ↓ 14% FD8, n = 4 [27] ↓ 17% in first 24 h, then stabilizing at ↓10–15% by FD 5, ↓ 8.4%, n = 3, R + 0 of 28-day flight; ↓ 13.1%, n = 6 [32] n = 3, R + 0 of 59-day flight; ↓ 15.9%, n = 3, R + 0 of 84-day flight [33] ↓10% within 1 week, n = 6 [34] ↓11.1%, n = 9, R + 0 of 28-, 59-, and 84-day flights [33]

Diastolic blood pressure

Mean arterial pressure Central venous pressure

Systemic vascular resistance Plasma volume

Red blood cell mass Echocardiographic findings Left ventricular end diastolic volume Left ventricular End systolic volume Stroke volume

Left ventricular mass

Cardiac output

↑ 4.60–4.97 cm c/w preflight supine, n = 3 [26] No change, n = 3 [26]

↓ 8–24% at 1, 3, and 5 months, n = 6 [23] ↓ up to 19% n = 2, and ↑up to 20% n = 1, measured periodically during 8-month flight [30] ↓ 10–16% at 1, 3, and 5 months, n = 6 [23]; ↓ 12–15%, n = 2, and ↑up to 20% n = 1, measured periodically during 8-month flight [30]

↑ 46% c/w preflight standing, n = 4 [35]; ↑ 56–77 ml, n = 3 [26]; ↑ 55% c/w preflight standing, ↑9% c/w supine, n = 6 [28]; ↑ 40% early in flight (n = 2), followed by return to preflight values [36] ↓ 12% c/w preflight, n = 4 postflight measurement after 10-day flight [37] ↓ 8% c/w preflight, n = 3, postflight measurement after 84-day flight [38] ↑ c/w prelaunch supine, FD1, n = 3 [26] ↓ 17%–20% at 1, 3, and 5 months, n = 6 [23] ↑c/w prelaunch seated, 29% FD1 and 22% FD 7/8, n = 4 [27]; ↑26% c/w preflight standing, unchanged c/w supine, n = 6 [28]; ↑ 18% c/w preflight standing, n = 4 [35]

Abbreviations: FD, flight day; FW, flight week; ↑, increase; ↓, decrease; n, subject number; c/w, compared with. Measured as part of a study of the effect of thigh cuffs on cardiovascular dynamics in space flight. Cuffs were worn 10 h each day, but measurements were taken before the cuffs were put on. a

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be expected to increase lung volumes. As described in the next section on pulmonary findings, the opposite is seen. This seeming paradox remains to be definitively resolved, and is discussed in detail in Chap. 16 and by Buckey [41]. Plasma volume loss also begins early, with a predominant mechanism being extravasation from the vascular space to the intracellular space, apparently because of increased capillary permeability [32]. A resulting increase in hematocrit is seen along with other factors leading to inhibition of erythropoietin [34]. Over the course of several days, stabilization of plasma volume is accompanied by a reduction in red blood cell mass to an appropriate space flight set point, with normalization of hematocrit [34]. The decrease in erythrocyte mass seems to involve a process of selective hemolytic removal of the youngest erythrocytes (neocytolysis), facilitating more rapid adaptation to the microgravity circulatory state [42]. This state represents a basic euvolemic set point for weightlessness (10–15% reduction in plasma volume, 10% reduction in erythrocyte mass). Diuresis is not observed to accompany the fluid shifting and resetting to lower plasma volume in the first days of flight, in part because of decreased fluid intake related to reduced thirst and space motion sickness and possibly due to intracellular fluid shifts. Further changes over time include a decrease in cardiac chamber dimensions to reflect the new volume status. New homeostatic conditions for central circulation seem to most closely mimic those associated with the terrestrial seated posture [26,43]. Eventual decreases in resting cardiac output, left ventricular mass, and chamber volumes are seen, stabilizing to reflect the new balance between physical activity, diet, and fluid volume status. Cardiopulmonary performance is discussed in a separate section below, but in general left ventricular contractile function is maintained as normal as assessed by echocardiography after 3-month [38] to 8-month periods of weightlessness [30]. Given that the baroreceptors, which normally help to mediate the rapid response to gravitational stresses to central circulation, are relatively unchallenged in zero G, downregulation of this function would be expected. Although the aortic and cardiopulmonary baroreceptors are difficult to test directly, the carotid baroreceptors may be selectively and temporarily deformed with a form-fitting pressure cuff. Under those conditions, the normal heart-rate and blood-pressure responses to carotid baroreflex activity are seen to be diminished both during [44] and after short-duration Shuttle flights [45,46]. Changes in these responses to Valsalva maneuvers and respiratory frequency R-R interval spectral power further suggest decreases in parasympathetic control of blood pressure and baroreflex gain during both short-duration [46,47] and longduration (9-month) flights [48]. Sympathetic neural control seems to be maintained, as ascertained by inflight responses to lower-body negative pressure (LBNP), which mimics the lower-extremity volume redistribution of assuming an upright posture on the ground. Increases in heart rate, blood pressure, and peripheral vascular resistance accompanied decreases in

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stroke volume, suggesting that the inflight status reflects primarily the relative fluid deficit with normal [49] or even exaggerated sympathetic response to orthostatic stress [50]. No evidence exists to suggest that the cardiovascular changes associated with normal adaptation to weightlessness are clinically threatening or functionally limiting of inflight mission requirements. Particular attention has been paid to the incidence of arrhythmias arising from space flight such as those involving ventricular bigeminy and profound bradycardia during an Apollo mission [51], paroxysmal supraventricular tachycardia arising during and persisting after EVA [52,53], and a run of ventricular tachycardia caught incidentally during a 24-h Holter study [54]. However, other stressors that may lead to arrhythmias are also present during space flight, including high physical workload, fatigue, psychological stress, hydrational challenges, and electrolyte changes. Attempts are made during astronaut selection to screen out those with underlying coronary artery disease, but the relatively high prevalence of this condition and the difficulties involved in screening it out with 100% accuracy cannot totally preclude the possibility of someone with coronary artery disease flying in space. In a few astronauts, clinical manifestations of coronary artery disease appeared within 2 years after space flight, and the arrhythmias noted may have reflected the presence of underlying disease. Closer systematic investigation into incidents of inflight arrhythmias has revealed no increase in incidence during Shuttle flights, either during normal activities [25] or during EVA [55]. Acceleration and vibrational forces, along with the factors noted above, are also known to induce cardiac arrhythmias. Cardiac monitoring during the more dynamic phases of flight was instituted beginning with the first space flights; crewmembers wore electrocardiographic monitors during launch and landing in the first three major U.S. programs, and they continue to do so in the Russian program. In parallel with space program experience, aviation medical studies involving hundreds of subjects have demonstrated that a wide variety of arrhythmic conditions normally accompany exposure to acceleration that are not associated with impairment and do not reflect underlying abnormalities [56]. Those studies involved healthy, non-deconditioned subjects exposed to +Gz accelerations up to 9 G. A follow-on study showed no difference between men and women [57]. These findings, coupled with observations during the early space program of a lack of negative clinical events correlated with these findings, led to the abandonment of cardiovascular monitoring during launch and landing phases early in the Space Shuttle program. Heart rate and rhythm are still monitored during EVA, where the physiological margins are lower and the workload is particularly high, as well as during inflight activities that may involve more specific risk of arrhythmogenic responses (e.g., LBNP and maximal exercise testing). In such cases, real-time management decisions can be made based on the cardiac findings, such as calling for rest in the EVA cycle or terminating the LBNP session.

2. Human Response to Space Flight

Respiratory System As is true of the cardiovascular system, the respiratory system is affected during the process of adaptation but is not functionally impaired during flight, and no reports have been made of difficulty in breathing or other primary respiratory complaints. However, the respiratory system is an open-loop system and unique in its potential for interaction with the environment, particularly in a sealed cabin with an artificial atmosphere void of the most prominent natural forces that normally remove particulates and heavy aerosols. Secondary effects, reactive symptoms to dust and contaminant exposure, may overlap with other expected effects of adaptation. Distinguishing between headward fluid shifting and atmospheric nuisance dust causing the often-reported nasal stuffiness can be difficult, and headaches early in the mission caused by a contaminant such as CO2 can be confused with space motion sickness. The risk of aspirating foreign particles in the weightless environment is higher than that on Earth, and mild cough reactions from such events are not uncommon. The risk is further elevated with activities that could cause inadvertent release of particulates, such as large-scale stowage transfer operations involving movement of fabric bags, and when minute ventilation is high, such as during exercise. Efforts are made to decrease the particulate levels during construction, outfitting, and ground processing of modules and payloads by carefully selecting materials and foods and by using standardized processes for handling fluids and particulates. Forced air circulation and use of high-efficiency particulate-absorbing filters on ISS actively reduce the atmospheric particulate burden there. High-risk activities such as cleanup of spills and transfer of some materials prompt crewmembers to don protective masks. Aerosols may be released from leaking fluid lines, as occurred when ethylene glycol coolant leaked onboard the Mir station, and particulates and contaminant gases can be released from pyrolysis events such as those that occurred on the Shuttle (STS-40) and the Mir station (further discussed in Chap. 21). The lungs themselves, easily deformable and well known to be sensitive to gravitational loads, are expected to undergo changes in weightlessness. Gravitational and other acceleration forces are particularly influential in a system whose function depends on regional interaction between substances of vastly different densities, namely gas-filled lung tissue and blood. The upright posture involves a gradient in which apical regions are less well perfused than basal regions, contributing to alveolar dead space and creating a regional mismatch between ventilation and perfusion. The supine posture reduces this mismatch, limiting the vertical gradient to the anteroposterior dimension of the lung. In a high +Gz environment, overall compliance of the respiratory system (lungs and chest) decreases. The diaphragm is displaced downward (caudally), resulting in an increase in functional residual capacity and tidal volume; reflex increases in abdominal wall tension and abdominal pressure prevent full diaphragmatic movement and reduce vital capacity [58]. However, functional reserves

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exist to maintain sufficient pulmonary gas exchange during transient high-G exposures and sustained moderate-G exposures in rotating rooms. The known changes of thoracic shape and upward movement of abdominal viscera seen in weightlessness represent the opposite of this condition, and they also influence chest wall mechanics. During a short-duration Shuttle flight as well as a long-duration flight on Mir, the abdominal contribution to tidal volume was shown to increase significantly [59]. A small number of Space Shuttle missions dedicated to life sciences investigations have produced precise measurements of pulmonary indices from crewmembers on these short-duration flights. These measurements are summarized in Table 2.3. Changes reflect the early process of adaptation, as forces of fluid regulation, cardiovascular dynamics, abdominal and chest shape change, and perfusion distribution strike a new balance. Performance of standard crew duties and exercise are not impaired. Neither oxygen uptake nor CO2 output change in microgravity [60]. The ventilatory response to hypoxia is attenuated in microgravity, persisting during a 16-day mission among five subjects and resolving quickly after return; however, ventilatory response to hypercapnia was unchanged from preflight values [61]. Decreases in tidal volume, with partially compensating increases in respiratory frequency, have been observed; this is

TABLE 2.3. Pulmonary changes associated with space flight. Variable Respiratory frequency Tidal volume Vital capacity

Short-term response (Max 17-day flight) ↑ 9% c/w preflight standing, n = 8, 2 Shuttle flights of 9 & 14 days [60] ↓ 15% c/w preflight standing, n = 8, 2 Shuttle flights of 9 & 14 days [60] ↓ 5% after 24 h c/w preflight standing, then resolve to normal by 72 h, n = 7, during 9 day flight [62]

Forced vital capacity ↓ 3–5% on FD2 c/w preflight standing, then resolved to normal by FD4, slightly ↑ by FD9, n = 4 [63] Peak expiratory flow ↓12.5% c/w preflight standing on FD2, 11.6% on rate FD4, and 5.0% on FD5, returned to norm by FD9, n = 4 [63]. Functional residual ↓ 15% c/w preflight standing but higher than preflight capacity supine, n = 7 [62]. ↓ slightly early inflight c/w preflight, n = 2, resolved to normal later inflight, n = 4 [36] Residual volume ↓ about18% c/w preflight standing, n = 4 [62] Alveolar ventilation Unchanged, n = 8, 2 Shuttle flights of 9 & 14 days [60] Tissue volume About 24 h, n = 2 no change; At FD9 & 10, n = 4, a 25% decrease c/w preflight controls (p < 0.001). (Concomitant reduction in stroke volume, to the extent that it was no longer significantly different from preflight control.) Pulmonary diffusing DLco and the membrane component (Dm) both capacity (DLco) increase 28% c/w preflight standing after 24 h, unchanged over 9 days, n = 4; DLco increased 13% about 24 h into flight, n = 2, maintained at 13% FD9/10, n = 4 (different method) Abbreviations: FD, flight day; c/w, compared with.

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fully compensated by an observed decrease in physiological and alveolar dead space, attributed to more uniform distribution of pulmonary perfusion in the weightless environment such that alveolar ventilation remains normal [60]. Decreases in residual volume relative to preflight standing and supine values presumably reflect the diminished regional apico-basal gradients seen on the ground [62]. Vital capacity [62] and forced vital capacity [63] each undergo slight decreases within 24 h of arriving in weightlessness, both resolving to normal within 3–4 days. This early decrease in vital capacity has been suggested to reflect the initial increase in intrathoracic blood volume, resolving as plasma volume decreases over the same time course [34,64]. Despite early concerns that pulmonary edema would result from thoracic fluid shifts, diffusing capacity has been seen to increase during flight [35,36], presumably because of more uniform capillary filling and the subsequent increase in effective surface area supporting diffusion [35]. Although investigations indicate that the gravitationally sensitive apico-basal gradients are largely absent in microgravity, cardiogenic oscillations in expired oxygen and CO2 persist [60,65], suggesting some nongravitational regional inhomogeneity in ventilation perfusion. This topic is further discussed in an excellent review by Prisk [64]. Little information is available on pulmonary variables during long-duration missions, although many of the acute changes in volumes seem to resolve early in the course of shortduration flights, and observations during exercise and EVA over the course of several months indicate no perceived limitation to pulmonary performance. During a 6-month mission, vital capacity and expiratory reserve volume, measured in two subjects, was seen to reflect preflight supine values on FDs 9 and 175 [66]. On the day after return to Earth, vital capacity had decreased by 30%, presumably because of decreases in expiratory reserve volume and inspiratory capacity attributed to weakening of respiratory muscles. Future activities on the ISS should help to further characterize the effects of longduration space flight, if any, on pulmonary function.

Musculoskeletal System The musculoskeletal system provides the framework and means of motion, locomotion, and force exertion for the human body. Muscle and bone are vital tissues that continually respond structurally and functionally to loads, increasing in mass and strength in response to sustained exposures to increasing loads and decreasing with diminishing loads. As such, the musculoskeletal system is directly shaped by the outside loads against which it must react and oppose. The skeletal system provides rigid attachment points for the skeletal muscle that moves the body and also applies direct loads to the bone at these points, further influencing bone structure. Working in concert, the muscles supplying the power and the bones supplying the framework and system of levers for force exertion, these two systems cannot, in practice, be considered separately.

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Bone Bone integrity and calcium homeostasis are issues of concern for long-duration space flight. Conditions of immobilization such as spinal cord injury [67,68] or deliberate bed rest [69,70] are well known to be accompanied by loss of bone mineral density (BMD). Measurable decreases in BMD have been reported in professional scuba divers, presumably caused by the decreased loading associated with water immersion [71]. Loss of mineral from weight-bearing bones has been well documented since the first long-duration space flights [72], in combination with loss of bone density, loss of body calcium and phosphate, and decreases in calcium absorption. The development of advanced assessment techniques and assays for metabolic markers over the past two decades has enabled a better understanding of the process, although the mechanistic details have yet to be fully identified. Bone mineral is lost preferentially from the weight-bearing bones, including the lower extremities, lower pelvis, and lumbar spine, during space flight. Loss in BMD at the rates incurred by space flight or bed rest typically requires several weeks to detect via imaging studies. For Skylab crewmembers, photon absorptiometry did not detect bone loss in the calcaneus in the crew on the 28-day flight, but showed a 7% loss for those on the 59-day flight and an 11.2% loss for those on the 84-day flight [69], with no losses seen in the distal radius or ulna. Crewmembers on the Mir station flying multimonth missions lost BMD at an average monthly rate of 0.3% from the total skeleton, with 97% of that loss coming from the pelvis and legs as assessed by magnetic resonance imaging and dual X-ray absorptiometry [73]. LeBlanc and colleagues used dual X-ray absorptiometry to define the rate and distribution of bone loss from long-duration missions in 18 cosmonauts (Table 2.4) [74]. In another study of 14 ISS crewmembers, BMD was shown to be lost at a rate of 0.9% per month at the spine, 1.4–1.5% per month at the hip, and 0.4% per month at the calcaneus [75]. Loss in BMD in these regions in ISS crewmembers (Figure 2.5) identifies these areas as targets for countermeasures [76]. Calcium loss from the skeletal system, which also serves as the body’s storage pool of this mineral, begins early in flight. During comprehensive metabolic monitoring studies on Skylab, TABLE 2.4. Changes in bone mineral density after 4–14.4 months of space flight [74]. Anatomical site Spine Neck Trochanter Total Pelvis Arm Leg *

No. of subjects 18 18 18 17 17 17 16

Percent change per month −1.06* −1.15* −1.56* −0.35* −1.35* −0.04 −0.34*

p < 0.01. Source: From A LeBlanc et al. [74]. Used with permission.

Standard deviation 0.63 0.84 0.99 0.25 0.54 0.88 0.33

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physical countermeasures may have a protective role against loss of BMD; such countermeasures are evolving, and it is hoped that new devices providing the means for heavy resistive exercise, soon to be available on ISS, will help to further mitigate bone loss. One such device, the advanced resistive exercise device, can provide axial loading of up to several hundred pounds for exercises such as squats and dead lifts.

Muscle

FIGURE 2.5. Mean percent change (± standard error) from preflight values in bone mineral density of 15 U.S. crewmembers after return from ISS Expeditions 1–12 [76]

crewmembers exhibited negative calcium balance, with increased urinary and fecal calcium excretion and decreased intestinal absorption of calcium [72]. Reduced intestinal absorption and increased urinary excretion were confirmed on a subsequent long-duration mission [77]. Another biochemical marker of skeletal turnover and breakdown, urinary hydroxyproline, was noted to be elevated in Skylab crewmembers [72], and more recently other markers of resorption, such as n-telopeptide and deoxypyrodinoline, have been consistently elevated during flight [78–80]. Markers of bone formation such as bone-specific alkaline phosphatase and osteocalcin have been either decreased [79] or unchanged [80] as a result of weightlessness. Increased resorption and diminished intestinal absorption of calcium seem to have central roles in the loss of BMD caused by space flight. Parathyroid hormone levels have been reported to be increased during [79] and immediately after long-duration flight [81], unchanged during short-duration flights [82] and after long-duration flights [80], and increased during short-duration flight [83]. Levels of active vitamin D (1,25-dihdroxycholecalciferol) were reduced during flight and unchanged immediately after landing from long-duration missions [80] and were found to increase during shorter flights [82]. The lack of ultraviolet light in the spacecraft environment probably contributes to the reported reductions in vitamin D stores (25-hydroxycholecalciferol) after space flight [80,84], and vitamin D supplements are given during flights aboard the ISS to ensure adequate levels of this factor. Loss of BMD seems to continue unabated in weightlessness and presumably would eventually lead to clinically relevant losses of BMD and increases in risk of fractures. Bone loss also carries an inherent risk of nephrolithiasis because of hypercalciuria, which begins upon first arrival to weightlessness (discussed further below). Structurally, decreases in BMD do not seem to breach the clinical threshold even in standard long-duration missions; no increase in the incidence of fractures attributable to bone loss has been seen during the postflight period, at least with current flight durations. Inflight

Skeletal muscle atrophy and loss of strength are long-known consequences of space flight. Like bone, skeletal muscle is also dynamic and depends on relative balances of demand based on loading forces and metabolic factors regulating synthesis and breakdown. Changes in muscle manifest more quickly than changes in bone, because bone involves more long-term deposition of mineral salts. Practically, this process is influenced by nutrition, exercise countermeasures, and individual genetic disposition. Muscle atrophy is associated with negative nitrogen balance, which was observed as early as the Apollo program and more thoroughly characterized in the Skylab program. Significant losses of urinary nitrogen and phosphorus were documented during these flights and associated with observed reduction in muscle tissue [72]. Losses were accentuated during the first week, most likely correlating with the relative anorexia accompanying the first several days of the flight. In postflight evaluations, corresponding losses of strength relative to preflight measurements, particularly in the lower extremities, were seen, with strength loss in extensors reaching nearly 20% and that in flexors ranging from 10% to 17% after the first two crewed Skylab missions [85]. After the first Skylab mission, in which physical countermeasures consisted only of bicycle ergometry, additional exercise capability was added to the next two missions; this additional capability consisted of mild resistive exercise and a slippery surface to serve as a surrogate treadmill to allow running and jumping under loads. Additional food was also supplied with the intent of increasing food intake. Muscle loss was much diminished compared with the loss experienced during the first mission, but still persisted [85]. Although coupled with comprehensive nutritional and metabolic studies, the Skylab data on muscle loss were influenced by the small sample size (only nine crewmembers total) and substantial variations in nutritional states and availability of exercise countermeasures among the missions. Subsequent flight experiments on the Space Shuttle and with Russian station crews have extended the Skylab findings and allowed better characterization of the effects of weightlessness on skeletal muscle, as noted briefly below. A basic understanding of skeletal muscle structure is helpful for interpreting space flight findings of muscle morphology. Demands on skeletal muscle with regard to power and endurance vary with required function and hence distribution throughout the body. As such, differences in morphology and supportive metabolism exist that serve to optimize functionality

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in these different roles. Broadly peaking, skeletal muscle can be distinguished by fiber type, driven by these structural and functional differences. The diameter, velocity of contraction, and ability to utilize different metabolic fuels are basic determinants of fiber type. Individual skeletal muscles consist of a combination of the three basic muscle fiber types, with their proportions depending on the action of that muscle as well as genetic influences. Type I fibers, slow-twitch fibers with slow contraction velocities, primarily utilize oxidative metabolism as an energy source and are resistant to fatigue. Type I fibers are relatively small in diameter, contain large amounts of myoglobin to enable oxygen utilization and delivery, and are rich in capillaries and mitochondria. These types of fibers are distributed in greater proportions in postural muscles, such as the lower extremities (soleus), back, and neck, which are nearly constantly active in maintaining posture in 1 G. Type II fibers are fast-twitch fibers with high contraction velocities and are further divided into IIa and IIb types. Type IIa fibers utilize oxidative and glycolytic metabolic energy sources, and so they also contain myoglobin and are relatively rich in capillaries and mitochondria. Type IIa fibers are moderately resistant to fatigue and are recruited for exertions requiring a high force output for a short amount of time. Type IIb fibers are relatively large in diameter and utilize primarily anaerobic energy sources such as glycogen and creatine phosphate; they contain low levels of myoglobin and relatively few capillaries and mitochondria. Type IIb fibers support high-power, short-duration exertions, such as lifting, sprinting and jumping, and they fatigue rapidly. Type IIb fibers are distributed in greater proportions in the arms and shoulders as well as the gastrocnemius. Measurement of muscle volume and cross-sectional area by imaging provides an objective means of assessing skeletal muscle changes associated with space flight. These changes can be augmented by strength and power assessments, along with the occasional histologic studies requiring muscle biopsy, to fully assess the effects of weightlessness on skeletal muscle. As expected, the postural muscles tend to be most affected in their relatively unloaded state in weightlessness. Calf muscle loss after the initial fluid-shifting response to weightlessness contributes to the “bird legs” appearance of crewmembers during space flight. Less expected was the rapidity with which these changes manifest themselves in weightlessness. Volumes of postural muscles in four individuals after an 8-day Shuttle flight, as assessed by magnetic resonance imaging at 24 h after landing, showed the following changes: posterior calf (soleus-gastrocnemius), −6.3%; anterior calf, −3.9%; hamstrings, −8.3%; quadriceps, −6.0%; and intrinsic back −10.3% [86]. Similar muscle group assessments in four individuals after a 17-day flight revealed a muscle volume decreases of 3−10% in all muscles measured [73]. In another study involving magnetic resonance imaging, three astronauts flying 9-, 15-, or 16-day flights had volumes of knee extensor, knee flexor, and plantar flexor muscles assessed before and after flight. All showed volume reductions, ranging from

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5.5% to 15.4% for knee extensor, 5.6–14.1% for knee flexor, and 8.8–15.9% for plantar flexor [87]. Postflight biopsies of vastus lateralis muscle after 5-day and 11-day Shuttle flights in eight astronauts showed 6–8% fewer type I fibers than preflight measurements. After the 5-day flight, cross-sectional areas were diminished by 11% for type I fibers and by 24% for type II fibers. The number of capillaries per fiber was diminished by 24%, although the ratio of capillaries to overall muscle cross-sectional area remained constant. Metabolic changes in energy substrate utilization also differed among fiber types; myofibrillar adenosine triphosphate activity was increased after flight in type II but not type I fibers [88]. Longduration flights, in which the steady-state effects of physical countermeasures are more influential, show similar volume losses, suggesting a plateau effect. Cosmonauts have shown loss of posterior calf volumes of 6–20% after 6-month flights on the Mir station [89]. Very little has been published regarding losses in upper extremity strength and mass since the early Skylab flights, when deliberate countermeasures targeting the arms were not available or in development. The second and third Skylab crews, which made use of a dedicated resistive exercise device, demonstrated negligible losses in strength except for arm extensors in the third crew, mostly accounted for by a single individual [85]. Since that time, more definitive countermeasures preserving upper extremity muscle groups have been available during long-duration missions. Investigations of strength loss subsequent to the Skylab era have helped to further characterize skeletal muscle behavior in space flight. Strength data from 17 individuals after Shuttle flights of up to 16 days are shown in Table 2.5, classified by concentric (muscle shortening against a load) and eccentric (muscle lengthening against a load) test contractions [90]. Again, more strength was lost in the lower extremities and postural muscles than in the upper extremities. Lambertz et al. found that after flights lasting 90–180 days, 14 individuals showed a mean 17% decrease in isometric plantar flexor torque during maximal voluntary contraction [91]. Postflight assessments of quadriceps and hamstring for 12 individuals after 4- to 6-month flights on the ISS are shown in Figure 2.6 [76]. Maximal power of the lower limb, as assessed by force platform measurements and by short, intense bouts of cycling, has been shown to decrease by 54% after 21 days of flight [92] and by 50% after 169- to 180-day flights [93]. Some have proposed that a new steady state is established after roughly 110 days in microgravity, and further losses in peak limb muscle torque would not be expected after this time [94]. In spite of the losses in muscle strength and mass due to atrophy, contraction velocity has consistently been elevated after both short-duration [95] and long-duration flights [91,96]. This phenomenon partially compensates for the mass loss to preserve muscle power. In a thoughtful review of muscle behavior in space flight, Fitts and colleagues noted that although loading is the guiding determinant of muscle size, the major mechanism for muscle protein loss and atro-

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TABLE 2.5. Mean percent changes (landing day vs preflight) in skeletal muscle strength in 17 crewmembers after Space Shuttle missions up to 16 days. Test mode Muscle group

Concentric

Eccentric

Back Abdomen Quadriceps Hamstrings Tibialis anterior Gastrocnemius/Soleus Deltoids Pectorals/Latissimus Biceps Triceps

−23 (±4)* −10 (±2)* −12 (±3)* −6 (±3) −8 (±4) 1 (±3) 1 (±5) 0 (±5) 6 (±6) 0 (±2)

−14 (±4)* −8 (±2)* −7 (±3) −1 (±0) −1 (±2) 2 (±4) −2 (±2) −6 (±2)* 1 (±2) 8 (±6)

*

p < 0.05. Source: From Greenisen et al. [90].

FIGURE 2.6. Mean percent change (± standard error) from preflight values in isokinetic strength of quadriceps (knee extension) and hamstring (knee flexion) for 15 crewmembers after return from ISS Expeditions 1–12 [76]

phy seems to be a decline in synthesis without an increase in muscle breakdown [94]. This observation underscores the importance of adequate nutritional support to augment physical countermeasures during space flight.

Inflight Physical Performance After reviewing the reactions of the body systems that contribute most directly to human physical performance, it seems appropriate to consider this aspect of crew capability during the inflight period as well. Apollo medical testing showed a significant postflight decrease in oxygen uptake for a given exercise load, with heart rate significantly elevated for a given level of oxygen consumption on return day as compared with preflight values [97]. Of all 27 of the Apollo crewmembers, 20 showed significant decreases in exercise tolerance on return day, which largely resolved within 24–36 h [8]. These findings, along with other early observations, prompted further

in-depth investigation on Skylab into human performance in anticipation of longer-duration missions. The constellation of factors associated with adaptation to weightlessness includes several that might be expected to decrease performance, such as blood volume loss, hypokinesia with resultant skeletal muscle loss, and nutritional deficits. Assessment and eventual optimization of human physical performance with regard to these and other medical variables broadly has a twofold aim: supporting the successful completion of mission objectives and ensuring crew health during and after the mission. The chief physical challenges associated with space flight are associated with EVAs, entry, and landing. Physical assessments and countermeasures are oriented in part toward these activities. A performance decrement may be tolerable if the required functionality is maintained with an adequate margin and sufficient capability returns after flight to support long-term crew health. Results from cardiovascular evaluations of exercise capacity reflect in part the method of assessment and whether that method accounts for the peculiarities and artifacts of weightlessness to make comparison with preflight findings meaningful. Cycle ergometry is relatively transparent to the effects of weightlessness, and metabolic rates associated with a given level of cycle exercise are unchanged from preflight levels [8]. The same may not be true in assessments of activities that normally require postural muscles for stability, such as upright locomotion and resistance-force assessments simulating weight lifting. Both inflight findings and ground predictions would seem to indicate a decrease in mechanical efficiency associated with treadmill exercise in weightlessness [98]. Therefore assessments of cardiovascular fitness are typically made by using graded cycle ergometry. Variables measured in these assessments typically include heart rate and blood pres. sure. Oxygen uptake [VO2] is a valuable integrated variable measured to assess exercise capacity, which reflects global cardiovascular function. Oxygen uptake has been calculated from heart rate and blood pressure and from preflight data, or it can be measured directly by analyzing metabolic gases, typically as part of a research protocol. Echocardiographic findings during inflight exercise have also contributed to our understanding of inflight cardiovascular fitness. Safety concerns preclude testing to maximum levels during flight, although crewmembers are not prohibited from exercising to max levels during personal exercise sessions. All assessments are monitored by inflight and ground personnel. Skylab crewmembers did not show appreciable inflight decrements in mechanical efficiency during cycle ergometry, and in fact six of the . nine crewmembers demonstrated a slight increase. Inflight VO2 decreased slightly in six crewmembers for a given. workload (determined as 75% of preflight maximum VO . 2), and . heart rate generally increased slightly for a givenVO2 [8].VO2 measured for four individuals during a 17-day Shuttle flight exercising at a workload corresponding to 85% of maximal capacity progressively decreased to a value of −11.3% on flight day 13 [99]. The change in estimated

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. VO2 for 15 ISS crewmembers during long-duration flight is depicted in Figure 2.7 [76]. Physician-cosmonaut Atkov and colleagues assessed echocardiographic variables during cycle exercise of two crewmembers during an 8-month space flight. Resting left-ventricular end-diastolic volume and stroke volume were lower during flight than before, and resting heart rate was 10–12 beats per minute faster, maintaining cardiac output at essentially unchanged levels. Measurements during exercise at 175 watts revealed decreases in stroke volume of 30% and 25% for the two crewmembers, with respective increases in heart rate of 16% and 11%, compared with preflight. An increase in cardiac output from exercise was 13–15% lower than preflight values at the same level of exercise, and was attributed to changes in heart rate only. Myocardial contractility was not compromised, suggesting that diminished circulating blood volume was primarily responsible for the decreases in stroke volume and left-ventricular end-diastolic volume [30]. These results have been corroborated by other long-duration flight studies aboard the Mir station [100] and aboard short-duration flights. Shykoff et al. noted a noted a lesser increase in cardiac output and a smaller stroke volume for a given workload in six crewmembers during two Shuttle flights [28]. EVAs primarily require upper body strength, which is generally preserved in weightlessness. However, preflight training during water immersion to simulate neutral buoyancy, while crewmembers are not deconditioned and are exercising normally, is highly demanding. Upper extremity soreness and fatigue after EVA training as well as actual EVA is common. Because upper body performance is crucial to the success of EVAs, physical countermeasures to maintain arm and shoulder strength in a high state of fitness, along with the means to monitor the effectiveness of countermeasures, are prudent during long-duration flight. In summary, crewmembers can maintain slightly diminished but nevertheless high levels of aerobic capacity and

FIGURE 2.7. Mean percent change (±. standard error) from preflight values in estimated oxygen uptake [ VO2] index for 15 crewmembers after return from ISS Expeditions 1–12 [76]

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upper extremity strength during flight. An increase in cardiac output in response to exercise primarily results from an increase in heart rate rather than a change in stroke volume, and in general cardiac output for a given workload does not attain the same level as before flight. Reduced blood volume rather than cardiac impairment seems to be the dominant effect influencing altered cardiovascular dynamics, and these effects are expected to be accentuated upon Earth return and upon transition from relative to absolute hypovolemia.

Neurological Findings On Earth the visual, vestibular, and somatosensory systems use gravity as a reference for orientation. In the absence of gravity, new strategies for positional sensing are used, most likely involving a reweighting of visual, otolith, and perhaps tactile and somatic signals [101]. Several sensorimotor changes have been demonstrated during flight, including slowed pointing responses [102], degraded manual tracking performance [103], attenuation of postural responses [104], and occasional illusory motion of the self and visual surround [105]. Like the cardiovascular and respiratory systems, the neurological system undergoes changes that by and large are not associated with impairment. Unlike changes in other systems, neurological changes are less likely to be manifested in standard observations, and clinical neurological tests are not available aboard the ISS. Sophisticated, directed investigative methods would be required to detect and quantify changes in neurological functioning during flight. The exception is space motion sickness, which does breach the clinical horizon and most likely results largely from this process of adaptation and reorientation. Other than that, clinically relevant, functional consequences of changes in neurological system functions are not problematic during flight. The major manifestations are in the form of reentry and postlanding phenomena. Chapter 17 discusses neurological findings in detail. The typical spacecraft environment is not particularly challenging with regard to body motion control. Spacecraft are relatively confined, and the stowage and placement systems rely on an artificially defined vertical. Crewmembers occasionally report transient disorientation, especially when moving to different modules, but in general these perceptions diminish with time and do not affect operations. Turning one’s attention to outside the spacecraft or station, as is needed for robotic operations, docking, and rendezvous activities, changes the sense of orientation and may induce greater motion control challenges. In these activities, operative cues rely largely on camera views and interpretation of numerical data to determine the positions of objects being manipulated in space. These views may be supplemented with dynamic virtual views, constructed in real time with positional data inputs and displayed to the crewmember. Such inputs augment whatever direct visual cues may be used, which are sensitive to lighting and orientation.

2. Human Response to Space Flight

Adaptation mechanisms seem to serve flight crews well during normal flight activities. Crewmembers have been able to perform complex tasks requiring fine motor control routinely during space flight, indicating adequate integrated functioning of the neurovestibular and somatosensory systems. Aside from the external operations noted above, typical on-board tasks include operation and sometimes intricate repair of equipment, animal dissection, wiring and soldering, among others. Beyond sensorimotor implications, the role of the neurological system in cardiovascular control and blood pressure regulation is probably the next most important consideration. Inflight investigations have shown exaggerated catecholamine responses to physical stress challenges such as exercise [106] and LBNP [50], indicating maintenance of the sympathoadrenal system. Vagal activity seems to be attenuated, as indicated by diminished vagal baroreflex gain in inflight measurements of response to the Valsalva maneuver [48,107] and diminished heart rate variability [48].

Renal and Endocrine Systems Renal function and hormonal regulation of body systems in response to physical challenges are complex and interactive, highly sensitive to outside influences, and often require specialized and rigorously controlled investigative techniques to isolate a relevant finding from other influences. In addition, conditions associated with space flight other than weightlessness can influence endocrine function, including physical and psychological stress, confinement, heat stress, and dietary changes. As such, much of the knowledge of endocrine system behavior in space flight is incomplete, and reported findings are at times contradictory and inconclusive. Findings that seem to be consistent across studies or those particularly relevant to understanding the clinical picture will be discussed here. Much of what is known relates to the role of the renal and endocrine systems in the adaptation of fluid and plasma volume regulation to weightlessness. Beyond the general observations seen in the acute stages of adaptation, most of these changes are clinically transparent but are described briefly here to be understood as possible new clinical norms. Many of the predicted findings with regard to renal and endocrine control of fluid regulation in weightlessness have not been realized. Decades ago, Gauer and Henry elucidated mechanisms whereby different process leading to an increase in intrathoracic volume would be sensed as an overall volume overload and elicit diuresis of water and salt, mediated in part by volume sensitive stretch receptors [108]. Indeed, water immersion, used as an analog for weightlessness, has long been known to cause a brisk water diuresis resulting from central fluid shift [109,110]. It was anticipated that neutralization of hydrostatic forces in weightlessness would have effects similar to those of immersion, with subsequent cardiac distension, baroreceptor stimulation, and decreases in antidiuretic hormone (ADH) levels and in the activity of

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the renin/angiotensin/aldosterone axis as fluid volume is reduced to a lower level. Although volume does contract fairly rapidly upon entering weightlessness, other findings are somewhat paradoxical when compared with a classical Gauer-Henry response. The absence of diuresis and decreases in fluid intake were noted during the Apollo [5] and Skylab [111] programs. However, it has taken more complicated payloads supporting sophisticated inflight investigations to further elucidate the events associated with fluid regulation. The well-documented findings of thoracic fluid shift, cardiac chamber expansion, and rapid volume contraction within the first 24 h of space flight occur against a backdrop of apparently decreased intrathoracic pressure, decreased urine output, and decreased oral fluid intake, as noted in the discussion on cardiovascular response, and has been described in both the US and Russian programs [15]. Arguably the most thorough inflight investigation to date on fluid regulation during short-duration flight has been the Spacelab Life Sciences (SLS)-1 and SLS-2 flight experiments described by Leach and colleagues [112]. To summarize, the lack of diuresis and low fluid intake were confirmed, with no change in serum osmolality. The glomerular filtration rate was seen to increase early and remain elevated for at least a week. Creatinine clearance was slightly decreased on flight day 1 (FD1) but normalized by FD2 and remained normalized thereafter. Volume contraction was most marked within the first 48 h and was characterized by a decrease in extracellular fluid, increase in intracellular fluid, and total body water remained unchanged. ADH levels increased by a factor of four on FD1, returning to preflight levels by FD2. This elevation in ADH may seem paradoxical in lieu of decreased thirst; however, ADH has been seen to increase in response to physical stress [113] and in response to motion sickness provoked via the Coriolis effect [114]. Plasma renin activity and aldosterone levels decreased significantly by FD1, then gradually increased toward normal levels. Atrial natriuretic peptide, which normally increases in response to the distention of atrial stretch receptors in volume overload, tended to decrease during the course of the flights. The SLS-1 and SLS-2 investigations confirmed that volume contraction does occur but that it is not primarily brought about by water or sodium diuresis. Interestingly, infusion of saline during space flight was associated with a significantly attenuated volume and sodium excretory response compared with preflight values when the subjects were supine; plasma norepinephrine and renin levels approximated preflight seated levels, whereas aldosterone levels were between preflight supine and seated levels [115]. These findings led Gerzer [116], Norsk [115], and others [117] to posit a previously unrecognized large body capacity for extravascular storage of sodium, uncoupled from normally understood water balance mechanisms. Further details on this and other investigations into fluid regulation in weightlessness are provided in Chap. 27.

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Another observation in the SLS studies was the inference of decreases in sweating and insensible fluid losses [112]. These variables were noted to be decreased in Skylab crewmembers by 11% relative to preflight values, and the decreases were attributed to the buildup of a sweat film during exercise owing to the absence of gravity and convective forces, exerting a suppressive effect on further sweat production [118]. These findings, along with the observation of increased core temperature for comparable levels of exercise and decreased sweating 5 days after return from long-duration space flight relative to preflight values [119] suggests that multiple mechanisms may affect thermoregulation during flight. Several factors associated with space flight interact to increase the risk of nephrolithiasis. Mobilization of calcium and phosphate from bone begins rapidly in weightlessness. Analyses of urine samples collected before and after Space Shuttle flights show significant increases in the relative supersaturation of the stone-forming salts calcium oxalate, calcium phosphate (brushite), and uric acid as well as low urine volume, low pH, and hypocitraturia [120]. Studies on long-duration flights involving inflight urine collection demonstrate similar findings of hypercalciuria and increases in urinary concentrations of stone-forming salts [121]. The relative hypovolemia associated with Earth return makes this a particularly vulnerable period [122]. One probable event of inflight nephrolithiasis occurred in the Salyut program [123], and several events have been seen clinically in the immediate postflight period after short-duration flights. This topic is discussed in detail in Chap. 13. Stein and colleagues conducted studies of inflight urinary hormone levels associated with the SLS-1 and SLS2 missions [124]. Norepinephrine levels were decreased but epinephrine levels were maintained at normal levels throughout the flights. Further analysis of the catecholamine findings revealed a sex difference in norepinephrine, with three female crewmembers showing essentially no change and four male crewmembers showing significant decreases [125]. Levels of free 3,5,3¢-triiodothyronine, prostaglandin E2, and its metabolite prostaglandin EM were decreased during flight relative to preflight levels, which could be related to muscle atrophy. Cortisol levels were significantly increased on FD1 only but tended to be higher than preflight values throughout the flights. In other studies, cortisol levels have been shown to remain unchanged [126] or to increase, possibly related to stress [127]. Concern has been expressed over suppression of thyroid function during flight from exposure to pharmacologic doses of iodine, used on the Space Shuttle to disinfect potable water. McMonigal et al. documented a transient increase of thyroid-stimulating hormone in postflight laboratory studies of Shuttle crewmembers suggestive of thyroid suppression, which resolved after installation of equipment that removes iodine before drinking the water [128]. No increase has been detected in the incidence of clinical thyroid disease associated with this iodine exposure.

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Inflight data from long-duration flights are fewer. Skylab studies of urinary hormone levels showed increases in aldosterone, cortisol, and total 17-ketosteroids, whereas epinephrine, norepinephrine, and ADH levels tended to be lower during flight than before. Plasma cortisol levels were also elevated, though not always significantly [111]. The 438-day flight of physician-cosmonaut Polyakov revealed that plasma renin activity, ADH, and aldosterone were maintained within normal clinical limits, but atrial natriuretic peptide levels remained lower during flight than before [129]. Both epinephrine and norepinephrine were significantly increased at 5 and 9 months but within normal limits in the early and late mission stages. Adrenocorticotropic hormone and cortisol did not show consistent changes [129]. A few other hormonal responses to space flight have been noted. Parathyroid hormone, which is relevant to calcium homeostasis and bone metabolism, is discussed in the preceding section on the musculoskeletal system. Insulin resistance is known to develop in individuals in sedentary conditions, and this has been observed in space flight [130,131]. Considering space flight to be a physiological stress, Strollo and colleagues studied four individuals, expecting a decrease in testicular androgens mediated through the pituitary gonadotropin luteinizing hormone. Salivary, urinary, and plasma testosterone were found to be diminished during flight, along with a decrease in sex drive as assessed by questionnaire. However, luteinizing hormone levels were found to be paradoxically increased [132]. The causes remain to be elucidated, although salivary testosterone levels were noted to recover by return day one.

Gastrointestinal System That gravity has a role in digestion is evident to anyone who has tried to eat while recumbent; there is a definite assist in assuming the upright position for swallowing and esophageal transit. Although the gastrointestinal (GI) tract follows a circuitous and convoluted route, the general gradient is favored by the upright posture. Arun has speculated that a “loss of polarity of propulsion” of digested material occurs in microgravity as the bowel floats but that this effect is partially compensated by movement that is driven by diaphragmatic excursions [133]. Bowel activity seems to be diminished during the first hours to days of flight, as assessed by electrogastrography [134] and by recording of bowel sounds [135]. This reduction in bowel activity seems to be related to space motion sickness, and by and large it clears after a few days. A study of GI function involving a lactulose-hydrogen breath test showed a trend toward increased transit time, but these findings, from only two individuals, were considered inconclusive [136]. Russian studies have documented hyperacidity during long-duration flights that seems to arise after about 3 months in flight [137]. This observation, along with evidence of slight hepatic and pancreatic enlargement on sonography (apparently due to edema), slowed gastric emptying and

2. Human Response to Space Flight

gastrointestinal motility, and mild pancreatic insufficiency are considered to reflect digestive tract adaptation to long-duration flight [131]. Nevertheless, digestion does not seem to be clinically problematic in weightlessness. Crew reports of esophageal reflux, abdominal distension, or other GI complaints do not seem to be more common in space than on Earth, with the possible exception of constipation. The weight loss typically seen associated with long-duration space flight can be primarily accounted for by decreased energy intake. Further study is warranted, however, to better define the effects of weightlessness on GI function with regard to nutritional utilization and the bioavailability of pharmacologic agents.

Inflight Clinical Laboratory Findings Laboratory studies have been an important part of preflight and postflight medical evaluations since the first space flights. Postflight findings, however, are almost certainly influenced by the multisystemic readaptation process associated with return to gravity and thereby reflect a combination of weightlessness and 1-G effects. Blood and urine samples are occasionally collected during short flights for investigational purposes; typically samples are stored frozen or otherwise preserved to allow postflight analysis in definitive ground-based laboratories. During long-duration flight, limited inflight analytical capability is available to support two main clinical functions—assessment of selected blood values that are either relevant to periodic health assessments or used for diagnosis and monitoring of a clinical problem. The results may also be used investigationally, but their primary worth is in determining clinical normative values for space flight and detecting potential health anomalies that may require remediation or further research. The Russian medical support program has used an onboard analyzer to periodically measure enzymes in blood samples during long-duration flight. Preflight baseline values are obtained for each variable to be measured inflight. In an assessment of 17 Mir station crewmembers, increases were seen in fasting levels of glutamic-oxaloacetic transaminase, glutamate pyruvic transaminase, total amylase activity, glucose, and total cholesterol; decreases were noted in creatinine kinase activity, hemoglobin, high-density lipoprotein, cholesterol, and the ratio of high-density to low-density lipoprotein. Despite these apparent changes, values remained within normal clinical limits [138]. The US space program has made use of a smaller clinical analyzer to assess primarily electrolyte values during periodic health evaluations aboard long-duration missions on the ISS [139]. The findings are inconclusive as yet, but suggest that most values remain within clinically normal ranges. Periodic inflight urinalysis is performed with chemical reagent sticks. Results are generally remarkable only for specific gravity tending to be high (between 1.025 and 1.030), reflecting a state of reduced hydration. No proteinuria has been seen, consistent with the observation that

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urinary albumin excretion is reduced in long-duration flight compared with preflight values [140].

Entry and Landing The cadence of entry and landing day varies considerably with the type of flight. Free-flying spacecraft such as the Apollo capsules and Shuttle simply reconfigure controlling software and systems and land. The Soyuz, and at times the Shuttle, may be returning after separation from an orbital station such as Mir or the ISS. If a mission involves crew rotations on an orbiting station, that implies a handover between the departing crew and the oncoming crew, which typically takes place over several time- and labor-intensive days. Crew rotations aboard the Space Shuttle may also involve cargo transfer, EVAs, and robotics activities during this period. Activity density during such docked operations is high, and often crewmembers depart with some degree of fatigue. The Shuttle usually loiters on orbit for a day or two after separation, whereas the Soyuz lands within a few hours after separating from the station. In anticipation of descent, crewmembers don the same pressure suits as are used for launch for protection in case of loss of pressure. The return from low Earth orbit is fairly brief. After a lowthrust braking burn that serves to lower the orbit to a point sufficient for atmospheric drag to further decelerate the spacecraft, less than 1 h remains until landing. As is the case for launch to orbit, the crew must pass again through the velocity barrier that sustains their orbit, decelerating from 7.8 km/s to 0 relative to the Earth surface. Acceleration loads are again present, but for landing the prime source of these loads is the braking effect of the atmosphere rather than engine power, with the direction of the loading dependent on vehicle and crew orientation to the entry velocity vector. In both launch and landing, physical loads beyond the orbital or terrestrial norms separate crewmembers from either endpoint. The nowdeconditioned crewmembers do not transition cleanly back to 1 G but rather pass through a hyperloaded state, inducing greater physiologic stress and influencing the clinical profile and readaptation process. It is during entry that the effects of gravity and the implications of the relative deconditioning are first felt. As is true for launch, landing is a dynamic and dangerous phase of flight, with critical control inputs and event monitoring required of crew and ground personnel. Moreover, for crews returning after a long-duration flight, formal high-fidelity training may have taken place more than 6 months earlier. For Soyuz crews, inflight refresher training is provided before landing with laptop-based simulator programs and procedural reviews. Shuttle flight crewmembers with piloting and monitoring duties are constrained to short duration flights. Crew duties during entry and landing vary, but as a minimum, required flight crew monitor engine operation during the deorbit burn and the postburn maneuvering, guidance and navi-

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gation, and vital spacecraft systems, being ready to assume manual control if needed to respond to contingencies. This monitoring requires vigilance and fairly intense concentration, as well as close communication with the ground and among other crewmembers. Control inputs and instrument scans may require occasional head movements, which may be both provocative and adaptive with regard to motion sickness. As noted in Chap. 1, each vehicle has a characteristic entry G-profile to which the crew is subject. The Space Shuttle is unique in that crewmembers are seated in the upright position, thereby incurring body +Gz loads during entry and landing. Crews returning from long-duration missions (for this purpose arbitrarily defined as 30 days) are situated in a recumbent seat system on the middeck to circumvent these loads, and thus take the prolonged 1.2 G primarily in the body +Gx direction. The Soyuz places all crewmembers in the recumbent position, as did the US space capsules. In either type of spacecraft, measures are taken to protect crewmembers from the effects of cardiovascular adaptation, which begins to transition from a state of relative to absolute hypovolemia at the first onset of G loads. Crewmembers begin a program of oral fluid and salt loading before the deorbit burn to increase their vascular volume, and they don anti-orthostatic garments beneath their launch and entry suits. The Shuttle suit accommodates a pneumatic anti-G garment with pressure bladders controlled by the crewmembers, along with active liquid cooling. Soyuz suits use gas cooling and accommodate a highly customized elastic garment, primarily for postlanding anti-G protection. Cardiovascular reactions are among the first to manifest during entry and landing. An increase in heart rate is a sensitive indicator of orthostatic stress and is expected during landing. Crewmembers returning on Soyuz undergo active monitoring by electrocardiography, sensed cardiac contractions, and respiratory rate. In a comparative study of 16 crewmembers returning on Soyuz after short (8–21 days, 4 subjects) or long (186–380 days, 12 subjects) Mir station flights, Kotovskaia and colleagues noted more pronounced sinus tachycardia and a greater frequency of arrhythmias, neurovestibular effects, labored breathing, speech difficulties, and petechial hematomas in the back in the long-duration crew as compared with the short-duration crew during entry monitoring [141]. Arrhythmias consisted primarily of isolated monomorphic extrasystoles for the short-duration crews, joined by polymorphic and occasional grouped extrasystoles for long-duration crews. However, no changes in consciousness and no visual disorders were noted, supporting the protective effect of crew orientation and anti-G countermeasures. In an investigation comparing three individuals returning in a recumbent position from a 4-month flight on the Mir station with a larger pool of upright Shuttle flight crewmembers returning from short-duration missions, heart rate was seen to be 25 beats per minutes lower in the recumbent crewmembers than their seated counterparts on prior missions. This difference was abolished upon standing, during which heart rate increased in both groups to the same extent [142]. This observation again

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supports the efficacy of recumbent seating in returning from weightlessness. Although the numbers are small, observations suggest that female crewmembers returning on the Soyuz are physiologically stressed to a greater extent than their male counterparts if the anti-G garment is not worn; use of the garment abolishes the sex difference [143]. Neurovestibular disturbances are also expected to begin with the onset of entry loads, as the otoconia again assume weight and the ability to signal independent of head movement, as visual cues transition from a three-dimensional reference frame to an inherent vertical, and as proprioceptors and other positional sensors detect direct and indirect effects of body weight and movement. Unlike monitoring for cardiac activity, direct monitoring of vestibular function is complicated and thus is not performed during landing. Subjective reports have been given of vestibular disturbances provoked by head movements out of the velocity vector. Cosmonauts report sensations of positional illusions and mild vertigo during entry, which are more frequent with longer exposures to weightlessness [141]. Crewmembers are taught to minimize provocative head movements and, as is true for the aviation environment, to “believe their instruments.” The Shuttle becomes a highly complex aircraft at the end of a mission, and it is precisely guided to a manual landing by the flight crew after flights of up to 17 days. Neurovestibular disturbances that may be occurring during entry seem to be largely compensated by training, task focus, and flight instruments, although continued analysis and vigilance in this area is warranted. Spacecraft landings are highly planned and rehearsed operations, with recovery personnel standing by to assist crewmembers and help ensure the safety of the vehicle. However, spacecraft can and have landed off target. In addition, emergency deorbit, either from a suddenly uninhabitable station (e.g., fire, loss of pressure) or from a major systems problem with the primary spacecraft, could cause a landing at an unplanned time. These possible scenarios compel the crew to maintain some degree of self-sufficiency and possibly require higher levels of performance in the postlanding period.

Postlanding Period At the words “contact” during landing in the Soyuz, or “wheelstop” during Shuttle landing, the dynamic phase of space flight is over and much of the psychological stress associated with space flight is relieved. Crew duties in the immediate postlanding period involve powering off unneeded equipment and ensuring safe configurations of engines and cooling systems that may be hazardous to recovery personnel. For nominal landings, none of these duties require that the crew stand or manipulate heavy loads before vehicle egress; for both Soyuz and Shuttle, crewmembers are typically aided by recovery and medical specialists within several minutes. Returning long-duration flyers describe a profound sense of “heaviness”

2. Human Response to Space Flight

in the minutes after landing, especially noted with the first limb movements made while unfastening the restraints. In spite of active cooling systems, heat stress is common for landing crews because of the pressure suit and vehicle heating during entry and on the ground after landing. Passive readaptation to normal gravity is occurring during this time. Many of the processes involved in adaptation to weightlessness now proceed in reverse during Earth readaptation. Returning to gravity and its resulting hydrostatic gradients and the reintroduction to the upright posture demand a return to the 1-G volume status and reawakening of regulatory circuits. Those systems most sensitive to loading forces, such as cardiovascular and volume control, muscle, and bone, both declare themselves during adaptation to weightlessness and are particularly affected during readaptation. As expected, the effects of this readaptation on performance are pronounced, because the functional capacity-to-demand ratio, which was more positive on entering weightlessness, is now decidedly negative upon returning to gravity. In addition, a neurovestibular system accustomed to weightlessness must now interpret gravitational cues and guide purposeful body and eye movements in Earth’s constant gravity. Although readaptation begins immediately, systems return to preflight functional levels at different rates. The dominant clinical entities associated with immediate return from space flight are orthostatic intolerance and neurovestibular impairment. They can occur individually or in combination, and entry adaptation syndrome may lead to emesis, which can further degrade volume status. These entities, which most affect human performance in the immediate postlanding period, are discussed in greater detail below. Further information on areas most affected can be found in systems-oriented chapters (cardiovascular, neurological, and musculoskeletal) elsewhere in this book.

Orthostatic Intolerance Functionally, orthostatic intolerance can be defined as an inability to maintain adequate central perfusion when assuming an upright posture in the performance of required nominal or reasonable-risk contingency activities. Cardiovascular and blood volume status associated with adaptation to weightlessness produces, upon landing, a state of acute hypovolemia and absolute anemia, which combine with decreases in baroreceptor sensitivity, cardiac mass, and lower-extremity muscle mass to diminish venous valvular function and render crewmembers more vulnerable to orthostatic intolerance. Consistent cardiovascular findings in the postflight period include decreased stroke volume and increased heart rate for crewmembers after both long-duration [38] and short-duration missions [12,144]. Convertino [145] and others have identified orthostatic intolerance as the most significant operational cardiovascular risk associated with space flight and have appropriately made orthostatic intolerance a major focus of study, both to determine its causation and to develop countermeasures for it.

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Investigationally, cardiovascular functionality in the postflight period is often equated with stand test results; however, the results require some interpretation. These tests were designed largely to delineate mechanisms of physiological response rather than to assess functionality, and they typically proceed to near-syncope or voluntary cessation by subjects due to symptoms. Orthostatic intolerance as determined by stand testing correlates with, but is not equivalent to, postflight functionality. In the hundreds of short-duration flight experiences to date, postflight syncope is rare. Remaining motionless in the upright position does not allow movement of the lower extremities or cycling of the venous valves to aid in augmenting the preload. Highly fit normovolemic individuals occasionally fail this test before flight, and some crewmembers have been upright and ambulating for 1 or 2 h after short-duration Shuttle flight before performing and failing to finish a stand test. Buckey et al. have noted that reported failure rates during investigational stand testing vary from 10% to as much as 64% depending on the working definition of orthostatic intolerance and methodologic variables such as tilt angle and duration of upright posture [12]. Thus, stand testing should be viewed as an objective and clinically useful tool to delineate mechanisms of orthostatic intolerance and guide the development of countermeasures, but it should not be used as a singular clinical assessment to determine postflight functionality. Stand testing does allow controlled and detailed comparisons of physiological characteristics between those who finish and those who do not. Given the hypovolemic state common to all returning crewmembers, those who are able to complete a stand test are distinguished from those who are not by relatively greater peripheral vascular resistance [12,146]. Previous findings suggest impairment of the baroreflex response associated with space flight [45,46], possibly most prominent in those crewmembers who cannot finish the test. Release of norepinephrine has been shown to be lower in those who do not finish relative to those who do [146]. More recent studies show that most of the baroreflex response to orthostatic stress remains functional following space flight [12,146,147]. The observation that sympathetic tone was maintained in six individuals who completed a stand test after a 16-day Shuttle flight [148] and that norepinephrine release induced by tyramine was not impaired after flight [146] suggests that the efferent limb of the baroreflex remains intact and that those who can finish the stand test are in part distinguished by their sympathetic response. Noting an increase in ADH and epinephrine in non-finishers, Meck and colleagues suggested that the afferent limb of the baroreflex also remains intact, pointing toward an impairment in central integration of this reflex resulting from space flight [146]. Although the exact mechanism limiting the vasoconstrictive response remains to be delineated, reduced blood volume and impaired ability to vasoconstrict appear to be the dominant factors associated with post-flight orthostatoic intolerance. Sex differences have also been observed during stand testing, with men faring better than women in completing stand test protocols [149].

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Further investigations may better delineate the mechanisms that maintain blood pressure after flight. However, crewmembers freshly returned from weightlessness are above all treated as clinically hypovolemic. Crewmembers are typically thirsty in the few hours after landing, and vigorous oral volume repletion is provided. Urine and sodium output are decreased on landing day, and a three-fold increase in ADH has been measured [112]. Maintaining cooling to prevent undue peripheral vascular dilatation is crucial. Use of a liquid-cooling garment during entry and landing has been associated with significantly lower heart rates upon standing after Shuttle flights, independent of use of the anti-G suit [150]. Doffing the entry suit as early as possible after landing is recommended to avoid further heat stress. Long-duration crewmembers are maintained in the recumbent position and are brought upright only as needed and tolerated for the first few hours. Showers, one of the first desires of returning crewmembers, are kept warm but not hot to avoid undue vasodilation. Recovery of function is rapid after short-duration flights, with improvements in heart rate responses observable over several hours. After the crew is recovered from the Shuttle and changes into normal clothing, short-duration crewmembers often perform a “walk-around” to inspect the vehicle within the first 90 min or so of landing. The vast majority are able to do this without difficulty. As plasma volume is replenished, the hematologic deficit is manifested by decreases in hematocrit and hemoglobin concentration. This drop induces erythropoietin release, which has been seen to increase the day after return for crewmembers returning after both short-duration [34] and long-duration missions [151], which in turn stimulates erythropoiesis and gradual complete replenishment of erythrocyte mass back to preflight baseline. Reticulocyte counts are low on landing day and begin to increase within a few days to a week [33]. Replenishment is complete by about 3 months after return, and some recovery may actually start during flight, after the first 1–2 months in weightlessness [152]. After the 84-day Skylab flight, observed decreases in left ventricular end-diastolic volume had completely recovered by 30 days after return [38]. Regulation of body fluid compartments after short-duration flight returns to normal within a week [112]. After a 430-day flight, the hormonal response to controlled LBNP stress had returned to normal by 3 months [153].

Neurovestibular Symptoms Essentially no significant subjective neurovestibular symptoms were noted during or after Mercury and Gemini flights, presumably because of the tight volume constraints of the spacecraft, which limited adaptation to weightlessness, and objective postflight findings were minimal [154]. The larger volume of the Apollo spacecraft, allowing freedom of movement and full adaptation to weightlessness, is thought to underlie the greater incidence of space motion sickness and more pronounced postflight symptoms seen in this program.

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Only limited studies were performed in the last few crews returning from the moon, but mild postural instability was noted for subjects standing with eyes closed for 3 days after landing, suggesting a shift toward reliance on visual cues for orientation and a lessening of vestibular and proprioceptive control [154]. The Skylab flight experience involved both longer flight durations and a significant increase in habitable volume, which allowed unhindered adaptation to weightlessness. During return, as was true for the Apollo crews, Skylab crewmembers had the added motion challenge of a sea landing followed by a helicopter transfer onto a recovery ship. Postflight changes in locomotion and other purposeful movements were noted in all returning crewmembers. Investigators noted that all crewmembers were able to walk immediately after exiting the spacecraft, albeit with a wide-stance shuffling gait and bentforward posture now very familiar to space crew recovery personnel. The crewmembers themselves reported that walking required conscious effort and that cornering was difficult and accompanied by the tendency to lean to the outside. Improvement was rapid, and few noticeable signs of ataxia or postural instability were noted by the second return day. Objective testing showed degradation in postural stability while standing upright and motionless, particularly with eyes closed, highlighting the increased reliance on visual cues. Vertigo induced by rapid head movement was also reported by all crewmembers; this improved gradually and completely resolved within 3–4 days after landing, except for one crewmember on the 84-day flight, who had persistent sensations of vertigo for up to 11 days after return [155]. In addition to the formal investigations the mechanisms of neurological adaptation accommodated by the U.S. Space Shuttle, this program has also allowed a relatively high volume of flight experiences, which has bolstered understanding of the degree of impairment after exposure to weightlessness. During the postflight “walk-around” noted above, flight surgeons can readily observe rapid improvements in locomotion and posture control over the course of this 20- to 30-min activity. Cornering and gait in particular improve to the extent that many returning crewmembers show minimal outward differences in normal ambulation within a few hours of landing. Flight surgeons conduct formal debriefings with members of Space Shuttle crews in addition to postlanding medical examinations. Both are considered clinical tools to assess function and landing experience rather than investigative activities. Debriefs and medical examinations are performed within a few hours of landing and again 3 days later, and both include queries about the presence of certain symptoms during the postflight period. They do not capture the duration of symptoms, nor are they tied to formal testing; as such, both are prone to subjectivity and the potential for reporting bias. However, debrief comments capture a broad spectrum of information and help to guide postflight activities. Bacal and colleagues retrospectively examined medical debrief comments from Space Shuttle missions over a period of 18 years with

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regard to neurovestibular symptoms. The number of responses to specific questions varied from 128 to 389. Symptoms were classified as absent, mild, moderate, or severe, with the classification generated by both the reporting crewmember and the recording flight surgeon. Three symptoms were noted in more than half the respondents—clumsiness in movements (69%), difficulty walking a straight line (66%), and persistent sensation aftereffects (60%). Most of these symptoms were noted as mild. Some degree of walking or standing vertigo was noted in about 30% of respondents, with the great majority again being in the mild category. Although not formally queried, the period of resolution for most of these symptoms was 1 day (the first return day), although minimal sensations may persist for a week. The incidence of postflight nausea (15%) and emesis (8%) of any degree is considerably lower than its counterpart syndrome after launch [156]. In such cases, readaptation sickness occasionally persists for a few days but typically resolves within 24 h. Postural assessments of 23 individuals after short-duration Space Shuttle flights revealed instability and confirmed an increased reliance on visual and somatosensory cues for maintaining orientation, which resolved in 4–8 days after landing [157]. Another investigation showed significant decreases in head rotation velocity on landing day as compared to before flight after short-duration flights [158]. Crewmembers on flights lasting 6 months or more show similar symptoms that essentially require more time to resolve. Two cosmonauts returning from a 1-year mission on Mir were noted to have “hypogravitational ataxia” for more than 2 weeks, along with anomalies in control of voluntary movements and gaze fixation [17]. Crewmembers flying standard 4- to 6-month tours on Mir or the ISS are usually able to ambulate unassisted on the day of or after landing, but they typically require deliberate concentration to do so and are appropriately conservative, avoiding sharp corners and abrupt stops and starts.

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diate prelaunch level may not be reflective of the usual long term level. The time required to return to a normative curve of bone density is known to exceed the time of exposure to weightlessness by a factor of 2 or 3, and complete recovery may require between 1 and 3 years [159,160]. Functional fitness assessments consisting of a variety of strength and endurance activities are done with U.S. crewmembers after long-duration missions to provide an overall gauge of functional ability. Selected results are shown in Figure 2.8. These assessments are not conducted before flight day five to avoid overexertion injuries in the immediate postflight period, but they should still reflect end-of-mission musculoskeletal capability. Some decrements remain at 5–days after return, but substantial functional ability remains and the variables measured typically return to or exceed preflight baseline levels within 30 days of landing. Further data from ISS crewmembers will help to better characterize the readaptation process to guide postlanding activity requirements and rehabilitation efforts and in anticipation of planetary exploration after prolonged transit in weightlessness.

Clinical Laboratory Values An integral part of ascertaining the effects of space flight on crew health has been clinical laboratory monitoring, and a broad program was initiated at the outset of the Space Shuttle program. Results are used by space medical personnel to identify health impacts and guide further examination of individuals as needed, in addition to determining health effects on the overall flying population. Results from this program have helped in establishing the clinical norms associated with short-duration flight. In examining preflight and postflight operational data for Shuttle flyers, Barratt and colleagues looked at differences between lab values taken 3 days before launch and those taken

Other Postflight Findings The timeline for complete recovery of all affected systems after exposure to weightlessness has not been well characterized. For crews on short-duration missions, this is largely because the crewmembers can perform most of their required duties without undue limitations and along a known trend of improvement after landing. Fluid volume, bone, and muscle are replenished and regulatory mechanisms are restored, and these systems are not directly monitored in the postflight period. Gradual return to accustomed preflight activities is done largely at the discretion of the crewmembers themselves, with participation of the medical team and further assessments only as clinically indicated after the 3-day postflight assessment. For long-duration flyers, a more rigorous and regulated program of rehabilitation incorporates assessments of muscle strength and bone density. Muscle strength returns within several weeks, although due to intensive training the imme-

FIGURE 2.8. Selected functional fitness variables for ISS crewmembers after space flights lasting 130–197 days. Data are shown as means ± standard error for 15 subjects. *Mean preflight value, number of repetitions; **Mean preflight value, force in pounds for a single maximum exertion

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within a couple of hours after landing [161]. Operational data collected over 50 sequential Shuttle missions were analyzed, with consideration limited to first-time flyers to avoid any reflight bias. Selected results are shown in Table 2.6, which emphasizes those modules that manifest significant changes. Globally, these values reflect physiological reaction to microgravity, a mild physiological stress reaction to entry and landing, and relative hypovolemia in the immediate postflight period. They were obtained during a period of transition in fluid regulation and volume status, and as such they do not indicate frank pathology. Preflight and landing-day variables

TABLE 2.6. Landing day vs preflight differences in blood chemistry, hematology, and endocrine variables in Space Shuttle crewmembers.

Biochemistry module Glucose (mg/dl) Uric acid (mg/dl) Creatinine (mg/dl) Alkaline phosphatase (U/L) Lactate dehydrogenase(U/L) Amylase (U/L) Sodium (mmol/L) Potassium (mmol/L) Phosphate (mg/dl) Magnesium (mg/dl) Carbon dioxide (mmol/L) Cholesterol (mg/dl) Triglycerides (mg/dl) High-density lipoprotein (mg/dl) Very low-density lipoprotein (mg/dl) Apolipoprotein A1 (mg/dl) Hematology module Red blood cells (1,000/mm3) Reticulocytes (%) Hematocrit (%) Hemoglobin (g/dl) Mean corpuscular volume (FL) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dl) Platelets (1,000/mm3) White blood cells (1,000/mm3) Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) Band cells (%) Endocrinology module Triiodothyronine (ng/dl) Thyroxine uptake (binding ratio) Thyroxine (µg/dl) Angiotensin (ng/ml/h) Cortisol (µg/dl)

N

Mean difference

SD

p value

93 89 93 89 89 89 93 93 89 89 88 88 89 84 84

8.65 −0.91 −0.03 −1.48 −7.19 −8.93 −0.85 −0.27 −0.43 −0.15 −1.26 −5.64 −9.79 −6.86 −1.88

18.77 0.86 0.15 6.87 21.44 17.68 2.69 0.44 0.76 0.18 3.44 20.33 30.67 8.78 6.55

0.0001 0.0001 0.0434 0.0448 0.0021 0.0001 0.003 0.0001 0.0001 0.0001 0.0009 0.0109 0.0034 0.0001 0.0101

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−16.27

25.25

0.0001

89 80 89 89 89 89 89

0.08 −0.16 0.27 0.6 −1.04 0.69 0.93

0.32 0.38 3.16 0.84 3.23 1.6 2.03

0.0166 0.0003 0.4155a 0.0001 0.003 0.0001 0.0001

88 89 89 89 90 88 87 87

14.52 1.31 17.81 −16.23 −0.46 −1.41 0.07 0.38

37.8 1.66 11 9.08 3.3 2.22 0.33 1.44

0.0005 0.0001 0.0001 0.0001 0.193a 0.0001 0.573a 0.0161

78 61 78 76 78

−17.2 0.03 0.45 3.07 −3.19

28 0.1 0.8 5 7.8

0.0001 0.004 0.0001 0.0001 0.0005

Abbreviation: SD, standard deviation. Preflight samples were taken under fasting conditions. p values are from paired t tests, a not significant but included for context.

were all within normal limits. The very small, albeit statistically significant, changes do not seem to be physiologically or clinically significant, and none of the averaged values fall outside of established clinical norms.

Postflight Clinical Disposition The responses to weightlessness and landing involve multisystemic physiologic changes and an acknowledged degree of impairment in comparison with preflight functionality. However any such impairments are typically mild and recover rapidly. On landing day after short-duration (up to 17-day) Space Shuttle flights, crewmembers are examined by flight surgeons, participate in limited debrief and investigational activities, and then almost without exception are discharged into the care of their families. A medical team is available continually for consultation and further clinical care as needed. Physical and laboratory examinations are repeated 3 days after landing, after which crewmembers return to their normal activities and duty, including driving, light exercise, and flight in high-performance aircraft, at their own discretion. After long-duration flights, dispositioning varies according to program. After initial medical assessments on landing day, crewmembers are usually kept in special facilities for observation and assistance. In the United States, crewmembers are transported home from the landing site on the day after landing, and if they show no evidence of complications such as debilitating orthostatic intolerance or neurovestibular impairment, they are typically released to their families on that day. For Soyuz landings, crewmembers are transported from the landing site in Kazakhstan back to the Gagarin Cosmonaut Training Center near Moscow and live in a rehabilitation facility for as long as needed. In both the US and Russian programs, a protracted period of physical rehabilitation begins after return and forms the core of all postflight activities. The three main elements of rehabilitation in the immediate postflight period are rest, passive exposure to normal gravity loads, and return to familiar surroundings. Activities and loading challenges are presented slowly and progressively as tolerated. A multidisciplinary team consisting of medical, physical training, psychological, and other specialists guide the process of full readaptation to gravity and normal life. Families are educated as to the expected effects of space flight and the progress of rehabilitation, and medical personnel are continually available for response to clinical events. Typically crewmembers are cleared for return to normal activities and duties by 30 days after return from long-duration flight.

Lunar Surface To date, human experience operating in the fractional gravity of another surface remains limited to the six Apollo missions to the moon. In all, 29 astronauts flew in the Apollo program,

2. Human Response to Space Flight

with 12 landing to spend a total of 4 man-weeks on the lunar surface. This experience allowed comparison of conditions of otherwise similar vehicles and flight profiles in attempts to isolate effects attributable to the stay in the one-sixth G lunar gravity. Cardiovascular deconditioning and reduced exercise capacity were known from earlier flight programs and neurovestibular disorders from the Apollo flights preceding the first moon landing. Thus, concern was high about these and other lesser known effects that might influence landing and surface performance. EVA experience and knowledge of crew performance in the EVA environment was still in a very early phase. However, with the first surface mission of Apollo 11, much of the concern in these areas was alleviated.

Cardiovascular Issues After launch, the Apollo crews typically spent 3–4 days in weightlessness during a period of Earth orbit, translunar coasting, and lunar orbit before landing on the lunar surface. Descent in the lunar excursion module took place with the crewmembers in a vertical standing position involving +Gz acceleration forces, during which the commander integrated information from flight instruments and outside visual cues while making piloting control inputs. Launching from the lunar surface in the module’s ascent stage after a period of one-sixth G exposure involved a transient phase of nearly 1+Gz. There were no crew reports of lightheadedness or visual disorders to suggest symptoms of orthostatic intolerance during these phases. Postflight response to cardiovascular challenges were expected to be different for moonwalkers than for other Apollo flyers who remained weightless, including orthostatic response to LBNP. However, no difference was found in resting and stressed heart rate between these two groups [162]. Interestingly, the cardiothoracic ratio, a radiographic index reflective of the heart size and position, was significantly decreased in those who remained weightless but was preserved in the moon-walking group [162]. Whether this was related to actual work effects on the heart, anthropometric changes influencing the heart shadow, or other influences remains unknown and a subject for further investigation. A crewmember on the Apollo 15 mission did manifest a period of bigeminal rhythm during surface activities, correlated with symptoms of extreme fatigue. A self-induced period of rest was taken before continuing with activities. This experience prompted the inclusion of anti-arrhythmic medications on subsequent flights; potassium supplements were also included to address the possibility that hypokalemia may have been involved. The affected crewmember was later found to have had undetected coronary disease at the time of the flight and experienced a myocardial infarct 18 months after the mission [51].

Neurovestibular Issues After the weightless period of translunar coast and lunar orbit, pilots of the lunar excursion modules were able to fly

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the spacecraft close to the lunar surface and effect landings, changing the coordinates of flight to accommodate terrain characteristics as needed [3]. There were no reports of vestibular illusions or disorientation during any of the dynamic lunar flight phases. Surface activities proceeded as crewmembers naturally adopted new, energy-efficient “loping” gaits more suitable to the reduced gravity. Severe constraints on time and spacecraft volume precluded any standard investigations of vestibular function during the Apollo lunar flights, although limited assessment of postural stability and purposeful movement by video imagery could be done as crewmembers discovered and tried new methods of locomotion. No incidents of vestibular illusions or disorientation were reported during surface activities among the 12 moon-walkers. Lunar gravity seems to be an adequate stimulus for otolith organs to define a gravitational vertical and guide posture control [154].

Other Aspects of Lunar Gravity Apollo surface activities were associated with clinical effects that probably resulted less from direct effects of reduced gravity and more from the increase in workload and physical exertion. Thermal stress, overuse injuries, and fatigue were seen in many of the missions during exploration activities that included equipment moving, sample collection, and surface drilling [51]. Indirect effects of reduced gravity, such as dust irritation because of lesser settling as compared with Earth, were noted. Thus the clinical response to fractional gravity may be viewed in terms of the activities required, rather like a construction workplace. Although Apollo crewmembers did not spend enough time on the lunar surface to show cumulative musculoskeletal changes, muscle and bone loss can be expected given sufficient time there. Adaptation must be viewed differently from adaptation to the weightless environment, in which the vast majority of crew time is spent operating normally in an unloaded state. Lunar crews will be expected to undertake heavy exertions and load manipulations during surface activities, donning heavy suits and life support systems while manipulating lunar material and equipment. The optimal balance among effects of lunar gravity, surface EVAs, and deliberate countermeasures during long-duration stays remains to be delineated.

Conclusions The past four decades have amply demonstrated that humans can tolerate space flight well for long periods in orbiting spacecraft. Historically, the direct causes of mortality have been accidents occurring during dynamic phases of flight. The vast majority of flight time has been spent in Earth orbit, but both in orbit and on the lunar surface, humans have demonstrated the ability to maintain adequate health and to work productively.

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The dominant condition associated with Earth orbit affecting human physiology and health is weightlessness, which induces predictable changes in crewmembers during adaptation. Acutely, these changes can induce adverse symptoms such as space motion sickness from neurovestibular adaptation and facial congestion associated with a rostral fluid shift. Typically these symptoms do not limit crew activity and resolve within a few days. Significant but clinically asymptomatic early changes include regulation to a lower plasma volume with a concomitant decrease in red blood cell mass, changes in cardiac and respiratory dynamics, and changes in anthropometry. Food intake is volitionally reduced and weight loss is common. Changes in skeletal muscle morphology are seen, and mass and strength in postural regions are reduced after several days. Aerobic fitness is reduced but does not limit inflight performance. Although bone demineralization begins almost immediately upon gravitational unloading, it is not detected following short-duration flights. Over periods of weeks to months, loss of postural bone mass accumulates to detectable thresholds, prompting the need for physical countermeasures to apply loads to these selected areas. Upon Earth return, readaptation to gravity involves a reverse of these processes. Some degree of clinical impairment in the immediate postflight period owing to orthostatic intolerance or neurovestibular symptoms is common. Such impairments resolve rapidly after short-duration flight but require more recovery time after longer exposures to weightlessness. Bone requires the longest recovery period, exceeding the time equivalent in weightlessness by probably a factor of two or three. Carefully guided rehabilitation activities are required to safely return crewmembers to preflight levels of health and fitness. Notably, the knowledge base of space medicine and physiology has been constructed from the flight experiences of healthy, highly screened professional flight crewmembers and a small but growing number of scientists and paying space flight participants. As the fledgling space tourist industry expands, individuals with a wider variety of health backgrounds will present themselves for possible space flight. Direct application of space medicine knowledge to a broader population should be done with caution; however, no specific contraindications to space flight have been found for the general population. Formal analysis of certifying and operational medical information as well as conducting deliberate studies should be considered in these new venues to expand clinical space medicine accordingly. Debate remains as to whether prolonged stays in weightlessness and further expeditions to the moon are safe enough for continuing operations or for taking the next steps outward without more detailed research findings. Historically, as humans have ventured into new environments, such as undersea and at high altitudes, steps were taken based on existing experience, information on analogous activities, and, when appropriate, targeted preliminary investigation. As operational milestones are established and reasonable safety assured,

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engineering and medical details are worked out in these environments to characterize human response and to further optimize human health and performance. The few explorers of the beginning stages are then joined by larger numbers to increase activity and productivity in these new environments. Human space flight is no exception. The transition in space from the few to the many is well underway. Currently we operate in a middle phase of this process, where the risk of adverse events associated with weightlessness is considered acceptable yet the “maladaptive” responses to weightlessness cannot be ignored. From a safety standpoint, current knowledge does not restrict us from continuing missions in weightlessness up to a year. However, investigating and documenting details of weightless physiology will inevitably reduce the overall risk of human occupancy. This effort will guide the development of effective strategies to mitigate health hazards and provide a more scholarly basis on which to practice modern medicine in this environment.

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E.S. Baker et al. 137. Tigranyan RA. Metabolic aspects of problems in stress in space flight. Problemy Kosmicheskoi Biologii 1985; 52:1–222. 138. Markin A, Strogonova L, Balashov O, Polyakov V, Tigner T. The dynamics of blood biochemical parameters in cosmonauts during long-term space flights. Acta Astronaut 1998; 42(1–8):247–253. 139. Smith SM, Davis-Street JE, Fontenot TB, Lane HW. Assessment of a portable clinical blood analyzer during space flight. Clin Chem 1997; 43(6 Pt 1):1056–1065. 140. Cirillo M, De Santo NG, Heer M, et al. Low urinary albumin excretion in astronauts during space missions. Nephron Physiol 2003; 93(4):102–105. 141. Kotovskaia AR, Vil’-Vil’iams I, Gavrilova LN, Elizarov S, Uliatovskii NV. Tolerance of +Gx by MIR 22–27 main crew in space flights. Aviakosm Ekolog Med 2001; 35(2):45050. 142. Jennings RT, Sawin CF, Barratt MR. Space operations. In: DeHart RL, Davis JR (eds.), Fundamentals of Aeropsace Medicine. Philadelphia, PA: Lippincott Williams and WIlkins; 2002:596–628. 143. Koloteva MI, Kotovskaia AR, Vil’-Vil’iams IF, Luk’ianiuk V, Gavrilova LN. G-tolerance of female cosmonauts during descent in space flights of 8 up to 169 days in duration Article in Russian. Aviakosm Ekolog Med 2001; 36(6):24–30. 144. Whitson PA, Charles JB, Williams WJ, Cintron NM. Changes in sympathoadrenal response to standing in humans after spaceflight. J Appl Physiol 1995; 79(2):428–433. 145. Convertino VA. Consequences of cardiovascular adaptation to spaceflight: Implications for the use of pharmacological countermeasures. Gravit Space Biol Bull 2005; 18(2):59–69. 146. Meck JV, Waters WW, Ziegler MG, et al. Mechanisms of postspaceflight orthostatic hypotension: Low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight. Am J Physiol Heart Circ Physiol 2004; 286(4): H1486–H1495. 147. Gharib C, Custaud MA. Orthostatic tolerance after spaceflight or simulated weightlessness by head-down bed-rest. Bull Acad Natl Med Article in French 2002; 186(4):733–746; discussion 47–9. 148. Levine BD, Pawelczyk JA, Ertl AC, et al. Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight. J Physiol 2002; 1(538):331–340. 149. Waters WW, Ziegler MG, Meck JV. Post-spaceflight orthostatic hypotension occurs mostly in women and is predicted by low vascular resistance. J Appl Physiol 2002; 92:586–594. 150. Perez SA, Charles JB, Fortner GW, Hurst VT, Meck JV. Cardiovascular effects of anti-G suit and cooling garment during space shuttle re-entry and landing. Aviat Space Environ Med 2003; 74(7):753–757. 151. Gunga HC, Kirsch K, Baartz F, et al. Erythropoietin under real and simulated microgravity conditions in humans. J Appl Physiol 1996; 81(2):761–773. 152. Kimzey SL. Hematology and Immunology Studies. In: Johnston RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC: Scientific and Technical Information Office, NASA; 1977:249–282. 153. Grigor’ev AI, Noskov VB, Poliakov VV, et al. Dynamic changes in the reactivity of the hormonal system regulation with the impact by LBNP sessions in long-term space mission. Article in Russian. Aviakosm Ekolog Med 1998; 32(3):18–23. 154. Homick JL, E. F. Miller I. Apollo flight crew vestibular assessment. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical

2. Human Response to Space Flight Results of Apollo. Washington, DC: Scientific and Technical Information Office, NASA; 1975:322–340. 155. Homick JL, Reschke MF. The effects of prolonged exposure to weightlessness on postural equilibrium. In: Johnston RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC: Scientific and Technical Information Office, NASA; 1977:104–112. 156. Bacal K, Billica R, Bishop S. Neurovestibular symptoms following space flight. J Vestib Res 2003; 13(2–3):93–102. 157. Black FO, Paloski WH, Doxey-Gasway DD, Reschke MF. Vestibular plasticity following orbital spaceflight: Recovery from postflight postural instability. Acta Otolaryngol Suppl 1995; 520(Pt.2):450–454. 158. Hlavacka F, Kornilova LN. Velocity of head movements and sensory-motor adaptation during and after short spaceflight. J Gravit Physiol 2004; 11(2):13–16.

57 159. Oganov VS. Changes in bone mineral density and human body composition in spaceflight. In: The Skeletal System, Weightlessness, and Osteoporosis. Moscow: Slovo; 2003:56–75. 160. Shackelford LC, LeBlanc A, Feiveson A, Oganov V. Bone loss in space: Shuttle/MIR experience and bed rest countermeasure program. In: First Biennial Space Biomedical Investigators’ Workshop. Houston, TX: NASA Johnson Space Center; 1999. 161. Barratt M, Houser S, Wear ML. Operational monitoring of preand post-flight blood parameters for first time shuttle flyers. In: 67th Annual Scientific Meeting, Aerospace Medical Association; 1997; 1997. 162. Hoffler GW, Johnson RL. Apollo flight crew cardiovascular evaluation. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: Scientific and Technical Information Office, NASA; 1975:226–264.

3 Medical Evaluations and Standards Gary Gray and Smith L. Johnston

Rationale Candidates for space flight are medically screened to ensure the success of each mission by providing healthy crews who are able to perform operational objectives. Screening is carried out according to a framework of medical standards based on operational requirements. Consistent application of medical standards helps to establish an information database against which the assumptions underlying the standards can be objectively reviewed. These standards are revised over time as additional findings are collected. The ultimate goal is to produce rational, evidence-based, refined standards that reflect the operational requirements and the medical risks involved in space flight. By doing so, potentially larger subsets of the population that are today excluded from space flight may be able to participate in future space exploration.

Objectives Selecting Healthy Candidates Well-considered standards are expected to ensure selection of spaceflight candidates who are healthy and likely to remain so throughout their careers, and who will meet defined medical requirements of their mission or missions. Medical testing is geared to three objectives: to identify those individuals with overt symptomatic disease, to identify asymptomatic disease in individuals with no apparent manifestations, and to identify individuals with a high probability of developing a flight-limiting disorder during their careers. In meeting this third objective defining and applying standards becomes most difficult. Estimating the probability of future disease is generally based on risk factors (typically related to biochemical, genetic, or lifestyle factors) that apply to entire populations, but for which extrapolation from population data to individual risk is imprecise. The lack of precision in applying population data on disease probability to individuals may lead to different

outcomes in different countries and agencies based on differences in the distribution of disease and risk factors.

Health Maintenance After Selection Medical screening after crew selection is based on the principles of preventive medicine. The objectives are to maintain health, detect disease early, and ensure medical fitness for ongoing training and operations. Screening programs are designed in the interests of the individual (to maintain health) and of the mission (to detect any medical problems that could affect the mission). Hickman points out that in aerospace medicine one generally encounters three types of individuals: (1) those with overt disease; (2) those with documented asymptomatic disease; and (3) those who have no symptoms but have abnormal test results [1]. The first type is the one most often encountered in clinical medicine—the patient with an overt disease. The latter two cases are more common to aerospace medicine. For the second case, the patient with documented but asymptomatic disease, aerospace medical flight disposition is based on both the natural history of the disorder and the pathophysiologic effects of that disorder in the often illdefined or poorly understood space environment. The relatively small number of spaceflight crewmembers means that it may take decades to derive sufficient epidemiologic data for evidence-based decisions. Aeromedical decisions made in the context of the space environment often rely on analogue data derived from military aviator populations. This generally results in conservative decisions about flight disposition for asymptomatic disease. The third case, a patient with no symptoms but abnormal test results, often requires further investigations. The probability of finding an abnormal test result during screening is directly proportional to the number of tests performed. This Type I, or alpha, error is seen when the null hypothesis is true and n independent statistical tests are performed. The probability that at least one test will appear to be statistically significant (p ≤ 0.05) is [1.0–(0.95)n]. If 10 tests are per59

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formed, there is a [1.0–(0.95)10] = 0.40 probability of a Type I error. If 20 tests are performed, there is a [1.0–(0.95)20] = 0.65 probability of a false-positive test result. Further, the spaceflight crew population represents a highly select group with a generally low prevalence of disease. Hence, applying clinical tests that have sensitivity and specificity characteristics typical for a clinical environment will result in frequent false-positive findings. In other words, the positive predictive value of a screening test decreases with decreasing prevalence of disease. Therefore we must understand the operating characteristics of medical screening procedures in the spaceflight crew population and the potential for falsepositive findings.

Operational Considerations An important goal for medical selection and subsequent medical evaluations is to certify that the crew is healthy. Conditions with the potential to compromise flight safety, such as a seizure disorder, are disqualifying. The disposition of other medical conditions is based on a risk-assessment, evidence-based model. NASA’s selection and retention standards should be related to bona fide mission requirements. For example, visual standards should be based on actual vision requirements for operational tasks (e.g., flying, performing extravehicular activities, controlling remote manipulators, or escaping in a contingency situation). Such data can be acquired from simulator environments or from actual operational settings. In many cases, however, standards are based on best estimates of operational requirements as made by physicians on space medicine boards. Every effort should be made in drafting and reviewing standards to objectively relate those standards to actual operational requirements. For spaceflight crewmembers, standards for selection and periodic evaluation reflect the operational role of the individual crewmember. In Space Shuttle operations, standards for pilot astronauts differ from those of mission specialists for mission-specific variables such as visual acuity. In the past, less-restrictive standards have been defined for crewmembers designated as payload specialists (i.e., non-career crewmembers who manage a specific Shuttle payload rather than Shuttle systems). Medical standards must further reflect the incremental risk associated with extended, long-duration, and, ultimately, exploration-class missions. The statistical risk of a medical event occurring increases with mission duration; this increase in risk must be reflected in medical standards and screening procedures. For example, experiencing an episode of renal colic would disqualify a trained mission specialist for extended or long-duration missions but perhaps not for short-duration Shuttle missions, since preflight sonographic screening can rule out significant retained calculi and the probability of developing a calculus during a brief Shuttle mission is very low.

G. Gray and S.L. Johnston

Establishing Normative Data A less obvious but important reason to define medical standards is the need for data to be obtained and pooled according to standards that have been consistently applied with a standardized, systematic approach. NASA’s Life Sciences effort has recognized the importance of this aspect of medical screening since the initial astronaut screening for Project Mercury in 1959, when medical screening data at the Lovelace Foundation were recorded on IBM color-coded punch cards [2]. This concept evolved into a standardized battery of medical tests to be performed on all Shuttle missions (the so-called baseline data collection), the goal of which was to establish an epidemiologic normative medical database in the space environment. This process, now known as medical assessment testing, continues in the International Space Station (ISS) era. Medical assessment testing is a vital aspect of medical screening that helps to address the quintessential occupational medicine question—namely, does an abnormal finding in an individual reflect an abnormal (pathologic) individual response or a normal physiologic response to an abnormal environment? Medical assessment testing, by developing longitudinal normative data, plays an important part in providing data to address this question in the environment of space. By establishing new population norms, medical assessment testing provides important space medicine information for current and future spaceflight crews and, eventually, space travelers. (Collating medical assessment test data has demonstrated, for example, that the microgravity environment is conducive to renal stone formation; medical screening procedures have been modified accordingly to identify crewmembers who are at risk of forming stones during flight.) In some respects, medical assessment testing seems to overlap with Life Sciences experimentation. However, medical assessment testing provides a longitudinal view of health that facilitates the definition of abnormality and new population norms in spaceflight crews. Medical assessment testing does not seek to study basic physiologic mechanisms in the space environment (Life Sciences) but rather to clarify the definition of normal vs. abnormal responses in the environment (Operational Space Medicine) for the greater good.

Select-In Versus Select-Out Concepts in Medical Screening Selection and retention standards are generally directed toward identifying and excluding persons who do not meet defined standards (e.g., those for vision or hearing). A greater challenge is the ability to identify those physical and psychological attributes that might be considered advantageous in the space environment. These concepts have been applied in the area of psychological assessment to identify individuals who have the “right stuff,” i.e., those who are not only technically

3. Medical Evaluations and Standards

competent but who can sustain the rigors of long-term space flight while maintaining their equanimity, demonstrating leadership when required, and remaining team players [3]. “Select-in” concepts can also be applied to physical attributes. Since its inception, the Russian selection system has included “functional loading tests” such as those that assess tolerance of hypoxia in an altitude chamber, tolerance of acceleration and high-g forces in the human centrifuge, and performance under conditions of high thermal loading and sleep deprivation. The results of these tests are included in the overall medical selection process for cosmonauts but are rarely used to exclude candidates. Although medical standards are generally based on the “select-out” principle, this is likely to change in the future as tests are developed with high individual specificity. For example, the multinational Human Genome Project currently under way will, within the next decade, facilitate identification of individuals with disease-causing genes (select-out). However, it may also allow us to identify individuals with a genetic makeup that is resistant to the health problems of expeditionary space missions, including radiation damage and bone mineral loss.

Evolution of Medical Standards Early in the human spaceflight program, selection standards for astronauts and cosmonauts were not defined. Because the risks of the space environment were largely unknown, the approach to medical screening in both the U.S. and the Russian programs was, by necessity, conservative and involved essentially testing everything that was possible to test. The first Mercury astronauts were medically selected in four phases [2]: an initial records review; an extremely thorough medical evaluation held at the Lovelace Foundation in Albuquerque,

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New Mexico; an evaluation to assess responses to environmental stressors such as acceleration and hypoxia at WrightPatterson Air Force Base in Dayton, Ohio; and psychological and psychiatric evaluations. The importance of maintaining a database of such information was recognized and implemented from the outset. The medical screening battery for the initial Mercury astronauts took 1 week to complete. Of the 100 military test pilots who were initially screened, 31 “very outstanding men” were selected to proceed in the program and to undergo the medical screening detailed in Table 3.1. (Findings from these 31 candidates are shown in Table 3.2.) Of the final 7 astronauts selected from that group of 31, 1 had visual acuity of less than 20/25, 5 had hearing loss of more than 15 dB, 1 had a vocal cord tumor (removed), and 1 had an abnormal lumbosacral spine. In the absence of defined standards, the 7 Mercury astronauts were chosen by a panel of both technical and medical representatives. In 1977, using medical standards from the U.S. Air Force, the U.S. Navy, the U.S. Department of Defense, and the Federal Aviation Authority, NASA developed specific astronaut medical standards that were incorporated into a working set of medical evaluation requirements. These standards continue to evolve; they were revised in 1991 to include the potential effects of space station missions and the long-duration nature of such missions. The ISS Multilateral Medical Operations Panel, which includes all ISS partners, adopted a further revision of these standards as the basis for ISS medical standards. Although the ultimate goal is to define common standards for all crewmembers who are involved in ISS operations, the process is challenging because of cultural, ethnic, and philosophical differences in the approach to medical screening among the countries and agencies that are participating in the ISS. Examples of such nuances in the Russian

Table 3.1. Medical screening tests conducted with mercury astronaut candidates at the Lovelace foundation. Test type Detailed history, including Physical examination

Radiography Laboratory analyses

Details Attitude of family members to hazardous flying Aviation history Proctosigmoidoscopy Ophthalmology, including dark adaptation studies, retinal photography Otolaryngology, including calorimetric stimulation tests Audiometry, including voice discrimination Cardiology, including ECG, vectorcardiography, ballistocardography, tilt table testing and a special screen for ASD and PFO based on measurement of arterial O2 saturation during Valsalva maneuvers Neurology, including nerve conduction studies, EMG, EEG Chest x ray (PA and lateral views), inspiration and expiration, cardiac fluoroscopy, barium enema, lumbosacral spine, teeth, sinuses Hematology, fasting blood sugar, cholesterol, blood group and type, serology, electrolytes, urea clearance, catecholamines, protein-bound iodine, protein electrophoresis, blood volume, carbon monoxide, total body water (tritiated water), liver function tests, urinalysis, 24-h urine ketogenic steroids and ketosteroids, throat cultures, stool examination and culture, total sperm counts, total body radiation count and body potassium, pulmonary function testing, maximum O2 uptake, body density

Abbreviations: ECG, electrocardiography; ASD, atrial septal defect; EEG, electroencephalography; EMG, electromyography; PA, posteroanterior; PFO, patent foramen ovale.

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Table 3.2. Summary of clinical findings in the initial 31 mercury astronaut candidates. Physical system Eyes

Ears, nose, and throat

Cardiovascular

Gastrointestinal

Genitourinary

Orthopedic

Neurological Dermatological

Finding Visual acuity <20/25 Convergence weakness Exophoria Borderline night vision Sinusitis and sinus cyst Hearing loss >15 dB Allergic rhinitis Chronic pharyngitis Cervical adenitis Deviated septum with obstruction Hyperactive caloric response Small Eustachian tube openings Vocal cord tumor Beta hemolytic strep carrier Hypertensive vascular disease Vasomotor instability on tilt table Increased carotid sinus sensitivity Retrocecal appendix Inverted cecum Dilated external inguinal rings Diverticulosis Fissure and pruritus ani Hemorrhoids Abnormal stool examination Abnormal urethral meatus Varicocele Orchitis (inactive) Testicular atrophy Prostatitis Glycosuria Abnormal dorsal spine Abnormal lumbosacral spine Tight hamstrings Osteochondrosis dessicans Borderline EEG Acne Epidermophytosis Seborrhea

5 2 2 2 7 19 6 1 1 8 1 2 1 3 1 2 1 1 1 3 2 1 5 2 2 2 3 2 1 1 3 5 1 1 1 1 1 2

Abbreviation: EEG, electroencephalography.

and U.S. cardiovascular standards are shown in Tables 3.3 and 3.4. The outcome of addressing these differences has been to define a set of evolving standards that reflects the need to meet mission objectives while providing flexibility for individual agencies to use equivalent methods for testing and to conduct additional screening depending on ethnic and cultural differences in disease prevalence. For example, upper gastrointestinal endoscopy is included in medical screening in Russia and Japan, where the incidence of gastric erosions and ulcers (in Russia) and gastric cancer (in Japan) is significantly higher than in the United States. Such variances in test methods and agency-specific requirements for testing that go beyond those defined in the basic medical requirements document are manifested in a matrix document that is reviewed and agreed upon by all involved agencies. These equivalence matrices, specific to each agency, revolve around a core of common medical standards that apply to all spaceflight crews.

Medical requirements are subject to a regular review process during which the standards are revised on the basis of factors such as new epidemiologic data derived from analysis of current standards procedures, normative population data derived from medical assessment testing, information derived from risk assessment of space flight, changes in operational requirements for a particular mission, and changes in medical support facilities available to crews during space flight. The development of new medical technologies may also result in revisions to medical standards; for example, successful radiofrequency ablation of a Wolff-Parkinson-White bypass tract allows medical qualification of candidates who would have been disqualified in the past.

Medical Procedures for Selection and Periodic Evaluation The following sections outline the procedures for selection and annual evaluation of ISS crews.

Outcomes of Medical Selection It is interesting to compare the first Mercury screening, in which seven astronauts were selected, with the results of the process carried out at the Canadian Space Agency in 1992 to select four astronaut finalists from an application pool of more than 5,000 men and women [4]. After initial aptitude/qualification screening by résumé review, 337 candidates underwent medical screening in three phases. NASA medical standards for mission specialists were used. Phase 1 screening involved the use of a detailed medical questionnaire. Of the 337 applicants given the questionnaire, 145 (43%) were disqualified (Table 3.5). Additional screening carried out on this group led to 51 candidates undergoing Phase 2 screening, which involved a baseline medical examination carried out by a flight surgeon at a Canadian military base. Of the 51 candidates who underwent Phase 2 medical examination, 10 (20%) were screened out. The final phase, Phase 3, of selection involved 1 week of psychiatric, and medical screening carried out at a hospital on an outpatient basis. Of the 20 finalists who underwent Phase 3 medical screening, which included all aspects of the NASA mission specialist screening battery, 4 (20%) were medically disqualified. The results of this screening are similar to the Mercury astronaut screening as well as the much larger NASA astronaut selections in the decades that followed (Table 3.6) [5]. Of 826 applicants to the NASA astronaut program, selected for interview, and medically screened from 1977 through 1991 using NASA standards, 190 (23%) were disqualified for medical reasons, the most common being inadequate vision (78, or 9.4%). The most common medical causes for rejection of NASA astronaut candidates in recent years are listed in Table 3.7.

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Table 3.3. Cardiovascular system disqualification standards for U.S. astronauts and Russian cosmonauts. United States

Russia

1. Clinically significant hypertrophy/dilation 2. Ejection fraction <50% 3. Elevated blood pressure (140/90) 4. Recurrent symptomatic orthostatic hypotension 5. Case-by-case history of pericarditis 6. Case-by-case history of myocarditis 7. Case-by-case history of endocarditis 8. Clinical evidence of coronary artery disease, with myocardial infarction and angina pectoris 9. History or findings of major congenital abnormalities of the heart or vessels History of atrial or ventricular septal defects or patent ductus, successfully repaired after 1 year, case-by-case 10. Persistent tachycardia with supine resting pulse rate >100 beats per minute Clinical evidence of cardiac arrhythmia or conduction defect on resting electrocardiography or Holter monitor abnormalities 11. Failure to meet NASA exercise stress test loads (maximum exercise, ergometer, heat load, LBNP, and orthostatic/antiorthostatic stress tests) 12. Peripheral vascular disease 13. Cardiac tumors of any type Cardiac tumors, unless benign and successfully resected without residual cardiac disease after 6 months are reviewed on a case-by-case basis

14. All valvular disorders of the heart, including mitral valve prolapse 15. History of recurrent thrombophlebitis or thrombophlebitis with persistent thrombus, evidence of circulatory obstruction, or deep venous incompetence 16. Varicose veins if more than mild in degree, or if associated with edema, skin ulceration, or scars from previous ulceration

Organic diseases of the cardiac muscle Intracardiac hemodynamic disturbances Hypertonic disease—all stages and forms Low tolerance of changes in body position Pericarditis Myocarditis Not specified Atherosclerosis, all cardiovascular system disease, cardiac rhythm disturbances all forms of cardiac failure Not specified

All cardiovascular diseases with cardiac rhythm disturbances

Decreased tolerance of physical loads Diseases of the peripheral vessels obliterating endarteritis Malignant tumors Benign tumors causing functional disruption of organs Numerous, benign, small-neoplasms (histologically confirmed lipomatosis) that do not disturb organ function, impede movement, or interfere with wearing special equipment are acceptable. Single benign tumors must be surgically removed with re-examination Organic disease of the cardiac valvular system—prolapsed mitral or tricuspid valves with pronounced regurgitation Disease of and consequences of trauma to peripheral vessels

Disease of and consequences of trauma to peripheral vessels

Abbreviation: LBNP, lower body negative pressure.

Table 3.5. Reasons for medical disqualification among 337 candidates for Canadian astronaut selection. Table 3.4. Cardiovascular system screening procedures for U.S. astronauts and Russian cosmonauts. Times performed in each country’s program Procedures Chest x ray Electrocardiography Echocardiography 24-h Holter monitoring Treadmill test Orthostatic and antiorthostatic tests Lower-body negative pressure tests Cycle ergometry stress test Heat load stress test Neuroendocrine/dynamic electrocardiography Capillaroscopy Phono/mechanocardiography

United States

Russia

S S, A S S S, A MS

S, A S, A, MS S, A, MS S, A, MS S, A, MS S, A, MS

MS

S, A, MS S, A, MS S, A, MS S, A, MS S, A, MS S, A, MS

Abbreviation: S, selection examination; A, annual examinations; MS, mission-specific examinations.

Reason for disqualification Phase 1. Medical Questionnaire (n = 337) Vision Migraine history Thyroid disorders Ears/Hearing Lungs/asthma Misc. (1 each); including Hodgkin’s disease, multiple sclerosis, Crohns, epilepsy, obesity, vertigo, others Totals Phase 2. Initial Medical Assessment (n = 51) Uncorrected visual acuity of <20/100 Cardiac Asthma Neurologic Obesity Totals Phase 3. Hospital-based Assessment (n = 20) Chronic sinusitis (evident on computed tomography) Ophthalmologic (retinal disease) Abnormal electroencephalogram Totals

No. (% of subgroup) disqualified 105 (31) 12 (3.6) 5 (1.5) 4 (1.2) 3 (0.8) 16 (4.7) 145 (43) 3 (5.8) 3 (5.8) 2 (3.9) 1 (1.9) 1 (1.9) 10 (20) 2 (10) 1 (5) 1 (5) 4 (20)

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Table 3.6. Requirements for astronaut selection and annual requalification examinations. Procedure Medical history Physical examination Otolaryngology Specialist examination Audiogram Tympanogram Sinus imaging Ophthalmology

Dental examination

Cardiopulmonary Exercise stress test Pulmonary function tests Resting ECG 24-h ECG monitor Echocardiogram Imaging Chest x ray Mammogram Bone densitometry Abdominal sonography Panorex Pelvic sonography Gastrointestinal Proctosigmoidoscopy Stool Culture Occult blood Ova and parasites Laboratory Blood work, including hematology, clinical biochemistry, immunology, endocrinology Urinalysis Tuberculin test (PPD) Screening for sexually transmitted diseases Musculoskeletal Aggregate joint movement Anthropometry Muscle mass Selected strength measurements Radiation exposure evaluation a b

Selection

Annual

Yes Full

Yes Full

Yes Yes If indicated If indicated Full examination, including: Visual acuity Color vision Depth perception Phorias Tonometry Perimetry Fundoscopy Retinal photos Corneal topography Clinical examination and imaging, to include panorex and complete periapical dental x rays within the previous 2 years

If indicated Yes

Yes Yes Yes Yes Yes

Periodica Yes Yes

Yes Women

If indicated Women over 40: every 2 years until age 50 then yearly First annual and every 3 years

No Yes Within the previous 2 years Women

Full examination, including: Visual acuity Color vision Depth perception Phorias Tonometry Perimetry Fundoscopy

Clinical examination with bite-wing x rays when clinically indicated

If clinically indicated

Yes

Periodicb

Yes Yes If indicated

If indicated Yes If indicated

Yes

Yes

Yes Yes Yes

Yes Yes Yes

Yes Yes Yes Yes Yes

Annual

At ages 30, 35, and 40, then biannually to age 50, then annually, or as otherwise indicated. Beginning at age 40, every 5 years to age 50, then every 3 years.

Military pilot screening also yields similar results, with a 21% rejection rate of finalist candidates in the Israeli Air Force [6] and a 14–18% rejection rate (general and academy candidates) among Royal Australian Air Force applicants [7]. Interestingly, the Israeli study followed selected candidates

through 1 year of flight training, during which time 7.4% were rejected for medical reasons that were not discovered during selection. Of these, 17% resulted from nondisclosure during the initial selection process. Many aspects of medical screening continue to rely on accurate historical information that is

3. Medical Evaluations and Standards

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Table 3.7. Most frequent causes for disqualification in U.S. astronaut selection. Physical system

Findings

Ophthalmologic

Distant visual acuity, depth perception, color vision, esotropia, refractive error, astigmatism, corneal distortion Dysrhythmias (supraventricular or ventricular tachycardias), hypertension, left bundle-branch block, pulmonary stenosis Sinusitis, allergic rhinitis, hearing loss Kidney stones, renal anomalies Abnormal thyroid Personality disorder, drug abuse, physical abuse Positive tuberculin test, chronic liver enzyme abnormalities, chronic headaches, irritable bowel syndrome, carbohydrate intolerance

Cardiovascular

Otolaryngologic Genitourinary Endocrine Psychological Other

not always entirely reliable, since candidates may be reluctant to divulge information that they perceive may be disqualifying. The Israelis found that a way to improve this accuracy was to concurrently obtain a history of the applicant from the applicant’s parents [6].

Mission-Specific Medical Screening In addition to the selection and annual health screening aspects of astronaut medical evaluations, which are similar to evaluations in aviation medicine, space medicine has the significant additional requirement for further screening leading up to and during missions of short duration (days), extended duration (weeks), and long duration (months to years). Long-duration missions (those lasting more than 30 days) include medical assessments at 180 days before launch (L – 180), L – 30 or L – 45, L – 7 or L – 10, L – 2, landing (or return) day (R + 0), R + 2, R + 3, R + 5-7, R + 10, R + 15, R + 20, and R + 30. Medical screening is also planned during long-duration missions every 30 days as well as before and after extravehicular activities and before landing. The rationale for these assessments is twofold: first to confirm a crewmember’s medical fitness to carry out the mission, and second to gather normative medical data with which to compare apparent excursions from the norm. Individual preflight data and population normative data are used to guide postflight rehabilitation activities and to evaluate return to preflight health and fitness to return to duty.

Selection vs. Retention Standards: The Waiver Process The goal of medical selection standards is to identify candidates with the requisite physical and mental attributes to accomplish mission objectives and to identify candidates who have no apparent evidence of potential career-limiting medical problems. For trained crews, training and mission

experience become significant factors in determining medical suitability for continuing crew duties. Although standards based on factors that might affect mission and flight safety are the same for selection and retention, standards that reflect mission objectives or personal crew health may differ for retention. This difference reflects both the expenditure of training resources as well as the operational mission experience of the crewmember. For example, hearing standards for selection are stricter than those for retention; this difference acknowledges the degradation in hearing thresholds that takes place with age and noise exposure and recognizes that these thresholds, while still within acceptable limits for mission requirements, are likely to be lower in older, experienced crewmembers. Trained crewmembers who fail to meet retention medical standards may still be considered for continuing duties through a waiver process, during which the crewmember’s medical condition is reviewed. Considerations include the crewmember’s ability to carry out training requirements, any potential risk to mission safety, possible risk to mission objectives, and risk to the individual from further deterioration of the condition with continued duties. A panel of flight surgeons develops and periodically assesses a risk-assessment model based on known variables related to the crewmember’s medical condition and operational experience as well as mission objectives. If the risk assessment is favorable, a waiver of a particular standard may be recommended to allow the crewmember to continue with limited or full duties, with monitoring and follow-up of the medical condition. Astronauts have been granted waivers for continuing duties for hearing loss that falls below standard, for certain cardiac arrhythmias (such as self-limited supraventricular tachycardia), and for nonmetastatic testicular cancer that has been removed with no sequelae. The waiver process has been carefully and successfully applied throughout the U.S. space program. Military and civilian aviation regulatory authorities use similar procedures.

Population Bias in Astronaut Medical Screening One outcome of the intensive medical screening and ongoing periodic health assessments that are in use for astronauts is the generation of a population base that differs greatly from the general population in terms of disease prevalence. Population studies in analogous population cohorts, such as airline pilots [8,9] and U.S. Air Force pilots [10], have identified a much lower incidence of cardiovascular and respiratory diseases, but a small excess risk of cancer (colon and brain cancer, malignant melanoma, and Hodgkin’s disease in commercial pilots and testicular and urinary bladder cancer in Air Force pilots) when compared to the general age, sex-matched, U.S. population. The prevalence of death from all accidental causes is higher in fliers, but the excess in cancer mortality is of

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concern. Airline pilots, like astronauts, are exposed to greater amounts of cosmic radiation and electromagnetic forces than are Earth-bound individuals, and the potential link between such exposure and long-term astronaut health continues to be a focus of study. Because of the difference between the highly select population resulting from astronaut medical selection and the general population, extrapolation of disease incidence and prevalence from other large studies are not likely to be valid. In the Framingham Study, a prospective, longitudinal population study of the residents of Framingham, Massachusetts, investigators defined the risk of a cardiovascular event on the basis of classic risk factors, including age, total and high-density lipoprotein cholesterol, blood pressure, and covariables (smoking, diabetes, and left ventricular hypertrophy) in the population [11]. Since the distribution and prevalence of standard risk factors in the astronaut population are often different from those in the Framingham population [12], extrapolation of the Framingham predictive equations to the astronaut population may not be valid. A further complication in terms of standard medical screening procedures is that the low prevalence of disease, such as cardiovascular disease in the highly select astronaut population, makes the predictive value of screening tests, such as exercise stress testing, extremely low (Bayes’ theorem). This low disease prevalence makes the probability of false-positive findings more likely than true-positive findings for many standard clinical tests—such as exercise stress testing—that have specificity in the 70–80% range. The implications of this are that in both initial and periodic screening, standard testing must be applied with a careful understanding of the probable meaning of positive (abnormal) findings, and tests with the highest possible specificity are preferable. These and other concerns about astronaut health are currently being addressed in an important initiative, the NASA Longitudinal Study of Astronaut Health. This long-term study, begun in 1994, is designed to follow current and former astronauts; its goals are to examine the incidence of acute and chronic morbidity and mortality of this group and to compare the risks of morbidity and mortality associated with the astronauts’ occupational exposures to the corresponding risks for a control population of civil service employees at Johnson Space Center in Houston. This prospective, longitudinal epidemiologic study will provide much-needed data on the health implications of occupational exposure in the environment of space, from short-duration flights through extended and longterm, low Earth orbit missions and, ultimately, expeditionary space exposures. The study will also provide ongoing prevalence data from which predictive equations for disease probability can be derived that are relevant to the astronaut population. A somewhat reassuring negative finding is that to date, no statistical difference in the incidence of cancer has been found between the control and astronaut populations, although an apparent trend toward a higher incidence in astronauts has been noted.

G. Gray and S.L. Johnston

Medical Standards for Future Space Exploration A return to Earth from low Earth orbit because of a medical event or an emergency is an expensive proposition that would seriously affect mission objectives. Nevertheless, such a return is possible and, in fact, has been done on at least three occasions from Russian space stations. One of these returns to Earth involved chronic prostatitis and sepsis; another involved a potentially serious cardiac dysrhythmia that had not been noted before flight [13]. The most likely scenarios prompting medical return, would involve subacute or escalating processes that allow some time for planning. However, if the need for return is urgent, Shuttle contingency plans allow an emergency landing to be made within several hours. Contingency plans for the ISS include the possibility of emergency evacuation and return to Earth within 24 h using a Soyuz or crew return vehicle (see Chap. 7). The choice of medical support provided on orbit is also based on the premise of a potential emergency return to Earth. In the realm of expeditionary missions to Mars, returning to Earth for a medical emergency will not be possible. Communication from an expeditionary spacecraft will be increasingly delayed the further the craft is from Earth; for example, a maximum round-trip communication delay of 44 min can be expected between Mars and Earth. Even a Mars “fly-past” with direct return to Earth may represent a 9-month round-trip, and most Mars mission scenarios involve mission durations of 18–36 months. Analysis of spaceflight data suggests that the risk of a serious medical event—which in nearEarth orbit would affect the mission by possibly requiring a medical evacuation to Earth—is approximately 0.06 per person-year of flight. This translates to 1 event per 2.8 years of spaceflight operations for a crew of six (see Chap. 7). Medical selection and provision of medical services for space expeditions thus takes on a new dimension. Onboard medical facilities for early expeditionary missions are likely to be more comprehensive than they are for Shuttle missions, for example, weight and space constraints will impose significant limits on the ability to provide medical care. Priority must be given to providing for contingency situations such as trauma or fire, and more emphasis should be placed on providing primary prevention of medical diseases through stringent preflight screening and treatment. The first crew to depart for Mars is likely to be the most intensely medically studied crew in the history of space flight. Medical technology has advanced at a pace exceeding even that of space technology in the past several decades. Medical technology will allow us to identify not only individuals with disease potential (screen-out procedures) but also individuals with characteristics that may make them resilient to the hazards of long-term space flight (screenin attributes). Within the next decade, the Human Genome

3. Medical Evaluations and Standards

Project is likely to have completed human genetic mapping, thereby providing tools with which to identify genetic markers for a host of human diseases. Noninvasive medical imaging will allow us to define organ structure, including vascular anatomy, and will facilitate our identification of individuals with lesions such as central arteriovenous malformations. Developments in radiation biotechnology may allow us to identify individuals whose cellular makeup is more resistant to radiation damage. This intensive medical evaluation, including genetic testing, that will be incorporated into future medical standards may create significant ethical dilemmas with respect to the selection process. For example, identifying a previously unidentified genetic marker of serious disease in a trained astronaut undergoing screening for an exploration mission may have not only serious career consequences, but it may also affect other life issues such as insurability. Before such testing is introduced, the issues associated with it must be scrutinized by medical ethicists as well as by flight surgeons who are involved in developing medical standards for flight. Ethical considerations should include the “greater good” of the mission, as well as the relative risks and benefits to the individual. Perhaps the biggest challenge in medical screening is the ability to develop tools with which to identify crewmembers with desirable psychological attributes to minimize the risk of individual dysfunction or interpersonal conflicts that might jeopardize mission safety or effectiveness. Although we have learned a great deal from human behavior in analogue environments (e.g., polar expeditions and nuclear submarines) as well as from isolation experiments, there clearly is a great deal left to learn about selecting individuals with “the right stuff” for long-term expeditionary space missions. The psychological aspects of space flight are discussed further in Chap. 19.

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References [1]. Hickman JR. The clinical basis for aeromedical decision making. AGARD Conference Proceedings 553, K1–12; 1994; Neuilly-Sur-Seine, France. [2]. Lovelace WR, Schwichtenberg AH, Luft UC, Secrest RR. Selection and maintenance program for astronauts for the National Aeronautics and Space Administration. Aerospace Med 1962; 33:667–684. [3]. Santy PA, Jones DR. An overview of international issues in astronaut psychologic selection. Aviat Space Environ Med 1994; 65:900–903. [4]. Gray GW. Selection of astronauts/medical issues: The 1992 Canadian astronaut selection. Can Aeronaut Space J 1996; 42:139–142. [5]. Pool SL, Nicogossian AE, Moseley EC, Uri JJ, Pepper LJ. Medical evaluations for astronaut selection and longitudinal studies. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1993:375–393. [6]. Froom P, Cyjon A, Lotem M, Ribak J, Gross M. Aircrew selection: A prospective study. Aviat Space Environ Med 1988; 59:165–167. [7]. DeHart RL, Stephenson EE, Kramer EF. Aircrew medical standards and their application in the Royal Australian Air Force. Aviat Space Environ Med 1976; 47:70–76. [8]. Band PR, Spinelli JJ, Ng VTY, Moody J, Gallagher RP. Mortality and cancer incidence in a cohort of commercial airline pilots. Aviat Space Environ Med 1990; 61:299–302. [9]. Irvine D, Davies DM. The mortality of British Airways pilots, 1966–1989: A proportional mortality study. Aviat Space Environ Med 1992; 63:276–279. [10]. Grayson JK, Lyons TJ. Cancer incidence in the United States Air Force Aircrew, 1975–1989. Aviat Space Environ Med 1996; 67:101–104. [11]. Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile. Circulation 1991; 83:356–362. [12]. Berry MA, Squires WG, Jackson AS. Fitness variables and the lipid profiles in United States astronauts. Aviat Space Environ Med 1980; 51:1222–1226. [13]. Newkirk D. Almanac of Soviet Manned Space Flight. Houston, TX: Gulf Publishing Company; 1990.

4 Spaceflight Medical Systems Terrance A. Taddeo and Cheryl W. Armstrong

Providing adequate medical care for spaceflight crews requires that appropriate diagnostic tools and treatment modalities be available to them throughout their mission. The challenge for mission planners is deciding what medical capability to provide and then packaging it in a way that meets the many unique constraints of space flight. Crews also must receive adequate training that will help them to make correct diagnoses and administer the appropriate level of care to an ill or injured crewmember. As discussed in Chap. 7, identification of appropriate levels of medical care is driven by the risks that have been identified in space flight. One practical way of identifying such risks is by studying risks among analogous populations, such as military pilots, submarine crews, and Antarctic winter-over research teams. From these groups, which undergo medical screening processes similar to those of spaceflight crews, the probabilities and risks of illness occurring during a mission can be estimated. Review of reported illnesses in U.S. and Russian spaceflight crews also can be useful, although such data were not available to medical mission planners in the earliest days of space flight. The duration of a space mission and the number of high-risk activities associated with it (e.g., extravehicular activities) will also influence decisions concerning the content of onboard medical systems. Mission planners must also consider environmental factors that are unique to the space environment—factors that include microgravity, radiation, toxicology, microbiology, and purity of reclaimed water. Finally, the unique physiological responses to space flight must also be examined—space adaptation syndrome, cardiovascular deconditioning, and bone demineralization, among others. Only by accounting for all of these factors can the best possible care and facilities be provided to spaceflight crews.

Space Medical Practitioners Two groups are charged with providing real-time care for spaceflight crews: the onboard crew medical officers (CMOs) and the ground medical support personnel. Although

communications resources may enable a ground-based flight surgeon to guide a CMO through a technical procedure, the extent of the CMO’s training will correlate strongly with medical success. The CMO’s skill level must therefore be taken into account in the selection of medical hardware. Medical hardware flown should be appropriate to the skill level and training of the crew. There is no sense in selecting medical hardware that a CMO has not been trained to use. Although including a physician in every spaceflight crew would greatly enhance mission safety [1], there are too few NASA astronaut-physicians for this to be possible. Flight rules now designate that each Space Shuttle crew of five to seven individuals must include two CMOs who, whether they are physicians or not, must complete a training syllabus designed to provide them with the basic knowledge and skills necessary to provide first-line care on orbit. Similarly, two CMOs are designated from the crew complement of three to six long-duration crewmembers on the International Space Station (ISS). These individuals are trained by flight surgeons and other operational personnel. The medical kits provided on various spacecraft (including the ISS, the Space Shuttle, and the Russian space station Mir) were and are designed to meet identified mission-specific risks and to account for any limitations in the medical background of the crew. CMOs are trained to a basic degree of competence through a series of structured classes and field exercises. Onboard refresher training for medical emergency procedures is included for long duration flights.

Medical Hardware Considerations The desired medical capability must be weighed against the limited resources available on board a spacecraft. Electrical power, potable water, and other consumables are valuable and limited commodities and are not always available for routine medical purposes. The most expensive and scarce commodity is crew time. Vehicle operations and maintenance tasks, payload operations, and other important activities compete 69

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with medical requirements for time in the crew schedule. To ensure that medical tasks are completed, the procedures must be simple and intuitive and must involve a minimal number of personnel. A medical evaluation procedure that is either awkward to perform or requires an inordinate amount of time to complete may not be completed. Also, an injured or ill crewmember will reduce the workforce for onboard activity significantly. Providing terrestrial standards of care to space crews requires careful planning and forethought. Mass, volume and power are extremely valuable on a spacecraft, and the medical systems flown must minimize their consumption of these assets. Priority must also be given to items with a long shelf life, stability at ambient temperature and humidity, and minimal maintenance requirements. Simple and intuitive designs for equipment will aid in its effective use, particularly by the nonmedical user who may handle the items very infrequently. This is especially important for resuscitation hardware. Microgravity itself presents many design challenges. For example, any process that includes gas-fluid separation will require centrifugal force or gas-fluid filter systems to act in place of gravity. Procedures that generate particulate or fluid contamination of the spacecraft, such as dental drilling, specimen handling, or surgical procedures, must be performed in specialized enclosures. Finally, restraint of operator, subject, and support items is a fundamental requirement in microgravity. In microgravity, most examination techniques are unchanged, and most of the standard diagnostic and therapeutic instruments need not be modified. Stethoscopes, otoscopes, venipuncture kits, and many other familiar items have been used successfully for years in space flight, once crews have become accustomed to moving and managing these items in weightlessness and adjusting for other factors such as high ambient noise and low light levels. The following subsections provide a discussion of selected medical equipment and capabilities and some of these unique considerations. Astronauts with spaceflight experience must be included in the design of new medical systems, as they have insight not available to ground engineers. Each new generation of hardware must reflect the hard won lessons of space medical operations.

Medical Restraint Systems Experience has shown that medical examinations, intravenous (IV) techniques, and other procedures can be accomplished in the microgravity environment without specialized restraint systems. However, more complicated medical procedures cannot be performed without the use of proper restraint systems to bring CMO, patient, and medical support items into close proximity. To support contingency events in which acute care would be required, the best solution is a dedicated medical restraint table that either can be deployed quickly or is always deployed and at the ready. Prototypes of such

T.A. Taddeo and C.W. Armstrong

systems have been tested during parabolic flight [2] and space flight [3]. The ideal medical restraint would accommodate the neutral body posture assumed in microgravity (by both patient and CMO) and would support basic procedures, such as simple wound repair, as well as more complex operations. This restraint also would incorporate interfaces for medical equipment and medical waste management, such as bodyfluid-saturated pads and discarded sterile packaging. For the near future, dedicated constantly deployed medical restraints are unlikely to be included in spacecraft because of volume constraints. Other available surfaces have been and will be used, however, such as cabin walls and galley tables. However, a smaller hybrid system consisting of a rapidly deployable surface attached to dedicated structural mounts offers a viable alternative. In an acute, life-threatening situation, the time to deploy a restraint is a critical factor that could well affect patient survival. These considerations contributed to the development of the current ISS crew medical restraint system. That system consists of a rapidly deployable rigid platform that quickly restrains both patient and operator in close proximity to the onboard medical system. This restraint system also affords electrical isolation from the station systems and rescuers should defibrillation be required.

Automated Ventilation Advanced airway handling methods have been developed for use in the weightless environment and have been taught to CMOs. Equipment for endotracheal intubation has been on hand on Skylab, Space Shuttle, Mir space station, and ISS missions. Some type of manual respirator has always been available during these programs, and a small automated ventilator also is now part of the ISS medical inventory. Because of electrical power constraints in spacecraft, the best option for automated ventilation is a compact pressuredriven ventilator that uses the storage pressure of respirable gas. On Earth, such ventilators are typically used for short-term acute care. For a patient who is incapable of adequate spontaneous respiration, the compact pressure-driven ventilator is a potentially lifesaving device that replaces a crewmember who would otherwise be required to give manual respirations with a bag device. As noted above, ample assistance may not be available should a medical crisis occur in flight. In the ground-based transport and acute roles, pressure-driven ventilators are generally powered by 100% oxygen. This immediately creates a problem in the enclosed environment of a spacecraft in that the patient-ventilator exhaust is nearly 90% oxygen, with the remaining 10% being expired CO2 and water vapor. In an enclosed cabin, ambient concentrations of oxygen can rise quickly and exceed flammability limits. A short-term option in such a contingency would be to add a diluent gas such as nitrogen to the cabin atmosphere to maintain safe concentrations. However, this option comes at a cost in consumables as overall atmospheric pressure bleeds off to maintain cabin pressure limits.

4. Spaceflight Medical Systems

Two potential solutions exist that could lessen that cost in consumables. The first would be to provide an overboard dump in which only the expired ventilator gas is vented overboard into space or into some vessel from which the gas may be reclaimed later. The second solution is to provide a dual-gas system (oxygen/nitrogen) and a gas blender that would allow the CMO to use only the oxygen concentration required to address a clinical need. This solution also would mitigate the potential problems of pulmonary oxygen toxicity, usually seen after 18 or more hours of breathing 100% oxygen, should ventilation be required for that length of time. However, since high concentrations of oxygen may still be needed to meet medical requirements, some combination of these 2 solutions may be optimal. Any future contingency respiratory capability should use a closed system that will minimize loss of consumables. Also, the use of an advanced technology such as molecular sieve beds would enable a gas delivery system to obtain and concentrate oxygen from the ambient cabin atmosphere before venting the exhaust directly back into the cabin, with a minimal effect on atmospheric composition.

Intravenous Fluid Therapy Administration of small doses of IV medications is not problematic in weightlessness. However, large volumes of fluids for hydration cannot be administered in the same manner as on Earth, by using gravity-driven free-flow devices or pumps that automatically separate air and fluid. The simplest means of providing IV fluids in weightlessness combines a soft fluid packaging with a surrounding pneumatic pressure device, such as a blood pressure cuff. Regulating the pressure and the size of the flow orifice provides a rough means of controlling the rate of fluid administration. Injection fluids must be specially packaged with a minimum amount of air, and care must be taken while preparing the infusion system to avoid introducing further air into the line. Additional air-fluid separation may be facilitated with an in-line filter system, or a “bubble trap.” More precisely regulated infusion rates, such as those required to administer continuous or controlled-dose medications, will require an automated pump. Prototypes of powered infusion pumps have been tested during space flight [1,4], and a small commercially available device has been adapted and included in the ISS inventory. Although prudence dictates maintaining at least a small stock of prepackaged IV fluids, storing large quantities of IV fluids would represent a significant overhead in launch mass and stowage. Moreover, most IV fluids have 1-year shelf lives. A more efficient use of resources would be to produce sterile injection-grade fluid as needed during flight from potable water. Exploration-class missions should have this capability. Technology to produce sterile injectiongrade fluid for space flight using ion exchange columns and premeasured electrolyte and drug aliquots has been extensively examined [5,6].

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Cardiac Defibrillation Contemporary advanced life support methods require the capability for cardiac monitoring and defibrillation. A monitor/ defibrillator may consist of an off-the-shelf item that has been modified for space flight, with capabilities for monitoring, defibrillation over a range of selected energy levels, and external cardiac pacing. Some unique considerations arise in microgravity. A notable example is the application of charged paddles to a patient’s chest, an act that normally requires a force of 11 kg (25 lbs) to ensure adequate electrical contact. Since the rescuer has no weight in microgravity, self-adhesive defibrillator pads (which are becoming more common in ground use) must be used. Insulation and electromagnetic interference shielding must also be considered to protect those delivering care from inadvertent electrical shock as well as to protect sensitive avionics from damaging electromagnetic interference pulses. As an acute response item, the monitor/defibrillator must be maintained in a state of readiness. Batteries must be charged to energize the capacitor, which delivers the direct current counter-shock, and the unit must be rapidly and easily accessible. Since much of the patient positioning and insulating requirements will be met by a medical restraint system, restraint deployment may be a rate-limiting step in delivering lifesaving defibrillation. The CMO must be well trained in the safe and effective use of the defibrillator, since situations requiring cardiac defibrillation, although rare, will very likely arise and require treatment well before ground consultation can be obtained.

Cardiopulmonary Resuscitation Common methods of closed-chest cardiac massage depend on the weight of the rescuer’s upper torso to drive the force of compression; however, this weight, and hence this force, are absent in microgravity. A restrained rescuer’s muscular power alone may provide adequate compressive force for a short time. Such methods have been tested during parabolic flight [7] and during space flight [8]. However, delivering compressions of adequate force can quickly become exhausting, particularly for crewmembers who have experienced musculoskeletal deconditioning during space flight. Effective compressions can be delivered more easily by the rescuer if he or she is reacting against an opposite surface with the feet rather than by being restrained in a more terrestrial-standard position at the patient’s side. This position requires no dedicated rescuer restraint, it uses combinations of extensor muscles throughout the body, and it keeps the area near the patient’s chest and head clear for airway and IV procedures. Alternatively, mechanical devices may be used, such as pneumatically powered “thumpers,” or simpler lever devices, such as those tested during the STS-40 (June 5 to June 14, 1991) Space Shuttle mission [8]. Such devices would be best integrated into an advanced medical restraint system.

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The On-Site Medical Checklist Like the medical support hardware, written medical procedures carried on board spacecraft for the use of crewmembers must be as user-friendly and as intuitive as possible. Preflight training with the hardware must use the same procedures as those to be used in space flight. Moreover, since training sessions with the hardware may have taken place months or even a year before use, documentation of the supporting procedures must be clearly and concisely written. Diagrams, photos, simple cue cards, logical grouping of items, and effective labeling can increase crew efficiency and effectiveness. These design principles are even more important as multinational crews, whose members are reading and writing in nonnative languages, work together on the ISS. Notably, the ISS Medical Checklist is a bilingual guide that is printed on facing pages in the two main operative languages of the ISS—English and Russian.

Medical Systems of Spacecraft and Space Stations Projects Mercury and Gemini Spaceflight medical systems have evolved from a few medications and monitoring devices to advanced life support hardware. The medical kit (see Figures 4.1 and 4.2) for the six piloted Project Mercury flights (May 5, 1961 to May 15, 1963) included an anti-motion-sickness drug, a stimulant, and a vasoconstrictor to treat shock. The astronauts’ electrocardiograph, blood pressure, respiratory rate, galvanic skin resistance, and rectal temperature were monitored by physicians on the ground [9].

FIGURE 4.1. Mercury medical kits containing items such as antibiotics, decongestants, stimulants, electrode paste, and medications to treat nausea and diarrhea. (Photo courtesy of NASA)

T.A. Taddeo and C.W. Armstrong

The number of medications flown increased slightly during the 10 crewed Project Gemini space flights (March 23, 1965 to November 15, 1966). The contents of the Gemini VII (December 4 to December 18, 1965) medical kit reflect this change (see Table 4.1 and Figure 4.3). In addition to the medical kit, medications were also carried in a separate survival package. The contents of the Gemini VI-A (December 15 to December 16, 1965) survival package medical kit included a stimulant, motion sickness medication (oral and injectable), pain medication (oral and injectable), an antibiotic, and aspirin [11].

The Apollo Program During the crewed Apollo Program flights (October 11, 1968 to December 19, 1972, consisting of two Earth orbit flights, two lunar orbit flights, one lunar swingby flight [Apollo 13, April 11 to April 17, 1970], and six lunar landing flights), separate medical kits were required for the command module and the lunar module (see Figures 4.4–4.6). These kits included primarily medications and bandage items. An auxiliary kit was added to the command module kits for Apollo 16 (April 16 to April 27, 1972) and Apollo 17 (December 7 to December 19, 1972). The contents of the Apollo commandmodule medical kit are listed in Table 4.2, and the contents of the lunar-module medical kit are listed in Table 4.3.

The Skylab Missions The 3 crewed Skylab missions lasted 28 days (May 25 to June 22, 1973), 59 days (July 28 to September 25, 1973), and 84 days (November 16, 1973 to February 8, 1974) and provided new challenges for medical support teams. Onboard medical

FIGURE 4.2. Mercury medical kit containing items such as saline solution, bandages, stimulants, and decongestants (Photo courtesy of NASA)

4. Spaceflight Medical Systems

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TABLE 4.1. Contents of the Gemini VII medical kit [10]. Medication

Indication

Dose

Amount

D-Amphetamine sulfate Aspirin-phenacetincaffeine Cyclizine HCl Diphenoxylate HCl Meperidine HCl Methyl cellulose solution Parenteral cyclizine

Stimulant Pain

5-mg tablets Tablets

8 16

Motion sickness Diarrhea Pain Eye lubricant Motion sickness

8 16 4 1 2

Parenteral meperidine HCl

Pain

Pseudoephedrine HCl Tetracycline HCl

Decongestant Antibiotic

Triprolidine HCl

Decongestant

50-mg tablets 2.5-mg tablets 100-mg tablets 15-ml bottle 45 mg (0.9-ml injector) 90 mg (0.9-ml injector) 60-mg tablets 250-mg coated tablets 2.5-mg tablets

2 16 16 16

FIGURE 4.5. Apollo clinical physiological monitoring kit and emergency medical kit (Photo courtesy of NASA)

FIGURE 4.3. Apollo medical kit containing items such as skin cream, antibiotic ointment, nasal spray, band-aids, and stimulants (Photo courtesy of NASA)

FIGURE 4.6. Apollo emergency medical kit (Photo courtesy of NASA)

The Space Shuttle

FIGURE 4.4. Apollo Command Module medical kit (Photo courtesy of NASA)

systems were upgraded to provide an enhanced drug formulary and capabilities including wound care, dental care, minor surgery, urinary catheterization, and microbiology assessment. Skylab astronauts received 80 h of paramedic-level training before launch. The contents of the Skylab medical kits are listed in Table 4.4.

The Shuttle Orbiter medical system (SOMS) has flown on all Space Shuttle flights and is designed to support a crew of five to seven for up to 20 days. A process exists to make necessary changes and upgrades to the SOMS, and over the course of more than 100 Space Shuttle flights, the SOMS has evolved to meet mission needs and to keep up with advances in medical therapy and pharmacology. This process of change and review also permits some degree of customization for each mission. The current SOMS comprises several subpacks, namely the emergency medical kit (EMK), the medications and bandages kit (MBK), the medical accessory kit (MAK), the airway medical accessory kit (AMAK), the contaminant cleanup

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T.A. Taddeo and C.W. Armstrong TABLE 4.2. Contents of the Apollo Command-Module medical kit [12]. Items Actifed (triprolidine/pseudoephedrine) Afrin (oxymetazoline) Ampicillin Aspirin Atropineb Bacitracin Benadryl (diphenhydramine)c Darvon (propoxyphene) Demerol (meperidine)b Dexedrine (d-amphetamine) Lidocaineb Lomotil (diphenoxylate) Marezine (cyclizine) Marezine (cyclizine)d Methylcellulose Multivitamins Mylanta (simethicone) Nasal emolient Neosporin (polymixin B) Ophthaine (proparacaine preparation) Pronestyl (procainamide)b Scopolamine-dexedrine Seconal (secobarbital) Seconal (secobarbital)c Skin cream Tetracycline Tetrahydrozoline HCle Tylenol (acetaminophen)c Band-aids Compress bandages

Indication Decongestant Decongestant Antibiotic Analgesic Cardiac arrhythmias Antibiotic Antihistamine Analgesic Analgesic Stimulant Cardiac arrhythmias Diarrhea Antihistamine Antihistamine Laxative

Formulation

Antiflatulent

Tablets Nose drops Tablets Tablets Injectable solution Eye ointment Tablets Tablets Injectable solution Tablets Injectable solution Tablets Injectable solution Tablets Capsules Tablets Tablets

Antibiotic Topical anesthetic Cardiac arrhythmias Motion sickness Sleeping aid Sleeping aid

Ointment Eye drops Tablets Tablets Tablets (100 mg) Tablets (50 mg)

Antibiotic

Tablets Eye drops Tablets

Analgesic

Amounta 60 3 60 72 12 1 8 18 6 12 12 24 3 24 2 20 40 1 1 or 2 1 80 12 21 12 1 Varied 1 14 12 2

a

Not all medications were carried in the amounts noted on all flights. Carried on Apollo-16 and -17 only. c Carried on Apollo-8 only. d Carried on the first 4 missions only. e Carried on Apollo-17 only. b

TABLE 4.3. Contents of the Apollo Lunar Module medical kit [12]. Items Actifed (triprolidine/pseudoephedrine) Afrin (oxymetazoline) Aspirin Atropine Darvon (propoxyphene) Demerol (meperidine) Dexedrine (d-amphetamine) Lidocaine Lomotil (diphenoxylate) Methylcellulose Neosporin (polymixin B) Pronestyl (procainamide) Seconal (secobarbital) Band-aids Compress bandages Urine collection and transfer devices a

Indication

Formulation

Decongestant Decongestant Analgesic Cardiac arrhythmias Analgesic Analgesic Stimulant Cardiac arrhythmias Diarrhea

Tablets Nose drops Tablets Injectable solution Tablets Injectable solution Tablets Injectable solution Tablets Eye drops Ointment Tablets Tablets

Antibiotic Cardiac arrhythmias Sleeping aid

Not all medications were carried in the amounts noted on all flights.

Amounta 8 1 12 4 4 2 4 8 12 1 1 12 6 6 2 6

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TABLE 4.4. Contents of the Skylab In-Flight Medical Support System [13]. Equipment Accumulator assembly Adhesive tape, Dermicel Adhesive tape, Micropore Air sampler Airway, pharyngeal Aneroid sphygmomanometer Applicator, dental Applicators, silver nitrate (12) Antibiotic lubricant Band-Aids (100) Barrier, sterile field (2) Batteries (8 AAA), (8 AA), (8 C) Betadine squares (4) Bili-Labstix/Urobilistix Binocular loupe Blood lancets (75) Calcium alginate balls (50) Can opener Cannula Capillary pipettes (50) Catheter, urinary Coagulase plasma CO2 accumulator assembly CO2 generators (24) Collection bag (3) Container, injectables Demerol injectors (5) Dermicel surgical tape Digital hand counter Disinfectant pads (60) Disposable bags (20) Dressing boot (Unna’s) Dressing, abdominal (6) Drug modules (2) Elastic wraps (3) Elevator Endotracheal tube Eye patch, cotton (8) Eye patch, plastic (2) File Filter strips (10) Fluorescein strips (12) Forceps, 6-in (3) Forceps, mandibular anterior Forceps, mandibular posterior Forceps, maxillary anterior Forceps, maxillary posterior Forceps, mosquito Forceps, splinter Forceps, tissue Gauze, dental Gauze, roller (6) Gauze squares 4 in. × 4 in. (24) 2 in. × 2 in. (12) 2 in. × 2 in. (20) Gauze squares, Betadine Gauze, Vaseline (6) Glass marking pencil (2) Gloves, examination (2 pair) Gloves, surgical (2 pair)

Kit Microbiology Bandage Bandage Bandage Therapeutic Diagnostic Bandage Bandage Catheterization Bandage Minor Surgery Diagnostic Minor Surgery Hematology/Urinalysis Diagnostic Hematology/Urinalysis Hematology/Urinalysis Not applicable Therapeutic Hematology/Urinalysis Catheterization Command Module Resupply Microbiology Microbiology Catheterization Therapeutic Therapeutic Hematology/Urinalysis Hematology/Urinalysis Not applicable Microbiology Bandage Bandage Drug Supply Module Bandage Dental Therapeutic Bandage Bandage Dental Microbiology Bandage Microbiology Dental Dental Dental Dental Minor Surgery Bandage Minor Surgery Dental Bandage Bandage Bandage Minor Surgery Bandage Minor Surgery Bandage Microbiology Hematology/Urinalysis Catheterization

Usage requirement No restriction No restriction No restriction Not applicable No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction Not applicable Physician use/approval required No restriction Physician use/approval required No restriction No restriction No restriction No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction No restriction Not applicable No restriction No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required No restriction Physician use/approval required No restriction No restriction No restriction

No restriction Physician use/approval required No restriction No restriction No restriction No restriction (continued)

76

T.A. Taddeo and C.W. Armstrong TABLE 4.4. (continued) Equipment Glucose (2) Heat sink Hemacheck assembly Hemoglobin meter Hemolysis applicators (50) Hemostat Hemostat, Crile, curved Hemostat, Crile, straight Hemostat, Kocher Hemostat Hydrogen peroxide Immersion oil bottles (3) Incubator Injectables container Lancets (75) Laryngoscope Lens (100×) Lens tissue Light bulbs (14) Loop holders (2) Light source, head-mounted Microscope Microscope stage Mirror/light Myringotomy knife Nasogastric tube Needle holder Needles, hypodermic 16-Gauge (2) 18-Gauge (2) 20-Gauge, 4 in. (1) 20-Gauge (2) 25-Gauge (4) 27-Gauge, 13/16 (3) Neurologic exam instruments Nozzle Ophthalmoscope Otoscope Otoscope specula (33) Oxidase strips (25) Petri dish, large (20) Petri dish, small (20) Pressure infusor assembly Probe Resupply container (2) Retractors, skin/muscle (ALMS) Scalers, curette Scalpel, #10 (2) Scalpel, #11 (2) Scissors Scissors, sharp/sharp Sedative restorative material (8) Sensitivity discs Ampicillin (50) Cephalothin (50) Erythromycin (50) Sulfasoxazole (Gantrisin) (50) Penicillin G (50) Tetracycline (50) Sensitivity disc dispenser (3) Silver nitrate applicators (12)

Kit

Usage requirement

Therapeutic Command Module Resupply Hematology/Urinalysis Hematology/Urinalysis Hematology/Urinalysis Catheterization Minor Surgery Minor Surgery Minor Surgery Therapeutic Command Module Resupply Microscope Not applicable Therapeutic Hematology/Urinalysis Therapeutic Drug Supply Module Microscope Diagnostic Microbiology Diagnostic Microscope Drug Supply Module Dental Diagnostic Catheterization Minor Surgery

Physician use/approval required No restriction No restriction No restriction No restriction No restriction Physician use/approval required Physician use/approval required Physician use/approval required No restriction No restriction No restriction Not applicable No restriction No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required No restriction Physician use/approval required

Therapeutic Therapeutic Command Module Medical Kit Therapeutic Therapeutic Dental Diagnostic Catheterization Diagnostic Diagnostic Diagnostic Command Module Resupply Command Module Resupply Command Module Resupply Not applicable Minor Surgery Command Module Resupply Minor Surgery Dental Minor Surgery Minor Surgery Bandage Minor Surgery Dental Command Module Resupply

No restriction No restriction Physician use/approval required No restriction No restriction No restriction Physician use/approval required Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required Physician use/approval required No restriction Physician use/approval required No restriction Physician use/approval required Physician use/approval required No restriction Physician use/approval required No restriction No restriction

Microbiology Bandage

No restriction No restriction (continued)

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77

TABLE 4.4. (continued) Equipment Slide dispenser (75 slides) Slide stainer Slide streaker (2) Slide stainer expendables Specific gravity refractometer Specula, disposable Sphygmomanometer Splint assembly (4) Sterile water (2) Steri-Strips (20) Stethoscope Stewart’s transport media (58) Streaking loops Suture material, chromic catgut; 000 with fingerstick (2 needle) Suture material, dermal #5-0 with fingerstick (2 needle) Suture material, silk, – 00 Swabs, cotton (24) Swabs, dry (20) Swabs, dry, crew nasal and throat samples (18) Swabs, dry, crew illness (12) Swabs, dry, cultural transport (48) Swabs, wet, antibiotic Sensitive (48) Swabs, wet, crew body sample (18) Swabs, wet, environ. surface sample (90) Syringe, dental Syringe, epinephrine Syringe, plastic, 2.5-cc (2) Syringe, plastic, 50-cc with needle (2) Syringe, 1-cc tubex holder Syringe, plastic with needle, 50-cc (3) Syringe, 2-cc tubex holder Syringe, 5-cc Syringe, with needle, 1-cc (6) Syringe Taxos A discs (50) Taxos P discs (50) Thermometer, oral (2) Three-way valve Tissue forceps Tongue depressor Tourniquet Towel Tracheostomy equipment (Unna’s) Boot dressing Urinary catheter Urine sample bag (6) Valve, three-way Vaseline gauze (6) Velcro, sticky-back (6) Vials (58) Water, sterile (2) Work table Zephiran (benzalkonium chloride) wipes (81)

Kit

Usage requirement

Microscope Not applicable Drug Supply Module Not applicable Hematology/Urinalysis Diagnostic Diagnostic Not applicable Command Module Resupply Bandage Diagnostic Command Module Resupply Microbiology Minor Surgery

No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required

Minor Surgery Minor Surgery Bandage Therapeutic Microbiology Microbiology Microbiology Microbiology Microbiology Microbiology Dental Therapeutic Therapeutic Therapeutic Therapeutic Therapeutic Therapeutic Therapeutic Microbiology Catheterization Command Module Resupply Command Module Resupply Diagnostic Command Module Medical Accessory Kit Minor Surgery Diagnostic Hematology/Urinalysis Catheterization Therapeutic Bandage Catheterization Microbiology Command Module Medical Accessory Kit Bandage Hematology/Urinalysis Command Module Resupply Command Module Resupply Minor Surgery Hematology/Urinalysis Catheterization

Physician use/approval required Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction No restriction Physician use/approval required Physician use/approval required No restriction No restriction No restriction No restriction No restriction Physician use/approval required No restriction Physician use/approval required No restriction No restriction No restriction No restriction No restriction No restriction

kit (CCK), the operational bioinstrumentation system, the electrode attachment kit, patient and rescuer restraints, and a resuscitator (see Figure 4.7). Only the EMK and the MBK flew on STS-1 (April 12 to April 14, 1981). The EMK contains injectable medications,

dental items, IV fluid administration equipment, and other diagnostic and therapeutic instruments. The MBK contains oral medications, topical medications, and bandages for treating most in-flight problems. Oral medications are in shrink-wrapped plastic bottles with attached tops and

78

FIGURE 4.7. Shuttle Orbiter Medical System. Following redesign in 2000, components include Saline Supply Bag, EENT Subpack, IV Administration Subpack, Trauma Subpack, Sharps Container, Drug Subpack, and Airway Subpack (Photo courtesy of NASA)

push-up dispensers for easy management in microgravity. Crewmembers record medication use in data logs stowed in the MBK. At the recommendation of an experienced Space Shuttle CMO, a space motion sickness kit was also developed. This kit, which is stowed in the pocket of the MBK, includes, in one convenient location, all of the items necessary for giving an intramuscular injection of promethazine, thus saving crew time early in the mission, when space motion sickness is most prevalent. The operational bioinstrumentation system and the electrode attachment kit were added to the SOMS in 1982. These two items can be used during a medical contingency to downlink a crewmember’s electrocardiogram waveform to the Mission Control Center. The SOMS was reevaluated in the wake of the STS-51-L Challenger accident (January 28, 1986), and the MAK, the CCK, patient and rescuer restraints, and a resuscitator were added for the return-to-flight mission, STS-26 (September 29 to October 3, 1988). The MAK, which contains additional IV fluid and urinary catheterization supplies, is used to stow additional mission-specific medical items. The CCK provides protective equipment, including gloves, goggles, masks, containment bags, and hazard identification labels—items used to protect the crew in the event of a hazardous spill or another contamination event. The restraints and resuscitator enhance the crew’s ability to perform cardiopulmonary resuscitation on board the Space Shuttle. After a review of the system by emergency medicine consultants in 1990, the AMAK was added. The AMAK allowed all of the airway management equipment to be located in a single place and added the capability for advanced airway procedures. In 1992, the CCK was redesigned, and a supplemental medical extended-duration Orbiter pack (MEDOP) was

T.A. Taddeo and C.W. Armstrong

developed. The CCK redesign reduced the overall size of the kit and added an eyewash capability to decontaminate the eyes. This Shuttle emergency eyewash was designed to interface with the Space Shuttle galley (as the water supply source) and the waste collection system (for disposing of the contaminated water). The Shuttle emergency eyewash design includes a pair of swim goggles and tubing with special interfaces for the galley and waste collection system. The MEDOP was designed specifically for extended-duration Orbiter missions (that is, for Space Shuttle missions lasting longer than 12 days). The MEDOP contains additional supplies located in the EMK or MBK as well as a skin stapler and a rapid test for oropharyngeal group A β-hemolytic streptococcal infection, among other unique items [15]. An IV accessory kit was developed in 1998. IV supplies are kept in the IV accessory kit, which is similar to the AMAK, for quick access. Although the IV accessory kit is not currently part of the Space Shuttle’s standard medical complement, it flew on four missions at crew surgeon request. Because of hazards posed by particular payloads and medical experiments, a defibrillator has been flown on two Space Shuttle missions. This commercial-off-the-shelf device was modified to meet flight certification specifications. In addition to the defibrillator, a cardiac drug kit and crew medical restraint system were developed. The cardiac drug kit contains primarily ACLS cardiac medications to be used with the defibrillator. The crew medical restraint system attaches to the middeck lockers and restrains a crewmember while rescuers provide that crewmember with appropriate medical care. The crew medical restraint system also ensures that the patient is electrically isolated, so that the defibrillator can be used without risk of damage to Space Shuttle systems from extraneous electrical current. The contents of the standard SOMS, excluding the MEDOP, are listed in Table 4.5. The SOMS package was redesigned after a review by a panel that included extramural experts in pharmacology and wilderness medicine. This redesign, finalized in 2000, improves the layout and user-friendliness of the system and mirrors the structure of the ISS medical kits. A key element is the use of dedicated subpacks, with each subpack serving a specific function or classification of care. The subpacks include an airway subpack, an IV administration subpack, a saline supply bag, a trauma subpack, an otolaryngologic (eye, ear, nose, and throat) subpack, and a drug subpack. No changes were recommended for the CCK. The MEDOP will continue to be manifested for missions lasting longer than 12 days. The new SOMS was first flown on the STS-98 mission in early 2001.

The Russian Space Station Mir The medical capability on the Mir space station (1986–2001) was a product of many years’ experience in long-duration space flight. Medical items carried on Mir were oriented toward supporting two or three crewmembers; these items were replenished continuously to support the permanent

4. Spaceflight Medical Systems

79

TABLE 4.5. Contents of the Shuttle Orbiter Medical System. Name Absorbant wipes Ace bandage Adaptic bandages Afrin (nasal spray) Air temperature monitors Airway Alcaine (Proparacaine eye drops)b Alcohol wipes Ambien (zolpidem) Ambulatory leg bag Amikin (amikacin)b Amoxil (amoxicillin)b Anusol-HC suppositories Ascriptin (aspirin) Atropineb Bactrim DS (trimethoprim/sulfamethoxasole)b Bags Chemical resistant Mess-up mitts Red bio-wipe Ziploc Band-aids Benadryl (diphenhydramine)b, injectable Benadryl (diphenhydramine), oral Biohazard identification labels Blistex lip balm Blood pressure cuff Butterfly infusion sets Catheter, Foley Chemstrip 10 Ciloxan (ciprofloxacin) ophthalmic solutionb Cipro (ciprofloxacin)b Claritin (loratadine) Cotton balls Cotton swabs Cough lozenges Cyclogyl (cyclopentolate)b Demerol (meperidine)b Dental kit Carver/file Mirror Needles Orangewood sticks Syringe Temporary filling Toothache kit Eugenol anesthetic drops Tweezers Cotton pellets Marcaine (bupivacaine)b Dexamethasoneb Dexedrine (dextroamphetamine)b Diamox (acetazolamide)b Drape, sterile

Amounta

Description 3 in. wide 3 in. × 3 in. 3-ml bottles 90–120 F 58–88 F Oral 15-ml bottle 10 mg 600-ml bag 250 mg/cc, 2-cc unit 500 mg 325-mg aspirin w/Maalox 1 mg/cc, 2-cc unit

16 in. H × 12 in. W Double stick tape closure 12 in. × 11.5 in. Tape closure 12 in. × 11.5 in. Tape closure 12 in. × 12 in. Ziploc closure 1 in. × 3 in. Sheer spot 50 mg/cc, 1-cc unit 25 mg

with aneroid sphyg 16 Fr, 30-cc balloon, silastic 0.3%, 2.5-ml bottle 500 mg 10 mg

5 mg dextromethorphan 1%, 15-ml bottle 50 mg/cc, 1-cc unit

Long: 27 G, 1.25 in. Short: 27 G, 0.75 in.

0.5% w/epinephrine 1:200,000 10 mg/cc, 1-cc unit 5 mg 250 mg

72 2 3 6 2 2 1 1 36 75 tablets 1 1 24 capsules 6 25 tablets 2 28 tablets 8 2 2 9 15 16 2 20 capsules 20 1 1 2 2 13 3 22 tablets 20 tablets 10 6 15 1 4 1 1 6 6 2 1 1 1

6 dental carpules 2 30 tablets 30 capsules 1 (continued)

80

T.A. Taddeo and C.W. Armstrong

TABLE 4.5. (continued) Name Dulcolax (bisacodyl) Duricef (cefadroxil)b Elastoplast tape Electrode attachment kit End-tidal CO2 detector Entex LA (long-acting) (phenylpropanolamine/guaifenesin) Epinephrineb Eye pads Finger splint Flagyl (metronidazole)b Fluorescein strips Forceps Fox shield Gauze pads Genoptic (gentamicin) ophthalmic ointmentb Gloves Gloves Gloves Goggles Haldol (haloperidol)b Hazard identification labels Hemostat Imodium (loperamide HCl) Isoptin (verapamil)b IV administration set IV intracatheters Kenalog (triamcinolone) cream Kerlix dressing Kling Laryngoscope Lever lock cannula Lidocaine/cardiac Lidocaine/cardiac injector Lotrimin (clotrimazole) cream Lubricant (water-soluble) Magnifying glass Masks, surgical Medical data logs Merocel Pope (posterior nasal packing) Morphine sulfateb Motrin (ibuprofen) Mycelex-7 (clotrimazole)b Mylanta Double Strength Narcan (naloxone)b Nasostat balloons Needles Neosporin Plus cream with lidocaine Nitroglycerin patchb Nitrostat (nitroglycerin tablets)b Op Site Operational Bioinstrumentation System Electrode attachment kit Operational Bioinstrumentation System belt w/signal conditioner Sternal harness Intravehicular activity cable Biomed cable Ophthalmoscope head

Amounta

Description 5 mg Suppository, 10 mg 500 mg 4 in. wide

75 mg phenylpropanolamine hydrochloride, 400 mg guaifenesin 1:1000, 1-cc unit

250 mg Blunt Metallic eye patch 4 in. × 4 in. 3.5-g tube Chemical resistant Nonsterile, surgical Sterile, surgical Eye protection 5 mg/cc, 1-cc unit Decals (6 each level) Small Curved 2 mg 2.5 mg/cc, 2-cc unit 18 G 20 G 15-g tube 4.5-in. wide 3-in.-wide gauze dressing Handle with med blade 20 mg/cc, 5-cc unit 15-g tube 3g 4× magnification Crew size + generic 10 cm 10 mg/cc, 1-cc unit 400 mg 100-mg suppositories 0.4 mg/cc, 1-cc unit 22 G, 1.5 in. 18 G, 1.5 in. 0.5-oz tube, 40-mg lidocaine 15 mg 0.4 mg (1/150) Transparent dressing Electrocardiograph monitor

30 tablets 6 20 capsules 1 roll 1 1 40 tablets 5 6 1 28 tablets 8 1 1 27 1 7 pair 9 pair 2 pair 7 2 30 1 1 32 capsules 2 2 2 2 1 1 roll 5 rolls 1 2 2 2 1 7 1 7 variable 3 3 30 tablets 7 24 tablets 2 2 2 2 1 1 25 6 1 1 each 1 2 2 1 (continued)

4. Spaceflight Medical Systems

81

TABLE 4.5. (continued) Name Ophthalmoscope spare bulb Otoscope Otoscope spare bulb Otoscope speculum Ovral-21 (norgestrel/ethinyl estradiol)b Patient/rescuer restraints Penrose tubing (tourniquet) Pepto Bismol PH strips Phazyme-125 (simethicone) Phenergan (promethazine) Phenergan (promethazine) Polysporin (polymyxin/bacitracin) Pope otowicks Povidone-iodine swabs Proventil (albuterol) inhalerb Pyridium (phenazopyridine) Radiation dosimeters Refresh (artificial tears, eye drops) Restoril (temazepam) Resuscitator Rimantadine Roller clamp irrigation assembly Ruler, plastic measurement Saline

Salt tablets Scalpels Scissors, curved Shuttle emergency eyewash Silvadene (silver sulfadiazine) cream Silver nitrate sticks Skin temperature monitors Space Motion Sickness Kit Alcohol wipes (10) Band-aids (10) Phenergan injectables (10)b Tubex injector (1) Splint Steri-Strip skin closures Stethoscope Suction device Sudafed (pseudoephedrine) Surgical Instrument Assembly Forceps, small point Needle holder Hemostat, small Tweezers, fine point Scissors, curved Suture

Syringes Tape, Dermicel

Amounta

Description

17-g container 200 mg

1 1 1 1 21 tablets 2 sets 2 24 tablets 10 strips 20 soft gel capsules 11 30 tablets 14 1 6 20 2 20 tablets

0.3 cc 15 mg

12 40 capsules

100 mg

42 tablets 1

100 ml 250 ml 500 ml 0.9% NaCl 1 g NaCl No. 10 No. 11 w/in surgical instrument assembly Irrigation goggles 20-g tube

3 1 2

50 mg/cc, 1-cc unit Oral, 25 mg Suppository, 25 mg 1-oz tube

84–106°F

Finger

Toomey syringe 30 mg

4-0 Dexon w/needle 5-0 Ethilon w/needle 4-0 Ethilon w/needle 3-0 Ethilon w/needle 2-0 Vicryl w/CT-1 needle 10 cc 3 cc 1 in. wide

128 tablets 2 1 1 pair 1 1 5 15 1

1 3 1 1 100 tablets 1 each

1 1 2 2 1 3 6 2 rolls (continued)

82

T.A. Taddeo and C.W. Armstrong

TABLE 4.5. (continued) Name Telfa pads Thermometers, disposable (Tempadot) Tongue depressors Tracheal tube Tracheostomy Kit Alcohol wipes Dissecting scissors Curved hemostats Tracheal hook Silk ties Tracheostomy tube Tracheostomy tube holder Scalpel Transparent dressing (Tegaderm) Tubex injector Tylenol (acetaminophen) Tylenol #3 (acetaminophen with Codeine)b Urine Test Package Chemstrip 10 Color chart Valium injectable (diazepam)b Valium, oral (diazepam)b VIRA-A (vidarabine) ophthalmic ointmentb VoSol HC otic solution Xylocaine (lidocaine)b Xylocaine (lidocaine) Plainb Y-Type catheter extension Zithromax (azithromycin)b

Description 0.5 in. wide 3 in. × 4 in. nonstick bandages 96–104°F with stylet

325 mg 300 mg acetaminophen with 30 mg codeine

5 mg/cc, 2-cc unit 5 mg 3%, 3.5-g tube 10-ml bottle 2% w/epinephrine, 1:100,000, 2-cc unit 2% without epinephrine, 2-cc unit 250 mg

Amounta 2 rolls 5 18 5 1 1

5 2 60 20 tablets 1 13 strips 2 30 tablets 1 1 1 1 2 18 tablets

a

Not all medications were carried in the amounts noted on all flights. b Indicates item to be used only after surgeon approval or as directed in medical checklist.

human presence on the station. Therapeutic items were distributed among several small, problem-oriented kits, an approach that provided convenient access for the crew and decreased the time required for resupply because the needed items were conveniently added to the next launch opportunity on either a Soyuz crew transport or a Progress freighter vehicle. Mir medical kits contained primarily medications, bandaging supplies, and splints (Table 4.6). Other diagnostic and medical monitoring equipment that were available on board the Mir included both a manual and an automatic blood pressure monitor; a 12-lead electrocardiograph; a rheoencephalograph; and devices to measure laboratory analysis values in blood (Reflotron) and urine (Urilux analyzer). Throughout the joint U.S.-Russian NASA-Mir Program (March 14, 1995 to June 12, 1998), the Mir space station was sequentially home to seven NASA astronauts and witnessed nine visiting US Space Shuttle missions (June 27, 1995 to June 12, 1998). To augment the Russian on-orbit medical capability and to add a small degree of advanced life support capabilities to the medical capabilities already extant on Mir, the Mir supplemental medical kit (MSMK) was developed. Minimal redundancy was present between the MSMK,

which was derived from the SOMS, and the Mir medical kits. Developed jointly by the U.S. and Russian medical communities, the MSMK was composed of reconfigured U.S. EMK, MBK, and MEDOP kits. Airway management items were included in the MEDOP, and astronauts and cosmonauts were trained accordingly in life support and airway handling. After the NASA-1 (March 14 to July 7, 1995)/Mir-18 mission, the Mir resupply kit was added to the MSMK system. The Mir resupply kit included a pulse oximeter, a portable clinical blood analyzer, and additional IV fluid. The Mir defibrillator, the cardiac drug kit, and the crew medical restraint system were added for the NASA-5 (May 15 to October 6, 1997), NASA-6 (September 25, 1997 to January 31, 1998), and NASA-7 (January 22 to June 12, 1998) increments. Items found in the MSMK are listed in Table 4.7.

The International Space Station NASA and the Russian Aviation and Space Agency each provide medical equipment for the ISS. The NASA-provided medical equipment is the crew health care system (CHeCS). As well as supplying traditional medical kits to the ISS,

4. Spaceflight Medical Systems

83

TABLE 4.6. Contents of the Mir medical kits.

TABLE 4.6. (continued)

Onboard Medications/Supplies Adhesive bandages, bactericidal Ammonia spirit (inhalant) Aspirin Atropine sulfate Bandage Belalgin (Analgin [dipyrone], belladonna, ethyl aminobenzoate, sodium hydrocarbinate) Caffeine Chloramphenicol (Levomycetin) Clemastine (Tavegil) Dressing pack Furosemide (Lasix) Metapyrin (Analgin [dipryone]) Menthyl valerate (Validol) Methyluracil ointment Nitrazepam (Radedorm) Nitroglycerin (Nitrostat) Oleandomycin/tetracycline (Oletrin) Ophthalmic spatula Papaverine (Papazol) Perphenazine (Aethaperazine) Phenibut (beta-phenyl-gamma-aminobutyric acid) Potassium/magnesium asparaginase (Panangin, Asparcam) Promedol (trimeperidine) Scissors Senadexin (Senokot, Senade) Sulfadimethoxine (Madribon) Tetracycline ointment Tusuprex (Libexin, prenoxdiazine hydrochloride) Verapamil (Isoptin) Splint Kit Splints (12) Bandage (4) Tourniquet Cardiovascular Medicine Kit Ammonia spirit (inhalant) Atropine sulfate injection Menthyl valerate (Validol) Moricizine HCl (Ethmozine) Nitroglycerin (Sustac Forte) Nitroglycerin (Trinitrolong) Papaverine (Papazol) Potassium/magnesium asparaginase (Panangin) Propranolol (Anaprilin) Trimeperidine (Promedol) Gastrointestinal and Urologic Kit Atropine sulfate 1% injection Baralgin (Analgin plus antispamodics) Charcoal, activated (Carbolen) Nifuroxazide (Ercefuryl) Nitroxoline Senadexin (Senokot, Senade) Sodium carbonate Triamterene (Triampur) Trimeperidine (Promedol) Trimethoprim/sulfamethoxazole (Bactrim) Vitamin K (Vicasol) Psychotropic Medications Glutaminic acid Nitrazepam (Radedorm) Phenibut (beta-phenyl-gamma-aminobutyric acid) Phenazepam Pyritinol (Encephabol)

Sydnocarb Tolfisopam (Grandaxin) Valerian extract Vitamin/mineral preparation (Pantogem) Aseptic Medicine Kit Brilliant green tincture Ethyl alcohol Iodine tincture Medicine for Burns and Injuries Brilliant green tincture Flucinar ointment (corticosteroid) Ethyl alcohol Iodine tincture Lincomycin ointment Lorindin C ointment (flumethasone, iodochlorhydroxyquinolone) Olasol spray (chloramphenicol, boric acid, ethyl aminobenzoate, sea buckthorn oil) Ophthalmic spatula Sulfacetamide solution (Sulamyd) Dressing Kit Bandage, 5 cm × 7 cm Bandage, adhesive Bandage, adhesive, bactericidal Bandage, elastic Dressing pack Gauze, 14 cm × 16 cm Gauze, 45 cm × 29 cm Scissors Tampons, cotton Waxed paper Antiphlogystic Medicine Kit #1 Aspirin Clemastine (Tavegil) Diclofenac (Voltaren) Dipyrone (Analgin) Erythromycin Pyrabutol (phenylbutazone, amidopyrine, dimethylaminoantipyrine) Sulfadimethoxine (Madribon) Tetracycline/oleandomycin (Oletetrin) Tusuprex (Libexin, prenoxdiazine hydrochloride) Antiphlogystic Medicine Kit #2 Ascorbic acid Camphomen aerosol Capsicum plaster Cefecon suppositories (salicylamide, caffeine, amidopyrine, phenacetin) Ethyl alcohol Nozzle Sulfacetamide solution (Sulamyd) Xylometazoline (Xilomesolin) Antiphlogystic Medicine Kit #3 Ascorbic acid Ampicillin/oxacillin (Ampiox) Bromehexine expectorant Doxycycline (Vibramycin) Nystatin Rimantadine Antiphlogystic Medicine Kit #4 Ethyl alcohol Faringosept Fluoroquinolone (Taravid) Gauze pads Sofradex drops (Neomycin B, gramicidin, dexamethasone) Syringes Syringe needles

(continued)

(continued)

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TABLE 4.6. (continued)

TABLE 4.6. (continued)

Tampons, cotton Prophylactic Medicine #1 Potassium/magnesium asparaginase (Asparcam) Potassium orotate (Orotas) Riboxine (Inosin-F) Prophylactic Medicine #2 Lactobacillus acidophilus/colibacillus (Bifidobacterium) Levamisole (Decaris) Prophylactic Medicine #3 Piracetam (Nootropil) Ointment Kit Bandage Clostridil peptidase/chloramphenicol (Iruxol) Nonivamide/nicoboxil (Finalgon) Solcoseryl ointment Spatula, plastic Troxevasin gel “Aspro” Kit Aspirin Aspirin dissolvable tablets Aspirin/caffeine (Aspro S Forte) Scissors Emergency Kit #1 Atropine sulfate injection Ethyl alcohol Gauze pads Lincomycin ointment (Linocin) Scissors Trimeperidine HCl (Promedol) Emergency Kit #2 Adrenaline 0.1% (epinephrine) Ampule saw Atropine sulfate Baralgin (Analgin plus antispasmodics) Bendazol HCl (Dibasol) Caffeine Dexamethasone (Dexacon) Diazepam 0.5% (Relanium, Valium) Drofaverine 2% (Nospa) Enclosure bag for manipulations Ethyl alcohol Fentanyl 0.005% (Duragesic) Furosemide (Lasix) Gauze pads Lidocaine 2% (Xylocaine) Lidocaine 10% (Xylocaine) Metapyrin (Analgin) Needles for injection Nikethamide (Cordiamine) Scissors Sectioned pack Sulfocamphocaine (sulfocamphoric acid, procaine) Syringes Syringes with needles Triplenamine (Suprastatin, chloropyramine) Vitamin K (Vicasol) Waste product pack Otorhinologic and Ophthalmologic Kit Adapter Atropine sulfate Aural extraction instrument

Aural probe with thread Aural speculum, large Brilliant green tincture Catheter Camphomen aerosol Ethyl alcohol Faringosept Forceps, bayonette Forceps, nasopharyngeal extraction Forceps, ophthalmic Gauze pads Gentamycin sulfate (Garamycin) Illuminator/protective cover, spare bulb Laryngeal mirror Light guide, nasal Lorindin C ointment (fulmethasone iodochlorhydroxyquinolone) Metapyrin (Analgin) Ophthalmic extraction instrument Ophthalmic loop Ophthalmic spatula Scissors, blunt Slit lamp (nozzle) Sulfacetamide solution (Sulamyd) Sulfadimethoxine (Madribon) Tampons, cotton Tetracycline ophthalmic ointment Turunda, anterior nasal tamponage Turunda, posterior nasal tamponage Turunda, ear Vitamin K (Vicasol) Xylometazoline (Xilomesolin) Stomatologic (Dental) Kit Aspirin Cement spatula Cutters Dental drill Dentine paste Drills, hand-operated Ethyl alcohol Excavator, double-ended Extractor, type 33 Extractor, type 51A Flask, sterilized instruments Forceps, curved dental Fuse Gauze pads Indomethacin (Indocin) Metapyrin (Analgin) Nozzle, angled Plugger Pulp extractors Promecon (Emete-Con, benzquinamide) Pyrcophen (dimethylaminoantipyrine, caffeine, analgin) Scraper, double-ended Smoother, double-ended Speculum, dental Scalpel, dental Tampons, cotton Tampons, small ball Tooth probe, angled Triplenamine (Suprastatin, chloropyramine) (continued)

Source: Data courtesy of the Institute of Biomedical Problems, Moscow.

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TABLE 4.7. Contents of the Mir supplemental medical kits [15]. Name Ace bandage Adaptic bandages Afrin (nasal spray) Air temperature monitors Airway Alcohol wipes Alupent (metaproterenol)b Ambien (zolpidem tartrate) Ambu bag, O2 reservoir Ambu mask Ambu O2 tubing Ambulatory leg bag Amikin (amikacin)b Amoxil (amoxicillin)b Anusol-HC suppositories Ascriptin (aspirin) Atropineb AYR (saline nasal mist) Bactrim DSb (trimethoprim/sulfamethoxazole) Bactroban (mypirocin) ointment Bags Ziploc Biohazard Band-Aids Bar-code index card Batteries

Benadryl (diphenhydramine)b, injectable Benadryl (diphenhydramine), oral Benzoin swabs Blistex lip balm Blood Analysis Items Alcohol wipes Band-Aids Battery Biohazard bags Capillary Tube Kit Capillary bulb Capillary tube Cartridges EC6+ EC8+ Gauze pads Gloves Lancet Portable clinical blood analyzer Portable clinical blood analyzer control solutions Level I Level II Tubex injector Blood pressure cuff Butterfly INT sets Cardiac Drug Kit Alcohol wipes Atropineb Butterfly INT set Dermicel tape Epinephrineb

Description 3 in. wide 3-in. × 3-in. nonadherent dressing 3-ml bottle 32–49°C (90–120°F) 13–31°C (58–88°F) Oral Ethyl alcohol 20 mg 10 mg

600-ml bag 250 mg/cc, 2-cc unit 500 mg

5 grain 1 mg/cc, 2-cc unit 8-ml bottle 2%, 30-g tube 12 in. × 12 in. 6 in. × 6 in. 1 in. × 3 in. AA Alkaline, 9 V DC, 10 V (defibrillator) 50 mg/cc, 1-cc unit 25 mg

Ethyl alcohol 1 in. × 3 in. Alkaline, 9 V 6 in. × 6 in.

2 in. × 2 in. Nonsterile Finger

Blue Red 1 ml 19 G 21 G Ethyl alcohol 1 mg/cc, 2-cc unit 21 G 0.5 in. wide 1:10,000, 10-cc unit

Amounta 2 6 6 2 2 1 114 30 tablets 75 tablets 1 1 1 1 2 24 capsules 60 tablets 6 50 tablets 3 3 56 tablets 1 2 10 51 3 2 4 3 5 50 capsules 11 1 20 26 4 10 1 kit 3 26 27 9 15 10 pair 26 1 3 3 2 1 2 4 1 4 1 1 1 roll 5 (continued)

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TABLE 4.7. (continued) Name Heparinb Tubex injector Verapamil (Isoptin)b with plunger Xylocaine (lidocaine)b, cardiac with plunger Catheters Intravenous intracatheters

Foley (bladder) Chemstrip 10-SG Ciloxan (ciprofloxacin)b ophthalmic solution Cipro (ciprofloxacin)b, oral Cotton balls Cotton swabs Cough lozenges Cyclogyl (cyclopentolate)b Dalmane (flurazepam) Debrox (urea hydrogen peroxide) Defibrillator Resupply Kit Batteries Electrocardiogram electrodes Multifunction electrodes Deltasone (prednisone)b Demerol (meperidine)b Dental items Carver file Mirror Needles Orangewood sticks Syringe Temporary filling Toothache kit – Eugenol anesthetic drops – Tweezers – Cotton pellets Marcaine (bupivacaine)b Dental floss Dycal (base) Dycal (catalyst) Dermicel tape Dexedrine (dextroamphetamine)b Diamox (acetazolamide)b Dilantin (phenytoin sodium)b, injectable Dilantin (phenytoin sodium)b, oral Drapes, sterile Dulcolax (bisacodyl), oral Dulcolax (bisacodyl), suppository Duricef (cefadroxil)b Ear loop Elastoplast tape Entex LA (phenylpropanolamine/guafenesin) Epinephrineb Erythromycinb Eye pads Flagyl (metronidazole)b Fluorescein strips

Amounta

Description 100 units/cc, 1-cc unit 2 ml 2.5 mg/cc, 2-cc unit 20 mg/cc, 5-cc unit

14 G 18 G 20 G 16 Fr, 5-ml balloon Urine test package 0.3%, 2.5-ml bottle 0.3%, 5-ml bottle 500 mg 5 per pack 2 per pack 1%, 15-ml bottle 15 mg 15-ml bottle DC, 10 V for electrocardiogram monitoring 10 mg 50 mg/cc, 1-cc unit

Long, 27 G Short, 27 G

0.5% w/epinephrine Single-use packet 13-g tube 11-g tube 1 in. wide 0.5 in. wide 5 mg 500 mg 50 mg/cc, 2-cc unit 100 mg 40 cm × 40 cm 5 mg 10 mg 500 mg for earwax removal 4 in. wide 75 mg of phenylpropanolamine hydrochloride, 400 mg of guafenesin 1:1000, 1-cc unit 1:10,000, 10-cc unit 250 mg 250 mg

1 1 1 1 2 1 2 5 8 2 13 strips 3 1 48 tablets 15 12 39 tablets 1 30 capsules 1 3 4 sets 3 sets 100 tablets 5 1 1 6 6 2 1 1 1 kit

6 dental carpules 1 1 1 1 roll 4 rolls 30 tablets 15 capsules 10 35 capsules 2 30 tablets 6 20 capsules 1 1 roll 80 tablets 8 5 48 tablets 6 28 tablets 8 (continued)

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TABLE 4.7. (continued) Name Forceps Small point Blunt Fox Shield Gauze pads Gloves Haldol (haloperidol)b Hemostats Small Curved Heparinb Hexadrol (dexamethasone)b with plunger Imodium (loperamide HCl) Injector (Tubex) Irrigation assembly, roller clamp Isoptin (verapamil)b with plunger Intravenous administration set Kenalog cream Kling Laryngoscope Lasix (furosemide)b Lotrimin cream (clotrimazole) Lubricant (water-soluble) Magill forceps Magnifying glass Medical data logs Merocel Pope (posterior nasal packing) Milk of Magnesia Morphine sulfateb Motrin (ibuprofen) Mylanta Double Strength Narcan (naloxone)b Nasostats Needles

Needle holder Neosporin Plus cream with lidocaine Nitroglycerin patchb Nitrostat, sublingualb (nitroglycerin) One-way valve and connecting tube Ophthalmoscope head Otoscope Otoscope speculum Penrose tubing (tourniquet) Pepto Bismol Phazyme-125 (simethicone) Phenerganb, injectable (promethazine) Phenergan, oral (promethazine) Phenergan, suppository (promethazine) Polysporin (polymyxin/bacitracin) Pope Otowicks Povidone-iodine (Betadine) swabs Pred Forte (prednisone acetate)b ophthalmic solution Prilosec (omeprazole)b Proparacaine eye dropsb Proventil (albuterol) inhaler

Description Surgical Instrument Assembly Metallic eye patch 4 in. × 4 in. 2 in. × 2 in. Sterile, surgical Nonsterile 5 mg/cc, 1-cc unit Surgical Instrument Assembly 100 units/cc, 1-cc unit 10 mg/cc, 1-cc unit 2 mg 2 ml 1 ml 2.5 mg/cc, 2-cc unit

15-g tube 3 in. wide Handle w/Miller blade 10 mg/cc, 2-cc unit 15-g tube 3g Magnification 4× 10 cm 10 mg/cc, 1-cc unit 400 mg 0.4 mg/cc, 1-cc unit 22 G, 1.5 in. 18 G, 1.5 in. 16 G, 1.5 in. Surgical Instrument Assembly 0.5-oz tube with 40 mg lidocaine 15 mg/24 h 0.4 mg (1/150)

Disposable

125 mg 50 mg/cc, 1-cc unit 25 mg 25 mg 1-oz tube

1%, 5-ml bottle 20 mg 5%, 15-ml bottle 17-g container

Amounta 1 2 1 27 15 4 pair 16 pair 2 1 1 11 2 2 64 capsules 4 2 1 3 2 3 2 4 rolls 1 5 2 9 1 1 6 expanded 3 60 tablets 6 100 tablets 24 tablets 2 2 4 4 2 1 1 1 25 tablets 1 1 1 10 2 48 tablets 20 capsules 4 30 tablets 14 2 6 35 2 60 tablets 1 1 (continued)

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TABLE 4.7. (continued) Name Pulse Oximetry Kit Adhesive finger sensor POx instruction card POx data card Reusable finger sensor Pulse oximeter Pyridium (phenazopyridine) Refresh (artificial tears, eye drops) Restoril (temazepam) Saline

Salt tablets (NaCl) Scalpels Scissors (curved) Seldane (terfenadine) Silvadene cream (silver sulfadiazine) Silver nitrate sticks Skin temperature monitors Soma (carisoprodol)b Steri-Strip skin closures Stethoscope Suction Items Suction cartridge Suction collection bag 70-cc syringe Suction tip Sudafed (pseudoephedrine) Surgical Instrument Assembly Forceps (small point) Needle holder Hemostat (small) Tweezers (fine point) Scissors (curved) Suture

Syringes

Tears Naturale (eye drops) Tegaderm (transparent dressing) Telfa pads Thermometers, disposable, oral Tobrex (tobramycin)b ophthalmic solution Tongue depressors Toradol (ketorolac tromethamine)b Tracheal tube Tracheostomy tube Tweezers (fine point) Tylenol (acetaminophen) Tylenol #3 (acetaminophen with codeine)b Urine Test Package Chemstrip 10-SG Color chart

Description

200 mg 0.3 ml 15 mg 100 ml 250 ml 500 ml 1g #10 #11 Surgical Instrument Assembly 60 mg 20-g tube 29–41°C (84–106°F) 350 mg

7 in. × 6 in.

30 mg

4-0 Dexon, with needle 5-0 Ethilon, with needle 4-0 Ethilon, with needle 3-0 Ethilon, with needle 2-0 Vicryl with CT-1 needle 10 cc 3 cc 70 cc 30-ml dropper bottle 10 cm × 12 cm 6 cm × 7 cm 3 in. × 4 in. 35.5–40.4°C (96–104°F) 0.3%, 5-ml bottle Sterile 30 mg/cc, 2-cc unit 7.5 mm with stylet 8.0 mm with stylet 5.5 mm cuffed Surgical Instrument Assembly 325 mg 30 mg of codeine and 300 mg of acetaminophen

Amounta 1 kit 2 1 1 1 1 35 tablets 20 40 capsules 1 2 3 20 tablets 3 2 2 pair 1 pair 56 tablets 2 5 15 25 tablets 4 1 1 2 1 2 180 tablets 1 kit

1 1 2 2 1 3 1 1 1 5 5 8 18 1 10 2 1 1 1 1 90 tablets 40 tablets 1 kit 13 strips 1 (continued)

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TABLE 4.7. (continued) Name Valium (diazepam)b, injectable Valium (diazepam)b, oral Vancocin (vancomycin)b VIRA-A (vidarabine ophthalmic ointment)b Voltaren (diclofenac sodium) VoSol HC otic solution Xylocaine (lidocaine)b with epinephrine Xylocaine (lidocaine)b Xylocaine (lidocaine)/cardiac with plungerb Zithromax (azithromycin)b Zovirax (acyclovir)b ointment a b

Description 5 mg/cc, 2-cc unit 5 mg 250 mg 3%, 3.5-g tube 50 mg 10-ml bottle 2% with epinephrine 1:100,000, 2-cc unit 2%, 2-cc unit 20 mg/cc, 5-cc unit 250 mg 15-g tube

Amounta 2 30 tablets 28 capsules 1 60 tablets 1 2 2 6 18 caplets 1

Not all medications were carried in the amounts noted on all flights. Indicates item to be used only after surgeon approval or as directed in checklist.

CHeCS incorporates exercise and monitoring equipment and environmental monitoring hardware. CHeCS consists of three subsystems: the countermeasures system (CMS), the environmental health system (EHS), and the health maintenance system (HMS). The CHeCS CMS consists of exercise hardware and monitoring devices. Exercise hardware includes a treadmill, a resistive exercise device, and a cycle ergometer. A portable computer, a heart rate monitor, and a blood pressure/electrocardiogram monitor make up the monitoring devices. In addition to daily exercise, crewmembers using the countermeasures system perform a fitness evaluation periodically to monitor their fitness levels, determine what degree of deconditioning has occurred, and modify their daily exercise prescription as needed. The EHS provides hardware with which to monitor the water, surfaces, and atmosphere of the ISS, aspects of the ISS environment that are essential to crew health. The EHS is subdivided into water quality, microbiology, radiation, toxicology, and acoustic monitoring. The water quality hardware includes the total organic carbon analyzer and the water sampler and archiver kit. These items provide in-flight and archival analysis of ISS potable water. Microbiology hardware includes the water microbiology kit, the surface sampler kit, and the microbial air sampler. The microbiology kits enable in-flight analysis of total colony count in potable water as well as counting bacteria and fungi on surfaces and in the atmosphere. Radiation hardware includes the tissue equivalent proportional counter, the intravehicular-charged particle directional spectrometer, the extravehicular-charged particle directional spectrometer, high rate dosimeters, radiation area monitors, and crew passive dosimeters. These devices provide the means for active and passive radiation monitoring.

Toxicology hardware includes the formaldehyde monitor kit, grab sample containers, the solid sorbent air sampler, the carbon dioxide monitor kit, compound specific analyzercombustion products, and the volatile organic analyzer. Inflight and archival sampling capabilities are also provided. Acoustic hardware includes an audio dosimeter, a sound level meter, and an acoustics countermeasures kit. ISS crewmembers are provided with custom-molded filtering and non-filtering ear plugs, as well as with noise-conditioning headsets. Noise levels on the ISS are monitored as needed. The HMS is designed to support routine minor medical needs, similar to ground first-aid, as well as basic and advanced life support for a crew of three for up to 180 days. Six components make up the HMS. The first component, the ambulatory medical pack, provides for daily needs and periodic health examinations. The second component, the crew contamination protection kit, protects the crew in the event of a toxic spill or contamination. The remaining four components—the advanced life support pack, the crew medical restraint system, a defibrillator, and the respiratory support pack (Figure 4.8)— provide for advanced life support and transport. The contents of the ambulatory medical pack and the advanced life support pack are listed in Table 4.8. The Russian medical support system is provided by the Russian Aviation and Space Agency. This assemblage is very similar to the Mir medical system, and consists of multiple problem-oriented medical kits, medical monitoring equipment, and countermeasures hardware. The overall system can be divided into six major subsystems: first-aid equipment, medical monitoring and observation hardware, microgravity countermeasures equipment, an individual dosimetric monitoring system, station cleaning and atmospheric monitoring equipment, and sanitary-hygiene support equipment. The contents of the first-aid equipment subsystem are listed in Table 4.9.

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Biomedical Crew Training

FIGURE 4.8. ISS Health Maintenance System. Components include (from left) defibrillator, Advanced Life Support Pack, Respiratory Support Pack, and Crew Medical Restraint System (Photo courtesy of NASA).

As a means of preparing for early crewed space flight, biomedical crew training was a product of military aviation medicine, focused primarily on the physiological aspects of high-speed and high-altitude flight. Flight training involved exposing crewmembers to extreme conditions such as jungle and desert environments (as part of survival training), centrifuges, altitude chambers, and a motion-based simulator [9]. As crew size, mission duration, and onboard medical capabilities increased, biomedical training began to focus more on medical treatment. For the three crewed Skylab missions, two CMOs were assigned to each crew. The prime and backup CMOs received 80 h of medical training at military and civilian medical facilities. Training ranged from basic physical examination and blood drawing techniques to supervised medical care in a local emergency department [17]. All Space Shuttle crewmembers receive between 8 and 11 h of medical instruction as part of mission-specific training, including space physiology, CO2 exposure training,

TABLE 4.8. Contents of the Ambulatory Medical Pack and Advanced Life Support Pack [16]. Name 16-G catheter 18-G catheter 20-G catheter 3-cc syringe 10-cc syringe 20-cc syringe Ace bandage Adaptic dressing Adenocard (adenosine)b Afrin nasal spray Air Temperature Monitors

Alcohol pads Ambien (zolpidem)b AMBU bag Amikacinb Amoxil (amoxicillin)b Anusol HC (hydrocortisone) Articulating paper Ascriptin (aspirin) Atropineb Automatic blood pressure cuff Ayr Saline Mist Bactrim DS (cotrimoxazole)b Bactroban cream Bandage scissors Band-aids Band-aids Benadryl (diphenhydramine) Benzoin swabs

Description 16 g × 1.25 in. 18 g × 1.25 in. 20 g × 1.25 in. with 22-g needle

3 in. 3 in. × 3 in. 2 ml @ 3 mg/ml 3-ml bottle OMNI Air Temp Monitor 90–120°F 58–88°F 10 mg 2 ml @ 250 mg/ml 500 mg 25-mg suppositories 325 mg 2 ml @ 1 mg/ml Lumiscope model #1085-M 8-ml bottle Double strength 30-g tube 3 in. × 1 in. Sheer Spot 25 mg

Amounta 2 2 2 2 1 1 2 6 3 20 2 2 106 50 tablets 1 4 84 tablets 6 1 pkg 150 tablets 2 1 10 56 tablets 1 2 100 26 50 capsules 20 (continued)

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TABLE 4.8. (continued) Name Blistex lip balm Blood pressure cuff Bretyliumb Butterfly needles Capillary bulbs Capillary tubes Carver/file Catheters Chemstrip 10 with specific gravity (SG) and color chart Chest drain valve Ciloxan ophthalmic solution (ciprofloxacin)b Cipro (ciprofloxacin)b Claritin (loratadine) Compazineb Cotton balls Cotton swabs Cough lozenges (dextromethorphan) Cyclogyl (cyclopentolate)b ophthalmic solution D5W solution Debrox otic drops Deltasone (prednisone)b Dental elevator Dental floss Dental forceps

Dental mirror Dental syringe Dexamethasoneb Dexedrine (dextroamphetamine)b Diamox (acetazolamide)b Diazepamb Diflucan (flurazepam) Dilantin (phenytoin) Diphenhydramineb Dopamineb Dulcolax (bisacodyl) Dulcolax (bisacodyl) Duricef (cefadroxil)b Dycal Base Dycal catalyst Ear curettes Elastoplast tape Electronic simulator Entex LA (phenylpropanolamine/guafenesin) Epinephrineb Epinephrine, cardiacb Endotreacheal tubes Explorer/probe Eye pads Eye shield Fingersplint Fingerstix Flagyl (metronidazole)b Fluorescein strips Foley catheters Furosemideb

Description 0.14-oz tube Cuff w/aneroid sphygmomanometer 10 ml @ 50 mg/ml 21 g 23 g with protective sheath 14 G, 2 in. Dipstick Heimlich 0.3%, 2.5 ml 500 mg 10 mg 25-mg suppositories

0.5 mg 2%, 15-ml bottle dextrose solution, 500 ml 15-ml bottle 10 mg size 301 size 34 single-use package size 17 size 151A size 10S Technitouch syringe 1 ml @ 10 mg/ml 2 ml @ 0.4 mg/ml 5 mg 250 mg 2 ml @ 5 mg/ml 150 mg 100 mg 1 ml @ 50 mg/ml 400 mg/500 cc D5W 10-mg suppositories 5 mg 500 mg 13 g 11 g 2.5 yards for portable clinical blood analyzer 400 mg 1 ml @ 1:1000 10 ml @ 0.1 mg/ml 7.0 mm with stylet 8.0 mm with stylet size 23/11 Fox metallic shield single-use, sterile 250 mg FUL-GLO Fluorescein sodium 16 Fr, 30-ml balloon 2 ml @ 10 mg/ml

Amounta 1 2 2 2 2 3 32 1 2 3 pkg 1 3 48 tablets 28 tablets 14 40 13 packages 54 1 1 1 100 tablets 1 1 1 1 1 1 1 1 2 2 10 tablets 50 tablets 3 3 35 tablets 3 1 6 30 tablets 40 capsules 1 1 2 1 1 80 tablets 3 5 1 1 1 6 1 1 30 28 tablets 8 2 10 (continued)

92

T.A. Taddeo and C.W. Armstrong TABLE 4.8. (continued) Name Gauze pads Haldol (haloperidol)b, injectable Haloperidolb, oral Hemostat Imodium (loperamide) Inderal (propanolol)b Intubation bulb Iodine pads Intravenous administration sets (powered) Intravenous administration sets (not powered) Intravenous flowmeter Intravenous infusion device Intravenous Kit Intravenous administration set (nonpowered) Y-type catheter Lever lock cannula 18 g catheter Cue card Intravenous pressure infusor Kenalog cream (triamcinolone) Kenalog in Orabase Kerlix dressing Kling dressing Laryngoscope blade Laryngoscope handle Leg bag Lever lock cannulas Lidocaineb Long needles Lotrimin (clotrimazole) cream Lubricant Magill forceps Magnifying glass Meperidineb Milk of magnesia Morphineb Motrin (ibuprofen) Mouth/throat mirrors Mylanta DS Narcan (Naloxone)b Nasal airway Nasogastric tube Needles Neosporin Plus cream Nitroglycerin patchesb Nitrostat (nitroglycerin tablets)b Nonsterile gloves Nortriptylineb Ophthalmoscope head Ophthalmoscope spare bulb Oral airway Otoscope Otoscope spare bulb Otoscope specula Ovral-21 (norgestrel/ethinyl estradiol) Portable Clinical Blood Analyzer Control ranges card Control solution kit Control solutions BK wipes

Description 4 in. × 4 in. 2 ml @ 5 mg/ml 5 mg size 5.5 in., curved, Kelly 2 mg 20 mg esophageal detector device 1% IMED™ 0–250 ml/h 1–1,000 ml/h

1L 0.1%, 15-g tube 0.1%, 5-g tube 4.5 in. 3 in. Macintosh, Size 3 Pediatric 600 ml Interlink 5 ml @ 20 mg/ml 27 g, 1.25 in. 15-g tube sterile, Surgi-Lube Adult 5× magnification 1 ml @ 50 mg/ml 2 ml @ 50 mg/ml 1 ml @ 10 mg/ml 2 ml @ 10 mg/ml 400 mg laryngeal mirror, size 3 double-strength 2 ml @ 0.4 mg/ml 7 mm 14 Fr 18 G, 1.5 in. with lidocaine 0.5-oz tube 15 mg/24 h (0.6 mg/h) 0.4 mg Latex, large 50 mg

90 mm

plastic

Amounta 57 2 400 tablets 1 64 capsules 24 tablets 1 10 2 2 1 1 1 kit

1 2 1 2 7 1 1 1 5 3 6 2 4 1 1 6 4 80 tablets 6 3 70 tablets 2 100 tablets 2 1 1 2 1 3 25 tablets 8 pair 400 capsules 1 1 1 1 1 20 42 tablets 1 1 kit

(continued)

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TABLE 4.8. (continued) Name Band-aids Tubex injector Gauze pads Peak flow meter Penlight Pepto Bismol Phazyme (simethicone) Phenergan (promethazine)b Phenytoinb Polysporin (polymyxin/bacitracin) ointment Polytrim ophthalmic solution Pope otowicks Pope posterior nasal packing Portable clinical blood analyzer Povidone-iodine (Betadine) swabs Pred Forte ophthalmic solution (prednisone acetate)b Prilosec (omeprazole)b Proparacaine ophthalmic solutionb Proventil inhalerb Prozac (fluoxetine Hydrochloride)b Pulse oximeter transducers Pulse oximeter with finger sensor Pyridium (phenazopyridine) Reflex hammer Refresh ophthalmic solution (artificial tears) Restoril (temazepam)b Resuscitation mask Romazicon (flumazenil)b Saline solution

SAM splint Scalpel Sharps container Short needles Silvadene cream (silver sulfadiazine) Silver nitrate sticks Skin staple remover Skin stapler Skin temperature monitor Sponges Sodium chloride Soma (carisoprodol)b Sterile drape Sterile gloves Steri-strips (skin closure) Stethoscope Stethoscope earpieces Suction curette tip Suction device Suction device collection bags Suction device ET catheter Suction device syringe Sudafed (pseudoephedrine)b Surgical Instrument Assembly Forceps (2) Hemostats (2) Needle driver (1)

Description

Spir-O-Flow pocket monitor model #100−0186 125 mg 25 mg 1 ml @ 50 mg/ml 2 ml @ 50 mg/ml 1-oz tube 10-ml bottle 10 cm, Merocel i-STAT™ single-use swabs 1%, 1-ml bottle 20 mg 0.5%, 15-ml bottle 17 g albuterol 20 mg Oxisensor II, D-25 Nellcor 200 mg single-use vials 15 mg Respironics 2 ml @ 0.1 mg/ml 0.9% NaCl 100-ml bag 500-ml bag 1-L bag 36-in. × 4.5-in. splint, instruction pamphlet #10 #11 Lexan box 27 g, 0.75 in. 1%, 20-g tube package of 5 6.0 in. × 2.5 in. Precise 15 shot crystalline temperature trend indicator 84–106°F 5-in. × 9-in. hermitage dressing 1g 350 mg 40 cm × 40 cm size 8 0.25 in. × 4 in. 0.5 in. × 4 in. spare earpieces

with Tygon tubing 70 cc 30 mg

Amounta

1 2 48 tablets 80 gel caps 30 tablets 6 10 2 1 6 3 1 32 1 30 capsules 1 2 400 capsules 2 1 20 tablets 1 20 80 capsules 1 4 1 2 3 1 3 2 1 6 2 2 pkg 1 2 15 4 128 tablets 25 tablets 4 5 pair 6 pkg 2 pkg 2 2 1 1 2 1 1 180 tablets 1 kit

(continued)

94

T.A. Taddeo and C.W. Armstrong TABLE 4.8. (continued) Name Iris scissors (1) Surgical Instrument Assembly Forceps (2) Hemostats (2) Needle Driver (1) Sutures w/needle 4-0 Dexon 5-0 Ethilon 4-0 Ethilon 3-0 Ethilon 2-0 Vicryl Syringe Tape Tears Naturale Tegaderm dressing Telfa pads Tempadot disposable thermometers Temporary filling (Cavit) Tobrex ophthalmic solutionb Tongue depressors Tonopen tip covers Tonopen tonometer Toothache Kit Eugenol Cotton pellets Tweezers Toprol XL (metoprolol succinate)b Toradol (ketorolac tromethamine)b Tourniquet Tracheostomy tube Tubex injector Tylenol (acetaminophen) Urinary straight catheters Urine human chorionic gonadotropin detector Urocit-K (potassium chloride)b Valium (diazepam)b, oral Vancocin (vancomycin)b Vaseline gauze Vasocidin ophthalmic ointmentb Verapamilb Vicodin (hydrocodone)b VIRA-A (vidarabine)b ophthalmic ointment Visual acuity card Voltaren (diclophenac) VoSol HC otic solution Xylocaine (lidocaine) jellyb Xylocaine with epinephrineb Y-type catheters Ziplock bags Zithromax (azithromycin)b Zovirax ointment (acyclovir)b a b

Description

Amounta 1 kit

10 cc, with Luer lock 0.5-in. roll 1-in. roll 30-ml bottle occlusive dressing 3 in. × 4 in. 35.5–40.4°C, oral, disposable tube 0.3%, 5-ml bottle wooden, sterile Latex model #23

50 mg 2 ml @ 30 mg/ml Penrose tubing cuffed, 5.5 mm plastic 325 mg 16 Fr 10 meq 5 mg 250 mg 3 in. × 18 in., sterile 3.5-g tube 2 ml @ 2.5 mg/ml 5 mg 3%, 3.5-g tube 50 mg 10-ml bottle 5 ml @ 20 mg/ml (2%) carpules, 2%, 1:100,000, 1.8 ml Interlink system Y-type catheter extension sets 8 in. × 8 in. 12 in. × 12 in. 250 mg 5%, 15-g tube

Not all medications were carried in the amounts noted on all flights. Indicates item to be used only after surgeon approval or as directed in medical checklist.

1 1 4 2 1 2 1 5 1 16 13 36 1 1 20 18 1 1 kit

20 2 1 1 3 300 tablets 2 2 45 30 tablets 28 tablets 2 1 3 36 tablets 1 1 60 tablets 1 1 10 2 7 8 20 tablets 1

4. Spaceflight Medical Systems

95

TABLE 4.9. Medical support system first aid equipment. Name Anti-Inflammatory Agents-1 Kit Aspirin Oletetrin [tetracycline/oleandomycin, Sigmamycin] Analgin [dipyrone, Novaldin] Artrotek Tavegil [Suprastin, clemastine fumarate, chloropyramine] Voltaren (diclofenac)/indomethacin/ortophen Erythromycin Tusuprex [Oxeladin, Libexin, prenoxdiazine hydrochloride] Sulfadimethoxine (Madribon) Anti-Inflammatory Agents-2 Kit “Cametonum” aërosolum Pepper plaster “Cefeconum” suppositories Ethyl alcohol Sulfacetamide sodium solution [Albucid-natricum] Halazolin [Otrivin] Tsiprolet Anti-Inflammatory Agents-3 Kit Ampiox [ampicillin/oxacillin] Doxycycline hydrochloride [Vibramycin] Nystatin Ascorbic acid Rimantadine Bromhexine [Bisolvon] Anti-Inflammatory Agents-4 Kit Falimint (5-nitro-2-propoxyacetanilide) Sofradex (Neomycin B, gramicidin, dexamethasone) Ethyl alcohol Disposable injection needles Disposable injection syringes Wipes Cotton balls Tarivid [ofloxacin] Pharyngosept [ambazone] Antiseptic Remedies Kit Iodine solution Viride nitens solution Ethyl alcohol Aspro (Aspirin) Medical Kit Aspirin (tablets) Aspirin (water-soluble tablets) Aspirin, Cardio Scissors Burns and Wounds Kit Olasol (chloramphenicol, boric acid, ethyl aminobenzoate, sea buckthorn oil) Lorinden C ointment Methyluracil ointment Flutsinar ointment Viride nitens solution Iodine solution Ethyl alcohol Spatula for applying ointment to the eyes Lincomycin/erythromycin ointment Sulfacetamide sodium solution [Albucid-natricum] Gentamicin sulfate solution [Garamycin] Cardiovascular Remedies Kit Kardiket Validol [menthyl valerate] Sustac forte [Nitro-Mac retard] Aetmozinum Papazol (papaverine)

Description

125,000 units 0.5 g

0.1 g 0.01 g 0.5 g

20% 0.05%

0.25 g 0.05 g 500,000 units 0.5 g 0.05 g 0.008 g or 0.004 g

14 cm × 16 cm 200 mg 0.1 g 5%, 0.8 ml 1%

100 mg, 300 mg

15.0 g 10% (10 g) 0.025% (15 g) 1% 5% (0.8 ml)

15 g 20%

0.06 g 6.4 mg 0.1 g

Amount

120 tablets 56 tablets 16 30 tablets TBD 68 tablets 48 tablets 56 tablets 1 3 packs 15 units 6 test tubes 2 squeezable droppers 2 units 80 81 capsules 18 capsules 36 tablets ~48 tablets 33 tablets 33 tablets 80 tablets 2 bottles 2 test tubes 2 units 2 units 2 units 3 packs 27 tablets 63 tablets 14 test tubes 14 test tubes 28 test tubes 45 24 90 1 pair 3 aerosols 1 tube 1 tube 1 tube 3 test tubes 14 test tubes 3 test tubes 1 unit 1 tube 2 squeezable droppers 2 20 18 tablets 16 tablets 80 tablets 34 tablets (continued)

96

T.A. Taddeo and C.W. Armstrong TABLE 4.9. (continued) Name Anaprilin [inderal] Obsidan Isoptin [verapamil, Finoptin] Athenolol Trinitrolong [nitroglycerin] Ammonium hydroxide [spirit of ammonia] Aethacizinum Atropine Enapren [enalapril] Dressing Pack Bandages Bandages Adhesive plaster Wipes Wipes Pack of dressings Bactericidal adhesive plaster Ace bandage (#1 and #2) Cotton balls Scissors Compress paper Emergency First-Aid Medical Kit Lidocaine Adrenaline Nospa [Drofaverine] Relanium (diazepam) Sulfocamphocainum (sulfocamphoric acid, procaine) Cordiamine [nikethamide] Lasix Lidocaine Caffeine Baralgin Dibazolum [bendazole hydrochloride] Analgin [Novaldin] Vicasol (vitamin K) Platyphyllin [papaverin] Suprastin [chloropyramine] Dexamethasone/prednisolone [Dacortin] Ethyl alcohol Gauze pads Atropine Scissors Bag for handling Syringes with needle Syringes with needle Needles Waste packet Appliance for opening ampoules (file) Package with section dividers Gastrointestinal And Urologic Remedies Kit Soda Senadexin (Senokot, Senade) Carbolen [activated charcoal] Biseptolum [Bactrim] Ercefuril [Imodium, loperamide HCl) Baralgin Nitroxoline Triampur (triamterene) Vicasol (vitamin K) Atropine Ointment Kit Solcoseryl ointment Troxerutin gel [Venoruton]

Description 0.04 g 40 mg 0.001–0.002 g 10% 0.05 g 0.1% (1.0 ml) 0.01/0.02 (g) 5 in. × 7 in. 5 in. × 5 in. 14 in. × 16 in. 45 in. × 29 in.

2% (2 ml) 0.1% (1 ml) 2% (2 ml) 0.5% (2 ml) 10% (2 ml) 2 ml 10% (2 ml) 5 ml 1% (2 ml) 50% (2 ml) 1% (1 ml) 0.2% (1 ml) 2% (1 ml)

x 0.1% (1 ml)

2 ml 5 ml

0.5 g

Amount 48 tablets 66 tablets 40 10 patches 3 test tubes 48 tablets 6 squeezable syringes ~20 2 units 2 units 1 unit 6 units 2 units 3 units 20 units 3 units 2 packs 1 unit 1 sheet 5 ampoules 2 ampoules 6 ampoules 4 ampoules 2 ampoules 2 ampoules 6 ampoules 4 ampoules 2 ampoules 6 ampoules 3 ampoules 3 ampoules 4 ampoules 3 ampoules 3 ampoules 5 ampoules 30 test tubes 30 units 8 squeezable syringes 1 unit 2 units 42 units 6 units 90 units 48 units 48 units 15 units

0.015 g 0.1% (1 ml)

24 tablets 48 tablets 32 tablets 70 tablets 27 capsules 56 tablets 48 tablets 33 tablets 16 tablets 6 squeezable syringes

20 g 2% (40 g)

2 tubes 2 tubes

0.25 g 480

0.05 g

(continued)

4. Spaceflight Medical Systems

97

TABLE 4.9. (continued) Name Finalgon ointment [nonivamide and butoxyethyl nicotinate] Plastic plates Bandages Heparin ointment [Liquaemin] Zovirax (eye ointment) Zovirax cream Kelestoderm (cream/ointment) Onboard Pharmacy Kit Radedorm [nitrezepam] Tavegil [clemastine fumarate, Suprastin, chloropyramine] Fenibut [beta-phenyl-gamma-aminobutyric acid] Tusuprex [Oxeladin, Libexin, prenoxdiazine hydrochloride] Panangin [Asparkam] [a preparation containing potassium and magnesium asparaginase] Senadexin (Senokot, Senade) Validol [menthyl valerate] Analgin [Novaldin] Aspirin Madribon (sulfadimethoxine) Levomycetin [chloramphenicol] Oletetrin [Sigmamycin] Caffeine Isoptin [verapamil, Finoptin) Nitroglycerin [Anginine] Belalgin Ammonium hydroxide [spirit of ammonia] Papazol Tetracycline ointment Methyluracil ointment Bactericidal adhesive plaster Bandages Dressings Scissors Spatulum for applying ointment to the eyes Atropine Furosemide [Lasix] Camphomen inhaler Preventive Remedies-1 Kit Riboxine [Inosie F] Panangin Potassium orotate [Dioron] Preventive Remedies-2 Kit Vetoron Decaris [Ascaridil] Vitrum Essentiale Preventive Remedies-3 Kit Nootropil (piracetam) Preventive Remedies-4 Kit Vitamins Psychotropic Remedies Kit Phenazepam Fenibut [beta-phenyl-gamma-aminobutyric acid] Persen Radedorm [nitrazepam] Pyritinol [Encephabol] Rudotel (medazepam) Glutamic acid Grandaxin [tolfisopam] Pantogam [hopantenic acid] Xanax [alprazolam] Splint Kit Splints

Description

Amount

15.0 g

2 tubes 2 units 2 units 1 tube 1 tube 1 tube 1

0.01 g or 0.005 g

9 tablets 9 tablets 16 tablets 24 tablets 16 tablets 24 tablets 9 tablets 14 tablets 14 tablets 14 tablets 8 tablets 16 tablets 17 tablets 16 tablets 25 tablets 16 tablets 1 test tube 10 tablets 1 tube 1 tube 20 units 5 units 1 package 1 pair 1 unit 4 squeezable syringes 6 tablets 1 unit

0.25 g 0.01 g

0.06 g 0.5 g 0.5 g 0.5 g 0.25 g 125,000 units 0.2 g 40 mg 0.0005 g 10% 3g 3g 3.8 × 3.8 1.5 × 6

0.1% (1 g)

0.2 g 0.5 g

150 mg

216 tablets 112 tablets 112 tablets TBD 24 tablets TBD TBD

0.4 g

180 capsules

0.001 g 0.25 g

66 tablets 80 tablets 33 68 tablets 48 tablets 48 40 tablets 68 tablets 16 tablets 40

0.1 g 0.25 g 50 mg 0.25 g

12 units (continued)

98

T.A. Taddeo and C.W. Armstrong

TABLE 4.9. (continued) Name

Description

Bandages Tourniquet First Aid Kit [in the Portable Survival Kit] Analgin (tablets) Tetracycline (lozenges) Sulfadimethoxine (tablets) Sydnocarb (tablets) Phenazepam (tablets) Diazoline (lozenges) Pantocide (tablets) Potassium permanganate (powder) Promedol (syringe tubes) Tetracycline ointment Lip balm Deet cream Gauze bandages Dressings Bactericidal adhesive plaster Razor blades Safety pins

5 cm × 10 cm

4 units 1 unit

Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10 Item 11 Item 12 Item 13.1 Item 13.2 Item 13.3

10 16 10 55* 6 10 40 1 package 6 units 1 package 1 package 3 packages 3 packages 2 packages 3 packages 3 packages 3 units

decompression sickness evaluation and treatment, cardiopulmonary resuscitation, and first aid. Two CMOs are selected from each crew by the mission commander. (As noted earlier in this chapter, these crewmembers typically do not have a medical background.) The CMOs receive an additional 7–10 h of training in diagnostics and therapeutics. CMO training is hands-on, using lifelike training mannequins to practice procedures such as injections, airway management, and wound care. Additional IV proficiency training is also offered, including training in a virtual-reality simulator and with human test subject volunteers. The overall emphasis of preflight training is on procedures, how to use the medical checklist, and how to make cogent medical observations so as to make the best use of ground consultation. When the defibrillator was flown on the two Space Shuttle missions (STS-90 and STS-95), advanced cardiac life support refresher training was conducted for the CMOs. The CMOs on both of these missions were physicians so the additional training requirements were minimal. MSMK training was based on the Space Shuttle CMO training flow, with additions to include the pulse oximeter and portable clinical blood analyzer. Training duration was increased from the standard Space Shuttle duration to accommodate the use of interpreters. All three Mir crewmembers received 21 h of MSMK training. The training template increased by 15 h when the Mir defibrillator and associated hardware were added, including training in advanced cardiac life support protocols. NASA provides crew training on all CHeCS equipment and associated in-flight activities for ISS crewmembers. Two or all three crewmembers are trained in the use of the EHS and countermeasures system hardware and procedures, depending on crew tasking. As was true in the Skylab and Space Shuttle

Amount

programs, two crewmembers are trained as CMOs. These crewmembers receive training in the HMS and associated medical procedures. Before HMS training, the CMOs are encouraged to participate in a field medical training course that consists of 20 h of classroom instruction and 50 h of clinical training in an emergency room, in an operating room, on an ambulance, and in an animal laboratory. As has been done in the Space Shuttle training program, CMOs are also given the opportunity to train with the IV virtual-reality simulator and with human test subject volunteers. In addition to preflight training, ISS crewmembers receive refresher training on board the ISS. Computer-based training on all CHeCS hardware is provided. CMOs are allowed 1 h per month for such training on the HMS; computer-based training for the EHS and countermeasures system is made available to the crew for refresher training, although this is optional and is not scheduled at a specific time. The multimedia computer-based training sessions allow crewmembers to work at their own pace and review the items they feel are necessary. At least once per increment, an HMS contingency drill will take place. The drill is one of several emergency drills in which the crew participates every other week. Other drills include those for response to fire/smoke, toxic spill, and rapid decompression. Crewmembers will not know which type of drill is planned, only that a drill is scheduled. The specific medical contingency scenario may change each time an HMS drill is scheduled. Finally, the monthly performance of medical evaluations by the CMO, involving simple physical examination and laboratory analysis, ensures that the CMO maintains some degree of proficiency in basic examination and specimen collection skills. The Gagarin Cosmonaut Training Center in Star City, Russia, provides crew training on all Russian medical support

4. Spaceflight Medical Systems

system equipment and associated in-flight activities. This includes training in medical response, countermeasures performance and physical evaluation, and some environmental monitoring. Baseline data are collected before flight to determine cosmonaut fitness for training and space flight and to aid in achieving the required level of functional reserves and psychological abilities corresponding to the tasks to be performed during the spaceflight phase.

Future Systems Next-generation CHeCS hardware is already in development. It is sometimes difficult to use cutting-edge medical technologies for spaceflight operations because of flight certification requirements and programmatic delays, as well as liability and regulatory challenges faced by the medical industry [18]. However, continual evaluation of mission needs and performance of flown medical systems will ensure a process of steady upgrades and improvements. The new CHeCS devices will expand onboard diagnostic and therapeutic capabilities, provide additional exercise countermeasures for a crew of six to seven, and enhance onboard environmental monitoring and analysis. Hardware currently under investigation is listed in Table 4.10. Space-faring nations are now examining the requirements for human missions beyond low-Earth orbit. These missions will test the limits of technical and human experience in maintaining crew mental and physical health. Future spaceflight medical systems must permit a well-trained medical officer to autonomously provide care for the crew while en route and on the lunar or Martian surface. New challenges to be met on these ambitious missions include acute radiation exposure, dust-related health problems, prolonged weightlessness, injury-causing gravitational loads, and other events associated with planetary surfaces.

TABLE 4.10. Hardware considered for inclusion in future crew health care systems. Total-organic-carbon analyzer (upgrade) Ion-selective electrode assembly (for water analysis) Long-term resistive exercise device Treadmill with vibration-isolation system (upgrade) Enhanced respiratory support system Medical bio-hazardous waste management system Portable gas analyzer Intravenous fluid system Digital spirometer Hand-grip dynamometer / Pinch-force dynamometer Critical care physiological monitoring system Microbiology diagnostics kit Enhanced microbial air sampler Incubator Neutron monitor Diagnostic sonography

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References 1. Polyakov VV. The physician-cosmonaut tasks in stabilizing the crew members’ health and increasing an effectiveness of their preparation for returning to Earth. Acta Astronautica 1991; 23:149–151. 2. Houtchens BA. Minor Surgery and Anesthesia Capabilities for Space Station Health Maintenance Facility (HMF). Unpublished document prepared under NASA-JSC Contract T-1419M; 1987. 3. Billica RD, Barratt MR. Inflight evaluation of apparatus and techniques for performance of medical and surgical procedures in microgravity: STS-40/SLS-1, SMIDEX Medical Restraint System. In: Spacelab Life Sciences-1 Final Report. Houston, TX: NASA–Johnson Space Center; 1994: 5-67–5-82. JSC-26786. 4. Lloyd C, Creager GJ. SMIDEX IV pump experiment. In: Spacelab Life Sciences-1 Final Report, Vol. 1. Houston, TX: NASA–Johnson Space Center; 1994: 5-83–5-88. JSC-26786. 5. Creager GJ. Formulation, preparation, and delivery of parenteral fluids for the Space Station Freedom Health Maintenance Facility. Paper presented at the 20th Intersociety Conference on Environmental Systems; July 9–12, 1990; Williamsburg, VA. SAE Technical Paper Series No. 901325. 6. McKinley BA. Sterile water for injection system for on-site production of IV fluids at Space Station Freedom HMF. Paper presented at the 20th Intersociety Conference on Environmental Systems; July 9–12, 1990; Williamsburg, VA. SAE Technical Paper Series No. 901324. 7. Barratt M, Billica R. Delivery of cardiopulmonary resuscitation in the microgravity environment. Presented at the 63rd Annual Scientific Meeting of the Aerospace Medical Association; May 10–14, 1992; Miami Beach, FL. 8. Billica RD, Pool SL, Nicogossian AE. Crew health-care programs. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1994: 402–423. 9. Billica RD, Jennings RT. Biomedical training of U.S. space crews. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1994: 394–400. 10. Berry CA. Medical care of space crews (medical care, equipment, and prophylaxis). In: Talbot JM, Genin AM (eds.), Space Medicine and Biotechnology. Vol. 3. Washington, DC: NASA Scientific and Technical Information Office; 1975:345– 371. NASA SP-374. Calvin M, Gazenko OG (series eds.), Foundations of Space Biology and Medicine. 11. Godwin R. Gemini 6—The NASA Mission Reports. Ontario, Canada: Apogee Books; 2000: 24. 12. Hawkins WR, Ziegleschmid JF. Clinical aspects of crew health. In: Johnson RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975: 43–81. NASA SP-368. 13. EVA & Experiments Branch, Crew Procedures Division. Inflight Medical Support System Checklist, All Skylab Missions, Final. Rev A. Houston, TX: NASA–Johnson Space Center; 1973. 14. Dempsey CA, Barratt MR. Evolution of in-flight medical care from Space Shuttle to International Space Station. Paper presented at the 26th International Conference on Environmental Systems; July 8– 11, 1996; Monterey, CA. SAE Technical Paper Series No. 961345. 15. Medical Operations, Space and Life Sciences Directorate. NASA 6 Mir Supplemental Medical Kit Checklist. Houston, TX: NASA–Johnson Space Center; 1997.

100 16. Biomedical Hardware Development and Engineering Office. Drug Subpack, Advanced Life Support Pack Installation Drawing. Rev A. Drawing No SKD42101650. Houston, TX: NASA–Johnson Space Center; 2000.

T.A. Taddeo and C.W. Armstrong 17. Shimamoto, S. Skylab Medical Training, Meeting Summary. Houston, TX: KRUG Life Sciences; 1991. 18. Butler, D. NAS9-97005 Annual Medical Technology Report. Houston, TX: Wyle Laboratories; 2000.

5 Acute Care Thomas H. Marshburn

After more than 40 years of human spaceflight operations, the U.S. and Russian spaceflight programs now have sufficient experience to identify the most common medical problems that occur in space. This experience base allows the development of means to diagnose and treat the medical problems anticipated to occur during flight—that is, to provide spaceflight crews with acute care. Acute care, in this sense, refers to the treatment of the common minor medical problems that can occur during crewed spaceflight missions. Acute care also refers to the assessment and stabilization of the more serious illnesses and injuries that can affect missions or cause significant crewmember morbidity. The high cost of space travel demands maximum performance from each crewmember during a mission both to maintain health and to accomplish mission objectives. Consequently, the common, relatively minor medical problems discussed in this chapter can significantly affect a mission. For instance, an ankle injury sustained by a crewmember during a long-duration space flight can result in an inability to perform the strenuous treadmill exercises that maintain muscle mass, lower-extremity proprioception, and aerobic capacity. This would further lead to diminished performance upon return to gravity (e.g., upon arrival to Mars or rapid egress from the Space Shuttle after landing). Likewise, an extravehicular activity (EVA) (i.e., a spacewalk) could be cancelled because of contact dermatitis or some minor hand injury that is not aggressively treated. Experience with human space flight has taught us that serious illnesses can occur during missions. The crew medical officer (CMO) who is assessing the seriously ill or injured crewmember faces several challenges. The CMO not only must correctly diagnose the problem so as to prevent either a premature end to the mission or an increase in crewmember morbidity from delaying return, but also must work with limited resources in an extreme environment, the effects of which on humans are poorly understood. This chapter summarizes the experience gained in diagnosing and treating acute medical problems in space and provides recommendations for treating expected problems in future space flights.

On-Orbit Medical Resources Ground-based flight surgeons provide each crewmember with medical care training and equipment appropriate for the mission, within the constraints of available payload weight and volume and crewmember training time. A medical kit, medical references, computer-based training, and consultation with members of the ground support team are all means by which flight surgeons deliver medical experience and knowledge to each spaceflight crew. All crewmembers can access and use nonprescription pharmaceuticals in the medical kit without reporting to either a CMO or the ground team, although they are requested to record in a personal file the type, dose, and frequency of medication used. Two members of each Space Shuttle crew are designated CMOs; CMOs are rarely physicians, but they have enough autonomy and training to assess and treat minor trauma and illnesses without calling the ground-based flight surgeon for immediate consultation. CMOs who are not physicians may use prescription medications only at the direction of the flight surgeon or after satisfying the circumstances cited in the medical procedures manual. The controlled-substance category and side effects of all medications supplied in the medical kits are listed in the procedures manual. The CMO has access to 2 on-orbit medical resources— the procedures manual and the private medical conference (PMC). The procedures manual is written and updated by ground-based flight surgeons. This manual has several unique characteristics. It contains a minimum of medical terminology, step-by-step procedures that reference only the limited hardware and pharmaceuticals available in the on-board medical kit, and a listing of possible side effects of the prescription drugs in the kit. Since human performance decrements would be detrimental to a mission, adverse side effects from medications are of primary concern in the pharmaceutical treatment of crewmembers. The on-orbit CMO also can confer with the ground-based flight surgeon through daily PMCs, which are considered an integral part of Space Shuttle operations. During the PMC, 101

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the Mission Control Center establishes a completely private link between the Space Shuttle crew and the flight surgeon. PMCs are held to enhance the medical capability of the crew and to allow the flight surgeon to communicate to the ground team any need for mission or timeline changes that have been driven by an onboard medical problem. PMCs are scheduled and conducted daily during a Space Shuttle flight, eliminating the need for the crew to use open airto-ground communications to request a private conference with the flight surgeon, thereby helping to maintain medical privacy as well as to facilitate proactive and anticipatory medical advice from the flight surgeon. PMCs typically last from 5–15 min. A PMC is also held daily during the first few days of a longduration mission to the International Space Station (ISS), during the period of acute adaptation to the new environment. On a long-duration ISS mission (or any other long-duration mission), after the first few flight days, PMCs are held weekly and at the request of the flight surgeon or the crew. The flight surgeon must provide to the ground control team a summary of the state of the health of the crew after each PMC. Although the flight surgeon and CMO make the medical diagnosis and treatment decisions for an affected crewmember, the mission commander is best able to assess the effect of the treatment plan on the mission as a whole. Before the conclusion of the PMC, the CMO, commander and the flight surgeon agree on the content of the PMC report to the ground team. In cases in which a medical problem on orbit does not result in timeline or mission changes, individual problems are not discussed or reported by the flight surgeon. In such cases, the PMC report typically states “no mission impact.” Medical privacy is paramount, both to maintain the trust between flight surgeon and each crewmember, which may take years to develop, and to prevent distraction from the mission by inordinate media attention. If the CMO and commander determine that the diagnosis or treatment of a crewmember’s medical problem will affect the mission, which will necessarily involve the flight control team in some fashion, the flight surgeon’s report will contain only the information needed to implement changes to the crew timeline and tasking or to modify plans for use of consumables (e.g., O2). All attempts are made to preserve the physician-patient relationship while also acting to best serve the interests of the mission. In such cases, a public statement is made noting the diagnosis, prognosis, and likely effect on the mission. This scheduled PMC is one of the most important components of medical care in space flight. By facilitating communication between the crew and ground-based medical support, the CMOs greatly expand their resources in knowledge and expertise while being assured of complete privacy; the flight surgeon can work with the ground team under established rules of communication to support the medical treatment of an ill or injured crewmember (as necessary); and the Medical Operations team at the NASA–Johnson Space Center can develop

T.H. Marshburn

a “non-attributable database” (in which incidents cannot be attributed to any identifiable individual) to better prepare for future medical contingencies.

Common Disorders Requiring Care in Space Space Motion Sickness Space motion sickness (SMS) is very common among astronauts and cosmonauts. Although it bears some resemblance to the motion sickness that is experienced on Earth, SMS is nonetheless part of a symptom complex that is unique to microgravity—that is, the space adaptation syndrome. The nausea and vomiting associated with SMS, one of the more deleterious symptoms of space adaptation syndrome, are very common during the first few days of entering a microgravity environment. SMS has been estimated to affect 67% of crewmembers on their first space flight [1]. Investigations into the etiology, prevention, and recovery from space adaptation syndrome are discussed more fully in Chap. 10. In this section, only the on-orbit treatment options available to crewmembers are discussed. Astronauts and cosmonauts experience SMS at different symptom intensities. Davis and colleagues used a symptom intensity score to evaluate symptoms experienced during the first 24 Space Shuttle flights [1]. Of the astronauts who experienced any symptoms, 47% had mild symptoms only, with no more than one episode of emesis and complete resolution in 36–48 h; 35% experienced moderate symptoms, with waxing and waning malaise, fewer than three episodes of emesis, and symptom resolution in 72 h; and 19% experienced severe symptoms, consisting of persistent malaise, three or more episodes of vomiting, and symptom persistence beyond 72 h [1]. Slight differences can be expected between SMS symptoms and those of terrestrial motion sickness. For example, crewmembers with SMS display less pallor and sweating, and more flushing and headache, than do people with terrestrial motion sickness. Nausea, vomiting, and general malaise are common to both syndromes. However, the vomiting associated with SMS can be sudden, often without antecedent nausea, can occur sporadically (one episode of emesis every few hours), and can be exacerbated by head movements and olfactory stimuli (e.g., the smell emitted from the waste containment system) [2]. Unfortunately, no physical sign or motion analog, other than prior spaceflight experience, has yet been discovered that can be used to predict the occurrence or severity of symptoms a particular crewmember will experience. In general, symptoms improve with subsequent flights. Despite an incomplete understanding of the etiology of SMS, the use of promethazine for treatment has met with success in the U.S. space program. Physician-astronaut James

5. Acute Care

Bagian performed the first intramuscular (IM) injection in space, using promethazine to treat SMS [3]. Approximately 60% of astronauts receiving IM promethazine since that time have reported a significant improvement in SMS symptoms in postflight debriefs [4]. Early in the Space Shuttle Program, the crewmembers occasionally took scopolamine with dextroamphetamine as prophylaxis for SMS [5]. This strategy was largely unsuccessful in reducing the symptoms associated with SMS and is no longer used. The antiemetic agent granisetron has been investigated in a ground-based study for its efficacy in preventing motion sickness, but it was no more effective than a placebo in that study [6]. During preflight training, flight surgeons teach CMOs how to give a dorsogluteal IM injection (see the section on “Procedures” later in this chapter). Although the injection is generally well tolerated in space flight, the occasional experience of local soreness at the injection site has led to attempts to use other routes of administration. The combination of operational demands in the intense workload of the first hours on orbit and limited flight opportunities have prevented the conduct of controlled trials to evaluate the efficacy of each route; however, the following observations have been made. Crewmembers have taken promethazine, 25 mg with 2.5– 5.0 mg of dextroamphetamine, orally while on the launch pad for SMS prophylaxis with variable success. (Commanders and pilots are prohibited from this practice.) Oral consumption of the same dose during flight is not generally successful, perhaps because of the reduced GI absorption associated with the ileus common upon introduction to microgravity [7]. Some crewmembers prefer the autonomy of self-administration that the rectal route provides, and have therefore taken a 25-mg suppository as soon after arriving on orbit as the workload allows. In general, however, this route of administration is not as effective as an IM injection. IM injection is the most common route of administration. Crewmembers have the option of receiving IM injection of promethazine from their CMO either as prophylaxis or after the onset of symptoms; about 30% of IM promethazine injections have been used immediately before sleep [4]. Because the sedative effects of promethazine might be expected to cause performance decrements, flight surgeons determine the level of sedation associated with promethazine for each astronaut or cosmonaut in preflight tests of oral preparations. No problems have been reported with in flight somnolence to date, nor has any evidence appeared of performance decrements during the early in-flight period from promethazine use [8]. Davis and colleagues speculate that the α-adrenergic effects of the excitement after arrival into the novel environment of orbital flight may largely override sedative effects [9]. Objective in-flight measures of crewmember vigilance and performance are being developed to aid in titration of antiemetic doses during critical phases of the mission. One such critical phase occurs during EVAs. During an EVA, the sedative effect of an antiemetic, considering the need for optimal performance by spacewalkers during critical tasks,

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must be weighed against the risk of emesis inside the spacesuit. For this reason, EVAs cannot be scheduled earlier than 72 h after arrival on orbit in the Space Shuttle Program. The flight surgeon and the EVA crewmembers are also required to conduct a PMC before EVAs to ascertain the extent of SMS and its resolution and to address any other medical issues that may have arisen. The crewmember’s sedative response to promethazine, established during preflight testing, is helpful in this determination. Antiemetics have been used before performing an EVA, although rarely. The first use of an antiemetic agent before EVA occurred during the Apollo Program [10]. In the Space Shuttle Program, persistent, mild residual SMS symptoms have similarly been treated by small doses of promethazine in combination with oral dextroamphetamine before EVAs. Severe or prolonged cases of SMS, although rare, can result in significant dehydration, so intravenous (IV) normal saline is available and can be administered on orbit. The techniques of venous cannulation and IV hydration are discussed briefly in the section on “Procedures” later in this chapter.

Trauma Superficial Trauma Findings from the Longitudinal Study of Astronaut Health being conducted at NASA–Johnson Space Center indicate that superficial skin trauma is one of the most common reasons for a Space Shuttle or Mir space station crewmember (during the joint U.S.—Russian flights of the NASA-Mir Program) to access the resources of the medical kit once symptoms of SMS have resolved. Superficial abrasions and minor cuts are inevitable on board a spacecraft, because construction, repair, and transfer operations as well as working with abrasive materials such as Velcro are a part of daily life during a mission. Minor contusions and bruises are common as crewmembers learn to propel and stabilize themselves in the novel microgravity environment. The hands often sustain such minor injuries, since astronauts or cosmonauts use them in space much more often for stability and propulsion than on the ground. Chafing from wearing the U.S. space suit (extravehicular mobility unit, EMU), particularly in areas subject to intertrigo and on the fingertips, is also common. Since the Apollo Program, spacewalking U.S. astronauts have often reported blunt nail trauma from working in the EVA suit gloves. Five of the 12 Moon-walking astronauts had at least one subungual hemorrhage of the hands [10]. The manual dexterity and tactile sensitivity required to perform EVA tasks demand that the fingertip be in close contact with the space suit glove, especially during preflight training. The resultant pressure often leads to nail elevation, which, with sufficient pressure and repeated trauma, can lead to damage to the nail matrix. This damage may be confused with onychomycosis, which can also occur with prolonged activity in the moist environment of the space suit glove. Placing water-resistant

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tape over benzoin on the nails has been moderately successful in preventing this problem. Muscle Strain and Overuse Syndromes Back pain is the most common muscular syndrome in space flight and is one of the most common physical complaints of spaceflight crewmembers. The pain seems to be caused by elongation of the ligamentous components of the vertebral spine, which is known to lengthen by 1–2% early in space flight because of unloading of the axial skeleton in microgravity [11]. The pain is spasmodic, is located in the paralumbar musculature, and can be intense enough to prevent sleep. The pain usually subsides after the first several days on orbit. Crewmembers have found relief from discomfort in many cases by positional changes, such as drawing their knees up to their chest. Restraint straps and the Soyuz reentry couch, which can be used to maintain a semifetal position during the sleep period, also may afford relief. Nonsteroidal anti-inflammatory agents are often accessed from the medical kit for relief as well. Several muscular strain syndromes are common during mission training and during flight. Shoulder rotator cuff, forearm lateral epicondylar, and lumbar strains are among the most common of these syndromes. One of the first recorded cases of in-flight shoulder strain in the U.S. space program was after an Apollo EVA that involved drilling operations on the lunar surface [10]. Given the compressed timelines during a space mission, crewmembers can be expected to sustain operations at a task without relief for hours at a time. If the work requires an unusual posture that demands limb positioning outside of the neutral position, muscle soreness and ligamentous strains can be expected. Such conditions most commonly occur during an EVA, when abduction and anterior rotation of the shoulders is required to position the hands properly within the space suit gloves. Work with a glove box also requires a similar position, and prolonged operations may result in a similar overuse syndrome. The flight surgeon can anticipate this problem before flight by closely monitoring the crew after sustained training sessions and by starting them on stretching and strengthening regimens under the guidance of physical trainers, if necessary, to eliminate pain and reduce the risk of further injury on orbit. Another common syndrome associated with sustained work at a laboratory bench or glove box in microgravity is lumbar and anterior abdominal muscular strain. Such strain is particularly common when toe/foot loops are the only hardware available for self-restraint. Proper body stabilization in microgravity requires three points of contact with a firm surface, which means that crewmembers can be expected to assume an uncomfortable posture for many hours at a time. To free the hands for delicate tasks in the glove box, for example, crewmembers may use toe loops and press their forehead against the firm surface of the glove box. Use of T-shaped “chairs” also allows crewmembers to maintain a stable posture close to the microgravity-neutral position, which helps to prevent

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some of the soreness in back and abdominal muscles. Since avoidance of strain is more effective than treating a strain once it has occurred, the flight surgeon needs to act as an advocate for the crew by encouraging the inclusion of properly designed restraint devices in the launch manifest. Rarely, the back pain that occurs in space flight is associated with lancinating pain or patchy paresthesias in the lower extremities. Mild distraction of sensory nerve roots may contribute to these symptoms. Although the symptoms are usually transitory, patchy anesthesia has persisted after space flight in some crewmembers. Postflight diagnostic imaging and neurologic investigations have not revealed the cause or any abnormalities after return. The CMO’s clinical evaluation is the only in-flight diagnostic modality available, and to date symptomatic treatment with anti-inflammatory agents, benzodiazipines for direct muscle relaxation, and stretching techniques have been sufficient to control symptoms. Lacerations Although no astronauts or cosmonauts have sustained lacerations of sufficient depth to require surgical repair during a space flight, minor lacerations and contusions occur often, and thus inclusion of repair hardware in an on-board medical kit is appropriate. For minor injuries, a variety of bandages are included; bandages are one of the most commonly accessed components in the medical kit. Handling flight checklists and Velcro are reported to be the most common sources of minor injuries. Recently developed Space Shuttle and ISS medical kits (see Chap. 4) also include tissue adhesives. No difficulties have been experienced to date using tissue adhesive terrestrial applicators in the microgravity environment (personal communication, Richard Linnehan, 1998). Even though the liquid adhesive does not tend to leave the operative field in microgravity, crewmembers currently apply it in a glove box or while using eye protection. The medical kits flown on the Space Shuttle and the ISS contain synthetic absorbable and nonabsorbable suture material with a small, sterile, minor surgery subpack for repair of deeper lacerations. The CMO also has the option of using tissue adhesives or small skin staples on orbit. Tissue adhesives would be used for wounds less than 5 cm (2 in.) long in nonmucosal facial lacerations and selected extremity and torso wounds [12]—except for the those on the hands, feet, and joints, since most studies that compare tissue adhesives with suturing have excluded hand and foot lacerations and lacerations that cross a joint [13]. Staples are also included in the medical kits to quickly close wounds in the scalp, trunk, and extremities—again excluding the hands and feet. Contraindications for use of staples on orbit are the same as those on the ground: wounds that are more than 12 h old, those that are grossly contaminated, or those that have devitalized margins or flaps. Because a crewmember could sustain a contaminated wound in a spacecraft (as discussed later in this section), the primary advantage of staples is the speed of closure, which

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may reduce the frequency of infectious complications. Use of staples on Earth, when these indications are followed, does not seem to increase the rate of cosmetic or infectious complications, although the staples are painful to remove and may be associated with inflammation [14–16]. The components of the surgery subpack in the Space Shuttle medical kit have been tested during parabolic flight [17,18]. To date, the greatest challenge of suturing in microgravity has been restraining the hardware. Magnetic pads have been tested [18], but they have been replaced by simple sterile pouches that are smaller, lighter, and more adequately restrain suturing tools. The elastic memory of suture helps it maintain a coil, and thereby keeps the entire length within close proximity of the surgical field. However, suture also floats above the surgical field, so contamination is still a possibility. Crewmembers who have performed animal surgery in space simply cut the suture to use the shortest length needed (personal communication, Richard Linnehan, 1998). Use of staples for wound closure has also been investigated in parabolic flight; the only matter of concern was maintaining control of the loose staples after they are removed [17]. Much has also been learned about the feasibility of hemostasis in parabolic flight and in space flight with animal models of surgery and surgical wound repair. Venous and capillary bleeding is easier to control in microgravity than on the ground, since surface tension forces overcome inertial forces in the absence of a gravity field, and blood tends to pool and form a dome around a wound. Arterial bleeding, however, has been more difficult to control in microgravity. Control of irrigant solutions is somewhat more difficult because low irrigation rates are necessary to prevent splashing. However, loose-weave absorbent gauze held next to the surgical field easily maintains adequate control of irrigant splash [18–21]. Prevention of wound infection may be a challenge in the microgravity environment. Superficial laceration infection rates of 50% have subjectively been noted by U.S. astronauts and flight surgeons [22]. Although minor infections are easily resolved with topical bactericidal ointments, their occurrence leads to the suspicion that infection rates in space may be slightly higher than on the ground. Whether direct effects of microgravity on humoral immunity, on atmospheric characteristics, or both, contribute to an increased wound infection rate remains unknown. (The function of the immune system in space flight is addressed in Chap. 15.) For example, the Space Shuttle atmosphere in microgravity contains more free-floating particulates than are found in one-g environments, where heavier particulates settle to the ground. The Space Shuttle atmosphere can contain 11 times the airborne particle mass concentration (for particles larger than 100 µm) than terrestrial indoor controls [23]. Airborne microorganisms also are associated with these heavier particles [20]. Investigations during both Space Shuttle and Mir missions have shown that the microbial content of spacecraft air increases with mission duration and also increases with elevations in

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temperature and humidity. Airborne bacterial concentrations on the Mir were generally comparable to Space Shuttle levels (120–325 colony forming units (CFU)/m3) [24], bacterial counts of up to 1,000 CFU/m3 have been noted during temperature elevations [25] after failure of the cooling system. By comparison, a conventional operating room particle count is 133–158 CFU/m3 [26]. The potential therefore exists for greater risk of airborne contamination of wounds. The ISS will likely experience similar temperature fluctuations, but high-efficiency particulate air filters that have been installed in the air revitalization system on the ISS may reduce the particle and microorganism burdens. HEPA filtering is planned for planetary exploration vehicles and habitats. Another potential source of infection is condensate, which can accumulate in space stations that rely on adequate, laminar intramodular airflow and a functioning water recovery system to remove excess moisture from the atmosphere. Condensate that is left to adhere to surfaces near waste collection systems has shown a microorganismal population similar to that in found in pond water. Bacterial mats with amoeboid species, ciliated protozoa, and spirochetes have been recovered from a collection of condensate. Lacerations sustained near waste management systems (which could occur during maintenance of those systems) or lacerations contaminated by condensate left standing in a remote area of the spacecraft should thus be considered “dirty” wounds. Adequate irrigation of lacerations is likely to be at least as important in preventing wound infection in space as it is on Earth [27]. Currently, sterile solutions for irrigation are very limited on board spacecraft. On-orbit instructions for irrigation specify that only sterile physiological saline be used, but potable water from the spacecraft galley can be used as well. Ground-based studies have demonstrated that irrigation of wounds with tap water can result in the same, or lower, infection rates as irrigation with sterile solutions [28]. The highest microbial counts from the Space Shuttle galley to date are 1,600 CFU/100 ml (measured after flight), and generally those counts are much lower. Microbial growth in uniodinated or inadequately iodinated Space Shuttle water is almost universally caused by a single organism, Burkholdera cepacia, a pseudomonad that is nonpathogenic in individuals with normal immune function. No literature exists regarding whether this microorganism has a role in wound contamination. Pasteurized Space Station water has shown very low microbial growth rates as well, although gram-positive species such as Staphylococcus aureus have been known to survive the pasteurization process on the Mir [25]. The iodinated water available in the Space Shuttle contains 3–4 parts per million (ppm) of free iodine. This water typically carries less than 1 CFU/100 ml of microbial growth, and it contains less than the 1% free iodine associated with tissue destruction [29]. Syringes and intracatheters are available in the medical kits for high-pressure irrigation of wounds. Blood products in an irrigant splash are more of a housekeeping concern than a

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biohazard, because crewmembers are well-screened for the presence of human immunodeficiency virus and for hepatitis A, B, and C. A loose-weave absorbent gauze placed next to the wound is therefore usually sufficient for catching splashing irrigant [19]. Particulate matter could also pose a biohazard to space crewmembers in terms of its possibly being retained in an open wound. Although safety restrictions limit use of glass or wood aboard spacecraft, sawing of coolant pipes and metal structural components, as was required on Mir [30], could result in retained metallic foreign bodies if a crewmember sustains a laceration. Particulates pose more of a risk of eye irritation or corneal abrasion than wound irritation. Diagnostic sonography will be available on the ISS (see Chap. 9); a 7.5MHz probe can detect plastic and wooden foreign bodies with 95–98% sensitivity and 89–98% specificity [31]. Updates for tetanus prophylaxis are also given to crewmembers before missions to cover them for the duration of the flight. Lidocaine and bupavicaine solutions (with and without epinephrine) are also available in the medical kits for local anesthesia in wound repair; pending results from actual experience on orbit, the principles of local tissue anesthesia are expected to be the same in space than on Earth. Lidocaine will be used for local anesthesia when return of normal sensation is desirable within a few hours. Bupivacaine is flown for situations in which longer periods of anesthesia (4–8 h) may be needed. For wound repair outside the scope of the CMO’s capabilities and outside the capability of the medical kit, wilderness medical principles apply. Currently, neither the Space Shuttle nor the ISS provides the capability for repairing complex wounds such as hand tendon, eyelid, or lacrimal sac lacerations. The hardware is not available, and the intense training schedule for Space Shuttle and ISS crewmembers does not allow time to train CMOs in procedures that are typically the purview of specialists in the terrestrial setting. Delayed primary care is therefore the only treatment option currently in low Earth orbit (LEO), and that option may be appropriate for some kinds of injuries. Hart and colleagues assert that care provided for flexor tendon injuries, for example, can be delayed as many as 10 days after injury with little change in outcome as compared with immediate definitive care [32]. Irrigation, antibiotics (if indicated), skin closure, and splinting can all be performed on orbit. As the number of crewmembers on future missions increases, serious consideration will be given to including a physician as a member of the crew. Relatively little is known about wound-healing rates in space flight. Anecdotal evidence from flight surgeons, astronauts, and cosmonauts indicates that superficial lacerations or phlebotomy wounds may take longer to heal in space than on Earth. No photo documentation or other objective measure of wound repair and healing has been conducted to date, although such a project is currently under way. Repaired surgical wounds in animals after short-duration

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space flight have shown increased inflammatory responses, reduced angiogenesis, and abnormal arrangement of collagen fibers, leading to decreased scar strength at the wound margins. These findings suggest an increased risk of wound dehiscence [33–35]. Gross observations, however, have not indicated any change in wound infection or dehiscence rates during the 1–2 days after surgery (personal communication, Linnehan, 1998). More research is needed in this area, since delays in wound healing will affect wound management principles such as time to suture or staple removal, which in turn will affect mission operations.

Musculoskeletal Trauma The Lower Extremities More significant trauma is also possible during space flight. The magnitude of forces involved in most terrestrial trauma events (falls, motor vehicle accidents) are largely absent in microgravity. However, the massive objects handled by crewmembers during EVA or during Space Shuttle-to-ISS transfer operations have sufficient momentum to cause injury, particularly in the larger spacecraft interior volumes of ISS. Moreover, the elastic restraint straps that are used to secure stowage items and stabilize crewmembers carry significant kinetic energy when they fail. Snapping of an exercise bungee cord or a treadmill harness can, and has, resulted in significant injury. Risk of injury also increases when the speed of crewmember translation between modules increases, which occurs in the activity-intense phases of a flight such as during an in-flight emergency response or a Space Shuttle-to-ISS transfer operation. In the U.S. space program, the Space Shuttle’s capacity to ferry a relatively large payload volume to the ISS demands rapid transfer of the constituents of that payload (supplies and experimental hardware) in a short time, increasing the risk of soft tissue injuries and fractures. In-flight ligamentous sprains have generally been mild in the U.S. Space Shuttle Program to date, usually occurring in the hands, the knees, and the ankles. Treatment has required little more than symptomatic therapy with nonsteroidal analgesics. Although crewmembers in microgravity are essentially non-weightbearing, they are at risk of more severe ligamentous injuries. Astronauts and cosmonauts exercise daily on a treadmill and other devices to minimize the muscle atrophy and bone mineral density loss known to occur with exposure to microgravity. For maximal training benefits, crewmembers adjust the treadmill harness tension to exert a load equal to 70–80% of the crewmember’s body weight, distributed over the crewmember’s hips and shoulders. These loads increase the risk of ankle injuries during treadmill exercise sessions. Also, spacewalking astronauts or cosmonauts have commented that repeated entry into and exiting from the foot restraints can result in soreness in the ankle and knee ligamentous structures. The motion consists of foot internal and external rota-

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tion with a compression or distraction force applied to the ankle and knee joints. The problem may be exacerbated in the crewmember with preexisting knee injuries, which is the most common orthopedic problem in the U.S. astronaut corps [36]. Prior meniscal or anterior cruciate ligament injuries may remanifest during these operations. Conceivably, then, an ankle sprain or a knee medial or lateral collateral ligament sprain could occur or be exacerbated during flight. Preflight injuries may place an astronaut or cosmonaut at a higher risk of injury during a mission as well. A survey conducted as part of the JSC Longitudinal Study of Astronaut Health showed that astronauts sustain nearly three times as many musculoskeletal injuries during the period beginning 1 year before flight to 1 year after flight than at other times. Both ankle and knee injuries tend to occur in the period before the mission, probably because of the high training intensity at that time. Therefore, weaknesses in knee and ankle ligamentous complexes can be expected in flight for those astronauts who are recovering from a previous injury. Inadvertent inversion of the foot with a sprain of the lateral ligamentous complex is the most common ankle sprain terrestrially [37]. The same injury occurring on orbit would most likely be less severe without the stronger inversion stress driven by the weight of a person in one-g. Presentation of an injured ankle will most likely differ in microgravity. Local edema from a ligamentous injury may be reduced in space flight, since diminished hydrostatic pressures in the lower extremities would result from cephalad total body water redistribution in microgravity. These shifts likely will achieve the same effect that elevation of the injured extremity would on Earth [38]. The examiner would then expect to see less swelling than would occur in one-g and thus could underestimate the degree of ligamentous injury. Although a CMO would not be expected to perform an expert physical examination, he or she could assess swelling and bruising and perform the squeeze test to rule out syndesmotic injury. Palpation about the ankle joint will help determine which ligaments are affected. The anterior drawer and talar tilt tests are of limited diagnostic accuracy, even in the hands of an experienced specialist [39–41]. These studies suggest that gentle stress testing immediately after the injury can provide useful information, in that laxity without pain is suggestive of a third-degree tear, and pain with minimal or no laxity is suggestive of a firstor second-degree tear [42]. As is true in terrestrial medicine, the examiner should rule out a fifth metatarsal or fibular head fracture in the examination as well. Not surprisingly, treatment options of an ankle sprain are limited on orbit. Cryotherapy will usually not be available because of limited refrigerator/freezer storage volume. If available, it should be applied early [43]. As noted above, the classic terrestrial principle of elevating the affected extremity to limit swelling is meaningless in microgravity. An injured crewmember should be able to continue most tasks and remain “non-weightbearing.” The available medical kits have sufficient supplies to compress the ankle with tape or elastic

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wrap, which has been shown to be beneficial for any grade of ankle sprain [44]. After a crewmember sustains an ankle sprain, expedient return to treadmill exercise is essential, because aggressive return to function is shown to hasten recovery and reduce functional limitations after an injury [43]. This could be accomplished by a treadmill program using lower tensions on the harness and by an exercise program using the cycle ergometer, bungee cords, and (on the Space Shuttle) rudder pedals to strengthen the ankle everters and the muscles of plantar and dorsiflexion. Crewmembers have found that they can simulate ambulation in a spacecraft cabin by providing counterpressure with their hands on an opposite wall. In this way, they can control the pressure on the ankle. Since estimates of healing time would be very important for future timeline planning, an accurate determination of degree of injury will be essential. Return to full function for ankle sprains, for instance, depends on the grade of the sprain. For a grade 1 sprain, the expected full return to function is 7 days; that for a grade 2 or 3 sprain can take several weeks [44]. The type of immobilization—such as a simple compressive dressing or splint for suspected syndesmotic injuries and fractures [45,46]—and the duration of treatment also depend on an accurate diagnosis. After assurance that no fracture or third-degree sprain is present, aggressive rehabilitation can begin. With no roentgenography capability on orbit to rule out fracture of an extremity, CMOs and flight surgeons will need to use established decision algorithms based on the findings from clinical and sonographic examinations. In such cases, the Ottawa Ankle Rules can be applied: crewmembers with ankle pain after trauma, with pain at further attempts at ambulation on the treadmill or on palpation of the lateral malleolus and medial malleolus, or indeed any crewmember over age 55 years, would be suspected of having sustained a fracture. However, in some studies [47,48], the Ottawa Ankle Rules have proven only 94–98.5% sensitive for detecting ankle fractures. Sonography, as noted above, is available on the ISS and is currently the only imaging modality available in spacecraft. Fortunately, sonography has recently shown to be useful for detecting occult ankle and foot fractures [49], and its sensitivity surpasses that of roentgenography for identifying the formation of callous after injury [50]. Splints (other than finger splints) are not available in the Space Shuttle medical kit because of volume constraints, although crewmembers have worn air stirrup ankle splints during flight to stabilize preflight injuries. (An ankle splint must fit inside a boot that is worn during launch and entry, and air bladders are opened inside of the boot to provide pressure relief in case of cabin depressurization.) Both the U.S. and Russian ISS medical kits carry a variety of splints, and splints can also be constructed from available on-orbit materials. Assessments of knee injuries would be similar to those on Earth, although the potential for a fracture would be unlikely without the added force applied by a one-g field. Several decision algorithms similar to the Ottawa Ankle Rules have been

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developed for knee injuries. A review of these algorithms indicates that the Pittsburgh Knee Rules allow sufficient specificity without sacrificing much more sensitivity than the Ottawa Knee Rules [51]. The Pittsburgh Knee Rules can be summarized as follows: A fracture can be considered very unlikely in the absence of blunt trauma in a person younger than 55 years if the head of the fibula and patella are not tender; if the person can flex the knee to 90 degrees, and if the person can bear weight immediately or simulate ambulation for about four steps. The Pittsburgh Knee Rules do not apply, however, if crewmembers have a history of surgery or prior fracture. Elements of the crewmember’s history and physical that will help the CMO determine whether an anterior cruciate ligament injury has taken place are whether the crewmember heard or felt a pop, whether swelling is present, and whether any mobility is lost. Pain upon simulated ambulation indicates a meniscal tear. Once both the patient and the CMO are sufficiently restrained, Lachman’s maneuver or the anterior drawer test can be performed. Although a compression dressing and knee immobilization can be achieved on orbit, no hardware is currently available on the ISS or Shuttle to support knee joint aspiration. Microgravity is less stressful than one-g on the extremities and axial skeleton, and ligamentous injuries of the lower extremities can be “worked around” in the course of most intravehicular tasks. Nevertheless, an injured crewmember’s ability to return to a gravity field remains a concern. The ability to perform safely at maximum capability upon arrival in a gravity field makes appropriate in-flight management of these injuries a necessity. Perhaps most important, the flight surgeon should ensure before launch that the assigned crewmembers are maintaining an adequate exercise training regimen that includes aerobic and anaerobic exercises so that the risk of on-orbit injury is minimized. The flight surgeon should ensure that the in-flight exercise schedule is maintained and that other mission activities do not interfere with maintaining that schedule. Hand Injuries Because the hands are used to provide stability and propulsion in microgravity, the chance of injuring them may be greater in space flight than on the ground. Standard terrestrial splinting practices can easily be implemented on orbit; however, establishing the presence or absence of a fracture will be problematic. Sonography has shown some success in delineating tendon injuries [52] but not in delineating scaphoid fractures [53]. The ability of sonography to detect phalangeal, metacarpal, or other carpal injuries is not known. Infectious tenosynovitis will also be of concern during a long-duration mission because of its profound operational impact owing to its morbidity when treatment is delayed. Staphylococcus aureus and Streptococcus pyogenes cause most hand-wound infections that are not caused by mammalian bites. Although the broad-spectrum parenteral antibiot-

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ics amikacin and imipenem are available on orbit, a complete course of treatment will have to involve the use of oral antibiotics because the parenteral agents are in limited supply.

Burns Eight instances of onboard combustion have been documented to date, four on the U.S. Space Shuttle and four on the Russian space stations Salyut and Mir [30,54]. Of particular note is the fire that took place during the Shuttle-Mir increment NASA-4 in February 1997. Lithium-perchlorate canisters were used on board Mir to supplement the Russian space station’s Elektron oxygen-generation system. One of these canisters caught fire, producing (by some accounts) a 1-m (3.28-ft)-long flame and releasing enough smoke to obscure visibility within seconds. A crewmember sustained second-degree burns of the forearm in association with this event. Clearly spaceflight medical kits must contain hardware and medications to support the treatment of burns. The Space Shuttle and ISS medical kits contain silver sulfadiazine, sterile gauze, parenteral opioid analgesics, and crystalloid solutions. As is usual in space flight, weight restrictions limit the ability to replace fluid volume in severe burns. The maximum quantity of crystalloid planned for ISS—about 12 L—would support a 70-kg (154-lb) crewmember who has sustained burns over 40% of his or her body for 24 h (following the Parkland prescription of 4 ml per kg per percentage of surface area burned), which is the minimum time needed to leave LEO, return to Earth, and deliver the patient to a definitive medical care facility. Given the high concentration of particulates present in spacecraft atmospheres, CMOs will have to pay special attention to secondary infection of burn wounds. With this in mind, antiseptic cleaning, debridement, and topical antimicrobial application can be performed with the resources provided in both the ISS and Space Shuttle medical kits. First-degree burns have occurred as a result of ultraviolet (UV) light exposure through unfiltered spacecraft windows. Sunlight that is not filtered by atmosphere or window coatings carries high-intensity UV rays (180–400 nm) that can cause dermal burns in seconds. The ISS windows consist of three fused silica panes, with a scratch pane that can be removed for high-quality imaging. When this pane is removed, the window admits a higher spectral range [55]. Skin exposure to sunlight for less than a minute through windows without this added filter has resulted in first-degree burns. The principles of management for first-degree burns are the same in space flight as on the ground, and adequate oral analgesics and topical antimicrobials are accordingly flown in medical kits.

Headache Headache relief is one of the most common reasons spaceflight crewmembers take oral analgesics during Space Shuttle

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missions [4]. A review of 89 Space Shuttle flights involving 508 crewmembers and 4,443 flight days by the JSC Longitudinal Study of Astronaut Health revealed headache in 304 (69%) of 439 men and 38 (55%) of 69 women. Headaches can afflict crewmembers with SMS, and they seem to be associated with the cephalad fluid shifts that occur soon after orbital insertion; however, headaches can also occur later during flight, even as late as several months into a mission [56]. This section reviews the most commonly suspected causes of headache in the unique environment of space flight and the well-screened space crew population, and suggests treatment options that can be used by crewmembers, CMOs, and flight surgeons. Headaches occurring during the first few days of space flight are most often associated with space adaptation syndrome, with nausea as an accompanying symptom. The headache is self-limiting and usually resolves along with other symptoms of space adaptation syndrome as the crewmember adapts to microgravity, usually within 72 h. Caffeine withdrawal, which can occur during any expedition to a remote site, can occur early in a space flight. Although caffeinated beverages are available to spaceflight crews, busy work schedules often preclude their preparation. Taste preferences also change on orbit, and crewmembers may choose not to maintain their usual caffeine intake. Therefore, caffeinecontaining oral medications should be provided for spaceflight crewmembers who are known to be susceptible to caffeine withdrawal symptoms. These medications can provide a substitute for colas or coffee, 8 oz (0.25 kg) of which contain approximately 35 mg and 85 mg of caffeine, respectively. Headaches that occur beyond the initial 72 h of microgravity exposure should alert the flight surgeon and CMO to consider the possibility of atmospheric contaminants. CO2 contamination, for example, is a well-known cause of headache. A concentration of CO2 of 2% or more in a cabin at sea level will produce headaches in humans [57] and is the suspected cause of some of the headaches that were experienced on board the Mir space station and the Space Shuttle. The average CO2 levels on the Space Shuttle are 0.26%. The onset of headaches in crews aboard Mir has led at least twice to the discovery that the CO2 removal system had failed [30]. Headaches can occur while crewmembers are working in small, poorly ventilated volumes such as behind panels or among tightly packed payloads. In cases such as these, archival air samples have not yet revealed a causative contaminant, perhaps because no sample has yet been collected at the specific location, and at the exact time, of symptom onset. Recent use of a portable CO2 sensor also has not demonstrated elevated CO2 levels in these areas. Therefore, as a cause of headache, the accumulation of CO2 in “pockets” in modules that otherwise display nominal CO2 readings has yet to be demonstrated. A distinct odor may precede headache onset. Crewmembers have identified “glue” or “adhesive” smells antecedent to their symptoms, suggesting that acetates or xylenes may be causative agents. Again, however, archival air samples have

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not yet demonstrated the presence of high levels of these compounds. Despite the inability to clearly identify a specific environmental cause for headaches in space flight, exposure to freshly scrubbed air results in symptom resolution in less than an hour in most cases. Crewmembers with headaches that develop while they are working in space modules that have no active air revitalization systems describe relief of symptoms after retreating to a module with contaminant removal systems that contain both activated charcoal and lithium hydroxide. (These modules are capable of removing CO2 as well as most low molecular weight volatile organic compounds.) Thus regardless of the cause of the headache, symptoms usually resolve with improvement of intramodular airflow, placement of portable fans by the worksite, or exposure to freshly scrubbed air. The CMO and flight surgeon can work with the ground control team to plan mission objectives around areas of suspicious airflow and to avoid accumulation of crewmembers in a single area. Carbon monoxide has been the known cause of headache in one case after a microimpurities filter overheated (see Chap. 21). The flight surgeon should presume that any crewmember with a headache at the time of a smoke alarm warning, with visual identification of smoke or fire, or with olfactory detection of smoke has been exposed to carbon monoxide. ISS flight rules dictate that crewmembers in this scenario should don oxygen masks and retreat to a module with uncontaminated air. One hundred percent oxygen is available in the Space Shuttle and the ISS for treatment of suspected carbon monoxide poisoning, although means of determining carboxyhemoglobin levels in real time are not available. Apart from headaches associated with the aforementioned causes, the flight surgeon and CMO must also consider endogenous causes of headache. During the medical screening necessary to become an astronaut or a cosmonaut, applicants with a history of migraine or cluster headache or with cardiovascular disease are disqualified. Computerized tomography or magnetic resonance imaging of the central neuroaxis of prospective candidates is not currently performed, and so subclinical central nervous system abnormalities may pass undetected. However, this will be implemented soon for long duration crewmembers. Endogenous causes of headache that the CMO and flight surgeon must consider include tension headaches, cluster headaches, trigeminal neuralgia, and temporal arteritis. Tension headaches are the most common cause of headaches in general, producing 78% of headaches in terrestrial practice [58]. The high workload of crewmembers during a mission makes tension headache a likely diagnosis for in-flight headaches after the first days on orbit. The age at first onset of cluster headaches and trigeminal neuralgia can be 40–50 years, a range only slightly older than that of the average U.S. astronaut. Similarly, temporal arteritis can become evident for the first time in individuals older than 50 years. Examination of a crewmember with a persistent headache that has no apparent cause should include documentation of

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vital signs and a directed physical examination. Signs and symptoms that should raise suspicion of serious intracranial abnormalities are headaches that increase in frequency and severity; headaches associated with mental status changes, fever, or meningeal signs; focal neurological deficits; and headaches that occur in individuals over 55 years of age [59]. The physical examination should evaluate the affected crewmember for otitis media and sinusitis (see the section on “Upper Respiratory Disorders” later in this chapter). Variableapplanation tonometry is available on the ISS, and glaucoma should also be considered, particularly in crewmembers with associated visual changes [59]. The fundoscopic examination should include a search for flame hemorrhages, papilloedema, and subhyaloid and retinal hemorrhages, which are diagnostic of subarachnoid hemorrhage in the age group of spacefarers. A focal finding on an in-flight neurologic examination (see Chap. 17) should heighten concern regarding significant intracranial abnormalities. Although few diagnostic and treatment modalities are available on spacecraft, pain control with non-narcotic analgesics such as acetaminophen, ibuprofen, and aspirin in addition to air purification and provision of 100% oxygen are available if needed. The flight surgeon must work with other members of the ground team in adjusting the mission timeline so that the crewmembers can avoid areas in which air contamination or accumulation of metabolites may have occurred. The flight surgeon should also remind crewmembers who are exhibiting symptoms that even if the symptoms resolve spontaneously, they should obtain an archival air sample from the area of the spacecraft occupied by the crewmember when the headache began. This practice may not aid in management of the medical problem for that crew, but it may enable a problem with contaminants to be identified and addressed for the benefit of future crews.

Sleep Disorders The risk of chronic fatigue in spaceflight crews is significant. The crewmembers’ drive to complete multiple mission objectives and the need for spacecraft maintenance into the period before sleep reduces the amount of sleep obtained during flight. Also, since orbital mechanics is the main driver of the crew mission schedule, crews must often sleep in shifts to accommodate launch, rendezvous, and landing times. Crewmembers can begin to experience a sleep debt before launch. Trainers and crews typically train heavily in the weeks before launch; and despite guidance given in the judicious use of bright lights, dark goggles, sedative-hypnotics and melatonin to regulate sleep and rest cycles, sleep debt can still accrue. Thus for ISS rendezvous missions, a launch slip of 24 h requires a 20-min phase advance in the sleep schedule (i.e., the crew must go to sleep 20 min earlier for each 24-h delay that occurs.) Schedulers of the on-orbit timeline abide by documented constraints to the amount of sleep shifting that can be imposed on a crew;

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nevertheless, the combination of sleep shifts, workload, and crew motivation for high work output can result in chronic sleep debt. Sleep medications are therefore among the most commonly used medications by spaceflight crews [4]. Non-benzodiazipine hypnotics that have a short onset of action and half-life, such as zolpidem, are being used with increasing frequency to assist in ensuring the onset of sleep. Melatonin is preferred, either alone or with zolpidem, by some crewmembers. Benzodiazipines such as temazepam are used less often. Guidelines for use of these medications are determined before launch and are discussed more fully in Chap. 20. Flight surgeons can also assist in preventing crewmember fatigue by limiting interruptions by ground control in the crew’s before- and after-sleep periods. Flight surgeons also monitor and protect the crew’s exercise time, which is particularly important during long-duration flights. In postflight debriefings, long-duration crewmembers have stated unanimously that the daily exercise period is one of the most important factors that promotes sleep onset and reduces the amount of time spent awake during the sleep period.

Skin Disorders Skin disorders are another common problem during space flight [4]. As discussed previously, the particulate components of spacecraft air may increase the risk of superficial infections in crewmembers with breaks in the skin from superficial cuts and abrasions. The relatively dry air on board Space Shuttles typically results in only minor drying of the skin during brief missions. More serious skin conditions such as folliculitis, contact dermatitis, and fungal infections can occur during longer-duration missions. Although the cause of these skin conditions has yet to be determined, contributing factors may include the higher humidity of space station atmospheres and the exposure of the crews to relatively exotic compounds. Space station maintenance operations demand close physical contact with substances such as ethylene glycol (which was used as a coolant on Mir), cadmium and nickel (constituents of anticorrosives in coolant lines), and urea (located near waste containment systems). Problems from contact with these materials can be prevented by using chemical-resistant gloves and suits to protect the skin during contingency operations and in-flight maintenance. Treatment of skin disorders depends on avoiding the source and treating with topical steroidal, antifungal, or antibacterial creams, alone or in combination. Since dermatologic problems lend themselves to video downlink, the flight surgeon and consultants can assist in the diagnosis. Cellulitis has occurred during space flight; treatment with oral antibiotics according to standard terrestrial protocols has been successful on orbit. Aggressive treatment is necessary to minimize performance degradation. EVA operations in particular cannot be effectively conducted while the crewmember has a distracting dermatologic problem.

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Eye Disorders Ocular injuries, in addition to being common, are among the most serious of ambulatory care disorders confronted during space flight. The microgravity environment increases the risk of eye injury and contamination from free-floating foreign bodies that would otherwise settle onto a surface in one-g. Failure of the elastic cords used to restrain hardware and tether crewmembers during exercise has resulted in both scleral and corneal injuries and abrasions. Crewmembers have sustained potentially vision-compromising eye injuries that have required topical antibiotic therapy, pain control, and reevaluation over several days. The flight surgeon should be aware of the mission phases when foreign body injuries are most likely. Perhaps the most hazardous time for this type of injury is during entry and transfer operations to a station and into a new module such as a cargo vehicle. The act of opening and entering new modules does not seem to pose a hazard, but as transfer operations begin, metal shavings, loose debris, and dust can be released [56]. For this reason, crews are advised to wear protective goggles during these operations. A magnifying lens, proparacaine drops, an ophthalmoscope with a cobalt-blue light filter, cotton-tipped swabs, pH strips, and fluorescein strips are available on orbit for diagnosis. Because no slit lamp is available, subtle injuries to the anterior chamber are difficult to detect. However, CMOs are trained to perform a complete primary ocular examination with lid eversion and examination with an ophthalmoscope. If a foreign body is suspected of being present, an effective initial technique for removing it is to place a bolus of drinking water over the affected orbit. In microgravity, the fluid forms a dome over the eye. This dome adheres via surface tension and creates a bath in which the crewmember can blink, which usually removes the foreign body. Water can then be absorbed and contained with a towel. Alternatively, a drink bag can be used to direct a low-velocity stream of potable water onto the eye, again using a towel for water containment. To prepare for such eventualities, Space Shuttle and ISS crewmembers are instructed to place a drinking bag of potable galley water in modules where activities will be performed that present a high risk of exposure to ocular foreign bodies. Space Shuttle and ISS medical kits also contain an emergency eyewash system for removing ocular foreign bodies and for treating ocular chemical exposure. The emergency eyewash system consists of goggles into which galley drinking water can be infused, creating a turbulent flow over the affected eye at a rate of 1 L/min [60]. CMO’s for Shuttle and ISS are also trained to remove foreign bodies from the eye with a moistened cotton-tipped swab or a 20-gauge needle. Eye burrs for removing more stubborn foreign bodies or rust rings are not available on the Space Shuttle or the ISS. Eye patches, including a metallic eye shield, are available for use as needed. However, CMOs are cautioned to limit the use of patches as needed for comfort only, because patching does not

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seem to enhance healing rates and may increase the risk of secondary infection [61]. Cycloplegics and topical ophthalmic antibiotic preparations such as gentamicin, erythromycin, and ciprofloxacin are easily stowed in spacecraft medical kits and have been included in the Space Shuttle and ISS medical kits as well. Because the CMO can reexamine an eye injury often, follow-up and early detection of complications or treatment failures should not be a problem on spaceflight missions. As the use of tissue adhesives increases in the microgravity environment, misplaced adhesive into the eye is a potential hazard. If a crewmember’s eye is thus contaminated, the medical kit contains sufficient ophthalmic ointment to apply to the affected eye. The eyelid should spontaneously open 1–4 days after treatment as the adhesive bond releases [62]. The ISS and Space Shuttle medical kits also contain ophthalmic antimicrobial preparations. The relatively high concentration of carbonaceous particles in spacecraft air, the frequent and potentially prolonged use of contact lenses, and the increased risk of ocular foreign bodies all increase the risk of bacterial keratitis and conjunctivitis. The dilation of conjunctival vessels associated with the cephalad fluid shifts at microgravity onset should not be confused with conjunctivitis. A crewmember’s eye must be carefully examined to rule out foreign body contamination for any case of unilateral “red eye.” Also, given the increasing use of soft contact lenses among members of the U.S. Astronaut Corps, preflight training includes the caution to remove lenses before sleep. Ciprofloxacin ointment and drops are flown in the Space Shuttle and ISS medical kits for treatment of contact lensassociated pseudomonas keratitis. In a contingency in which a portion of the station is rendered uninhabitable, as occurred after the collision between the Progress and the Mir in 1997, ISS crewmembers can be separated from their lens cleaning and storage system. ISS crewmembers who wear lenses are now cautioned to carry back-up spectacles with them at all times. Although applying ophthalmic solutions poses little difficulty in microgravity, a significant amount of solution is wasted with each application. Titration of a dose into single drops is difficult because of the lack of gravity-induced separation of air and fluid in the bottle, which results in inconsistent doses of solution with each application. For this reason, ointments are used for serious infections such as corneal ulcers, where prudent use of a limited supply of antibiotic is necessary to ensure that a complete antibiotic course is available. Judicious use of ocular antibiotics applies to the treatment of the red eye on orbit as well. Conjunctivitis, for example, is generally self-limiting, showing cure or significant improvement by 2–5 days in 64% of patients, but use of topical antibiotics is associated with an improved clinical remission rate [63]. UV keratitis can and has also occurred on orbit [56]. Unfiltered sunlight, as noted above, can cause ocular injury in seconds. Crews are instructed to wear UV protection at all times when Earth-observing at any window that does not block UV

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light, and the medical kit contains sufficient means to treat UV keratitis should it occur. Proparacaine is used to facilitate the examination, and a short-acting cycloplegic and antibiotic ointment or drops is then applied. Eye patches are available as needed for comfort. Hydrocodone and acetaminophen in oral preparations are also available for pain control. The pain and loss of visual acuity associated with UV keratitis is usually resolved in 24 h.

Gastrointestinal Disorders Upper gastrointestinal problems have not significantly affected spaceflight operations to date, but mild complaints suggestive of gastritis and esophageal reflux are commonly reported by space flyers. These symptoms are generally self-limited and are usually relieved by the over-the-counter medications (simethicone and antacids) flown in the medical kit. The source of these symptoms is unknown, as no attempts have been made to document esophageal motility or changes in lower esophageal sphincter tone during space flight. Water dispenser malfunctions in an early Apollo mission [10] and some Space Shuttle missions resulted in air being entrained into the water stream, which produced mild gastritis symptoms that were easily treated with simethicone. Gastroesophageal reflux symptoms have been reported after a large meal or ingestion of a large bolus of fluid (which is required before reentry to offset postflight orthostasis from intravascular depletion). Constipation, which can have a greater effect on operations, is also a common problem for crewmembers upon introduction to microgravity, most likely because of the large bowel ileus, as noted in physical examinations by astronaut physicians [64,65] and in experimental investigations of gastrointestinal motility [66]. The decrease in bowel sounds noted on physical examination, associated with increased transit time of foodstuffs through the colon, is probably exacerbated by dehydration from SMS and homeostatic hormonal responses to fluid redistribution. Russian cosmonauts undergo bowel preparations before launch to reduce the need for bowel movements in the Soyuz spacecraft while in transit to Mir. Some U.S. astronauts also follow this practice, whereas others use a liquid diet for 2–3 days before launch. Bowel preparation is not a preflight requirement in the U.S. space program. Oral and rectal bowel stimulants and psyllium wafers are available on orbit for constipation. Crewmembers also need to maintain hydration, and aggressive resolution of SMS symptoms is needed in the early in-flight period to allow oral rehydration. Sufficient hardware is available to perform enemas as needed. Constipation usually resolves in the first few days on orbit, although crewmembers have gone as long as 1 week upon arrival on orbit without defecation. Gastroenteritis is a less likely condition, although a few crewmembers have experienced a combination of nausea, vomiting, and diarrhea in the first week of space flight. Diarrhea and fever are not components of SMS, and thus they

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distinguish SMS from gastric disturbances of infectious cause. Theoretically, preflight quarantine of spaceflight crews reduces the incidence of viral gastroenteritis during flight, but breaches can conceivably occur. Peculiarities of the clinical evaluation of hydration status and challenges to parenteral fluid administration in microgravity are discussed later in this chapter in the section on “Procedures.” Evaluation of abdominal pain, particularly cases of right lower quadrant abdominal pain, may prove to be one of the most difficult diagnostic dilemmas on orbit. Abdominal pain, a diagnostic dilemma on Earth, may present in a substantially different way in microgravity. Movement of abdominal organs in microgravity is not well described, so the positioning of the mesentery, the stomach, and the appendix is unknown. During laparoscopy of an insufflated abdomen of a porcine subject during parabolic flight, mesenteric retraction of viscera towards the diaphragm was noted at the onset of simulated microgravity [67]. Russian sonographic investigations of the human abdomen, conducted on a Mir flight, described elevation of the diaphragm and increases in hepatic, splenic, and renal volumes that persisted 4 months into that long-duration mission [68] and were thought to be due to normal anatomic changes associated with the absence of gravity. These results raise the question of whether changes in the position of the appendix and peritoneum in microgravity may affect the classic presentation of appendicitis. Given the lack of onboard imaging modalities, information obtained from the physical examination of a crewmember with abdominal pain will be of paramount importance to further decision making. The differential diagnosis in the medically screened population of astronauts and cosmonauts is less extensive than is seen in terrestrial medicine. Vascular abnormalities and mesenteric ischemia are very unlikely causes of abdominal pain. Indeed, crewmembers undergo sonographic evaluation of the abdomen and pelvis as part of astronaut selection and again 30 days before a long-duration flight; thus gross abnormalities would be detected before flight. Ureteral colic may be difficult to distinguish from appendicitis in space; the crew and ground flight controllers of a Salyut mission were faced with this dilemma [56]. Even though pregnancy is contraindicated during exposure to space radiation, a urine pregnancy test is available in the ISS medical kit to rule out ectopic pregnancy. Any differences in the presentation of or risks associated with pelvic pain in microgravity vs. those on Earth are unknown at this time. However, no abdominal symptoms or shoulder pain have been described by female crewmembers to date that would suggest an increased risk of endometriosis caused by microgravity enhancement of ectopic endometrial implantation [19]. On the ISS, sonography will most likely be used to evaluate a crewmember with abdominal pain. Sonography will be of particular use in distinguishing ureteral colic from appendicitis. Although technologic advances continue to improve the accuracy of sonography in the evaluation of appendicitis, the examination remains highly dependent on the skill of the

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operator [69]. Because the onboard sonographer will probably have had limited experience, training, or skill maintenance, appropriate downlink of captured images may be necessary to consult with experts on the ground. However, the flight surgeon will need to compete with other consoles in the Mission Control Center for the bandwidth required for realtime continuous downlink of images. Also, the ISS, in certain orientations, can shadow ground stations by antennae, trusses, modules, and solar arrays, thereby blocking communication with the ground. Limitations on the availability of satellites or ground stations can lead to loss of communications for 50– 70% of the time during ISS operations. For exploration-class missions, the round-trip time of a communications signal renders real-time consultations impractical. Therefore, maximizing the capabilities of the on-orbit CMOs is paramount, and in-flight training and onboard mentoring programs for this purpose are being developed by NASA and the international space medical community. No surgical capability exists on the Space Shuttle or the ISS, which makes parenteral antibiotics the only treatment option for abdominal abscesses before an ill crewmember can be returned to Earth from a space mission in LEO. Although the optimal antibiotic regimen for medically managing appendicitis in adults has yet to be established, in general the use of parenteral antibiotics that cover aerobic and anaerobic organisms is relatively successful. Oral metronidazole has shown some efficacy in the medical management of appendicitis [70]. Imipenem and metronidazole are present in space medical kits and would be used to attempt stabilization of the ill crewmember before return to Earth. Gastric decompression, essential to reduce peristalsis, can also be accomplished on orbit [71]. Administration of morphine sulfate to a crewmember who has acute nonbiliary abdominal pain will be considered, because such treatment can effectively relieve pain and may not affect the ability of CMOs to accurately evaluate the patient [72]. Any analgesia would be administered in close consultation with the flight surgeon and other ground consultants.

Upper Respiratory Disorders Nasopharyngeal congestion is another common problem for astronauts and cosmonauts in the early period of exposure to microgravity. Facial swelling from cephalad fluid shifts has been well-documented, and nasal congestion is a frequent associated complaint. Although nasal congestion poses minimal risk to the crew, it can distract from mission tasks and increase insensible fluid loss from mouth breathing. Intranasal oxymetazolone is used most often for this condition, followed by anti-allergenics and diphenyhydramine. It has become increasingly apparent from crew comments and flight surgeon observations that adequate filtering of the spacecraft air also lessens nasal congestion. Supporting this contention is the fact that some Space Shuttle crewmembers have noted a rapid onset of nasal congestion immediately after accidental

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blockage of the Orbiter cabin air-cleaner filter between the middeck and flight deck. Removal of the blockage results in rapid relief of symptoms. Sinusitis, although not a prominent disorder among spaceflight crews, can be promoted by cephalad fluid shifts and the resultant engorgement of sinus mucosal vasculature. It is important to distinguish true bacterial sinusitis from uncomplicated sinus congestion; even though evidence exists to support the use of antibiotics for bacterial sinusitis for 7–14 days [73], profligate use of antibiotics for presumed sinusitis will strain on-orbit supplies as well as predispose a crewmember to infection by resistant organisms. In one review, clinical findings of tenderness to palpation over the sinus areas, elevated body temperature, and purulent rhinorrhea were found to be 58% sensitive and 88% specific in detecting sinusitis that is treatable with antibiotics [74] in comparison to the gold standard of antral aspiration [75]. Sonography, when available to the ISS CMO, may be useful as well. A review of five studies evaluating sonography for diagnosing maxillary sinusitis showed it to be 83% sensitive and 88% specific [74]. Although mucosal thickening is not easily visualized on sonography, a sinus that is partially or fully filled with secretions can transmit ultrasound waves. The effect of microgravity on the diagnostic accuracy of sonography is not known, although the “layering” of secretions that forms a typical sign on x-ray evaluations would not be present in microgravity. Other upper airway inflammatory processes that can occur commonly on the ground can also occur in space flight; the preflight 7-day quarantine used by the U.S. and Russian programs was established to limit viral or bacterial infections in crewmembers. The flight surgeon and the CMO must still consider upper airway inflammation in the differential diagnosis of pharyngitis, however. Since breaches in preflight quarantine are possible, treatment of a crewmember with pharyngitis in the first days of a space flight is similar to that on the ground. Carrier states are known to occur in the astronaut or cosmonaut population, both in the quarantine period and during flight; lateral transmission of Staphylococcus aureus between crewmembers during missions has been documented [76]. Changes in the crew’s immunity secondary to the stress of the high workload, sleep debt, or an as yet undetermined effect of space flight may reactivate these pathogens, resulting in clinical disease. Clinically based predictions of the presence of bacterial pharyngitis are relatively poor. As noted above, headache and rhinorrhea in spacecraft have multiple causes and are not necessarily suggestive of upper airway infection. Sore throat, cervical lymphadenopathy, and fever are more suggestive of bacterial pharyngitis [77]. A rapid streptococcal immunoassay is available in ISS medical kits that may assist in diagnosing bacterial pharyngitis. Generally, treatment is recommended when the clinical picture is clear, the symptoms noted above are present, and findings on a rapid strep test are positive; however, in giving such treatment, the CMO accepts the possibility of unnecessary treatment of crewmembers who do

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not have disease and that of unnecessarily depleting the on-orbit supply of oral antibiotics [78]. An advantage in on-orbit medical care is the opportunity for close, frequent reevaluations, so crewmembers with negative findings on a rapid strep test or an unclear clinical picture can be easily followed without the need for overly aggressive early treatment [75]. Several classes of oral antibiotics are available in Space Shuttle and ISS medical kits, including penicillins, β-lactamase penicillins, macrolides, and cephalosporins. These antibiotics can be used to reduce the incidence of suppurative complications and perhaps shorten the duration of symptoms [77]. Because the ambient spacecraft atmospheric pressure changes regularly in the course of mission operations, otitis media suspected during space flight must be aggressively treated with oral antibiotics and decongestants. Moreover, microgravity may change the physical presentation of otitis media with effusion, as exudate would not “layer out” behind the tympanic membrane. Otherwise the principles of clinical diagnosis of otitis media and its treatment are no different in space flight than in terrestrial practice. The dry air present in the Space Shuttle atmosphere in combination with cephalad fluid shifts may predispose crewmembers to nosebleeds. The lack of gravity also prevents free blood from descending into the nasal alae early in the nosebleed, so more blood may be present in the nasopharynx at the time of presentation than in one-G. Shuttle and ISS medical kits are stocked with cotton pledgets, topical decongestants and anesthetic, silver nitrate sticks, and nasal packing as needed to treat anterior epistaxis. Foley catheters can also be used for posterior bleeds; in that technique, the catheter is inserted through the nasopharynx into the posterior pharynx and its balloon is inflated and then drawn back to tamponade the posterior nasopharynx [79].

Pulmonary Disorders Pulmonary problems unique to space flight include exposure to exotic atmospheric contaminants and inhalation of foreign bodies. Hydrazine, ammonia, ethylene glycol fumes, and the products of pyrolysis can produce disorders ranging from minor irritation of the upper airway to disruption of pulmonary capillary/alveolar integrity with resultant adult respiratory distress syndrome. Although pulmonary infections do not seem to occur at a higher rate in space flight than on Earth in a standard medical practice [80], infections are a risk if breaches in infection defense are present secondary to pulmonary injury. Inhalation of toxic substances or aspiration of foreign bodies are two of the most likely examples of such an injury. Since neither roentgenographic nor bronchoscopic imaging capability will exist on board spacecraft in the near future, accurate assessment by the CMO will be essential. The relatively noisy environment of spacecraft will make auscultation, the traditional chest physical examination technique, difficult. Moreover, auscultation is not sufficiently accurate to confirm the presence or

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absence of pneumonia. Recent evaluations of the accuracy and interobserver reliability of auscultation in detecting pneumonia (with the chest x-ray used as the gold standard) show that auscultation alone has a sensitivity of less than 70% and a specificity less than 75% [81]. Thus a high degree of suspicion will have to be maintained when a crewmember has a productive cough and fever. Crewmembers are always at increased risk of inhaling foreign bodies during space flight, particularly during activities that increase minute ventilation (e.g., exercise). Sudden onset of cough accompanied by a local monotonic wheeze on auscultation would suggest foreign body aspiration. The CMO must assess all anatomic lung segments in the physical examination, since the classic gravity-dependent segments may not be at increased risk in microgravity. An affected crewmember should be followed closely for atelectasis or pneumonia development in lung segments distal to the occlusion. Toxic contamination of the spacecraft atmosphere can also lead to significant pulmonary injury. Firsthand experience with this problem unfortunately occurred in July 1975 at the end of the Apollo-Soyuz Test Project, when the three-member Apollo crew was exposed to 250 ppm of nitrogen tetroxide, an oxidizer commonly used in spacecraft propulsion systems, for 4–5 min during the atmospheric reentry of the Apollo command module. Initial symptoms were eye burning with tearing, burning and itching of the skin, chest tightness with retrosternal burning, and nonproductive cough upon deep inhalation. The crewmembers’ lungs were clear on initial examination after splashdown and recovery, but radiologic evidence of pulmonary edema was present a day later [82]. They recovered fully, without sequelae. Nitrogen tetroxide is a gas that decomposes into nitric acid and other compounds on contact with the water in mucous membranes. In sufficient amounts, it is highly irritating to upper airway passages; less severe exposures may produce only cough and coryza. Indeed, this presentation is first in a typical triphasic progression of injury manifestation after significant pulmonary exposure to nitrogen tetroxide. Within 3–30 h, one can expect onset of pulmonary edema and adult respiratory distress syndrome. Bronchiolitis obliterans can then affect 50% of survivors. Intubation and respiratory support with application of positive end-expiratory pressure (PEEP) is necessary for patients with hypoxemia. Treatment with steroids is controversial; trials with human subjects have not shown steroids to be effective after nitrogen tetroxide exposure [83]. Hydrazine gas, a propellant used in both the Space Shuttle and the ISS, is also extremely irritating to upper airway passages, skin, and eyes. Similar damage to the lower pulmonary tree can ensue with significant exposure [83]. Ammonia, which is used as a coolant on the Space Shuttle and the ISS, presents another pulmonary hazard. Any contamination of the spacecraft atmosphere by ammonia would require simultaneous breaches in several barriers [84] or passage into the cabin via a contaminated space suit exposed during EVA. Ammonia is very irritating to upper

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airway passages, but crewmembers can adapt to exposures of limited severity. A few seconds of ammonia gas exposure cause inflammation of the conjunctiva and pharynx, pharyngeal and retrosternal pain with cough, and dyspnea, but no abnormalities on x-rays. Hypoxemia from chemical burns to the tracheobronchial tree may be delayed by 1–2 days. The presence of rales and wheezing can predict the onset of adult respiratory distress syndrome and progression to worsening hypoxemia that can take weeks or longer to resolve. However, quick removal of the affected crewmember from the source can limit pulmonary injury, with symptomatic improvement in a week and complete recovery in 1–2 months. Conversely, some victims have developed moderate obstructive pulmonary dysfunction presenting as reactive airway disease 2–6 months after exposure [84]. The first steps in preventing injury are to protect the crewmembers and contain the contaminant. Crews can don oxygen masks that cover the eyes and mucous membranes of the nose and mouth. Skin protection should be maintained with use of gloves and chemical-resistant suits. Any contaminated clothing should be disposed of in wet trash containment systems that entrain air through filters and dump the air overboard. EVA-related contamination can take place if a reaction control system jet leaks or fires inadvertently with impingement on the space suit; the spacecraft atmosphere becomes contaminated when the crewmember returns to the spacecraft. The onset of irritation, cough, and coryza in other crewmembers immediately after an EVA should raise suspicion of such contamination. The source of the contamination can be removed by the EVA crewmember returning to the airlock and exposing the space suit to the sun, which “bakes out” or sublimates the contaminant from the suit [85]. Primary treatment and stabilization of crewmembers can be accomplished with the hardware provided on the Space Shuttle and the ISS. After the exposed crewmember is removed from the source of the offending contaminant and an initial assessment is performed, β-adrenergic aerosols are available to treat reactive airway manifestations. Parabolic-flight studies showed that albuterol aerosol dispensers operate similarly in simulated microgravity and on the ground, dispensing a 90-µg dose per activation as expected [86]. Repeat examinations and pulse oximetry monitoring should be continued for at least 24 h. Carbon monoxide diffusion capacity studies of normal crewmembers during space flight have also indicated that thoracic fluid shifts do not produce subclinical pulmonary edema, so any hypoxemia could not be attributed to a normal physiologic response to microgravity [87]. The onset of hypoxemia mandates consideration of return to Earth (for missions in LEO) and provision of 100% oxygen. Increasing levels of ventilation support up to intubation and mechanical ventilation can be accomplished on the ISS. Similar principles apply to crewmembers who are exposed to toxic pyrolytic products after a spacecraft fire. Shuttle and ISS flight rules mandate that crewmembers don oxygen masks when a fire is detected. Real-time monitoring of spacecraft air

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for carbon monoxide, hydrogen chloride, and hydrogen cyanide is possible with portable chemical and infrared sensors available on both the Space Shuttle and the ISS. Crewmembers experiencing symptoms after exposure to combustion products must be monitored for 24 h for signs of pulmonary edema and hypoxemia. This was done after the Mir space station fire in 1997, when the onboard CMO set up an airway station and continued reevaluation of his crewmates over 24 h. This episode led to the design of new Space Shuttle medical kits that allow easier access to airway equipment with better hardware restraint. For spaceflight crews who will return to the Moon or go on to explore Mars, exposure of spacecraft cabin interiors to native dust may cause cough and airway irritation to airway passages. One Moon-walking astronaut relayed after landing that the lunar soil caused “breathing problems,” although no evidence of a medical problem was reported during flight and postflight examinations were normal. Some Moon-walking astronauts reported that lunar dust caused nasopharyngeal irritation as well [88].

Allergic Reactions A severe allergic reaction could be disastrous during a space mission. All crewmembers are tested before a flight for their responses to common medications in the Space Shuttle and ISS medical kits to determine any unexpected allergic responses or adverse side effects. An allergic response to these medications is not disqualifying for space flight, but it allows appropriate planning of the medical kit inventory. Other antigens that could initiate an anaphylactic response are tracers and markers used in life sciences experiments, although these markers are evaluated carefully with the crewmembers before flight. The clinical manifestations of vasodilatation-induced hypotension in microgravity are unknown, but presumably the presentation would be different without a gravity gradient to exacerbate orthostatic hypotension. Items in the Space Shuttle and ISS medical kits for treating allergic reactions include subcutaneous epinephrine, parenteral and oral steroids, β-agonist aerosols, and IV fluid supplementation. The challenge for treatment on board spacecraft is the need for rapid response in microgravity. The medical kits therefore contain epinephrine autoinjectors, syringes filled with 1:1,000 epinephrine and diphenhydramine, steroids, and β-aerosols packaged together in an easily accessible location and restrained on Nomex fabric pallets.

Dental Disorders Dental problems are one of the most common reasons for evacuation from submarines and surface ships [89]. Although dental care is of paramount importance for crewmembers who are preparing for space flight, dental trauma or infections can and have occurred during missions. For example, in the Russian space program, the forces associated with the vibrations and

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accelerations during launch have dislodged crewmembers’ crowns. Dental trauma is also possible through the use of the mouth as a convenient means of holding tools such as flashlights when working in enclosed areas. CMOs are trained to stabilize fractured teeth and perform temporary crown replacement, and the Space Shuttle medical kit contains sufficient supplies to perform these procedures. Russian and ISS medical kits also contain tooth-extraction tools for dental trauma or for infection that has not responded to other means of treatment. Sufficient oral and parenteral antibiotics are also on board Russian and U.S. spacecraft to treat apical abscesses. Lower light levels, limited dental training for CMOs, limited supplies, and the need to restrain tools remain the most significant challenges for assessing and treating dental problems on orbit (see Chap. 26).

Urologic Disorders Urologic problems during space flight can involve ureteral stones, urinary tract infections, urinary hesitancy, and urinary retention. Prostate infections have occurred at least twice during space missions [10,30], and available documentation indicates that one case led to the return of the crew from LEO. Urologic problems in space flight are addressed in detail in Chap. 13, and only general principles are described here. Astronauts and cosmonauts are theoretically prone to ureteral stone formation in the first hours of arrival on orbit and immediately after return to Earth. Although no episodes of ureteral colic have occurred during flight in the U.S. space program, it almost caused the deorbit of a Russian Salyut crew from LEO [30]. The on-orbit challenge, in addition to pain management, will be diagnosis, since IV pyelography or other roentgenographic evaluation will not be available. Clinical presentation of ureteral colic is not expected to differ substantially on orbit from that on Earth. Standard terrestrial urine dipsticks can be used to assist in the diagnosis, but urine hemoccult tests are only 67% accurate (for more than five red blood cells per high-power field) for making a definitive diagnosis [90]. Sonography, available on the ISS, may be used to visualize significant hydroureter or hydronephrosis. Parenteral nonsteroidal anti-inflammatory agents are carried in the ISS medical kits, and both the Space Shuttle and the ISS medical kits contain parenteral opioid analgesics for pain management of ureteral colic. The only concern is the limited supply of analgesics. Substantial parenteral analgesia cannot be maintained for much longer than 24 h using the medical kits on either spacecraft. Medical management will focus on maintaining adequate hydration and monitoring for fever or sonographic evidence of hydronephrosis from complete ureteral obstruction. A stone visualized by sonography that is larger than 8 mm (0.3 in.) is not likely to pass and may require surgical removal [91]. Oral and parenteral antibiotics that cover the common offending organisms are available in the Space Shuttle and the ISS medical kits. E. coli is thought to be the most common cause of urinary tract infection in space flight (as it is on Earth),

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but this has yet to be verified because urine cultures have not been available in flight. Broad-spectrum coverage of Pseudomonas spp. is necessary as well, because this was the offending organism in a case of urosepsis in the Apollo Program [10]. Urinalysis is available to assist in the diagnosis of urinary tract infections, but measurement of blood leukocytes is not currently possible with the ISS or Space Shuttle medical kits. Urinary retention has occurred on a few occasions during space flight. Urethral catheterization with leg bag drainage is possible and has been performed in space flight. Simultaneously restraining hardware while maintaining sterility is the most significant difficulty in performing catheterization in microgravity. Wearing a leg bag in microgravity by itself does not affect intravehicular operations, although the increased potential for urine reflux from the catheter into the bladder may predispose crewmembers to urinary tract infection [17]. Reasons for a possible increased rate of urinary hesitancy during space flight missions are discussed in Chap. 13. The flight surgeon must be aware of the amount of promethazine used by crewmembers for treatment of SMS, as its anticholinergic activity may add to any predisposition for urinary retention.

Cardiac Problems As spaceflight missions increase in duration, complexity of payloads, and number of high-risk activities (e.g., EVAs), the need for on-site cardiac life support capability has increased as well. The 1990s have seen acceptance of smaller, more autonomous, and user-friendly defibrillator units outside of traditional hospital and emergency medical service settings in terrestrial medical care. A defibrillator is now part of the medical inventory on some Space Shuttle and all ISS flights. Medical care in space flight is approaching the terrestrial ambulance-level medical care. The first defibrillator flown in space (on the fifth NASAMir mission of the joint U.S.–Russian Phase I program, May 15–October 6, 1997) was left on board the Mir space station. Since that time, Space Shuttle medical payload manifests have included defibrillators and cardiac medications on specific missions, if required by the unique characteristics of that mission and its payload activities. Although the astronaut and cosmonaut populations are extensively screened for cardiovascular disease before flight, episodes of arrhythmia and symptoms suggestive of cardiac ischemia have nevertheless occurred during flight. During the Apollo Program, a crewmember experienced a 14-s run of bigeminy during flight, concomitant with a feeling of extreme fatigue. That same crewmember experienced a myocardial infarction 2 years later, from which he recovered [10]. The Russian medical community terminated one mission early because of an episode of paroxysmal supraventricular tachycardia [31]. In at least one other incidence, a cosmonaut was placed on cardiac medications for symptoms suggestive of ischemic heart disease (personal communication, V. Bogomolov, 2002). Moreover, long-duration space flight may

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predispose crewmembers to arrhythmias. Review of electrocardiographic tracings during EVA [92] and the results of inflight Holter monitoring during Space Shuttle missions [93] do not show a predisposition to arrhythmias during shortduration space flight, but limited data suggest this may not be true for long-duration space flight [94]. Also, electrocution remains a potential cause of cardiac arrhythmia during a mission. The electrical power systems (28 Vdc on the Space Shuttle and 120 Vdc on the ISS) represent a potential electrical injury hazard. Finally, depressurization in preparation for EVA exposes crewmembers to an increased risk of cardiopulmonary decompression sickness (DCS), which may require advanced cardiac life support (ACLS) capability as well. The effects of microgravity on the symptoms and clinical manifestations of ischemic heart disease are unknown. A crewmember may be reluctant to assign early symptoms of chest pain, diaphoresis, or dyspnea to cardiac causes because of reliance on extensive medical screening performed before the mission and because of reluctance to cause unnecessary mission impact. Because an astronaut’s or cosmonaut’s awake pulse rate and diastolic blood pressure are nominally about 10% lower on orbit than on Earth [38], ischemic symptoms may not become apparent until the crewmember is participating in some vigorous activity that significantly increases myocardial demand (e.g., exercise on the treadmill or performance of an EVA). Evaluation of a crewmember with ischemic heart disease will probably rely heavily on the clinical impression of the CMO and on consultation with the flight surgeon and ground specialists. Some degree of jugular venous distension is present in all crewmembers in space flight because of the cephalad movement of intravascular volume. Signs and symptoms of cardiac ischemia—diaphoresis, nausea, shortness of breath— are expected to be similar in space and on Earth, but this is not certain. Auscultation will be difficult on orbit because of high ambient noise levels, so subtle murmurs and perhaps even rales will be difficult to detect. Dependent edema would probably not be a prominent feature in a crewmember with significant myocardial injury and subsequent decrement in ejection fraction, although edema would presumably be present in a general distribution as well as in the face or upper extremities. Although sonography will be available on the ISS, the ability to determine wall motion abnormalities or valvular damage will depend on the severity of disease, the skill of the CMO, and the bandwidth availability for real-time assessment of images with terrestrial consultants. In the U.S. space program, rhythms can be monitored on orbit with a 5-lead electrocardiograph on the ISS and a 3-lead electrocardiograph on Space Shuttle flights. Relative resting bradycardiac and decreased diastolic pressures are known to be associated with space flight, and further manifestations of ischemic disease on electrocardiography in microgravity are unknown. Treatment in space would follow standard terrestrial regimens: O2 via nasal cannula or non-rebreather mask, intravas-

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cular saline as needed, and aspirin, sublingual nitroglycerin, morphine sulfate, and β-blockers, all of which are available to the crew as needed. ISS medical kits contain sufficient epinephrine and lidocaine to provide two runs through the ACLS pulseless ventricular tachycardia–ventricular fibrillation algorithm [95,96]. Vasopressin and amiodarone are not yet included in the ISS medical kits pending resolution of packaging and storage issues. Some aspects of ACLS, however, are unique to the spaceflight environment. In the case of the full arrest, transfer of the affected crewmember to the ACLS location, where space must be dedicated for restraint hardware, access to 100% oxygen, and ACLS medications will be necessary. Fortunately, transfer of an unconscious crewmember is much easier in microgravity than on Earth, so the time to cardioversion could be shorter than on Earth. Multiple simulations during parabolic flight demonstrate that a CMO could easily perform rescue breathing while transporting an unconscious patient [97–99]. These simulations assessed the effectiveness of a variety of cardiac compression techniques. In general, the rescuer could deliver adequate compressions, as measured by mannequin compression recordings, either from the patient’s side by using a waist restraint or by planting his or her feet on a surface opposite the patient and placing his or her hands in the standard position. In the inverted position, thrusts are delivered by knee and elbow extension. This method has been simulated on orbit as well (Figure 5.1). Both of these options seem to be successful because they simultaneously allow adequate compressions and positional stability. Performing cardiopulmonary resuscitation with one hand (while the other is used to restrain the provider), with the provider either aside or straddling the patient, was too fatiguing and allowed too much movement between provider and patient [17]. External mechanical and pneumatic compression devices have also been evaluated in Space Shuttle and parabolic flights. Given the required deployment time and lack of significant improvement in compression efficacy, these devices have not been considered for use in spacecraft [17]. In general, restraining the provider and the patient is of paramount importance throughout resuscitation. Engineering constraints do not officially allow free-floating cardioversion at this time [17] to avoid unintentional grounding through wires or other floating hardware and exposing critical spacecraft-control electronics to damaging electrical pulses. Defibrillation units are tested to comply with electromagnetic field limits during charging, defibrillation, and pacing. A crew medical restraint system flown on the ISS allows electrical isolation of the patient from the module. This restraint system also serves as a stable platform on which the providers can restrain the patient, themselves, and their hardware. Consistent training of CMOs with choreographed resuscitation procedures is one of the best safeguards against inadvertent grounding through the providers. Hardware restraint is a significant challenge for performing a resuscitation in microgravity. Hardware and instru-

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FIGURE 5.1. Astronaut Dan Bursch demonstrating posture and positioning for performing cardiopulmonary resuscitation chest compressions using the crew medical restraint system in the U.S. Laboratory Module of the ISS (Photo courtesy of NASA)

ments are inevitably misplaced in the flurry of activity surrounding a simulated-microgravity resuscitation. Blood products, packaging, and used hardware that ordinarily fall to the floor in a terrestrial resuscitation will float in microgravity. Thus CMOs are trained to be constantly aware of equipment placement, and straps, waste bags, and needle containers are incorporated in the design of the medical kits, floor layout, and restraint system to restrain critical hardware and waste. Microgravity allows a wide variety of unique approaches to attaining a definitive airway in patients in respiratory distress. Restraint of the patient is essential for adequate direct laryngoscopy; that restraint is provided by the crew medical restraint system. To perform direct laryngoscopy in microgravity, the provider can use his or her knees to grasp the head of the restraint system or even grasp the head or shoulders of the patient so as to establish adequate stability for excellent visualization. Microgravity also allows the CMO to float above the patient and to more easily perform blind digital intubation. Investigators have evaluated intubation from the side of the patient for those cases in which the patient’s head is close to a bulkhead or another structure. Although possible, this technique requires more time because of difficulties in restraining the rescuer. However, the expected low success rate of intubation via direct laryngoscopy by minimally trained personnel has led to use of the intubating laryngeal mask airway as the primary method of attaining a definitive airway during space flight [100]. A definitive airway should be secured before the affected crewmember is transported to the ground, either by Space Shuttle, Soyuz, or a future dedicated return vehicle [17]. Methods of saliva containment in simulated microgravity are different from those in terrestrial practice because of the sur-

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face tension forces that cause secretions to adhere to oropharyngeal surfaces. A manual suction device, developed to allow one-handed operation, has been tested in parabolic flight and is part of the current ISS medical airway kit [101]. Ensuring proper endotracheal tube placement in space flight is expected to be the same as on the ground, with a couple of notable exceptions. Low ambient light levels may make accurate reading of colorimetric end-tidal CO2 difficult, and relatively high ambient noise levels will limit auscultation. For these reasons, an esophageal detector bulb is provided in the ISS medical kit. Drugs for ACLS will be given by means of an endotracheal tube or by intravenous injection. Pulmonary function studies in microgravity during the Apollo-Soyuz Test Project missions [102] and those performed later by West and colleagues [87] suggest that no significant barriers exist to using the endotracheal route for drug administration in microgravity. The lack of sedimentation of aerosolized droplets in microgravity can result in decreased deposition of medication [103]. How this difference would affect medications delivered by the endotracheal route is unknown. Guidelines from the American Heart Association suggest that the recipient’s arms be elevated to facilitate the flow of intravenously injected medications through the venous system to the central circulation. Obviously, this will not help in microgravity, and IV medications will have to be “chased” with saline boluses.

Procedures Intramuscular Injection Promethazine is most commonly given in space flight by IM injection; IM injection is in fact the most commonly performed in-flight medical procedure in the U.S. Space Shuttle Program [4]. CMOs use syringes from the SOMS kit that are filled on the ground before flight to minimize the need to remove bubbles from the solution. Although the injection itself differs little from terrestrial IM injections, the CMO must ensure adequate restraint of both himself or herself and the patient. The most common technique for preventing inadvertent movement is for patients to stabilize themselves in the corner of a cabin. IM injections are almost always delivered into the superior gluteal area to prevent subsequent limitation of motion of the upper extremities from the muscle soreness that occasionally results from the procedure.

Intravenous Catheterization CMOs and mission specialists performing biomedical investigations have inserted IV catheters on orbit in antecubital veins with success rates similar to those in ground operations. The greatest challenges in accomplishing venous catheterization in microgravity are again restraint of hardware and patient. A rapid and common means of restraint is to apply a strip of

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duct tape, adhesive side facing out, near the workstation. IV tubing, saline locks, alcohol wipes, iodine swabs, and trash are stuck to the tape and easily kept in place and within reach. Several kinds of sharps containers are available, including foam blocks and metal containers with hinged lids; both have been used successfully. Phlebotomy and catheterization are otherwise somewhat easier in microgravity once the CMO and patient are well restrained. No obvious differences have been observed in flashback or fluid flow through IV tubing, and blood control is rendered simpler by the predominance of surface tension in the absence of gravity. Air elimination filters that use a hygroscopic membrane were shown to perform adequately in removing air bubbles in the continuous microgravity conditions of the Spacelab Life Sciences-1 mission (STS-40). The filters can dry out, however, and a continuous pressure head is required to maintain filter filling. Such pressure can be provided by squeezing the IV bag or by placing the bag in a blood pressure cuff and inflating it to between 50 and 75 mmHg [104].

Resconstitution of Medications Fluid reconstitution of drug powders offers some challenges in space flight. A bubble in a bag of normal saline or a vial, for instance, does not float to the “top.” If the container is agitated, froth forms, which makes accurate aspiration of a desired volume difficult. Syringes cannot be “thumped” to send bubbles toward the needle hub. Therefore, at present all parenteral medications and saline bags are stored in a form in which bubbles are removed before flight. Parenteral medications in powdered form are desirable because of their smaller storage volume and generally longer shelf life; thus an understanding of how these medications can be reconstituted in microgravity is necessary. Flight surgeons and space crews have used several techniques to create a single air–fluid level, both in parabolic flight and on orbit. All of these techniques involve spinning the IV bag or syringe to centripetally drive the fluid away from the center of spin and against the outlet port (e.g., the needle). IV doses of medications mixed on orbit are not as consistently titrated manually as on the ground. Several mixing devices have been developed for use on orbit, but none has been so effective as to be worth its cost in terms of weight and volume [105].

Other Procedures Cricothyrotomy, tonometry, thoracostomy, laparoscopy, diagnostic peritoneal lavage, throacic, or abdominal sonography, and urethral catheterization have all been performed with animal models in parabolic flight. The general principles of restraining hardware, patient, and operator apply for each procedure. The investigators who performed these procedures have established that once familiarity with self-stabilization and locomotion in microgravity are attained, any of these

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procedures can be performed with some modifications. Other considerations for surgical care in the microgravity environment are addressed in Chap. 6.

Transport Specific techniques for transporting patients from a spacecraft in LEO to a definitive care facility on the ground vary depending on which rescue vehicle is used (i.e., Soyuz, Space Shuttle, a U.S. crew return vehicle) and the medical problem being experienced. The parabolic flight and Space Shuttle investigations mentioned earlier in this chapter revealed a series of basic principles that can be applied in all emergency deorbit scenarios. Specifically, at least 24 h from the moment of declaration for deorbit until delivery of a patient to a definitive medical care facility on the ground will be required to deorbit an injured or ill crewmember. Stabilizing the patient before transport is as important in space flight as in terrestrial emergency service settings. IVs, monitors, a ventilator, and an airway need to be secured in preparation for return [17]. Monitors available to the CMO during reentry will be limited; such monitors currently consist of pulse oximetry and monitoring provided by the defibrillator. An automatic blood pressure monitor will be available as well. Injured or ill crewmembers will not be transported in their pressure suits, as patient access is too limited. Returning an ill crewmember to the one-G environment in a recumbent position is both desirable and possible in the Space Shuttle. Also, an injured or ill crewmember returning in the Space Shuttle does so in a supine position, with lower extremities flexed at the hip and knees, so that the lower legs can rest in a forward middeck locker [98]. Return in a crew return vehicle or Soyuz offers other challenges; these issues are covered in Chap. 7.

Conclusions Further refinement of these and other spaceflight medical procedures, application of new technologies in the microgravity environment, and better understanding of human physiology in space flight are all areas of ongoing investigation. Two other issues now being actively addressed are also critical to the success of treating an acutely ill or injured spaceflight crewmember: first, the optimal training schedule and environment for CMOs and astronaut physicians, to ensure expertise in medical procedures relevant to space flight; and second, development of means to transport a critically ill patient, with a pharmacopoeia that is necessarily limited in volume and scope, using predefined procedures that are specifically relevant to spaceflight operations. Resolution of these issues will enhance the medical capabilities of spaceflight crews in LEO and will be essential to medical operations during expeditionary spaceflight missions.

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121 61. Bertolini J, Pelucio M. The red eye. Emerg Med Clin North Am 1995; 13:561–579. 62. Rubin S, Hallagen L. Lids, lacrimals, and lashes. Emergency treatment of the eye. Emerg Med Clin North Am 1995; 133:561–579. 63. Sheikh A, Hurwitz B, Cave J. Antibiotics for acute bacterial conjunctivitis. Cochrane Database Syst Rev 2000; (2):CD001211. Review. 64. Harris BA Jr, Billica RD, Bishop SL, et al. Physical examination during space flight. Mayo Clin Proc 1997; 72:301–308. 65. Thornton WE, Moore TP. Neurological studies: Bowel sounds. In: Space Shuttle Medical Detailed Supplemental Objectives (DSOs). Unpublished NASA document. Houston, TX: NASA– Johnson Space Center; 1986:235–238. 66. Putcha L, Cintron NM. Pharmacokinetic consequences of spaceflight. Ann NY Acad Sci 1991; 618:615–618. 67. Campbell MR, Billica RD, Johnston SL. Animal surgery in microgravity. Aviat Space Environ Med 1993; 64:58–62. 68. Gazenko OG, Gazenko OG, Grigoriev AI, et al. Review of the major results of medical research during the flight of the second prime crew of the Mir space station. Kosm Biol Aviakosm Med 1990; 23:3–11. 69. Rao PM, Boland GW. Imaging of acute right lower abdominal quadrant pain. Clin Radiol 1998; 53:639–649. 70. Banani SA, Talei A. Can oral metronidazole substitute parenteral drug therapy in acute appendicitis? A new policy in the management of simple or complicated appendicitis with localized peritonitis: A randomized controlled clinical trial. Am Surg 1999; 65:411–416. 71. Trott AT, Lucas RH. Acute abdominal pain. In: Rosen P, Barkin R (eds.), Emergency Medicine: Concepts and Clinical Practice. 4th edn. St. Louis, MO.: Mosby; 1998:1888–1903. 72. Brewster GS, Herbert ME, Hoffman JR. Medical myth: Analgesia should not be given to patients with an acute abdomen because it obscures the diagnosis. West J Med 2000; 172:209–210. 73. Williams JW Jr, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. (Cochrane Review). Cochrane Database Syst Rev 2000; (2):CD000243. Review. 74. de Bock GH, Houwing-Duistermaat JJ, Springer MP, et al. Sensitivity and specificity of diagnostic tests in acute maxillary sinusitis determined by maximum likelihood in the absence of an external standard. J Clin Epidemiol 1994; 47:1343–1352. 75. Stewart MH, Siff JE, Cydulka RK. Evaluation of the patient with sore throat, earache, and sinusitis: An evidence-based approach. Emerg Med Clin North Am 1999; 17:153–187. 76. Pierson DL, Chidambaram M, Heath JD, et al. Epidemiology of Staphylococcus aureus during space flight. FEMS Immunol Med Microbiol 1996; 16:273–281. 77. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev 2000; (4):CD000023. 78. Melio FR, Holmes DK. Upper respiratory tract infections. In: Rosen P, Barkin R (eds.), Emergency Medicine: Concept and Clinical Practice. 4th edn. St. Louis, MO: Mosby; 1998:1529– 1553. 79. Pfaff JA, Moore GP. Ear, nose, and throat emergencies. In: Rosen P, Barkin R (eds.), Emergency Medicine: Concepts and Clinical Practice. 4th edn. St. Louis, MO.: Mosby; 1998:2720– 2729. 80. Baisden DL, Effenhauser RK, Wear ML. Inflight medical events in the shuttle program [abstract]. Aviat Space Environ Med 2000; 71:3.

122 81. Wipf JE, Lipsky BA, Hirschmann JV, et al. Diagnosing pneumonia by physical examination: Relevant or relic? Arch Intern Med 1999; 159:1082–1087. 82. Nicogossian AE, LaPinta CK, Burchard EC, et al. Crew health. In: Nicogossian AE (ed.), The Apollo-Soyuz Test Project: Medical Report. Washington, DC: NASA Headquarters; 1977. NASA SP-411. 83. Eyer P. Gases. In: Marquaardt H, Schafer SG, McClellan RO, Welsch F (eds.), Toxicology. New York, NY: Academic Press; 1999:805–832. 84. Wong KL. Ammonia. In: National Research Council Committee on Toxicology (eds.), Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1. Washington, DC: National Academy Press; 1994:39–59. 85. Fotedar LK, Brown PF. Environmental contamination along EVA translation paths. Unpublished independent assessment report from Lockheed-Martin Co. Houston, TX: NASA–Johnson Space Center; 1997. JSC-LM97-152. 86. Lloyd CW, Fox JL, Martin WJ, et al. Aerosolized Medications during Parabolic Flight—Phase 2: Metered Dose Sample Acquisition. Houston, TX: NASA–Johnson Space Center; 1991:231–240. NASA TM 104755. 87. West JB, Elliott AR, Guy HJ, et al. Pulmonary function in space. JAMA 1997; 277:1957–1961. 88. Harris JR. Dust Control and Protection for Planetary Exploration. Prepared under Lockheed Engineering and Sciences Co. Contract NAS 9-17900. Houston, TX: NASA–Johnson Space Center; 1992. JSC-25975. 89. Nice DS. A Survey of US Navy Medical Communications and Evacuations at Sea. San Diego, CA: Naval Health Research Center; 1984. AD-A145 937. 90. Bove P. Reexamining the value of hematuria testing in patients with acute flank pain. J Urol 1999; 162:685. 91. Harwood-Nuss AL, Etheredge W, McKenna I. Urologic emergencies. In: Rosen P, Barkin R (eds.), Emergency Medicine: Concepts and Clinical Practice. 4th edn. St. Louis, MO.: Mosby; 1998:2227–2261. 92. Rossum AC, Wood ML, Bishop SL, et al. Evaluation of cardiac rhythm disturbances during extravehicular activity. Am J Cardiol 1997; 79:1153–1155. 93. Fritsch-Yelle JM, Charles JB, Crockett MJ, et al. Microgravity decreases heart rate and arterial pressure in humans. J Appl Physiol 1996; 80:910–914. 94. Fritsch-Yelle JM, Leuenberger UA, D’Aunno DS, et al. An episode of ventricular tachycardia during long-duration spaceflight. Am J Cardiol 1998; 81:1391–1392. 95. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiac life

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6 Surgical Capabilities Mark R. Campbell and Roger D. Billica

Although no surgical procedures have been performed on humans during space flight, the risk of a problem arising that requires surgical intervention is nonetheless real. From a timeweighted standpoint, until the advent of long-duration missions in the U.S. Skylab program and the Russian Salyut and Mir programs, the probability of an in-flight problem arising that would require a surgical solution was small; thus clinical experience and expertise in performing surgery on humans in microgravity remained quite limited. The lack of on-site surgical expertise was keenly felt when Russian space program officials were faced with the possible medical evacuation of a Salyut 7 cosmonaut who was experiencing abdominal pain thought to be due to appendicitis. Although that episode turned out to have been caused by probable ureterolithiasis rather than appendicitis—the cosmonaut recovered and did not require an early return to Earth—this experience nonetheless underscored a pressing need in space flight. With further increases in crew size and mission duration projected in the near future for the International Space Station (ISS) and the exploration-class missions that will follow, the likelihood of events occurring in space flight that will require surgery will also increase. Moreover, the probability of trauma (including penetrating trauma, lacerations, crush injuries, and thermal and electrical burns) occurring will increase as astronauts and cosmonauts conduct ISS construction-related extravehicular activities that involve manipulation of highmass hardware. A surgical need could also be precipitated by exercise countermeasures, which may lead to minor and major orthopedic injuries. Routine surgical diseases such as appendicitis and cholecystitis can occur indiscriminately at seemingly random times. The physiological changes and deconditioning effects of prolonged weightlessness will influence surgical diseases and treatment in predictable as well as unknown ways. Finally, the possibility of previously unknown surgical problems in the unexplored long-duration microgravity environment must be considered. Analog remote medical care systems (e.g., equipment, instruments, and personnel) have been studied to ascertain the incidence and risk of surgical events. The authors of

these studies have suggested that illnesses or injuries that will require major surgery will be rare.[1,2] However, as these authors have noted, when such illnesses or injuries do occur, the effect could be disastrous—possibly leading to a mission abort or a partial crew return. At the very least, an event requiring that major surgery be performed on a crewmember will greatly affect the overall mission and necessitate a large amount of resources to be treated successfully. Although illnesses and injuries that require minor surgery will probably be more common, they will also pose challenges in the microgravity environment.

The Challenges of Performing Surgery in Space Flight Numerous challenges will arise in performing even minor surgical procedures in microgravity (Table 6.1). Some of the challenges that will need to be addressed include achieving adequate anesthesia, maintaining a sterile field and technique, providing appropriate lighting and exposure, maintaining hemostasis, deploying instruments, and restraining the operator and patient. The current weight and volume restrictions on spacecraft severely limit the availability of surgical and anesthetic equipment to cover all but the most likely situations. The surgical capability of any medical care system in space flight also will be limited by the surgical capability and training of the crew medical officers (CMOs), those members of the crew specially tasked with and trained for rendering medical aid to their crewmates. Current limits on crew size and capabilities make it impossible to provide CMOs with the intensive training needed to handle major surgical procedures. Even if a clinically competent and experienced surgeon is a crewmember, it is highly doubtful that that individual would be able to perform successful major surgery with minimal staff support, minimal resources, and possibly months of surgical inactivity. The risk that the surgeon-crewmember might actually be the patient must also be considered. 123

124 TABLE 6.1. Issues to be considered for performing surgery in microgravity. Restraining patient, operator(s), and equipment Providing and maintaining sterile field Providing appropriate lighting and exposure Managing wastes, including sharps disposal Maintaining hemostasis Preventing contamination of the closed-loop spacecraft environment Accounting for the lack of gravitational retraction during surgical procedures Providing suction and drainage Providing anesthesia and appropriate monitoring Managing fluid levels and blood replacement Providing capabilities for imaging and surgical diagnosis Accounting for changes in endoscopic techniques Accounting for changes in physiology Accounting for changes in fluid dynamics that affect the behavior of bleeding and drainage Accounting for changes in physical landmarks (shifting of internal organs) Providing appropriate support during recovery

TABLE 6.2. Surgical issues addressed in the NASA microgravity program. Dental care and intervention Wound closure techniques Airway management and percutaneous tracheostomy Advanced life support, including cardiopulmonary resuscitation and defibrillation Chest tube placement and drainage Peritoneal lavage Hemostasis Prevention of cabin atmosphere contamination from bleeding and drainage fluids Bandaging and splinting Sterile technique and maintenance of sterile field Patient, operator, and equipment restraint Surgical instrument organization, restraint and logistics Trash management and handling of sharp disposal Bladder drainage with Foley catheterization Percutaneous drainage procedures Suction techniques and drainage behavior of fluids Monitoring technology Sonographic imaging Intravenous fluids and therapy General anesthesia techniques Endoscopy technique and technology, including laparoscopy, thorascopy, and cystoscopy Telemedicine direction of surgical procedures

Concerns have also been raised regarding the unknown effects of microgravity on surgical bleeding, the need to prevent contamination of the spacecraft atmosphere, and the need to protect the operative field from the relatively high particulate content of the spacecraft atmosphere. Physicians who have experience in microgravity quickly raise a host of other issues related to surgical capabilities during space flight, including basic questions regarding diagnosis and imaging, the positioning of tubes, techniques for suction and drainage, the management of waste, and many other concerns. Some of the simplest functions that we take for granted on Earth—such as restraint and positioning of the patient and accessibility of instruments—could be factors that limit the successful performance of surgery in space. Research involving animal surgery in

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the simulated microgravity produced during parabolic flight (Table 6.2) has explored many of these issues. These studies have led to the conclusion that after the patient, operator, instruments, and equipment have been properly restrained, surgical procedures may be more difficult to perform than in 1 G, but are nonetheless feasible in microgravity.

Challenges in Exploration-Class Missions In future exploration-class missions to the Moon or Mars, the on-board medical care system must become more capable and autonomous as the crew size expands and the time required to return an ill or injured crewmember to Earth to reach definitive medical care (defined as the quality of medical care that is available only in a hospital setting) increases. The time to reach definitive medical care from the ISS may be as brief as 24 h but from a lunar base would be at best several days and from a Mars expedition would be more than 9 months. This issue is discussed further in Chap. 7. Mortality and morbidity related to illness and injury have accounted for more failures and delays in terrestrial expeditions and new exploration than have defective transportation systems. Historically, these failures and delays can be attributed to the long separation of the terrestrial expeditions from definitive medical care. This has not been the case for space travel thus far, but becomes a more serious consideration for the exploration activities now planned. The medical care system on a future Mars expedition, for example, will need to be autonomous because of the extremely long separation from definitive medical care. Planning for exploration-class missions must include judicious analysis of the limitations on mass, volume, power, and medical training and careful balancing of those limitations against the need for comprehensive medical and surgical care capability, including the need for surgical interventions (see Table 6.3). A system that includes a CMO and greater on-board surgical capability than past space missions will be necessary because of the increased risks inherent in an exploration-class mission and the need to reduce the effect of such risks on the mission and on crew health. Such a capability may be provided through a combination of traditional resources and newer innovative technologies now in devel-

TABLE 6.3. Mission-related factors affecting surgical care. Remoteness and correspondingly long periods to reach definitive medical care Communication delays Limited medical care resources (weight, power, volume, lighting) Microgravity Physiological changes of long-duration space flight Limited crew training and experience Radiation exposure Enclosed environment Psychological stresses Possible delays in wound healing Possible immunosuppression affecting healing and the incidence of disease

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opment, such as “smart” medical systems, medical informatics, telemedicine, and telerobotics.

Surgical Care System Capabilities The capabilities of the CMO and the medical hardware available on board will determine the surgical capabilities of any future spaceflight medical care system; however, the CMO’s training is the factor that will most limit capability [3–5]. Medical and surgical hardware is subject to strict limits in terms of weight, volume, and electrical power required. Moreover, all of the hardware must function accurately and reliably in the microgravity environment after extended storage time with minimal checkout and maintenance and without expert operators or repair technicians on site. Hardware will probably be available on future space flights to perform surgical procedures that will be beyond the capability of the CMO, but the availability of such hardware will also allow flexibility in handling a variety of surgical problems on board. Reviews of other remote medical care systems underscore not only the importance of emphasizing CMO training but also the need to consider the possibility of using medical treatment for diseases traditionally considered “surgical,” such as appendicitis, during space flight. Assessments of space medicine requirements and training with regard to crew selection have emphasized the importance of surgical capability and have proposed 2–3 years’ surgical training for future CMOs for long-duration exploration-class space flights such as a Mars expedition [6]. Telemedical consultation, a recent modality with which substantial clinical experience has yet to be accumulated, will be important to augment the clinical experience necessary for spaceflight medicine. Although clinical experience with telemedicine is limited, telemedicine has been shown to be valuable in remote-care environments. Nevertheless, a Mars expedition will face the problem of significant communication delays because of the long distances involved; two-way communication times will range from about 8–56 min, depending on the orbital configuration of the Earth and Mars, making telemedicine awkward and real-time input impossible [7].

Surgical Capabilities During Previous Missions Early space missions had only rudimentary medical kits on board until the longer-duration Skylab missions [8] (see also Chap. 4). A minor surgical kit that allowed laceration closure was included for the first time on Skylab, as was expanded diagnostic and medical therapeutic hardware. The Space Shuttle’s medical system, which is used today, contains the components of a minor surgical kit for laceration closure using conventional suturing techniques, but the components are individually wrapped, making the logistics of actually performing a surgical procedure more difficult than if an integrated system were used. Local anesthetics are available

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as well as laceration closure techniques that do not require substantial surgical skills (Steri-strips, Dermabond adhesive, and staples). The hardware available on the Russian space station Mir was similar to the Space Shuttle medical system in its capabilities.

Surgical Capability for the International Space Station An advanced life support pack is included on board the ISS [9] to allow advanced cardiac life support, including ventilation and defibrillation, and advanced trauma life support. The invasive portions of these procedures have been evaluated in parabolic flight using animal models to validate their feasibility [10]. Because evacuating a seriously ill or injured crewmember from the ISS to a definitive ground medical facility would take 6–24 h depending on the evacuation spacecraft available (currently a Russian Soyuz capsule), the surgical capabilities of the ISS medical care system need not be extensive. Current ISS procedures do not require that a physician be on board, and the CMO has only 80 h of medical training; thus the ISS surgical hardware does not provide the capability for major surgical procedures such as thoracotomy, exploratory laparotomy, vascular repair, or invasive orthopedic procedures. The emphasis instead is on stabilization, medical transport, and initial advanced life support capability [11].

Future Surgical Systems As exploration-class activities such as constructing a lunar base or an expedition to Mars become a reality, the time required to reach definitive care will greatly increase, as will the need for surgical capabilities in the medical care facility. The medical care facility for these programs may be similar in size and capability to the Health Maintenance Facility that was originally planned for Space Station Freedom [12,13]. That facility weighed 5,291 kg (2,400 lb) and displaced 30.5 m3 (100 ft3) in volume. It consisted of a microgravity surgical workstation, which was similar to an operating table and was designed to restrain both the patient and the operator. It also was to have had a digitized x-ray capability, a ventilator, a defibrillator, monitors, an intravenous pump, a medical computer, storage for medical and surgical supplies, and a microgravity suction unit. That suction unit used centrifugal force [13,14] to separate air/fluid mixtures and allowed the measurement and containment of biological fluids (urine, blood, gastric contents, and pleural fluid). The effects of new and evolving technologies on future surgical care systems for exploration-class space flights are difficult to predict. Many fascinating possibilities are being considered, and new choices will certainly emerge. The major effect that these technologies are expected to have on surgical care will be to reduce the impact of remoteness, short-

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ages of resources, and limited surgical skills. For example, hemoglobin-based oxygen carriers, developed as a substitute for blood transfusions, would greatly affect a CMO’s ability to resuscitate a trauma patient during space flight. Developments in nanorobotics, smart medical systems, computer medical informatics, noninvasive sensors and diagnostics, and telemedicine all have the potential to increase the autonomy of the remote surgical team. It is hoped that the development and validation of these technologies will allow a paradigm shift in the requirements for traditional surgical capabilities for space flight and will also provide feasible solutions to reducing medical and surgical risks.

Experience from Analog Environments The Russian experience in long-duration space flights has been helpful in verifying that medical issues will affect the mission in terms of lost crew work time, diminished crew performance, and, in some instances, early crew return. Most of the medical events that have taken place occurred 2–6 months into the mission, well after the acute period of physiological and psychological adaptation. Although most medical care issues have been minor, medical evacuations have been necessary during Russian space flights. These evacuations resulted from specific medical events, but they were also enhanced by the psychological stress of long-duration space flights. The experiences of non-spacefarers using various remote medical care systems have also been helpful in predicting the incidence of specific surgical diseases and the ability to medically treat some diseases that have classically been considered surgical. Epidemiologic studies of analog populations, especially those on U.S. Navy submarine [1,2,15,16] and Antarctic [17] expeditions, indicate that major surgical events, although rare, are catastrophic to the mission, as they often require medical evacuation. On the other hand, suspected appendicitis (a so-called minor surgical disease) was, in combination with psychiatric events, the most common cause of medical evacuation from patrol submarines. The incidence of minor surgical diseases in analog populations seems to range between 1 per 8,000 to 1 per 13,000 persondays [1,2]. This rate translates to a single event every 3–6 years for a six-person space station. Analysis of other remote care medical systems reveals that some surgical diseases can be treated medically in combination with careful and continuous evaluation of the patient. The successful nonsurgical treatment of acute appendicitis in the crews of both British Royal Navy Polaris submarines and U.S. Navy submarines is well documented [1,2,15,16]. The U.S. Navy protocol for treating suspected acute appendicitis consists of bowel rest, intravenous fluids, and antibiotics such as cefoxitin and gentamycin. Patients are evacuated when possible, and evacuation is expeditious if improvement is not immediately evident, as was true for 5% of those cases in the British Royal Navy and 15% of those in the U.S. Navy expe-

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riences. The incidence of appendicitis in these analog populations has been reported as 1–2 per 100,000 person-days, [1,2,15–17] which would be equivalent to 1–2 cases every 45 years in a six-person space station.

Surgical Research in Simulated-Microgravity Environments Neutral Buoyancy Research has only recently begun into surgical techniques to be used in microgravity. Although neutral buoyancy (underwater) evaluations of surgical techniques have been suggested [18], such evaluations are not as feasible or as realistic as those conducted in a true microgravity environment, because surgical fluids interact with the water environment far differently than they do with an air environment. The water environment negates the predominant effects of surface tension forces on surgical fluids such as blood. Moreover, the water interacts with the operator to create resistance and drag with any movements, and thus each individual piece of hardware and tissue component must be made neutrally buoyant so that their behavior mimics that in microgravity.

Parabolic Flight Program Parabolic flight (Figure 6.1) is the only method to investigate surgical techniques in near-weightlessness without actually going into space. In the NASA Microgravity Program, the aircraft is typically flown in 40 parabolas for each mission, with each parabola generating approximately 25 s of free fall (weightlessness) followed by a 25-s 1.8-G pullout (Figure 6.2). The short duration of the microgravity window and its alternation with hypergravity windows are obvious limitations to applying parabolic flight experience to space flight; however, parabolic flight remains the best simulation of microgravity available on Earth for this purpose.

Findings from Parabolic Flight Studies Russian investigators performed limited surgical procedures (laparotomy and celiotomy) on locally anesthetized rabbits in parabolic flight in 1967 [19,20]. A closed, transparent surgical canopy and magnetic instrument holder were used. The reports, which were observational and brief, stated that no problems were encountered in controlling venous bleeding, as the blood typically pooled at the site of injury. Arterial bleeding, however, formed droplet streams that contaminated the atmosphere and canopy wall. Also noted was that bowel evisceration during the laparotomy could affect visualization and could make abdominal wall closure difficult. Altered proprioception in the short-duration microgravity environment reportedly caused past pointing and overreaching. The overall

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and restraining equipment, providing appropriate lighting and exposure, and using conventional suturing techniques have been evaluated and successfully performed in parabolic flight [23,24]. However, these simulations have also shown that certain basic procedures must be relearned. For instance, glove packages must be restrained during gloving and gloves must be removed with great care and minimal disturbance. Because of their surface tension properties, conventional antiseptics such as Betadine and Duraprep are easily adaptable for use in microgravity. Finally, use of commercial sterile surgical drapes that have an adhesive surface that can be applied directly to the surgical site greatly simplifies the otherwise cumbersome procedure of draping in weightlessness.

Need for Restraint FIGURE 6.1. The NASA KC-135 in parabolic flight. The aircraft is beginning another parabola that will produce about 25 s of weightlessness. Usually 40 parabolas are flown on a typical mission (Photo courtesy of NASA)

FIGURE 6.2. Flight profile of the NASA KC-135. Each parabolic maneuver gives 25 s of weightlessness followed by a 1.8 G pullout

conclusion was that surgery was possible in microgravity without major difficulties. U.S. parabolic flight research to examine surgical techniques in weightlessness has also established several important concepts. Surgical procedures in weightlessness can be performed with no more difficulty than in the 1-G environment if the principle of restraining the patient, the operating personnel, and the surgical hardware is adhered to [21]. Surgical bleeding and free blood may be adequately controlled by local methods such as the use of sponges and suction [22]. The experience of medical personnel in simulations aboard Skylab and Space Shuttle as well as in neutral buoyancy and parabolic flight indicates that many aspects of performing a surgical procedure are feasible in space flight. Simulations involving prepping and draping, gloving, deploying

Restraining the patient, the operating personnel, and all surgical hardware is a critical consideration in providing effective surgical care in microgravity. Clearly the patient—even if fully awake, conscious, and cooperative—must be rigidly restrained. The operating personnel also must be securely restrained and yet be able to move their arms and hands freely. Restraint has been shown to enable the use of standard surgical techniques and the maintenance of sterile fields. Several options have been examined to facilitate instrument and supply restraint, such as procedure-oriented kits, small surgical packs deployed on an adjacent wall, magnetic surgical trays, and a sterile surgical restraint scrub suit that allows supplies and instruments to be restrained in the chest area [25]. Procedure-oriented kits offer an advantage over individually packaged instruments because all of the supplies that are necessary for the procedure are already available and organized on a sterile field. The disadvantage is that the entire kit is contaminated if only one item is needed. Velcro, elastic cords, and magnetic areas can be used to stabilize supplies. A plastic-lined pocket, a guarded Styrofoam block (for sharp objects), and an adhesive pad area (for suture ends) allow trash disposal. Sterile instruments and supplies should be restrained in such a way as to allow efficient, organized, and conventional procedures and to maintain sterile technique in space flight. Conventional operating room concepts, such as a surgical tray for immediately needed sterile items and a surgical back table for eventually needed sterile items, should be incorporated in the procedures. Trash items must be disposed of securely and safely without compromising sterile technique. Indeed, the orderly disposal of discarded supplies is critical in the small volume of a spacecraft, particularly given the rigid constraints on atmospheric contamination. The spacecraft atmosphere must also be protected against the surgical debris generated, especially if bleeding occurs, irrigation is used, or pus and other infectious fluids are encountered. Restraining operating personnel has been simpler than anticipated. The initial concept of using waist belts and shoe cleats that engage an omnigrid floor, as proposed for the Health Maintenance Facility [13,14], has been discarded. Instead, a

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simple, low-placed horizontal bar, which allows the operator’s feet to be placed underneath, has been found to provide secure but flexible restraint. Currently, a floor-level, easily stored crew medical restraint system is present on the ISS; earlier versions of this device were flown on Mir and Space Shuttle missions (Chap. 4). Although this restraint system is designed for transporting a critically injured crewmember, it also allows the patient, operating personnel, and supplies to be restrained for minor surgical procedures. Despite the usefulness of the crew medical restraint system, a rigid, stable, waist-level table with multiple capabilities is still considered a more optimal configuration for a procedureoriented restraint system. Such a system would need to be compact, lightweight, and flexible enough to accommodate crewmembers of different body sizes and positions, including the microgravity neutral body position that is characterized by slight flexion of the knees, hips, shoulders, elbows, wrists, and cervical spine (see Chap. 2). The need for more complex medical restraint systems will increase as the medical environment on board spacecraft becomes more independent. The first surgical simulations performed in parabolic flight demonstrated that if operating personnel and instruments were not restrained, even simple tasks such as draping a patient became extremely awkward. With restraint, the parabolic flight environment was not found to be much different from the 1-G environment. Simulations of minor surgical procedures on the Spacelab Life Sciences-1 (STS-40) and the Neurolab Space Shuttle (STS-90) missions and during parabolic flight also confirm that surgery in weightlessness may be performed with little more difficulty than in the 1-G environment if the principle of restraint is adhered to.

Bleeding and Hemostasis A major concern regarding surgical procedures in microgravity has been the behavior and control of arterial and venous bleeding. A related concern regards the potential for contamination of the fragile, closed-loop spacecraft atmosphere with surgical debris and blood, and whether such contamination could reasonably be prevented [26]. Mutke, in a 1978 study [27], conceptualized operating through an advanced inflatable, Lexan surgical bubble. Soviet investigators had actually built several early versions of this concept and flown them in parabolic flight simulations [19,28]. Markham and Rock, in the United States, also tested several prototypes simulating laceration closure on a mannequin in parabolic flight [29–32]. Their prototype, which required inflation, was able to contain floating instruments and fluids ejected from a syringe. A NASA team evaluated a similar closed-system surgical overhead canopy in parabolic flight (Figure 6.3) [28]. During surgical procedures on anesthetized animals, this team examined the behavior of arterial and venous bleeding and the ability to control bleeding and prevent atmospheric contamination. Venous bleeding was subjectively increased over terrestrial norms, possibly because of the lack of venous wall compression in weightlessness. Also, both arterial and venous bleeding

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FIGURE 6.3. A prototype surgical canopy is tested with a mannequin arm during a zero gravity maneuver in parabolic flight. Human operators are restrained at the feet and waist, with arms inserted into sterile glove ports. A magnetic surgical instrument tray is in the foreground; at the opposite end is an outlet for providing laminar airflow to carry away escaping fluids and surgical debris (Photo courtesy of NASA)

were found to form large fluid domes that adhered closely to the bleeding tissue because of the surface tension forces unopposed by gravity. Bleeding escaped local control methods (e.g., suction and surgical sponges) only when an arterial droplet streams were allowed to form. This finding was consistent with results of previous experiments in which citrated bovine blood ejected from a syringe was used inside a glovebox during parabolic flight to simulate arterial and venous bleeding (Figure 6.4) [26]. Those investigators concluded that the surgical overhead canopy (Figure 6.5) would be useful if uncontrolled arterial bleeding was present, if large amounts of surgical debris were generated, if large amounts of irrigation fluid were used, or if pus was encountered. Other investigators have proposed the use of large, inflatable environments that would surround the patient, operator, and supplies during surgical procedures in microgravity. Although such an arrangement may seem impractical, the prototype hardware has surprisingly low weight and storage volume. Laser surgical techniques have also been suggested as a means of effecting bloodless surgical procedures in weightlessness [33]. These techniques could be useful if the tools were miniaturized (handheld and battery-powered) and their safety validated. (Electrocautery devices generate too much radiofrequency interference to be practical in a spacecraft, so their use is not currently considered feasible.) Another approach to preventing atmosphere contamination was the concept of generating laminar airflow over the operative field to sweep up surgical debris and transport the debris to a collecting suction apparatus. NASA has evaluated a laminar airflow device in parabolic flight using mannequins and surgery on animals. This device controlled the bleeding that escaped local control methods and cleared the operative site of debris that would have otherwise impaired visibility. However,

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FIGURE 6.4. Blood pooling in weightlessness, which is characteristic of most bleeding whether the source is arterial or venous. Large fluid domes are formed due to surface tension forces at the bleeding site, largely preventing dispersion into the enclosed cabin

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first time in parabolic flight seemed to be unchanged from such ventilation in the 1-G environment. Respiratory mechanics and performance of artificial ventilation hardware were not affected to a clinically significant degree. The adjunct procedures of intravenous infusion, laceration closure, and Foley catheter drainage were also achieved without difficulty. Although cardiopulmonary resuscitation is more difficult to perform in weightlessness, it can be done effectively if both the patient and the CMO are properly restrained. Although the basic trauma support procedures of venous cutdown, cricothyroidotomy, peritoneal lavage, and chest tube insertion were found to be no more difficult to perform in microgravity than in the 1-G environment, restraint principles had to be observed, and management of fluid infusions and drainage required minor modifications of hardware and techniques. These modifications include degassing all infusion bags and lines, using pressure pumps instead of gravity flow, keeping drainage tubes as short and as large in diameter as possible to negate the effects of surface tension and capillary action, and eliminating all possible communication to the cabin atmosphere to prevent leakage. Percutaneous peritoneal lavage, although it required less training to perform, was found to be dangerous in weightlessness because of the additional pressure of the bowel on the anterior abdominal wall, a direct effect of the microgravity environment that created a high risk of bowel perforation. Although an open peritoneal lavage technique was shown to be feasible in microgravity, it required additional training and experience. Also, the lack of 1-G capillary fluid pull and the increased effects of fluid surface tension forces in weightlessness led to decreased drainage of peritoneal lavage fluid. A Heimlich valve and a Sorenson drainage system were used to provide chest tube drainage and fluid collection with minimal equipment. This combination eliminated the risk of atmospheric contamination and also provided the capability to use autotransfusion to drain blood from a hemothorax (Figure 6.6). The use

FIGURE 6.5. An arterial droplet stream forming from an incision made in the abdominal aorta of an animal model in microgravity as viewed through an overhead surgical canopy. Operators have access to the surgical site via arm portholes. This could easily be converted into a non-dispersible fluid dome that remained adherent to the wound. Some droplets have been stopped on the surface of the surgical canopy. Instruments are well restrained on the surgical tray

that experience indicated that the use of standard surgical techniques would be adequate to control most surgical bleeding in weightlessness because of the formation of large, nondispersing fluid domes that adhere to the bleeding surface.

Advanced Cardiac and Trauma Life Support In a series of dedicated parabolic flight experiments, NASA space medicine experts evaluated the feasibility and practicality of many standard techniques used for cardiac and trauma life support. Initial basic and advanced cardiac and trauma support procedures could be performed in parabolic flight despite limitations in having only minimal equipment available and using a nonphysician CMO. Artificial ventilation performed for the

FIGURE 6.6. Chest tube placement in an animal model demonstrating the passive drainage of a simulated hemothorax. Fluid flows “up” without difficulty in weightlessness. This was performed using a Heimlich valve and a Sorenson drainage system, which gives the capability of immediate autotransfusion (Photo courtesy of NASA)

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of a percutaneous dilational technique for chest tube insertion resulted in a procedure that required minimal CMO training and minimal equipment, was technically easier to perform, and further decreased the risk of atmospheric contamination. Suturing the wound tightly around the chest tube was found to be more important in microgravity than expected to control fluid leakage and to prevent contamination. Performance of the procedure by a nonsurgical physician required a minimal amount of training, on the order of 1 h of ground instruction. Telemedicine was found not only to be feasible but also of clear benefit in this project, because it facilitated the insertion of a chest tube under the direction of a remotely located general surgeon. Chest tube drainage was still effective in weightlessness when passive drainage systems (without suction) were used because of inherent intrathoracic pressure. The Sorenson drainage system used for these experiments had previously been proposed for the autotransfusion of chest tube contents from a traumatic hemothorax. Immediate autotransfusion of blood collected from a hemothorax without further processing or anticoagulation has been shown to be safe and effective, especially in remote medical care situations [34–36]. The 1-G disadvantage of using a short or a relatively anterior chest tube, in which removal of thoracic fluid is limited because of dependent pooling, should not be a factor in the microgravity environment. In microgravity, hemothorax fluid distributes itself uniformly as an adherent sheet along the chest wall, and neither the length of the chest tube nor its position in the chest cavity should influence the drainage flow rate. Some loculation of fluid also occurs in microgravity within the chest cavity because of surface tension forces.

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procedure. Finally, such a system would provide for disposal of dry trash, biological waste, and any instruments with sharp edges or points.

Atmospheric Contamination Another theoretical concern associated with performing a surgical procedure during space flight (as compared with a standard operating room) is that of contamination of the operative site by the relatively dirty spacecraft atmosphere, which could increase the incidence of wound infection. The amounts of particulates and colony-forming units in spacecraft atmospheres are higher than in a conventional operating room atmosphere by a factor of 10 [21]. In microgravity, particles tend to be larger and are composed mostly of scurf—organic particles from skin sloughing. Moreover, in light of preliminary evidence that the relative numbers of pathogenic bacteria on skin and surfaces may increase during long-duration space flights and that in-flight medical facilities may be located near waste-management facilities or kitchen or exercise areas on future spacecraft, concerns have been expressed that the atmosphere may contaminate wounds in microgravity. This concern may be mitigated through the use of surgical overhead canopy and laminar flow devices, which have been shown to lower these counts logarithmically [22]. The rate at which clean wounds become infected may also be higher in space than on the ground because of possible immunosuppression and altered cellular responses in healing of wounds and suppression of infections (Chap. 15) in addition to the high particulate counts in the spacecraft atmosphere.

Patient Monitoring Although a standard medical monitoring system (including electrocardiography and measures of blood pressure and ventilatory parameters) functioned normally in parabolic flight, the hardware setup and the logistical management of the large number of tubes and wires would be problematic if it were the responsibility of a single CMO. A more selfcontained, centrally located, and easily deployable system would be better. Wires and tubing should be kept as short as possible to prevent interference with other hardware floating in the microgravity environment. Another form of patient monitoring that has been considered is a “trauma pod” that could be rapidly deployed and transported and provide restraint for the operator and the patient [37]. Such a trauma pod could be used for advanced cardiac and trauma life support operative procedures as well as for more routine medical examinations. The pod would contain surgical hardware, instruments, and supplies for logistical efficiency and rapid deployment, and it would reduce the intense labor required to perform a procedure in weightlessness. By providing routing interfaces, the trauma pod concept would also ease the difficulties caused by wires and medical tubing in weightlessness that interfere with even a simple

Surgical Endoscopy The feasibility of performing a laparoscopy in microgravity has been questioned, with concerns focusing on the potential for impaired visualization from the lack of bowel retraction in the absence of gravity and from floating debris such as blood. In response to these concerns, parabolic flight experiments were designed to investigate the feasibility of performing laparoscopy and thorascopy on anesthetized animals in simulated microgravity [38]. These experiments showed that use of sophisticated endoscopic surgical tools is indeed feasible and valuable in weightlessness but only when the CMO has the ability, training, and experience to use them and when the necessary supporting functions are in place. Cavitary endoscopy in microgravity also has the advantage of acting as a natural containment bubble that protects the operative site from the high-particulate spacecraft atmosphere and contains surgical debris and fluids. Laparoscopic surgery has been performed successfully in parabolic flight. Visualization was not impaired, apparently because of the elastic mesentery tethering the bowel and the surface tension forces present that cause any surgical debris and blood to adhere to the abdominal wall [39]. In microgravity, the

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bowel does not float within the abdomen or fall into the pelvis, as it would in 1-G, because of this mesenteric influence, which although minor in the presence of gravity, becomes predominant in microgravity. In 1-G, the abdominal cavity in a supine individual forms a flattened oval because of the weight of that person’s anterior abdominal wall. The round shapes assumed during microgravity increase the anterior-to-posterior diameter and are better suited for laparoscopic visualization and manipulation because they increase the laparoscopic domain. Thorascopy, on the other hand, was found to be extremely difficult in weightlessness because of the loss of the gravitational retraction of the mediastinum, which is critical to visualization. More complicated techniques such as selective bronchial intubation and chest insufflation will probably be required to make thorascopy a feasible procedure. The technical difficulty of establishing a pneumoperitoneum without the high risk of bowel perforation, the miniaturization of laparoscopic support hardware, and the availability of laparoscopically trained CMOs are other issues that prevent laparoscopy from being a practical component of any present in-flight medical care system. Also, because large amounts of support equipment and specialized laparoscopic instruments are required to perform even a simple laparoscopic procedure, such a capability would be difficult to justify in a medical care system that has strict weight and volume limitations. More important, laparoscopy requires considerable experience and proficiency and is usually performed only by highly trained surgeons. This requirement would severely limit CMO selection. The ability to treat surgical complications that might arise would likewise be limited in a remote medical care system. On Earth, the incidence of laparoscopic complications depends greatly on the experience of the operator. Nevertheless, future development of technologies could well make laparoscopy in weightlessness more feasible. The most important of these developments would be miniaturization of the large, bulky support equipment, such as the video monitor, video camera, insufflator, and fiber-optic light source. Minimally invasive surgery can have the substantial potential advantage of requiring only local anesthesia. In the future, these procedures may be performed with abdominal wall lift devices that would eliminate the need for CO2 insufflation. The effect of such retracting lift devices is to pull the anterior abdominal wall anteriorly, thereby enlarging the volume of the intra-abdominal cavity while mesenteric attachments maintain the bowel in place. This approach would greatly simplify the procedure and reduce the logistical support required. Methods of controlling hemorrhage that are easier than endoscopic suturing include the use of fibrin glue injectors, laser technology, and advanced stapling devices. Replacing the video display with three-dimensional stereoscopic, virtualreality headgear and with remote surgical telerobotics is also actively being investigated [40–44]. Telerobotics and telepresence will allow a logarithmic increase in surgical precision, because a 1-cm (0.4-in.) control input can be translated into a

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1-mm (0.04-in.) manipulation at the surgical site. Teleprescence surgery could also allow a surgical procedure to be performed at a remote location. Telerobotics can enhance both images and dexterity in a surgical procedure, but telerobotics currently requires enormous hardware logistics and extensive training even for the on-site personnel. These techniques also naturally lend themselves to real-time telemedicine consultation and telementoring if no communication delays are present [45]. Unfortunately, use of these techniques in space will be limited by the long communication delays that make them impractical; even the 2-s delay that occurs in low-Earth orbit (owing to indirect satellite routing) is crippling to the performance of remote telerobotic surgery. Endoscopic urologic stenting to treat ureterolithiasis in conjunction with telemedicine monitoring has been shown to be feasible in parabolic flight [46]. On Earth laparoscopic surgery has rapidly evolved into a system that is technically easier, consistently more successful, and more broadly applicable. In future long-duration space exploration missions, the presence of more surgically capable CMOs will allow laparoscopic procedures to be performed instead of open surgical procedures.

Experience with Surgical Procedures in Space In April 1998, the crew of the Space Shuttle STS-90 Neurolab mission performed the first survivable surgical procedure on animals in space. In this procedure, a leg wound was created in adult rats to inject an isotope tracer in the rats’ thigh muscle. The wound was then closed with Dermabond adhesive. Other, more complicated surgical dissections (i.e., craniectomy, C-section, laminectomy with spinal cord removal) were also performed on adult rats that did not survive by experimental design. The results of the Neurolab mission validated several concepts of surgery in space. First, the surgical procedures within the scope of the Neurolab experiments were no more difficult to perform in microgravity than in 1-G. Second, the surgical procedures that were performed in space flight were similar to those performed in parabolic flight, thus validating the parabolic research model. Third, space flight was not associated with any changes in surgical dexterity, proprioception, or fine hand-muscle motor control. Fourth, good restraint of the patient, operator, and all of the equipment was, as expected, of utmost importance. Fifth, surgeons must anticipate logistics and diligently restrain all equipment, supplies, instruments, and discarded trash. For this reason, procedures will take longer to perform in microgravity than in 1-G. Sixth, in the absence of gravity, fluids coalesce and do not disperse because surface tension forces predominate; thus blood and other body fluids were easy to control by using simple measures such as sponging. Seventh, special care was needed in the use of sharp objects such as scalpels and needles; simple measures, such as

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calling out “sharps on deck,” increased the safety awareness of the surgical team. Finally, no subjective gross changes in wound healing were noted; however, no objective measures of wound healing were used. As noted by Dr. David Williams of the Canadian Space Agency, who served as a crewmember on the Neurolab mission, if appropriate restraints are provided, surgical procedures are feasible if the individual operator has adequate 1-G surgical skills.

Limitations to Surgical Care in Space Successful surgical care on Earth depends on many factors, including the diagnostic capability that is available, preoperative preparation, intraoperative logistical support, ability to provide postoperative care, and the availability of specialty consultations and safe medical evacuation to a center that can provide more definitive medical care as needed. The presence of a surgeon who is well-trained, technically skillful, and proficient is also an important determinant. Surgical care in space will, by necessity, have limitations, including the skill level of the surgical operator, the available medical hardware, the altered environment of microgravity, and the state of the physiologically compromised patient. Regardless of the Earth-based surgical capabilities and experience of an operator, that operator’s technical skills may well be limited by changes in proprioception, a lack of experience in operating in a microgravity environment, and the need to be restrained in microgravity. From the experience gained thus far from parabolic flight and space flight, the time required to perform a given operation in low Earth orbit is estimated to increase by a factor of 1.5–3 because of the need for restraint, meticulous control of bleeding, and careful specialized handling of logistics and fluids. This situation may be worse on exploration missions, where ground resources are even more remote. On a Mars expedition, for example, the delay in communications will limit the utility of consultation. Moreover, in that setting, evacuation to a facility that could provide a higher level of care or more definitive care will not be an option. The medical care system infrastructure will therefore obviously be limited in diagnostic and therapeutic options.

Need for Specialized Equipment Medical and surgical hardware must be accurate, reliable (as remote repair will be difficult), simple (as expert operators will be unavailable), and have very long lifetimes. Most hardware items will not be specifically developed for flight; rather, commercially available equipment will be only minimally modified to withstand vibration and to function in microgravity. Hardware items also must be composed of nonflammable materials that are not subject to prolonged off-gassing, which would exclude many plastics. Given the complexities of the engineering and flight certification processes, the lead time from system design to flight is often 5–10 years.

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Biological fluids in weightlessness must be evacuated, separated from air suspensions (as air–fluid levels do not exist in microgravity), collected and contained, measured, and disposed of. Active suction pumps that use rotational centrifugal force to separate gas from liquid have been studied in parabolic flight and were proposed for the Health Maintenance Facility of Space Station Freedom [13]. This concept may be revived and refined for future use on the ISS or other crewed installations.

Resource Limitations and Trade-Offs Medical and surgical hardware in space flight will always be limited because of constraints on its volume, weight, and electrical power; hence a long-duration space flight crew may encounter medical events that will overwhelm the onboard medical care system. The NASA space medicine team has carefully analyzed what medical problems are most likely to be encountered and will constitute the most serious danger to the crew and mission [47]. This research will help in designing a medical care system that will be able to handle those medical events that are most commonly encountered, have a substantial effect on crewmember health, or could affect the mission. Providing supplies and equipment for the most common and most serious medical events will enable treatment of other, less common or less serious medical events. Many rare but nonetheless serious surgical events will not be provided for, and such events could overwhelm the system’s ability to respond adequately. Many vascular injuries, for example, would be untreatable because of lack of operator expertise even though the equipment may be available. Logistics may prevent stocking the equipment to treat many orthopedic injuries, for which operator expertise may not be as critical.

Effects of Physiological Adaptation on Surgical Care The microgravity-adapted physiological state may well affect the surgical patient in terms of preoperative preparation, intraoperative response to surgical stress, and postoperative recovery [48]. The process by which the body adapts to microgravity has been relatively well described, albeit incompletely investigated. (Specific descriptions and references are given in Chap. 2.) The effects of such adaptation include cardiovascular deconditioning (10–20% loss of stroke volume), shifts in fluid and electrolyte levels, muscular deconditioning, neurovestibular deconditioning, short-term gastrointestinal disturbances, changes in pharmacokinetics, sustained calcium loss, osteoporotic changes, protein catabolism, psychological stress (which has affected medical care in previous Russian flights), radiation exposure, changes in cellular immune function that affect the immune response and wound healing, blunting of the baroreceptor response to blood pressure changes, decreased

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lung volumes, loss of red blood cell mass, and decreases of about 15% in circulating blood volume. The physiology underlying wound healing in microgravity is unknown and requires further investigation. Cellular immune functions seem to be altered and suppressed in microgravity; consistent spaceflight findings have included neutropenia; lymphocytopenia; reductions in the populations, activity, and responses of T cells; decreases in cellular motility and changes in morphologic characteristics, and decreased production of cellular mediators such as interleukins [49]. Changes in cell-mediated immunity have been demonstrated in the form of delayed cutaneous hypersensitivity [50], which certainly would affect the initial inflammatory stages of wound healing and increase the incidence of postoperative infection and sepsis. Surgical diseases with an infectious etiology, such as appendicitis, could conceivably be more prevalent incidence during a long-duration space flight. Because wound healing is essentially a cellular function, the possibility that delayed repair occurs in weightlessness needs to be explored [51]. This need is further complicated by a lack of understanding of the complex cellular processes that occur during normal wound healing. Preliminary studies of rats that have been incised on the ground before being flown in space indicate that the inflammatory phase of wound healing might be prolonged in space flight. In those studies, cellularity was decreased, collagen content was lower by 62%, and the response to exogenous stimuli (a platelet-derived growth factor) was blunted [52]. Tensiometric analysis showed decreased wound strength and abnormal arrangements of collagen fibers. Bone healing studies in rats sent aboard a Russian biosatellite have shown reduced callus formation, decreased numbers and activities of osteoblasts, and reduced angiogenesis [53]. Similar studies of rats flown on the Space Shuttle have shown delayed chondrogenesis and angiogenesis [54]. Studies of wounds created in space and healed in space have not been done. Notably, because healing is accelerated in 1-G in the rat model, any exposure to gravitational forces during flight, even for only a brief period, would render the results of such a study invalid.

Resuscitation and Patient Transport On Earth, a class I hemorrhage in a trauma patient involves a circulating blood volume loss of about 15%, which is the normal physiological state for space crewmembers on longduration flights. The combination of lower volume with cardiovascular deconditioning, blunting of the baroreceptor reflex, and loss of red blood cell mass and plasma volume decreases the ability of a spaceflight trauma patient to respond to blood loss and shock. Analogous hypovolemic effects can be replicated by the lower-body negative pressure device, a research tool used during space flight to simulate orthostatic G-load and provide a cardiovascular stressor against which to evaluate cardiovascular deconditioning (see

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Chap. 16). The decreased ability of crewmembers to tolerate lower-body negative pressure, as shown by increasing tachycardia and hypotension, after about 2 months on Skylab [55] suggests a decrease in the ability to tolerate blood loss or shock in space. A reduction in the ability to tolerate blood loss or shock during space flight may have other repercussions as well. For instance, the “golden hour,” the period immediately after significant trauma in which intervention has the greatest effect on outcome, may well be shorter in space. But even if the shock responses in weightlessness are not overly fragile as compared with Earth-normal, a medical evacuation back to Earth for definitive care could be devastating to a patient who is in shock. A crewmember undergoing a medical return on the Space Shuttle will be kept recumbent on the middeck floor and experience 1.2 G in a chest-to-back (+Gx) axis for several minutes. Extraction of such a crewmember after landing will maintain the patient in the recumbent position, as orthostatic hypotension and near-syncope are known to occur even in uninjured crewmembers on return to Earth. The Soyuz, which can also be used as an evacuation vehicle, lands with the crew in a recumbent position, exposing crewmembers to a higher peak load (4 +Gx) but for a shorter period. Research with primates involving controlled hemorrhage followed by centrifugation to mimic atmospheric reentry forces has shown that exposure to reentry acceleration forces has no adverse effects unless the hemorrhage is severe (class III or IV, or 30–50% loss of blood volume) or the forces are excessive (8 G instead of 1.8 G) [56]. Since uninjured but deconditioned crewmembers returning to Earth typically display many of the hypovolemic characteristics of a class I hemorrhage (15% loss of circulating blood volume [750 ml blood loss] manifested as minimal tachycardia and orthostatic hypotension), a true class I hemorrhage in space may respond much like a class II hemorrhage on return to Earth (i.e., 15–30% blood loss, manifested as tachycardia, tachypnea, and increased pulse pressure). Therefore, any trauma patient in space is likely to have a decreased ability to tolerate the return to 1-G during a medical evacuation. Given that deconditioning, hemorrhage, and reentry acceleration forces will all have adverse effects on a patient in shock, restoration of adequate blood volume while still in space will be critical for ill or injured crewmembers before they can be safely evacuated to Earth. The development of hemoglobin-based oxygen carriers (artificial blood) may help the care providers to resuscitate a traumatized crewmember before medical evacuation [57]. In addition to the relative hypovolemia experienced by all returning space flyers, crewmembers returning from a long-duration space flight during a medical evacuation will have an increased risk of complicating factors such as nausea and vomiting from neurovestibular effects, limited cardiac output, immunosuppression, delayed wound healing, mild anemia, weakening from muscle atrophy, and pathologic fractures.

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Management of the Surgical Abdomen

Management of Fractures

Although blunt abdominal trauma would be fairly unlikely in space flight, such an injury could be overwhelming to diagnose and treat definitively [48]. Fortunately, only 10% of all blunt traumas to the abdomen are expected to require exploratory laparotomy. The nonsurgical treatment of blunt abdominal injuries—including hepatic, splenic, and renal injuries—in patients who are hemodynamically stable is becoming more common. However, this nonoperative treatment requires sophisticated diagnostic imaging and the ability to closely monitor the patient. Moreover, it also assumes the ability to surgically intervene if conservative treatment is unsuccessful. The concept of “damage-control exploratory laparotomy” [58] in remote medical care situations can be applicable to space, given adequate skills and resources. This concept involves limited surgery to control major bleeding and enteric spillage, but it also involves a planned subsequent reoperation. The benefit from staging procedures in this way would facilitate logistical planning as well as allowing time for additional specialty consultation from the ground and possibly time to permit medical evacuation to a higher level of care. Therefore, laparoscopic trauma surgery or exploratory laparotomy should be feasible during space flight if adequate operator skills and surgical equipment are available. [59]

It is hoped that the lack of gravity will greatly decrease the overall incidence of blunt trauma and orthopedic injuries sustained by long-duration spaceflight crews. However, the lack of gravity might also make fractures more likely because of the osteoporotic condition induced by the chronic loss of calcium in weightlessness and the muscle atrophy that occurs in deconditioning. The diagnosis of fractures will be based on clinical and physical examination findings alone unless an imaging capability is present. Probably most fractures can be diagnosed and successfully treated by clinical means, without the use of diagnostic imaging. Unfortunately, the treatment of orthopedic injuries requires resources that consume large amounts of space and can negatively affect the environment of a long-duration spacecraft. Indeed, the open surgical treatment of fractures requires hardware individualized to the specific procedure. Plaster casting requires mixing plaster with water and is impractical for space flight. Fiberglass casting materials are associated with large amounts of off-gassing, which is incompatible with the closed-loop environments. Yet despite these drawbacks, most fractures can be adequately splinted and treated with simple materials such as flexible aluminized splints and elastic bandages. A universal external fixation device would suffice as an option for more complex fractures if imaging and surgical expertise were available. Fracture stabilization often requires gravity to effect or maintain reduction, and manual traction of fractures will be difficult to apply in microgravity. As is true for surgical intervention, rigid restraint of the operator and the patient will be needed, and universal external fixation devices will need to be used to treat many fractures. Experimental evidence shows that bone healing is delayed in space [52]. Moreover, many lower-extremity fractures show delays in healing if no weight is borne across the fracture site. The muscle atrophy from deconditioning could also affect fracture healing by not providing sufficient fracture-site impaction force, which normally influences the regenerative process. On the other hand, the lack of gravity may make fracture reduction easier to achieve and maintain, and injuries such as a broken leg in an astronaut or cosmonaut who does not need to bear weight on that limb may prove far less debilitating during the healing process.

Management of Chest Trauma in Space Most chest trauma can be adequately treated with chest tube drainage and supportive therapy alone. Injuries beyond this level can often require extraordinary infrastructure, logistics, and surgical skill to manage even in the conventional clinical situation. Stabilization to the extent possible and immediate transport to ground facilities would be required for such cases.

Management of Closed Head Injuries Closed head injuries might be worse in space than on Earth since weightlessness is physiologically similar to being in a continuous 6-degree head-down tilt. Intracerebral pressure has never been measured in space (although intraocular pressure has been shown to increase in weightlessness), but such an increase would adversely affect any neurologic trauma. The capability of placing burr holes in space was discussed and equipment was manifested for such a procedure during early preliminary planning for the Health Maintenance Facility on Space Station Freedom, but it has not been seriously pursued since that time.

Anesthesia Anesthesia will be more difficult to administer during space flight [60], especially if it is the responsibility of a crewmember who is not the CMO. At present, inhalation anesthetics cannot be used, as volatile gases would quickly contaminate and overwhelm the closed-loop environment of a long-duration space vehicle. Inhalation agents will always be dangerous no matter how sophisticated the anesthesia

6. Surgical Capabilities

machine is in containing the inhalation agent and scavenging the exhalation for overboard dumping. Because spinal anesthesia depends on gravity to establish the affected dermatome, it cannot be used in weightlessness. Regional and epidural blocks require skill and experience far beyond the level expected of a CMO. Intravenous anesthesia with ventilator support and monitoring should not be difficult except that it requires the full attention of a trained crewmember. Intravenous anesthesia, ventilation, and monitoring oxygenation level, end-tidal CO2, central venous pressure, and cardiac function have all been shown to be feasible in parabolic flight tests with animals. Local anesthetics present no additional difficulty in weightlessness and have been manifested in in-flight medical kits in the Russian space station programs and in the United States space program since Skylab.

Future of Surgical Care in Space Because the time to reach definitive medical care on Earth will be extremely long and rescue or medical evacuation will not be an option, future long-duration space flights—such as a Mars expedition—will require a medical care system of greater surgical capability [3]. Increased capabilities must be provided in the face of the increased limitations on surgical care expected in the long-duration weightless environment. Such capabilities will require a surgically capable CMO and an advanced life support system that will allow restraint of the patient, the operators, and all of the equipment in an integrated fashion. Laparoscopy will need to be a surgical option, as it is advantageous in terms of isolating the surgical environment and the spacecraft environment from each other. Diagnostic laparoscopy may need to be used because other diagnostic options may not be available. Laparoscopic equipment for use in space will be simpler and smaller than what is conventionally available. Techniques that avoid insufflation and provide a telemedicine downlink to surgical consultants are expected to be present on board. New technologies, such as the use of artificial blood, will be incorporated into the medical/surgical care system as they are developed for conventional use. Unconventional diagnostic techniques will occasionally be required in the spaceflight environment. Digital radiography, with downlink of data to radiological consultants, will eventually be available; however, because organ position will be altered by the weightless environment, accurate surgical diagnoses will require special consideration. Free air under the diaphragm, air–fluid interfaces in an obstructed bowel, and pneumohemothorax will probably appear radically different in space [61]. Sonographic equipment, with its lesser weight, volume, and power requirements, could be used instead of computed tomography scanning; sonography can be valuable in the initial evaluation of trauma as well

135

as in determining the presence of hemoperitoneum, hemothorax, and pneumothorax [62–64]. Whether weightlessness will limit the usefulness of sonography in detecting these entities is unknown and will require further research. Sonography in conventional settings depends on gravity to loculate fluids and air in specific portals (splenorenal recess, hepatorenal recess, and rectovestibular pouch) where they can be easily detected. Such loculation will probably be greatly diminished or absent in weightlessness, making its detection much more difficult. Recent studies of animals in parabolic flight have shown that relatively small amounts of fluid can be detected in the abdominal cavity in simulated weightlessness. Thus, fluid can be detected in the location where it is created and does not easily drain away posteriorly as it would in 1-G. Fluid was found in the usual 1-G sonographic portals (but only after the parabolic flight 2-G maneuver). Fluid can also be more readily detected in bowel interloop locations in microgravity than in 1-G [65]. Air (pneumothorax) and fluid (hemothorax) in the thoracic cavity could also be detected in weightlessness. In a conventional 1-G pneumothorax, a large anterior air pocket is created that is visible sonographically as a loss of “lung sliding.” [60,64] In microgravity, the lung is more centrally located and the pneumothorax is diffuse rather than loculated. Although this situation reduces the sensitivity of sonography in microgravity as compared with 1-G, sonography can still detect even a small pneumothorax. The fluid in the chest cavity in microgravity is more diffuse rather than being posteriorly loculated, but it can still be detected readily. Moreover, the diffuse distribution of air or fluids in weightlessness means that there is no need to place a chest tube anteriorly for a pneumothorax or posteriorly for a hemothorax. Unconventional therapy for surgical diseases will probably be necessary [65]. The nonsurgical treatment of hemoperitoneum from blunt trauma [48] and the medical (nonsurgical) treatment of acute appendicitis will be safe options if the patient can be accurately evaluated and monitored. Capability for conventional open surgical techniques will need to be available if nonsurgical or laparoscopic treatment fails. When and if a surgical procedure is performed, the surgical skills of the operator will, in large part, determine the success of the procedure.

References 1. Wilken DD. Significant medical experiences aboard Polaris submarines: A review of 360 patrols during the period 19631967. US Naval Submarine Medical Center Report 560, Groton, CT; 1969. 2. Tansey WA, Wilson JM, Schaefer KE. Analysis of health data from 10 years of Polaris submarine patrols. Undersea Biomedical Res 1979; 6 Suppl:S217–S246. 3. Campbell MR. Future surgical care in space. Surgical Services Management 1997; 3:13.

136 4. Campbell MR. Surgical care in space. Tex Med 1998; 94:69–74. 5. Campbell MR. Surgical care in space. Aviat Space Environ Med 1999; 70:181–184. 6. McGinnis P, Harris B. The re-emergence of space medicine as a distinct discipline. Aviat Space Environ Med 1998; 69: 1107–1111. 7. Davis JR. Medical issues for a mission to Mars. Aviat Space Environ Med 1999; 70:162–168. 8. Musgrave S. Surgical aspects of space flight. Surg Annu 1976; 8:1–23. 9. Barratt MR. Medical support for the international space station. Aviat Space Environ Med 1998; 70:155–161. 10. Campbell MR, Billica RD, Johnston SL 3rd, et al. Performance of advanced trauma life support procedures in microgravity. Aviat Space Environ Med 2002; 73:907–912. 11. Boyce J. Medical care and transport in space flight. Problems in Critical Care 1990; 4:534–555. 12. Billica RD, Doarn CR. A health maintenance facility for space station Freedom. Cutis 1991; 48:315–318. 13. Houtchens B. Medical care systems for long duration space missions. Clin Chem 1992; 39:13–21. 14. McCuaig K, Houtchens B. Management of trauma and emergency surgery in space. J Trauma 1992; 33:610–625. 15. Rice BH. Conservative nonsurgical management of appendicitis. US Naval Submarine Medical Center Report 444, Groton, CT; 1969. 16. Glover SD, Taylor EW. Surgical problems presenting at sea during 100 British Polaris submarine patrols. J R Nav Med Serv 1981; 67:65–69. 17. Lugg DJ. Antarctic epidemiology: A survey of ANARE stations 1947–1972. In: Polar Human Biology. Chicago, IL: Year Book Medical Publishers; 1974:93–105. 18. Satava RM. Surgery in space. Phase I: Basic surgical principles in a simulated space environment. Surgery 1988; 103:633–637. 19. Stazhadze LL, Goncharov IB, Neumyzakin IP, et al. Anesthesia, surgical aid and resuscitation in manned space missions. Acta Astronautica 1981; 8:1109. 20. Yaroshenko GL, Terentiev VG, Mokrov MN. Characteristics of surgical intervention in conditions of weightlessness. Voenn Med Zh 1967; 10:69–70. 21. Campbell MR, Billica RD, Johnston SL. Animal surgery in microgravity. Aviat Space Environ Med 1993; 64:58–62. 22. Campbell MR, Billica RD, Johnston SL. Surgical bleeding in microgravity. Surg Gynecol Obstet 1993; 177:121–125. 23. McCuaig K. Aseptic technique in microgravity. Surg Gynecol Obstet 1992; 175:466–476. 24. McCuaig K. Surgical problems in space: An overview. J Clin Pharmacol 1994; 34:513–517. 25. Campbell MR, Dawson DL, Melton S, et al. Surgical instrument restraint in weightlessness. Aviat Space Environ Med 2001; 72:871–876. 26. McCuaig K, Lloyd C, Gosbee J, et al. Simulation of blood flow in microgravity. Am J Surg 1992; 164:114–123. 27. Mutke HG. Equipment for surgical interventions and childbirth in weightlessness. Acta Astronautica 1981; 8:399–403. 28. Campbell MR, Billica RD. A review of microgravity surgical investigations. Aviat Space Environ Med 1992; 62:524–528. 29. Markham SM, Rock JA. Microgravity testing of a surgical isolation containment system for space station use. Aviat Space Environ Med 1991; 62:691–693.

M.R. Campbell and R.D. Billica 30. Markham S, Rock J. Deploying and testing an expandable surgical chamber in microgravity. Aviat Space Environ Med 1989; 60: 76–79. 31. Rock J. An expandable surgical chamber for use in a weightless environment. Aviat Space Environ Med 1984; 55:403–404. 32. Rock JA, Fortney SM. Medical and surgical considerations for women in spaceflight. Obstet Gynecol Surv 1984; 39: 525–535. 33. Colvard MD, Kuo P, Caleb R. Laser surgical procedures in the operational KC-135 aviation environment. Aviat Space Environ Med 1992; 63:619–623. 34. Schweitzer EJ, Hauer JM, Swan KG, et al. Use of the Heimlich valve in a compact autotransfusion device. J Trauma 1987; 27: 537–542. 35. Mattox KL, Walker LE, Beall AC, et al. Blood availability for the trauma patient—Autotransfusion. J Trauma 1975; 15:663–669. 36. Rumisek JD. Autotransfusion of shed blood: An untapped battlefield resource. Mil Med 1982; 147:193–196. 37. Campbell MR. Surgical care in space: A review. J Am Coll Surg 2002; 194:802–812. 38. Campbell MR, Kirkpatrick AW, Billica RD, et al. Endoscopic surgery in weightlessness: The investigation of basic principles for surgery in space. Surg Endosc 2001; 15:1413–1418. 39. Campbell MR, Billica RD, Jennings R, et al. Laparoscopic surgery in weightlessness. Surg Endosc 1996; 10:111–117. 40. Satava RM. 3-D Vision technology applied to advanced minimally invasive surgery systems. Surg Endosc 1993; 7:429–431. 41. Green PS, Piantaniada TA, Hill JW, et al. Teleprescence: Dexterous procedures in a virtual operating field. Am Surg 1991; 57:192. 42. Satava RM, Green PS. The next generation: Telepresence surgery—Current status and implications for endoscopy. Gastrointest Endosc 1992; 38:277. 43. Bowersox JC, Cordts PR, LaPorta J. Use of an intuitive telemanipulator system for remote trauma surgery: An experimental study. J Am Coll Surg 1998; 186:615–621. 44. Bowersox JC. Telepresence surgery. Br J Surg 1996; 83:433– 434. 45. Satava RM. Minimally invasive surgery and its role in space exploration. Surg Endosc 2001; 15:1530. 46. Jones J, Johnston S, Campbell M, et al. Endoscopic surgery and telemedicine in microgravity: Developing contingency procedures for exploratory class space flight. Urology 1999; 53: 892–897. 47. Billica RD, Simmons SC, Mathes KL, et al. Perception of medical risk of spaceflight. Aviat Space Environ Med 1996; 67:467– 473. 48. Kirkpatrick AW, Campbell MR, Novinkov OL, et al. Blunt trauma and operative care in microgravity: A review of microgravity physiology and surgical investigations with implications for critical care and operative treatment in space. J Am Coll Surg 1997; 184:441–453. 49. Taylor G, Neale L, Dardano J. Immunological analysis of U.S. Space Shuttle crewmembers. Aviat Space Environ Med 1986; 57:213–217. 50. Taylor G, Janney R. In vivo testing confirms a blunting of the human cell-mediated immune mechanism during spaceflight. J Leukoc Biol 1992; 51:129–132. 51. Sears JK, Arzenyi ZE. Cutaneous wound healing in space. Cutis 1991; 48:307–308.

6. Surgical Capabilities 52. Davidson J, Aquino A, Woodward S, et al. Sustained microgravity reduces intrinsic wound healing and growth factor responses in the rat. FASEB J 1999; 13:325–329. 53. Kaplansky A, Durnova G, Burkovskaya T, et al. The effect of microgravity on bone fracture healing in rats flown on Cosmos 2044. Physiologist 1991; 34:S196–S199. 54. Kirchen ME, O’Connor KM, Gruber HE, et al. Effects of microgravity on bone healing in a rat fibular osteotomy model. Clin Orthop 1995; 318:231–242. 55. Johnson RL, Hoffler GW, Nicogossian AE, et al. Lower body negative pressure: Third manned Skylab mission. In: Johnston RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC: US Government Printing Office; 1977:284– 312. NASA SP-377. 56. Hamilton GC, Stepaniak PC, Stizza D, et al. Considerations for medical transport from space station via assured crew return vehicle (ACRV). Unpublished final report, NASA Grant NAG-9-263, 1989. 57. Kirkpatrick AW, Dulchavsky SA, Boulanger BR, et al. Extraterrestrial resuscitation of hemorrhagic shock: Fluids. J Trauma 2001; 50:162–168. 58. Hirschberg A, Mattox K. “Damage control” in trauma surgery. Br J Trauma 1993; 80:1501–1502.

137 59. Kirkpatrick AW, Campbell MR, Brenneman FD, et al. Trauma laparotomy in space: A discussion of the potential indications, conduct of operation, and technical support for the treatment of abdominal trauma during long-duration space exploration. Presented at the 28th International Conference of Environmental Systems, Danvers, MA, 13–16 July 1998. SAE Technical Paper Series 981601. 60. Norfleet W. Anesthetic concerns of spaceflight. Anesthesiology 2000; 92:1219–1222. 61. Hart R, Campbell MR. Digital radiography in space. Aviat Space Environ Med 2002; 73:601–606. 62. Rozzyski G, Ochsner M, Jaffin J, et al. Prospective evaluation of surgeon’s use of ultrasound in the evaluation of trauma patients. J Trauma 1993; 34:516–527. 63. Sargsyan AE, Hamilton D, Kirkpatrick AW, et al. Ultrasound evaluation of the magnitude of pneumothorax: A new concept. Am Surg 2001; 67:232–236. 64. Dulchavsky S, Schwartz K, Hamilton D, et al. Prospective evaluation of thoracic ultrasound in the detection of pneumothorax. J Trauma 1999; 47:970–971. 65. Kirkpatrick AW, Nicolaou S, Campbell MR, et al. Percutaneous aspiration of fluid for management of peritonitis in space. Aviat Space Environ Med 2002; 73:925–930.

7 Medical Evacuation and Vehicles for Transport Smith L. Johnston, Brian A. Arenare, and Kieran T. Smart

Space is a uniquely remote and hazardous environment. For humans to live and work effectively in low earth orbit (LEO), significant technological support must be provided to overcome the physical and psychological challenges of space flight. This operational environment places great demands on a crew, particularly during emergency situations, where the life of a crewmember may rest in the hands of a colleague or a Crew Medical Officer (CMO). In four decades of human space flight and exploration, our knowledge, activities, and capabilities have grown tremendously. In nearly 70 person-years of the world’s various agencies, medical treatment of ill or injured crewmembers has been required with a low yet regular frequency. Between 1971 and 2005, one evacuation, two early returns to earth, and several emergent medical events have occurred during space flight. From this experience and that of analogous remote environments, it is possible to estimate the likelihood of a serious medical event, defined as one that would require emergency room care in a terrestrial setting, for a crew aboard a low earth-orbiting platform such as the International Space Station (ISS). For a full crew complement of six or seven individuals, as is ultimately planned for the ISS, such a medical contingency may be anticipated to occur, on average, approximately once every two and a half years. Most of these would likely be managed using onboard medical capabilities. The likelihood of a critically ill or injured crewmember requiring transport to a terrestrial definitive medical care facility (DMCF) is estimated to be lower—once or twice over the planned 15-year lifespan of the ISS. Whether in a terrestrial, aviation, ship-borne, or space environment, the priorities of triage and the principles of medical evacuation remain constant. These priorities are predicated on several factors [1]: Severity of the illness or injury Environmental conditions at the scene and during medical transport ● Capabilities and proficiency of the first responders ● Available medical care, equipment and capabilities ● Telecommunications capabilities ● ●

Safety and performance of the transport vehicle Time and duration of medical transport ● Safety of the transport flight profile ● Onboard medical capabilities during transport ● Medical capabilities of the receiving facility ● ●

These factors affect the care of ill or injured patients in any environment, from large urban areas to small community hospitals and clinics, as well as remote isolated environments such as cruise ships, submarines, oil platforms, military deployments, wilderness base camps, and low earth orbit (LEO) platforms like the ISS. Shen has described clinical care in such remote environments as “fourth-world medicine,” which he defines to be clinical practice in a remote, hazardous environment with advanced technology diagnostic, therapeutic, and evacuation capabilities to augment limited medical officer training and support [2]. This chapter will examine key aspects of present-day terrestrial and spaceflight medical transport and evacuation, enumerate current challenges, and suggest possible solutions for future spaceflight activities [3–5]. We will discuss present and future standards of care on the ISS, and current vehicles including the Russian Soyuz and the U.S. Space Shuttle. We will also address programs such as the NASA-JSC X-38, and the Orbital Space Plane (OSP) [6–9]. These concepts are applicable to the development of future platforms such as the CEV (Crew Exploration Vehicle). Topics addressed will include: 1. Likelihood and types of spaceflight medical events requiring evacuation [10] 2. Standards of spaceflight medical care and projected capabilities for LEO space stations, lunar exploration, and inter-planetary missions [11] 3. Physiological de-conditioning of astronauts returning from long duration microgravity exposure 4. Psychological aspects of crew performance in medical emergencies after long duration space flight 5. Inherent risks associated with spaceflight medical evacuation due to the microgravity environment and the dynamics of reentry and landing [12,13]

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6. Medical requirements and capabilities of an LEO transport and return vehicle [14,15] 7. Human factors for crew work stations in vehicles such as the crew return vehicle (CRV) 8. Ethical issues and medical standards for evacuation from LEO and other space environments where return to definitive medical care is delayed or impossible (such as a Mars surface station).

Evidence-Based Evacuation Risk—The Need for Transport Longer duration missions aboard the ISS require planning for a variety of potential adverse medical events. These events include possible medical evacuations, both urgent and anticipated. As previous missions have shown, no matter how carefully a spaceflight crew is selected, screened, and medically supported, illness, accidents, life support system malfunctions, and logistic support problems may still occur. Though every effort is made to limit these risks, a medical event that exceeds onboard medical support capabilities should be anticipated and programmed as far as possible. Risk analysis is the first step in any medical contingency planning and is essential to justify allocation of time and resources. Successful planning could determine the difference between serious inflight morbidity or mortality and a favorable outcome with expedient and appropriate evacuation to a DMCF on earth. Since human space exploration began with the launch of Yuri Gagarin on Vostock 1 on April 12, 1961, more than 400 astronauts and cosmonauts have flown. Twenty-one fatalities have occurred to date from five catastrophic events, along with multiple other mishaps that could have potentially resulted in fatality [16,17]. Launch aborts, aborts to lower than planned orbits, and mishaps during reentry have each presented lifethreatening circumstances, and in several cases resulted in fatalities. A chronology of these spaceflight events, including flight contingencies, fatalities, near-fatalities, and significant medical events, is detailed in Table 7.1 [18]. While this list is not comprehensive, these events illustrate the complex human hazards associated with the spaceflight environment and the variety and nature of risks. The range of events described in Table 7.1 illustrates the medical scenarios that are addressed by three basic Design Reference Missions (DRM) used by NASA as operational and development guidelines for an emergency transport vehicle [19]: DRM-1—Loss of crew return or re-supply capability, e.g., loss of nominal transportation vehicle (Shuttle or Soyuz from the ISS) ● DRM-2—Escape from a time-critical ISS emergency, e.g., fire, decompression, environmental control system failure ● DRM-3—Full or partial crew return due to a medical emergency ●

S.L. Johnston et al.

The DRM-3 or medical evacuation mission will be the primary focus of this chapter. A DRM-2 scenario also carries the possibility of one or more crewmembers becoming ill or injured while evacuating from a time-critical event such as a fire, a contaminated station atmosphere, or a rapid decompression. This requires a transport/evacuation vehicle to have some stand-alone emergency medical equipment, along with cabin purge and atmospheric scrubbing capabilities. Due to airway reactivity from potential contaminant exposures, the vehicle’s stand-alone medical kit should be heavily augmented for respiratory problems. Such an event actually happened to three American astronauts returning from the Apollo-Soyuz mission in 1975. The Apollo crew was exposed to nitrogen tetroxide (N2O4) gas when inadvertent reaction control system (RCS) firings allowed the gas to enter the command module through the cabin relief valve, which was open during landing. All three crewmembers required 100% oxygen, anti-inflammatory medication, and bronchodilator therapy after landing, and were hospitalized for chemical pneumonitis for three to seven days.

Medical Event Risk Analysis Using Analog, Mir Cosmonaut, and Astronaut Populations Epidemiological risk data obtained from ground-analog populations, cosmonauts in long duration space flight, analog military and civilian populations, and data gathered by NASA Medical Operations since 1959 on astronauts, provide a source of representative medical events that might occur aboard a space station. The extrapolation of ground-based data to the space environment must be qualified for several reasons. At best, ground-based study populations can be only rough analogs to astronauts and cosmonauts. Space flight poses unique operational and occupational risks that are not duplicated on the ground and which are compounded by isolation from medical attention and preventive measures that might be used on earth. As a result, only approximate estimates can be made in attempting to predict frequency and type of medical events and their potential mission consequences in future LEO space activities or during a voyage to the Moon or Mars. To facilitate contingency planning, medical event incidence rates, expressed as events per person-year, are generated to anticipate the likelihood of a possible evacuation occurrence for a crew of up to seven onboard the ISS. We consider three examples of risk models derived from unique populations. The first is a ground-based analog population representing medical evacuations from the U.S. National Science Foundation’s (NSF) Polar Medicine Program at McMurdo Antarctic Station [20]. The second involves hospitalizations among U.S. astronauts from 1959 to the present. The third looks at actual Russian cosmonaut inflight events and evacuation data from 1971 to 1999.

7. Medical Evacuation and Vehicles for Transport

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TABLE 7.1. Spaceflight contingencies, morbidity and mortality, 1961–2003. Date

Mission

3/23/61

Soyuz ground test

5/16/63

Mercury 9

3/18/65 – 3/19/65

Voskhod 2

3/16/66

Gemini 8

6/5/66

Gemini 9

1/27/67

Apollo 1

4/24/67

Soyuz 1

1/18/69

Soyuz 5

4/11/70 – 4/17/70

Apollo 13

4/23/71 – 4/25/71

Soyuz 10

6/29/71

Soyuz 11

12/72 4/5/75

Apollo 17 Soyuz 18-A

7/24/75

Apollo-Soyuz

8/24/76

Soyuz 21/Salyut 5

10/16/76

Soyuz 23

11/11/82 9/26/83

Salyut 7 Soyuz T-10

6/85 – 9/85 11/21/85

Soyuz T-13 Salyut 7

1/28/86

STS-51L

1987

Mir 2

6/91

STS-40

1995

Mir 18

1995 1996

Mir 18 Mir 22

2/23/97

Mir 23

1997

Mir 23

6/25/97

Mir 23

2/98

Mir 24

2/1/2003

STS-107

Description Cosmonaut Bondarenko died on March 23, 1961 in a spacecraft simulator fire with 100% oxygen environment. Elevated CO2 levels and loss of power to control system, required manual reentry. Manual deorbit, and service module failed to separate during reentry, landed 1,200 miles off target. Crew rescued next day. Docked vehicles rotated out of control near structural limits. Crew landed early—waited overnight before ocean recovery. Astronaut’s helmet faceplate continually fogged over during EVA, impairing vision. Fire in crew module during ground test, with 100% oxygen environment. Three crewmembers, Chaffee, Grissom, and White, perished. Parachute system did not deploy after reentry; capsule destroyed on impact, resulting in death of cosmonaut Komarov. Spacecraft tumbled during entry, landing 2,000 km off target, with hard impact. Cosmonaut had minor injuries. Mission to moon aborted after oxygen tank ruptured. Crew returned safely. One crewmember developed urosepsis. Failed docking with Salyut 1. During landing Soyuz air supply became contaminated and cosmonaut lost consciousness. Cabin pressure failure during reentry. Three crewmembers, Dobrovolsky, Volkov, and Patsayev perished. Back strain from drilling core sample during walk on lunar surface. Launch vehicle malfunction, second stage abort subjecting crew to nearly 20 +Gx. Crew landed in Eastern Russia, rescued the next day. Crewmember suffered minor internal injuries. Apollo crewmembers developed airway reactivity/pneumonitis from toxic contaminants during reentry, requiring hospitalization Mission curtailed due to crewmember illness—related to Environmental Control Systems problem After failure to dock with Salyut 6, capsule landed in blizzard conditions at night onto ice-covered Lake Tengiz; rescue team unable to recover capsule until next morning. Acute abdominal pain probable kidney stone, resolved on-orbit. Launch abort due to pad fire, crew landed safely via capsule escape system. Hypothermia and CO2 toxicity during reactivation of Salyut 7. Crewmember became ill with prostatitis and urosepsis. Return to earth required 56 days into a 216-day mission. Solid rocket booster seal failure resulted in Shuttle destruction 73 s into flight. Seven crewmembers perished (Jarvis, McCauliffe, McNair, Onizuka, Resnik, Scobee, Smith) Crewmember developed tachy-dysrhythmia during EVA, returned early on next mission of opportunity. Freezer motor malfunction causing formaldehyde toxicity and headaches, exacerbated by cabin noise Crewmember experienced episode of asymptomatic, sustained ventricular tachycardia. No mission impact. Traumatic eye injury resolved with onboard treatment. One week preflight crewmember developed EKG changes and was disqualified from the mission. Fire due to oxygen generator; smoke and potentially toxic fumes in station. Mild second degree burns and reactive airway changes. Onboard treatment given. Three crewmembers experienced upper airway irritation and dermal reaction following exposure to ethylene glycol. Progress re-supply vehicle collided with Spektr module during manual docking, resulting in station depressurization. Three crewmembers exposed to elevated carbon monoxide, with headache symptoms. Space Shuttle Columbia was destroyed on entry, all crew were lost (Anderson, Brown, Chawla, Clark, Husband, McCool, Ramon).

Source: Data from NASA records and Gonzales et al. [66]; Percy and Raasch [81]; Manley et al. [82]; Burluka and Dimitiadi [93].

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Antarctic stations provide useful study analogs for space exploration programs. The Antarctic environment is one of the most extreme on earth, with temperature and humidity at the South Pole more similar to that on Mars than to the rest of earth [21]. Like spaceflight missions, the remoteness of Antarctic stations requires that they have stand-alone medical care capabilities. Evacuation capabilities are limited and may be non-existent for up to eight months due to weather, seasonal lighting, and sea-ice conditions. Additionally, their populations are medically screened and have epidemiological characteristics similar to those of spaceflight populations [22,23]. Since 1954, the NSF Polar Program, with its three polar stations, has averaged one fatality each year [24]. The largest Antarctic station is McMurdo, typically with 1200 occupants during the four austral summer months (November to February) and 125 occupants during the eight winter-over months (March to October). The station has no evacuation capabilities during the winter season. In 1998, a physician at the station was diagnosed with breast cancer and began chemotherapy treatment prior to evacuation. A dangerous winter airdrop of chemotherapy agents and ultrasound equipment was partially successful, as only the chemotherapy agents survived the drop to remain intact. This experience underscores the remoteness and inaccessibility of such a location and suggests a need for more than a single expeditionary medical officer to be trained, in the event this individual becomes ill, injured, or otherwise incapacitated. Medical evacuation rates at McMurdo Station have been studied retrospectively over a five-year period from 1992 to 1996 [25]. Over five summer deployments, each of four months duration, 71 total medical evacuations took place. These are summarized by disease or pathology category in Table 7.2. Each summer deployment (20 months cumulative time) consisted of 1,200 individuals, yielding 2,000 total person-years for analysis. The incidence of medical evacuation from McMurdo station is calculated as 3.55 evacuations per operational month, equivalent to a five-year average annual incidence of 0.036 evacuations per person-year overall. With roughly comparable medical capabilities of McMurdo station and ISS, the evacuation rates for the space station can be approximated. Extrapolating from the Antarctic analog population to a full ISS crew of seven yields an estimate of approximately 0.25 evacuations from ISS per year. Thus, a possible evacuation event might be anticipated to occur onboard ISS about once every four years for the full crew complement in this model. Were a flight-ready aircraft maintained at McMurdo at all times, the ISS analogy would be more accurate. From McMurdo, minimal round-trip aeromedical transport time, from request for transfer to arrival at the referral DMCF in Christchurch, New Zealand, is 20 h at best. Flight time by C130 Hercules aircraft is about 15 h, but due to weather, the need for ground preparation prior to transportation, and margin for equipment failure, actual transport time is often greater

S.L. Johnston et al. TABLE 7.2. Incidence of medical evacuation events from McMurdo Station, Antarctica 1992–1996 (Total = 71). Category Trauma (by system) Orthopedic Surgical Dental Ophthalmology Neurology Cardiopulmonary Arrhythmia Angina Pneumonia Pulmonary embolism Lung carcinoma Dental Conditions Internal Medicine Insulin dependent diabetes mellitus Deep vein thrombosis Other Ob-Gyn Breast disorders Gynecology Genito-Urological Kidney stone Testicular carcinoma Prostatitis Urinary tract infection Psychiatric Surgical Neurology

Number (%) 34 (48%) 23 5 3 2 1 8 (11%) 2 3 1 1 1 7 (10%) 6 (8%) 2 1 3 5 (7%) 4 1 4 (6%) 1 1 1 1 3 (4%) 2 (3%) 2 (3%)

Source: Data from: Billica et al. [28].

than 48 h. By comparison, the approximate time required for a Shuttle to be prepared on demand for a LEO emergency evacuation attempt is likely to be not less than thirty days. During the early design evaluations of Space Station Freedom and up to the Challenger tragedy of 1986, Shuttle evacuation from the space station was considered an optimum method of emergency crew return. However, later program reevaluation assessed this option as no longer viable for emergency rescue [26,27]. It is apparent that an existing onsite return capability, as with the Soyuz spacecraft on ISS, compared to a requirement for dispatch of a rescue craft when a medical event occurs, offers clear logistical advantages. In many respects, the medical events that would necessitate evacuation from the Antarctic station are similar to several of the serious medical events associated with space flight (Tables 7.2 and 7.3) [28]. We can anticipate that treatment capabilities required for rescue from the ISS will be roughly analogous to those of McMurdo station, though there will be unique differences due to microgravity. Both are isolated outposts, where rescue is difficult at best and impossible at times and where medical treatment will be required onsite. It should be noted, however, that in the event of a medical evacuation, the Soyuz is not comparable to a C-130 with dedicated medical equipment and personnel onboard.

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TABLE 7.3. Representative non-fatal significant medical events during space flight (1961–1999). Total = 20. (U.S. and Russian events summarized from Table 7.1). Category Trauma Orthopedic Skin exposure to glycol Second degree burns Other Cardiopulmonary Dysrhythmias Toxic inhalation/pneumonitis Reactive airway disorders Internal medicine Chronic headache Cellulitis upper extremity Other unspecified GU Renal stone Prostatitis Urosepsis a

Number of events 1 1 1 1

TABLE 7.4. ISS medical event classification. Class Class I medical event Class II medical event Class II a

Class II b

3a 3 3

Class II c

1a 1 1

Class II x

1 1a 2

Class III medical event

Early crew return due to event in this category.

Significant medical events occurring during space flight have generally not been related to orthopedic or surgical trauma. More common, for example, are respiratory problems due to atmospheric contamination in the closed cabin environment. Morbidity from gravity-based events on earth (e.g., falls) and other accidental injuries (e.g., motor vehicle accidents) is not represented in weightlessness. Additionally, common metabolic conditions such as insulindependent diabetes mellitus, which would have been noted in the astronaut population by thorough pre-flight medical screening and evaluation, are very unlikely to occur during space flight of moderate duration. Medical screening standards are therefore an important factor in medical risk analysis and are discussed in Chap. 3. An even more valuable study population than Antarctic winterover crew is of course the astronauts themselves, though the astronaut population sample size is a limitation. A study conducted in 1999 to estimate the occurrence, type, and severity of injury and illness onboard the ISS used retrospective data review of records from the NASA JSC Longitudinal Study of Astronaut Health (LSAH) to characterize astronaut hospitalizations [29]. The LSAH archives comprise hospitalization data collected from 1959 to the present. A group of NASA and Canadian Space Agency (CSA) flight surgeons evaluated non-flight injuries and illnesses sustained by active astronauts during normal activities. Classification criteria were developed according to likelihood, mission impact, and medical management required if the disorder occurred during space flight (Table 7.4). Each event was characterized according to whether, if it had occurred inflight, satisfactory treatment could have been accomplished utilizing the Health Maintenance System (HMS), a component of the Crew Health Care System (known as CHeCS), currently deployed on ISS.

Description No mission impact, e.g. minor muscle strain. Significant medical event requiring use of the ISS HMS. Manageable with the HMS and not likely to require evacuation or affect mission duration, e.g. prostatitis. Manageable with the HMS but may require the astronaut to return at next available opportunity for further evaluation and treatment, e.g. breast mass. Manageable with the HMS but may necessitate emergent evacuation if condition does not improve or worsens, e.g. cardiac dysrhythmia. An event unlikely to occur in a microgravity environment or one that would be detected in a pre-mission evaluation, e.g. herniated nucleus pulposis. An event requiring emergent evacuation from the ISS, e.g. acute appendicitis, cerebral hemorrhage.

The results, shown in Tables 7.5–7.7, describe the individual medical events. There were a total of 88 hospitalizations distributed among active U.S. astronauts between 1959 and 1999. This 40-year time period represents a total of 2,715 person-years. An estimate of potential evacuation events applicable to the ISS setting can be made by subtracting from the total hospitalizations the Class II x events (n = 13) that are either unlikely to occur in a microgravity environment or that would be detected and effectively screened out in a pre-mission evaluation. The anticipated evacuation incidence is about 0.02 events per person-year. If it is assumed that an onboard HMS can be used to manage events that would otherwise require evacuation (Class II c, n = 15) the anticipated evacuation incidence is reduced further and may approach about 0.01 per person-year. In effect, availability of an onboard HMS can significantly decrease the likelihood of a medically necessary evacuation. The importance of a well-equipped and staffed onboard medical system for risk mitigation is evident. The most useful and directly applicable data for estimating spaceflight medical evacuation risk stems from careful analysis of actual spaceflight medical events. The Russian space program has returned three cosmonauts prematurely for medical reasons in 41.5 person-years of space flight, resulting in an overall rate of about one evacuation per 14 person-years. Only one of these was from the Mir station, which operated from February 1986 to May 2000, resulting in a Mir evacuation rate of one per 31 person-years. Risk data from the populations discussed here, Antarctic station evacuations, LSAH astronaut hospitalizations, spaceflight medical events, and the NASA Medical Operations risk study [30,31] provide a basis for estimating ISS evacuation event incidence rates for a seven member crew (Table 7.8).

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TABLE 7.5. Class IIa LSAH astronaut hospitalizations 1959–1999 (Total = 88).

Table 7.6. Class IIIa LSAH astronaut hospitalizations 1959–1999 (Total = 15).

Class IIa medical events (n = 17)

Class IIb medical events (n = 28)

Class III—medical events (n = 15)

Ventricular tachycardia, exercise-induced Infectious colitis Abdominal pain, right lower quadrant Internal hemorrhoids Urinary tract infection

Paroxysmal idiopathic atrial fibrillation Diarrhea, clostridium difficile Meniere’s Disease (2)

50% total body surface area burn/30% third degree burn Diffuse chemical pneumonitis from toxic inhalation (of nitrogen tetroxide) (3) Anaphylactoid reaction to intravenous tracer Acute appendicitis Ruptured retroperitoneal appendix Pancreatitis/choledocholithiasis Nephrolithiasis Cholecystitis Cholelithiasis Retinal detachment Cervical spinal stenosis with central cord syndrome Cervical spondylosis with brown-sequard syndrome Metastatic malignant melanoma

Severe epistaxis Traumatic subluxation of left shoulder Neck pain Cellulitis Post-herpetic neuralgia Fracture of the 4th metacarpal Fracture of the 5th metacarpal Fracture of the tip of terminal phalanx Freiberg’s disease (incomplete fracture without displacement of the fragments) Cartilaginous loose bodies in joint Minor superficial surgical wound infection Irritated compound nevus

Transient exercise-induced visual loss Thyroid papillary carcinoma with lymph node metastases Thyroid nodule (2) Asymmetric goiter Paralysis of right vocal cord Inguinal Hernia, left (1), right (3), bilateral (1) Testicular trauma with fluid collection Impingement syndrome of shoulder Left infrascapular Pain with paresthesia of left fingers Fracture of lateral malleolus Fracture of 5th metatarsal

Anterior cruciate ligament tear (2) Meniscus tear, medial (3), lateral (2) Anterior talofibular ligament tear

Class IIc medical events (n = 15)

Class IIx medical events (n = 14)

Traumatic pneumothorax Hemopneumothorax

Near syncope Incidental finding of anomaly of the coronary artery Fracture of the left 4th through 10th ribs Cervical radiculopathy/cervical spondylosis Back pain/lumbar radiculopathy Lumbar radiculopathy secondary to HNP C5–6 HNP and osteophyte C7 radiculopathy secondary to HNP Severe lumbosacral spasm Comminuted fracture of left radius & ulna Compound fracture of left ankle & right hand Fracture of first 4 metatarsals of left foot Symptomatic buried hardware in left foot

Pneumonia Viral pneumonitis and pleuritis Cardiac arrhythmia Abdominal pain with bloody diarrhea Active duodenal ulcer Cholelithiasis/chronic cholecystitis Acute diverticulitis Left flank pain Hemorrhagic corpus luteum Dysmenorrhea Corneal ulcer Shoulder dislocation Septic arthritis of knee Infectious mononucleosis

Abbreviation: HNP, herniated nucleus pulposis. a Class II—Ground-based significant medical events requiring ISS HMS intervention if occurring on-orbit.

a Class III—Ground-based significant medical events requiring evacuation if occurring on-orbit.

Table 7.7. Categories of LSAH astronaut hospitalizations 1959–1999. Total hospitalizations

88

Trauma Neurological Gastrointestinal infections Surgical Pulmonary Musculoskeletal Other

14 12 9 8 7 4 34

can be expected to occur approximately once every 5.6 years for a crew of three and every 2.4 years for a crew of seven occupying ISS, while a Class III medical evacuation event might be expected to occur one to three times during the fifteen-year life of the ISS for a crew of seven. This latent possibility, in fact, drove the initial development of a medical evacuation capability, as well as a requirement for an unsuited configuration during return to allow airway access, physiological monitoring, and intervention, where appropriate, none of which are currently feasible on the Soyuz. This has resulted in NASA medical experts addressing the requirements for more advanced treatment of ill and injured crewmembers prior to return from the ISS on the Soyuz. It is noteworthy that these estimates are based solely upon primary medical events and do not consider possible failures of onboard life support systems or non-medical emergencies such as vehicle system failures.

Standards of Medical Care in Space Flight Using the most conservative rates from the NASA Medical Risk study, a Class II event (significant medical event requiring the HMS, with potential for mission impact and or evacuation)

After examining evacuation risk, the next considerations are the requirements and capabilities of space-based medical care systems for long duration flight. Since NASA’s Skylab

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Table 7.8. Evacuation estimates for ISS from ground analog and inflight populations.

Population

Evacuation events Estimated incidence (Events/person-years) (Events per person-year)

Estimated yearly Estimated time evacuation rate between evacuations (Evacuations/year) (Years/evacuation)

Analog 1. 1992–1996 McMurdo station Total 71

71/2000

0.035

0.135 (3 crew) 0.249 (7 crew)

9 years (3 crew) 4 years (7 crew)

2. LSAH astronaut hospitalizations Class IIc (15) and III (15) i.e. events requiring evacuation

30/2715

0.011

0.033 (3 crew) 0.077 (7 crew)

30 years (3 crew) 13 years (7 crew)

3. Cosmonaut evacuations (primarily long-duration flight) All events—1959 to 2000 3/42

0.071

Medical events only

2/42

0.048

Mir station—1987 to 5/2000

1/31

0.032

0.213 (3 crew) 0.500 (7 crew) 0.144 (3 crew) 0.333 (7 crew) 0.096 (3 crew) 0.226 (7 crew)

4.5 years (3 crew) 2 years (7 crew) 7 years (3 crew) 3 years (7 crew) 12 years (3 crew) 4.5 years (7 crew)

4. Astronaut evacuations (primarily short-duration flight) 1961 to 2000

0/19

0.000

–

–

5. NASA medical risk study Likely mission impact/possible evacuation, Class II

0.059

Critical medical events Requiring evacuation, Class III

0.010

0.177 (3 crew) 0.410 (7 crew) 0.030 (3 crew) 0.070 (7 crew)

5.5 years (3 crew) 2.4 years (7 crew) 35 years (3 crew) 14 years (7 crew)

Inflight

Source: Data from: Billica et al. [28].

program, this has been an ongoing process culminating in the development of the CHeCS equipment for the ISS. Physicians and medical support personnel have been involved with flight since the earliest days. The French physician JeanFrancois Pilâtre de Rozier was one of two crewmembers of the first manned balloon flight in 1783. Aeromedical transport as well has evolved throughout the history of flight. In fact, the very first aeromedical evacuation took place in 1860 during the Franco-Prussian war when 160 wounded soldiers were evacuated over enemy lines by hot air balloons. In the United States, air evacuation began soon after the Wright brothers flew in 1903. By World War II, the use of aircraft to carry injured soldiers had become widespread, and flight crews were being specifically trained for medical transport [32]. Helicopter evacuation to Mobile Army Surgical Hospital (MASH) units began during the Korean War and continued in the Vietnam War era, with decreasing transport time contributing to improved battlefield survival. By the 1970s, civilian aeromedical emergency care began in earnest in the United States. Since then, standards of care for the medical treatment, stabilization, and transportation of patients by air have steadily evolved along with ground-based standards. Advancements in the fields of emergency medicine, triage, and evacuation have contributed significantly to the safety, efficiency, and acceptance of aeromedical transport. Technical developments in medical sensors, equipment miniaturization, telecommunications, and emerging life support and therapeutic modalities, along with advanced ambulance

capabilities, helicopter and fixed-wing aircraft designs, have contributed to the utilization and success of aeromedical transport. For those patients with moderate to severe non-mortal injuries, emergency aeromedical transport is considered to reduce risk of subsequent mortality by about 25–50%, with negligible added mortality risk from air accidents (0.006 per transport) [21]. Terrestrial ground and air ambulance standards of care are an appropriate starting point to develop standards for Advanced Life Support (ALS) stabilization and transport/ evacuation capabilities for space flight. Human space flight has always provided a means of return for crewmembers in the event of an emergency. This may be the transport vehicle itself, such as Apollo, Soyuz, or Shuttle, or in the case of space stations, a dedicated return vehicle that is attached and periodically rotated, remaining ready for use. The ISS, like Mir, has used the Russian Soyuz vehicle for crew rotation and contingency return capability. In the late 1990s, NASA began design of a dedicated CRV, and for the long term, other alternative vehicles such as the Orbital Space Plane were considered. The ALS standards of care for the ISS HMS and the CRV evolved from standards of care set forth by the American Heart Association’s Cardiopulmonary Resuscitation (CPR) and Advanced Cardiac Life Support (ACLS) programs, the American College of Surgeons’ Advanced Trauma Life Support (ATLS) program, the U.S. Naval and NASA Hyperbaric Medicine Teams, and the NASA Medical Operation’s Advanced Projects Team.

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Efforts to develop the equipment, techniques, and training protocols for the delivery of emergent healthcare to an astronaut population in the unique environment of space have been significant and ongoing at NASA JSC for many years. Ground models, reduced gravity parabolic flights, and space-based simulations have all been utilized in the development of ALS capabilities [33–36]. An ALS animal model for performing parabolic-flight microgravity ACLS and ATLS research and training has also been developed and is used to train flight surgeons and provide supplemental training for crewmembers of both the Shuttle and ISS [37]. These efforts have led to the inclusion of limited ALS capabilities, including cardiac defibrillators, airway management items, and cardiac drugs on the Mir station and the ISS [38–40]. The ALS capabilities of the ISS HMS are discussed further in Chaps. 4 and 5. An inflight CMO or a ground-based flight surgeon must address two paramount considerations in making a triage decision: 1. The unique pathophysiologic conditions of a returning crewmember 2. The capabilities and risks of the transport/evacuation vehicle to be utilized Several other elements contribute to the success of this decision. First is the training of the designated crew medical officer (CMO) in assessing an injured companion and the ability to send a diagnostic evaluation to the flight surgeon. Currently ISS crewmembers receive approximately 80 h of medical training, enhanced where feasible with “hands-on” clinical activities because the CMO is not a physician in most cases. CMO training is a mix of basic and advanced medical topics. Though crewmembers are trained in ACLS protocols, they do not have the experience of a full-time practicing emergency medical technician (EMT) or paramedic. Additionally, the typically intensive training schedules that crewmembers follow in the pre-mission phase may affect the completion of their medical training. A second element is readily available and secure telecommunications. Contingencies must be addressed to manage medical events if these capabilities are not available at all times to the crew, Mission Control, and the flight surgeon [41,42]. Processes, procedures, and training are developed to enable crewmembers to medically intervene without ground support should this be necessary [43–45]. The minimum standards for spaceflight ALS (Table 7.9) are based upon U.S. standards for ground transport via ambulance. These represent the desired capabilities of a first responder in an ISS emergency care scenario. Projected medical capabilities (Table 7.10) reflect the anticipated diagnostic and therapeutic standards of care necessary for LEO, lunar, and planetary mission scenarios, derived from various working groups within NASA Medical Operations. These are regularly updated to incorporate advanced biotechnologies, medical informatics, and enhanced CMO training and skills.

S.L. Johnston et al. TABLE 7.9. Required medical capabilities for minimum care standards on ISS. Level of care Basic Intermediate

Augmented

Advanced

Minimum capabilities required Basic CPR and first aid, including splinting and bandaging Limited or modified ACLS, and ATLS capabilities: Crew medical restraint system (CMRS) Intravenous and intramuscular therapeutics Electrocardiography monitoring Defibrillation Airway management including medical suction Mechanical ventilation Limited or modified hyperbaric treatment (using the combined pressure of cabin and EVA suit) 24-h medical evacuation time to definitive medical care facility with hyperbaric chamber capability.

Abbreviations: CPR, cardiopulmonary resuscitation; ACLS, advanced cardiac life support; ATLS, advanced trauma life support; EVA, extravehicular activity.

Pathophysiology of Deconditioned Returning Crewmembers Another step in the delineation of spaceflight medical transport and evacuation capabilities requires discussion of the deleterious effects of microgravity exposure on the physiologic state of a crewmember returning to a one-G environment. Chap. 2 addresses the known physiologic changes from long duration exposure to microgravity [46]. This section will summarize the pathophysiologic state encountered during the transition from zero G to one G and greater, occurring during the medical transport of an ill or injured crewmember to an earth-based DMCF. During re-adaptation to earth gravity, three physiological systems are significantly compromised: (1) musculoskeletal, (2) neurovestibular, and (3) cardiovascular. These physiologic decrements produce serious functional and performance limitations for returning deconditioned crewmembers [47,48]. Returning from missions of up to 14 days, such as are typical for Shuttle and ISS Soyuz taxi flights, most crewmembers are sufficiently readapted to be able to walk satisfactorily, though with a slightly abnormal gait, within 30–60 min following landing. During the NASA Skylab and Shuttle-Mir programs, involving long duration flights of one to several months, returning crewmembers were occasionally unable to ambulate normally for several hours, due to neurovestibular and cardiovascular compromise, made worse by the musculoskeletal deconditioning accompanying weightlessness. From these limitations arise many of the human system engineering requirements for a dedicated crew return vehicle (CRV), which are described later in this chapter. The influence of these effects on design can be illustrated as follows:

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Table 7.10. Projected Medical Capabilities for Low Earth Orbit and Beyond (Moon, Earth/Sun and Earth/ Moon Libration Points, and Mars) Advanced Life Support Capabilities

CMO Training

Time to DMCF - 24 hours LEO (ISS)

Skill Level

Specialized Restraint Systems IV/IM Medications Oral & Endotracheal Airway /Cricothyrotomy Automated Pneumatic Ventilator Blood Pressure Monitoring and Pulse Oximetry BLS protocols

Emergency Medical Technician

Informatics/Telemedicine remote medical direction Defibrillator with external cardiac pacing ECG Monitoring IV Fluids Modified ACLS & ATLS protocols

Paramedic

Hyperbaric Treatment Ultrasonography (Abdominal, Cardiac, Thoracic)

Physician

Lunar Missions / Stable Lagrangian Platforms Time to DMCF - Days to Weeks LEO / ISS capabilities with augmented supplies Radiation Shelter

Physician and Paramedic -orParamedic and Paramedic with advanced training

Mars and Other Expeditionary Missions Time to DMCF 9 to 30 months Lunar capabilities with augmented supplies Stand-Alone Capabilities: • Limited Surgical Intervention • Banked or Synthetic Blood • Banked Bone Marrow • Informatics/Expert Systems/Clinical decision-support tools Radiographic / MRI Diagnostic Imaging • Recuperation and Convalescence Capabilities

Physician (with surgical training) and Paramedic -orPhysician and Paramedic with advanced training

Abbreviations: ACLS, Advanced Cardiac Life Support; ATLS, Advanced Trauma Life Support; BLS, Basic Life Support; CMO, Crew Medical Officer; CPR, Cardio Pulmonary Resuscitation; CMRS, Crew Medical Restraint System; DMCF, Definitive Medical Care Facility; ECG, Electrocardiograph; EMT, Emergency Medical Technician; IM, Intra Muscular; IV, Intra Venous; LEO, Low Earth Orbit.

Musculoskeletal System Limitations

Cardiovascular System Limitations

In designing any manually actuated mechanism such as a crank or switch for the opening of an emergency hatch on landing that might be operated by any crewmember, the maximum torque required has been calculated based on a 20% loss of upper extremity muscle strength for a fifth percentile Japanese female (NASA’s anthropometric design range limits are to accommodate a fifth percentile Japanese female up to a 95th percentile U.S. male).

Returning crewmembers, due to their orthostatic intolerance, must be placed in a recumbent position to minimize the +Gz forces present during reentry and landing. This may preclude steps that would nominally require the crew to assume an upright posture. The immediate re-adaptive state of deconditioned long– duration crewmembers (> 30 day) upon reentry and exposure to a one-G environment is illustrated by the extent of physiological decrement (Table 7.11) and their general physical condition and overall appearance. Of even greater concern is the return to Earth of an ill or injured crewmember in a severely compromised physiologic state. Some returning long duration crewmembers may be unable to make any physical effort on their own behalf, and their physiologic responses may be altered. This is an area where more research is necessary to understand

Neurovestibular System Limitations In designing crew and piloting command capabilities for obstacle avoidance and maneuvering during landing of a CRV, head and eye movements, particularly rapid ones, must be minimized due to delayed target tracking and possible incapacitating Coriolis-like effects.

148 Table 7.11. Typical physiologic decrements associated with long duration space flight. Musculoskeletal strength Upper extremities—average decrease 20% Lower extremities—average decrease 40% Paravertebral / spinal—average decrease 40% Weight-bearing bone mass decreased on average 1–2% for each month on orbit Neurovestibular readaptation Target acquisition delayed >2 s, limiting fine motor control Neuro-kinesthetic/positional Rapid head movement may cause incapacitation Nausea and vomiting Cardiovascular/orthostatic intolerance Intravascular volume loss 6–12% Syncope possible with exposure to positive Gz forces on entry and standing Baroreceptor/autonomic nervous system dysfunction Decreased cardiac muscle size and filling Source: Data from: Space Biology and Medicine [46]; Bioastronautics Data Book [47]; Nicogossian et al. [48].

basic physiologic responses of the deconditioned organism to pathologic processes following exposure to long duration microgravity. It is reasonable to surmise that some otherwise healthy, returning, deconditioned crewmembers, on exposure to reentry and landing acceleration forces, may be unable to aid another crewmember, may be unable to egress their seat for thirty minutes to several hours, and possibly may be completely incapacitated. This degraded physiologic state poses severe limitations for high G ballistic reentry, water landing, and unaided vehicle egress. Some of these changes may have a significant effect on performance in relation to crew emergency operations. There are particular difficulties for pilots in the situation, however unlikely, that automated control systems fail to function normally. Control of the spacecraft may require a number of human abilities including arm-hand steadiness, finger dexterity, hand-eye coordination, perception speed, and rapid reaction time against a background of decreased motor function and the effects of prolonged weightlessness and confinement [49]. For example, the significant changes that occur in the accuracy of psychomotor performance combined with the postural changes that occur in response to weightlessness result in a tendency to past point until adaptation occurs [50]. This decrease in dexterity can pose potential problems for the manipulation of control panels, displays, and mechanical systems during an emergency return to earth [51]. However, for standard Shuttle missions of up to 18 days, manual control of landing has been routinely and successfully accomplished. The decision to utilize an unscheduled or emergency return may be problematic both medically and logistically. A crewmember with compromised cardiac function could be placed at increased risk by returning to earth prematurely following a cardiac event. This must be taken into consideration when deciding whether to recuperate in LEO before transport to a DMCF. For example, the deconditioned crewmember

S.L. Johnston et al.

suffering a myocardial infarct several months into a LEO mission would be further compromised if returned while in the acute injury phase. LEO evaluation and rehabilitation with low levels of artificial gravity from a human centrifuge might be the therapy of choice, rather than immediately subjecting the patient to the insults and risk of reentry and landing, with their associated acceleration forces. However, the capability and the personnel must be onboard to provide supportive treatment and facilitate such a course of action.

Psychological Deconditioning of Returning Crewmembers In an emergency situation crewmembers are called upon to act with decisive, clear, and correct actions to prevent a crisis from deepening and to preserve their own lives and the lives of their colleagues. These and other aspects of functioning in space relating to the human-machine interface and the crew’s living and working environment may affect their capabilities, and so present some of the most significant challenges for an ISS crew. These psychological effects directly relate to the problems of emergency medical capabilities, particularly in light of the additional physiological stresses that such situations may place on a crew. The adverse effects of confinement, isolation, noise, environmental challenges, and the group dynamics associated with these situations, have been well documented in analog situations such as the Antarctic and on submarines [52–54]. Additional psychological stressors may arise from limited communications, on-orbit equipment failures, difficult living conditions, and high workloads, particularly in emergencies. These may be compounded by crew interpersonal tensions, multi-cultural issues, lack of privacy, and deprivation of the usual sensory and motor stimulation [55]. In space, isolation can lead to sleep disturbances, headaches, irritability, anxiety, depression, boredom, restlessness, anger, homesickness, and loneliness. These physiological findings are particularly relevant to the actions and performance of crews in emergency medical situations, where time is of the essence and effective leadership and decision-making are paramount. These issues are further discussed in Chap. 19.

Human Factors Challenges of Crew Return Vehicle Design For any crew return vehicle, there are substantial human factors challenges in designing the environmental systems, seat and cockpit configurations, medical systems, restraint systems, and extraction capabilities for the transport of crewmembers within NASA’s required anthropometry range. The CRV concept is used here as a generic reference design to discuss vehicle attributes in support of medical evacuation capability. These investigations and findings will facilitate incorporation of desirable attributes into new vehicle programs.

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The current formal ISS program requirement is to accommodate the fifth percentile Japanese female to a 95th percentile U.S. male [56]. These affect not only the design of the vehicle as a whole but also individual activities such as flight control and medical support. A primary driver for a crew return vehicle is the requirement to accommodate a “shirt-sleeve” environment if needed, due to the urgency of its mission, the need to have access to the patient, and the time and difficulty of donning pressure suits in a small, enclosed volume. This will facilitate a more environmentally and user-friendly cockpit operable without the mobility restrictions imposed on suited crewmembers. Unique limitations in the CRV affect how the CMO provides medical care to the patient, including restricted motion due to the forces of reentry. These limitations drive requirements for medical equipment controls and supplies that are positioned to allow access to the patient and monitoring equipment during different phases of flight. A returning crewmember requiring respiratory support can serve as an example. If a patient is being manually ventilated via bag mask, the CMO in the CRV will encounter difficulty sustaining this once perceptible acceleration forces are encountered. However, if the patient is mechanically ventilated, the CMO could adjust the settings with the aid of remote access to ventilator controls and readout. This situation arises due to the seating limitations that will place the CMO in a reclined position and therefore unable to reach over to the patient. Additionally, human factors play an important role in the design of less complex components. For example the patient’s restraints must be activated and adjusted by another crewmember [57,58]. The design of the CRV patient restraint system must consider these factors, including the provision of an interface for advanced life support equipment, such as a ventilator, defibrillator, oxygen supply, and intravenous (IV) infusion [59,60]. The crewmember’s degraded condition will also drive search and rescue (SAR) team requirements such as response time and medical capabilities. In particular the crew may be unable to extract themselves from the vehicle after landing; therefore the SAR team must be familiar with aspects of spaceflight deconditioning and utilize appropriate crew extraction techniques. The internal layout of the CRV should also facilitate crew extraction, with the CMO and the patient situated directly under the hatch opening. Optimally, this would mean that they are last to enter the vehicle and first to leave it. The NASA JSC Graphics Research and Analysis Facility Laboratory uses three-dimensional modeling to determine the minimum space necessary for crewmembers in various predictable activities. While there is arguably an ideal volume required to execute a rescue mission, the designers are usually required to work with the fixed volume and constraints of a specific vehicle. With vehicles such as the Soyuz and X-38, the volume available is considerably reduced due to the limitations of the vehicle shell, internal equipment and supplies, and the operator functions. For comparison, habitable volumes of various vehicles are shown in Table 7.12.

149 Table 7.12. Habitable volumes for various spacecraft. Vehicle Space shuttle orbiter Apollo command module Mercury spacecraft Proposed X-38/Crew Return Vehicle Soyuz descent module Gemini spacecraft Ground ambulance —box type

Habitable volume (m3)

Crew

Volume per crewmember (m3)

65.8 6.2 1.7 12.2

7 3 1 7

9.4 2.1 1.7 1.7

4.0 2.6 11.0

3 2 2+ patient

1.3 1.3 3.6

Designers of a crew medical rescue system should also be aware of the requirement to implement protocols and procedures in an international and multicultural environment [61–64]. These should be clear, intuitive, and perhaps more visually oriented to optimize understanding by an individual working in a second language. Finally, a crew return capability for medical emergencies requires the development of procedures and checklists. Applying usability and human factors analysis to evaluate medical procedures will ensure that crew performance is maximized and not affected by a poorly designed interface. This will enable an easier, more accurate and rapid response from the crew, thereby enhancing safety and increasing the likelihood of a successful outcome [65,66].

Risks in Aeromedical Transport and Evacuation Factored into any decision to use aeromedical transport must be the added risk inherent in evacuation and transport itself. Sometimes, this added risk outweighs any marginal benefit of immediate transport. EMS medevac, rescue operations, and hospital transfers are not risk-free, and injuries occur each year. However, the aeromedical transport fatality rate due to air mishaps is quite low, approximately six per 100,000 transports [20]. There will be occasions, given the hazards of the evacuation process and availability of onboard medical care, when definitive treatment may be deferred despite evacuation capability. For example, aboard commercial ocean freighters or cruise ships, patients with acute abdominal processes, such as acute appendicitis, are seldom evacuated by air even when within helicopter range but are often managed non-operatively and may be transported ship-to-ship before definitive land-based care is reached [67]. Many aircraft have been adapted to the air ambulance role, each with its strengths and limitations. The unique requirements of spaceflight medical transport present an opportunity to design a dedicated transport vehicle with medical capabilities de novo. As in design of air ambulances, factors such as cabin space and environment, access for patient loading, useful load, weight and balance, and flight performance must be carefully balanced. Emergency medical transport and evacuation

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from an orbiting space vehicle clearly carries additional risks as well. While it is difficult to assess these risks given the limited current experience base, they may be viewed as occurring along an evacuation timeline, with each phase presenting unique environmental hazards and corresponding risks. The major risks and suggested mitigation actions are outlined in Table 7.13.

NASA’s Crew Return Vehicle Development The need for an evacuation capability from a LEO space station derives from basic principles underlying escape and egress systems of the earliest manned spacecraft [68–72]. In 1957 before humans were launched into orbit, Petersen [73] and Romick [74] proposed earth-based designs for crew recovery from disabled manned space vehicles. The following year in 1958, Elricke Krufft of NASA presented a paper concerning,

“the considerations required in the use of a “lifeboat” for space operations [75]. He suggested that a possible solution to the rescue of astronauts in a stricken space vehicle could involve the use of another vehicle already in space for the specific purpose of early unplanned return. As early as 1963 the problems of interoperability and lack of commonality were acknowledged in a paper by Jack James [76], which states; “Many of the future problems involving space rendezvous… may be largely avoided by the early development of a universal, all service, all vehicle docking/coupling mechanism. Improved crew safety and mission reliability are… by products”. From the beginnings of the space age, engineers and scientists have made conscious efforts to minimize the inherent danger to humans from the space environment. Indeed with the launch of Gagarin in Vostok 1 on April 12 1961, the mission was planned such that in the event of a human or mechanical malfunction the vehicle would automatically re-enter the

Table 7.13. Risks associated with spaceflight medical evacuation and transport. Timeline event

Risks

Decision to transport/evacuate Delayed or premature decision Incorrect decision (e.g., medical condition likely to worsen with evacuation) Major mission impact

Risk mitigation design factors Anticipate possible scenarios Establish standing flight rules to guide decisions

Allow real-time crew decisions independent of ground support if communication fails Cabin environment Space-limited medical access for monitoring, proceCockpit configuration Evacuation timeline dures, and resuscitation Non-suited configuration is zero-fault-tolerant cabin Life support system consumables adequate to evacuation environment to entire CRV crew for depressurization timeline or toxic atmosphere event Crew time constraint of ~3 h from departing station to landing Medical capabilities of vehicle Suited configuration limits medical access, especially Design allows unsuited transport; seat design allows CMO for airway management and resuscitation access to patient. Autonomous reentry Limited landing opportunities Large cross-range capability, along with deorbit opportunity every 2 or 3 orbits Thermal, noise, and vibration issues Low entry G profile Acceleration profile on re-entry—Nominal vs. ballistic Autonomous, unpowered return Chute deceleration effects Controlled re-entry G limits: 4 +Gx, 1 +/−Gy, 0.5 +Gz Landing Limited sight and obstruction avoidance May be autonomous Land impact vs. water impact Inertial Navigation System, Global Positioning System guidance Potential impact injuries Steerable parafoil to limit landing speeds Landing site selection & navaids Recumbent crew seating Landing impact attenuation system Egress and rescue Impaired performance in one G due to deconditioning Prelanding Countermeasures— Fluid loading Unaided egress may not be possible Pharmacologic, sympathomimetics Land vs. water egress Remote environment exposure anti-G-suits Risk to Search and rescue (SAR) personnel Crew survival training unplanned deployment, toxic propellants, unspent SAR readiness and exercises pyrotechnics SAR/ground force availability and response time Evacuation to DMCF Additional transport event Medical Operations Contingency Support and Implementation Plan to define requirements for U.S. and international emergency landing sites. Medical facility capabilities at landing site may be diminished ● ●

●

7. Medical Evacuation and Vehicles for Transport

Earth’s atmosphere after 10 days even if the retro-rockets failed to fire. Food supplies for the same period were carried onboard. As such, the vehicle was automated except for the need for Gagarin to orient it for the de-orbit burn. Like other Vostok pilots, Gagarin ejected from the craft before touchdown to ensure a safe return. The escape system concepts that have been developed for earth return fall into two broad classes; lifting bodies and ballistic entry types [77,78].

Lifting Bodies Lifting body spacecraft are considered to have several advantages over other vehicle types. With expanded cross range afforded by the wing and lifting surface, the number of available landing opportunities to specific sites is increased. Acceleration loads during entry may be limited to about 1.5 G. Both qualities are considered important when returning ill, injured, or deconditioned space station crewmembers to Earth. Additionally, wheeled runway landings are possible, permitting simple, precision recovery at many sites around the world [11,79]. NASA began with the Dynamic Soaring Vehicle (DynaSoar) X-20 program, conceived in the 1940s after the capture of research produced by Nazi Germany based on the proposals of E. Sanger in the 1930s. The Dyna-Soar program ran from 1957 to its cancellation in 1963. This precursor of the Space Shuttle, intended for a variety of peaceful missions by the USAF and NASA, including space rescue, was designed to land on a runway. The Soviet Union began to investigate lifting bodies for space applications in the 1960s with the Spiral program, in response to the USAF Dyna-Soar project. The NASA Langley Vehicle Analysis Branch began the development of the HL-10, M2-F3, and X-24 lifting bodies in the 1960s and in the 1980s the HL-20 Crew Emergency Rescue Vehicle, a proposal to backup or replace the Shuttle after the Challenger accident in 1986. A full-size engineering research model of the HL-20 was constructed for studying crew seating arrangements, habitability, equipment layout, and crew ingress and egress [80].

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In the 1980s NASA had expended considerable effort to determine the need for escape and rescue provisions of manned space stations [81,82], particularly for the planned Space Station Freedom, and the Assured Crew Return Vehicle (ACRV) program. With the transfer of NASA space station efforts from the Freedom program to the ISS, crew return concepts shifted once again. With the X-38, NASA had considered another lifting body design, based on the X-24 lifting body shape. The X-24 was originally developed in the 1960s as part of the USAF’s Maneuverable Entry Research Vehicle (MERV) effort, flown as a precursor to the subsequent Space Shuttle Program. The X-38 CRV concept drew heavily on the findings of this program (Figure 7.1). NASA’s CRV program involved an innovative new spacecraft designed to return up to seven crewmembers to earth from ISS. The mission profile included launch to orbit in the Space Shuttle payload bay, then docking to the ISS and remaining in a standby condition until needed for a contingency return. Following the de-orbit burn and jettison of the engine module, the vehicle would glide unpowered from orbit and then use a steerable parafoil parachute for its final descent to landing. Though its primary use is as an emergency “lifeboat,” the CRV could be modified for other uses, such as an international transfer spacecraft that could be launched on other boosters like the European Ariane 5. It is envisioned that this vehicle could provide the capability to evacuate all seven members of a full ISS crew. The operational vehicle dimensions of the CRV as planned were a length of 9.14 m and a width of 4.42 m, which enabled it to fit into the Shuttle bay. The internal volume as planned was 11.8 m3 with a mass of 11,340 kg [82].

Ballistic Vehicles The earliest planned U.S. space station, the USAF Manned Orbital Laboratory (MOL), intended to use a Gemini capsule for primary transportation and emergency return to earth. Although this program did not materialize, the subsequent Skylab program utilized the three-crewmember Apollo capsule

FIGURE 7.1. The X-24a Lifting Body (A) developed and tested during the 1960s, and the X-38 (B) under consideration at one time as a rescue vehicle for the International Space Station (Photos courtesy of NASA).

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in a similar fashion. A modification of the Apollo Capsule was evaluated to accommodate six crewmembers in the event that an Earth-originated rescue was needed. This capsule was later considered as part of the early post-Challenger ACRV studies [19]. In the late 1980s the European Space Agency (ESA) developed the concept of an Apollo type capsule for use as a potential Crew Rescue Vehicle during studies for the free flying Columbus European Space Station (ESS). The main mission of the permanently docked Escape Vehicle was to allow the evacuation of and separation from ESS, followed by safe return to earth and recovery of the entire crew by ground teams [83,84]. Subsequent to the Challenger accident, the Crew Emergency Return Vehicle office was established at NASA Johnson Space Center to examine alternatives to using the Shuttle as a main rescue vehicle [85]. One such development by the JSC engineering team was the Simplified Crew Rescue Alternative Module (SCRAM), conceived as a low cost water lander configured to seat up to eight crewmembers and to sustain them for 24 h [86]. The vehicle consisted of a pressurized crew module to be attached to the ISS with an on orbit life of up to 10 years once delivered. The aim was to use compatible tried and tested technology and existing search and rescue capabilities to minimize operational costs.

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the ISS. Originally conceived to dock with a booster stage in orbit, thereafter to be propelled around the moon, Soyuz was later modified to fly crews to earth-orbiting Space Stations such as Salyut and later Mir [90]. In this capacity, it has served reliably and safely for over three decades with the exception of the decompression event of Soyuz 11 in 1971, which prompted re-design efforts and operational protective measures.

Russian and NASA Crew Return Vehicle Capabilities As of this writing, the only human-rated transport spacecraft in current use are the U.S. Space Shuttle and the Russian Soyuz. In 1992 the United States considered the modification of Soyuz capsules to fit the U.S. astronaut population for use as a crew return vehicle [91]. Designed for use as a “commuter” spacecraft to shuttle to and from a large orbiting station, its habitable volume is only 4 m3 in the descent module compartment. Therefore, the design of the baseline Soyuz descent module has serious limitations for medical missions (Figure 7.3).

Soyuz The Russian Space Agency has provided escape and rescue capability with a Soyuz spacecraft permanently available at the Salyut and Mir Space Stations [87–89]. The Soyuz is the default return vehicle for the ISS in the assembly phase (Figure 7.2). Designed in the 1960s, the first manned Soyuz flight ended in tragedy with the death of Vladimir Komarov on April 24th 1967, due to failure of the landing chute to deploy. Despite this setback, the problem was resolved, and the vehicle was made operational. Soyuz accumulated a substantial field history before being upgraded beginning in 1980 with the Soyuz T. From 1987 onwards, the TM series Soyuz has been operational and has supported missions to Mir and

FIGURE 7.2. The Soyuz TM vehicles with the basic Soyuz design have successfully ferried crews to and from orbital space stations for three decades.

FIGURE 7.3. Details of the Soyuz Descent Module showing the tight quarters, with crewmembers positioned in the launch and landing couches.

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Table 7.14. Selected anthropometry and mass limits for the Soyuz TM, Soyuz TMA, and NASA Space Shuttle.

Min standing height cm (in.) Min seated height cm (in.) Min weight kg (lbs) Max standing height cm (in.) Max seated height cm (in.) Max weight kg (lbs)

Soyuz TM

Soyuz TMA

NASA limits (Space Shuttle)

164 (64.6)

150 (59.0)

148.6 (58.5)

80 (31.5)

80 (31.5)

Not defined

50 (110)

50 (110)

40 (88)

182 (71.7)

190 (74.8)

193.04 (76)

94 (37.0)

99 (37.8)

Not defined

85 (187)

95 (209)

109.32 (241)

The Soyuz also accommodates a limited range of crewmember height and weight, compared with NASA’s anthropometric design limits (Table 7.14) [56,92]. The data gathered and maintained by the NASA JSC Anthropology laboratory derived from the Astronaut population during crew selection assessments. Because initial astronaut selection criteria were based on U.S. vehicles, a significant fraction of the U.S. astronaut population would not fit in the standard Soyuz TM. Several studies have been performed on the spacecraft to widen the anthropometry envelope and better understand how these limitations might affect its role in medical transport. These studies have led to Soyuz modifications such as elevating the main instrument panel to accommodate the legs and knees of taller crewmembers, seat changes to allow better musculoskeletal support of injured crewmembers, and stowage changes to accommodate medical equipment. This most recent round of upgrades has produced the Soyuz TMA, which entered service in 2003. NASA astronauts who fly on the Soyuz, and initial ISS crews, who will depend upon it as an emergency return vehicle, must be selected based on Soyuz anthropometric requirements [93].

Patient Accessibility and Treatment Capabilities

to a loss of pressure scenario. Each option has distinct features, advantages, and disadvantages. The Soyuz and the Shuttle are flight-proven operational transport vehicles. A crew return vehicle would be developed in part as a dedicated medical evacuation spacecraft, designed with a priority on specific medical requirements and human-factors concepts as high priority. This has a significant influence on the type of medical monitoring equipment that can be used and the level of intervention possible during free flight after undocking from the ISS. In terms of medical equipment and supplies available for patient treatment, the Soyuz and a future CRV or OSP are quite different. Differences in available medical equipment and capacity to manage particular medical scenarios for each vehicle’s configuration are shown in Table 7.15. With further assessment of the relative capabilities of the suited and un-suited configurations for different types of medical events, we can better estimate an overall relative capability of one versus the other. To this end, a panel of NASA Flight Surgeons estimated the relative projected medical care capabilities for specific events, by quartiles, of the suited versus unsuited configurations (Table 7.16). For each medical event category, an overall fractional capability of the suited configuration relative to the unsuited configuration can then be made (assuming equal event frequencies within each category). This is shown in Table 7.16 as Estimated % Relative Capability for Category. When this relative capability is weighted by the incidence of each medical event category, an overall relative capability of the suited configuration is estimated to be approximately 54%. In other words, the suited configuration during return to earth does not provide appropriate capability for handling about one-half of the potential events that would prompt medical return. This overall estimate agrees well with prior published estimates of 60%. For critical respiratory and circulatory events, the medical mission capabilities of the suited configuration are only about 17% and 10%, respectively, of the unsuited (CRV) configuration. This degraded capability for respiratory and circulatory

Table 7.15. Medical capabilities in transport and evacuation from the ISS: Suited vs. unsuited. Medical capability

The differences between the Soyuz and the Shuttle are largely a result of the internal volume, equipment accessibility, and crew station and seat layout. For any spaceflight medical transport and evacuation vehicle, required use or non-use of a full pressure suit is one of the most fundamental crewmember configuration decision points. This choice affects vehicle design, flight medical hardware, and projected medical procedure capabilities. Clearly, a cabin environment that permits an ill or injured crewmember to return to earth in an un-suited, “shirtsleeve” setting allows better access for medical monitoring and intervention. On the other hand, a pressure suit provides enhanced “livable atmosphere” protection and fault tolerance

Patient assessment Exposure/airway access Patient restraint device/ cervical–spine restraint Second provider assist Advanced life support pack Diagnostic equipment Pharmaceuticals Intravenous fluids Oxygen supply—100% Cardiac monitor Defibrillator, blood pressure monitor, pulse oximeter Survival kit (post landing)

Un-suited (Crew Return Vehicle)

Suited (Soyuz-TM)

limited present present with patient restraints possible sub-packs present present present ventilator & mask present present

minimal minimal possible

present

present

minimal some supplies minimal limited possible suit possible minimal

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Table 7.16. Projected relative medical capabilities of suited (unmodified Soyuz-TM) vs. unsuited (CRV) configurations. Incidence Medical event requiring (per 100 transport/evacuation person-yrs) Trauma and toxicity Anaphylactic reaction Respiratory depression Major fracture Gastrointestinal Severe gastroenteritis Ileus Appendicitis Pancreatitis Cholecystitis Neurologic/psychiatric Vertigo Psychosis Seizure activity Intracranial bleed Cerebral aneurysm Cerebrovascular accident Respiratory Pneumothorax Pneumonia Toxic pneumonitis DCS chokes Reactive airway Airway obstruction Respiratory arrest Acute respiratory distress syndrome Pulmonary embolus Circulatory Dysrhythmia Coronary disease/ angina Myocardial infarction Shock—hypovolemic Shock—anaphylactic Genitourinary Renal calculi Urosepsis Pylonephritis Infectious disease Sepsis Meningitis Dermatology Cellulitis/abscess Urticaria Exfoliative dermatitis General internal medicine Cancer Endocrine/nutritional/others Total ~ 6 events / 100 person-years

Estimated % rela- Incidencetive capability for weighted suited category % capability

1.72

66%

19%

0.87

50%

7%

0.8

46%

6%

0.60

17%

2%

0.43

10%

1%

0.34

42%

2%

0.30

38%

2%

0.28

100%

5%

0.6

100%

10%

any evacuation scenario. The estimated combined crew risk of a medical event potentially requiring evacuation is about 0.06 multiplied by 3, or 0.18 per person-year, that is, an anticipated evacuation about once in five or six years. This estimated risk is comparable with that from actual Russian spaceflight experience. Beginning with the assembly complete phase, marked by crew occupancy of seven individuals, we may anticipate a combined crew medical event evacuation risk of 0.06 multiplied by 7 crewmembers, or 0.42 per person-year, or about once in 30 months. For critical, life-threatening respiratory or circulatory events considered independently, the combined risk estimate is about one evacuation in 14 years, or effectively once during the design life of the station. Thus anticipating the occurrence and type of a significant medical event onboard a space station drives the necessary implementation and design of that station’s evacuation and escape system.

Medical Requirements for a NASA Crew Return Vehicle CRV type vehicles must meet well-established baseline requirements for human crew operations. Documented requirements parameters include vehicle and system performance, environmental control specifications, human factors guidelines, medical limitations, and mission support requirements [94]. The aim of medical requirements is to ensure that a vehicle built to transport ill or injured crewmembers will meet the minimum standards for patient care during a return mission from the ISS. It is vital to the success of the CRV program that these requirements are clearly defined and fulfilled. Based on these guidelines, the NASA Medical Operations Branch has developed a specific set of minimal medical requirements for a dedicated ISS Crew Return Vehicle. These requirements are not intended as design solutions but merely as a guide for the vehicle designers as they develop concepts for the crew compartment of the CRV [95–97]. The medical requirements are subdivided into those addressing patient care, crew compartment configuration, and crew compartment environmental control and life support systems (ECLSS) systems.

Patient Care Equipment and Supplies 5.94

54 %

care is primarily due to loss of patient exposure and airway access in the suited configuration. During the assembly phase with a permanent crew of three individuals, only the suited configuration (unmodified Soyuz-TM) escape vehicle will be available to accommodate

Medical life support adequate for a minimum of one ill or injured crewmember including, but not limited to ventilation, physiological monitoring with defibrillation, intravenous fluid therapy, and pharmacotherapy, are identified requirements. In addition, emergency medical and survival kits are essential to cover injuries and illnesses during any mission phase, including after landing until the arrival of search and rescue forces.

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Timeline

Crew Medical Officer Station

To ensure that the patient transport time is minimized, the CRV medical mission timeline must ensure that the maximum time from ISS separation to landing does not exceed three hours. This figure was derived from the projected capabilities of the vehicle and the medical requirements to minimize transport time.

Within the crew compartment area, the medical mission configuration requires specialized seats, restraints, and medical equipment interfaces and displays to accommodate the ill or injured crewmember and CMO. These must be able to support an incapacitated crewmember on a mechanical ventilator, provide electrical isolation for defibrillation, allow access to medical equipment, patient and CMO interfaces, and allow ready access to the vehicle’s hatch.

Crew Compartment Configuration The crew seat and cockpit design of the CRV should accommodate the full planned crew complement of the ISS, and address re-entry, chute, and impact acceleration forces and crashworthiness. The following specific protective attributes, which must be incorporated into vehicle operations and design. Head-torso-lower extremity centerline axis alignment. Seatback angle 0° (preferred) to 12°; neck < 20°; hip, knee, ankle 90° relative to the local horizontal axis defined by the prevailing velocity vector. ● Five-point restraint system adjustable to accommodate 5–95% of the anthropometric envelope and prevent occupant flail movements and cockpit projectiles, including for an unconscious patient. ● Head restraint with lightweight communication and protection systems that allow a fixed visual reference point. ● Crew displays and controls that minimize crewmember head and arm movement and effort during re-entry. ● Vehicle spin and rotation limits not exceeding 5 rpm sustained due to crew intolerance (neurovestibular provocation). ● Adequate attenuation properties to minimize G loading in all axes of the human body with a limit on sustained (>1 s) entry accelerations to no greater than +/−4 Gx, +/− 1 Gy, and +/−0.5 Gz in the body axis. This is designed to minimize orthostatic stress and allow the crewmember a degree of movement under G. A further driver to limit acceleration loads would be underlying illness or injury, that might increase sensitivity to such forces such as blood loss or pulmonary atelectasis. ● Parachute deploy load limits (acceleration-time profiles) for deconditioned crew are shown in Figure 7.4 [98–101]. ● ●

FIGURE 7.4. De-conditioned crew load limits for parachute deploy.

Communications Dedicated real-time medical communications capabilities are required between the CRV and Mission Control Center-Houston (MCC-H). These would include the means to support the transfer of medical data, including but not limited to, ECG and realtime video, whenever possible. In addition, voice communication between the CRV and SAR forces should be available.

Seating and Displays The seat position for the CMO must allow access to medical equipment, controls, and displays and to dedicated airto-ground communications. In a seven crewmember CRV configuration, a rear row seat position would be designated for an ill or injured crewmember due to proximity to the aft egress hatch, while the parallel seat position would accommodate a crew medical officer (CMO). The aim is to allow the CRV pilot entry first, followed by remaining ISS crew, and lastly the CMO and injured crewmember. This will allow the pilots to start the vehicle unhindered and will facilitate extraction of the injured crew first after landing (Figure 7.5).

Extraction The entire crew returning from ISS may be incapacitated for several hours due to neurovestibular, cardiovascular, and

FIGURE 7.5. Mockup of the prototype X-38 CRV interior; this vehicle would accommodate seven crewmembers and position the patient and medical attendant just below the main overhead access hatch (Photo courtesy of NASA).

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musculoskeletal deconditioning. Therefore, vehicle design should accommodate the extraction of all incapacitated crewmembers by search and rescue forces without help from the crewmembers themselves, with the injured crew extracted first.

Landing Impact Forces Impact deceleration limits should be such that risk of serious or incapacitating injury as defined by the Brinkley Dynamic Response Model [98] in a deconditioned and ill or injured crewmember is no greater than 0.5%. This is a figure that research and analysis have shown to be an acceptable level of risk to the crewmember to prevent further injury, while allowing vehicle designers a degree of latitude in developing a method of landing. This however is a difficult figure to assess. Much of the data is based on Apollo capsule research, which measured peak forces higher than those more likely to be encountered in a conventionally landed vehicle. The impact limits established in ACRV studies in the 1990’s were 10 +/−Gx for 0.2 s, 5 +/− Gy for 0.2 s and 5 +/− Gz for 0.2 s [101,102].

Crew Compartment Environmental Control and Life Support Cabin Atmosphere The atmosphere and environment of a CRV vehicle should maintain a comfortable level of temperature, humidity, and ventilation for the duration of the mission to enable shirtsleeve operation. Cabin atmosphere should be regulated according to the values in Table 7.17 [58,103]. This capability should extend beyond landing to include adequate time for the removal of the deconditioned or ill or injured crewmembers. The vehicle will need an enduring ECLSS capability, as the system will need to cope with the heat build-up during re-entry and landing, which may contribTable 7.17. Crew Return Vehicle environmental control and life support system design parameters. Parameter Total pressure Partial pressure (pp) Carbon Dioxide pp Oxygen pp Nitrogen Relative humidity Atmospheric temperature Dew point Intramodule circulation Intermodule ventilation Fire suppression Oxygen concentration level Particulate concentration (0.5–100 mm diameter) Temperature of surfaces Atmospheric leakage per module

Range 14.2–14.9 psi 0.102–0.147 psi 2.83–3.35 psi <11.6 psi 25%–70% 17.8–26.7°C 4.4–15.6°C 0.051–0.2 m/s 66 ± 2.4 Liters/s 10.50% Average <0.05 mg/m3 4°C
ute to orthostasis and motion sickness problems among crewmembers. The vehicle should also be capable of purging the interior environment of toxic products. This will also allow the CRV to act as a safe haven where astronauts could take refuge while the ISS environmental control system scrubs a toxin, controls a fire, or repressurizes the station. Pressurization. Loss of pressure is a credible ISS failure, and the lowest pressure at which a crewmember can survive on 100% oxygen for a significant period of time is about 3.0 psi (155 mmHg), or the equivalent atmospheric pressure of 11,600 m (38,000 ft) in altitude. In fact the earliest EVA suit concepts and some high altitude pressure suits, such as utilized for aircraft like the SR-71 Blackbird, were as low as 2.8 psi. The re-pressurization rate limit—from 3.0 psi to the nominal 14.7 psi within 30 min, at a rate not to exceed 13.4 psi/min—is set to avoid problems with middle ear blockage and barotrauma. Although survivable, decompression from the station cabin atmosphere pressure to such a minimum pressure would likely involve some degree of decompression sickness (DCS), so crew should remain on 100% O2 for several hours to mitigate this risk after such an event. It is important to note however, that the threshold for crew action and evacuation from the ISS is currently set well above 3.0 psi (see Chap. 23). Oxygen. Emergency and supplemental O2 is required for use in event of toxic atmospheric contamination or a cabin depressurization. This is required for a period long enough to restore an adequate breathing environment and treat embarrassed respiration of exposed crewmembers. In addition the vehicle needs to provide independent 100% breathing O2 for the ill or injured crewmember at a maximum rate of 20 liters per minute for up to four hours. This will ensure that there is adequate O2 for the patient from ISS separation to evacuation by search and rescue after landing. This in turn necessitates a means for dumping or recycling the exhaled O2 so that cabin concentration limits are not exceeded with consequent flammability risks. Post-landing Recovery. Crew recovery after evacuation from a vehicle such as the ISS does not end until the crew has reached definitive medical care. Requirements and procedures have been and continue to be developed to ensure that an injured or ill crewmember will reach a DMCF within a pre-determined period from station evacuation. This has consequences for the requirements placed on the recovery vehicle and the SAR forces, as a result of the time required to land a vehicle and where it will land. For example a CRV type vehicle that can depart the Space Station and land within three hours in multiple locations requires the SAR team to respond more quickly and to more locations than for a typical Soyuz landing. For a Soyuz landing, local SAR teams (augmented by NASA personnel where U.S. Astronauts are on board) are utilized in locating the capsule and extracting the crewmembers. The Soyuz Descent Module is equipped with radio and light beacons to assist in determining its location. Future CRV requirements for crew recovery will be developed to some extent around the vehicle’s re-entry capabilities

7. Medical Evacuation and Vehicles for Transport

and potential landing sites. The vehicle itself will need to be equipped with adequate survival equipment and provisions in the event that SAR forces cannot reach the crew for an extended period of time. In the Russian space program, this has occurred on more than one occasion, with the crew isolated for the first several to 24 h. Recovery of a crew in an emergency return is different from the well-choreographed and planned nominal landings of both the Soyuz and Shuttle. Emergency recovery is not without danger to SAR forces, in large part due to the many toxic substances carried by spacecraft for propulsion and cooling. This is compounded if the vehicle lands in a remote and inaccessible area of the world. Specific plans are in place for crew recovery at different locations where a crew may land, whether the return vehicle used is a Shuttle or Soyuz, and whether the crew is returning from a short or long duration mission. The required capabilities of recovery forces are specified in NASA documentation and include rescue personnel, crewmember extraction capabilities, and medical evacuation capability via ground or aircraft. SAR forces at all potential landing sites are required to be familiar with the space vehicles used for evacuation. These plans also take into account whether there is a planned or emergency evacuation of the space station. For a future CRV that would land in the continental United States, comprehensive vehicle-specific training is planned for SAR forces. In addition secure communications between MCC Houston, the SAR team, and the returning vehicle are mandated for the success of a medical mission [104,105]. In summary, the design goals and requirements described give an indication of the challenges faced by the design team of a CRV to accommodate the effects of spaceflight deconditioning of the crew and accommodate the pathophysiological condition of an ill or injured crewmember.

Ethical Issues of Medical Evacuations from LEO While the practice of Space Medicine shares many commonalties with terrestrial preventive medicine, it also requires exercising unique medical experience and judgment. Like other fields of preventive and occupational medicine, aerospace medicine emphasizes optimizing workplace performance of essentially healthy individuals. Medical decision making concerning civil and military aviators and astronauts regularly involves weighing priorities between the safety, well-being, and career livelihood of an individual and the attainment of mission success. Achieving and maintaining this balance permeates every phase of space medicine practice, including mission design, development and prescription of countermeasures, astronaut and crew selection, training, mission preparation and execution, inflight medical monitoring, and long-term astronaut follow-up. Unlike terrestrial medical practice, the potential hazards of the space environment pose unique challenges involving the

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safety, survival, and successful return to earth of individual astronauts and even entire crews. Long-term space flight itself poses additional inherent risks. Prudence dictates careful deliberation of possible medical events well in advance of their occurrence, including consideration of pre-flight preparation, inflight management, return capabilities, potential positive or adverse outcomes, and mission impact. NASA Medical Operations has, over several decades, adopted risk management guidelines aimed at minimizing individual risk while maintaining overall mission effectiveness. Longer-duration LEO and expeditionary flights to other planets present the possibility that other limitations on certain types of missions may be required, such as a career limit of one or two ISS type missions for a few crewmembers based on cumulative radiation exposure. While every sort of inflight medical contingency cannot be predicted, generalized onboard protocols for anticipated medical scenarios can provide a framework for crew and ground personnel decisions. Despite such forethought, any medical event requiring evacuation from LEO will inevitably involve real-time judgment. Where possible, therefore, effective communication between an ill or injured crewmember, an onboard medical provider, ground-based medical support (flight surgeon), and overall mission support (flight director and mission managers) will be important to facilitate integrated decision-making. However, the crew in LEO must be prepared and equipped to make independent decisions; with expeditionary missions, this is likely to be the norm in the initial phases of a medical emergency. In many ways, a vehicle capable of assuring crew return from LEO in a medical evacuation poses more questions than it does answers. While some scenarios may be unambiguous, e.g., irreparable station depressurization, others are less clear. How long should a well-trained CMO with relatively limited onboard resources care for an acutely ill crewmember on orbit before calling for evacuation to a DMCF? If there is a single transport vehicle, does the entire crew evacuate, ending the mission, or only the ill crewmember and the medical provider? How do the risks of evacuation and landing compare to those of administering further care on orbit? Does the occurrence of a predictably fatal illness or injury alter medical evacuation decisions? In view of other mission objectives and potential additional risks, what responsibility does a crew have to recover and return a deceased crewmember? Though difficult questions, these raise ethical issues worthy of advance consideration. While flight rules and decision algorithms governing medical evacuation are designed to minimize real-time deliberation, it will ultimately be a weighty responsibility for a flight surgeon and flight director to determine, with the onboard crew, the need for medical evacuation. The frontier medical-legal issues raised by such questions are numerous. The broad groundwork underlying these issues and questions lies in the U.S. Space Act and the United Nations Space Treaty. Therefore, as space agencies have accepted the moral obligation to address medical emergencies from the

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earliest days of human space flight, the agencies have a legal duty, in the form of these international treaties, to provide for crew rescue. The first of several treaties related to crew rescue was the Treaty on Principles Governing the Activities of States in the Exploration and Uses of Outer Space, including the Moon and other Celestial Bodies. In a tragic coincidence, this treaty was signed on January 27, 1967, the day Grissom, White, and Chaffee died in the capsule of Apollo 1. The treaty identifies principles related to the rendering of all possible assistance on Earth and in space, the prompt and safe return of crew, and the dissemination of information about possible hazards. The second treaty, the Agreement on the Rescue of Astronauts, the Return of Astronauts, and the Return of Objects Launched into Space was signed in December 1968, soon after Komarov perished in the capsule of Soyuz 1 on its return to earth. The Rescue treaty specifically requires immediate notification of accidents, provision of rescue and assistance to spacecraft personnel, and their prompt and safe return to the launching authority. More recently, these matters have been addressed specifically with regard to crew return from the ISS by the partnering international space medical community and their respective agency management. Memoranda of Understanding, which define partner roles in the ISS, have been elevated to international treaty status. Though partner nations have reached consensus on a few specific concerns, such as standardizing medical care inflight and for ground support, discussion of other topics is ongoing and questions remain. What constitutes a medical disability resulting from illness or accidental injury during space flight? How is investigation of the causes of an accident resulting in medical disability conducted? What nation or nations maintain jurisdiction onboard an International Space Station? Does a hosting nation have liability for medical consequences of a guest crewmember’s injury or illness? How do we train, qualify, and certify space medicine physicians, and ensure their competence and currency? What differences, if any, should exist between standards for groundbased versus inflight care providers? Addressing these questions as well as the technical challenges is a fundamental step toward readying ourselves for further space exploration.

Beyond Earth Orbit—The Moon and Mars Potential medical transport and evacuation scenarios turn even more complex in considering a mission beyond earth orbit. Compared to a transport time of several hours from LEO, evacuation from a Moon base or a space station at one of five earthmoon fixed Lagrangian libration points would require several days at best. For a Mars mission, the one-way communication time may be up to 20 min duration and there may not be evacuation capability at all. Clearly, injuries and illnesses that would be potentially treatable on a LEO space station will carry more threatening implications if they occur in remote space.

S.L. Johnston et al.

For many reasons including medical concerns, missions beyond LEO will require levels of spacecraft and crew autonomy and self-sufficiency beyond what is currently realized. Just as fault-tolerant design of vehicle components and systems will be enhanced, crewmembers will be more highly cross-trained. The crew of a Mars or other deep space mission will likely have to anticipate how to carry their objectives through to completion despite possible incapacitation or loss of a crewmember. Additional onboard capability to manage a disabling medical condition over the relatively long-time frame of several months may be required, as well as means to deal with a deceased crewmember. In a much greater context, the expansion into the solar system will be in a staged fashion, with decreasing capabilities expected at increasingly remote sites. Medical evacuation from a deep space mission, for instance to the asteroids, may well be to a fall-back position on Mars where a greater level of care is available, rather than by default back to very distant Earth. Exploratory missions truly mark a change in potential risks to both the mission and individuals. Issues such as crew selection criteria, age at mission start, optimization of physical and mental condition, informed consent of mission risks, notification of family of medical events, and mission-consequence long-term health effects are just some of the concerns attending medical operations planning for future.

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56. Man-Systems Integration Standards, NASA-STD-3000 Vol. I, Sec. 3.0, Rev. B, July 1995. 57. Smart K. Considerations for crew rescue from the ISS, J Br Interplanet Soc March/April 2001, Vol. 54 no. 3/4. 58. Smart K. Issues in life support and human factors in crew rescue from the ISS. Life Support Biosph Sci 2001; 7(4):319–325. 59. Johnston SL, Jones JA, Ross CE, Cerimele CJ, Fox JL. NASA International Space Station (ISS) Crew Return Vehicle (CRV) Seat and Cockpit Configuration and Design Challenges, NASA Medical Operations, NASA Johnson Space Center, Houston, TX. 70th Annual Scientific Meeting of the Aerospace Medical Association, Detroit, MI, 1998. 60. Space Biology and Medicine, 1996, Life Support and Habitability Vol ll, American Institute of Aeronautics and Astronautics. 61. Nicholas JM, Fouchee HC (1990), Organization selection and training of crews for extended spaceflight, findings from analogues and implications, J Spacecr 1990; 27(8). 62. Kanas N. Psychosocial value of space simulation for extended spaceflight, Adv Space Biol Med 1997; 6:81–91. 63. Palinkas Psychosocial effects of adjustment in Antarctica: Lessons for long duration Spaceflight. J Spacecr Rockets 1990; 27(5):471–477. 64. Manzey D, Lorenz B, Poljakov V. Mental performance in extreme environments: Results from a performance monitoring study during a 438-day spaceflight. Ergonomics 1998; 41(4):537–559. 65. Sanchez M. A Human factors evaluation of a methodology for pressurized crew module acceptability for zero-gravity ingress of spacecraft. PhD Thesis Department of Industrial Engineering, University of Houston, Dec. 1999. 66. Gonzales et al. An integrated logistics support system for training crew medical officers in advanced cardiac life support management. Comput Methods Progs Biomed 1999:59:115–129. 67. Owen M, Galea ER, Lawrence PJ, Filippidis L. AASK, aircraft accident statistics and knowledge—A database of human experience in evacuation, derived from aviation accident reports. Aeronautical Journal (0001-9240), 1998; 102(1017):353–363. 68. Kane F. A Thirty Year Perspective on Manned Space Safety and Rescue: Where We’ve Been; Where We Are; Where We Are Going. In: Space Safety and Rescue 1084-5, San Diego, CA 1984, pp. 61–88, IAA 84-270. 69. Kovit B. Space Rescue, Space and Aeronautics, May 1966; 99–103. 70. Griswold HR, Trusch RB. Emergency and rescue considerations for manned space missions. Acta Astronaut 1981; 8(9): 1123–1133. 71. Housten S et al. (1992), Space Rescue System Definition, IAA 92-338, pp. 123–139. 72. Armstrong H, Haber H, Strughold H. Aeromedical problems of space travel. Aviation Medicine, 1949:383–417. 73. Petersen NV. Recovery techniques for manned earth satellites. Proceedings of the VIII International Astronomical Congress 1957, pp. 310–319. American Institute of Aeronautics and Astronautics. 74. Romick DC, Knight RE, Black S. A preliminary design of a medium sized ferry rocket vehicle of the Meteor concept, Proceedings of the VIII International Astronomical Congress 1957, pp. 349–358, American Institute of Aeronautics and Astronautics. 75. Krufft E. The considerations required in the use of a “lifeboat,” Second International Symposium on Physics and Medicine of

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8 Telemedicine Scott C. Simmons, Douglas R. Hamilton, and P. Vernon McDonald

The delivery of medical care in space is complicated by factors such as microgravity, extreme resource constraints, hazardous environments, and extreme distance from definitive medical care facilities. In addition, although the crew medical officers—those personnel required to provide in-flight medical care—are typically not physicians, after receiving a minimal amount of medical training (16–20 h for the Space Shuttle Program and about 80 h for the International Space Station [ISS] Program), they are responsible for tending to ill or injured colleagues. One method of mitigating the lack of training and experience for crew medical officers is by remote consultation with medical experts on Earth, or telemedicine. Obtaining a consensus on the definition of telemedicine is difficult. Any definition would include at least two key components: geographic separation between medical expertise and the medical care provider and telecommunication or computer-mediated interaction. A simple definition of telemedicine might be “the practice of medicine across a distance using telecommunication.” According to this definition, clinical space medicine has used telemedicine since the dawn of human space exploration. To expand on this simple definition, Grigsby and associates have developed a useful list of functional categories of telemedicine applications: (1) initial urgent evaluation of patients, triage decisions, and pretransfer arrangements; (2) medical and surgical follow-up and medication checks; (3) supervision and consultation for primary care encounters in sites where a physician is not available; (4) routine consultations and second opinions based on history, physical findings, and available test data; (5) transmission of diagnostic images; (6) extended diagnostic workups or short-term management of self-limited conditions; (7) management of chronic diseases and conditions requiring a specialist not available locally; (8) transmission of medical data; (9) public health, preventive medicine, and patient education [1]. Almost all of these telemedicine functions have been used in the U.S. and Russian space programs, although most experience until recently involved remote monitoring of biomedical

and environmental parameters and voice-only consultation via space-to-ground communication loops. When sensor and communication technologies were first implemented, they represented the state of the art in both terrestrial telemedicine and space telemedicine. With the recent proliferation of computers, high-speed telecommunications, and the Internet, telemedicine is being implemented much more widely on Earth and in space, and more robust capabilities are being used daily in clinical practice [2]. The ISS and future planetary exploration-class missions (e.g., to Mars) will require the incorporation of contemporary telemedicine concepts and technology, tempered by the resource restraints and operational realities of space medicine. This chapter provides an understanding of current telemedicine theory and applications, a historical perspective of space telemedicine, and a prospective view of telemedicine for the ISS and beyond.

Fundamental Telemedicine Concepts The first U.S. telemedicine consultation, for telepsychiatry, was performed in the 1950s using closed-circuit television [3]. Telemedicine did not receive much attention within the U.S. health care community until the 1990s, however. The growth of telemedicine can be attributed to three major factors. First, advances in computer, telecommunication, and imaging technologies enabled telemedicine to become practical and accessible. Second, the current focus on managed care, health care process reengineering, and national health care reform has stimulated industry and federal government interest in telemedicine, which has led to a concomitant increase in federal and state funding of telemedicine projects. Third, the ubiquity of the Internet has resulted in more widespread familiarity with distributed collaboration [2]. The application of telemedicine for space flight was born out of necessity, since nonmedical in-flight personnel and physical resource limitations demanded that access to medical 163

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expertise be provided via telecommunications. Simply stated, this was the only way for crews to gain access to medical expertise when in space. The practice of medicine on Earth, where many rural and inner city communities are classified as “underserved,” is fraught with similar problems of access to medical care. Underserved communities often lack primary care physicians, clinical care facilities, or both. To receive specialized medical care, patients in these communities often must travel to a major university medical center or to a large hospital many miles away. Current terrestrial telemedicine research and development is focused on improving access to medical care in all of these situations.

Modalities There are three basic and distinct modalities of telemedicine interaction: real-time, store-and-forward, and just-in-time interactions. All three are classified by latency, or delay, of telecommunications. Real-time (synchronous) telemedicine involves little or no perceptible latency. Real-time interactions include full-motion videoconferencing or a telephone conversation. In store-and-forward telemedicine, data are collected and stored off line and transmitted (or forwarded) to the destination site at a later time. Familiar store-and-forward interactions include electronic mail, facsimile, and voice mail, all of which are used quite effectively in contemporary home and office environments. A store-and-forward consultation may have a latency of more than 24 h; however, this is not much different from referring a patient to a specialist who may not actually see the referred patient for days or weeks. Somewhere temporally between store-and-forward and real-time telemedicine is the just-in-time interaction. The just-intime concept may be uniquely related to space medicine, and both clinical and operational factors distinguish just-in-time interactions from real-time or store-and-forward encounters. Just-in-time means that data are literally received “just in time” to influence the current or active patient encounter. For example, critical-care monitoring data from an astronaut or a cosmonaut on a planetary exploration mission may be transmitted to Earth continuously, in what might be expected to constitute real time. However, because of the great distance from Earth, the Mission Control Center (MCC) may not receive these data until several minutes later. (Mars communications would require 3.5–20 min to reach Earth for one way travel, depending on the relative positions of Earth and Mars.) Naturally in this situation, CMOs would have to manage emergent problems locally; but delayed data would be received “just in time” for flight surgeons on Earth to still provide meaningful input on patient management via this type of interaction. Data are considered to be “just in time” when the feedback— after having been received, processed, and returned—arrives just in time to influence the clinical outcome of the medical event. The latency of data arriving from a vehicle on its way to

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Mars may preclude a ground-based flight surgeon from assisting crewmembers in managing an acute emergency, such as a myocardial infarction. The ability of the flight surgeon to influence the outcome of a medical event depends on the type of event and the time delay (distance from Earth). Most telemedicine programs involve real-time encounters, using high-bandwidth (384 kbps to 5 Mbps) videoconferencing systems. This real-time, videoconferencing model of telemedicine often involves the interaction between the primary care physician who is attending to a patient and the medical specialist. Video cameras are used to view the patient, and special adapters are used to affix medical video instruments with specialized small video cameras. This model has several limitations, including the lack of available bandwidth in the medically underserved environments that would benefit from telemedicine, the expense associated with such systems, and scheduling requirements (having two medical care providers simultaneously available, one at each end). These systems also require technical support personnel to install and maintain the systems and establish communication links. Despite these limitations, videoconferencing is often a critical part of telemedicine in clinical applications that require real-time interaction. The assessment of neuromuscular function, including range of motion and gait, and telepsychiatry are two clinical examples that often require real-time interaction. More recently, remote consultation for trauma is taking advantage of such telecommunication systems. Videoconferencing is also valuable when the remote user is unfamiliar with operating the telemedicine equipment or is inexperienced in conducting certain clinical studies (e.g., ultrasonography) that may require telementoring during a particular medical procedure. With the worldwide expansion and widespread use of the Internet and continuous advancements in personal computer (PC) technology, the utility of store-and-forward telemedicine has grown steadily. File attachments—whether text documents, database files, still images, or audio and video clips— can be appended to electronic mail messages. Radiology, dermatology, and pathology are clinical specialties that adopted store-and-forward telemedicine very early. Two contributing factors were that these specialties already involved a level of abstraction from the patient and that their mode of practice often depends on visual media for presentation of static images. The United States Armed Forces Institute of Pathology has provided telepathology consultations since 1992 [4]. The American College of Radiology, in collaboration with the National Electrical Manufacturers Association, was one of the first of a collection of specialty societies to develop a standard for digital imaging—the Digital Imaging and Communications in Medicine (DICOM) standard. This standard addresses image display requirements (e.g., spatial and temporal resolution, levels of gray), image attributes, clinical reporting associated with the images, and messaging. Currently, DICOM is the only standard for the electronic transmittal and storage of medical images.

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Effectiveness

Digital Imagery

Several factors can influence the effectiveness of telemedicine. Bandwidth, or the data-carrying capacity of a communications system, is the most influential factor. If a plumbing system is used as a metaphor for bandwidth, the bandwidth is the size of the pipe. More “water” (representing data) can flow through a large “pipe” than through a small pipe. The smallest pipe within the system network thus influences the overall bandwidth of the system. For example, a dial-up connection to the Internet that uses a standard telephone line and 56-kbps modem is limited to the bandwidth of that connection, regardless of whether much higher bandwidth connections are present downstream. System bandwidth relates to the amount of data that passes through a connection per unit time. However, this does not always relate to the amount of information that is transferred per unit time. Hierarchically, data precede information and information precedes knowledge. As such, high-bandwidth communication of data does not necessarily lead to high bandwidth communication of information. An example of this is the bandwidth of a common telephone line versus a high-fidelity stereo. If the design requirements for a communication system that is supporting a conversation include the ability to understand the spoken word, the connection needs to be approximately onefifth the bandwidth of a standard off-the-shelf stereo. The amount of bandwidth required to transmit medical information is highly dependent on the medical scenario, the skill of the medical care providers at both ends of the communications link, and the type of medical data being exchanged. In the case of a myocardial infarction, for example, where emergency intervention is almost always required, the medical expertise at the patient’s bedside will determine the bandwidth required to remotely support this clinical scenario. If the point-of-care provider is a skilled emergency medical technician, in most cases only a telephone link is required since the information is preprocessed at the remote location. Similarly in most cases, the bandwidth required to support a medical event increases with the difference in the level of expertise between the point-ofcare provider and the remote medical support. Furthermore, a telecommunications network consists not only of data pipes, but these data also must travel through myriad “bottlenecks”—e.g., switches, routers, and gateways—that can affect latency as well. A second, major factor is the distance the data must travel. Ordinarily, in terrestrial applications, distance is not influential. However, because data travel at a finite speed, distance is a major concern for space travel beyond Earth’s orbit. Thus, the greater the distance, the longer the travel time between the location of origin and the remote expertise. Temporal delays can grow to the extent that they preclude fluid real-time interactions. Also, with the prospect of data transmission over millions of kilometers (miles)—as in the case of space missions that travel beyond low Earth orbit—communication latencies can stretch into tens of minutes, thereby compromising the benefit of telemedicine for certain scenarios.

Digitally processing and storing images, video, and audio offers several distinct advantages over traditional analog storage-and-retrieval methods. Unlike analog systems that access data serially, or temporally, digital systems can access data randomly. Duplication of digital data is “lossless” between generations; that is, no data are lost between the copies and the originals. Data in a digital format can also be easily manipulated (filtered or enhanced) by commonly available personal computers (PCs). However, the processing and transmission of video is problematic due to the tremendous amount of data contained within a video stream. The National Television Standards Committee (NTSC) video standard is the broadcast video standard used in the United States. In the NTSC standard, each second of video contains 30 frames, and each frame of broadcast-quality video contains approximately 7.4 × 106 bits of information (640 × 480 pixels per frame × 24 bits color depth per pixel), or roughly 1 megabyte (8 bits per byte). Compression techniques are therefore employed to more effectively use processing power and bandwidth and are applied to both still images (e.g., joint photographic experts group (JPEG) ) and video. The digital video industry standard is the Motion Picture Experts Group (MPEG) standard, which actually comprises two standards. MPEG-1 was developed to play 320 × 240 video at 30 frames per second from a single-speed CD-ROM (compact disk-read only memory) drive (150 kbps). MPEG-2, which became available in its final form in 1995, was designed for cable and satellite television and for the video and movie production industry. MPEG4 is not currently supported by most internet based video compression systems but will most likely appear on the market soon. MPEG4 supports streaming video, multimedia, speech synthesis and many other features including a foreground-background coding technique. MPEG4 will likely supplant MPEG2 for broadcast applications since it uses about one-half the bandwidth for equivalent video and audio quality. An important fact to consider when using videoconferencing in telemedicine is that the compression algorithms that are used for videoconferencing are all highly sensitive to rapid image changes. This is because rapid changes produce a “tiling” effect. Tiling is the appearance of obvious rectangular “sub-images,” or tiles, within an overall image. A rapid change in an image, such as from movement or lighting, causes this effect. Tiling occurs because the real-time compression algorithms try to estimate the next video frame. The stochastic nature of many video images will occasionally overwhelm the compression algorithm’s ability to predict the next set of pixels per tiles, and tiling is the result.

Clinical Efficacy of Telemedicine Historically, telemedicine programs were supported mainly by grant funding, and most programs were conducted as demonstrations of the feasibility of telemedicine and supporting

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technologies. The focus of the few formal evaluations that were conducted often involved the technical performance of systems. Clinical assessments were subjective. These early concept demonstrations and evaluation efforts were important for introducing telemedicine concepts and for demonstrating the clinical applicability that telemedical care could provide. For telemedicine to be integrated into daily clinical practice, more rigorous assessments of the efficacy of telemedicine must be conducted. Although clinical evaluations such as these have increasingly appeared in the literature since the mid 1990s, little quantitative analysis has been done on the efficacy of telemedicine. The body of formal research into the clinical efficacy of telemedicine exists in several broad categories. These categories include diagnostic agreement or reliability between telemedicine diagnosis and conventional diagnosis; the time required to receive specialty consultation; outcomes assessment; and the impact of telemedicine on patient access to care. One method of telemedicine clinical validation is to measure the diagnostic agreement (reliability) between a “gold standard” diagnosis and telediagnosis. A gold standard diagnosis is the normal method of patient assessment—usually a physician’s hands-on patient examination or a specialist’s review of traditional diagnostic studies. Examples of gold-standard comparisons include radiographic plain films vs. digitized films, or local patient auscultation vs. tele-auscultation. Nitzkin and colleagues performed perhaps the most comprehensive study of the diagnostic reliability of telemedicine when they measured the agreement between a “criterion standard” assessment and an alternative telemedicine assessment [5]. These investigators also examined the use of telemedicine for cardiac and pulmonary auscultation, echocardiography, electrocardiography, electroencephalography, obstetric ultrasonography, ophthalmologic examination, physical therapy assessment, and chest radiography. They pointed out that interobserver variability is a significant factor associated with this sort of assessment, and they cited findings from the literature that demonstrate clinically significant variability among observers using conventional techniques ranging from 15 to 30%. This study tried to account for interobserver variability by also examining the agreement between conventional examinations of the different physicians who reviewed the data and comparing these to the criterion standard. Using the results of their study (Table 8.1), Nitzkin and colleagues made several salient observations and drew some notable conclusions [5]. They observed that diagnostic reliability correlated strongly with a physician’s experience in and knowledge of the limitations of telemedicine; the remote operator’s experience affected diagnostic reliability; and the adjustment of equipment settings greatly affected the detection of abnormalities and the rate of false negatives. These observations all point out the importance of training and standardization of techniques in telemedicine. Several studies have recently determined the efficacy of telemedicine for dermatology (tele-dermatology) in both real-

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time and store-and-forward modes. The U.S. Army’s Walter Reed Army Medical Center has, since May 1998, used a storeand-forward, Web browser-based tele-dermatology system [6]. An assessment of 113 randomly selected dermatology cases demonstrated 93.8% diagnostic agreement, and only one case (0.8%) was found to be misdiagnosed [7]. In a study of real-time tele-dermatology, Phillips and colleagues investigated the effect of telemedicine on the assessment of skin tumors by comparing the findings of a dermatologist who saw patients in person with the findings of another dermatologist who remotely examined patients using a videoconferencing link [8]. The two dermatologists agreed absolutely on 59% of the 107 skin tumors evaluated, and a kappa analysis showed that telemedicine did not significantly influence the recommendation to perform a skin biopsy. Roth and colleagues compared the diagnostic accuracy of 35-mm photographic slides of wounds to digitized images of the slides (spatial resolution 640 × 425, JPEG compression) using six physician observers who first examined the slides and then the digitized images [9]. The study measured 87% (p = 0.004) overall agreement between the diagnosis and treatment from the slides and the digitized images. From this the authors concluded that the use of consumer-grade digital photography would be efficacious in tele-assessment of wound healing. An exhaustive review of the telemedicine evaluation and validation literature is beyond the scope of this chapter. Suffice it to say that similar results to those cited have been demonstrated in studies of telemedicine in other clinical specialties, including in otolaryngology, psychiatry, radiology, pathology, cardiology, and neurology. An interesting byproduct of telemedicine, one that is common throughout the specialties, is a learning effect in which the remote user at the patient’s site becomes less dependent on the tele-consult as the user becomes educated from previous interactions with specialists. Although more rigorous analyses will and should be conducted, the findings to date coupled with anecdotal evidence suggest the efficacy of telemedicine in terrestrial settings. The experience required to support crewed space missions using telemedicine will benefit greatly from the lessons learned from the terrestrial telemedicine experience.

TABLE 8.1. Diagnostic agreement among clinical studies. Clinical study Ophthalmology, physical therapy and cardiac auscultation Pulmonary auscultation and reading of chest films from video Tracings (ECG, EEG) and images (echocardiography, obstetric and telemedicine physical therapy assessment) Source: Nitzkin et al. [5].

Agreement (identical or similar to criterion standard) 91.2% conventional 86.5% telemedicine. Inconclusive; abnormalities only detected after “default” settings were adjusted. 92% for both conventional

8. Telemedicine

Space Telemedicine History The U.S. and Russian space programs pioneered the use of telemedicine in space flight. In both space programs, early missions were limited to using small space capsules crewed by correspondingly small crews. These missions required the intensive efforts of skilled test pilots and technical officers. Since members of the early astronaut and cosmonaut corps primarily were drawn from military aviators and engineers, few opportunities were available to include onboard medical or life sciences expertise. Operational realities dictated that space medicine and life science operations rely primarily on remote support from Earth-based facilities, and scientists and engineers had to develop innovative means for remote physiological and environmental monitoring. This resulted in the development of new systems and techniques for biomedical signal acquisition, conditioning, and telemetry—techniques that are the foundation of today’s clinical intensive care environment.

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radiation dose, and three passive dosimeters [14]. The dosimeters were placed at different locations on the crewmember’s body to determine dosage at specific areas of interest. Radiation data was not available real-time. Other parameters were monitored and transmitted to Earth during EVAs, primarily to determine metabolic rate during the activities. Metabolic rate was estimated by measuring the inlet and outlet temperatures of the cooling garment that the EVA astronaut wore and could also be estimated from heart rate and oxygen consumption measurements [15]. As in previous programs, biomedical data were transmitted to the launch control centers and the MCCs and were monitored continuously by the flight surgeon in the MCC. These data were particularly important for the flight surgeon to monitor off-nominal events such as the environmental control system failure of Apollo 13 (April 11–17, 1970) and the cardiac dysrhythmias experienced by crewmembers during the lunar EVAs of Apollo 15 (July 26 to August 7, 1971).

Skylab and the Apollo-Soyuz Test Project

Telemedicine in the U.S. Space Program Mercury and Gemini Project Mercury (August 1959 to May 1963) marked the first U.S. crewed presence in space. The biomedical instrumentation on early Mercury flights included electrocardiogram (ECG), blood pressure, respiration rate, galvanic skin resistance, and rectal temperature [10]. Project Gemini (April 1964 to November 1966) provided the medical knowledge and experience in human adaptation to the space environment that enabled human lunar exploration during the Apollo missions. All Gemini crewmembers wore biomedical monitoring harnesses during the 10 crewed missions. These harnesses provided two ECG leads and voice, respiratory rate, body temperature, and blood pressure monitoring [11]. The two-man Gemini crews also wore passive radiation dosimeters. Crewmembers who participated in extravehicular activities (EVAs) were fitted with leads for ECG and respiratory rate measurement [12]. Additional monitoring was included in the 14-day Gemini GT-7 mission (December 4–18,1965), when electroencephalogram signals were measured during sleep by four scalp electrodes affixed to each crewmember [11]. All biomedical data, except radiation dosimetry data, were transmitted directly to Earth.

Apollo Crewmembers in the Apollo Program (February 1966 to August 1971) wore biosensor harnesses throughout all mission phases. Biomedical monitors included a two-lead ECG, a cardiotachometer for measuring heart rate, an impedance pneumograph, and a thermistor to measure body temperature [13]. In addition to the biosensor harnesses, each crewmember wore a personal radiation dosimeter, which measured accumulated

The Skylab Program (May 1973 to February 1974), which initiated the U.S. experience with long-duration space flight, was also the first U.S. spaceflight program in which continuous biomedical monitoring was not performed. Instead the Skylab Operational Bioinstrumentation System transmitted crew biomedical information to Earth during certain critical mission activities, including launch, docking, EVA, suited intravehicular activity, undocking, and return. In addition, biomedical monitoring associated with specific experiments and radiation monitoring was conducted. The Skylab program saw the first flight of a U.S. physician in space, Dr. Joseph Kerwin. Biomedical monitoring during the aforementioned critical mission phases included measuring ECG, respiratory rate (via impedance pneumogram), body temperature, and heart rate [16]. The noninvasive automated blood pressure measuring system measured systolic and diastolic blood pressures during lower body negative pressure and metabolic activity experiments [17]. A vectorcardiograph monitored cardiac electrical activity during these investigations and during the in-flight vectorcardiogram investigations [18]. Metabolic activity experiment was supported by a metabolic analyzer that measured oxygen consumption, CO2 production, minute volume, respiratory exchange ratio, and tidal volume during exercise activity on the cycle ergometer [19]. Although the vectorcardiograph was developed for particular investigations, it could also have been used clinically for cardiac monitoring, though the need never arose. In addition to biomedical monitoring, weekly audio-only private medical conferences took place in which crewmembers consulted with flight surgeons at the Johnson Space Center (JSC) in Houston, Texas. Crewmembers could also request conferences on an ad hoc basis if specific health issues arose requiring flight surgeon consultation. Two Skylab crewmembers per mission received approximately 80 h of preflight

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medical training, and the ability of these medically trained crewmembers to describe their findings and observations was critical to the conduct of voice-only private medical conferences. The crewmembers developed a “verbal shorthand” method of describing observations, sometimes referring to figures from the Skylab Medical Checklist. During the nine-day Apollo-Soyuz Test Project (July 15 to July 24, 1974), ECG and respiration rate were monitored during periods of exercise and during launch and landing procedures. As in the Apollo and Skylab Programs, each U.S. crewmember was also assigned a personal radiation dosimeter and a passive dosimeter to measure radiation [20]. Over the course of these early phases of U.S. human space flight, the practice of space telemedicine underwent three notable changes. The first was the transition from continuous physiological monitoring and communication of medical data to the model of intermittent and context-specific monitoring, due in part to a growing understanding of human physiological responses to weightlessness. The second change was the integration of real-time communication of digital data with store-and-forward digital data communication, thereby preserving the precious communications bandwidth. The third change was the development of techniques and procedures for communicating medical observations and the emergence of remote verbal consultation with a physician in the form of a private medical conference. Such a verbal exchange represents the implementation of the most basic element of the patient-physician encounter in space.

Space Shuttle Both biomedical and cabin parameter monitoring continue to be a primary component of telemedicine in the Space Shuttle Program (April 1981–present). Cabin atmosphere parameters are continually monitored, and crewmember ECGs are monitored during hazardous operations, such as EVAs or certain medical experiments. Daily private medical conferences between the crew surgeon in the MCC-Houston Flight Control Room and the crew on board the Space Shuttle are a routine part of Space Shuttle operations. These conferences have contributed significantly to minimizing operational impacts of medical events. Until recently, private medical conferences used only air-to-ground voice communications. In the mid-1990s, two-way videoconferencing became an option via the Orbiter communications adapter (OCA) system. Flown initially as an operational flight experiment, OCA represented the first mission operations communications link to use the transmission control protocol/Internet protocol (TCP/IP) communication standard. This is notable because TCP/IP is the core standard for everyday use of the Internet. The OCA videoconferencing system on the Space Shuttle operates at approximately 128 kbps, which enables crewmembers and the flight surgeon to see each other with low-resolution images. In comparison, in typical terrestrial telemedicine applications with greater bandwidths (384 kbps to 1 Mbps) and modern video compression algorithms, the codec—a code-decoder used to convert analog to digital signals and back again, usually

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on the same chip—produces images that are considered to be of acceptable diagnostic quality, depending on the amount of motion required for a particular application. Despite its lowresolution images, the OCA videoconferencing is useful for face-to-face interactions and is well suited for conducting private family conferences in which, during lengthier Space Shuttle missions, crewmembers can visit with family members. The deployment of the OCA presented the opportunity for space medicine experts to use commercial-off-the-shelf (COTS) medical information system technology. However, challenges remained, in part a result of the relatively long round-trip satellite communication latencies of about 1.6 s. Because of these communication latencies, many COTS software products were found to operate poorly since they could not tolerate such excessive communication latencies.

Telemedicine in the Russian Space Program The first Russian spacecraft, Vostok and Voskhod, were quite similar in design. The main differences between the spacecraft were that Vostok carried a crew of two and ejection seats, and Voskhod carried a crew of three, without ejection seats. Biomedical monitoring of the cosmonauts traveling on board these spacecraft included ECG, heart rate, electroencephalogram, electromyography, and galvanic skin response [21]. Soyuz missions used essentially the same biomedical monitors as were used in the Vostok and Voskhod missions. The Soyuz vehicle, which in its current design consists of two cabins separated by a hatch, typically supports crews of two to three cosmonauts. Among the many jobs the Soyuz has performed has been servicing the Salyut and Mir space stations. A total of seven Salyut missions were launched during the Salyut Program (April 1971 to September 1986). The Salyut missions were as short as eight days (Salyut-6) and as long as 237 days (Salyut-7). Crewmembers conducted many medical experiments during these missions to determine cosmonauts’ responses to space flight and to select effective countermeasures to space deconditioning. Psychological issues were also seriously addressed for the first time in the Salyut Program, and the crewmembers were allowed two-way personal communication with their family members [22]. The Mir station, the first element of which was launched in 1986, was the next-generation Russian space station. Mir was outfitted with amenities, including private sleeping compartments, that provided a greater degree of comfort than had been seen in the Salyut stations. In addition, two-way communications with families, flight controllers, friends, and celebrities provided psychological support for Mir crewmembers [23]. On board Mir, real-time detailed physiological monitoring of exercise performance, medical experiments, and medical diagnostic evaluations during long-duration space flight became a well-established practice. The hardware suite available on the space station included a 12-lead ECG, the means to monitor respiratory rate and blood pressure, and several derived central hemodynamic parameters such as central venous pressure and cardiac output.

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Space-Based Telemedicine Investigations Two major in-flight telemedicine investigations have been conducted in the Space Shuttle Program. These have served to prove the feasibility of new diagnostic capabilities that were not a routine part of operational space medicine. One telemedicine investigation, the video fundus camera, was originally developed to support NASA’s biomedical research program. The portable dynamic fundus instrument, or video fundus camera, was developed to decrease the time required to train astronaut crews to take photographs of the retina for a flight experiment that examined the effects of zero-gravity on the retinal blood vessels. The device used a special adapter to project retinal images on a video chip instead of on the usual 35-mm film. Use of the video fundus camera resulted in a marked decrease in training time. Since the video images captured by the device were of excellent quality, the video device was used in addition to the 35-mm film version. The instrument was flown on six Space Shuttle missions. Video images of the retina were downlinked, using the video fundus camera, during the STS-50 mission (July 1992). A more extensive in-flight evaluation of clinical telemedicine capabilities was conducted in an experiment during the STS-89 mission (January 1998). Over three flight days, nonphysician astronaut CMOs performed focused physical examinations using the telemedicine instrumentation pack (TIP) (Figure 8.1). TIP was developed to extend the CMO’s capabilities by allowing the CMO to perform a multimedia medical exam and consult with flight surgeons at the MCC at JSC. During the STS-89 flight experiment, video, audio, and other examination biomedical data were transmitted from the TIP on board the Space Shuttle Endeavour to a telemedicine workstation at the MCC-Houston. The objectives were to evaluate: (1) the ability of the TIP to capture medical data on board the Orbiter and send these data to the MCC, (2) the quality of these data from a clinical perspective, (3) the usability of TIP in the microgravity environment, (4) the operational feasibility of using the TIP for interactive (real-time) air-to-ground medical examination, (5) and the operational utility of just-in-time and store-and-forward in-flight medical exams using the TIP. TIP enables a user to collect, store, and transmit a variety of clinically relevant data to a remote PC workstation (a telemedicine workstation). A flight surgeon working at this remote workstation can receive, display, and manipulate information transmitted from the TIP. The TIP has an embedded computer at its core and uses a remote-head charge-coupled device video camera that can be attached to a variety of medical imaging instruments—including an otoscope, ophthalmoscope, and a macro lens for live NTSC video streaming or capturing still images. The device also contains a digital electronic stethoscope for remote auscultation and is capable of monitoring ECG, blood pressure, pulse rate, and oxygen saturation. The TIP evaluation was conducted on three consecutive flight days in the presleep period after a private medical experiment used both the Space Shuttle Ku-band and S-band communication systems to transmit data to and from

Figure 8.1. Telemedicine instrumentation pack (TIP). Video, audio, and other biomedical data were transmitted from the TIP aboard the Shuttle Endeavour to a telemedicine workstation at the Mission Control Center during Mission STS—89. The TIP was designed to fit in a standard Shuttle mid-deck locker

the Space Shuttle and the MCC-Houston. The Ku-band system can support data communications (2 Mbps) and video downlink at the same time. The S-band system provides two bidirectional loops for voice conferencing. Crewmembers used handheld microphones to speak, via the S-band system, to the flight surgeon on the ground, and they monitored the surgeon’s voice on the Space Shuttle audio system. To maintain privacy for crewmembers, the air-to-ground conversation between the flight surgeon and the Space Shuttle was secured. The physical exam the CMOs performed was a focused procedure to assess the utility of devices installed in the TIP. The physical exam techniques commonly taught in CMO training for Space Shuttle medical operations were modified to include the use of devices supported by the TIP. These physical exam techniques include examination of the lungs and heart with a stethoscope, the eyes with an ophthalmoscope, the ears with an otoscope, and the skin with a small camera using a macro lens. Other vital signs were also measured using automatic equipment such as blood pressure, pulse oximetry, and electrocardiograms. Crewmembers were able to successfully conduct all three examination sessions, requiring an average of 51 min to complete (range: 45–58 min). The ECG acquired was a standard three-lead

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electrode system, which produces a standard rhythm strip output on the TIP screen. The quality of the acquired rhythm strips was comparable to that obtained by common three-lead systems found in many commercial defibrillators. The CMO easily read pulse oximetry using the TIP screen. Auscultation results revealed normal sounds that were easy to hear above the Space Shuttle background noise. All biophysical data points were downloaded from the Space Shuttle within minutes, and the flight surgeon and clinical consultants performed quality control. Video images were acquired by a macro lens, an otoscope, and an ophthalmoscope. The macro lens exam was conducted to establish the clinical utility of acquiring superficial images of the skin and other dermatological structures. Tympanic images acquired on orbit using the otoscope clearly revealed a nondependent distribution of intra-auricular fluid. The ground-based consulting team visualized valsalva maneuvers. The external auditory meatus and other external auricular landmarks were well visualized. The ophthalmoscope was effective for performing a foreign object survey as well as conjunctiva, corneal, and iris exams, and it was also effective for producing images of sufficient diagnostic quality. A retinal exam was not attempted due to the limited training available for the crew and the need for application of topical pharmacological agents. The video portions of all three examination sessions were downlinked in real time. Real-time video from the generalview Space Shuttle camera enabled consultants to observe the conduct of the exam, including placement of monitoring sensors and transducers. Still images captured by the crew were downlinked to the telemedicine workstation. It was the unanimous consensus of the ground-based flight surgeons that all data acquired during this evaluation could have been used effectively for real-time or just-in-time clinical decisions. During the last physical examination session, communications via the Ku-band antenna (required for wide bandwidth and video communication) were not available on orbit and the CMO conducted the entire biomedical exam without any observation by or direction from the flight surgeon. This experiment demonstrated that a non-medically trained crew can successfully collect clinically useful biomedical data that prove the feasibility of store-and-forward telemedicine [24,25].

Space Telemedicine Concepts Applied in Terrestrial Health Settings Space Technology Applied to Rural Papago Advanced Health Care In 1975, NASA applied its communications expertise to a terrestrial telemedicine project. NASA and the Indian Health Service performed a two-year telemedicine project

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on the Papago Indian Reservation near Tuscon, Arizona. This project, called Space Technology Applied to Rural Papago Advanced Health Care (STARPAHC), involved mobile health units that were linked to an Indian Health Service hospital using a microwave communication system. Non-physician medical personnel performed examinations aboard the mobile health units, and video-based, audiobased, and text-based medical data were transmitted to the Indian Health Service hospital’s staff for review. Diagnostic imagery obtained for transmission included radiography, microscopy, otoscopy, and ophthalmoscopy. Fuchs stated that the project’s major benefit was providing access to health care resources not previously available in the local area [26].

Other Telemedicine Projects NASA has more recently provided satellite communications for several national and international telemedicine projects. The first projects, applications technology satellite-1 (ATS-1) and its follow-on, ATS-6, were used to provide “teleconsultation services” in telemedicine experiments that involved 14 villages in the central Alaskan Tanana Service unit [27]. NASA provided ATS-3 for both the American Red Cross and the Pan American Health Organization to support the medical relief effort after the 1985 Mexico City earthquake, in which there were as many as 10,000 casualties [21]. In December 1988, a major earthquake devastated much of Soviet Armenia, resulting in 150,000 casualties. NASA quickly developed a plan for using telemedicine via satellite and landlines to provide medical relief for victims. Because of several technical and logistical difficulties, the system was not operational until May 1989. Since the system could not be used to deal with emergent health problems, the focus was shifted to follow-up consultations. Rayman reported that these follow-up telemedicine consultations with specialists at The Uniformed Services University of the Health Sciences (Bethesda, Maryland), the University of Maryland Institute of Emergency Medical Services (Baltimore, Maryland), The University of Texas Health Science Center (Houston, Texas), and the Latter Day Saints Hospital/University of Utah (Salt Lake City, Utah) resulted in a change from original diagnoses in 25% of cases and altered treatment in 24% of the cases. [28] One month after the Armenian earthquake relief project began, a major gas explosion from a rail mishap occurred near the city of Ufa, capital of the Bashkir Republic (a member of the Russian Federation), which resulted in 1,200 casualties. Within 3 weeks of this explosion, the NASA-led telemedicine system was adapted to provide burn victims with consultative support. Along with providing needed medical support to disaster stricken populations, this project, later called the “Spacebridge to Armenia and Ufa,” provided NASA with a wealth of practical knowledge in using satellite systems for telemedicine.

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Internet Spacebridge Because of the progress made by the U.S.—Russian collaboration during the “Spacebridge to Armenia and Ufa” project, and to explore the telemedicine applications of emerging Internet and Worldwide Web (WWW) technologies, NASA next undertook the “Spacebridge to Russia” Internet telemedicine project. The goals of the project were to: (1) Further develop operational space telemedicine and (2) test and verify the use of the Internet for telemedicine and (3) promote terrestrial applications of NASA’s telemedicine and telecommunications technologies [29]. The “Spacebridge to Russia” project involved deploying UNIX-based computer workstations at several United States and Russian sites, which were connected via the Internet, using both interactive (real-time) and storeand-forward modes of telemedicine. The multicast backbone (MBONE)—an open standard for simultaneous, multi-point communications using the Internet—was used for interactive consults and lectures. For store-and-forward telemedicine, a NASA-developed hypertext multimedia medical record was viewed and navigated using a Web browser [2]. Cases were posted to two mirrored servers in the U.S. and Russia. Any consultant who had proper authorization credentials could review a case and post recommendations to the servers. The “Spacebridge to Russia” project had several significant implications for the future of both terrestrial and space telemedicine [2,29]. The project demonstrated the feasibility of using the Internet for telemedicine. Open-source data representation and protocol standards enabled physicians from different cultures and time zones to use disparate PC platforms to collaborate on cases in a store-and-forward manner. Also, contemporary Internet security features ensured that only authorized personnel could view patient-specific information. The significance of this project will be evident as future, multilateral space missions incorporate Internet-like technologies for telemedicine.

Advanced Communications Technology Satellite NASA has recently completed operation of the experimental advanced communications technology satellite (ACTS) program that will further advance the capabilities of satellite communication. This satellite is operated in the highfrequency Ka-band, which has a large available bandwidth. The ACTS was available for experiments in several fields, including telemedicine. During the winter of 1994, JSC completed a telemedicine experiment using ACTS and a video fundus camera. During eight sessions conducted over four weekends, medical specialists at JSC performed telemedicine medical examinations on 29 patients from the Fitzsimons Army Medical Center (redesignated U.S. Army Garrison Fitzsimons since 1995), Aurora, Colorado. A video fundus camera was used for video fundoscopy and intravenous fluorescein angiography. B-scan ultrasonography and three-dimensional stereo imaging were also performed. Each consultant at JSC individually made a

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diagnosis before group discussions took place in which a consensus diagnosis was determined. These diagnoses were then compared to the patient’s medical record. The kappa score for agreement between the consensus diagnoses and the known diagnoses (from the medical record) was 0.9378 (p < 0.001). This study thus demonstrated the clinical utility of the fundus camera and the ACTS for telemedicine.

Terrestrial Telemedicine Instrumentation Pack (Tip) Evaluations Evaluations of different TIP embodiments were conducted by researchers throughout the design and development process. The first terrestrial prototype was clinically evaluated during 1994 in a family medicine clinic in Dickinson, Texas. This prototype was connected via a 1/2 T1 (768 kbps) videoconferencing system to the University of Texas Medical Branch at Galveston, Texas. Nurses at the center used the TIP to examine patients and to consult with otolaryngology, dermatology, and ophthalmology experts at the Galveston facility. The study provided useful technical, training, and human factors information that was applied to the design of the TIP. In August 1998, the JSC Medical Operations Branch delivered a TIP unit to St. Vincent Hospital and Health Center in Billings, Montana, to be used in the Montana Partners in Health Telemedicine Network. This network, developed to enhance delivery of healthcare to rural Montana, is supported by a Telemedicine Grant through the U.S. Department of Commerce Telecommunications and Information Infrastructure Assistance Program. The original partners in this project included St. Vincent Hospital and Health Center; the Indian Health Service, Billings, Montana; the Crow/Northern Cheyenne Hospital, Crow Agency; and the Northern Cheyenne Clinic, Lame Deer, Montana. Funds for constructing the TIP for the project were provided by the JSC Technology Transfer and Commercialization Office, whose mission is to “transfer and enable commercialization of NASA technologies to the private sector to create jobs, improve productivity, and increase competitiveness of United States companies.” A short pilot study, which used the TIP to provide home care to the “inactive” diabetic population, was conducted in the Northern Cheyenne reservation located in southeastern Montana. For the purpose of this study, inactive diabetics were defined as individuals with a known diagnosis of diabetes who had not received care in the Lame Deer clinic within a year or more. Of the 488 diabetes patients on the reservation, approximately 170 were considered inactive at the time the study was initiated. This target population was chosen for several reasons: (1) Management of diabetes and its complications are of major concern in the Native American population. (2) The Indian Health Service has an existing standard of care for patients with diabetes, including baseline studies and physical examination criteria. This protocol addresses a wide variety of potential diabetic complications, including skin ulcers, hypertension, and ocular and cardiovascular disease.

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Therefore, use of the TIP as an adjunct to the standard diabetes protocol tested all of TIP’s capabilities in a head-to-toe diabetes examination. (3) The study offered an opportunity to reach out to the inactive diabetic patients who were not coming into the clinic. The primary goal of the project was to evaluate the TIP in this particular environment with this target patient population to determine improvements in the design and operation of integrated, portable medical systems that can be applied in space medicine. The secondary goal was to evaluate the utility of such systems for terrestrial applications. On the whole, this initial evaluation project met expectations. The TIP and telemedicine demonstrated potential clinical benefits in this population, and patients were satisfied and excited about their experience. However, process and workflow issues remained problematic. These must be addressed in future project phases. On the basis of the findings from this pilot project, investigators made recommendations to: (1) deploy TIP in satellite clinics, (2) cluster home visits geographically, (3) improve case turnaround, (4) provide more training and practice for TIP users, and (5) study the clinical efficacy and effectiveness of this approach. Investigators also recommended using Partners in Health Telemedicine Network specialists as integral members of the health care team since, in the delivery of telemedicine care, such individuals become critical. Finally, as the logical extension of successful store-and-forward telemedicine, a recommendation was made to explore the utility of real-time telemedicine applications.

Operation Strong Angel NASA has formally identified the need to develop technologies and procedures to manage trauma and acute medical problems as fundamental to space operations. Increased mission duration and the additional risk associated with construction of the ISS have necessitated an expansion of existing on-orbit medical care capabilities. The ability of portable critical care monitors to provide real-time patient data from a remote environment via a satellite communication network was evaluated as a part of the U.S. Navy’s Operation Strong Angel humanitarian relief exercise in Hawaii [30]. “Strong Angel” was an experiment in combined civil and military operations for humanitarian assistance performed as an extension to the RIMPAC 2000 Naval exercise conducted jointly by the Pacific Rim countries. This international exercise took place in the waters off Hawaii from May 30 to July 6, 2000, and brought together the maritime forces of Australia, Canada, Chile, Japan, the Republic of Korea, the United Kingdom, and the United States of America for training operations. More than 50 ships, 200 aircraft, and 22,000 sailors, airmen, marines, soldiers, and coastguardsmen were involved. Strong Angel was based on a scenario in which several thousand ethnic minority civilians fled to a neighboring region as a result of a campaign of oppression. The government of the neighboring region did not possess the

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logistical capabilities to deal with a significant refugee crisis and requested international humanitarian assistance. This came in the form of “Strong Angel.” Further evaluations of portable critical care monitors conducted during Operation Strong Angel included the usability of the remote interface, clinical functionality in harsh environments, and engineering design with respect to potential use on the ISS. During the operation, ten critical care monitors demonstrated designs and functionality consistent with ISS performance requirements, but only three of these critical care monitors supported communication over the satellite communication network. All three required a secondary network gateway computer to translate proprietary protocols to TCP/IP. Since proprietary communication protocols have typically prevented critical care monitors from integrating with standard TCP/IP intranets and the Internet, adoption of medical device communication standards by these vendors will benefit telemedicine both terrestrially and on the ISS.

Telemedicine and Medical Data Management in the International Space Station Program Space medicine operations in support of ISS crewmembers represent a paradigm shift from Space Shuttle medical operations. The ISS medical capability is embodied in the integrated medical system that comprises the U.S. crew health care system (CHeCS) and a suite of Russian medical devices and supporting infrastructure. Because the medical system on board the ISS is a hybrid, new requirements were necessary to acquire, transmit, distribute, integrate, and archive significant amounts of private medical data. These data, which are acquired by disparate systems, require timely, reliable, and secure distribution to different program participants with a vested interest in ISS medical data. Thus, episodic telemedicine consults are now embedded in a continuous effort to provide care at a distance for the ISS crew. This effort includes providing ambulatory care, emergent care, prevention and countermeasures, and environmental monitoring. To accommodate this varied and continuously growing array of data, the Space Medicine Division at JSC is in the process of making a transition to a fully electronic system in support of mission medical operations. The first phase of this effort is seen in the installation of an electronic patient record-keeping system at the JSC clinics. The utility of this electronic patient record system and of its supporting communications and data management infrastructure will be expanded to accommodate all of the participants in ISS medical operations. Heavy emphasis is being placed on the development of Web-enabled access to multiple data sources using desktop integration of these data to facilitate analysis and reporting.

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The capabilities of the space medicine data systems are designed to be compatible with MCC and JSC information technology standards for communication and security. The global requirements that ISS space medicine operations must fulfill and that motivate the need for a secure network include the following: 1. Securely manage all crewmember health-related data/ information originating from both on-orbit (ISS, Space Shuttle, etc.) and ground-based (preflight data entry, etc.) data sources. 2. Provide a means by which to facilitate the secure management and transmission of all pertinent crew health-related data, both internal and external to the MCC-Houston. 3. Provide the flight surgeon with the ability to quickly and securely access all pertinent crew health-related data and information as necessary (i.e., real-time, etc.) throughout a mission and, at the point of care, to enable rapid decisionmaking and provide high quality health care to the crew. 4. Provide secure, remote access/connectivity to healthrelated data and information, systems, and applications to all pertinent remote clients (e.g., electronic medical record) and consultants. 5. Provide a coordinated plan and resources for securely storing and managing all crew health-related information and data. 6. Provide an automated data transmission/distribution system that will enable secure and reliable communication, data translation and transformation, monitoring and alerting, and routing of data and information among systems, applications, and data stores to provide overall integration between application, system, and database functions without the need to develop and maintain custom pointto-point interfaces. 7. Provide the capability to process information-sharing protocol data that are stored in the orbital data reduction complex for inclusion in the medical data repository. 8. Provide the capability to process and display ISS telemetry. 9. Provide commanding authority to medical devices. 10. Provide the capability for private, multicast video conferencing.

Onboard Network Architecture The ISS is equipped with several networks that are designed to support a variety of operations. Relevant medical data communication systems are shown in Figure 8.2. Command and control of mission-critical systems is achieved via a 1553 bus—the highly reliable communications protocol used commonly in high-performance aircraft. NASA medical devices were designed to nominally communicate via one of four CHeCS 1553 data buses to one of several centralized computers (Figure 8.2). The ISS is also equipped with an operational local area network (an Ops LAN) to provide an alternative communications path to the 1553 and to provide the capability for video

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teleconferencing. A file server computer is linked to other laptops via the Ops LAN, a radio frequency and wired Ethernet network of approximately 700 kbps bandwidth. The medical equipment computer (MEC) is connected to the Ops LAN. The payload Ethernet consists of standard 10BaseT Ethernet lines and protocols and two payload Ethernet hub gateways, located in the U.S. Laboratory module, that provide a 10 Mbps data rate. The payload fiber-optic network is used to send high-rate payload and a limited amount of systems data to the ground via the Ku-band and to route high-rate data between payloads on board the ISS. This network provides a bandwidth of 100 Mbps.

Space-to-Ground Communications Space-to-ground communications capabilities on the U.S. orbital segment are based on two systems: S-band and Ku-band. The S-band communications system is used for primary command and control of the ISS. It provides air-to-ground voice communications and is used to downlink critical system telemetry data either in real time or in store-and-forward format. The S-band provides a forward bandwidth (to the ISS) of 72 kbps and a return bandwidth (to the ground) of 192 kbps. When it is implemented within the command and control architecture and with other operational factors considered, however, the actual bandwidth available for space-to-ground medical data transfers is approximately 60 kbps. The Ku-band is nominally a payloads resource with oneway data transfer supporting payload file transfer, some payload system telemetry, and the ISS video system. The Ku-band provides a total bandwidth of 50 Mbps to the ground from 12 channels. Its subsystem overhead uses approximately 6.8 Mbps, leaving about 43.2 Mbps of useable capacity. One channel of the Ku-band is dedicated to the Ops LAN network that provides 6 Mbps downlink and 3 Mbps uplink for operations. The Ops LAN connects many operational computers to the space-to-ground link and thus offers an Internet-like connection with the ISS. Communications with the U.S. orbital segment are nominally provided using two high-bandwidth tracking, data, and relay system satellites (TDRSS). Signal reception is highly directional, particularly for high bandwidth Ku coverage, requiring precise antenna pointing and tracking. TDRSS coverage may be compromised by impingement of the ISS structure itself into the reception path as well as non-overlap in TDRSS satellite coverage. Consequently, communications with the ISS is not continuous. Indeed, expected coverage during the assembly complete phase is estimated in the 55–65% range. A third tracking, data, and relay system satellite is available and permits coverage to rise to over 90% during contingencies such as systems failures or medical events requiring ground communication. However, access to this resource is not immediate, and the decision to call on it is made only by the Flight Director. As a result, communication with the crew and onboard systems is subject to regular losses of signal.

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Figure 8.2. Medical data communication systems. The ISS is equipped with several networks designed to support a variety of mission operations. This diagram illustrates at a high level the relevant data communication pathways used to transfer medical information

The Russian Segment of the ISS can communicate with the MCC-Moscow using direct space-to-ground links during times when the ISS is within the range of ground tracking stations. This communications capability can be expanded by using Russian satellites when tracking stations are not in range. The flow of station telemetry into the MCC-Houston and the MCC-Moscow can be facilitated by either Russian or U.S. space-to-ground networks. During certain high-risk activities, such as Space Shuttle or Soyuz docking or undocking with the ISS, the use of both networks is preferred to provide telemetry to the MCC-Houston and the MCC-Moscow. The ability to command the ISS using either of these space-toground communication assets is also preferred during highrisk activities. Medical data are transferred using both of the communication systems and arrive in a timely manner to the lead flight surgeon in the MCC-Houston.

Ground Segment Communications from the U.S. orbital segment pass through White Sands, New Mexico, and are routed to either JSC (operations data), or to the Marshall Space Flight Center in Hunts-

ville, Alabama (payloads data). Each of the partner control centers is linked to the MCC-Houston through an “external interface system.” Inside the MCC-Houston are several isolated networks. Data communicated via the S-band pass into the Ops LAN. This network is considered mission critical and therefore is fully redundant and highly secure. Data from the OCA/Kuband are passed on to the OCA LAN. Finally, flight control disciplines have access to the JSC network for email and general office services. NASA space medicine has established a dedicated data center at JSC. This center is protected by its own firewall and is connected to users by virtual private network (VPN) technology. Access is carefully controlled to protect the private medical data stored on the servers in this center. The center contains the electronic medical record with live interfaces to the clinical laboratory information system at JSC and the Longitudinal Study of Astronaut Health (LSAH) epidemiological database. These interfaces operate on a middleware “interface engine” system. The data center also supports an FTP [final transfer protocol] server, which acts as a central repository for all ISS medical data.

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Implications for Telemedicine From a medical perspective, understanding the network and communications systems infrastructure of the ISS is crucial since these systems will provide the infrastructure by which care is provided at a distance. Issues of latency, bandwidth, availability, quality of service, etc., influence exactly what the nature will be of that “care at a distance.” Simply, these technical factors play a fundamental role in defining the medical support concept of operations. Thus, if we know that using the S-band provides a communication bandwidth that is equivalent to a 56-kbps modem and, moreover, that this bandwidth is only periodically available, we know that very careful decisions must be made regarding the resources placed on board the ISS. It also means that the medical expertise of the flight surgeon on the ground can be relied upon simply by invoking the command to “Call Surgeon!” The promulgation of the Internet is another contributing force of change that must be acknowledged when considering how to evolve the ISS medical concept of operations. Several key Internet technology developments—including VPN, public/private key infrastructure (PKI), high-speed commercial connectivity, interface engines, and partner collaboration tools—have caused us to rethink our mission support philosophy. Traditionally, ground support of mission operations has been largely centralized and, for the most part, wholly contained within large MCCs. The development of networked collaboration and associated technology enables a distributed vision for mission support, in which centralized support centers are augmented by “on-call” mission support personnel outside the centers. For ISS medical operations, this could result in on-call flight surgeon and biomedical engineer support from their offices or homes. Also, this would enable peerto-peer collaboration between the crew surgeon or surgeons in the MCC-Houston and medical personnel in international control centers or agency offices. This approach may be more practical, and potentially more cost-effective, than the traditional around-the-clock support philosophy.

Current Utilization for ISS Telemedicine It is important for the flight surgeon to understand the sources, accessibility, and reliability of data that will permit medical decision-making. Medical data are transmitted from the ISS to the flight surgeon in the MCC-Houston via a variety of pathways. The current operational flow of data from onboard systems to the ground control team is depicted schematically in Figure 8.3. A central component of this system is the MEC, which is intended to serve as the primary control, display, and downlink interface for ISS medical data. This personal notebook computer, which is a variant of the generic ISS notebook computer or portable computing system, is dedicated to CHeCS. CHeCS systems with communication interfaces compatible with the MEC will initially download their data to the MEC, where these data will be stored on the hard drive for later

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downlink. Other CHeCS systems will store data locally on PCMCIA cards [personal computer memory card international association cards; now more typically known as PC cards] that will be removed from their respective devices and inserted into the MEC for subsequent data transfer. The CHeCS portable clinical blood analyzer has direct data interface capabilities that may be exploited in the future. Current procedures call for portable clinical blood analyzer data to be entered by keyboard into a database on the MEC. Using existing data transmission capabilities should eliminate transcription errors and facilitate direct incorporation of these data into a digital mission medical record. Another method allows users to directly enter data into the MEC using the MEC keyboard. The In-flight Examination Program, an electronic medical record that is optimized for spaceflight examinations and for CHeCS-specific diagnostic studies, is resident on the MEC for clinical data entry. Files stored on the MEC can be transferred via the Ku-band/OCA system or 1553 data dumps. Although most CHeCS data will be stored and forwarded, certain devices can downlink data in a real-time mode, either via one of the four CHeCS 1553 buses available in different ISS locations or through the MEC. The CHeCS 1553 buses connect directly to the payload computer for real-time downlink from the MEC. Also, other medical devices, including the defibrillator, blood pressure/ECG monitor, volatile organic analyzer, and several radiation monitors (the tissue-equivalent proportional counter and the extravehicular and intravehiclar charged-particle directional spectrometers), have this capability. The defibrillator can transmit a single-lead ECG “rhythm strip” in real time via the 1553 bus and payload computer, and the blood pressure/ECG monitor can telemeter three ECG leads in via the MEC. In addition to real-time downlink, these 1553-enabled devices can buffer their data in memory and perform subsequent “normal” or “extended” data dumps, depending on communications availability. Other methods of data flow include the crew verbally delivering data or sending e-mail. The latter two categories pose particular problems for accurately communicating and archiving these data, since the nature, format, and content of the message are much less formal than the other examples we described above. Private medical conferences, nominally intended as private video teleconferences between a crewmember and a ground flight surgeon, are an important element of medical care for the ISS. One might consider this as equivalent to the history-taking portion of any patient encounter. However, these conversations facilitate and establish a rapport between physician and patient, and these opportunities for one-on-one personal communication are vital components in maintaining a healthy crew, especially during a long-duration mission. Therefore, the psychological aspect of these interactions should not be underestimated. Finally, medical data may also be acquired from nominally investigative systems such as the metabolic gas analyzer and sonograph and communicated to JSC via the Marshall Space Flight Center and its Telescience Center. Consequently, the flight surgeon discipline and integrated medical group generally face a significant challenge when it

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Figure 8.3. Medical data are transmitted from the ISS to the Flight Surgeon in MCC-H via a variety of pathways. This schematic depicts the current operational flow of data from onboard systems to the ground control team. A central component of this system is the Medical Equipment Computer (MEC), which is intended to serve as the primary control, display and downlink interface for ISS medical data

comes to developing an integrated plan for medical data handling simply due to the fact that the method, pathway, and medium for communicating these data varies significantly. The result is a heavy manual role in receiving, capturing, integrating, and comprehending these data. However, efforts are under way to semi-automate this process by using stateof-the-art medical data management tools where possible.

Commercial-off-the-Shelf (COTS) Enhancements Diagnostic imagery is a key component of telemedical capabilities. In particular, ultrasound is increasingly becoming an adjunct to plain film x-ray. Space-relevant applications of this technology may include the detection of renal calculi, hemoperitoneum, and pneumo- and hemothoraces. The Human Research Facility, which is currently on board the ISS, has an ultrasound system (the HDI 5000 (Advanced Technology Laboratories, recently bought by Phillips Medical Systems) ) as part of its life sciences research hardware complement for echocardiographic and other ultrasound imaging. Although the system is nominally intended for research purposes, the

HDI 5000 system is available for use as a clinical diagnostic device. However, implementation of this clinical capability raised several questions, including: (1) Can the Human Research Facility ultrasound and the ISS communications infrastructure be integrated to deliver real-time streaming video to the flight surgeon? (2) Can this system deliver the minimal field rate and resolution requirements to permit reliable and accurate diagnoses? (3) Can a minimally trained CMO capture reliable diagnostic images? (4) Are terrestrial sonographic diagnostic protocols appropriate and efficacious in weightlessness? These and other implementation issues have been addressed in a manner that demonstrates a prototypical evolution of a telemedicine capability (see Chap. 10, Medical Imaging). Specifically, the solution emerged from a confluence of constraints. Among these constraints were communication bandwidth and system integration (technology), skill level of the local care provider and remote care provider (training), and definition of appropriate diagnostic protocols (clinical and anatomical). The human factors of using these devices in a clinical scenario under the conditions of microgravity also

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The Future: Telemedicine for Exploration-Class Missions

Figure 8.4. This ISS crewmember is positioned in a comfortable manner in front of the Health Research Facility. It can be seen that the ergonomics involving the use of standard interface devices such as the display, keyboard and mouse may not be the most optimal in microgravity for medical situations (Photo courtesy of NASA)

must be considered. The terrestrial approach to using keyboards and mouse pointers is complicated in microgravity. Most COTS medical devices rely on gravity to facilitate the patient and caregiver encounter. These ergonomic assumptions may need to be reengineered for microgravity environments (Figure 8.4). Initially, as in previous space programs, ISS medical operations will rely on the observations and diagnostic judgment of CMOs, who are not usually physicians. Since a CMO is required to describe an observation or a physical finding to a flight surgeon on Earth, potentially critical crew health or mission decisions would be made on the CMO’s interpretation of a heart sound, a rash or lesion, or an otoscopic or ophthalmoscopic exam. The capability to transfer images, video, auscultation, and other data directly to the flight surgeon so that he or she can virtually make an observation can provide an increased level of diagnostic confidence.

Designing an exploration-class mission telemedicine system must consider myriad factors, including mission profile, users, intended use, information sources, and available technologies. The first Mars exploration missions may take place with an international crew of four to six persons. Assuming there are no major developments in propulsion technology, the entire trip may last 900–1,000 days, with a 600-day stay on the Martian surface and 180 days required each way for interplanetary transport. This mission will expose crewmembers to hazardous, confined, and engineered environments during the entire period. It is likely that at least one of the Mars crewmembers will be a physician, and one of the other crewmembers will be a CMO with some degree of medical training. The other crewmembers should also be able to interact with the system— usually as patients—and they also may enter or browse some of their own data. This predicates that the information system be designed to accommodate both medically sophisticated and unsophisticated users. On Earth, flight surgeons, mission controllers, and medical specialty consultants should use similar user interfaces for support continuity. Current medical operations concepts rely on non-physician CMOs who have minimal medical experience and who are supported by extensive communications with Earth-based medical personnel. This philosophy is also predicated on the ability to return to Earth for definitive care, as these missions are wholly conducted within low Earth orbit. Missions outside low Earth orbit, including crewed Mars exploration, will require a paradigm shift in medical support. Crewmember illness or injury will have to be treated in flight, as the Mars crew will be from 35 million to 230 million miles away, making return to Earth for medical treatment unfeasible. Traveling at 299,338 kilometers per second (186,000 miles per second), radio communication will require up to 20 min to reach Mars from Earth. Extended periods of communication blackout may leave the Mars explorers without Earth contact for weeks. Crews will therefore have to manage acute medical events and recover from chronic complications without assistance. These potential maladies, including permanent incapacitation or injury, will require unique applications of telemedicine. As mentioned previously, bandwidth “bottlenecks” and barriers (routers, firewalls, switches, etc.) minimally affect communications latency on Earth because the distances are short (relative to light-seconds). However, distance will substantially affect latency during planetary exploration missions. As a result of the latency involved in planetary mission communications, telemedicine will be primarily conducted in a store-and-forward mode. Although real-time consultation with Earth will not be possible during emergent care, the Mars mission telemedicine system should record and transmit data real time from the onboard medical instrumentation and biomedical monitoring systems. This will enable subsequent

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review by the onboard crew physician and Earth-based medical personnel. The store-and-forward approach will be useful for specialty consultation, patient follow-up after emergencies, and preventive medicine. However, if missions involved multiple inhabited Mars bases or pressurized rovers, real-time or just-in-time telemedicine could be practiced between sites. Medical tele-presence, or tele-intervention, is another concept related to telemedicine. This involves direct patient intervention from a distance and includes tele-surgery. Latency makes tele-intervention from Earth impractical for the Mars missions. The communications infrastructure for a Mars mission will be similar to low Earth orbit. A constellation of satellites similar in function to TDRSS will be needed in Mars orbit to facilitate communication with the surgeon console when a direct “line of sight” with Earth does not exist. The unique environments that are associated with space travel and remote Earth settings, such as Antarctica and undersea habitats, may have adaptation patterns similar to those expected to occur during Mars missions. Countermeasures to the deleterious effects of space flight have been developed in both the U.S. and Russian space programs and will be used during Mars exploration missions. Each crewmember will have a countermeasures “prescription” to follow. Both the prescription and the biomedical data monitored during execution of the countermeasures program will need to be tracked by the crewmember, the crew physician, and the Earth-based medical personnel. Routine tests of crew physiologic metrics will be useful to determine the efficacy of the countermeasure prescription and to track the course of crew health. Environmental monitors will also be linked to the system, so environmental variables, including radiation, pressure, contaminants, temperature, etc., can be logged in the electronic medical record used in medical diagnoses and treatment. Biomedical monitoring during EVA will likely include internal suit parameters (air temperature, humidity, space suit pressure, etc.), physiologic variables (ECG, metabolic rate, skin temperature, etc.), and external environmental variables (radiation type and dosage, external temperature, etc.), which must be automatically entered into the system. Automated entry of periodic physical and psychological monitoring data will help chart the progress of the countermeasures regimen and would include data obtained during exercise or tests of orthostatic tolerance, motor skills, and cognitive ability. Normal preventive health care operations will include periodic multimedia wellness examinations. The Mars telemedicine system will acquire inputs from an array of sensors and devices. A variety of imaging sensors will acquire time-based (video) and still images from specialized medical cameras, endoscopes, and noninvasive imaging devices (i.e., sonography or roentgenography). Biomedical sensors will measure physical (blood pressure, heart sounds), electrical (ECG), and chemical (blood and urine chemistry) aspects of crewmember physiology. Examiner observations and comments will also

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need to be recorded in the system. These may take the form of progress notes via text or voice recordings. In the event of an illness or injury, the health informatics system must be able to collect a plethora of information and present it to the crew physician in a manageable form. A Mars telemedicine system will benefit from developments in several technologies. A critical assumption is that these technologies will be available from three to five years before Mars departure so that sufficient time is available for integration within the Mars health care system. All Mars systems will benefit from advances in computer, telecommunication, manufacturing (microtechnology and nanotechnology), and power technology. Developments in sensor and imaging technologies will reduce or eliminate the invasiveness of medical diagnosis. Improvements in the way humans interact with instrumentation, computers, and data will offer perhaps the greatest effects on an exploration telemedicine system. Advances in display technology—including large, low-power, flat panels, pen and touch-screen interfaces, heads-up displays, and holography— will benefit Mars-based and Earth-based users. Voice and handwriting recognition will enable a more natural interface. These technological advances can occur on Earth because of its friendly radiation environment. Radiation can cause catastrophic failures in electronic equipment which uses advanced high density microelectronic circuits, such as that commonly found in currently manufactured medical electronics. The ability for radiation to cause equipment failures will increase with further electronic miniaturization. The use of modern technology in medicine is usually born out of an evidenced based requirement for it use clinically and therefore the capability and features of future medical hardware will most likely also be a medical requirement. Given that we will not walk on the Moon for at least another 10 years, will we be able to use COTS medical technology? Will we accept legacy medical hardware for future exploration missions or build “non-COTS” advanced radiation hardened medical hardware? The unique requirements of crew health prevention and monitoring during the past 40 years of space travel has mandated that the space medicine discipline depends on telemedicine as the major means of delivering health care. This paradigm will be dominant until significant medical technology and skill becomes resident on orbit. The cost of creating advanced clinical care capability on-orbit prevents this from happening, and currently deorbiting and returning a patient to a tertiary care facility on earth is a more effective and inexpensive solution to mitigate risk of the most serious illness and injury. If advanced medical capability is not present, the ability to monitor crew health and to prevent illness during missions will require the use of telemedicine. The amount of reliance on Earth-based medical support needed for an exploration-class mission is not well known; however, high-fidelity, long-duration simulations on Earth and on the ISS may help address these issues. The role of telemedicine in exploration-class missions will probably be similar to its present role on Earth: as a

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subset of health informatics that serves as the transport means for the exchange of medical information. Because no terrestrial telemedicine paradigms create a 5- to 20-min delay of real-time data streams, the unique requirements of space travel will again challenge our ability to remotely deliver medical care.

References 1. Grigsby J, Schlenker RE, Kaehny MM, et al. Analytic framework for evaluation of telemedicine. Telemed J 1995; 1:31–39. 2. Sargsyan AE, Doarn CR, Simmons SC. Internet and World Wide Web technologies for medical management and remote access to clinical expertise. Texas Med 1998; 94:75–80. 3. Wittson CL, Dutton R. A new tool in psychiatric education. Mental Hospitals 1956; 7:11–14. 4. Elsayed AM. Telepathology service at the Armed Forces Institute of Pathology. Presented at the American Institute of Aeronauts and Astronauts Life Sciences and Space Medicine Conference, Houston, TX, April 1995. 5. Nitzkin JL, Zhu N, Marier RL. Reliability of telemedicine examination. Telemed J 1977; 3:141–158. 6. Welch ML, Pak HS, Poropatich RK. The impact of the Webbased store and forward teledermatology consult system in the national capital area. (Abstract) Telemed J 1999; 5:41. 7. Pak HS, Welch ML, Poropatich RK, et al. Preliminary data from diagnostic agreement study: Teledermatology vs. in-person evaluation. (Abstract) Telemed J 1999; 5:41. 8. Phillips CM, Burke WA, Allen MH, et al. Reliability of telemedicine in evaluating skin tumors. Telemed J 1998; 4:5–9. 9. Roth AC, Reid JC, Puckett CL, et al. Digital images in the diagnosis of wound healing problems. Plast Reconstr Surg 1999; 103:483–486. 10. Link M. Space Medicine in Project Mercury. Washington, DC: U.S. Government Printing Office; 1965. NASA SP-4003. 11. Berry CA, Catterson AD. Pre-Gemini medical predictions versus Gemini flight results. In: Gemini Summary Conference. Washington, DC: U.S. Government Printing Office; 1967: 197–218. NASA SP-138. 12. Kelly GF, Coons DO. Medical aspects of Gemini extravehicular activities. In: Gemini Summary Conference. Washington, DC: U.S. Government Printing Office; 1967:107–125. NASA SP-138. 13. Luchzowski SM. Bioinstrumentation. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975: 485–493. NASA SP-368. 14. Bailey JV. Radiation protection and instrumentation. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975:105–113. NASA SP-368.

179 15. Waligora JM, Horrigan DJ. Metabolism and heat dissipation during Apollo EVA periods. In: Biomedical Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975:115– 128. NASA SP-368. 16. Luczkowski SM. Skylab hardware report: Operational bioinstrumentation system. In: Johnston RS, Dietlein LF (eds.), Biomedical Results of Skylab. Washington, DC: U.S. Government Printing Office; 1977:481–484. NASA SP-377. 17. Nolte RW. Automated blood pressure measuring system (M092). In: Johnston RS, Dietlein LF (eds.), Biomedical Results of Skylab. Washington, DC: U.S. Government Printing Office; 1977:431–423. NASA SP-377. 18. Linott J, Costello MJ. Vectorcardiograph. In: Johnston RS, Dietlein LF (eds.), Biomedical Results of Skylab. Washington, DC: U.S. Government Printing Office; 1977:433–435. NASA SP-377. 19. Lemke HU. Future directions in electronic image handling. Investig Radiol 1993; 28:S79–S81. 20. Bailey JV. In-flight radiation. In: Nicogossian AE (ed.), The ApolloSoyuz Test Project Medical Report. Springfield, VA: National Technical Information Service; 1977:29–31. NASA SP-411. 21. Nicogossian AE, Garshnek V. Historical perspectives. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine, 2nd ed. Philadelphia, PA: Lea & Febiger; 1989. 22. Lebedev V. Diary of a Cosmonaut: 211 Days in Space. Houston, TX: Phytoresource Research Incorporated Information Service; 1988. 23. Bogomolov W, Popova IA, Egorov AD, et al. The results of medical research during the 326-day flight of the second principal expedition on the orbital complex Mir. Presented at the Second U.S./U.S.S.R Joint Working Group Conference on Space Biology in Medicine, Washington, DC, Sept. 16–24, 1988. 24. Advanced Projects Section, KRUG Life Sciences. Report of the initial in-flight evaluation of the telemedicine instrumentation pack (DSO 334). Houston, TX: NSAA–Johnson Space Center; 1998. JSC 28288. 25. Simmons SC, Melton SL, Johannesen JC, et al. Initial evaluation of the telemedicine instrumentation pack aboard Space Shuttle Endeavour. Poster presented at the American Telemedicine Association Annual Meeting, Orlando, FL, Apr. 1998. 26. Fuchs M. Provider attitudes toward STARPAC: A telemedicine project on the Papago Reservation. Medical Care 1979; 17:59–68. 27. Foote DR. The far north: Satellite communication for rural health care in Alaska. J Commun 1977; 173–182. 28. Rayman RB. Telemedicine: Military applications. Aviat Space Environ Med 1992; 63:135–137. 29. Doarn CR, Nicogossian AE, Merrell RC. Applications of telemedicine in the United States space program. Telemed J 1988; 4:19–30. 30. Beck G, Djordjevic B, Halacka K, et al. Evaluation of critical care monitors using satellite network for space and terrestrial applications. Presented at the 2001 Meeting of the Society of Critical Care Medicine, Orlando, FL, Jan. 2001.

9 Medical Imaging Ashot E. Sargsyan

It has been more than 100 years since Wilhelm Conrad Roentgen took the first diagnostic images using X-rays [1]. The early applications of medical imaging sought to diagnose simple pathology such as bone fracture or foreign bodies. Today, medical imaging has become a discrete medical discipline and an essential part of prevention, diagnosis, and treatment standards throughout the world, revolutionizing virtually every aspect of clinical medicine. A number of imaging modalities are routinely employed not only to rule out overt disease or injury but also to reveal anatomical abnormality and dysfunction of organs, often well ahead of clinical manifestations. The advent of human space flight has brought about the need for physicians to remotely monitor space crews for signs of mission—impacting medical problems. Some of these early space biomedical systems were developed before similar technological advancements for terrestrial medicine were even considered [2]. Presently, the technological level of terrestrial health care has surpassed biomedical systems originally developed for space programs, and the challenge to space medicine is to determine which terrestrial medical technology should be adapted for space use and when that should occur. Spaceflight medical risks have become more apparent with long duration missions to low Earth orbit (LEO) aboard space stations such as Skylab, Mir, and the International Space Station (ISS) [3,4]. Under these circumstances, crewmembers with any existing subclinical deviations from the norm are in space for a fairly long period where the weightless environment presents a number of novel and potentially exacerbating factors. Although the crews are trained and equipped to handle minor medical conditions, a serious event could rapidly overwhelm the modest onboard medical capability and would almost certainly qualify as a medical emergency. Many of the conditions that could occur in space might present significant diagnostic and therapeutic challenges to even the most modern terrestrial health care facility. These factors conspire to limit the ability of a flight surgeon to make difficult decisions, such as discerning between initiating a medical evacuation back to Earth or remaining on orbit for treatment and additional observation. Obviously, these critical decisions should

be based, if possible, on objective information and scientific, evidence-based approaches so that the best possible outcome is achieved with minimal impact to the mission.

History of Diagnostic Imaging in Space Medical imaging experiments during space missions of the 1970s and 1980s were part of aggressive biomedical research programs, which were primarily focused on physiological changes in microgravity and on the ability of humans to live and function in space for extended periods of time and return to normal health upon completion of their missions. In-flight imaging was first performed in 1982 aboard the Salyut-6 and Soyuz-T6/Salyut-7 orbital complexes in a joint Soviet-French research study [5–7]. B-mode quantitative echocardiography with M-mode was performed with various cardiac measurements, as well as continuous-wave Doppler measurements in superficial arteries. A relatively recent technology advance at the time, B-mode consisted of grayscale tomographic frames updated many times a second, thus providing a live (real-time) picture of the heart in motion. M-mode, a live recording of cardiac motion along a selected axis vs. time, however, was still useful in objectively quantifying the changes in chamber size and other dimensions throughout the cardiac cycle. After this pilot study, further investigations were performed on the Soyuz T/Salyut-7 orbital complex, which was visited by six long-duration (65–237 days) and five short-term (8–12 days) crews during 1982–1986. Ultrasound imaging was validated extensively during the longest of these missions (Soyuz T10) by physician-cosmonaut Oleg Atkov, who performed serial sonographic examinations of 15 cosmonauts on orbit. A successful abdominal ultrasound examination was performed and documented for the first time during this mission, and hemodynamic assessments were combined with research to develop improved ultrasound techniques and equipment for use onboard space stations [8]. A series of French and Soviet experiments were later conducted aboard the Soyuz TM/Mir orbital complex beginning in 1988 [9–11]. In addition to 181

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echocardiography, the latter study for the first time included complex vascular imaging tasks at higher ultrasound frequencies, with concurrent Doppler measurements of blood flow in central and peripheral vasculature. Another very important experience in this Soviet-French program was the successful performance of real-time remote guidance of the cosmonaut-operator with limited preflight training by experts at a remote location; a ground communications segment was added to link the space-based operator with an expert outside Russia [11]. These complex procedures were undertaken to demonstrate new in-flight training techniques and to enhance operator performance and the resulting scientific value of the study. However, the operational implications of the concept of ground-based expertise and remote feedback and guidance were significant and remain so in the era of the ISS. The first two echocardiographic series performed in the U.S. space program took place aboard the STS-51D (April 1985) and STS-51G (June 1985) Space Shuttle missions, the latter in cooperation with French scientists. The ADR-4000 (Advanced Technology Laboratories, ATL, USA) portable mechanical sector scanner used had undergone substantial modifications to comply with the spaceflight requirements. Studies involved precision cardiovascular measurements and once again demonstrated feasibility of sophisticated and technically demanding imaging studies in microgravity [12]. The same device was flown on three more Shuttle missions between 1990 and 1992, later to be replaced by another modified echocardiography system (Hewlett Packard, USA) on STS-55 in 1993. Between 1992 and 1995, NASA flew a modified Biosound Genesis II scanner (AERIS) with advanced Doppler capabilities aboard three more Shuttle missions (STS-50, 65, and 71) and the long duration Mir-18 mission. Thus, by the mid 1990s, eight different imaging devices had been flown in LEO, all of them sonographic imagers, and most of the essential aspects of this modality were explored in space to some extent. The success of these experiments and demonstrations has justified modification and delivery of a sophisticated multipurpose ultrasound system (HDI-5000 from ATL/Philips, USA) for the laboratory module of the ISS as part of the Human Research Facility (HRF) [13]. Although its primary purpose is to support advanced biomedical and cardiovascular research in space, this instrument has also been recognized as an important asset for operational space medicine.

Application of Imaging Modalities in Space Medicine Modern diagnostic imaging methods could be considered as promising potential additions to existing space health care systems, to enable effective mitigation of medical risks for LEO and future exploration-class missions. As the required degree of clinical autonomy increases with mission duration, size of the crew, and distance from Earth, so will the demand increase for enhanced space-based health care systems. Some aspects of

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such enhancements have been addressed in literature [14–16]. As remote sensing of other planets provides more data and space propulsion systems undergo dramatic improvements, it seems more and more likely that health-related matters rather than engineering challenges will dominate the concerns for interplanetary missions [17,18]. Therefore, focused attention to the medical support of future missions is warranted, certainly including the use of ISS as a test bed for technology development. The introduction of medical imaging into the space health care systems seems to be an obvious requirement, yet a number of clinical questions and operational problems become evident. Does the known and estimated medical risk in space warrant the expense of placing diagnostic imaging hardware aboard a spacecraft? How should diagnostic imaging procedures be conducted in the space environment? How much effort should we dedicate to “pure” science versus improvement of the operational medical capability, and what are the possibilities for dual-purpose systems? Can various medical imaging modalities in space help rule out pathology in a manner that minimizes mission impact and maximizes crew health and performance? How should the terrestrial diagnostic procedures and protocols be modified to work effectively in space? Who should perform the studies, and can those individuals be adequately trained, given the paucity of medical training time for ISS crews? How should the data be transmitted back to Earth for interpretation, and how effective can such interactions be? To what extent would medical visualization data change the triage, treatment, and outcome of specific illnesses and injuries? Some of these and related questions and problems are discussed in this chapter.

Conventional Radiography and Fluoroscopy Standard X-ray capability could play a leading role in diagnosing many conditions that may occur in space. Visualization of lung parenchyma seems to be an obvious application, which would be sensitive for many conditions in microgravity. Foreign body inhalation may lead to atelectasis and/or secondary pneumonia, and a radio-opaque foreign body itself would be possible to identify, localize, and describe with chest radiography. Inhalation of fuel or oxidizer vapors, as happened during the Apollo-Soyuz mission, could result in serious pneumonitis. Given the limited ability to treat pulmonary injury of these types on orbit, a means of following the effects of exposure would provide the flight surgeon with the necessary information to advise the flight control team regarding the need for crew return. Although the risk of deep vein thrombosis (DVT) in space remains controversial, some experts believe that lower extremity hypodynamia and blood changes may be predisposing factors. Pulmonary embolism with infarction would be a condition where conventional chest X-ray would be the diagnostic modality of choice. For some conditions, such as pneumothorax and pleural effusion, microgravity may reduce the sensitivity of this method to an unacceptably low level, as the

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gravity-dependent anatomy of these conditions would change and might produce excessive false negative results. Radiography may be applied to gastrointestinal pathology in space to rule out foreign bodies, inflammatory conditions, or ileus. However, many of the radiological diagnostic representations of obstruction and perforation, such as gas-fluid levels, are gravitationally determined and may not be present in microgravity. The role of oral contrast agents must also be examined for microgravity conditions; according to preliminary observations, these may still be helpful if used with knowledge of their altered distribution patterns. Intravenous (IV) administration of iodinated contrast might be indicated in ureteral obstruction or other conditions that normally require intravenous pyelography (IVP). However, little is known of the behavior and effects of IV contrast agents in conditions of space flight. With the appreciable incidence of anaphylactic and hypersensitivity reactions to these agents, as well as extremely limited means of response, sonography would most likely be the method of choice for diagnosing most renal and other urological pathology. Radiography would probably be the most sensitive imaging modality for ruling out, confirming, or describing fractures, and for monitoring bone healing. These and other considerations had driven radiography to be considered in the initial designs of the Space Station Freedom in the late 1980s [19,20]. However, hardware limitations, budget cuts, and changing medical requirements resulted in its removal. Thus, even with the use of the latest X-ray electronics and highly sensitive digital detector arrays [21,22], the power consumption, potential for electromagnetic interference with station electronics, weight, and volume have not yet justified placement of radiographic capability aboard any existing spacecraft. Radiography may be a medical requirement for the space medicine clinics of exploration class planetary bases. Although fractional lunar (1/6 g) and Martian (1/3 g) gravity may still compromise the practical significance of some gravity-dependent radiological signs, radiography will be necessary, as a minimum, for evaluating bones and for suspected pulmonary conditions, conventional as well as occupationally or environmentally derived. For example, the effects of recurrent inhalation of even minute quantities of the pervasive lunar or Martian dust may induce syndromes analogous to occupational lung diseases and may require periodic imaging for screening to complement pulmonary function tests in monitoring for signs of pneumoconiosis and associated pathology. Attempts have been made to build highly portable radiographic devices based on low energy “pure” gamma-emitters, such as iodine 125 [23]. In spite of occasional reports of successful experiments, such devices have not gained popularity due to numerous inherent limitations. For space applications, they would deserve serious consideration if relevant conditions, such as metallic foreign bodies in extremity tissues or small bone fractures, occurred with substantial prevalence. Space medicine should closely monitor new developments

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in technology of radiography, looking for systems with automated exposure control that would combine more effective and electromagnetically unobtrusive X-ray sources and larger sensor arrays or other detector systems with both high sensitivity and wide dynamic range. A solid analysis of many aspects of the future of radiography in space is given by Hart and Campbell [24].

Computed Tomography With only modest radiation exposures, present-day CT scanners produce quality high-resolution images of any part of the body in a standardized, easy-to-interpret format. Currently, diagnostic sonography successfully “competes” with CT terrestrially in most abdominal and soft-tissue applications; however CT remains the method of choice for intracranial, craniofacial, pulmonary and mediastinal, and some retroperitoneal disorders. The technology has advanced over recent years with the advent of high-performance helical scanners with significantly increased speed and computing power [25]. However, today’s CT scanners are still too heavy, consume too much power, produce too much heat, and occupy too much volume to be considered for use aboard spacecraft. Their maintenance is complicated, and some of their components, such as X-ray tube cooling and power subsystems, would require a radical and very costly redesign to operate properly in microgravity. Of the above listed factors, power consumption alone is prohibitive for space use and will probably remain so until drastically more effectual X-ray sources are developed. Space medicine is not the only area that might benefit from CT miniaturization. A steady demand exists for intraoperative and bedside computed tomography, which has driven development of commercial devices that can be moved into and out of operating rooms or intensive care units. However, these devices employ a classical terrestrial hardware design, utilizing a massive gantry and heavy power and cooling components. Should an effective X-ray source with low electromagnetic interference and power consumption become available, CT might be seriously reconsidered for use in space. In microgravity, an attractive possibility exists to replace rotation of the X-ray tube and the opposing detector array with safe rotation of the properly positioned and constrained patient. Taking advantage of microgravity, such an approach would eliminate the need for the bulky gantry, with both the X-ray source and the detector array fixed on existing structures of the station, such as an opening between adjacent modules (Figure 9.1). The patient rotation mechanism would require a position sensor to provide data for CT reconstruction calculations. By substituting longitudinal translation for rotation, radiographic images in standard projections (known and used as topograms for CT positioning) could be acquired. Furthermore, CT can be expected to be the mainstay of imaging facilities at future extraterrestrial bases with large numbers of inhabitants.

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Figure 9.1. A hypothetical system for X-ray computed tomography in microgravity: 1- X-ray source; 2- detector array; 3- fan-shaped X-ray beam; 4- subject; 5- the axis of subject rotation; 6- fixed ISS structure; 7- subject restraint system with position markers

Magnetic Resonance Imaging Since the initial clinical applications devised and realized by Raymond Damadian and colleagues in the 1970s [26,27], MRI has revolutionized clinical medicine. MRI is of great value to space medicine terrestrially for its unsurpassed imaging fidelity in revealing musculoskeletal and spinal pathology and for its capability to noninvasively screen the central nervous system for asymptomatic conditions such as vascular and parenchymal malformations. In space, MRI would be of enormous scientific value in enhancing the knowledge of space physiology and adaptation and in evaluating effectiveness of bone and muscle-preserving physical countermeasures. However, in spite of its great value, MRI cannot be installed aboard present spacecraft. MRI scanners are heavy, power-intensive, and prohibitively large. Furthermore, the high-density magnetic fields created by diagnostic MRI systems will not be tolerated by the sensitive avionics aboard spacecraft. Certainly, new magnet configurations, along with advances in high-temperature superconductivity and radio electronics, already show the possibility to dramatically reduce the mass, power and volume of clinical MRI technology. Space biomedical engineers are closely monitoring the developments in this advancing area of noninvasive diagnostic imaging.

Nuclear Imaging Most nuclear imaging techniques, both static and dynamic, were initially based on the detection of primary or secondary gamma radiation emitted by radiopharmaceuticals administered

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orally or intravenously and eventually accumulated via metabolic uptake in the organs or tissues of interest. The use of positronemitting isotopes and high-resolution dual-and single-photon tomographic systems has established a new capability to evaluate metabolic structural disorders. A limited number of nuclear imaging techniques, if available, could be useful for medical diagnostics or monitoring in space. These might include bone scintigraphy for evaluating bone loss and fractures or nuclear lung perfusion and ventilation scans for suspected pulmonary embolism, pneumonitis, or atelectasis. However, gamma-scintillation cameras are inherently heavy due to the need for collimation and precise detector positioning and may require constant flow of power to maintain multiple detectors in a calibrated state. The operational challenges associated with any single aspect of supply and/or production, processing, and handling of radiolabeled agents in space, radiation shielding, or even waste management would prohibitively impact mission operations. All of these factors have effectively precluded the use of these imaging methods in space.

Electron Beam Computed Tomography Since the early 1990s, electron-beam computed tomography (EBCT) has been steadily growing in popularity and acceptance as a noninvasive screening tool for coronary artery disease (CAD). Although it has demonstrated the capability to predict coronary incidents in asymptomatic populations [28], it is only slowly becoming incorporated into medical screening standards. EBCT is also extensively studied as a clinical evaluation tool. With the use of contrast enhancements, the method may be accepted soon as standard for clinical situations other than CAD, primarily those associated with the lungs and the respiratory tract [29–32]. EBCT may replace cardiac catheterization and coronary angiography in older astronauts (cosmonauts) with risk factors for or symptoms of CAD. EBCT would be an excellent adjunct to functional and imaging studies such as exercise stress testing and exercise 99m Tc or 201Tl-scintigraphy, the predictive ability of which is doubtful for occult CAD in asymptomatic individuals. As the age of space crewmembers increases, EBCT will probably be used as a screening tool for astronaut selection and retention purposes. Equipment size and complexity preclude the use of EBCT during space flight for the foreseeable future.

Endoscopy Gastrointestinal (GI), pulmonary, or urologic endoscopy is often the method of choice to evaluate and treat disease or injury in these regions. Some examples of medical scenarios that would require endoscopic evaluation and possibly treatment in space include upper-GI conditions (emesis-induced Mallory-Weiss tears related to space motion sickness, stress ulcers, a foreign body in the esophagus), pulmonary aspiration of foreign bodies, conditions requiring bronchial lavage, and

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urolithiasis. Diagnostic or therapeutic endoscopy has not been considered a necessary on-orbit capability, since the probability of medical events requiring this mode of imaging in space is fairly low and the necessary degree of proficiency is currently not possible to achieve in non-physician crewmembers. Nonetheless, many aspects of endoscopy have been studied in conditions of simulated microgravity. In 1999, Jones and colleagues [33] successfully performed complicated urologic endoscopic procedures on an animal model in parabolic flight. NASA Medical Operations has also investigated the feasibility of surgical endoscopy (thoracoscopy and laparoscopy) using a microgravity animal model [34]. In most of these experiments conducted on the KC-135 microgravity laboratory aircraft, associated gas insufflation and biohazardous fluid containment were managed successfully. Interestingly, a “cold” light source needed for these techniques had already been spaceflight-tested on the STS-89 Space Shuttle mission as part of the Telemedicine Instrumentation Pack experiment [35]. Although many of the aspects of microgravity endoscopy remain unknown or controversial, enough knowledge and experience has been accumulated to confirm its technical feasibility and diagnostic utility. Endoscopic manipulation is considered invasive and inherently risky and requires extensive training and experience to be performed safely and effectively. In this regard, the comprehensive trials of tele-mentoring of laparoscopy offer some optimism for the future use of endoscopy by astronauts in low earth orbit [36,37].

Optical Imaging To date, known injuries in space have been limited to superficial soft tissue trauma. Probable conditions requiring skin and mucosal images include burns, frostbite, superficial infection, orofacial pathology, local or generalized edema, and any dermatological condition. Verbal description of a lesion would rarely be satisfactory for clinical decision-making. Further, in any serious condition, objective data on the patient’s general habitus would greatly enhance the ground-based flight surgeon’s ability to fully perceive the essence and severity of the condition at hand. Therefore, the capability to perform both general and close-up photography of diagnostic quality may be critically important. Although photographic equipment is available on any spacecraft, the color perception in actual lighting conditions, macro imaging capability, and timely image transfer options should be considered with medical applications in mind. Full-motion or near full-motion video downlink would be important to obtain objective data from certain types of abnormalities noted during physical examination, to conduct reasonably detailed neurological and orthopedic exams, and to guide the crew medical officer through complicated life support or interventional diagnostic or therapeutic procedures. NASA has successfully tested aboard a Space Shuttle mission a special fundus camera for retinal imaging, as well as a video system for acquisition and transmission of real-time

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ophthalmoscopy, otoscopy, and close-up skin and mucosal examination data as a subsystem of the Telemedicine Instrumentation Pack. As with photography, spacecraft video acquisition and transmission modes and quality must be designed to reasonably satisfy the needs of space medicine. Image fidelity must be tested in advance for utility in supporting foreseeable medical applications. For example, the ISS Video Baseband Signal Processor (VBSP) had been tested by NASA in laboratory conditions for its ability to digitally convert and transmit medical video at various frame rate and resolution settings.

Diagnostic Ultrasound In the late 1990s, sonography became the second most widely used imaging modality in the United States; sales of ultrasound equipment grew at unprecedented rates to exceed those of any other category of medical imaging equipment [38]. Diagnostic ultrasound addresses a large and ever-growing array of medical and surgical conditions. Ultrasound has long been a method of choice for many specific conditions, such as cholelithiasis or pericarditis; in others, it has been recognized as a second-choice or backup modality, used especially when the imaging technology of choice (X-ray, CT scanning, or MRI) is not available within the appropriate clinical timeframe. Some ultrasound applications, although used in North America as secondary or alternative procedures, are well established as primary evaluation steps in other parts of the world (for example, sonography of adrenal glands, gastrointestinal tract, or ureters). Finally, new applications for ultrasound are being developed and clinically implemented at a remarkably high rate [38]. Ultrasound imaging is an area of diagnostic medicine that is well regulated in North America, with standards and training requirements based on routine radiological practices and patient flow patterns in hospital and outpatient imaging departments. Typically, a trained technician captures representative sonographic stills from numerous real-time video frames using pre-established scanning and documenting protocols and provides these stills to a radiologist for subsequent interpretation. In other medical cultures, including some of those represented in the ISS partnership (most European countries, Russia, Japan), sonographic services are less standardized and regulated. In these cultures, sonographic imagery is acquired by a physician-radiologist rather than a technician and interpreted in real-time. In the space medicine setting, elements of all the abovementioned diagnostic paradigms may be employed. In the multinational operational environment of ISS, contributions from several medical cultures are shaping many medical procedures. The cooperative experience with medical support of international space programs has shown significant promise [39]. Thus, ultrasound is uniformly recognized terrestrially as a valid diagnostic tool in many conditions, some of which, such as urolithiasis, have already been encountered in space.

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Ocular, abdominal, and soft tissue trauma, pneumothorax, acute localized infections, and complications of toxic inhalation are a few examples of maladies that ultrasound could be used to evaluate. Numerous reports have confirmed the high diagnostic value of ultrasound for clinical conditions in which it is not considered the first choice diagnostic modality [40–42]. In the absence of other diagnostic imaging modalities in space, ultrasonic methods and techniques must be developed specifically for space use. Ultrasound is the most feasible imaging modality for space medicine because of its relatively small volume and power requirements and safe non-ionizing, noninvasive characteristics. The feasibility of ultrasonic imaging in human space flight has been demonstrated and well documented [6,8,11,43–45]. This versatile clinical diagnostic tool is now deployed aboard the ISS. On September 13, 2002, NASA astronaut and scientist Peggy A. Whitson conducted operational testing of the hardware in a series of discrete imaging procedures, employing real-time video downlink and receiving expert guidance from the Mission Control Center in Houston (Figure 9.2).

Portable and Specialized Sonography Systems Recent miniaturization of sonographic hardware has facilitated implementation of ultrasound imaging outside the standard tertiary care imaging departments even in the United States [46]. Ultrasound imaging is increasingly carried out in small clinics, sometimes by private general practitioners and specialists such as cardiologists, gynecologists, ophthalmologists, and urologists. In many of these deployments, ultrasound data are acquired using minimal customized protocols with data interpreted in real time, often without formal image archival. These focused, problem-based examinations are used to rule out or confirm specific pathology [47–50]. One of the

Figure 9.2. NASA astronaut Peggy Whitson during operational ultrasound imaging test on orbit (Photo courtesy of NASA)

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main advantages of focused, front line applications of portable scanners is quicker availability of results in the overall evaluation and initial management and triage process. In many cases, an ultrasound examination by the imaging experts would not be possible because of constraints on time, distance, or personnel. Portable devices are also gaining increasing attention for potential applications in military medicine, aeromedical transport, and other settings with limited resources, time-critical operations, and rapidly changing environments [51–53]. The HRF Ultrasound on ISS is a large and complex researchoriented system that can handle any ultrasound imaging task. Such luxury would hardly be afforded merely for operational purposes, and the ISS medical system takes advantage of its presence. Smaller devices with reasonable image quality [23] would be chosen to equip spacecraft for dedicated medical monitoring and risk mitigation purposes. In mid 2002, the world market of commercial devices included more than 40 different portable systems [46]. Terrestrial precedents already exist for the use of standard computer platforms for control, data processing, and display, thus reducing the volume of dedicated ultrasound hardware down to that of the necessary probes and analog components (Figure 9.3). Future spacebased medical hardware, including that for imaging, will most likely be integrated with the centralized power, data processing, and communication resources of the vehicle.

Three-Dimensional Ultrasound Three-dimensional (3D) reconstruction in tomographic methods such as CT, MRI, or positron emission tomography (PET), where precise spatial coordinates of data points are known and volume data are routinely acquired, have long been established as valid clinical image processing and presentation techniques. Multiplanar display and 3D reconstruction and rendering of B-mode and color Doppler

Figure 9.3. A commercial, laptop-based, ultrasound device (Photo courtesy of NASA)

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ultrasound images have also been advocated for clinical use, especially in obstetric ultrasound where congenital malformations are routinely sought and described [54,55]. Threedimensional rendering has been explored for other areas of ultrasonography as well, such as in ophthalmology [56] and neonatology [57]. During the 1990s, a multi-center project (SOLUS-3D) was conducted by the European Commission Biomedicine & Health Research Program. Coordinated by Cambridge University (UK), multiple clinical and research centers throughout Europe studied 3D-ultrasound imaging, primarily in obstetrics and gynecology, in an attempt to standardize clinical utilization. Conventional 2D ultrasound probes equipped with six electromagnetic spatial locators were used to acquire “spatially registered” series of 2D images. Volume data sets could then be calculated in any discretional slicing plane, with subsequent volume or surface rendering [58,59]. Several commercial vendors have developed similar hardware and software to acquire spatially tagged (3D or volume) data for analysis, while preserving the freehand nature of conventional 2D ultrasound scanning. Promising clinical results with such systems have been published by several authors [3,55,60]. Although attractive in several respects, these techniques have not gained wide acceptance for abdominal and vascular imaging due to their non-real-time nature, as opposed to the traditional 2D (B-mode) ultrasound. Primary acquisition of volumetric data (as opposed to storage of serial spatially tagged 2-D data arrays described in the previous paragraph) has been proposed for operational use in space. The more extensive data obtained might compensate for the lack of training and proficiency of astronauts in exploratory-class missions by allowing ground teams to reconstruct full 3-D imagery and retrospectively select the most clinically useful views. Indeed, communication latency from a few seconds to several minutes could effectively confound real-time interaction and feedback. This alternative approach with special 3-D-capable probes is effective for static targets but often presents a challenge when patients are unable to hold their breath long enough. The imaging procedure may be unduly complicated because of the need to transmit large data arrays before their quality and fitness for given clinical questions are verified. Therefore, a free hand 3-D ultrasound approach seems to offer far more promise for use in space, as it preserves the advantages of real-time scanning with an added capability to manipulate 3-D data sets off-line. Standard preacquired volume blocks of exemplary ultrasound data might be used as advanced computer-based training tools for astronaut Crew Medical Officers (CMOs), since training and proficiency testing systems using pre-acquired data blocks are effective and available commercially [61–63]. With due recognition of the potential of 3-D ultrasound, only real-time 2-D ultrasound with remote guidance is being considered for use as a medical diagnostic capability on ISS. This would probably satisfy the current needs for space medicine practice in LEO where real-time remote guidance is available.

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Three-dimensional techniques must be thoroughly considered for future space missions, as they are further refined terrestrially and adapted for commonly used computer platforms.

Diagnostic Imaging Before and After Space Flight The lifelong monitoring of astronaut health begins in the initial selection process. A comprehensive medical evaluation determines whether the subject meets the medical standards to qualify for astronaut training and future space flights. The initial medical screening program for ISS crewmembers requires several imaging tests (Table 9.1). Medical imaging is also performed at certain intervals during the career of the astronauts and in the preflight and postflight phases of both long- and short-duration space missions. Although the general approach in the ISS program is to maximally follow analogous terrestrial health screening standards (e.g., mammography, chest X-ray, or colonoscopy), some groups advocate more rigorous screening to include cerebral MRI angiography, gastrointestinal endoscopy, or coronary angiography in older astronaut candidates.

Diagnostic Imaging in Space The Role of Imaging in Medical Risk Mitigation Medical risk mitigation policies throughout the last 40 years of human space flight have called for onboard treatment of minor illness or injury and medical evacuation of a seriously ill or injured crewmember to an appropriate terrestrial medical facility. However, such a determination may be extremely complicated (Table 9.2). Because of the inability during flight to properly address all medical conditions in the differential diagnosis of presenting symptoms, those possibilities with the most severe impact will probably determine further decisions. Such conservatism, although aimed at improving the chances of survival and recovery, inevitably increases the risk of unnecessary evacuation. Decision making may be further encumbered if two or more leading conditions call for different management, stabilization, and transport modalities. For example, moderate to severe chest pain and dyspnea could suggest spontaneous pneumothorax, pulmonary embolism, myocardial ischemia, varicella-zoster ganglionitis, acute pericarditis, or aortic dissection. The flight surgeon may find it difficult to weigh the risks of further onboard management and observation against those inherent in an emergency return, including reentry gravitational loading, lack of advanced monitoring and life support capability, and possible delays in rescue and transportation to a definitive care facility after landing. Furthermore, the line between minor and serious is blurred even with a well-established diagnosis and can be crossed rapidly during the course of illness in both directions.

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Table 9.1. Required preflight imaging studies in the ISS program. Imaging test

At selection

At annual evaluation

Sinus X-rays Panorex Bite-wing X-rays

If clinically indicated No Yes Updated every 5 years Yes If clinically indicated

Echocardiography

Yes

Chest X-ray

Yes

Mammography

Yes

Abdominal ultrasound Pelvic ultrasound (women)

Yes Yes

Proctosigmoidoscopy

Yes

EGDS

Yes (RSA, NASDA only) CSA only RSA only RSA only If clinically indicated (RSA only)

Cerebral MRI angiography Head and spine MRI Intravenous pyelography Selective coronary angiography

No; If clinically indicated (CSA) Every 5 y

Before flight

After return

Notes/acronyms

— — If clinically indicated (on long flights, at L–30/45 d) —

— — —

—

—

—

—

—

—

Posteroanterior and lateral Per clinical guidelines for age and history

L –180 d (for long flights) L –180 d (for long flights)

R +3, +6, +10 d — —

Every 2 y for ages 40–50; annually for ages > 50 No; every 5 y (CSA) Annually (RSA) No every 5 y (CSA) Every 3 y for ages 40–50; every 2 y for ages 50–56; annually for age > 56 NASDA only

—

—

—

—

—

No Every 5 y Every 5 y No

— — — —

— — — —

Esophago-gastro-duodenoscopy — — For ages > 45

Abbreviations: CSA, Canadian Space Agency; RSA, Russian [Aviation and] Space Agency; L−, days before launch; R+, days after landing; NASDA, Japanese Space Agency; y, year; d, days.

Table 9.2. Factors considered by flight surgeons in clinical decision-making. Comprehensive diagnosis and prognosis

Spacecraft environment and resources Onboard treatment options and resources

Scenarios of emergency deorbit and emergency medical services (EMS) support

Control, confidence, and ethical aspects

Presenting complaints and their evolvement Physical exam data (objective and subjective status) and respective trends Objective diagnostic and monitoring information (by real-time telemetry, file transfer, and crew call-downs), and respective trends Predictions based on available data and trends, terrestrial and space-based evidence, and precedents (if applicable) Objective data from spacecraft systems (telemetry and crew reports) Predictions based on calculations, trends, and precedents Relevant onboard expertise (crew training, demonstrated and expected proficiency) Availability of medical procedures and computer-based (written) knowledge base Availability and supply of medications, instruments, consumables, and other items Availability of ground-based expertise support to the provider onboard Capability to evaluate treatment effectiveness and mitigate inherent and iatrogenic complications Deorbit opportunities and their physiological profile Availability of monitoring and life support aboard the rescue vehicle Time/distance to definitive care facility Availability of life support, monitoring, and treatment options upon landing and en-route to definitive care facility Availability and technical adequacy of necessary types of communications Effectiveness of information exchange, given the pressure of the situation

A further example is two cases of nephrolithiasis with identical presentation that may require different management and have different outcomes depending on the degree and location of the obstruction, presence of urinary tract infection, and other individual factors. Obstructions with higher chances of spontaneous resolution may be treated on orbit, thus avoiding unnecessary disruption of the mission and saving the space program many millions of dollars. Major obstructions should

be rapidly diagnosed and medical evacuation scheduled to a primary landing site while the patient is still stable and the stock of adequate medications to control pain or treat infection is not yet depleted. An appropriate management plan in this example is directly dependent on diagnostic imaging to provide objective information on the size and location of the obstructing calculus, the degree of obstruction, and the presence of other calculi in the urinary system.

9. Medical Imaging

189

Implications of Altered Gravity for Medical Imaging Diagnostic imaging procedures have evolved over years to take advantage of the omnipresent force of Earth’s gravity. Factors and properties such as density, buoyancy, capillary action, and surface tension act on various combinations of gas, fluid, solid matter, and biological tissue to determine many aspects of normal and pathological anatomy. Fluids normally concentrate in dependent areas, which can be the sentinel finding for many life—threatening medical conditions, such as intracavitary hemorrhage. Constituents with lower density, such as air or lipid-rich matter, float above the fluid whereas those with higher density, such as calculi or debris, sink or form horizontal layers. As a result, gravity-based imaging techniques using specific patient orientation are used extensively in several areas of clinical imaging, and resulting images are interpreted with gravitational effects in mind. Gravity is also exploited to modify the mutual position of organs and tissues to better expose the areas of interest for physical examination and imaging. For example, echocardiography is usually performed in left lateral decubitus position to gain better access to the periapical areas of the heart and to avoid lung interference. Vertical body or extremity positioning is often used to enhance venous filling. However, in the foreseeable future of low earth orbit operations, lack of gravity will remain a fact of human space flight. In weightless conditions, the position of an object or distribution of a fluid collection is determined by the combined effect of weaker, and often random or unidentified factors, such as viscosity and composition of the fluid and its interaction with the given tissue surface, tissue and organ compliance, various pressure fluctuations and gradients, peristalsis, surface tension, and small accelerations. The resulting diagnostic imaging representations should therefore be expected to differ from usual terrestrial patterns, possibly in unpredictable ways. These diagnostic challenges can be illustrated by the behavior of pathological pleural fluid in microgravity. On Earth, pleural fluid is distributed in a characteristic pattern within the lowermost part of the pleural cavity with respect to gravity, resulting in the classical picture of blunted costo-phrenic angles commonly seen on standard upright X-ray images.

In microgravity, pleural fluids (blood or exudate) would likely distribute relatively evenly over the whole pleural surface, including the lung fissures and mediastinal pleura, and thus would decrease the net opacification expected in the lower portions of the thorax if X-ray images were taken. The somewhat increased opacification over the entire lung would probably make it difficult to distinguish between parenchymal and pleural nature of the underlying pathology. In cases with massive hydrothorax or hemothorax and some degree of compressive atelectasis, opacification would probably be more pronounced along the pulmonary perimeter, and the borders of the lung fields would be blurred; however, the presence of a well distributed but small to moderate effusion on a chest X-ray could still be confused with an interstitial lung process. Intraabdominal hemorrhage, sinus exudate, lung abscess, ileus with dilated bowel loops, and bladder calculi are all conditions where certain aspects of the disease anatomy are directly determined by the direction of the gravity vector. Several examples of such conditions are listed in Table 9.3, with a description of the expected or proven change in disease anatomy. Thus, unless all aspects of an imaging technique and its specific application are reconsidered for use in space, their applicability in the absence of the gravity may prove to be significantly affected. A terrestrial gold standard imaging procedure may not provide clinically relevant information in microgravity, whereas a less standard imaging method may actually be the method of choice for the same condition. This has been observed by NASA investigators using an animal model in parabolic flight to evaluate a small quantity of pleural fluid, which in microgravity might easily be overlooked radiographically. These experiments suggest that sonography under the same conditions should have high diagnostic accuracy (Figure 9.4). Artificial gravity may one day move from science fiction books to the drawing boards, but it will probably be a fraction of Earth’s gravity and may still remain operationally impractical for the employment of diagnostic imaging. Although no data exist on the relative contribution of gravity vs. other forces and factors in medical imaging, experience in normal terrestrial and parabolic flight conditions suggests that lunar and Martian levels of gravity would result in imaging conditions close to terrestrial norms. Processes of gravity-induced distribution, sedimentation, and separation will occur at lower

Table 9.3. Examples of altered anatomic appearance of disease in microgravity conditions. Condition Calculus in the urinary bladder Pleural effusion Ileus Intra-abdominal hemorrhage

Terrestrial (established patterns)

Microgravity (demonstrated or expected patterns)

Most dependent location (posterior wall/trigone in supine position) Costopleural sinus Horizontal levels of gas over fluid in distended bowel loops (cups); altered peristalsis, increased diameter Most dependent areas (Rectovesical/rectouterine, Morison’s, and splenorenal spaces) fill first

Random position; may be difficult to rule out (identify) due to atypical position Distribution over a large surface Insufficient data; fluid may “adhere” to bowel walls with the gas forming a centrally located bubble, or multiple bubbles Bleeding site fills first and spreads locally; blood may accumulate between bowel loops and under the abdominal wall, and spread over time to a large mesothelial surface

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A.E. Sargsyan

Figure 9.4. A layer of pleural fluid is clearly seen (arrows) on this ultrasound image taken in the zero gravity phase of a KC-135 parabolic flight

Figure 9.5. The Human Research Facility (HRF) Ultrasound System, delivered and installed during the ISS Expedition Two

rates and may be less pronounced in these circumstances and must be considered.

and thoracic pathology in microgravity [18,44,47,64]. Most of these studies have employed animal models in parabolic flight aboard KC-135 aircraft. The ISS Ultrasound System is a “space-adapted” version of an advanced multipurpose ultrasound system widely used in tertiary care centers throughout North America and in other countries (HDI-5000, ATL/Philips, Bothell, WA, USA) (Figure 9.5). Equipped with a complement of three probes and supported by operationally and clinically valid procedures, it can significantly enhance the ability to diagnose, describe, and monitor a wide variety of medical and surgical conditions. Upon reviewing the relevant information accumulated to date, a list of medical conditions has been suggested to include those sensitive to detection, staging, or description in space by sonographic technology. Some of these conditions are listed in Table 9.4 and include trauma, ocular and dental conditions, cardiovascular pathology, urinary tract conditions, biliary obstruction, acute and chronic infectious and inflammatory conditions, and soft tissue infection. In the paradigm of a space station in LEO, the ability to transfer data between the point of acquisition and the expert on the ground is limited by the telecommunication system of the spacecraft. This system is not necessarily optimal for this specific application, is not available on demand, and causes some deterioration of signal quality with partial loss of potentially important information. There are frequent interruptions in video and audio links between the spacecraft and the experts in Mission Control Center. Figure 9.6 compares two experimental images taken during ground tests; obviously, the transmission through the ISS video baseband signal processor causes noticeable degradation. Further, the communications pathway for both video and voice introduces a transmission delay of up to two seconds, making the real-time interaction even more demanding. These technical

Diagnostic Imaging on Transport Spacecraft Medical imaging capability for Space Shuttle missions lasting less than 2 weeks has been limited to real-time transmission or recording of sonographic images or standard video and digital photography. Pre-Shuttle NASA spacecraft (except Skylab stations) and the Russian Soyuz capsules have had minimal medical capabilities, and none have been equipped with any imaging capability. Specialized medical imaging on the Space Shuttle has been used only for experimental purposes and has not been considered as part of a standard medical system. However, long-duration missions of the future to Mars or other remote destinations of the solar system will probably have highly portable medical imaging capabilities and a trained crew to handle the most likely medical emergencies autonomously. Upon arrival at a planetary base, the medical hardware would be deployed as part of the base’s medical facility.

Diagnostic Imaging Aboard ISS and Future Space Stations in Low Earth Orbit The HRF Ultrasound is the only piece of specialized medical imaging hardware currently available on ISS. The ISS Program has recognized its operational value for mitigating medical risk and considers it necessary for maintaining an acceptable level of contingency medical care. This decision was largely based on the results of numerous studies conducted by NASA and affiliated medical organizations, which investigated the role and requirements of diagnostic ultrasound and minimally invasive surgical endoscopy in abdominal, retroperitoneal,

Table 9.4. Examples of conditions subject to ultrasound imaging in space.

Application/condition

Possible ultrasound findings

Abdomen/retroperitoneum/thorax Acute appendicitis Thickened walls of appendix; non-compressibility, increased diameter, increased blood flow demonstrated by Color Doppler; if complicated—free fluid; localized fluid/infiltrate, changes in bowel peristalsis. Demonstration of normal appendix or other cause of symptoms rules out appendicitis in most cases. Failure to identify appendix does not rule out appendicitis. Acute diverticulitis Non-specific findings of focal bowel wall thickening and changes in surrounding fat/tissues; possible identification of the diverticulum, abscess formation, or associated fistula Blunt abdominal trauma Free fluid at the site of injury; free fluid elsewhere in contiguous perito(includes internal bleeding) neum; organ hematoma; capsular disruption; changes in peristalsis. Retroperitoneal hematoma Detection of hematoma; possible abdominal fluid and/or signs of ileus Inflammatory bowel disease Hollow viscus perforation (peptic ulcer, trauma) Pneumothorax

Pleural effusion and hemothorax

Thickened/infiltrated (hypoechoic) wall of terminal ileum, decreased or absent peristalsis Pneumoperitoneum; changes in peristalsis, free fluid Absent sliding of the lung, mirror-image artifact, absent “comet tails.” In severely symptomatic cases expect same over entire hemithorax, displacement of the mediastinal structures Demonstration of fluid separation between parietal and visceral pleura. Expect wide area of distribution in 0 G. Requires follow-up if negative

Hepatobiliary, pancreas and spleen Liver enlargement/diffuse Changes in shape, margins, size, relative echogeneity, echo-texture, vascuprocess (e.g., toxic) lar pattern Liver or splenic hematoma Focal irregularity; Doppler signs of a space occupying lesion (S.O.L.); subcapsular hematomas (Typical pattern of hypoechoic crescent-shaped “addition”) Hepatic abscess Demonstration of a gradually forming focal irregularity which assumes a round shape; Doppler signs of S.O.L. Biliary hypertension due to Dilation of intrahepatic bile ducts and extrahepatic ducts proximal to the obstruction cause; possible dilation of the gallbladder; possible dilatation of the pacreatic duct Abnormal content of the gall- Demonstration of irregular echogenicity of gallbladder content; stones bladder—sludge, blood clots, readily visualized; data will differ from terrestrial calculi, pneumobilia Acute cholecystitis (calculous Thickened/infiltrated walls; possible peritoneal reaction; possible wall or acalculous) irregularity Splenic enlargement Changes in shape, relative position, size, relative echogenicity Splenic infarct Wedge-shaped zone of irregularity/low echogenicity Acute pancreatitis; pancreatic Enlargement, low echogenicity; possible irregularity; possible dilation of hematoma the duct; possible free fluid and renal changes in severe cases Genitourinary/pelvic Renal calcifications/calculi

Demonstration of calcifications and/or stones; typical pattern of obstruction if impacted Ureteral obstruction/renal colic Demonstration of renal pelvic distention/ureteral dilation proximal to the (stone, blood clot in trauma, stone; renal enlargement; possible demonstration of the cause urinary reflux) Demonstration of “ureteral jets” or asymmetry/absence thereof contributes to diagnosis Acute pyelonephritis and renal Renal enlargement, shape, low relative echogenicity, possible focal lesions/ abscess irregularity, possible signs of obstruction; demonstration of abscess (Focal lesion of varying echogenicity, irregular contour of the kidney) Renal trauma Zone of irregularity with associated perirenal changes; usually diagnostic in clinical context; Power/Color Doppler essential to evaluate damage and stage/classify Acute diffuse pathology, renal Renal enlargement, shape, high relative echogenicity, medullo-cortical enlargement (e.g., toxic contrast, change in renal vascular resistivity (pulsed Doppler) exposure, ATN) Renal vein thrombosis Changes in size, echogenicity, shape, arterial flow pattern (Pulsed Doppler); actual thrombus may be visualized; procedure may be complicated and time-consuming

NASA KC-135 Terrestrial use supporting data Common and increasing

A – N/S; H – N/S; SN

ISS supporting data (human) N/S, G

Known but A- N/S; H-N/S uncommon

N/S, G

Common

SN, G

Common, secondary Common

A – SN, SP; H - SN A – N/S; H – N/S

N/S, G

H – N/S

N/S, G

Known but A – SP, SN; H-N/S N/S, G uncommon Uncommon, A – SN, SP; H SN, G rapidly - SN increasing Common A – SN, SP; H SN, G - SN Common

A-SN, SP; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common Common Common

A – SN; H - SN A – SN; H - SN A – SN; H - SN

SN, G SN, G SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN, SP; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – SN; H - SN

SN, G

Common

A – N/S; H - SN

N/S, G

(continued)

Table 9.4. (continued)

Application/condition

Possible ultrasound findings

Bladder calculi or blood clots

Demonstration of a calculus or displaceable irregularly echogenic structure in the bladder lumen; location may be atypical in 0 G Bladder infection Demonstration of turbid urine in the bladder; no layering in 0 G; thickening of bladder walls; color Doppler interrogation causes “stirring” of echogenic matter Urinary retention Distended bladder, possibly vesico-ureteral reflux with ureteral, pelvic, and calyceal dilatation Acute prostatitis/relapse and Enlarged prostate, irregularity of texture, contour irregularity, possibly prostatic abscess solitary or confluent hypoechoic focus, low echogeneity; “chronic” background changes, e.g., calcifications Testicular torsion Changes in echo-texture and asymmetry in echogeneity Critical information derived from Color Doppler data (vascularity) and Pulsed Doppler (spectral characteristics) Normal pregnancy; incomplete Demonstration of gestational sac, thickened and echogenic endometrium; abortion or blighted ovum typical pattern of complications Ectopic gestation Adnexal mass, free pelvic fluid, thickened endometrium; possible demonstration of heartbeat Pelvic inflammatory disease A variety of sonographic patterns; requires extensive air-to-ground interac(PID) tion, may require follow-up and lab support to R/O ectopic gestation Ophthalmic Retinal detachment Typical pattern of retinal separation of various degree and topography Retrovitreal and intra-vitreal Typical patterns of irregularly altered echogeneity hemorrhage Lens displacement (subluxation Failure to visualize lens in normal position; Demonstration of the lens in or dislocation) abnormal position or location Other trauma (anterior segDemonstration of hyphema, distortion of the iris, and other trauma ment) anatomy Superficial Sialoadenitis Hypoechoic gland, enlarged and tender, rounded, possibly dilated ductal system Subacute thyroiditis Relatively hypoechoic gland, enlargement (compare to baseline), irregular texture Superficial infections (celluli- Respective patterns, typical tis, lymphadenitis, cutaneous abscess, necrotizing cellulitis) Lymphadenopathy Cardiovascular Pericardial effusion Demonstration of fluid separation of pericardium Deep venous thombosis (lower Lack of compressibility, visualization of thrombus, absent or abnormal extremities) flow May be time-consuming. Technique may differ in 0 g vs. 1 g Superficial venous thrombosis Lack of compressibility, visualization of thrombus, absent or abnormal (post-injection, post-catheter) flow. Venous gas embolism (decom- Demonstration of VGE in B-mode and Power Doppler; pulsed-Doppler pression) may be used additionally (Duplex or Color-Duplex mode) Musculoskeletal, dental Superficial bone fractures (rib, Characteristic disruption of cortical bone reflection; Distortion of the bone mandible, zygomatico-maxcontour; soft tissue reaction/edema/hematoma illary complex, skull) Long bone fractures Similar to other fractures; additional techniques (such as axial rotation) may enhance study Muscle tears/hematoma Hypoechoic zone, irregularity, local enlargement, displacement of adjacent structures Tendon rupture Disruption of the normal pattern, asymmetry, hypoechoic zone; may demonstrate contracted muscle Articular effusion/hematoma Demonstration of fluid in the articular space Periapical abscess Translabial/transbuccal demonstration of a hypoechoic periapical focus Other Verification of endotracheal (ET)intubation

Demonstration of ET in trachea, demonstration of normal lung motion with respiration, ruling out tube in esophagus

NASA KC-135 Terrestrial use supporting data

ISS supporting data (human)

Common

SN, G

Common

A – SN, SP; H - SN A – SP (sim)

Common

A – SP; H – SN

SN, G

Common

H – SN

SN, G

Common

Not available A – NA; (H – N/S) NA

Common

NA

NA, G

Common

NA

NA, G

Common

NA

NA, G

Common Common

A – NA; H – SN A – NA; H – SN

NA, G NA, G

Uncommon

A – NA; H – SN

NA, G

Uncommon

A – NA; H – SN

NA, G

Known but A – NA; H – SN uncommon Common A – NA; H – SN

NA, G

Common

A – NA; H – SN

SN, G

Common

A – NA; H – SN

SN, G

Common Common

A – SN; H – SN NA

SN, G NA

Common

N/S

NA

Uncommon

NA

NA, G

SN, G

Known but A – SN; H – SN Uncommon

SN, G

Known but uncommon Known but uncommon Known but uncommon Uncommon Anecdotal reports

H – SN

NA, G

H – SN

N/S, G

H – SN

N/S, G

NA NA

NA, G NA, G

Anecdotal reports

NA

NA, G

Abbreviations: A, animal experiments; H, Human experiments; G, Ground simulations (human) support feasibility on ISS; SP, specific imaging protocol demonstrated (pathology); SN, specific imaging protocol demonstrated normal data (sufficient data to rule out; condition would have been diagnosed if present); N/S, nonspecific imaging data support feasibility; NA, data not available.

9. Medical Imaging

193 Table 9.5. Ultrasound probes for space medicine applications. Applications

Figure 9.6. Sample echocardiography frames before (left) and after (right) transmission to the ground

circumstances must be taken into account along with the other more obvious factors, such as operator and groundbased expert training, psychological aspects, and remote guidance approaches.

Ultrasound Probe Needs for Space Medicine A choice of ultrasound probes must be available on board to fully realize the diagnostic potential of any ultrasound system. The types of probes recommended for space medicine purposes are listed in Table 9.5. A set of three probes is necessary and currently available on board ISS for meeting the majority of foreseeable imaging needs. Additional probes may be advantageous in some specific imaging situations and would also provide desirable redundancy. Curved array probes. A curved array probe acquires fan-shaped images through a relatively small window. These probes with relatively low (2–5 MHz) frequencies are primarily used for abdominal and transvesical pelvic imaging. An important feature of broadband probes is a uniformly high resolution throughout the field of view. If a curved array probe is unavailable, a phased array (cardiac) probe may provide a lower resolution alternative for the majority of abdominal applications. It may even be preferable in large subjects, in cases of excessive bowel gas or when its smaller flat face is needed to minimize pressure in the area of trauma, or in cases requiring small acoustic windows in the presence of wounds, dressings, or other impediments. In the ISS Ultrasound system, a broadband curved array probe operating in the 2–5 MHz range (designated “C5-2”) is the primary choice for abdominal or pelvic application.

Frequency (MHz)

Primary probe Curved-array (convex) Phased-array

Alternative (second choice)

Abdominal/pelvic

2–5

Cardiac

2–4

Superficial organs and tissues; musculoskeletal; chest wall/ribs; pneumothorax evaluation; peripheral vascular; ophthalmic; dental

7.5–12 (depths Linear < 5 cm)

Phased-array (lower resolution) Curved-array (extremely limited access due to large probe face) 5- to 7.5-MHz, linear or convex

5–8 MHz (depths > 5 cm)

3- to 5-MHz, linear or convex

Linear

Linear array probes. Linear array probes of modern ultrasound equipment usually operate at higher frequencies (7 MHz and above) to resolve small parts and subtle tissue interfaces with excellent clarity, tissue contrast, and detail resolution. Within relatively shallow depths, (e.g., up to 5–7 cm with a 5–12 MHz broadband probe), these probes acquire rectangular images of very high spatial and contrast resolution. In the ISS ultrasound system, the “L12-5” probe with a 4-cm-long narrow face is the probe of choice for the most superficial anatomical structures, such as the anterior segment of the eye, the median nerve, thyroid and salivary glands, breast, scrotum, or tendons of the hand and wrist. This probe has proven to be the best choice for screening for pneumothorax through visualizing the parietal-visceral pleural interface. Pending development of respective protocols, this probe will also support evaluation in certain dental and facial conditions, mainly periapical abscesses and paranasal sinus exudates. Of special interest for space medicine is its ability to provide the finest detail of muscle, fasciae, tendons, ligaments, bursae, and small joints, as well as the surfaces of superficially positioned bones. Thanks to its excellent spectral and color Doppler performance at shallow depths, it will also enable evaluation for suspected testicular torsion or epididymitis, thyroiditis, vascular aneurism or thrombosis, and a number of ocular vascular conditions. The ISS Ultrasound system can also be equipped with another linear array probe (“L7-4”) with a longer (50 mm) face and lower operating frequency range (4–7 MHz). Lower frequencies of this probe would ensure deeper penetration (up to 10–12 cm), with a relatively reduced spatial resolution. The 4–7 MHz probe is ideal for evaluation of DVT, and for examination of long bone surfaces and soft tissues of the trunk and lower extremities. In smaller subjects, this probe is suitable for high-definition imaging of the vermiform appendix and other superficially located abdominal structures. In the absence of this probe, a curved array 2–5 MHz probe would overcome the penetration deficiency of the

194

5–12 MHz probe but with severely compromised image clarity and resolution. Phased-array probes. Phased array probes are primarily used for cardiac imaging. They are small and easy to handle, have a very small footprint (face), and allow acquisition of wide sector-shaped images through small windows such as intercostals, spaces with a depth of view of up to 22 cm. Aboard the ISS, a phased array probe is available to support echocardiography in suspected cardiac conditions such as pericarditis and myocardial or valvular dysfunction. It can also serve as a backup probe for the majority of abdominal and pelvic applications.

Operational Issues in Space Diagnostic Imaging Communications Support for a Space-Based Imaging System For the most part, the current paradigm of medical imaging in space involves a one-way space to ground pathway for medical imaging data. Recent experience using existing diagnostic imaging hardware on orbit and in simulations (KC-135 and ground-based laboratory experiments) suggests that real-time transmission of ultrasound video and reliable two-way audio communication are essential to effective data acquisition. The diagnosis of any medical condition in space is challenging due to complicating factors such as microgravity, aberrant clinical presentation of disease, and the separation between the operator and the specific expertise on the ground. Autonomous acquisition of images by CMOs on orbit depends on the type of imaging modality employed and the training they have received. Without making unrealistic assumptions regarding their training and proficiency, it is expected that experts familiar with the specific aspects of space medicine and space-based imaging will perform realtime guidance and real-time or subsequent data evaluation and clinical interpretation. Detailed technical aspects of data transmission are outside of the scope of this chapter and are discussed in great detail in Chap. 11.

Operator Factors for Imaging Procedures in Space Training and Responsibility ISS crewmembers are likely to have little or no professional medical background and to receive only limited CMO training. Introduction of any imaging capability would require a carefully thought-out combination of preflight classroom and hands-on training, appropriate use of preflight and in-flight computer-based refresher training tools, and the use of onboard reference tools (cue cards and written procedures) combined with real-time guidance during data acquisition. The amount and content of pre-flight training and practice depend directly

A.E. Sargsyan

on the target set of knowledge and skills for performing the given set of imaging procedures. Imaging modalities differ widely in the in requirements for operator skills. A system with standard positioning and operation, such as a standard X-ray or CT machine or a scintillation camera, might require only modest skill and experience if detailed written procedures were available. Realistically, diagnostic ultrasound is very operator-dependent; application and manipulation of the transducer with continuous real-time adjustment of the equipment controls and scanning sequence are vital to acquiring useful diagnostic information. Space medicine experts agree that the expertise and confidence necessary to independently perform an ultrasound exam in space cannot be expected aboard the ISS. Considering the time lag between the limited preflight ultrasound training and the actual inflight medical event, it is indeed reasonable to assume that the CMO does not possess the expertise to independently acquire clinically useful ultrasound data. Limited on-board computer-based training (CBT) tools, although very important, cannot compensate for the lack of skill and training. Therefore, remote feedback and instruction are needed for guidance in clinical situations. Indeed, no matter how detailed and standardized the imaging procedures and specific scanning protocols are, anatomical variability of normal and affected structures, random factors (such as bowel gas or acoustical artifacts), and a large variety of possible diagnostic signs still require real-time data assessment and feedback. A standard ultrasound exam involves continuous control over probe position and pressure and equipment settings by the operator during the procedure, as well as specific cooperation on the part of the subject (such as holding breath or changing position). The procedure is occasionally interrupted by “freezing” selected frames for measurements, post-processing, annotations, transmission, or storage for future viewing and analysis. It takes months of training and years of practice to acquire knowledge, skills, and eye-hand coordination for confident and efficient ultrasound image acquisition. Wide variability exists among sonographers in their ability to think in three dimensions while conducting real-time 2-D examinations. Furthermore, one must remember that diagnostic ultrasound can be applied in nearly any area of the human body and in a large number of conditions, in which the anatomy at the site of abnormality is never exactly the same and also tends to change over time. A medical event on orbit would place high expectations on the CMO to acquire useful data. Besides the imaging procedure, the CMO will also be responsible for other aspects of crew medical support, for communicating with the flight surgeon, and possibly for other non-medical tasks. Preflight training and practice is critical, mainly to familiarize the crewmember with the general imaging technique and to build confidence in the end-to-end imaging system and imaging procedures that involve provision of expert guidance. However, allocation of large blocks of preflight training time for any standby capability, especially one unlikely to be

9. Medical Imaging

realized, is difficult to justify. Even with a relatively large amount of preflight training, the required skill set would hardly be achieved and maintained by a CMO without prior medical training. As a result, ultrasound training for ISS CMOs is limited to hardware use, familiarization with the basic examination technique and terminology, and limited scanning practice in simulated flight conditions under remote guidance from an ultrasound expert. Computer-based training and reference tools. Several training paradigms have been explored to overcome the inexperienced operator problem. Provision of computer-based training and reference tools is certainly a tested approach used widely by nonmedical disciplines for space flight. These could be used by the CMO for both scheduled inflight training and for preparation for contingency ultrasound examination and would consist of the following: Computer-based version of the preflight training session (refresher) ● A presentation on general scanning technique and procedures (multimedia) ● Presentations on specific imaging applications (multimedia) with procedure video clips and respective sequences of typical representative images to assist the CMO in recognizing the target patterns. These would be essential for independent data acquisition without remote real-time monitoring and guidance—a situation possible during communication outages or in missions beyond LEO. ● Sets of baseline preflight ultrasound images of all crewmembers, acquired by a standardized protocol; to be used immediately before or during the examination of the respective crewmember for comparison, as well as to serve as general reference material. Copies of these baseline data sets would also be available to the ground-based expert during data acquisition and interpretation. ●

Remote guidance. The third necessary measure to compensate for the lack of onboard expertise is a system of realtime remote guidance of a CMO by an expert on the ground. The author believes that this component of an imaging support system is essential to ensuring quality data acquisition and confident interpretation. Remote guidance for this purpose has been demonstrated during an experiment aboard a Russian spacecraft by a group of Russian and French scientists [11]. NASA has conducted numerous ground-based simulations, and their success has been reported to the space medicine and telemedicine communities. These experiments have involved operators of various backgrounds, including astronauts, and have uniformly resulted in diagnostic information of acceptable quality. Having completed preflight ultrasound training and practice, the CMO is cognitively prepared to perform an imaging study in continuous real-time communication with an expert on the ground, who in turn is able to consistently issue distinct commands in a confident and patient manner, and to identify and interpret received information in real time. This unique

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and highly professional interaction, once performed in a realistic preflight simulation, allows the CMO to rely on provided expertise and avoid frustration and doubt regarding the value of the activity he or she had not been sufficiently trained for. An important component of remote imaging guidance is the convention among all participants on the exact terminology to be used for remote instruction that includes terms denoting probe positioning and movements, anatomical landmarks, scanning directions, and instrument controls. The first version of the ISS ultrasound cue card is shown in Figure 9.7. Identical copies of the card are available to both the onboard CMO and the ground expert. The card identifies instrument controls, basic probe manipulation techniques, and anatomical locations for probe application. Cue cards of this type constitute an essential part of the remote guidance technique developed by NASA for the operational use of ultrasound on ISS. Before testing on ISS, NASA conducted multiple studies in laboratory conditions and in parabolic flight.

Operator Positioning and Stability The lack of gravity and the spacecraft environment impose challenges in terms of operator positioning and stability during various manipulations of the imaging hardware and the

Figure 9.7. This ultrasound imaging reference chart (cue card) has been successfully used during real-time remotely guided imaging sessions aboard ISS

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subject. For example, for the operator to perform abdominal, renal, or pelvic examinations with optimal performance, all of the following conditions must be satisfied in a mutually compatible way: The subject must be stabilized in the immediate vicinity of the ultrasound system, within easy reach of the probes. Unless self-scanning is anticipated, the crew medical restraint system (CMRS) is ideal and should be deployed to maximize the results. ● The operator’s position must be sufficiently comfortable to perform the examination for at least 45–60 min. Operator restraints and other stabilization techniques must be used to maintain a stable position with both hands available for the imaging procedure. The operator must be able to consistently exert a contact force of up to 5 pounds and occasionally higher on the probe anywhere over the entire region of interest on the subject’s body. Examples of the most effective subject-operator positions are shown in Figure 9.8, as determined during NASA KC-135 experiments conducted in 2002. ● The ultrasound monitor must be easily viewable at an angle close to 90 degrees and must be set at a distance to allow perception of image detail and other information displayed. ●

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Acceptable lighting conditions must exist to ensure comfortable viewing and to avoid monitor glare. ● Equipment controls (in case of ISS Ultrasound, the keyboard) must be within easy reach for the other hand (the one not holding the probe) during the entire examination. ● The operator must wear a voice-activated audio communications headset to receive near-real-time feedback and guidance from a remote expert at the Mission Control Center. ● Deployment of the operator, patient, and imaging hardware must be globally compatible with the medical equipment setup used for emergency medical treatment and life support activities. ● Care should be taken to avoid interference from other crewmembers during their translations within the spacecraft. When this chapter was written, successful self-scanning had already been demonstrated on ISS with minimal foot restraint. However, self-scanning may not be possible for several considerations, including patient distress or preflight training and proficiency factors. The above listed conditions are believed to be achievable using the currently deployed HRF Ultrasound on the ISS. However, further study and demonstration of ISSspecific positioning and scanning techniques is warranted.

Figure 9.8. Various positioning and restraining options can be used depending on circumstances. The Crew Medical Restraint System (CMRS), shown here being tested in parabolic flight, provides the best mechanical stability (Photo courtesy of NASA)

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Psychological Factors Any potentially serious clinical situation requiring imaging, especially if associated with subject distress and urgency, would inevitably be psychologically challenging for all involved: the subject, the onsite care provider (operator), and the ground medical team. The stress of the situation and time pressure would probably influence the baseline ability of the CMO to perform the task, and may render him or her unable to focus on the imaging task. The CMO would feel enormous responsibility for performing necessary procedures efficiently and with proper precision. Preflight training and preparation and confident in-flight feedback and guidance are essential to prevent operator frustration and to achieve effective and efficient data acquisition. Embedding a remotely guided scanning practice session in the preflight training flow is key to introducing a necessary degree of confidence in the CMO(s), the ultrasound guidance expert, and the crew surgeon.

Subject Positioning for Imaging Procedures Patient positioning techniques in medical imaging must be standardized to stabilize the body, maintain and control specific spatial relationships between the emitting and detector hardware and the area of interest, and to maintain a specific spatial relationship between two or more body parts or organs. As much as possible, subject positioning should take advantage of the effects of microgravity. Microgravity poses unique challenges regarding patient positioning. For imaging purposes, positions such as “prone” or “semi-decubitus” may retain some meaning only in relation to a surface, such as the ISS Crew Medical Restraint System (CMRS) or imaging hardware and do not imply any specific gravitational vectors within the body. To communicate positional or directional information reliably and efficiently, a preestablished convention is necessary for terminology and anatomical references. Otherwise, use of such terms may be misleading. Stability of a subject’s position relative to the imaging system is highly desirable and often critical. In some imaging techniques, such as X-ray or MRI, the patient’s position is assumed to have remained unchanged throughout the data acquisition process. On the ground, the subject is normally able to maintain a stable position and avoid movement when instructed to do so. In the absence of gravity, no initial position relative to any reference, such as to the imaging system, ensures stability, as any force inevitably leads to a momentum directed away from the point of its application. Manipulation of the subject and application of radiation shielding, probes, electrodes, etc. would therefore disturb the given position. Therefore, application of restraints, such as elastic cords or fabric belts, will be necessary. Furthermore, it is well known that the relaxed neutral body posture in space (sometimes referred to as fetal), as determined by the relatively higher flexor tone, features flexion in the spine and extremities, thus potentially interfering with access to some

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areas of interest. For many imaging techniques, such as echocardiography, abdominal ultrasound, or spinal X-ray, a more extended position is strongly preferred or even necessary. Therefore, a restraining capability may be necessary to immobilize and stabilize the patient, and to modify his or her body position. For ultrasound imaging, CMRS deployment is highly desirable in all cases (except self-scanning) and essential if a timeconsuming, complicated study is expected or the subject is in distress and may need advanced medical intervention and care. Restraint on the CMRS is the best available means to stabilize both the subject and the operator and ensure unhindered performance of the operator during extended periods with minimal fatigue.

Training of Remote Guidance Expert Little information is available on the presentation and course of disease and injury in conditions of space flight, as well as on many aspects of underlying pathophysiology and disease anatomy. A certain degree of familiarity of the radiologist with human space flight and space physiology could significantly aid data interpretation. Close interaction of the radiologist with a flight surgeon is a critical factor for ensuring overall success of imaging in space. The remotely guiding ultrasound expert, who is not necessarily the same person as the interpreting radiologist, must be trained in advance (including space medicine familiarization and actual remote guidance practice in the laboratory setting), and must be familiar with mission control console techniques and etiquette to provide effective support. The current NASA station for remote guidance training simulates an adjustable satellite delay for both video and audio, thus allowing the trainee to acquire basic skills for live space-to-ground interaction. In the current ISS configuration, the communications delay is approximately 2 s.

Mission Limitations on Imaging Hardware and Use Flight Equipment The unique factors of space flight drive numerous requirements and constraints to hardware and its operating procedures, beyond any terrestrial standards. Accelerations and vibrations at launch, continuous microgravity, fluctuations in ambient pressure, lack of effective heat exchange through convection, and relatively high levels of radiation may damage the equipment or cause performance decrements, errors, and outages during its operation. Overheated plastics may produce harmful gaseous contaminants in the sealed spacecraft cabin. Equipment must also meet noise generation standards. Finally, rack-mounted hardware must be made compatible with the power, data, cooling, caution and warning, and fire suppression systems of the rack and vehicle.

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Indeed, any household or office device nowadays undergoes rigorous performance, availability, and safety testing. Space hardware is usually acquired or built to a stricter set of standards with a comprehensive scrutiny of fire and electrical safety risks and electromagnetic emissions. Safety concerns may render many otherwise worthwhile projects unsuitable for space flight. Thus, however well built and reliable it may seem, a piece of diagnostic equipment is likely to require some, and often extensive, redesign and modification before becoming spaceflight-certified. This modification may include repackaging of electronic components, replacement of housing and the power supply unit, and addition of cooling, fire detection, and possibly fire suppression components.

Weight and Volume Limitations The weight and volume of most modern diagnostic devices are prohibitive for space flight. Diagnostic ultrasound is about the only imaging modality that reasonably fits in the current constraints, with some commercially available devices weighing as little as 2.5 kg. A partial solution to these problems is the use of standard portable computers as control and data display platforms for medical devices. Remaining functional components of diagnostic systems can be combined in smaller integrated packages. Future diagnostic devices may be further integrated to share other components, such as power units or display subsystems.

Power Electric power is a precious resource on any spacecraft. Systems and payloads are all designed to be as energy-efficient as the current technology allows. Transport spacecraft (such as Apollo or Soyuz capsules) would require extensive redesign and modification work to accommodate any new piece of hardware. The Space Shuttle can supply up to 5 amps of its nominal 28VDC to middeck payloads during on-orbit operations. Continuous power used by an individual middeck payload is limited to 115 W for no more than 8 h or no more than 200 W peak for periods of 10 s or less. When outfitted with the now retired Spacelab laboratory, the Shuttle was capable of distributing a total of 7 kW maximum continuous (12 kW peak) power to its subsystems and experiments during on-orbit phases. Space laboratories like Mir or ISS, on the other hand, are designed to power a large array of permanent and temporary experimental equipment. For any energy user, both nominal and peak consumption limits are still strictly defined and observed. Should any device fail to fit within the limits of the given user group, its flight certification or use would be threatened. In the final configuration, the ISS electrical power system is planned to have a maximal output of 110 kW, with a payload power allocation of up to 30 kW. However, energy needs of some standard imaging hardware are still notoriously high. For example, an average computed tomography (CT) system might consume 25 kW or higher power continuously, with

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peak wattage of 75 kW or more. Extensive and costly modifications of the onboard electrical power system would be required to accommodate a diagnostic device with such high power consumption, even if it fits in the overall power capability of the station. Furthermore, the thermal control system of the station would be seriously challenged to remove the heat generated by such hardware, as gravity-driven convection effects are absent in space. Power users are prioritized in terms of their importance for safe operation of vehicle systems. Experience with the Mir station demonstrated how power shortage caused by electrical system failures, solar panel damage, or suboptimal vehicle orientation can affect spacecraft systems and various users. In adverse conditions, devices with modest power needs have a far better chance of receiving electrical power allocations than their higher power competitors.

Diagnostic Imaging in Exploration-Class Missions The possible contribution of medical imaging to medical support systems for interplanetary flights and lunar or Martian bases deserves special consideration. With clinical autonomy being a more critical mission factor, such endeavors would require a unique and largely self-sufficient combination of hardware, clinically current medical expertise, and other resources necessary to satisfy countermeasure and rehabilitation demands, provide environmental monitoring, and handle any foreseeable “maladaptation, illness and injury” that are “likely to be the pace-limiting variables in efforts to expand the presence of humans into the solar system” [18]. The most universal suite of imaging hardware, chosen through analysis of existing evidence, expert opinions, and most current technology, will probably have to be custom-built or heavily modified to satisfy the specific requirements for use both en-route and upon arrival at the destination. Of these constraints, small weight and volume, long shelf-life and radiation stability, serviceability, and means to upgrade, modular structure, and compatibility with shared power, computing, and communication resources will be the primary considerations. Although an Earth-orbiting station can be supported almost on demand by expertise on the ground, interplanetary missions do not offer such luxury due to the sheer distances involved. Unlike LEO missions, flights to remote planets such as Mars or beyond have extremely limited, if any, mission abort options for returning ill or injured crewmembers, any of which would most certainly take longer than the natural course of any acute illness. In addition, a large communication delay effectively prevents live conversation and near-real-time data transfers, leaving no choice but to exchange messages in a manner similar to present-day e-mail. Therefore, a considerable clinical capability must be available aboard the interplanetary vehicle, and the crew must possess training and skills to perform acute medical care procedures independently.

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Selected Medical Problems and Imaging Solutions Perception of medical risks in human space flight has been published based on the information accumulated in human space flight and several terrestrial analog populations [4]. From 2000–2002 NASA developed a specialized database that lists possible medical conditions for space flight for the purposes of determining medical capability. Ultrasound has been identified as a key imaging modality in the diagnosis and/or treatment of over 50% of these conditions, including blunt and penetrating trauma, cardiovascular pathology, nephrolithiasis and urinary obstruction, biliary obstruction, and acute and chronic infections. The conditions discussed in the section that follows are considered to be possible in the setting of human space flight or are known or expected to present unique diagnostic challenges in microgravity. These selections also illustrate the magnitude of differences that the spaceflight environment may introduce into imaging techniques, interpretation, and impact.

Pneumothorax and Other Pleural and Pulmonary Conditions Pneumothorax is commonly seen in patients with trauma involving penetrating chest wounds and blast lung injuries and those receiving positive-pressure ventilation; in many others the precipitating event remains unclear. Radiography or CT illustrating a classic gravitationally dependent hypodensity in the involved hemithorax usually confirms the diagnosis. Since the late 1980s, case reports and papers on ultrasound diagnosis of pneumothorax have been published [64–67]. Accordingly, NASA has investigated the use of ultrasound imaging for the diagnosis of pneumothorax in space flight and remote areas lacking radiographic capabilities. A pneumothorax animal model was developed to test the capabilities of using ultrasound for this condition in microgravity [68]. A case report of ultrasound diagnosis of pneumothorax secondary to a gunshot wound has also been published [69]. Concurrently, in prospective human trials in cooperation with NASA [70], thoracic sonography was shown to reliably diagnose pneumothorax in the emergency room setting, with a 98% sensitivity and a 100% specificity. Presence of the classic lung-sliding pattern was shown to confidently exclude clinically significant pneumothorax. Subcutaneous emphysema was the only limiting factor and was one reason for the initial study to fall short of 100% sensitivity. One patient had a negative chest xray when the ultrasound was found to be positive; the X-ray taken 1 h later was positive. Largely due to these efforts, an expansion of the Focused Assessment by Sonography in Trauma (FAST) examination to include thoracic ultrasound is becoming a standard in many trauma centers. NASA, in collaboration with academic medical centers, has found that the ultrasound sign of “partial lung sliding”

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can infer modest (limited) pneumothorax, which increases the negative predictive value of this technique (Figure 9.9). It can be hypothesized that high-quality CT would probably be diagnostic of pneumothorax in microgravity, but the accuracy of chest radiography for the same purpose might be unacceptably low because of inconsistent distribution of air and fluid in the absence of gravity. In September 2002, for the first time in history of space flight, NASA scientist astronaut Peggy A. Whitson, assisted by a remote expert in the Mission Control Center, successfully demonstrated typical patterns of normal pleural interface in microgravity. Free pleural fluid, either exudate or blood, would present a diagnostic challenge in space even to a skilled physician, primarily due to its unusual distribution. Animal studies conducted by NASA in parabolic flight have clearly shown that pleural fluid redistributes upon transition to microgravity, partly shifting towards the mediastinum and partly forming a uniform layer around the lung, as previously discussed. The amount of fluid in the dependent portions (measured as the degree of separation between parietal and visceral pleura) markedly decreases upon insertion into microgravity, whereas the separation elsewhere in the chest increases. Wide distribution of fluid in the thorax increases the choice of sites for probe application. The use of intercostal spaces in areas with minimal muscle mass, such as the midaxillary line, can reveal even small separation of pleural layers using high frequency, high-resolution probes. Although no data exist for microgravity chest x-rays with these clinical situations, it is logical to assume that radiography would have a high detection threshold

Figure 9.9. Partial pneumothorax with hemothorax showing pleural separation by blood (thick white arrows) and by air (thin white arrows). The black arrow points to a segment with a normal visceroparietal interface

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and poor overall sensitivity, with the exception of large tension pneumothoraces with apparent compressive atelectasis.

Pulmonary Parenchymal Pathology In the absence of radiography and CT on-orbit, pulmonary parenchymal pathology may be easily overlooked, especially if lung auscultation is difficult due to ambient noise. Historical medical events and known environmental hazards in past and current space programs indicate that a potential exists for parenchymal processes, such as pneumonitis following a toxic inhalation. Although the normal aerated parenchyma is not easily visualized by ultrasound, areas of lung consolidation can be directly identified and monitored. Over the past decade, terrestrial experience in ultrasound has advanced the ability to detect chemical or infectious pulmonary inflammation, [71,72] subpleural abscesses [73], and compressive or obstructive atelectasis in previously healthy lungs. Similar procedures should be possible with astronauts in microgravity environments.

Blunt Abdominal Trauma, Peritoneal Fluid, and Gas Clinicians rely heavily on CT and sonography to assist in diagnosing intraperitoneal injury. As conventional radiography and CT are not available aboard existing spacecraft, diagnostic ultrasound will remain the principal imaging modality for abdominal trauma and peritoneal disease evaluation. Abdominal trauma sonography, specifically the FAST examination, has replaced diagnostic peritoneal lavage (DPL) and CT as screening tests of choice in most trauma centers in United States [74]. A positive FAST exam has been proven to provide a definitive indication of intraabdominal hemorrhage in appropriate settings. It is a rapid, safe, effective, repeatable, and transmittable imaging tool that can screen for the presence of intracavitary hemorrhage (peritoneal, pericardial, and pleural) or visceral leakage, and help estimate the magnitude of the bleeding or leakage in most cases. Preliminary animal and human trials have also shown that FAST can be expanded to effectively diagnose or exclude traumatic pneumothorax [68,70]. The ultrasound equipment available on ISS provides the capability of performing FAST. The ability to detect abnormal fluid collections relies on the demonstration of sonolucent areas (fluid stripes) in typical gravitationally determined anatomical locations; both CT and sonography have traditionally relied on these fluid collections as markers of organ injury. The behavior of intracavitary fluid remained poorly studied in weightlessness until NASA’s comprehensive experiments in the microgravity of parabolic flight in 1999. These experiments resulted in a number of findings, enriching the understanding of sonographic signs of blunt abdominal trauma in both 1 g and microgravity. It was demonstrated and confirmed that free fluid in the absence of gravity does not readily localize to the predicted terrestrial anatomic sites, and signs of its presence must be sought and interpreted

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differently. Erroneous interpretations of trauma sonograms in 0 g might render the study non-diagnostic or even misleading. Small quantities of fluid such as blood tend to remain in the place of origin, initially enveloping adjacent mesothelial surfaces, such as bowel loops, by the virtue of the dominant force—surface tension (Figure 9.10). As more blood accumulates from a point of hemorrhage, it tends to form localized collections and slowly spreads according to the intraperitoneal anatomy and adjacent organ compliance. For example, blood would reach the pelvis rather sooner from the left inframesocolic space or even the left subphrenic space, compared to the right inframesocolic space, where a much larger volume of blood would have to accumulate before it could spread over the small bowel mesentery. Thus, although the basic FAST exam locations remain valid in microgravity, an additional scanning step called abdominal sweep is necessary to rule out or detect blood collections in terrestrially atypical locations, particularly between loops of the small bowel and in visceroparietal spaces. Pneumoperitoneum may also be diagnosed by sonography in microgravity, although the detection threshold and possible pitfalls have not been clearly determined. In the previously mentioned animal experiments, quantities of insufflated gas as small as several milliliters were readily detectable. These data confirmed previously published reports [75,76].

Acute Appendicitis The wide variety of signs and symptoms of acute abdomen, combined with the peculiar setting of space travel, make ruling out a suspected acute appendicitis a very challenging clinical task. Any acute right lower quadrant (RLQ) pain and tenderness would elicit an extensive differential diagnosis,

Figure 9.10. A small hemoperitoneum in the zero gravity phase of parabolic flight. Bowel loops in the vicinity of the bleeding are wrapped in a thin layer of blood, seen as contouring of the bowel sections

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among which acute appendicitis would be considered in any non-appendectomized crewmember. Aboard the ISS, diagnostic ultrasound would be the only imaging method available to conduct a focused study to rule out or confirm a variety of possible conditions, including appendicitis and its complications, renal colic, diverticulitis, Crohn’s disease, female pelvic pathology, and other less frequently occurring conditions. Imaging signs of acute appendicitis and its complications have been thoroughly described [64,77,78]. Although these signs are not expected to differ substantially in space, the clinical presentation and course may be aberrant, further complicating the flight surgeon’s task. Among the abundant publications, data on the effect of CT and diagnostic ultrasound on acute appendicitis management vary greatly. Despite considerable skepticism expressed by some [79,80], many radiologists assert that both methods have a definitely positive influence on patient management, in particular a measurable reduction of unnecessary appendectomies [64]. Most experts suggest that a high index of clinical suspicion should exist for appendicitis before using either imaging technique to confirm the diagnosis [81]. A normal appendix is visualized sonographically in 2–10% of healthy individuals, although a higher success rate can be achieved over time with consistent systematic approach and operator training. The following statement by Puylaert clearly characterizes the negative findings in suspected appendicitis: “If a normal appendix is visualized in its full length, appendicitis can be excluded. However, this is rarely the case. In practice, the only means to exclude appendicitis is to demonstrate an alternative condition, which in most cases is possible by US [ultrasound] alone.” [78] The ultrasound imaging procedure evaluating RLQ pain must also include thorough visualization of the right kidney, as much of the right ureter as possible, the gallbladder and bile ducts, the pancreas, the cecal area, ileal loops with a search for enlarged mesenteric lymph nodes, the urinary bladder with bilateral demonstration of “ureteral jets,” the uterus with the right adnexa, and the peritoneal cavity for localized or free fluid. In some cases, the study may also include contralateral organs and tissues, or abdominal wall and psoas muscles. Such a broad study performed by an experienced sonographer requires 15–30 min to complete. The same study performed in LEO under real-time remote guidance would require enormous patience and concentration and could take considerably longer. An inconclusive imaging report in a RLQ pain episode, including a failure to visualize the appendix or otherwise provide a solution to the diagnostic problem, should warrant at least another imaging session. From the author’s own experience, the imaging conditions in the lower abdomen change drastically over time because of the dynamics of intestinal contents and peristalsis, bladder filling, abdominal guarding, and the degree of patient and operator anxiety or concentration and cooperation with the examination. For these reasons, imaging experts should be proactive in recommending focused

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ultrasound exams not only in positive cases to monitor the disease anatomy and the efficacy of treatment, but also to make repeated attempts to add confidence to previously inconclusive or negative studies.

Decompression Sickness Injury from decompression sickness (DCS), a potential result of rapid transition to a lower ambient pressure, has been recognized and studied for over a century. Risk mitigation strategies for spaceflight DCS have evolved since the first human missions, particularly those involving extravehicular activities (EVA) and their attendant decompression from cabin to suit pressure. As our space activities broaden to involve construction of large and complex habitats, pressure-suited workers must assemble, repair, and maintain these structures with precision and efficiency. The large amount of EVA time required for assembly and maintenance of the International Space Station, along with the station’s unique EVA-related operational constraints, raise priorities for addressing likelihood, prevention, and potentially intervention and treatment of DCS. The mechanisms by which DCS bubbles form in body tissues and fluids remain controversial, as does the relationship between the magnitude of this gas phase and the clinical manifestations of decompression sickness. Human hypobaric experiments have been conducted by the Altitude Protection Laboratory [82–84] and by NASA [85,86] in collaboration with several academic and government laboratories. The U.S. Navy Experimental Diving Unit (NEDU) is also conducting a large prospective study of decompression effects using transthoracic echocardiography (TTE). This multiyear evaluation of procedures for rapid decompression from shallow depth saturation will add considerably to the body of knowledge accumulated to date. TTE is used by many investigators to determine the extent of gas phase formation by visual quantification of venous gas emboli (VGE) in the right and left heart chambers. It has been demonstrated that bubble crossover and penetration into the left circulation is associated with a higher probability of clinically overt decompression sickness [82]. Detection of arterial gas embolism on bubble crossover during ultrasound evaluation is thought to signify an increased risk of type II DCS. NASA Space Medicine and NEDU have also conducted saturation diving experiments in a hyperbaric chamber complex to determine if the ISS ultrasound equipment can be used to detect VGE and what training would be required for space medical care providers to acquire such information. During these experiments, bubbles were successfully detected not only in the cardiac chambers but also in peripheral veins of lower extremities, such as the popliteal and anterior tibial veins. For the first time, real-time power Doppler mapping was compared with conventional duplex echocardiography and was shown to have comparable and possibly better bubble detection ability. The power Doppler technique takes advantage of shifts in the original frequency of the ultrasonic beam due to reflection from

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moving targets (Doppler shifts), or of ultrasonic noise emitted by the bubbles under the influence of ultrasonic energy. Such frequency shifts, detected along with their spatial coordinates, are shown on the images in color, with the brightness proportional to the amount (power) of the shifted ultrasound measured. It remains an open question whether ultrasound imaging will ever be used operationally in space during or after decompression events with high DCS potential; non-imaging Doppler detection and monitoring of VGE in the course of extravehicular activity is far more feasible although the operational value of such monitoring is debated. Preflight screening for patent foramen ovale (PFO) is believed by some to be a justified measure to lower the risk of life—threatening DCS during operational decompression exposures, such as in diving and EVA. In conventional clinical settings, paradoxical air embolism in neurosurgery is another reason for PFO screening studies [87–89]. The current gold standard for identifying PFO is contrast-enhanced transesophageal echocardiography (c-TEE). Less invasive alternatives to this method is contrast-enhanced transcranial Doppler ultrasonography (c-TCD) and contrast-enhanced TTE (c-TTE). According to Stendel and colleagues [89], c-TCD is a highly sensitive and highly specific method for detecting a PFO, whereas C-TTE is unreliable for this purpose.

Ophthalmic Trauma The first ophthalmic sonographic image was published in 1956 [90], and since then sonography has evolved to offer crucial diagnostic information in many ophthalmic conditions, including complications of ocular trauma. It is especially helpful when visual inspection is impossible to perform or does not provide a definitive diagnosis. In the past, dedicated ophthalmic ultrasound systems were superior to multipurpose systems for diagnosing ophthalmic injury and illness, thanks to the use of single-crystal, high frequency probes focused at fixed low depths, and to acceptability of low frame rates. However, this is no longer the case because modern multipurpose systems employ sophisticated focusing and image optimization techniques that are not feasible for the smaller systems. Ultrasound in ophthalmology is used in three distinct clinical applications: ultrasound biometry that pursues precise distance measurements, ultrasound biomicroscopy (UBM) limited to the anterior segment, and general-purpose scanning. UBM uses extremely high frequencies (50 MHz and higher) and provides very high resolution on the order of tens of microns within shallow depths of about one cm [91]. Modern generalpurpose ophthalmic scanners provide excellent images of the posterior chamber, the fundus, and orbital structures such as orbital adipose tissue, optic nerve, vessels, and muscles. Other imaging modalities in ophthalmology include CT and MRI to primarily rule out facial trauma with orbital fractures, intraorbital masses, and suspected foreign bodies. Astronauts undergo extensive ophthalmologic examination at selection and during annual certifying examinations, including

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periodic retinal imagery and corneal topography. With actual missions, preflight and postflight ophthalmologic examinations include only visual (optical) inspection by hand held ophthalmoscope, although any imaging modality is available if clinically warranted. In-flight eye examinations are extremely limited because of lack of specialized equipment and CMO expertise. Although biometry and UBM have limited practical significance for space medicine, general scanning with a multipurpose ultrasound device can be of great value in certain conditions. The ISS Ultrasound system is equipped with a 12-MHz probe capable of producing ophthalmic images of excellent quality. To prevent iatrogenic trauma in an environment devoid of gravity-stabilizing postures and fixation, safety precautions must be strictly observed. Standard scanning protocols and real-time interaction with an expert are necessary for efficient and dependable diagnostic evaluation. Currently, ISS ultrasound stands as the main source of objective anatomic information for the crew surgeon and ground-based ophthalmologists. As of today, only singular cases of minor eye trauma have been observed in space. However, the risks of serious eye injury are present. Airborne objects, the cluttered environment of a research laboratory, the use of elastic cords and pressurized gases can all be considered risk factors for ocular and periorbital trauma. Complications of ocular trauma, such as recurrent hyphema or retro-vitreal hemorrhage, may evolve over a period of 5–10 days; therefore, after a blunt impact, ultrasound follow-up would be normally required, especially with persistent or progressive symptoms. Ultrasound evaluation of the eye on the ISS would be indicated in any case of trauma with the following findings: Disturbance of vision of any extent Suspected globe penetration with or without a foreign body ● Any abnormal finding during visual inspection of the globe ● Significant pain or any other persisting symptom ● Edema or bruising of periorbital tissues and eyelids ● ●

In the absence of slit lamp or other imaging options, diagnostic ultrasound may seek to obtain information that is normally outside the scope of standard ocular ultrasound. Some portions of the ophthalmic ultrasound examination may be best performed through self-examination, in order to better coordinate probe position with the direction of gaze during scanning and to keep the probe pressure below the discomfort threshold. NASA has conducted ground-based and parabolic flight simulations of remotely guided ophthalmic ultrasound in healthy volunteers with promising preliminary results. These protocols developed specifically for microgravity involve remote viewing of the ultrasound output video in near real time (2-s delay) and verbal guidance of the subject through discrete steps of a self-examination protocol. Volunteers with no prior experience consistently found self-examination feasible and practical and generated imaging sequences of diagnostic quality. The basic protocols and scanning options are presented in Table 9.6.

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Table 9.6. Image-guided interventional procedures. Ultrasound guidance and control procedures demonstrated on board the KC-135 Imaging support and verification of ureteral stent placement Imaging support and verification of surgical thoracostomy Image-guided aspiration and drainage of intra-abdominal fluid Image-guided percutaneous suprapubic cystostomy Imaging support and verification of Foley catheter placement Imaging support of laparoscopy Imaging support of thoracoscopy

Other possible applications for ultrasound guidance in microgravity Soft tissue infection/abscess, to direct incision Soft tissue or intracavitary infection/abscess, to direct puncture to aspirate Image guidance for percutaneous pleural aspiration/thoracostomy Image guided punctures to deliver pharmaceuticals Image guided central venous access Image guided removal of foreign body

Figure 9.11. High-resolution ultrasonic sections of the human eye. Once acquired, these images are largely self-explanatory. 1- sagittal section of the anterior segment; 2- coronal section through the iris

Sample images obtained by an inexperienced operator with remote guidance on equipment identical to HRF Ultrasound are shown in Figure 9.11.

Urolithiasis, Urinary Obstruction, and Retention Urinary supersaturation with stone-forming salts and possible changes in urine chemistry in microgravity may increase the lithogenic properties of the urine, leading over time to development of urolithiasis [92–94]. Renal colic has been observed during space flight at least once and shortly after landing in other crewmembers. Some of these episodes might have had a significant influence on the mission had they occurred during

flight. Although the prognosis in most cases is excellent, careful diagnostic consideration, observation, and analgesia are required. The differential diagnosis of the signs and symptoms of acute renal colic is quite varied, and some form of noninvasive imaging is usually used. Associated pathology, such as acute pyelonephritis in space would require immediate attention and, if left untreated, could have devastating consequences. At present, the space-based diagnostic experience for renal colic is minimal; therefore it is fair to assume that diagnosis may be based on presenting complaints, scarce physical examination data, and indirect data derived from urinalysis. Among potentially useful imaging capabilities, such as standard or helical CT, ultrasound, intravenous pyelography (IVP), plain radiography, and urologic endoscopy, ultrasound is the most universal and practical to provide imaging coverage of urolithiasis and its complications. In case of suspected renal colic, even with mild symptoms, ultrasound should be treated as an emergency procedure, and 30 min of net imaging time should be allocated. The patient must be reasonably hydrated and have a full bladder. Due to considerable variation of normal kidney anatomy, standard sets of preflight baseline images of both kidneys should be available to the expert on the ground. As renal colic may be associated with both severe pain with restlessness and transient ileus, imaging conditions may be unfavorable. The renal ultrasound protocol includes imaging the kidneys, the entire bladder volume (calculi may be in “blind spot” locations due to microgravity), ureteral orifices, bladder neck (with as much of the prostate and urethra as possible), and intramural ureters. Attempts should be made to track the ureters from the orifices backwards and upwards, from the renal pelvis and ureteropelvic junction (UPJ) downwards, and at the iliac vessel crossing. In case of ambiguous or negative results, the study must proceed with a search for other causes. A follow-up imaging session or monitoring schedule must be recommended. The extent of renal pelvic dilatation is not always reliable in determining the degree of ureteral obstruction, especially when acute renal infection is present. A useful supplementary technique to assess ureteral patency or ipsilateral diuresis is demonstration of “ureteral jets” (or of the lack thereof) in “color” or “power” Doppler modes. A typical image of a ureteral jet, acquired aboard the ISS, is shown in Figure 9.12. Despite a usually favorable overall prognosis, it is easy to foresee a scenario leading to evacuation of a crewmember

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Figure 9.12. The ureteral jet (arrows) confirms patency and function of the respective ureter. This image file was captured aboard the ISS and downloaded during a subsequent communication session

from orbit with urolithiasis, especially if a second calculus is detected or even suspected in the urinary system. Prevention of unnecessary evacuation is a prime focus of imaging and management. The following is an example of an ultrasound report in a case of urolithiasis with good chances of a favorable outcome: Imaging is complicated by bowel gas interference, restless condition of the patient, and limited time. The right kidney is 13.5 × 6.0 × 5.0 cm; collecting system is apparently dilated. The UPJ seems to be free from obstruction. The right ureter is possible to track down to the lower pole level, with a cross-section of up to 6 mm. No stones or other abnormalities are identified within the kidney, UPJ, and the bladder lumen. Through the bladder window, a small calculus (−2 to 3 mm) is identified in the intramural segment of the right ureter (at 9 mm from the orifice), with a fluid-filled lumen proximal to the calculus. Orifices remain symmetrical. In the power Doppler mode, detectable ureteral jets are absent on the right side, while strong jets are seen contralaterally. Sonography of the left kidney is unremarkable. Conclusion: Sonographic picture is consistent with a small calculus in the intramural segment of the right ureter, with a significant degree of obstruction. Follow-up imaging is recommended (full bladder is required).

Urinary retention has been observed in space. The probability of retention is higher in the very initial phase of adaptation to space microgravity, and certain medications used to combat motion sickness, particularly those with anticholinergic properties such as promethazine, may contribute to its development. The flight surgeon’s decision regarding onetime drainage with a Foley catheter or percutaneous drainage with temporary cystostomy would be greatly facilitated if objective data were available on the actual volume of the bladder and the status of the antireflux mechanisms. Gaping ureteral orifices with distended upper urinary tract would be easily identified by real-time ultrasound and would probably be considered an indication for intervention, especially if the reflux is bilateral or accompanied by symptoms of infection. If percutaneous drainage is indicated and an appropriate sterile kit is available, ultrasound would add a considerable margin of safety and confidence to the procedure. In case of Foley catheter placement, ultrasound may be used to verify proper

A.E. Sargsyan

Figure 9.13. The cortical layer of a long bone (arrows) demonstrates discontinuity, angulation, and possible tissue interposition. A fracture can thus be diagnosed

placement and inflation and adequate resolution of the reflux. Urinary retention and vesico-uretero-pelvic reflux have been observed and percutaneous drainage successfully performed, in an animal model during a KC-135 experiment. The procedure, performed with proper precautions under sonographic guidance by a physician, did not present any significant challenges in the free-fall condition.

Bone Fractures Large mass handling in complex facilities such as the ISS makes fractures a possibility, especially of small or superficial bones. As ultrasound may be the only available diagnostic imaging capability, its clinical utility in identifying bone fractures is of interest to space medicine. NASA investigators in a collaborative study have sought to determine the accuracy of ultrasound as performed by physicians in an emergency room setting in identifying fractures of the humerus and femur. The physicians involved had been trained using a standardized multimedia presentation. Preliminary data indicate that ultrasound is very sensitive and moderately specific for detecting acute traumatic fractures of long bones in a setting with limited data acquisition and interpretation expertise. Discontinuity of cortical bone is the primary sign of fracture (Figure 9.13).

The Role of Imaging in Interventional Procedures In recent decades, Interventional Radiology has gradually evolved into a distinct interdisciplinary branch of clinical medicine. This trend of expanding the therapeutic and surgical role of imaging disciplines and imaging specialists, first observed in angiography, has been followed in conventional radiology, ultrasound, CT, and other visualization disciplines. Interventional radiology and minimally invasive surgery go hand-in-hand as more clinical conditions are diagnosed,

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staged or described, and treated without major surgical trauma, ensuring lower morbidity, cost, and personnel involvement and shorter hospital stays. As the only imaging option aboard the ISS, the therapeutic applications of ultrasound deserve special attention. Focused investigations conducted by NASA space medicine and affiliated experts have already demonstrated feasibility of several possible image-guided interventions for the microgravity environment; many others are expected to be possible. Some examples of both groups are listed in Table 9.6. The degree of clinical autonomy required; the level of medical risk accepted by a given program, will determine the extent of sophistication of the medical support system and the list of medical interventions available on board. As an example, peritonitis during an interplanetary mission may require image-guided drainage as an essential procedure to facilitate recovery [95]. Another example of a potentially useful application is verification of endotracheal tube placement, since in the noisy spacecraft environment determining placement by chest auscultation may be difficult [96,97]. The role of imaging in therapy is certainly not limited to guided interventions. If the given pathology site or signs are subject to ultrasound evaluation, it may be the only objective means of monitoring progress of a disease or effectiveness of the treatment, thus directly supporting decision-making by the ground medical support personnel.

Conclusions In its continuous efforts to refine the preventive and clinical care capabilities aboard the ISS, the participating international space medicine community has recognized medical imaging as a required component of the station’s integrated medical support system. High-resolution optical imaging and sonography are currently available to support clinical decision-making in a potential medical event. Information has begun to accrue regarding human anatomy in microgravity as determined by ultrasound, and techniques and technology are being developed further to enable this very useful imaging modality for space flight.

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Part 2 Spaceflight Clinical Medicine

10 Space and Entry Motion Sickness Hernando J. Ortega Jr. and Deborah L. Harm

One of the most significant clinical and operational challenges experienced by spaceflight crews during the first few days in microgravity is space motion sickness (SMS) [1–3]. SMS was among the first adverse medical conditions encountered by humans as they ventured outside of Earth’s gravity. Because of SMS, decreased human performance is the main risk during the critical first days of space flight. Activities typically performed early that may be disrupted include payload activation, satellite deployment, rendezvous, and docking. SMS symptoms—particularly malaise, loss of initiative, and nausea—can range from being mildly distracting to physically debilitating. Physiologic systems operate effectively by maintaining homeostasis across a broad range of physiologic functions in Earth’s 1-G environment. Exposure to the microgravity environment of space flight elicits a large collection of physiologic changes and symptoms (including headward fluid shifts, headaches, back pain, and cardiovascular, bone, and muscle changes) that is collectively referred to as space adaptation syndrome. SMS may be considered a component of space adaptation syndrome. Over time, individuals adapt to the weightless environment, and many initial physiologic changes return to normal 1-G values. SMS is not a sickness as such, but it is generally thought to be a natural response to the adaptation of the neurosensory and perceptual systems to microgravity [4]. Individuals who exhibit symptoms of SMS should therefore not be viewed as abnormal. Similarly, when crewmembers return to Earth, their physiologic systems must readapt to the 1-G environment. The collection of physiologic changes during the initial postflight period is referred to as Earth-readaptation syndrome, and the postflight motion sickness component is here referred to as entry motion sickness (EMS). EMS is an operational concern for two reasons, first because EMS may adversely affect the ability of a pilot to control a vehicle on reentry or the ability of any crewmember to perform an emergency egress after landing, and second because readaptation and EMS can also become a concern for an exploration-class (e.g., Mars) mission [2]. SMS can be defined as a state of diminished health characterized by symptoms that occur in response to the unaccustomed

motion environment of microgravity [5]. It is typically a self-limited and variable symptom complex that resembles terrestrial motion sickness in onset, symptoms, and course. EMS is a similar syndrome, one that is associated with the readaptation process upon return to a gravitational field. The next four subsections are a review of the signs, symptoms, laboratory findings, epidemiology, and neurophysiology of SMS and EMS. Next, theories of etiology and possible mechanisms involved in motion sickness are briefly discussed. Finally, the last two sections describe the diagnosis and treatment of SMS and EMS.

Symptoms, Signs, and Laboratory Findings Large individual differences are apparent in the signs and symptoms and the physiologic and biochemical correlates of all forms of motion sickness. Moreover, no diagnostic laboratory tests exist for motion sickness. Next is presented a general characterization of SMS and EMS, with a summary of the biochemical correlates of terrestrial motion sickness and SMS.

Symptoms and Signs The overt symptoms of SMS, which are similar to the symptoms of acute terrestrial motion sickness, typically consist of stomach awareness, headache, drowsiness, nausea, vomiting, pallor, sweating, and dizziness [3,6,7]. In an inflight investigation during a Shuttle mission, SMS was seen to differ from terrestrial motion sickness in the relative lack of sweating and pallor. These manifestations were partly explained by the low humidity of the spacecraft and possibly the facial swelling caused by fluid shifts experienced by crewmembers in microgravity [8]. Gastric motility, as measured by auscultation and bowel sound recordings, is drastically reduced [9]. Vomiting, should it occur, is more frequent early rather than later in the course of SMS. It can crescendo quite suddenly, often without prodromal symptoms, and can produce significant relief of symptoms. Emesis episodes are typically separated by 1–3 h 211

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or more. In the absence of oral intake, vomiting may not recur. Malaise, loss of appetite, loss of initiative, and irritability are also almost universal symptoms in SMS [10]. EMS symptoms are similar to SMS symptoms, but Russian reports [11] (pertaining primarily to crewmembers who are returning from space flights lasting about 6 months) suggest that the symptoms can be more severe than those of SMS. Other physiologic adaptations to microgravity complicate the clinical picture. Changes in orthostatic tolerance, muscular strength and coordination and posture and locomotion, can affect the clinical presentation of symptoms after atmospheric entry. The magnitude of other physiologic changes may mask or potentiate symptoms of EMS. Orthostatic intolerance may produce a feeling of light-headedness (commonly referred to as “dizziness”), pallor, nausea, or headache. Decreases in muscular strength may lead to rapid fatigue and malaise. Changes in the control of head posture [12,13] and changes in sensorymotor control have also been implicated in motion sickness [13,14]. Thus, microgravity-induced changes in central muscular coordination and postural control may be involved in the generation of EMS symptoms.

Laboratory Findings Operational constraints limit the opportunity to obtain samples of crewmembers’ body fluids during space flight. Moreover, the myriad physiologic changes that can affect plasma levels and urinary excretion of electrolytes and hormones (e.g., changes in blood volume, metabolism, renal function, stress) complicate any interpretation of the relationships between biochemical factors and SMS. Therefore, the findings presented here should be interpreted cautiously.

Electrolytes Motion sickness is not associated with significant changes in serum electrolytes or glucose [15]. However, changes in electrolytes might be expected if severe vomiting persists, resulting in a volume-contracted state with possible hypochloremic metabolic alkalosis. In the presence of hypovolemia, sodium will be spared, and further cation losses will lead to worsening alkalosis, hypokalemia, or both [16,17]. In a series of 47 Space Shuttle flights, crewmembers who did not exhibit symptoms of SMS had statistically higher preflight levels of serum chloride and uric acid than preflight values of astronauts who exhibited SMS. Those astronauts without SMS also exhibited lower urine specific gravity, osmolality, and phosphate levels than susceptible crewmembers. However, these sets of values were well within normal clinical ranges in both groups [18]. Also, laboratory values from seven astronauts, taken 24–48 h into flight, showed decreases in plasma Na+ and serum osmolality (compared with preflight values) that did not correlate with SMS symptoms. Neither did the development of SMS correlate with higher serum Cl− and Mg2+ concentrations during this period [18], although again, any changes observed remained within clinical norms.

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Hormones Thyroid-function measures, insulin levels, and most gastrointestinal humoral peptide levels do not change significantly in terrestrial motion sickness. Stress-related hormones do change, however, in the presence of motion sickness, most notably increases in plasma cortisol, growth hormone, prolactin, antidiuretic hormone (ADH), adrenal corticotropic hormone (ACTH), and catecholamines [3,6,15,19]. Compared with people who are not sick, people experiencing motion sickness have markedly higher plasma cortisol levels. Symptomatic patients also exhibit increased vasoactive intestinal polypeptide, which decreases gastrointestinal motility [19]. Increased levels of corticotropin-releasing factor, ACTH, and ADH seem to be associated with lesser susceptibility to motion sickness [20]. Before flight, low-normal levels of serum uric acid, creatinine, and thyroxine have been observed in individuals with low tolerance to SMS, suggesting that metabolic rate may play a role in their susceptibility to SMS. Crewmembers who are not susceptible have higher preflight levels of plasma cortisol than their more susceptible counterparts, although the levels are not outside clinical norms [3,21]. Increases in plasma growth hormone, cortisol, ACTH, and ADH have been found in all space flight crews examined during the first few days on orbit, along with a decrease in aldosterone on flight day 1 [18,21,22]. As is the case for terrestrial motion sickness, higher serum levels of stress-related hormones before and during flight seem to be associated with lower susceptibility to SMS [18,21]. On return from space, plasma growth hormone, ACTH, and ADH again increase in space flight crews relative to preflight values, but serum cortisol levels are variable (some unchanged from preflight levels, some slightly decreased). Plasma aldosterone seems to increases to the high end of clinical normal in all returning crewmembers examined [22,23]. Thus, at least some of the stress-hormone responses seen upon return to 1-G are also seen upon entry into microgravity. No associations between postflight stress hormone levels and EMS symptoms have been reported.

Epidemiology The Russian cosmonaut Gherman Titov, on the 25-h Vostok 2 mission (the second crewed space mission in 1961), was the first person to report experiencing SMS. He was also the first person to spend longer than 2 h in space. The first reported U.S. experience occurred during the Apollo 8 mission (in December 1968), when all three crewmembers experienced some degree of SMS [24]. Most of the experience in the U.S. space program has been with short-duration flights, those lasting from several days to 2 weeks. EMS has rarely been observed after these short flights. Although both the U.S. and Russian space programs have seen EMS after brief missions, including as short as 4 days [11], longer-duration space flight generally correlates with greater

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incidence and severity of EMS. Russian investigators have long reported a very high (> 90%) incidence of EMS and other findings related to readaptation [11]. The difference is most noticeable when long-duration space flight crewmembers experience the same landing event as their short-duration counterparts. This occurred on some Soyuz crew rotation missions and in the NASA-Mir Program, in which seven U.S. astronauts served as crewmembers on the Mir space station during missions lasting 115–188 days. In those flights, the crews returning from long space flights clearly experienced more EMS and Earth-readaptation syndrome symptoms in the period immediately after landing than did those returning from shorter missions.

Incidence Table 10.1 summarizes the prevalence of SMS over the U.S. and Russian space programs [3,4]. In the Space Shuttle Program, the overall incidence of SMS is about 73% among those flying for the first time [2,25]. Cases are generally classified as mild, moderate, or severe (Table 10.2). In general, ∼49% of cases are mild, 36% are moderate, and only 15% are severe [25]. The overall incidence in the Russian experience is about 50% [11]. Since head movements are known to play an important role in SMS, having less freedom of movement likely has a protective function. Many crewmembers and investigators believe that the relatively low incidence of SMS reported in the early days of crewed space flight reflects the smaller size of the cabins, and resulting limitation in crew movement, in those spacecraft (Table 10.1). No SMS was reported by astronauts in either Project Mercury or Project Gemini [26], whereas 35% of the Project Apollo astronauts and 60% of the astronauts aboard Skylab developed SMS [25]. Although

the Russian space capsules are slightly larger than their U.S. counterparts, they still are much smaller than the current Space Shuttle. In the Space Shuttle, crews are released suddenly into a large habitable volume after an 8½-min ride to orbit. They must doff their launch-and-entry suits, an activity that involves significant head movements. Crews on board the Russian Soyuz craft, by comparison, spend 1–2 days in a much smaller volume before reaching the much larger volumes of the Mir or the International Space Station. Therefore it is possible that the large volume of the Space Shuttle, combined with the high level of activity experienced immediately upon orbital insertion, may account for the difference in the prevalence of SMS between astronauts and cosmonauts. Interestingly, even though no SMS was reported during the Gemini space flights, caloric intake was particularly low for many crewmembers, suggesting the presence of a loss of appetite that could have resulted from mild SMS [27]. Underreporting by crewmembers is a possibility, although experiencing SMS has absolutely no career-limiting implications with regard to medical standards. Male and female astronauts seem to be affected in equal proportions by SMS, and age does not seem to affect incidence. Pilots, mission specialists, and other crewmembers also are affected equally. Those who are susceptible during their first space flight usually have SMS on subsequent flights. Although previous SMS is the best predictor for future SMS, repeat exposure seems to result in the same or less severe symptoms than those experienced during previous flights [25]. Aerobic fitness is not related to SMS symptoms or severity [28]. Interestingly, a preflight diet that is high in protein and low in carbohydrates may have been associated with SMS symptoms during the Skylab program [29].

Table 10.1. Reports of space motion sickness in the U.S. and Russian space programs. No. crew member-flights

Program Mercury Gemini Apollo Command Module Lunar Module Skylab Apollo-Soyuz Test Project Space Shuttle 1981–1986 1988–1998 Total (mean %), US programs Vostok Voskhod Soyuz Apollo-Soyuz Test Project Salyut-5 Salyut-6 Mir Total (mean %), Russian programs a

3

Plus 50–90 additional m from other modules.

6 20 33

No. reporting SMS symptoms (%) 0 (0) 0 (0) 11 (33)

9 3

5 (56) 0 (0)

85 315 471

57 (67) 252 (80) 325 (70)

6 5 38 2 6 27

1 (17) 3 (60) 21 (55) 2 (100) 2 (33) 12 (44)

84

41 (49)

Habitable spacecraft volume, m3 1.7 2.55 5.95 4.5 275 5.95 71

5 5 10 10 70 90 90a

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TABLE 10.2. Space motion sickness grading criteria. Severity (score) None (0) Mild (1)

Moderate (2)

Severe (3)

Symptoms and signs None except for mild, transient headache or mild decrease in appetite. One to several symptoms of a mild nature; may be transient and only brought on as the result of head movements; no operational impact; may include single episode of retching or vomiting; all symptoms resolve in 36–48 h. Several symptoms of a relatively persistent nature that may wax and wane; loss of appetite; general malaise, lethargy, and epigastric discomfort may be the dominant symptoms; includes no more than two episodes of vomiting; minimal operational impact; all symptoms resolve in 72 h. Several symptoms of a relatively persistent nature that may wax and wane; in addition to loss of appetite and stomach discomfort, malaise, lethargy, or both are pronounced; strong desire not to move head; includes more than two episodes of vomiting; significant performance decrement may be apparent; symptoms may persist beyond 72 h.

Source: Davis et al. [25]. Used with permission.

Only one episode of what was probably EMS was reported during the Apollo program. The Skylab 2 astronauts, who had spent a total of 28 days in low Earth orbit in May and June 1973, reportedly experienced “seasickness” on the recovery ship immediately after splashdown. Since the seas were rough, the contribution of EMS to these symptoms is unclear. However, since this mission lasted almost a month, it seems likely that EMS contributed to this postflight illness. Drug prophylaxis with scopolamine before entry seems to have been successful in minimizing problems on subsequent Skylab flights [30]. As noted previously, EMS is rarely observed after short Space Shuttle missions. The incidence of EMS after longer Space Shuttle missions is similar to that reported by Russian investigators after missions lasting up to 2 weeks. In the Russian experience, EMS reportedly afflicts 27% of the cosmonauts after short-duration missions (4–14 days) and 92% after longer-duration missions (those lasting several months to 1 year) [11]. The Russian reports also indicate that EMS symptoms generally occur in cosmonauts who had SMS; however, 11% of the cosmonauts who experienced little or no SMS did experience EMS. EMS may be complicated by the crewmembers’ relative state of dehydration upon return and orthostatic intolerance after landing. Further details of these problems are discussed in Chap. 16.

Influencing and Precipitating Factors Anyone who has a functioning vestibular system can, under the right conditions, experience motion sickness [31–33]. The incidence and severity of that sickness varies as a function of the specific stimulus conditions (i.e., type of sensory conflict) as well as the intensity and duration of the stimulus [34,35]. Even when stimulus conditions are of a mild to moderate intensity, such as those that occur in weightlessness, the

chronic nature of exposure to those conditions may partially explain the high incidence of SMS. Whether an individual experiences motion sickness in a given set of circumstances also depends on his or her susceptibility. Individual differences in physiologic and psychological factors as well as past experiences contribute to susceptibility [35,36]. Factors that serve to attenuate motion sickness include concentration on performing a task [37], applying strong tactile inputs (e.g., strapping oneself tightly in a seat), closing one’s eyes, and restricting activity [4,13]. Factors that seem to worsen SMS include distasteful or unpleasant sights, noxious odors, certain foods, excessive warmth, loss of 1-G orientation, and head movements [2–4]. Microgravity by itself may not induce SMS, as evidenced by the lack of symptoms reported during the Mercury and Gemini flights. Head movements, which were relatively minimal in the close confines of those small spacecraft, are associated with the development of SMS symptoms, and they also exacerbate existing symptoms [10,38]. Pitch head movements (chin up or down) are the most provocative, followed by roll and yaw [10,13,38]. Lackner and colleagues [13,39] suggested that changes in head and limb sensory-motor control patterns induced by altered gravitoinertial forces may be an etiologic factor in SMS [13,14]. Restricting head motion has been shown to reduce SMS symptoms [40]; however, those who minimize head movements—unlike avoiding other inciting factors—seem to have the symptoms for longer periods. Although head movements worsen SMS symptoms, they are necessary to facilitate neurovestibular adaptation to microgravity [41,42]. Similarly, EMS symptoms are induced or exacerbated by warmth and head movements during atmospheric reentry and in the early postflight period. The most vulnerable crewmembers are those who are required to make several head movements during reentry. On the Space Shuttle, for example, it is the flight engineer (Mission Specialist 2) who must make frequent head turns to monitor panels and throw switches. Again, head movements likely serve a dual role, one that is both provocative and adaptive.

Time Course Initial symptoms of SMS can occur within minutes of exposure to microgravity. Symptoms typically increase over a period of hours until they plateau at a certain intensity. Several instances have been reported of delays in the onset of symptoms, some lasting as long as 48 h after arrival on orbit. In many of these cases, the individuals had been medicated with scopolamine, which seems to have had the desired effect of suppressing SMS symptoms but also apparently delayed the normal adaptation to microgravity [43]. Resolution of symptoms typically occurs after about 30–48 h of exposure to microgravity [3,4]. Some cases have resolved as quickly as 12 h after orbital insertion, and most cases are completely resolved within 4–7 days [44]. Rare cases in particularly susceptible individuals may not fully resolve at all over 14 days

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of space flight [7]. Russian investigators report that 25% of the cosmonauts have symptoms lasting 14 days or longer, and 17% of cosmonauts on long-duration missions (i.e., 83–365 days) periodically develop symptoms throughout the flight [45,46]. Nevertheless, the typically rapid adaptation gives SMS a greater relative effect on shorter-duration missions and minimizes its importance on long-duration missions [47]. EMS follows a time course similar to that of SMS. Symptoms can begin quite early, within minutes of G onset (that is, at the entry interface). Some crewmembers who have exhibited no symptoms during entry and landing begin to develop symptoms as soon as they stand for egress. EMS symptoms tend to crescendo rapidly, then taper off over time. Symptom severity seems to correlate with time spent on orbit; as mission length and recovery extends past certain thresholds, symptom severity increases. For missions 20 days in length or less, functional recovery should be complete in about 7 days. For 3- to 6-month missions, those suffering from EMS symptoms should expect a minimum of 30 days of recovery time. These represent conservative guidelines which will be refined as further data is analyzed. Some “relapse” phenomena have been reported during the course of recovery after landing. Exposure to some inertial environments (i.e., turning a corner in a car, lying in bed in darkness, etc.) can bring on a sudden return to an early postflight state of adaptation. This, in turn, can elicit mild to severe EMS symptoms several days to a week after return to Earth. Recovery from such relapses generally is more rapid than immediately after flight.

Anatomy and Physiology Despite a large body of research concerning motion sickness, the specific mechanisms involved are still largely unknown. However, it is widely accepted that the vestibular system is involved and that both the central and autonomic nervous systems play important roles in the expression of motion sickness. The following subsection provides a brief overview of the anatomy and physiology of the vestibular system and of its central connections that are thought to be involved in motion sickness.

The Vestibular System The dense petrous portion of the temporal bone contains and protects the complicated, three-dimensional system comprising the human vestibular system. Within its carved-out bony labyrinth lies the membranous labyrinth—the tubular soft tissue of the actual sensing organs. The two vestibular sensors are the otolith organs located within the vestibule and the semicircular canals (Figure 10.1). The two otolith organs, the utricle and the saccule, are arranged in orthogonal planes. The utricle is in the horizontal (axial) plane, and the saccule is oriented in the sagittal plane. The otolith organs sense head tilt with respect to gravity and linear acceleration along the X, Y, and Z axes.

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FIGURE 10.1. Artist’s rendering of the human vestibular system

A small, specialized piece of neuroepithelium, called the macula, is located on the wall of both the utricle and the saccule. The epithelium is covered by a gelatinous layer in which calcium carbonate crystals (otoliths or otoconia) are embedded. Hair cells, which transduce information about acceleration, project into the gelatinous layer. Acceleration forces displace the otoconia, causing a deflection of these hair cells. This deflection or bending produces depolarization of the hair cells, transducing mechanical energy (acceleration) into neural signals. The hair cells in the macula are oriented in different directions such that a diverse pattern of excitation occurs for various head positions and acceleration forces in different directions. Even in a resting position, nerve fibers from the hair cells transmit neural signals that indicate the gravity vector. The three semicircular canals (anterior, posterior, and horizontal) are fluid-filled loops that sense angular accelerations of the head in the pitch, roll, and yaw planes. The three canals are arranged at right angles to each other to represent the three planes in space. At the end of each is an enlarged portion known as the ampulla, which contains the neurosensory apparatus—the crista ampullaris. Atop the crista is a gelatinous mass (cupula) into which sensory hair cells project. Inertial movement of the endolymph produces deflection of the cupula, and the hair cells transduce angular movement of the head into neural energy. Animal studies have suggested the possibility that exposure to microgravity produces changes in the otolith and canal end organs or changes in the neural components (hair cells, synapses) that alter vestibular function and contribute to changes in central sensory integration functions [4].

Central Neural Connections Vestibular afferents form part of the eighth cranial nerve, which relays inputs from the vestibular end organs to the brain’s vestibular nuclei, located in the brainstem approximately at the

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junction of the medulla and pons (superior, medial, lateral, and inferior vestibular nuclei). Some fibers pass directly to areas in the cerebellum. Neural pathways from the vestibular nuclei project to areas in the medulla, the cerebellum (to oculomotor and spinal-motor control systems), and the cerebral cortex. Both the vestibular nuclei and the vestibulocerebellum receive inputs from other sensory systems that are concerned with perception of the body position and movement. The entire system operates reflexively to stabilize vision, and to coordinate limb, trunk, and head movements so as to maintain balance. Because most of the signs and symptoms of motion sickness are autonomically mediated, understanding the role of the vestibular system in autonomic regulation is important. The most direct pathway for vestibular modulation of autonomic responses involved in motion sickness is via efferent projections from the medial and inferior vestibular nuclei to the nucleus tractus solitarius and the dorsal motor nucleus of the vagus. Other pathways that may be involved include vestibular projections to the lateral tegmental field of the reticular formation or to the caudal ventrolateral medulla. Finally, the cerebellum may be another route through which vestibular inputs may modulate autonomic activity [48].

Etiology The two major theories that have been proposed to explain SMS are the sensory conflict theory (also known as the sensory mismatch or sensory rearrangement theory) and the fluid shift theory. Although both theories have merit and neither is ideal, the sensory conflict theory remains the most accepted overall explanation for motion sickness. In this subsection, these two theories are briefly described, as is an otolith asymmetry hypothesis that has been advanced specifically to explain SMS and hypotheses concerning sensory adaptation to space flight.

Sensory Conflict Theory The sensory conflict theory of Reason and Brand [49] has withstood more than 20 years of debate and remains the most accepted overall explanation of motion sickness etiology. Briefly, the sensory conflict theory assumes that under normal gravity conditions, human orientation and movement is based on several sensory inputs to the central nervous system. The vestibular system provides information relating to linear and angular acceleration and position with respect to gravity; the visual system provides information relating to body orientation with respect to the visual world; and the touch, the pressure, and the kinesthetic systems provide information relating to limb and body position. When the environment is altered in such a way that this information does not match previously stored neural patterns, motion sickness may occur.

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The lack of an effective gravity stimulus to some of the sensory systems during space flight changes the relationships among the various sensory inputs, thereby creating sensory conflict. These altered relationships initiate adaptive processes. Two hypotheses have been proposed to explain sensory adaptation to microgravity: the sensory compensation and the otolith tilt-translation reinterpretation (OTTR) hypothesis. These hypotheses are described briefly in the following paragraphs.

Sensory Compensation Sensory compensation occurs when the input from one sensory system is attenuated and the inputs from other sensory systems are augmented. In the absence of an appropriate gravity signal in weightlessness, information from other sensory modalities can be used to maintain spatial orientation and movement control [50–53]. For example, astronauts often report increasing their reliance on visual information to maintain spatial orientation [51,52].

Otolith Tilt-Translation Reinterpretation Because of the fundamental equivalence between linear acceleration and gravity, signals from the otolith are ambiguous by nature. The otolith organs signal both head tilt with respect to gravity and linear acceleration, which is perceived as translational movement. In the microgravity of space flight, the otolith organs do not respond to head tilt, but they still respond to linear acceleration. The OTTR hypothesis suggests that because gravity stimulation is absent in microgravity, any interpretation of otolith signals as tilt is meaningless. Therefore, during adaptation to weightlessness, the brain reinterprets all otolith signals as linear translation. Until this adaptation is complete, an altered relationship exists among signals from the semicircular canals, otolith organs, and neck proprioceptors that normally indicate head tilt (i.e., there is sensory conflict). Thus, on return to Earth’s 1-G, the brain must reestablish a gravity interpretation of tilt. Sensory conflict theory explains much in general, but little in specifics. It does not explain, for example, the specific mechanisms by which symptoms are produced in either SMS or motion sickness, nor does it explain those cases in which conflict exists but no symptoms occur. This theory also does not address the observation that adaptation cannot occur without conflict. Finally, the sensory conflict theory does not provide any predictive power regarding who will display symptoms under which types of sensory conflict.

Fluid Shift Theory Since most launches require that the crew assume a supine position with legs raised for a few hours before liftoff, a central fluid shift begins on the launch pad and continues in microgravity. This fluid shift has been theorized to raise intracranial pressure and cerebrospinal fluid or endolymph pressure in the inner ear, thus producing symptoms similar to those seen in patients with

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increased intracranial pressure due to a space-occupying lesion or obstruction (vomiting, dizziness, headache) [8]. This theory has drawbacks similar to those associated with the sensory conflict theory, namely a lack of predictive power and difficulty accounting for asymptomatic individuals. It also fails to explain episodes of EMS. However, in studies investigating the possibility that fluid shifts are involved in SMS, the time course of adaptation to the fluid shifts did match to some extent the time course of SMS. Studies in which analogs were used to mimic the fluid shift (bed rest and 6-degree head-down tilt) failed to show that the ensuing fluid shift produced either motion sickness or an increased susceptibility to motion sickness [53,54]. Over time, this theory has been discounted because of better understanding of the nature of the fluid shifts [55] and observations that actual central pressure decreases in space [56]. However, the definitive studies have yet to be completed.

Otolith Asymmetry Hypothesis von Baumgarten and Kornilova and colleagues [57–59] have proposed a mechanism complementary to the sensory conflict theory to explain adaptation to weightlessness, readaptation to Earth gravity, and individual differences in SMS susceptibility. Their otolith asymmetry hypothesis states that individuals experience subtle differences in otolith mass between the left and right otolith maculae that are well compensated for on Earth. In space flight, however, the difference in mass generates asymmetrical afferent signals, leading to SMS. A similar imbalance would occur upon return to Earth, resulting in sensory-motor disturbances and EMS. Diamond and Markham have proposed an ocular counter-rolling test that measures this mismatch and may predict SMS [60–62]. As is true for the sensory conflict and fluid shift theories, the otolith asymmetry hypothesis is limited in its ability to fully explain and predict SMS and EMS. For example, if the loss of compensation for otolith asymmetry in space flight was sufficient to produce SMS, then crewmembers should develop symptoms without making head movements. However, as discussed earlier, movement is required for SMS symptoms to occur. In addition, since otolith asymmetry is present during the free-fall phase of parabolic flight, one would expect that motion sickness during parabolic flight would predict SMS during orbital flight. To date, however, no evidence has been found to suggest that astronauts who become motion-sick during parabolic flight are more likely to experience SMS than their non-motion-sick counterparts.

Diagnosis Clinical The diagnosis of SMS is made by history of recent exposure to microgravity and reported motion sickness symptoms. No

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laboratory or other confirmatory data are needed to guide therapeutic decisions. Flight surgeons generally categorize the cases as mild, moderate, or severe as shown in Table 10.2 [25]. The diagnosis of EMS is based on motion-sickness symptoms after recent return from microgravity conditions. Although no formal grading system has been established, categories similar to those for SMS (Table 10.2) are used.

Differential Diagnosis The differential diagnosis of SMS would include acute gastroenteritis and possible exposure to toxins. The preflight Health Stabilization Program observed in the U.S. and Russian space programs, which involves a 1-week period during which access to the crew is strictly controlled and restricted to medically screened individuals, makes an infectious etiology unlikely. Close monitoring of onboard food and water sanitation immediately before flight also minimizes infectious etiologies [63]. Cabin telemetry may provide clues regarding possible exposures to toxins in flight. Flight surgeons, who are members of the flight control team that provides real-time mission support from the Mission Control Center, keep abreast of hazardous payloads, possible contingency scenarios, and actual untoward events. The most likely atmospheric contaminant that could produce symptoms mimicking SMS is CO2. Exposure to 3–10% CO2 concentrations can produce headache, malaise, dizziness, and nausea. Indeed, local buildup of CO2 may become common in space flight because of the lack of convective currents in microgravity and other ventilation defects in spacecraft. CO2 withdrawal can also produce similar symptoms. If the air revitalization system on a spacecraft malfunctions early in space flight, SMS vs. CO2 vs. exposure to other toxins might be considered. Recommended actions include avoiding certain areas or conditions (e.g., a closed sleep station) and redirecting fans or airflow. If payload containment is breached early during the flight, the presence of SMS symptoms may complicate evaluation of the toxic exposure. Many compounds can be flown as middeck payloads; familiarization with the toxicology of all payloads is thus critical to provide proper medical support to the crew. The Space Shuttle utility compounds that are most likely to produce symptoms mimicking those of SMS are the propellants hydrazine and monomethylhydrazine. These compounds are not found inside the spacecraft, and exposure is not likely, but may be inadvertently brought inside on a contaminated suit following extravehicular activity. Exposure to these propellants can cause dizziness, nausea, vomiting, and behavioral changes. Since exposure to both compounds generally affects other physiologic systems as well (the eyes, respiratory tract, skin, and central nervous system), this may be helpful in making the differential diagnosis. A differential diagnosis of EMS also includes acute gastroenteritis and possible exposure to toxins. Flight surgeons must thus be knowledgeable concerning the medical conditions that can occur in space flight. The Space Shuttle food

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supply is carefully monitored, thereby making an infectious etiology unlikely in the immediate postflight period; any food or fluids consumed on board the crew transport vehicle and at the baseline data collection facility should be considered as possible infectious sources.

Therapy and Prognosis Education Flight surgeons currently discuss the natural course of SMS and EMS with crews during routine medical training preflight. Crewmembers are counseled on provocative stimuli, such as head movements and loss of 1-G vertical orientation, and ways of mitigating the effects of SMS. Practically, this counseling involves instructing crewmembers to move slowly and to “bend down” to access an item at knee level so as to maintain a visual vertical reference rather than pitching upside down during the first hours and days of space flight. Crewmembers are also advised to avoid excessive heat and noxious odors and to maintain adequate hydration in flight during the course of symptoms. Flight controllers and mission planners are also educated on the effects of SMS and EMS on crew performance. Space Shuttle flight rules currently prohibit scheduling of critical activities (extravehicular activities) within 3 days of reaching orbit [1]. Mission planners also attempt to lighten crew activities during the first 1 or 2 days because of known decreases in performance ability.

H.J. Ortega Jr. and D.L. Harm

multiple flight experiences report benefits from prophylaxis. Currently, some astronauts take an oral combination of 25 mg promethazine with 5 mg dextroamphetamine (“PhenDex”) prophylactically in the final hours before launch. Anecdotal evidence from a few individuals suggests that this regimen is effective and acceptable, despite earlier concerns from the medical community about performance effects [69]. Promethazine does not seem to delay adaptation [1], and it may actually hasten adaptation to provocative motion [70]. The use of prophylactic medications is most appropriate for crewmembers who are known to be susceptible to SMS. Currently no known ground-based tests predict SMS susceptibility [3,71]. The best predictor is a history of SMS. Therefore, NASA flight surgeons recommend that first-time flyers forego drug prophylaxis to determine whether they will need medications on future flights. In addition, because of potential adverse performance effects, the primary Space Shuttle flight crew (i.e., the commander, the pilot, and the flight engineer) are not allowed to take antimotion-sickness medications before launch. Medications are also occasionally used to prevent EMS. Some astronauts who have histories of moderate to severe postflight symptoms have taken PhenDex or meclizine following the deorbit burn to mitigate the symptoms. Because of the global physiologic readaptation processes that start immediately on exposure to re-entry g forces, the effectiveness of this practice remains unknown. As noted earlier, given the potential risk of drug side effects impairing piloting performance, Space Shuttle pilots and commanders do not use prophylactic medications.

Preflight Adaptation Training Prophylaxis Pharmacologic interventions remain the most effective way of preventing SMS. However, oral treatment after symptom development is complicated by variable drug bioavailability that may be related to changes in metabolic rate and decreased gastrointestinal motility and absorption [1]. Early efforts at prophylaxis used a combination of 0.4 mg scopolamine and 5 mg dextroamphetamine (“ScopeDex”) that had been effective in treating seasickness and other types of motion sickness [64–66]. ScopeDex was found to prevent the development of SMS symptoms in only a few cases, and even then, its withdrawal led to rebound illness. ScopeDex is no longer used by astronauts [43]. These observations are consistent with ground-based research findings [67]. Numerous other antimotion-sickness medications used to treat terrestrial motion sickness have met with varying degrees of success [43,68], e.g., diphenhydramine, dimenhydrinate, meclizine, and chlorpromazine. A review of postflight medical debriefing records from 112 astronauts who flew between 1996 and 2000 suggests that the use of prophylactic drugs does not appreciably alter the incidence or severity of SMS (J.B. Clark, M.D. personal communication, 2001). However, some individuals with

Preflight adaptation training may hold promise as a countermeasure for SMS. Training devices and procedures designed to adapt astronauts to novel sensory and perceptual conditions resembling those of weightlessness continue to be developed [3,50,72]. The general concept is that, with repeated exposure to these conditions, astronauts can develop sensory-motor programs appropriate for microgravity and can learn to rapidly switch from 1-G to microgravity programs and vice versa (in other words, they can become “dual-adapted”). This state of “dual adaptation” is thought to facilitate adaptation to microgravity and readaptation to Earth, thereby reducing both SMS and EMS. This training includes education, demonstration, and experience with a variety of perceptual illusions and novel sensory inputs. One evaluation of this training found a 33% improvement in SMS symptoms in participating crewmembers as compared with those who had not participated in the training [73]. The improvement was similar in both first-time and experienced flyers. The Russian space program uses extensive preflight motion training [74]. In that program, preflight vestibular training has primarily involved Coriolis (cross-coupled angular) acceleration generated by a variety of devices such as rotating chairs.

10. Space and Entry Motion Sickness

Similar preflight training was used early in the U.S. space program but was abandoned when it failed to mitigate SMS during flight. Moreover, the preflight training with Coriolis acceleration does not duplicate the sensory conflicts encountered in weightlessness [11,74]. Although cosmonauts continue to use this type of training, the incidence of SMS symptoms in Russian and U.S. space flight crews is similar. Adaptation to one sensory-conflict situation (e.g., those generated by Coriolis accelerations or parabolic flight) does not necessarily apply to other sensory conflict situations, particularly when the conflict differs considerably from one situation to the other. The approach taken in the U.S. space program to develop preflight adaptation training is based on duplicating, to the extent possible, the sensory conditions encountered during space flight. Two task-trainers and procedures are being developed and investigated. The first device, the device for orientation and motion environments (DOME), was designed to allow stabilization of graviceptors. Although gravity cannot be eliminated on Earth, its contribution to spatial orientation in the simulated environment can be negated by keeping the gravity vector constant with respect to the trainee as the trainee changes orientations or makes head movements within that environment. Perceived changes in orientation and motion are produced by changing the visual environment around the fixed trainee, who can still engage in simulated motion. This condition is similar to microgravity in that angular head movements can be made in pitch and roll without a changing gravity vector. The DOME is a 3.66-meter (12-foot) spherical dome with an interior virtualreality system designed for virtual performance of operational-type tasks. In addition, DOME training will also include practice in navigating to various locations within a space flight environment (Space Shuttle, Spacelab, International Space Station) from different starting orientations to reduce spatial disorientation on orbit. The second device, the tilt-translation device (TTD), is based on the OTTR hypothesis of adaptation to microgravity. The TTD is designed to evoke reinterpretation of otolith tilt signals as linear motion, achieved by providing an appropriate phase relation between movement of the visual world and head tilts (Figure 10.2). The TTD is a 1-degree-of-freedom tilting platform on which the subject is seated in a car seat in either a pitch or roll configuration. A visual surround mounted on the TTD platform moves linearly, parallel to the subject. Threedimensional black stripes line the inside walls of the device, and 4 successively smaller outlined black squares are attached to its end panels. A 270-degree phase relation between tilt and surround motion best supports reinterpretation of otolith signals as linear translation, as evidenced by perpetual reports of linear self-motion, decreased vertical compensatory eye movement gain (similar to those observed in crewmembers on orbit) and decreased postural stability (similar to that observed in crewmembers after landing). More detailed descriptions of these devices and their underlying concepts are available elsewhere [3,4,72,75].

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Long-duration space flight missions will probably require on-orbit countermeasures to maintain a dual-adapted state. Many scientists believe that readaptation to gravity would be enhanced by frequent exposure to simulated gravitational states on board a spacecraft. This situation would require some type of onboard human-rated centrifuge or complete spacecraft rotation to produce an inertial force similar to gravity and would be coupled with physical countermeasures to maintain bone and muscle mass. This solution, although potentially effective [12], raises many operational and engineering issues that will need to be addressed [76].

Treatment During and After Flight The most effective in-flight treatment for SMS found to date is parenteral (usually intramuscular) administration of promethazine, in doses of 25–50 mg [1,2]. A suppository form has reportedly resolved symptoms effectively as well [1]. Although drowsiness has been reported infrequently [1,77], promethazine is best administered just before sleep to reduce the risk that possible drowsiness or lethargy would affect mission activities [1,2], A crewmember who is already ill will feel better after treatment, and this improvement may help limit negative effects on performance. The excitement of space flight and engagement in critical tasks can also help to counteract the soporific effects of the medication [70]. Once on orbit, some crewmembers tend to minimize head movements and to move the head, neck, and torso as a unit, which minimizes changes in sensory and motor control patterns. Reducing the cabin temperature or staying close to a fan seems to help crewmembers who are prone to or affected by SMS. Crewmembers should carry emesis bags in quick-access locations because of the potential for sudden vomiting. Avoiding noxious odors and free-floating emesis in the confined microgravity of a spacecraft are practical considerations. Some crewmembers reduce their oral intake and modify their diet to avoid fats and protein. The importance of maintaining hydration with clear liquids and advancing diets as tolerated is emphasized. However, those crewmembers experiencing severe symptoms should continue to take nothing by mouth, and the administration of intravenous fluid should be considered. Both symptoms and treatment of EMS can significantly affect crewmember participation in postflight activities, including life science experiments and critical debriefings, and therefore must be monitored carefully and methodically. Currently, NASA flight surgeons make use of medications as needed after landing to treat moderate to severe symptoms. Meclizine, given in 25- to 50-mg doses, seems to be effective provided that the crewmember can tolerate oral medications. However, rigorous studies have yet to be done to confirm this observation. Promethazine (25–50 mg, given intramuscularly or as a suppository) is quite effective and is indicated for uncontrollable or large-volume emesis. Fluids are administered as needed, either orally or intravenously, to

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H.J. Ortega Jr. and D.L. Harm

FIGURE 10.2. A and B, the NASA tilt-translation device used at NASA-Johnson Space Center for preflight vestibular-adaptation training (Photos courtesy of NASA)

replace lost volume and to maintain hydration. Because EMS, unlike SMS, occurs in a setting of acute relative dehydration and cardiovascular compromise, the threshold for administering intravenous fluid supplementation should be accordingly lower. The relative contributions of cardiovascular compromise and EMS during this period can be clarified by simple orthostatic assessment of pulse and blood pressure between recumbent and sitting or standing positions, if tolerated, while limiting the crewmember’s head movements. The managing flight surgeon may guide crewmembers affected by EMS in gentle challenges to adaptation, such as making small but progressive head movements. Avoidance of large, rapid head movements, particularly in the pitch and roll planes, is advisable during the early postflight period. Caution is also recommended immediately after landing while the launch-and-entry suits are being removed.

Prognosis SMS is a self-limited illness, and most who experience it will overcome it quickly as they adapt to microgravity. Typically, a single intramuscular dose of promethazine (usually 50 mg) will resolve the acute symptoms. Rarely will moderate to severe cases require dosing beyond flight day 2, and only a very few cases (<1%) will have persistent symptoms [1]. EMS is also self-limited, but the recovery time tends to be related to the time spent on orbit, lengthening with longer-duration missions. Return-to-flight status is typically accomplished within 7 days after missions lasting less than 2 weeks. The NASA-Mir Program protocol considered returning U.S. astronauts for flying duties on an individual basis at 30 days after return. Also, it is important to note that certain motion stimuli

may cause “relapse” or “toggling” to an earlier stage of readaptation days to weeks after return from space flight [4].

Conclusions SMS can be considered a variant of motion sickness that occurs in microgravity. Its time course and nature make SMS operationally significant during the first few days of space flight [25]. The disorder is typically self-limiting, and treatment is symptomatic. Intramuscular promethazine is the current drug of choice for treatment of moderate to severe SMS; it should be given before the sleep period on flight day one to minimize performance effects. Other forms of promethazine may also provide relief of symptoms. In a short-duration space flight, adaptation should be sufficiently complete in approximately 3 days. Long-duration space flight produces more problems with EMS and readaptation to Earth gravity. EMS symptoms seem to respond to oral meclizine (25–50 mg) and to intramuscular or rectal doses of promethazine (25–50 mg). Complete recovery time with no detectable findings will vary according to the length of the mission, but 7 days can be expected for space flights lasting 1–2 weeks and about 30 days for missions lasting several months.

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221 Astronautical Federation, Malaga, Spain, 1989. International Astronautical Federation. 22. Leach Huntoon C, Cintron NM, Whitson PA. Endocrine and biochemical functions. In: Nicogossian AE, Leach Huntoon C, Pool SL, (eds.), Space Physiology and Medicine, 3rd edn. Philadelphia, PA: Lea & Febiger; 1994:334–350. 23. Leach CS. Biochemical and hematological changes after shortterm space flight. Microgravity Quarterly. 1991; 2:69–75. 24. Hawkins WR, Zieglschmid JF. Clinical aspects of crew health. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: U.S. Government Printing Office; 1975:43–81. NASA SP-368. 25. Davis JR, Vanderploeg JM, Santy PA, et al. Space motion sickness during 24 flights of the space shuttle. Aviat Space Environ Med 1988; 59:1185–1189. 26. Homick JL. Motion sickness: General background and methods, Space Adaptation Syndrome Drug Workshop, Houston, TX, 1985. Space Biomedical Research Institute, USRA Division of Space Biomedicine. 27. Dietlein LF. Summary and conclusions. In: Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington DC: U.S. Government Printing Office; 1975:571–579. NASA SP-368. 28. Jennings RT, Davis JR, Santy PA. Comparison of aerobic fitness and space motion sickness in the space shuttle program. Aviat Space Environ Med 1988; 58:448–451. 29. Simanonok KE, Kohl RL, Charles JB. The relationship between space sickness and preflight diet. Physiologist 1993; 36:S90–S91. 30. Homick JL. Space motion sickness. Acta Astronautica 1979; 6:1259–1272. 31. Kennedy RS, Graybiel A, McDonough RC, et al. Symptomatology under storm conditions in the North Atlantic in control subjects and in persons with bilateral labyrinthine defects. Acta Otolaryngol 1968; 66:533–540. 32. Igarashi M. Role of the vestibular end organs in experimental motion sickness: A primate model. In: Crampton GH (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press, Inc.; 1990:43–48. 33. Crampton GH. Neurophysiology of motion sickness. In: Crampton GH (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press, Inc.; 1990:29–42. 34. Guignard JC, McCauley ME. The accelerative stimulus for motion sickness. In: Crampton GH (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press, Inc.; 1990:123–152. 35. Dobie TG, May JG. Cognitive-behavioral management of motion sickness. Aviat Space Environ Med 1994; 65:C1–C2. 36. Mirabile CS. Motion sickness susceptibility and behavior. In: Crampton GH (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press, Inc.; 1990:391–410. 37. Kohl RL. Mechanisms of selective attention and space motion sickness. Aviat Space Environ Med 1987; 58:1130–1132. 38. Oman CM, Lichtenberg BK, Money KE. Space motion sickness monitoring experiment: Spacelab-1. In: Crampton GW (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press, Inc.; 1990:217–246. 39. Lackner JR, DiZio P. Altered sensory-motor control of the head as an etiological factor in space-motion sickness. Percept Mot Skills 1989; 68:784–786. 40. Johnson WH, Mayne JW. Stimulus required to produce motion sickness. Restriction of head movements as a preventative of

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11 Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome William T. Norfleet

The three maladies to be discussed in this chapter—decompression sickness, arterial gas embolism, and ebullism—all arise from changes in ambient atmospheric pressure, which is the pressure of the gas immediately surrounding an individual. In space flight, the largest planned change in ambient atmospheric pressure is associated with extravehicular activities (EVAs) that take place as the crew moves back and forth between the crew cabin and the environment outside, where they wear pressurized suits. The cabin atmospheric pressure in all current spacecraft typically approximates the atmospheric pressure found at sea level, namely 1 atm absolute pressure (ata) (or 101 kPa). From a strictly physiological point of view, this design specification is probably not optimal, but it serves other interests such as simplifying the conduct of biomedical research. Selected space suit pressures represent a compromise between engineering concerns, which dictate that the internal pressure of a space suit be low to maximize flexibility, and physiological risks. (The space suit used in the current U.S. space program, the extravehicular mobility unit, is pressurized to 30 kPa (4.3 psia); the Orlan suit, used in the current Russian space program, is pressurized to 38 kPa (5.5 psia).) Consequently, crewmembers performing EVAs experience substantial shifts in ambient atmospheric pressure. Unplanned crew cabin or space suit decompressions are also possible while living and working in the hard vacuum of space. The pathophysiological consequences of such exposures are the subject of this chapter [1].

Nomenclature Various schemes have been used to classify the spectrum of disorders arising from changes in ambient pressure. The term decompression illness has been used to refer to all of these disorders, including such heterogeneous experiences as arterial gas embolism (AGE) and trauma to enclosed gas spaces, such as the thorax, sinuses, and middle ear. The subset of diseases caused by gas bubbles that evolve from inert gas dissolved within tissues is commonly referred to as decom-

pression sickness (DCS). DCS that occurs during diving is termed hyperbaric DCS; the syndrome that arises from aerospace operations is called hypobaric or altitude DCS. Although DCS has traditionally been subdivided into two types, differences among the definitions of subtypes by the U.S. Navy, the U.S. Air Force, and civilian diving organizations have made direct comparisons among databases difficult. These differences have also hindered discussion of diagnosis, prognosis, and ability to return to duty. In the original definition in 1960 [1], type I DCS was considered less serious than type II DCS. The U.S. Navy later defined DCS as follows: Type I decompression sickness includes joint pain (musculoskeletal or pain-only symptoms) and symptoms involving the skin (cutaneous symptoms), or swelling and pain in lymph nodes. Type II, or serious symptoms, are divided into neurological and cardiorespiratory symptoms. Type I symptoms may or may not be present at the same time [2]. The U.S. Air Force modified this scheme to include the “type I peripheral nervous system case [3].” Since the presence of a diagnosis of type II DCS in the medical history of a U.S. Air Force aviator would have career implications that seem out of proportion to the real risk of recurrence in a future hypobaric exposure, the motivation for this change arose more from administrative concerns than from biomedical knowledge. Medical practice within the U.S. Air Force thus evolved such that paresthesias of limited anatomic distribution that resolve without sequelae are labeled “type I peripheral nervous system DCS” rather than type II DCS. This divergence of classification methods can substantially complicate interpretation of data from field experience and laboratory experimentation. To confuse matters further, even the U.S. Navy Diving Manual deviates from its own classification scheme by creating the “patchy peripheral paresthesias” category, which is treated separately in determination of return to duty [4]. Several schemes have been proposed to replace the type I/type II classification, including those by Wirjosemito et al. [5]. and Dutka [6]. One such scheme [6] dispenses with all conventional subset classifications of decompression illness and instead uses descriptions of the clinical symptoms and 223

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course [e.g., “abrupt paresthetic DCI” (decompression illness)]. Bove [7] pointed out that this scheme disregards the basic pathophysiology of the disorder; for example, a myocardial infarction would be referred to in this scheme as an “abrupt painful chest illness,” terminology that fails to communicate vital information. No clear consensus has emerged concerning the best nomenclature for DCS. In this chapter, we will use the type I and II classification scheme as defined in the current U.S. Navy Diving Manual [2].

Decompression Sickness Although procedures for hypobaric exposures with a low risk of DCS have been developed and effective treatments for hypobaric DCS exist, little is known of the pathophysiology of DCS. Nevertheless, it is clear that the disorder involves bubbles. The remainder of this section constitutes a review of the processes of bubble formation and resolution, the probable sites of bubble formation within the body, the interactions of bubbles with nearby tissue, the uptake and elimination of the inert gas that drives bubble formation, the pathophysiology of DCS in specific organ systems, and treatment of the disorder.

Bubble Formation Bubbles can form when the sum of partial pressures of gases dissolved in a liquid plus the vapor pressure of the liquid itself exceeds the hydrostatic pressure in that liquid. When this criterion is met, bubble formation is not instantaneous and substantial supersaturation can occur without gas formation. In fact, in pure water at 1 ata without existing bubbles, more than 100 ata of gas can be held in solution before de novo gas formation takes place [8,9]. In contrast, bubbles have been observed in humans after modest dives [7.8 m (25 ft)] [10] and space flight EVA simulations [3,700 m (12,000 ft)] [11]. Thus, the process of bubble formation in humans clearly differs from that which takes place in a beaker of still water. Possible modifying factors for bubble formation are numerous. Preexisting gas nuclei may obviate the need for de novo gas formation. Gas may simply diffuse into and enlarge gaseous nuclei. Experimental evidence to support this notion can be found from studies with rats in which dives began with a very short duration, deep pressure spike designed to crush preexisting nuclei. This pressure excursion protected against DCS in subsequent decompressions [12]. Similar findings have been obtained with shrimp [13]. However, conflicting data have also been reported—a hydrostatic pressure spike had no effect on bubble formation in adult crabs [14]. Thus the role of preformed nuclei in the generation of DCS may have been overstated, at least in lower animals [15,16]. Another factor that may influence the development of a gas phase in humans after decompression and may also explain the genesis of gas micronuclei is the generation of

W.T. Norfleet

negative pressures in tissues as a result of movement and locomotion. When two closely opposed tissue surfaces are forced to separate, fluid must flow into the widening gap to fill that gap, but the viscous properties of the fluid tend to oppose this flow. The resulting negative pressure in this gap can be tremendous, large enough to cavitate the fluid. A similar phenomenon occurs when two tissue planes slide against each other, a process called tribonucleation [17]. Hemmingsen demonstrated the importance of locomotion in generating bubbles in vivo during experiments in which the development of bubbles within crabs was compared between crabs left free to scurry around after decompression and crabs whose legs were immobilized. More bubbles were seen in the free-roaming crabs [18]. Studies in fish throughout their development also established the importance of movement in generating bubbles [15]. Hemmingsen [16] provides an excellent review of in vivo and in vitro bubble formation.

Sites of in Vivo Bubble Formation Where in the body do bubbles form that cause disease? The precise location is largely unknown. For considerations of where bubbles might form, tissue compartments can be categorized as intravascular (arterial, capillary, or venous) or extravascular (intracellular or interstitial). The arterial circulation seems an unlikely site for intravascular bubble formation. In most circumstances, inert gas tensions in arterial blood are in equilibrium with alveolar gas, so arterial blood is not supersaturated with inert gas. Moreover, arterial blood is pressurized hydrostatically by the heart, which further impedes any gas formation. Nevertheless, circulating bubbles have been detected in arterial blood, and these microemboli may be responsible for certain forms of DCS. The source of bubbles is likely to be transpulmonary or right-to-left shunting of the bubbles from the venous circulation [19–23]. Venous blood has been shown to contain significant numbers of circulating microbubbles after even modest, asymptomatic decompressions [10]. Bubble formation within venous blood seems unlikely, however, at least when the vessels are at rest. In a study in which the blood-filled venae cavae of several species were excised, placed in saline, and decompressed to altitudes well in excess of those that produce DCS, no bubbles formed [24]. The ultimate source of venous bubbles is unclear. Venous bubbles may form in capillary beds and be swept into the central venous circulation, or they may arise in extravascular tissues and migrate into the circulation. Regardless of their source, in most circumstances circulating venous microbubbles do not seem to be the proximate cause of disease since the magnitude of their numbers correlates only very loosely with the likelihood of disease development [25,26]. With some notable exceptions, circulating venous microbubbles are only the “fellow travelers” of those bubbles that actually cause disease. Within the extravascular compartment, bubble formation within cells seems to be uncommon. Cells and unicellular

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

organisms are quite resistant to bubble formation [27]; the intracellular environment is not conducive to bubble formation, as demonstrated by the fact that microscopic particles that serve as a nidus for bubble formation in water fail to form bubbles when ingested by Tetrahymena [28]. By process of elimination, this leaves the interstitial space as a possible site for the formation of bubbles that cause DCS symptoms. In some tissues, experimental evidence exists to support this notion. For example, in situ interstitial gas formation—the so-called autochthonous bubbles—has been observed in spinal cord tissue after decompression [29]. In contrast, experimental evidence suggests that bubbles cannot form in the brain and kidney under operationally realistic pressure profiles [30]; disease in these organs is probably caused by arterial microbubbles originating in other tissues. Attempts to document extravascular bubbles in rabbits exposed to hypobaric conditions have failed [31,32]. It seems that bubbles formed in situ may cause some forms of DCS, whereas emboli originating in remote sites may cause other manifestations. For many forms of DCS, such as the common, pain-only limb “bends,” the site of formation of the provocative bubbles has not been demonstrated.

Interactions of Bubbles with Nearby Tissue What is it about the presence of a bubble that causes disease? Broadly speaking, the effects of a bubble are both mechanical and nonmechanical. Mechanical effects include embolization of capillary beds by circulating microbubbles, with consequent ischemia. Expanding interstitial bubbles may also compress surrounding tissue, causing ultrastructural damage and raising local tissue pressure to the point that circulation is compromised. Finally, bubble accumulation in venules and veins may inhibit venous drainage, with consequent tissue edema, ischemia, and perhaps interstitial bubble formation as dissolved inert gas that otherwise would have been swept out of the tissue in solution remains sequestered in the tissue and comes out of solution. In many clinical situations, the nonmechanical effects of bubbles may be more important than their mechanical presence. Indeed, the presence of bubbles in tissues is often of no clinical consequence [33]. On the other hand, the onset of symptoms sometimes occurs so long after a pressure excursion that when the symptoms finally begin, the continued presence of actual gas bubbles seems unlikely (e.g., Bason) [34]. Apparently, the presence of bubbles in body tissues serves as a nidus for the initiation of biochemical and cellular processes that, once begun, can lead to morbidity and mortality, even after the offending bubble has disappeared. Some of the nonmechanical effects of bubbles may be initiated at the interface of bubbles with blood or interstitial fluid, an interface that demarcates regions of vastly different physiochemical properties. Proteins that interact at this interface can undergo conformational changes [35]. The presence of bubbles in blood affects many enzymatic systems, including complement factors, coagulation factors, kinins, and fibrinolytic systems [36–41]. Leukocytes and platelets have been

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shown to adhere to bubbles [42,43]. The results can include pain, edema, coagulation, reduction in local tissue perfusion, and leukocyte chemotaxis. Experimental observations that bridge the mechanical–nonmechanical paradigm include denuding of capillary endothelium by bubbles with subsequent inflammation [42,44] and peroxidation of myelin initiated by the release of free iron [45] when hemorrhage occurs around autochthonous bubbles in spinal tissue [46]. The combined effects of bubbles may explain the many-faceted clinical presentation of DCS as well as the observation in many cases that symptoms may persist or even begin well beyond the expected longevity of a bubble within a tissue.

Inert Gas Uptake and Elimination Because bubble formation in tissues, driven by inert gas supersaturation, is thought to be the initiating factor in DCS, measurement of inert gas tension at the sites of formation of harmful bubbles would provide highly relevant data. However, since the precise location of the microenvironments that produce such bubbles is unknown, these data unfortunately cannot be acquired. As a substitute for these kinds of measurements, many investigators (e.g., Anderson et al.) have analyzed whole-body inert gas elimination [47], but whole-body gas elimination does not necessarily reflect gas exchange in the tissues of interest. Gas exchange has also been studied in experimentally induced subcutaneous gas pockets [48], but these studies also require a leap of faith to draw conclusions regarding gas exchange in clinically relevant tissues. Despite this dearth of fundamental knowledge, humans have already been exposed, with varying degrees of success, to a wide variety of pressure-time profiles. Data inferred from these profiles have been used to develop mathematical models of inert gas exchange. Such models are useful for extrapolating between known regions of the pressure-time continuum and, to a lesser extent, for venturing into new extremes. Although describing the wide variety of mathematical models that has been advanced is beyond the scope of this text (cf. Vann & Thalmann [49]), brief consideration of one method is relevant—not because it represents the state of the art but rather because it has been used to govern Space Shuttle operations [50]. This method is used primarily for modeling inert gas elimination during O2 “prebreathing” periods and step-reductions in ambient pressure. This approach is not new; its origins are the work of Haldane [51]. Briefly stated, the assumption, which is based on empirical evidence, is that inert gas elimination can be modeled by dividing the body into several conceptual compartments, each of which has its own rate constant for elimination of inert gas: Pt = P0 + [(Pa − P0)(1 − e −kt)] where Pt = inert gas partial pressure in tissue after t minutes P0 = initial inert gas partial pressure

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Pa = inert gas partial pressure in inspired gas (although use of alveolar or arterial gas pressure would be more correct in physiological terms) t = exposure time in minutes k = compartment rate constant (k is related to the inert gas half-time t1/2 by k = 0.693/t1/2) In a typical operational scenario, only the compartment with the longest gas-elimination rate (empirically determined as having a half-time of 360 min) governs decompression. The partial pressure of inert gas in tissue can be compared with ambient atmospheric pressure as an indication of the decompression “stress”: TR = Pt/Pamb where TR = tissue ratio Pamb = ambient atmospheric pressure This method is useful in determining conditions under which bubbles will form. As noted earlier in this chapter, bubbles can form when the sum of partial pressures of gas dissolved in a liquid exceeds the hydrostatic pressure in that liquid. The process of bubble formation is also subject to many other factors that make substantial supersaturation possible before bubble formation takes place. Finally, the presence of bubbles in tissue does not invariably lead to disease. The net result of these deliberations is the realization that for a significant number of symptom-producing bubbles to form at all, the TR must be greater than 1.0. Similarly, when the TR is much greater than 1.0, DCS is likely. In other words, the risk of DCS is a function of TR. This rather simplistic approach to quantifying the risk of DCS has some utility, although it does not account for many factors that are known to modify the risk. Nominal Space Shuttle operations have avoided situations in which the TR would exceed 1.65.

Pathophysiology DCS manifestations are often diffuse, multifocal, and protean. Multiple organ systems can be involved simultaneously. Although bubbles serve as the initiating agent, the disease can persist and probably even progress after the bubbles have been resorbed. Since clinicians who resolutely seek the “one lesion” are likely to be frustrated in attempting to characterize the clinical manifestations of a case of DCS [52,53], the following discussion of the effects of DCS on organ systems should be read with the understanding that simultaneous, interacting disease can occur in many systems.

Hyperbaric Versus Hypobaric Decompression Sickness Much of our current understanding of the pathophysiology of hypobaric DCS has been derived by extrapolation from experience with hyperbaric DCS. Although the two situations are

analogous, they are fundamentally different in terms of pressure profile, the importance of gases other than inert gases, the time course of bubble formation, the scenario at symptom onset, and the natural history of the disease. These differences are expanded upon below. Pressure Profile A typical dive begins with an individual at sea level whose tissues contain a dissolved mass of inert gas that is in equilibrium with the inert gas in the surrounding atmosphere. The diver is said to be “saturated” with air at 1 ata that contains approximately 80% inert gas (in this case, nitrogen). During the course of the dive, the individual descends to some depth and quickly returns to the surface. The diver has accomplished a “downward” excursion from saturation conditions; in other words, ambient pressure increases as the diver descends. In terms of inert gas uptake and elimination, the diver has absorbed inert gas from the air breathed during the course of the dive and then eliminated this gas during a process that begins upon initiation of ascent but continues for some period after return to the usual sea-level environment. The typical spacewalker’s pressure profile is fundamentally different. The typical spacewalker also begins the day saturated in specified conditions, but the pressure profile involves a reduction in ambient pressure, i.e., an “upward” excursion from saturation. Inert gas is eliminated during the course of the pressure excursion, not afterwards. Most important for the spacewalker, every exposure ends with a compression, not a decompression. In this respect, hypobaric and hyperbaric operations are as different as they can be. Importance of Gases Other Than Inert Gases In addition to inert gases such as N2, other gases are also dissolved in body tissues. For example, CO2 is generated by cellular processes and is maintained by the circulatory and ventilatory systems at a tension of approximately 5.3 kPa. The tension of water vapor in tissues, a function of body temperature, is constant at 6.3 kPa. In the diver, these tensions are trivial compared to the tension of the inert gas, which can reach 6,600 kPa in very deep dives [54]. Consequently, in considering the physics of bubble formation in divers, gas species other than inert gas can largely be ignored. The ambient atmospheric suit pressure of the spacewalker, in contrast, is typically only about 30 kPa, so the contributions of water vapor and CO2 (and, to a lesser extent, that of O2) to bubble formation and resolution are very important. As an example, under equilibrium conditions when breathing air at a depth of 10 m (33 ft), 8% of the volume of a bubble consists of species other than N2; at an altitude of 9,100 m (30,000 ft), 56% of the bubble volume consists of these species. This factor may explain why some mathematical models of inert gas uptake and elimination that work well for divers may fail when applied to spacewalkers.

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

Time Course of Bubble Formation The physical principles underlying the formation of a bubble from dissolved gas are complex. For the purpose of this discussion, it is useful to note that a bubble of a given volume will form more slowly under hypobaric conditions than it will in hyperbaric conditions. For example, Piccard [55] observed that the same volume of gas was liberated from water saturated with air at 5 ata when the water was decompressed to 1 ata as when water at 1 ata was decompressed to 0.2 ata. Piccard went on to say that “In the first case the bulk of dissolved air had escaped after 5 s, while in case 2, several minutes elapsed before the gas production even approximately ceased.” Bubble formation may be sufficiently slowed under hypobaric conditions to allow physiological processes to eliminate some inert gas from tissues before a significant gas phase has had time to evolve. Scenario at Symptom Onset The typical diver is at risk of developing DCS only upon return to the surface, when the job is completed and the diver is “home.” In contrast, symptom onset for spacewalkers most likely occurs while they are still engaged in EVAs. So if DCS occurs, the spacewalker’s job is more likely to be disrupted by it, and symptom onset is more likely to occur in the midst of an already hazardous operation.

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TABLE 11.1. Manifestations of decompression sickness from 140 patients during 136,696 exposures in U.S. Navy altitude chambers, 1981–1988a. Clinical manifestations Joint and limb pain Extremity paresthesia Numbness Muscular weakness Dizziness Headache Nausea and vomiting Visual disturbances Fatigue and malaise Apprehension Mental confusion Disorientation Hyperventilation Paralysis Pruritis Muscle spasm Skin mottling Ataxia Chokes Unconsciousness Slurred speech Vertical nystagmus Abdominal pain Hot and cold flashes Difficulty forming words

Patients (No.)

Patients (%)

99 46 33 24 22 12 11 10 8 7 7 7 5 4 3 3 2 2 1 1 1 1 1 1 1

70.7 32.9 23.5 17.1 15.7 8.6 7.8 7.9 5.7 5.0 5.0 5.0 3.6 2.9 2.1 2.1 1.4 1.4 0.7 0.7 0.7 0.7 0.7 0.7 0.7

Source: Bason [34]. a More than a single manifestation can occur in an individual patient.

Natural History of Decompression Sickness Typically, hypobaric DCS is less severe than hyperbaric DCS, is less likely to cause neurologic or other sequelae, and is more amenable to treatment. Meaningful comparisons between databases from the hyperbaric and hypobaric communities therefore require careful definition of what exactly constitutes a “hit.” For example, operational managers in the hypobaric arena might be willing to accept an overall risk of DCS that exceeds the risk that would be considered acceptable to their colleagues in the diving world, because the incidence of cases with serious, lasting injury in the hypobaric world is relatively low. Despite these distinctions between hypobaric and hyperbaric decompression physiology, much can be learned about the pathophysiology of hypobaric DCS by considering experience from diving operations, especially decompression from saturation diving. In fact, the microgravity environment may blend elements of both flying and diving operations, involving, for example, fluid shifts analogous to those of the immersed diver and pressure excursions similar to those encountered by the aviator. Consequently, the following discussion draws heavily from diving and hyperbaric physiology. Information regarding manifestations of hypobaric DCS can be derived from the thousands of human exposures in hypobaric chambers conducted as part of flight crew training by the world’s armed forces every year. Table 11.1 depicts the manifestations and incidence of DCS and related disorders encountered by the U.S. Navy from 1981 to 1988

[34]. (A notable clinical manifestation not represented in this table is death. Hypobaric DCS can kill, albeit rarely.) [56–58] From 1985 to 1987, the U.S. Air Force experienced 282 cases of DCS in the course of 239,343 hypobaric chamber exposures; 89% of these cases were classified as type I and 11% were classified as type II [59]. From 1984 to 1989, the U.S. Army had 42 cases of DCS in 21,498 exposures, but no breakdown of clinical presentation was reported [60]. (Interestingly, military organizations outside of North America report fewer cases of altitude DCS yearly.) [61] Few diseases, if any, are as diverse in their manifestations as DCS. The expressions of DCS in specific organ systems are considered in the following discussion.

Blood The nature of the interaction of bubbles with blood was discussed earlier in this chapter. Blood also plays many roles in the pathophysiology of DCS by serving as a conduit for gaseous microemboli to the pulmonic and systemic vasculature, transporting leukocytes and platelets to bubble-damaged vascular endothelium and tissues, and participating in local inflammatory reactions. Since patients with DCS frequently display hemoconcentration and a decline in intravascular volume [39,62,63], fluid therapy is the cornerstone of treatment for the disease. Additional therapeutic maneuvers to counteract observed changes in blood, such as administering heparin

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and low-molecular-weight dextran, have not yet been found to be of clinical value.

Musculoskeletal System A common form of DCS, especially in hypobaric realms, is pain in and around extremity joints—“the bends.” Symptoms of the bends typically begin with a sense of fullness around a joint and may progress to an aching or a throbbing pain that can be severe. The pain is sometimes well localized, but it can also be fleeting and migratory. In contrast to conventional musculoskeletal injuries, the affected area is usually not tender to touch and the pain is not markedly worsened by joint movement. Alleviating factors include pressurizing the patient in a hyperbaric chamber and, in some cases, inflating a blood pressure cuff around the affected area. Pain in areas other than the extremities, especially truncal pain, is thought to be a more sinister form of DCS, reflecting involvement of spinal nerve roots or the spinal cord itself. To date, DCS of the sternoclavicular joint has not been recorded, an observation that can be useful because essentially all diving involves a good deal of upper-extremity stress and strain that can produce non-DCS symptoms. Patterns of joint involvement in hypobaric DCS differ markedly from those of the hyperbaric condition. Table 11.2 reflects the experience of the U.S. Navy [34]. In the U.S. Navy report, 64% of cases involved the upper extremities. By contrast, experimentation at NASA produced DCS in the upper extremities in only 11% of cases [64]. Patterns of exercise and activity influence the distribution of symptoms. DCS tends to occur in the upper extremities in individuals who do push-ups at altitude and in the lower extremities of those who do deep knee bends [62]. The precise etiology of bends pain is unknown, although both mechanical and nonmechanical effects of bubbles probably contribute to it. The mere presence of moderate amounts of gas in joint spaces and around articular cartilage, which

may arise in the course of daily activities [33], actually does not cause pain; but expanding gas volume in a poorly compliant tissue containing sensory nerves such as tendons could cause pain. Patterns of blood flow in this tissue seem to be conducive to poor inert gas elimination [65], and injecting lactated Ringer’s solution into the tendons can cause pain similar to that of DCS. Possible nonmechanical effects include the initiation by bubbles of a cascade of humoral mediators of the inflammatory response. The fact that the pain frequently resolves rapidly and completely upon pressurization in a hyperbaric chamber or upon application of a blood pressure cuff argues against an inflammatory response being a major contributor in such cases, however. Long-Term Sequelae A feared, long-term consequence of diving, especially of saturation and experimental diving, is aseptic dysbaric osteonecrosis of weight-bearing bones such as of the femoral head [66]. Fortunately, hypobaric exposures do not seem to produce this problem [67]. Since many factors can cause aseptic osteonecrosis, a relatively small incidence of the dysbaric form may still exist in the larger aviator population that has yet to be detected.

Nervous System Broadly speaking, DCS of the central nervous system manifests as cerebral and spinal forms. Involvement of peripheral nerves also seems possible. Numerous reports and oral tradition have indicated that in divers spinal cord involvement is more common than cerebral DCS and that the converse is true in aviators. However, recent studies suggest that cerebral involvement may occur as often as spinal disease in divers [53,68–71] and that a wide variety of central nervous system symptoms arise from hypobaric exposures (Table 11.1). Spinal Decompression Sickness

TABLE 11.2. Site of type I decompression sickness resulting from exposures in U.S. Navy altitude chambers, 1981–1988. Symptom site Elbows Shoulders Knees Arms Wrists Hips Legs Ankles Fingers Feet Hands Heels Source: Bason [34].

No. of incidents 34 30 29 10 9 5 4 4 2 2 1 1

Spinal DCS is all too common in divers and frequently involves the lower thoracic and upper lumbar cord [72]. DCS classically manifests as the rapid onset of paraplegia, paraparesis, and urinary retention after surfacing, sometimes preceded by prodromal abdominal or girdle pain [73]. More typically, the patient reports paresthesias of one or more limbs in a pattern that varies with time and defies discrete neuroanatomic localization of the lesions. Hypoesthesia and paresis may also be present. The etiology of spinal DCS is not entirely clear and may simultaneously involve more than one bubble-related mechanism. Microembolization of the spinal cord is probably not a significant contributor in most cases because the anatomic distribution of injury does not seem to follow a vascular pattern [74]. A mechanism backed by considerable experimental evidence involves bubble congestion of the epidural venous plexus that drains the cord [20,75,76]. This valveless venous plexus surrounds the dura-enclosed spinal cord, occupying

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

much of the space bounded by the spinal canal [77,78]. Bubbles within the plexus and back pressure reflected ultimately from pulmonary circulation are thought to cause engorgement of this plexus, stasis of the blood, intravascular sludging, and, ultimately, infarction of the cord. In humans, the pattern of cord injury in DCS does not match that observed from venous infarction of the cord from other causes [79]. This mechanism does not now seem to be the major, proximate cause of spinal DCS, although it may play a role in spinal DCS. Because arterial and venous mechanisms do not seem to be major causes of spinal DCS, phenomena within the cord tissue have been considered [29]. Of particular interest is the concept that autochthonous bubbles form within or adjacent to myelin nerve sheaths and compress nearby axons [46,80]. Because myelin makes up a greater proportion of cord white matter than gray matter, white matter would be expected to be more involved in spinal DCS if autochthonous bubbles were a factor. Since opportunities to examine the cord tissue of divers with spinal DCS obviously are limited (although lesions involving predominantly white matter have been reported) [81–85], animal models of spinal DCS have been developed. In these models, the cords of stricken animals contain numerous gas-filled, space-occupying lesions in white matter that are consistent with the concept of autochthonous bubbles [73,86]. Interpretation of these animal studies is complex, given the need to consider the implications of the magnitude of decompression stress, the time at which the animals were killed in relation to that stress, and the conditions under which the tissue was fixed and examined. Nevertheless, the weight of the evidence seems to favor a mechanism for spinal DCS involving expansion of short-lived autochthonous bubbles, mechanical disruption of nearby tissue, pressure-induced local ischemia, and perhaps peroxidation of myelin initiated by free iron released when hemorrhage occurs around autochthonous bubbles. Bubbles in the epidural plexus may contribute to the formation of autochthonous bubbles by slowing venous drainage and perfusion of the cord, thereby delaying inert gas elimination from the cord. This would permit gas that otherwise would have been washed out of the cord to participate in autochthonous bubble expansion. Bubbles seem to form much more readily in the epidural venous plexus than in other vasculature [76]. Hence, both the autochthonous and epidural bubbles may play roles in generating spinal DCS. Although the contribution of autochthonous bubbles to spinal DCS is fairly well established in divers, at least two factors may diminish the formation of such bubbles in aviators or spacewalkers. First, as noted above, bubble formation is inherently slower in a hypobaric setting than in a hyperbaric setting. If the pace of inert gas elimination from the cord (estimated to have a time constant of about 15 min for white matter) [87] exceeds the rate of bubble formation in the cord, spinal DCS would be avoided. Second, a threshold decompression stress for generation of autochthonous bubbles has been identified for hyperbaric conditions. Bubble formation

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in dogs exposed to hyperbaric air for 4 h was much more common at pressures greater than 3.6 ata than at lower pressures [88]. How such a threshold translates to hypobaric conditions remains unclear. In any event, spinal DCS has been reported in aviators, albeit rarely [5]. Cord white matter injury has been observed in humans [89] and animals [90] that were exposed to altitude, although gray matter involvement was also seen in these studies, perhaps implying simultaneous gas embolization of the cord. The pathophysiology of hypobaric spinal DCS has yet to be firmly established. Cerebral Decompression Sickness Cerebral DCS, as discussed above, probably arises from embolization of the brain by circulating bubbles rather than by bubble formation within the brain itself. Simultaneous involvement of many loci may occur, and the clinical manifestations of disease are diverse. These include unconsciousness, convulsions, hemiplegia, visual disturbances, mentation difficulties, headaches, and subtle personality changes. More is involved in the pathophysiology of the disorder than simple obstruction of vasculature by gaseous emboli. Gas that is carried to the brain in arterial blood has been observed to pass rather quickly through the brain [91], leaving behind damaged capillary endothelium and a loss of the blood–brain barrier [92–94]. In the wake of these bubbles, a chain of events is initiated that includes adhesion of leukocytes to damaged tissue [95]; indeed, granulocytopenic dogs are relatively resistant to neurologic damage produced by air injected into the carotid artery. Autoregulation of blood flow is lost along with a progressive, patchy decline in perfusion and neurologic function [91,96]. The disturbance in the blood–brain barrier can be short-lived, lasting about 3 h, but it can also recur 72 h later, perhaps because of the “maturation phenomenon” in neural injury [94]. Disruption of the blood– brain barrier has also been observed in rabbits exposed to altitude without detectable intracerebral intravascular bubbles or mechanical endothelial disruption. The mechanism for these changes remains obscure [32]. If cerebral DCS arises from embolization of the brain by circulating microbubbles, then where do those bubbles come from? As can be concluded from the prior discussion of bubble formation, bubbles probably do not arise within systemic arterial blood, and an extension of that argument would suggest that bubbles do not form in pulmonary capillaries. Thus the most likely source of the offending bubbles is venous bubbles that have managed to either travel through the pulmonary circulation or to bypass it. As discussed in more detail below, the lungs are highly effective at filtering all but intense bubble loads. Consequently, attention has focused recently on determining the role in the pathophysiology of neurologic DCS of pathways that permit venous bubbles to bypass the lungs and reach the left atrium. Collectively, such pathways are referred to as interatrial shunts. The archetypical—but by no means only—interatrial shunt is the patent foramen ovale. Indirect but highly relevant (and far more abundant) findings

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are concerned with the pathophysiology of thromboembolic cryptogenic stroke; interatrial shunts seem to play a significant role in this disorder [97–99]. Interatrial shunts also seem to be important in some, but not all, cases of hyperbaric cerebral and high-spinal DCS [100,101]. Only very limited information has been published concerning the role of shunts in altitude neurologic DCS. No increased prevalence of shunts was found in a group of military personnel who seemed to have developed this disease [102,103], but the pressure profiles to which they were exposed (short durations at high altitudes) were not likely to have generated venous gas emboli. A recent review of this topic pointed out that the size and location of shunts are important determinants of their clinical significance [104]. Shunts are common, but important shunts are not, so future investigations may be more insightful if they focus on the important shunts rather than the totality of shunts. Decompression Sickness of Peripheral Nerves DCS of peripheral nerves, a diagnosis recognized by some organizations including the U.S. Air Force, is discussed in standard textbooks of aerospace physiology [105]. When neurologic involvement is confined to a portion of an extremity, it is reasonable to postulate that a peripheral nerve is involved. This idea is supported by some case reports [106,107]. However, since symptoms in a portion of an extremity could also be produced by disease in a spinal nerve root, the pattern of neurologic dysfunction in this case might follow a dermatomal distribution. Bubbles have been observed in epineural and intraneural vessels of sciatic nerves of rabbits exposed without prebreathe to 13,716 m (45,000 ft) [31]. In humans, the incidence and pathophysiology of peripheral nerve DCS is not well characterized. Long-Term Sequelae The relatively intense interest in neurologic DCS reflects the fact that it can cause permanent, disabling sequelae. Fortunately, in the vast majority of cases treated promptly with hyperbaric therapy, overt disease is cured. Nevertheless, concerns remain, particularly in the diving community, regarding the possible occurrence of subtle disease that either persists after treatment or accumulates during the course of repeated, apparently uneventful exposures, such as inconspicuous cord damage or the “punch-drunk diver [108–110].” A single case report describes the autopsy findings of a diver who died of unrelated trauma within days of apparently successful hyperbaric therapy for spinal DCS; autopsy revealed extensive damage of the lower cervical and upper thoracic cord [82]. Similarly, a dog that had apparently recovered completely from altitude DCS was found at necropsy to have suffered massive cord and brain stem lesions [111]. Whether hypobaric exposures might also produce subtle, long-term neurologic damage is unknown. A mail survey of retired high-altitude U.S. Air Force pilots revealed an unexpectedly high incidence of DCS in those who

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flew U-2 operations (75% of the respondents reported developing DCS at least once in their career that was not brought to the attention of a flight surgeon) but no unusual long-term health problems [112]. Drawing conclusions regarding the long-term consequences of altitude DCS from this uncontrolled, retrospective, survey-based study is difficult. In summary, no one has yet described long-term disease in aviators that can be traced back to distant, resolved hypobaric DCS, but neither has much effort has been directed to acquiring this information.

Cardiopulmonary System Bubbles that are carried in the venous circulation will eventually reach the pulmonary capillary vasculature and embolize the lung. In severe cases, these gaseous microemboli produce a syndrome known as “the chokes,” a syndrome characterized by dyspnea, cough, retrosternal pain, and cardiovascular collapse [113]. Although the lung is highly effective in removing bubbles from the circulation and preventing embolization of important systemic capillary beds in tissues such as the brain and spinal cord, large bubble loads can overwhelm its filtering effect [21,22,114,115]. Bubbles that lodge in the lungs remain in place for many min, at least during air breathing [116,117], providing an adequate period for the development of significant interactions with surrounding pulmonary tissues. For example, microvascular permeability has been observed to increase after gas embolization, resulting in transient pulmonary edema [118]. Also, leukocyte counts and lysophosphatidylcholine levels are increased in bronchoalveolar lavage fluid after decompression in rats [119]. These interactions of gaseous microemboli with pulmonary vasculature can impair O2 transport by the lung [23]. Pulmonary emboli are also thought to impair O2 transport by altering the matching of regional ventilation and perfusion, increasing the velocity of blood flow through non-embolized capillaries, and opening intrapulmonary arteriovenous shunts [120,121].

Skin and Lymphatic System Cutaneous manifestations of DCS (“skin bends”) include pruritis; mild, limited macular eruptions; and deep, extensive, purple “marbling.” Mild pruritis is common during or shortly after hypobaric chamber flights and is not itself a cause for concern [62,122]. Limited, mild rashes occur less frequently but are also thought to be innocuous. Extensive marbling does seem to be associated with more sinister pathology such as cardiovascular instability [122] and neurologic involvement [123]. These phenomena are thought to arise from an inflammatory reaction to bubbles present in cutaneous tissues or vasculature. Localized soft tissue edema has occurred in divers, apparently as a result of the obstruction of lymphatic vessels by bubbles [124,125]. Understanding of the pathophysiology of skin bends has been enhanced by studying the formation of skin lesions in

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

divers who breathe an N2-based gas mix while they are in a chamber containing a He-based gas. Under these conditions, bubbles can form in skin without any change in ambient pressure, a phenomenon known as isobaric inert gas counterdiffusion [126]. Under more conventional conditions, however, direct transfer of inert gas across skin from the surrounding atmosphere may not be as important in the genesis of skin bends as changes in regional skin blood flow. As an example, a patch of skin that is compressed against a cold, metal surface may be more likely to be afflicted than skin that is warm and well perfused.

Work-Up and Differential Diagnosis of Decompression Sickness Despite dramatic advances in medical technology in recent years, a history and physical examination evaluation are still the best means of gathering diagnostic information from a patient suspected of having DCS. Although promising results were previously reported by Adkisson and colleagues [71], the use of advanced methods such as computer tomography [127], magnetic resonance imaging [128], single photon emission tomography [129], and positron emission tomography [130] has no proven role in the diagnosis or follow-up of DCS. However, future developments may well change this situation (reviewed by Hanson and Jordan) [131]. Chest radiography may be useful in the future for detecting generalized pulmonary edema arising from gas embolization of the lung [132], wayward free gas (e.g., pneumothorax and mediastinal emphysema), and aspiration. Since no sensitive and specific test exists for DCS, the diagnosis is, to a large extent, one of exclusion. Unfortunately, establishing a firm diagnosis of DCS can be difficult even in hindsight. Both dysbaric and nondysbaric disease processes must be considered. In equivocal causes, some comfort can be found in the fact that hyperbaric therapy is a rather lowrisk therapeutic intervention. Yet in the rush to conclusions, care must be taken to avoid withholding appropriate therapy through misdiagnosis, such as assuming that chest pain with respiratory distress is “the chokes” when, in fact, myocardial ischemia has developed and an entirely different course of therapy is urgently needed. Diagnostic dilemmas become even more intense when the patient’s location is geographically remote. Since the nature of the symptoms at onset does not predict the eventual severity of the case, little solace can be derived from determining that “it’s only limb bends.” Such circumstances call for a high index of suspicion for DCS and a low threshold for making the decision to transport the patient to a hyperbaric facility.

Clinical Course of Decompression Sickness The clinical course of hypobaric DCS is influenced by several factors, including the duration of O2 prebreathe and altitude exposure; the altitude reached; the magnitude and type of exercise, if

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any, during prebreathe and altitude exposure; the time until initiation of treatment; and the type of treatment administered. (Risk factors for altitude DCS are discussed further in Chap. 12.) Just as all dives are not equal, all hypobaric exposures are not the same. Most acute human exposures to hypobaric conditions occur during physiological training courses for aviators, primarily armed forces personnel; a wide variety of protocols are, or have been, in use to address these (cf. Garrett and Bradshaw [133]). However, most of these exposures might be characterized as involving short “prebreathes”; that is, they involve short exposures to modest altitudes, with little or no exercise performed at altitude. Definitive diagnostic and therapeutic resources are usually available immediately. This situation can be contrasted with current EVA operations. These activities involve relatively long “prebreathe” periods (up to 4 h), long exposures (roughly 6 h), high altitudes [9,100 m ( 30,000 ft)], modest exercise, and remote treatment resources. By some measures, these two types of activities are as different as they can be, and so clinical experience with one type of operation may not be applicable to other contexts. Since no cases of DCS have been formally reported in the course of EVAs conducted by any country, outcomes of physiological training activities are discussed here to characterize the clinical course of altitude DCS. However, caution is urged in extrapolating these results into different operational contexts such as space flight. In the experience of U.S. Air Force physiologic training, the onset of the signs and symptoms of DCS occurred as early as during the altitude exposure itself to as long as 36 h after return to ground level [59,134]. The median time of onset was 2 h after return to ground level. From a pathophysiologic viewpoint, it is interesting to note that most cases of hypobaric DCS appeared hours after termination of the hypobaric exposure. Type I cases accounted for 89% of the total, and the other 11% were type II. About three fourths of the patients received hyperbaric therapy (see below). All patients seemed to have had complete resolution of clinical disease. The U.S. Navy observed symptom onset at altitude in 46% of the cases and at ground level in the remaining 54% of the cases [135]. Of those cases that began at ground level, the median time of onset was about 1 h after flight, and 4% of the cases began more than 20 h after exposure. The case mix was evenly divided between type I and type II disease (see Tables 11.1 and 11.2 for specifics). Hyperbaric therapy was administered to 84% of the patients, and about 4% of those patients continued to have mild symptoms after treatment. Experience with hypobaric DCS has also been gained through laboratory studies of human subjects exposed to pressure profiles similar to those experienced during EVA operations [64,136–139]. It is important to understand the limitations of these studies, however. In these investigations, DCS was generally treated immediately and definitively at the onset of symptoms that were, by some measures, mild. These results contributed little to the understanding of the natural history of DCS or its refractoriness to therapy in any other

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context. Specifically, in operations of the International Space Station, treatment of DCS will not be immediate and may not be definitive. The course of DCS in spaceflight operations may therefore be much more malignant than that observed in terrestrial studies of similar pressure–time profiles. All of these considerations indicate that altitude DCS arising from physiological training profiles is usually fairly mild and is generally responsive to prompt therapy. Nevertheless, it must be recalled that spectacular exceptions to this benign picture of altitude DCS, including death [57], have been reported.

Treatment Four fundamental therapeutic interventions are known to be effective in treating altitude DCS: (1) increasing the ambient pressure; (2) increasing the partial pressure of inspired O2; (3) using fluids to maintain intravascular euvolemia; and (4) providing supportive care such as airway management, cardiac life support, urinary bladder catheterization, and so on. Although other therapies have been suggested, these four interventions represent the cornerstone of treatment. With this overall perspective in mind, we will discuss therapeutic interventions in order of escalating invasiveness.

Do Nothing Approach Even if a subject is still in a hypobaric environment, very mild symptoms do not necessarily demand immediate action. To date, more than 1,000 subjects have been exposed to pressure profiles similar to those used during Space Shuttle EVA operations [64,136,137,139]. A variety of DCS symptoms have been observed, ranging from mild musculoskeletal pain to, rarely, cardiovascular instability and severe central nervous system dysfunction. In many of these cases, subjects were not returned to sea-level conditions unless (1) the study protocol was completed, (2) type II DCS was diagnosed, or (3) type I DCS reached a severity that impaired performance of some manual task. Some subjects developed type I symptoms that were mild or intermittent and therefore did not meet termination criteria; these symptoms either did not progress or actually resolved during the course of the 3- to 6-h protocol. This approach did not seem to put these subjects at an outstanding risk of serious sequelae such as recurrence of symptoms at ground level or progression to type II DCS. Thus, in this particular context, doing nothing in the face of mild, type I DCS seems defensible. From the perspective of overall risk management, though, a hyperbaric physician was in attendance and a fully staffed clinical hyperbaric treatment chamber was present down the hall, providing the option of a clear, definitive course of action if benign disease became more sinister.

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of pressurization to ground level (that is, the pressure from which the hypobaric excursion originated). In one report, 37% of altitude DCS cases with onset at altitude resolved upon descent, although 17% of these case relapsed [135]. Although no definitive study has been performed to specifically evaluate this intervention alone (pressurization is usually combined with a period of O2 breathing as a minimal treatment for established DCS), it seems likely that pressurization alone could diminish or terminate some early, mild cases of DCS [140]. In operational environments with limited treatment capabilities such as space flight, relatively early termination of exposures that are producing symptoms may forestall serious disease. (This strategy, of course, conflicts with the “do nothing” strategy described above, and the decision of which approach to take will be influenced by the specific operational context in question.)

Ground-Level Oxygen “Postbreathe” In recent years, ground-level oxygen (GLO) breathing has been established as a treatment modality for altitude DCS [105,141]. This treatment seems effective for preventing recurrence of type I symptoms that resolve during descent as well as for treating mild type I symptoms that persist to ground level. Table 11.3 shows study results of the efficacy of GLO. A success rate of 77% has been reported in treating type I altitude DCS with GLO alone [142]. In one study [143], symptoms that resolved during descent did not recur in 99.2% of cases treated with GLO; in another study [142], that percentage was 96.2%. Whether to treat type I symptoms that begin at ground level with GLO alone is controversial. Indeed, most investigators do not consider GLO to be appropriate as the sole therapy for any type II symptoms or any recurrent symptoms. TABLE 11.3. Efficacy of ground-level oxygen treatment for altitude decompression sickness. Clinical course

Total No. of cases

Return to Ground-Level Ambient Pressure

Initial onset of DCS at altitude Asymptomatic upon return to ground Received HBO Received GLO; symptoms recurred Resolved with HBO Symptomatic upon return to ground Received immediate HBO Received GLO Successful GLO Unsuccessful GLO, successful HBO Initial onset of DCS at ground level Received immediate HBO Received GLO Successful GLO without recurrence Successful GLO but with recurrence Successful HBO Unsuccessful GLO Successful HBO

In various hypobaric operations, complete and lasting resolution of symptoms has been observed during the course

Abbreviations: GLO, ground-level O2; HBO, hyperbaric O2. Source: With permission from Rudge [142].

104 78 0 3 3 26 6 20 12 8 117 39 78 40 5 5 33 33

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GLO has come into clinical use more by consensus among practitioners than by science. In other words, most practitioners have found that GLO works reasonably well, but resources and opportunities have not been available to perform a systematic, rigorous clinical trial to establish the efficacy of GLO relative to conventional hyperbaric therapy. Similarly, a “dose-response” curve has not been established to determine the optimal length of GLO. A 2-h period is currently common [141]. GLO might best be thought of as a means of prevention rather than as a means of treatment. It is effective in forestalling the recurrence of symptoms that disappear during repressurization. For symptoms that persist to ground level, a single session of GLO can also be used while preparations are made for transport to a hyperbaric facility. If the patient is cured with a 2-h course of GLO, transport can be put on hold while the patient is carefully observed for recurrence. The criteria that determine whether a patient is a candidate for GLO are fairly strict. In particular, those patients with type II DCS are not generally considered candidates. Consequently, it is important for type II DCS to be actively excluded with some confidence. For this to be accomplished, the patient with type II DCS must be examined by a knowledgeable and experienced practitioner who is capable of performing a good neurologic examination. Only if a thorough neurologic examination is “clean” should GLO be considered appropriate as sole therapy.

Hyperbaric Oxygen Therapy Originally developed to treat the bends in divers, hyperbaric oxygen (HBO) therapy has become the mainstay of therapy for altitude DCS. HBO therapy, as the name implies, involves both the application of increased atmospheric pressure and the provision of high inspired partial pressures of O2. Four salutary effects are achieved. First, HBO therapy minimizes bubble volume by compression, according to Boyle’s law [the volume of a bubble at 2.8 ata, which is equivalent to a depth of 18 m (the usual depth of a treatment “dive”), is about 36% of that at sea level]. Second, HBO therapy maximizes the gradient between the partial pressure of the inert gas in the bubbles (which is raised as the bubbles are compressed) and that of the surrounding tissue (which approaches zero when pure O2 is breathed), thereby accelerating resorption of gas. Third, HBO therapy enhances delivery of O2 to tissues rendered ischemic by DCS-induced microvascular disease. Fourth, HBO therapy brings to bear other therapeutic effects of high partial pressures of O2 such as a reduction of tissue edema and intracranial pressure [144,145] and inhibition of platelet aggregation and leukocyte adhesion to damaged capillary endothelium [146,147]. In many cases of altitude DCS, particularly those in which treatment has been delayed or in which clinical improvement continues during the course of repeated treatments over many days, HBO has been observed to be effective long after tissue bubbles would be expected to have resolved. In these cases,

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the third and fourth factors above may be producing a beneficial effect. If, in fact, what is being treated in these cases is not a tissue gas phase but rather the aftermath of bubbles that have since disappeared, then the benefits of HBO depend upon the absolute partial pressure of O2 administered. The compression of a gas phase by the first and second factors noted above is not involved. In such cases, O2 can be thought of as a drug with a “dose” expressed in terms of partial pressure. A chamber is used simply as a means of delivering O2 at a dose in excess of 1 ata. As discussed later in this chapter, the typical dose of O2 involved in HBO is 2.8 ata. Unfortunately, as is true for virtually any drug, O2 has its sinister side as well, a side that manifests itself as pulmonary and neurologic toxicity. Since both of these side effects depend on dose, the risk of toxicity can be managed by limiting the dose of O2 given to the patient. These issues are considered in more detail in the remainder of this section. Pulmonary Oxygen Toxicity Most clinicians are familiar with the “chemical burn” induced in pulmonary tissue when intubated patients undergo ventilation for many hours with a fraction of inspired O2 that exceeds about 0.5. Detailed studies of human volunteers breathing pure O2 without interruption in a hyperbaric chamber [148] indicate that significant toxicity (defined as a 2% reduction in vital capacity) begins to develop after about 615 min of O2 breathing at 1 ata. As would be expected, this time limit decreases as chamber pressure increases (Figure 11.1). A method has been developed to normalize periods of O2 breathing at a variety of partial pressures to units with which clinicians are more familiar. In this method, a unit of pulmonary toxic dose (UPTD) induces the same amount of pulmonary stress as breathing pure O2 for 1 min at 1 ata. As mentioned previously, significant toxicity begins to appear after about 615 min of O2 breathing at sea level. So in terms of the UPTD method, a dose of 615 UPTDs [or in terms preferred by some authors, a cumulative pulmonary toxicity dose (CPTD)] is the maximum dose that can be administered without inducing clinically significant disease. Specifically [149], UPTD(or CPTD) = tx *(0.5/[Px − 0.5]−0.833) where tx is the duration of O2 breathing in minutes and Px is the partial pressure of O2 in ata. According to this scheme, 615 UPTDs are reached after pure O2 is breathed for 615 min at sea level and after pure O2 is breathed for about 173 min at 2.8 ata. During HBO treatments, a guideline has been empirically established that limits CPTD exposures to 1,425 [149]. This limit corresponds to a decrement in vital capacity of 10%. As is true for all practice guidelines, this limit can be exceeded when the benefits of further hyperbaric O2 seem to exceed the risks. The CPTD scheme is useful for estimating the magnitude of pulmonary toxicity present during prolonged or repeated hyperbaric treatments, especially for an unconscious patient who cannot

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W.T. Norfleet TABLE 11.4. Oxygen toxicity symptoms reported during oxygen-tolerance tests (1972–1981). Sign/symptom Convulsion Muscle twitching Dizziness Nausea Visual changes Unconsciousness Other

% of total signs/symptoms 34 24 17 7 7 3 7

Source: Butler & Knafelc [150]. Used with permission.

spontaneous respirations return before hypoxemia develops. Fifteen minutes after recovery from an episode of O2 toxicity, O2 therapy can usually be resumed without further difficulty.

Treatment Tables Figure 11.1. Decrements in pulmonary vital capacity induced by oxygen breathing [148]. Used with permission.

report the development of typical symptoms such as a dry cough and burning or substernal chest pain with inspiration. Neurologic Oxygen Toxicity The most dramatic manifestation of neurologic O2 toxicity is a grand mal seizure. Such a seizure may be preceded by prodromal signs and symptoms. Phenomena observed during the course of O2-tolerance tests administered by the U.S. Navy from 1972 to 1981 (O2 breathing at 2.8 ata in a dry chamber) are shown in Table 11.4 [150]. Although no clear threshold dose of O2 has been established for developing neurologic O2 toxicity, grand mal seizures are extremely uncommon in healthy individuals who are breathing pure gas from good equipment at a partial pressure of O2 of less than 1.3 ata. Conversely, exposure to O2 at 6 ata can produce these seizures in minutes. Several factors are thought to lower the threshold for developing neurologic O2 toxicity, among them preexisting central nervous system disease, fever, immersion in water, hypercapnea, corticosteriods, thyrotoxicosis, cold exposure, and heavy exercise [151–153]. Conversely, a wide variety of interventions have been found to extend tolerance to O2. The most useful of these is interruption of O2 breathing with short periods of air breathing, a method that seems to forestall both neurologic and pulmonary toxicity [154,155]. An O2 seizure, although pyrotechnic in its manifestations, does not seem to do any lasting harm to the patient. Since O2 seizures are self-limited, no treatment is generally required other than removing the O2 mask or hood, protecting the patient from trauma, and conventional airway management [156]. The clinical situation is atypical in that the patient is extremely well oxygenated before seizure onset—which is, in fact, the problem—and

With this information in mind, some general design specifications can be established for the ideal hyperbaric treatment table. Such a table shall (1) maximize the partial pressure of inspired O2, (2) minimize the partial pressure of inspired inert gas, (3) maximize the duration of O2 breathing, (4) avoid neurologic and pulmonary O2 toxicity, notwithstanding specifications (1)–(3); (5) maximize the probability of cure, (6) minimize the time required for treatment, and (7) minimize the risk of inducing DCS in the patient’s in-chamber tender. Because some of these specifications conflict with one another, a grand compromise will be required. If the partial pressure of O2 exceeds something like 3 ata, the risk of neurologic O2 toxicity will drastically limit the duration that O2 can be breathed. “Air breaks,” periods in which the patient breathes air rather than O2, should be incorporated to forestall O2 toxicity. If the dive is such that the tender picks up a significant burden of dissolved inert gas, the tender should breathe O2 near the end of the table to reduce the risk of developing DCS. The ascent from 3 ata to the surface should be accomplished gradually or in stages to extend the duration of O2 breathing and permit early detection of deterioration in the patient’s condition. Clinical experience and laboratory findings gained over the past few decades have generated a degree of consensus regarding the optimal partial pressure of O2 for initial treatment of DCS. Tables constructed around O2 delivered at 2.8 ata have proven successful in treating both altitude [34] and diving [157] casualties. Laboratory studies of an animal model of hyperbaric DCS indicate that the optimum partial pressure of O2 in this setting is 2.0–2.5 ata [158,159]. Most modern clinical treatment tables center on administering 2.8 ata of O2. The table that seems to strike the best and most effective balance among the conflicting specifications for an ideal table is U.S. Navy Treatment Table 6 (TT6) (Figure 11.2) [160] and closely related versions published by other branches of the U.S. armed forces and by other govern-

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Treatment Table 6 1. Descent rate - 20 ft/minute 2. Ascent rate - not to exceed 1 ft/minute. Do not compensate for slower ascent rates. Compensate for faster rates by halting the ascent. 3. Time on oxygen begins on arrival at 60 feet. 4. If oxygen breathing must be interrupted because of CNS Oxygen Toxicity, allow 15 minutes after the reaction has entirely subsided and resume schedule at point of interruption (see paragraph 21-5.5.6.1.1). 5. Table 6 can be lengthened up to 2 additional 25-minute periods at 50 feet (20 minutes on oxygen and 5 minutes on air), or up to 2 additional 75-minute periods at 30 feet (15 minutes on air and 60 minutes on oxygen), or both. 6. Tender breathes 100 percent O2 during the last 30 minutes at 30 fsw and during ascent to the surface for an unmodified table or where there has been only a single extension at 30 or 60 feet. If there has been more than one extension, the O2 breathing at 30 feet is increased to 60 minutes. If the tender has a hyperbaric exposure within the past 12 hours an additional 60-minute O2 period is taken at 30 feet.

Figure 11.2. U.S. Navy Treatment Table 6. From the U.S. Navy Diving Manual [160]

mental and commercial entities. Notable features of TT6 include a maximum depth of 2.8 ata, prolonged periods of O2 breathing interspersed with short air breaks, a gradual depressurization to 1.9 ata, a prolonged stage at 1.9 ata, and a gradual decompression to the surface during which time the tender also breathes O2. The total duration of the table is 4 h and 45 min, although extensions at 2.8 ata or 1.9 ata can be made as the patient’s condition dictates. This table, as well as all of the other tables published in the U.S. Navy Diving Manual, was developed with divers in mind, but it has been found to be highly effective in treating altitude DCS as well. A closely related table to TT6 is U.S. Navy Treatment Table 5 (TT5) (Figure 11.3) [160]. TT5 differs from TT6 in that the stages at 2.8 ata and 1.9 ata are truncated, yielding a total duration of 2 h and 15 min. This table is intended only for type I symptoms. If all symptoms are

not resolved within 10 min of arrival at 2.8 ata, transition to TT6 is mandatory. TT5 can also be used for follow-up treatments of residual disease. Notably, TT5 has the reputation of failing to prevent recurrence of symptoms after an apparently successful initial treatment [161], although good results have been reported [162]. Most practitioners prefer to do a full TT6, if they are going to do a dive at all, and “get it over with.” Nevertheless, TT5 might still be considered in treating equivocal or very mild cases, but the practitioner should be prepared for retreatment at odd hours. The ultimate in truncation of TT6 is the so-called test of pressure, which involves compression to 2.8 ata while breathing O2 as a means of differentiating type I symptoms from nondysbaric forms of musculoskeletal pain such as trauma. The approach concludes that if symptoms are alleviated by pressure, DCS is present and TT5 or TT6 is indi-

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cated; but if symptoms are totally unchanged, DCS is not present and further hyperbaric therapy is not warranted. Unfortunately, clinical practice is rarely so straightforward. Symptoms that may be equivocal to begin with are often reported at depth to be “maybe a little better.” It therefore usually seems prudent to give the patient the benefit of the doubt and to proceed with more definitive treatment. The U.S. Navy Diving Manual reflects this approach—for divers, at least—by stating that “once recompression to 60 ft is done, Treatment Table 5 will be used even if it was decided symptoms were probably not decompression sickness. Direct ascent to the surface is done only in emergencies.” The ultimate in extension of TT6 is the Catalina table [163]. In it, the stages at 2.8 ata and 1.9 ata are greatly prolonged, with up to 8 O2-to-air cycles at 2.8 ata and 18 cycles at 1.9 ata. The Catalina table is used primarily for patients who continue to have serious disease after completing the stages at 2.8 ata or 1.9 ata in a TT6, or for patients who show decompensation during depressurization from one of these stages. As might be expected, considerable O2 stress is imposed on pulmonary tissues by this exposure. These four tables (TT6, TT5, test of pressure, and Catalina table) constitute the core of hyperbaric treatment tables for DCS. TT6 is used to initially treat the vast majority of cases. Unfortunately, some patients do not respond completely to the first HBO treatment. For these patients, additional “tailing treatments” can be performed. The choice of the specific table used for tailing treatments depends on many factors, including the severity of symptoms, the “trajectory” of the clinical course (e.g., rapid improvement, rapid decompensation, stubbornly stable, etc.), the pulmonary status, the fatigue of the chamber crew, the availability of tenders, and local custom. The range of responses extends from an immediate initiation of a TT6 to daily TT5s or, even more simply, to a 90-min excursion to 2.4 ata while breathing O2 on a “25 min on, 5 min off” basis. Lengthy treatment programs have been reported in the diving literature, some including over 30 individual daily dives [164]. Precisely when to terminate further tailing treatments is unclear. A consensus may be developing among practitioners, however, that further improvement is unlikely if no change is observed over the course of two or three tailing treatments [165]. Many other treatment tables exist, but these have little or no applicability to altitude DCS except perhaps for the U.S. Navy Treatment Table 7, which might, in the words of the U.S. Navy Diving Manual, be used as a “heroic measure” to treat a life-threatening disease that worsens when decompression during treatment is attempted. These more “exotic” tables are useful in treating divers who have been exposed to environmental conditions far afield from those of the aviator or spacewalker, such as very deep, very prolonged He/O2 dives. Tables are also available to perform hyperbaric therapy if O2 is unavailable (air is breathed throughout), but these are less likely to cure the patient than TT6 and are more likely to induce DCS in the patient’s tender [157]. The reader is referred to comprehensive sources

W.T. Norfleet

such as the U.S. Navy Diving Manual [160] and the National Oceanic and Atmospheric Administration Diving Manual [166] for additional information on these tables as well as on treatment algorithms that can be used for table selection.

Adjunct Therapy An important part of treating any case of DCS is providing fluids to maintain intravascular euvolemia. Hemoconcentration occurs commonly in DCS [39], as does extravasation of plasma. Fluids should be provided by conventional clinical methods, with recognition of the fact that catheterization of the urinary bladder will be necessary in some cases of type II DCS. A case could be made for excluding glucose from intravenous fluids administered to patients with neurologic involvement [167]. In addition to pressure, O2, fluids, and supportive care, many adjunctive therapies have been investigated [41]. A truncated list of these therapies includes lidocaine [123,168,169], corticosteroids [170,171], perfluorocarbons [172], aspirin, and dipyridamole [173,174]. That at least some of these interventions should be effective is a reasonable hypothesis that is backed by laboratory findings and some clinical case reports. However, their clinical efficacy in treating DCS has yet to be definitively established. Perhaps, in the future, as we learn more about the pathophysiology of DCS, the beneficial effects of hyperbaric O2 will be reproduced by other agents, and some or all cases of DCS will be treated solely with methods that do not involve cumbersome hyperbaric chambers.

Treatment in Space Flight Given the substantial decompression stress involved in Space Shuttle and International Space Station operations, some DCS associated with EVAs seems inevitable, although the magnitude of this risk is unclear. Laboratory investigations indicate that most cases will be mild [64,136,137]. Indeed, mild type I DCS might not even be recognized by a crewmember given the discomfort of the space suit, the focus of the crewmember on the task at hand, and the fact that analgesic drugs are used before and after EVAs [175]. However, serious DCS, including cardiovascular instability and severe cognitive impairment, has been observed during laboratory studies, even though subjects were carefully monitored for the onset of such disease and were rapidly and definitively treated when illness was detected [176] (JM Waligora, personal communication). Consequently, a small but real risk of serious DCS seems to exist in current spaceflight operations. If hyperbaric treatment of altitude DCS is delayed, the efficacy of hyperbaric therapy is reduced [177]. To prevent such delays, Space Station Freedom (which was cancelled in 1992) included a structure that was designed to function both as an airlock and a multiplace, monolock hyperbaric treatment chamber. This on-site treatment capability would have afforded the station crew many advantages, among them the ability to halt the progression of disease at an early stage, to effect a cure with a single treatment, to avoid the costs of an evacuation, to reduce the requirement for oxygen “prebreathing”

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Treatment Table 5 1. Descent rate - 20 ft/minute 2. Ascent rate - not to exceed 1 ft/minute. Do not compensate for slower ascent rates. Compensate for faster rates by halting the ascent. 3. Time on oxygen begins on arrival at 60 feet. 4. If oxygen breathing must be interrupted because of CNS Oxygen Toxicity, allow 15 minutes after the reaction has entirely subsided and resume schedule at point of interruption (see paragraph 21-5.5.6.1.1). 5. Treatment Table may be extended two oxygen-breathing periods at the 30foot stop. No air break required between oxygen-breathing periods or prior to ascent. 6. Tender breathes 100 percent O2 during ascent from the 30-foot stop to the surface. If the tender has a previous hyperbaric exposure in the previous 12 hours, an additional 20 minutes of oxygen breathing is required prior to ascent.

Figure 11.3. U.S. Navy Treatment Table 5. From the U.S. Navy Diving Manual [160]

until inconvenient forms of DCS appear without unduly risking the eruption of catastrophic forms of disease, and, finally, to return the crew promptly to full duty status, operating under a “treat it and forget it” philosophy. Indeed, accrual of similar benefits is the rationale for the requirement by organizations such as the U.S. Navy and he U.S. Occupational Safety and Health Administration for on-site hyperbaric chambers when stressful diving profiles are being undertaken. The International Space Station includes no such hyperbaric capability. The equivalent of GLO can be provided by keeping the patient in his or her space suit. Also, delivery of nearly 100% O2 at a pressure as great as 1.54 ata is possible through ‘overpressurization’ of the EMU with installation of the bends-treatment apparatus in the space suit [178]. If a crewmember requires hyperbaric therapy, however, evacuation to a terrestrial facility via a highly exotic and extremely expensive mode of transport will be the only option, a process that may require in excess of 24 h, particularly if landing does not take place within easy reach of a modern medical center (as discussed in Chap. 7). Given the time required for transport, the decision to evacuate a patient will need to be made early and easily to decrease the risk of the disease progressing into its permanently disabling or lethal forms.

Disposition and Return to Duty Decisions about whether an individual can resume duties that require re-exposure to decompression stresses are complex. A host of issues, both scientific and social, are involved. Since regulations established by the U.S. armed forces for the return of pilots and divers to duty vary enormously, cases are often referred to a medical certification board that considers them on a case-by-case and therefore somewhat arbitrary basis. NASA has developed a document that establishes its policy for return of aircraft and spacecraft crews to duty after DCS and AGE events [179] (Table 11.5). These criteria are not necessarily the best, but they are the most contemporary attempt to strike an effective compromise among the many conflicting concerns at work in these situations.

Arterial Gas Embolism Only a thumbnail sketch of the pathophysiology and treatment of AGE is presented here because AGE occurs rarely in the aerospace environment, generally in the setting of a rapid depressurization. The problem is of much greater concern in

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TABLE 11.5. Medical status after decompression-related events. Situation

Time to duty

Time to reduced pressure exposure

Medical evaluation and status

Minor DCS (type I)

24 h after resolution of symptoms.

Aircraft/Chamber Operations/ Immersion Facilities: MO/FS evaluation. AMB review not required. Space flight: CMO evaluation and PMC as soon as practical. AMB review not required.

Minor DCS repetitive event (type I)

24 h after resolution of symptoms.

Aircraft/Chamber Operations/ Immersion Facilities: 72 h after resolution of symptoms. Spaceflight: 72 h if symptoms resolve upon repressurization, otherwise 7 days after symptoms resolve. Case-by-case consideration. AMB review required.

Serious DCS (type II)

48 h after resolution of symptoms.

Case by case consideration. AMB review required.

Arterial gas embolism

Case-by-case consideration.

Case-by-case consideration. AMB review required.

Aircraft/Chamber Operations/Immersion Facilities: MO/FS evaluation. Space flight: CMO evaluation and PMC as soon as practical. All require AMB waiver for return to reduced-pressure environments. Aircraft/Chamber Operations/Immersion Facilities: MO/FS evaluation. Space flight: CMO evaluation and PMC as soon as practical. All require AMB waiver for return to duty and reduced-pressure environments. Aircraft/Chamber Operations/Immersion Facilities: MO/FS evaluation. Space flight: CMO evaluation and PMC as soon as practical. All require AMB waiver for return to duty and reduced-pressure environments.

Repetitive Event—Subject has incurred a Type I or II DCS event within the past 30 days for ground-based exposure. For spaceflight operation, repetitive event is a more than one Type I in a given mission. This table above summarizes JPG 1800.3 and covers all personnel for aircraft operations, immersion facilities, chamber operations, and spaceflight. The current astronaut selection/retention policy is outlined in JSC-24834, “Astronaut Medical Standards.” Mild Decompression Sickness DCS (Type I): symptoms involving joint pain, peripheral nervous system, or simple skin bends. Mild Decompression Sickness DCS (Type I)—Repetitive: symptoms involving joint pain, peripheral nervous system, or simple skin bends which have occurred previously within the past 30 days for ground-based exposure or with in a single flight for spaceflight operation. Serious DCS (Type II): symptoms involving the central nervous system, cardiovascular system (circulatory collapse/shock), pulmonary system (chokes), or skin marbling. Arterial Gas Embolism: evolved gas producing symptoms and signs consistent with passage of the gas to the arterial circulation; i.e., severe neurological manifestations. All medical data relating to a decompression disorder will be kept confidential and consistent with the Privacy Act. Current definitions are clinically based on, and consistent with, commercial and military diving and aviation policies. No administrative decision on flying duties will be based on Doppler-detectable bubbles. All in-flight DCS events that do not resolve with available treatment options, as well as complicated type II events, may be grounds for medical return and mission termination. Abbreviations: DCS, decompression sickness; MO, medical officer; FS, flight surgeon; CMO, crew medical officer; PMC, private medical conference; AMB, aerospace medicine board.

diving and in some clinical practice settings, such as in cardiopulmonary bypass and laparoscopy. Additional information can be found in an excellent review of AGE treatment by Moon and Gorman [180].

Pathophysiology If a person is exposed to a reduction in ambient pressure, intrathoracic gas expands as described by Boyle’s law. If the gas is not vented from the thorax as intrathoracic gas enlarges (e.g., if the subject closes his or her glottis or if the decompression is extremely rapid), lung volume will increase. As lung volume exceeds total lung capacity (and, in some persons, at lesser volumes) [181], structural failure of lung tissue occurs. This releases gas from the alveoli, a

process known as “volutrauma [182–184].” Free gas can track through tissue planes into the mediastinum, where it produces mediastinal emphysema; into subcutaneous tissues, especially those superior to the clavicles, where it generates subcutaneous emphysema; into the pleural space, where it results in a pneumothorax; or into the intravascular space, where it gives rise to AGE. Intrathoracic trauma is often described as arising from pulmonary overpressurization, but this is not strictly true; for example, an anesthetized, intubated, and paralyzed dog that has its thorax “splinted” with thoracic and abdominal binders (to limit lung expansion) can tolerate much higher intrathoracic pressures than a dog without binders [185]. This makes sense because transalveolar pressure gradients are determined by the elastic recoil of the lungs, not by intrathoracic pressure.

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

Hence, it seems that overexpansion of the lungs is what does the damage, not overpressurization. The interaction of arterial gas emboli with tissue capillary beds is complex. Much experimental work has focused on the effects of bubbles in the brain. These bubbles can clear from brain vasculature surprising quickly, but many abnormal tissue responses remain [91,96,186–188]. Any capillary bed is subject to embolization, including cerebral, coronary, and spinal tissues. Under the right circumstances, a combination of AGE and DCS can occur. Although AGE usually has an identifiable cause, such as breath-holding during decompression, not all cases are “deserved.” This is particularly true during submarine escape training operations in which divers make carefully supervised free ascents. Occasional cases of AGE occur despite the performance of thorough qualifying physical examinations and the use of proper technique throughout ascent [185,189]. AGE must therefore always be part of the differential diagnosis when evaluating a patient that has become ill after a decompression.

Clinical Presentation Neurologic dysfunction occurring minutes after a decompression is the hallmark of AGE [190]. In 41 cases of pure AGE (i.e., with little coexisting inert gas burden) presenting as sudden loss of consciousness, collapse took place within the first minute after surfacing in 33% of the patients and within 5 min in 100% of the patients [191]. Other associated signs and symptoms may include hemoptysis, respiratory distress or cardiovascular collapse from a pneumothorax, supraclavicular crepitus from subcutaneous emphysema, and hoarseness from mediastinal emphysema (Table 11.6) [105]. Other etiologies that are associated with aerospace operations include hypoxemia (secondary to, for example, loss of O2 supply or loss of ambient pressure), contaminated breathing gas, and DCS. Diagnosis is based largely on history and physical examination, because no single laboratory test is definitive; for example, a chest radiograph may be normal despite clear evidence of AGE [192].

Clinical Course and Treatment Some cases of AGE undergo complete clinical resolution without treatment. Although 21% of AGE cases reported by Leitch and Green resolved completely and permanently without therapy [193], rapid administration of ground-level O2 is clearly beneficial [68]. The longstanding recommendation that, during transport to a chamber, patients should be maintained in the 30-degree Trendelenberg position with left-lateral tilt probably does no good and may worsen elevated intracranial pressure [194,195]. HBO is indicated, although controversy exists regarding the best treatment table for AGE. Traditionally, U.S. Navy Treatment Table 6A (TT6A) has been used. This table is similar to TT6 except that an initial excursion to 6 ata is included in it.

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TABLE 11.6. Signs and symptoms in scuba-related gas embolism. Sign/symptom

% of cases

Loss of consciousness Extremity paresis Seizure Extremity numbness Vertigo Mediastinal emphysema Nausea and vomiting Chest pain Subcutaneous emphysema Aphasia Blindness Cognitive impairment

70 54 38 31 31 23 23 15 15 8 8 8

Source: Heimbach & Sheffield [105].

Some laboratory studies indicate that TT6 may be as good as or perhaps better than TT6A for AGE [196]. This thinking is reflected in the current version of the U.S. Navy Diving Manual [180], which calls for all patients to be compressed initially to 2.8 ata (i.e., to begin TT6), with deeper excursion on a TT6A reserved for patients who do not improve within 20 min at 2.8 ata. Therefore, selection of TT6 for the initial treatment of AGE is justifiable. As with DCS, a wide variety of potentially useful tables exist for AGE cases that do not respond to TT6 and TT6A, especially for patients who decompensate during the large decompression from 6 ata to 2.8 ata in TT6A. The recommendations concerning administering O2, fluids, and supportive care that were described above for the treatment of DCS also apply to AGE. In fact, the case for adjunctive therapies such as corticosteroids, lidocaine, and others, is much stronger in AGE than in DCS, although the use of such agents is not yet considered the standard of care [180,193,195].

Disposition and Return to Duty Disposition and return to duty issues for AGE are handled much as they are handled for DCS. Certainly, the cause of any “undeserved” AGE episode such as undiagnosed bronchospastic disease or an anatomic pulmonary abnormality should be sought, and the implications of any new revelations on fitness for further exposure to pressure excursions should be considered. Truly undeserved AGE may be cause for disqualification from future “pressure work.”

Ebullism Syndrome This brief discussion of the ebullism syndrome focuses on three major points: (1) that the syndrome is not just a particularly severe form of DCS but has its own unique qualities; (2) that humans may be able to survive exposure to hard vacuum

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for a few minutes; and (3) that modest efforts to prepare treatment plans for the ebullism syndrome are not entirely futile.

Pathophysiology The ebullism syndrome arises when an individual is exposed to an ambient pressure that is less than the vapor pressure of body fluids at normothermic temperature, about 6 kPa [197]. Whereas DCS is primarily characterized by the formation in tissues of the gas phase of inert gas, ebullism is characterized by the formation of the gas phase of water. Consequently, O2 prebreathing, no matter how extensive, cannot prevent the syndrome since it will arise even when the body is devoid of dissolved inert gas. During exposure to near-vacuum, bubbles form in all body structures including all tissues, cavities, and potential spaces such as the pleura. However, local tissue hydrostatic pressure may limit or eliminate water vapor formation; for example, for as long as blood pressure remains normal, the pressure of arterial blood will remain above 6 kPa, thus preventing water vapor formation. Tightly wrapping an extremity may prevent vapor formation within that extremity. On the other hand, normal central venous pressure is only slightly above ambient pressure, so bubble formation occurs readily within the venae cavae, obstructing venous return to the heart [198]. Indeed, cardiac output has been observed to virtually cease within 15 s after animals are exposed to near-vacuum [111,199]. Since pleural pressure is negative relative to ambient pressure, vapor forms rapidly within this potential space. Similarly, vapor formation readily occurs in the ocular conjunctivae and the epithelium of the airways—a phase transition that cools these structures. Bubble formation is not instantaneous, and tissues can tolerate extreme hypobaric pressures for some time [199]. Significantly, exposure to near-vacuum was required for 90 s before substantial pulmonary damage occurred in dogs [90]. Similarly, bubble resolution is not instantaneous upon recompression. Once a bubble forms, gases dissolved in the fluid surrounding the bubble will diffuse into that bubble until all partial pressures are equalized [198]. Bubbles consequently will contain water vapor, O2, CO2, and a quantity of N2 that depends on the state of inert gas elimination from the body at the time of extreme depressurization. Reversal of this process upon repressurization takes time. Therefore, an individual exposed to near-vacuum may be burdened with substantial quantities of intravascular gas after repressurization. The amount of inert gas dissolved in the tissues at the time of the excursion seems to be an important determinant of the time course of bubble resolution and the degree of tissue damage that occurs. For example, pulmonary edema is less and survival is greater in animals that are denitrogenated before depressurization [90]. Animal studies indicate that the pulmonary system is particularly affected in the ebullism syndrome. The formation of water vapor within alveoli during decompression followed

W.T. Norfleet

by the collapse of this vapor upon repressurization leads to massive atelectasis that greatly impedes pulmonary gas exchange. Reestablishing pulmonary function is consequently a priority in the treatment of the disorder. This type of pulmonary damage is not typical of DCS, so the treatments of the ebullism syndrome and DCS are not identical. Additional features of the syndrome include anoxia throughout the excursion below 6 kPa, probable coincident DCS, and possible AGE from pulmonary volutrauma, particularly if the decompression was “explosive [200,201].” The length of time that humans can be exposed to extreme hypobaric conditions without morbidity or mortality is unknown. To date, published laboratory studies with animals have limited applicability to this question because the animals usually received little or no treatment after exposure. For what it is worth, 14 of 15 dogs in one study survived an exposure to near-vacuum for 2 min without an O2 “prebreathe [111].” In another study, all ten dogs survived exposure to near-vacuum for 2 min with little O2 prebreathe [202]. In another study, 17 chimpanzees that were trained to perform complex tasks were exposed to near-vacuum for up to 210 s after 4 h of denitrogenation; 16 of the chimps survived, and none of the survivors showed performance decrements [203]. Finally, in another of the more rigorous studies of the ebullism syndrome, Bancroft et al. [202]. showed that exposure to hard vacuum was a much greater physiological insult than was breathing 100% N2 at 1 ata for an equivalent time. Two human exposures to near-vacuum have occurred. In an accident in an industrial vacuum chamber, an individual was rapidly decompressed without preoxygenation from sea level to less than 4 kPa ambient pressure and was maintained at near-vacuum for 3–5 min [204]. Although this person had a stormy clinical course that required intensive care, bilateral chest tubes, and multiple HBO treatments, he eventually recovered completely. The other incident involved testing a pressure suit at the Johnson Space Center during the 1960s. The failure of a hose fitting resulted in very rapid depressurization (after extensive O2 prebreathing) from about 25 kPa to less than 4 kPa. The subject of this depressurization recalled feeling the saliva on the tip of his tongue begin to boil as he slipped into unconsciousness. Repressurization was accomplished immediately, and the subject went home for lunch.

Clinical Presentation, Clinical Course, and Treatment The clinical picture of the ebullism syndrome includes severe cerebral anoxia, pulmonary atelectasis, cardiovascular collapse, venous gas embolism, AGE, DCS, and possibly pneumothorax and various forms of barotrauma. The probability of survival seems to fall off rapidly as the duration of exposure increases on a time scale measured in seconds rather than minutes. Obviously, rapid repressurization is critical. But beyond this, the optimum therapy for the ebullism syndrome

11. Decompression-Related Disorders: Decompression Sickness, Arterial Gas Embolism, and Ebullism Syndrome

has not yet been established. Clearly after repressurization, reestablishing pulmonary function will be a priority with emphasis on reversing atelectasis and decompressing any tension pneumothorax. Supportive care and fluids are to be given as needed, and HBO may be helpful. Two humans and many experimental animals have survived exposure to near-vacuum for several minutes, so aggressive therapy is not necessarily a futile gesture.

Disposition and Return to Duty Given the rarity of the ebullism syndrome, little can be said with confidence regarding disposition and return to duty after exposure. The case may be as simple as the one that occurred at the Johnson Space Center. Conversely, if the patient described by Kolesari and Kindwall [204] had been a spaceflight crewmember, an enormous list of issues would have needed to be addressed. Those who first deliberate over such cases will be writing the book on the subject.

Conclusions Decompression illness is a risk in EVA operations. Specifically, all EVA protocols currently approved for Shuttle and ISS operations carry a reasonable possibility of serious DCS. The absolute magnitude of this risk is a matter of uncertainty and debate, but the existence of a real risk seems clear. This chapter was written in an attempt to provide guidance to practitioners of space medicine confronted with a patient with decompression illness and to aid practitioners who participate in operational planning as they address issues related to decompression illness. The principles of operational risk management are useful in such deliberations;—namely (1) identify risk, (2) mitigate risk, (3) whenever possible, eliminate risk, and (4) accept no unnecessary risk [205]. Consequently, this chapter has outlined what causes the various forms of decompression illness, what harm it can cause the patient, how it can be treated, and how the occurrence of cases of it can be reduced or, in some instances, eliminated.

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12 Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness Jonathan B. Clark

The physiological zone from sea level to 3,048 m (10,000 ft) encompasses the pressure to which humans are well adapted, although if appropriately acclimated they can survive the summit of Earth’s highest mountain (Mt. Everest at 4,448 m/29,028 ft) without supplemental oxygen. Continuing to altitudes above this, artificial systems are required to supply needed oxygen and, eventually, sufficient ambient pressure. The most effective means of preventing physiological problems in aircraft and spacecraft is to provide cabin pressurization so that occupants are never exposed to pressures outside the physiological zone. Failure of structures, hardware, or procedures may unfortunately lead to unwanted and hazardous decompression events. This chapter will review cabin pressurization schemes, events that might lead to loss of pressure, and two major medical concerns of decompression: barotrauma and altitude sickness.

Cabin Pressurization Human aircraft and spacecraft occupants may be maintained in rarefied atmospheres with personal support equipment such as supplemental oxygen systems and pressure suits. However, the risk of hypoxia and decompression-related disorders may also be mitigated by pressurizing the habitable cabin volume. This eliminates the need for personal supplemental oxygen, allowing crew and passengers to move freely unencumbered by oxygen masks and hoses or other life support equipment. The incidence of trapped gas effects (pain in gastrointestinal tract, middle ear, and sinuses) is reduced by smaller cabin pressure changes that are controlled and predictable during ascent and descent. In addition, cabin temperature, humidity and ventilation can be controlled within desired comfort levels. Prolonged passenger flights, air evacuation, and troop movements can be accomplished with a minimum of fatigue and discomfort. There are structural and operational disadvantages to cabinwide pressurization. An increased weight of the pressure vessel is typically required to maintain structural integrity, which

limits maximum performance and payload capacity. Additional maintenance, equipment, and power are required to support the environmental control system. Finally, recirculation of cabin air might foster the spread of combustion products, contaminants, infectious particles, and odors throughout the cabin atmosphere.

Methods of Maintaining Cabin Pressure The two main modalities of maintaining pressure greater than ambient involve the conventional cabin and the sealed cabin. The conventional method for increasing aircraft cabin pressure is to use ambient air, forced into the cabin by means of a compressor. Cabin pressure and ventilation are maintained by varying the amount of air introduced into the cabin and the amount released through adjustable outflow valves. A high differential requires an aircraft structure that is physically stronger and therefore heavier than that required for a lower differential. Cabin pressurization represents an engineering and physiologic tradeoff; the increased structural weight decreases the payload carrying capacity of the aircraft. Pressurization requires energy expenditure in the form of bleed air from the compressor stage of the jet turbine engine. The larger the differential, the more power required to provide the desired pressure and less power available for aircraft thrust. Conventional cabin pressurization utilizes two types of pressurization schedules, the isobaric and the isobaric-differential schemes. Isobaric control refers to the condition where the cabin pressure is maintained at a constant altitude or pressure regardless of the ambient pressure decrease, after a certain altitude is reached. This pressurization system is found in most cargo and passenger air transport aircraft, which typically maintain a cabin pressure equivalent to 2,438 m (8,000 ft) altitude throughout flight. Tactical jet aircraft are equipped with an isobaricdifferential pressurization system. This pressurization system senses both cabin and ambient pressure and maintains the cabin pressure on the basis of a fixed pressure differential. Tactical jet aircraft typically maintain a 5 psi isobaric-differential pressur247

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ization schedule. As the aircraft ascends, the cabin is depressurized to 2,438 m (8,000 ft) altitude. From this altitude to approximately 7,010 m (23,000 ft), cabin pressure remains at 2,438 m equivalent altitude (isobaric range). From 7,010 m up to the operating ceiling of the aircraft, cabin pressure is maintained at a pressure differential of 5 psi above ambient. If an aircraft is flying at an altitude of 12,192 m (40,000 ft), with an outside pressure of 2.72 psi, the aircraft pressurization system will maintain a pressure of 7.72 psi, or 5,029 m (16,500 ft) as the equivalent cabin altitude. In the increasing rarefied altitudes above 24,380 m (80,000 ft), cabin pressurization cannot be maintained by the conventional method delivered by a jet turbine engine. At these very high altitudes, the ambient air is so thin the jet engine does not receive sufficient air for compression; compressor turbine blades stall, and pressurization fails. At this point, sealed cabins must be used to maintain an adequate habitable environment. This sealed cabin system is utilized at extremely high altitudes and in the vacuum of space. Pressurized gas is carried on the aircraft or spacecraft and metered into the pressure vessel of the habitable space. In this closed system, metabolic byproducts are removed and the cabin gas is recirculated to conserve the gas supply. Before space flight, very high altitude experimental aircraft such as the X-15 used this scheme.

J.B. Clark

Spacecraft Pressurization: The U.S. Shuttle The Atmosphere Revitalization Pressure Control System (ARPCS) controls the Space Shuttle crew cabin pressure to 14.7 psia, +/− 0.2 psia, with an average of 80% nitrogen and 20% oxygen mixture. Oxygen partial pressure is maintained between 2.95 psia and 3.45 psia, with sufficient diluent nitrogen added to achieve a cabin total pressure of 14.7 psia. The orbiter crew compartment provides a life-sustaining environment for a crew of up to eight. The crew cabin volume with the airlock inside the middeck is 65.8 m3 (cubic m) (2,325 ft3); if the airlock is located outside of the middeck in the payload bay, a recently added modification option, the crew cabin volume expands to 74.3 m3 (2,625 ft3). For extravehicular activity requirements, only the airlock is depressurized and repressurized. The pressurization system consists of two gaseous oxygen and two gaseous nitrogen systems, as shown in Figure 12.1. The two oxygen systems are supplied by a cryogenic supercritical oxygen storage system, which also supplies oxygen to the orbiter’s electrical power-generating fuel cells. For normal on-orbit operations, one of two oxygen and nitrogen supply systems is used, while both are used for the more time-critical launch and entry phases. The primary and secondary oxygen and nitrogen gas supply systems have a crossover capability to provide partial system redundancy in case of failures. These

FIGURE 12.1. Schematic of the Space Shuttle pressure control system. Cryo = cryogenic, Cab = cabin, N2 = nitrogen, Emer = emergency, O2 = oxygen, LEH = launch and entry helmet, psi = pounds per square inch, EMU = extravehicular mobility unit, reg = regulator, tk = tank

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

systems provide the makeup cabin oxygen gas consumed by the flight crew, as well as nitrogen for pressurizing the potable supply water and waste water tanks and repressurizing the airlock following EVA. An average of 0.8 kg (1.76 lb) of oxygen is consumed per flight crewmember per day. Up to 3.5 kg (7.7 lb) of nitrogen and 7.3 kg (15 lb) of oxygen are used per day to make up normal loss of crew cabin atmosphere to space and metabolic usage. The cabin atmosphere caution and warning light is illuminated for cabin pressure below 13.8 psia or above 15.4 psia, ppO2 below 2.7 psia or above 3.6 psia, oxygen flow rate above 5 lb per hour, or nitrogen flow rate above 5 lb per hour. An alarm will sound if the pressure decreases at 0.08 psi per minute or greater, indicating a dangerous cabin leak. The normal cabin pressure loss rate (dP/dT) is 0 psi per minute, plus or minus 0.01 psi, for nominal operations; that is, the small leak rate is well below the detection threshold for the caution and warning system. Two cabin relief valves in parallel provide overpressurization protection of the crew module above 16 psi differential (psid). The positive pressure relief valve opens at 16 psid and re-seats at 15.5 psid. About 1 h and 30 min before lift-off, the crew module cabin is pressurized to approximately 16.7 psi to check for leaks in the crew cabin and to assess relief valve function. Should the crew cabin pressure ever become lower than the pressure outside the crew cabin, as might occur during a rapid descent, two negative pressure relief valves in parallel will open at a differential of 0.2–0.7 psid, permitting flow of ambient pressure into the crew cabin.

Decompression Decompression is a serious concern in space and is one of the three emergency (Class I) alarms on the International Space Station (ISS); the other two are fire and toxic atmosphere. Decompression alarms prompting emergency crew action sound when a pressure differential of greater than 1.0 psi/hour is detected and the pressure drops 0.4 psi (21 mmHg). Cabin depressurization may be part of nominal procedures, such as staged decompression of the cabin prior to an EVA, depressurization of the airlock to final EVA suit pressure, or cabin equalization following atmospheric reentry. Contingency depressurization can result from structural penetration from a collision with orbital debris or a micrometeoroid, structural failure of a valve, module, or seal, collision with an approaching spacecraft, or procedural error. Because of the pervasive risk of orbital debris impact and the complexity of determining risk and minimizing damage of associated hypervelocity impacts, a detailed discussion on this topic is warranted.

Orbital Debris Orbital debris is composed mainly of derelict spacecraft and upper stage launch vehicles, payload carriers, debris from upper stage explosions or collisions, solid rocket motor effluents, and

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tiny flecks of paint released by thermal stress or small particle impacts. Objects greater than 10 cm in diameter are referred to as large objects and are routinely detected and tracked from the ground and cataloged for comparison with viable spacecraft orbits. Objects between 1 and 10 cm in diameter may be detectable but are not large enough for tracking and avoidance maneuvers. These are referred to as risk objects; they carry sufficient kinetic energy to inflict major structural damage on manned spacecraft. Over 9,000 objects larger than 10 cm are known to exist in earth orbit, and estimates for the number of particles between 1 and 10 cm in diameter are greater than 100,000. Objects smaller than 1 cm in diameter are most commonly referred to as small debris or microdebris. The number of particles smaller than 1 cm probably exceeds tens of millions. Orbital debris fragments are typically composed of aluminum (density 2.78 g/cc3) with an average size of 0.5 mm in diameter. The estimated mass of synthetic objects orbiting within 2000 km of the Earth’s surface is about 2,000,000 kg. These objects are in mostly high inclination orbits and pass one another at an average relative velocity of 10 km/sec (about 22,000 mph). In contrast to spacecraft debris, natural meteoroid flux is much lower, with only about 200 kg of meteoroid mass within 2000 km of the Earth’s surface at any given time. Meteoroid mass consists mainly of particles averaging 0.1 mm in size with a density of 0.5 gm/cc3, traveling at a greater velocity of 20 km/s. The trajectories of large orbital debris objects may be determined and are tracked routinely by the U.S. Space Surveillance Network (SSN) using ground based radars and optical telescopes. This allows for planned avoidance maneuvers for propulsive spacecraft to avert collisions. Although groundbased optical systems are intended for tracking satellites above 5000 km, they are capable of detecting orbital debris at lower altitudes with a resolution of about 5 cm at 500 km altitude. The Haystack Radar is able to obtain statistical data on debris flux for particles 1 cm and larger at 500 km altitude. The Goldstone Deep Space Network radars are capable of detecting 2 mm objects at 1000 km altitude, although their primary mission is to monitor deep space probes. Optical systems have fields of view ranging from 1 to 6 degrees while the most sensitive radars (Haystack and Goldstone) have fields of view of a few hundredths of a degree. The lifetimes of satellites and debris in Earth-orbit are a function of altitude (atmospheric density) and ballistic coefficients. The denser the object, the less the object will react to atmospheric drag. An object with a large area and low mass (e.g. aluminum foil) will decay much faster and have a shorter orbital life than a fragment with a small area and a high mass (e.g. ball bearing). Satellites in circular orbits at altitudes of 200–400 km reenter the atmosphere within months unless reboosted. At 400–900 km orbital altitudes, orbital lifetimes range from years to hundreds of years depending upon the mass and area of the satellite. The combination of a variable atmosphere and unknown ballistic coefficients of space

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objects makes decay and reentry prediction inexact. During the peak solar cycle, occurring every 11 years, greater atmospheric drag and enhanced natural decay rates occur as increased solar activity heats and expands the Earth’s upper atmosphere. With this heating, the upper atmosphere density increases below 600 km, causing orbits of satellites and debris to decay more rapidly depending on altitude and size. Orbital debris from fragmentation may result from explosion or collision between orbital objects [1]. Explosive mechanisms include catastrophic failure of internal components (such as batteries), propellant-related explosions (high energy explosions), failure of pressurized tanks (low energy explosions), and intentional destruction. Low energy explosions typically produce fewer small objects than high-energy explosions. In LEO, a hypervelocity collision would typically produce many more small objects than a high-energy explosion since the impact and resultant shock wave melts and vaporizes satellite materials. Spacecraft failure due to orbital debris impact has not been definitively documented, although it is the prime suspect in the breakup of Kosmos 1275 based on the size and velocity distribution of the fragments following the breakup. A primary spacecraft design driver is the determination of an acceptable level of risk. The specified level of risk of manned space programs from Apollo to the present has varied

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from .01 to .05 probability of penetration over the lifetime of the space system. The actual level of risk experienced by these spacecraft was significantly less than specified because other design requirements made the spacecraft structurally more robust. Earlier manned space programs only addressed the natural meteoroid environment, while the Space Shuttle and ISS address both the natural meteoroid and the orbital debris environments. The ISS has been designed to protect critical areas against the highest probability particles of 1.4 cm and smaller, which accounts for 99.8% of the debris population. Figure 12.2 illustrates the flux of orbital debris based on particle or fragment size. Flux is much lower as size increases, and it is seen that objects greater than 1 cm in size are largely of artificial origin. The effects of orbital debris collisions depend on velocity, angle of impact, and mass of the debris. Most impacting particles will be the size of grains of sand, which will cause degradation of sensitive surfaces such as optical lenses and solar panels. For example, Russian engineers reported it necessary to replace window covers on the Mir station and to shield its exterior light bulbs due to damage from orbital debris. For debris less than 0.01 cm, surface pitting and erosion are the primary effects. Debris of sizes 0.01–1 cm produce significant impact damage, depending upon system vulnerability and defensive design provisions. For

FIGURE 12.2. The relative populations of orbital debris items based on particle or fragment size, determined as cross-sectional flux per m2 of exposed surface area per year. Orbital debris curve is determined by tracking radars and impact analysis for altitudes between 300 and 600 km. For comparison, the flux of natural material (meteoroids) is shown. The vast majority of objects larger than 1 cm are of artificial origin

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FIGURE 12.3. Impact damage to shuttle nose cone (left) and outer window (right) resulting form orbital debris impact

debris larger than about 0.1 cm, structural damage becomes an important consideration. Objects larger than 1 cm can produce catastrophic damage. It is currently practical in LEO to shield against debris particles up to 1 cm in diameter and a mass of 1.46 g (0.05 oz). For larger debris, shielding becomes impractical due largely to the mass of the shielding material, and the only useful strategy is collision avoidance. Examination of Space Shuttle exterior surfaces has provided direct evidence of small orbital debris impact after each mission [2]. The Shuttle windows leading edges, and radiator panels on the payload bay doors experience impacts that are observable postflight, as evidenced by small pits and craters as seen in Figure 12.3. The Long Duration Exposure Facility, launched and retrieved by the Space Shuttle, remained in orbit for 69 months. On post-landing examination, its surface was covered with more than 32,000 impact craters visible to the unaided eye, the largest being about 0.63 cm in diameter. Analysis indicates that approximately one-half of the larger craters were of orbital debris origin and one-half were meteoroids. Nearly all of the smallest craters are due to orbital debris, primarily aluminum oxide flakes. Risk reduction plans include shielding structures such as optical surface covers against the highest probability impacting particles, and improving collision avoidance maneuvers. For the Space Shuttle, a warning envelope is generated when an object is forecast to enter a volume 25 km ahead or behind and 10 km above, below or to the side of the spacecraft’s projected flight path. When the object is forecast to enter a volume 5 km ahead or behind or 2 km above, below, or to the side, a propulsive collision avoidance maneuver is initiated. Hypervelocity impact testing is used to determine the effects of shape, density, and velocity of impacting particles

on spacecraft systems and to establish impact modeling methods. Although involving velocities of only up to 7 km/sec, one third of typical orbital impact velocities, these models allow analysis of the response of spacecraft to internal shock-wave propagation, material phase change, deformation, perforation, and long-term structural effects. NASA uses a computer model called BUMPER to determine risks of meteoroid and orbital debris impact damage and critical penetration for spacecraft. This applies to overall risk of collision as well as the most likely areas impacted. The forward and side surfaces with respect to the velocity vector (direction of travel) of ISS are exposed to the highest concentration of orbital debris impacts. As such, these areas are designed with the heaviest shielding to increase the protection of crew and critical equipment. The risk of debris impact compromising cabin atmosphere is represented as Probability of No Penetration (PNP) and is defined as the probability of not sustaining a critical penetration over a 10-year lifespan of ISS. The PNP changes with vehicle attitude and its corresponding cross-sectional area with respect to the velocity vector. As ISS is assembled and additional research modules added, more cross-sectional area will be exposed and vulnerable to impact debris and the PNP will decrease. The latest predictions based on BUMPER calculations show a PNP of 0.67 for the 10-year period following first element launch. Assessed PNP calculated for the 15 year lifetime of the ISS is 0.52, equating to a 48% risk of penetration. Most of these events would involve subacute pressure losses that will be amenable to recovery procedures, such as sealing off the affected module. In contrast, the chance of station evacuation due to a more devastating meteoroid or debris collision over the 15-year lifetime of ISS is estimated at 15%. Penetration hazards may be divided into three major threats to the vehicle and crew: hazards due to wall breach, fragmentation,

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and atmospheric compromise [3]. Wall breach hazards include depressurization, cabin atmosphere venting, and structural failure of the pressure vessel. Fragment hazards arise from the primary object (micrometeor or orbital debris) or more likely secondary fragments damaging critical vehicle components or injuring crew. Atmospheric hazards include shock wave overpressure (blast), temperature, and flash effects. Loss of vehicle attitude control could occur with a new directional propulsive force stemming from cabin atmosphere venting, depending on size of breach (thrust) and location with respect to center of spacecraft mass (moment arm). Decompression events in space can range from barely detectable pressure loss to catastrophic events. Cabin decompression occurred with the collision of a Progress cargo vessel with the Mir space station during the Mir-24 mission in 1997. In this instance, the crew quickly isolated the leaking module from the remainder of the station and continued the mission. A more devastating event occurred with the decompression of the Soyuz 11 capsule on reentry due to a procedural error, resulting in the deaths of cosmonauts Dobrovolsky, Volkov, and Patsayev in 1971. In this case, the crew did not have adequate access to isolate the leak. Survivability of the pressure vessel is crucial; closely related to survivability is the concept of redundancy. Redundant systems are physically separated on a spacecraft, allowing damage to one or more systems while still allowing the spacecraft to continue functioning. The optimum protection system includes the best combination of shielding, mission design, operations, and redundancy on the basis of expected safety benefits, weight requirements, spacecraft reliability, performance levels, and costs. Recent advances in material science, such as composites, ceramics, fabrics, and layered materials, have allowed new methods of constructing spacecraft pressure vessels that may be more resilient to impact damage and catastrophic failure. These advanced materials could also produce less secondary hazard debris and could capture collision products. Decompression also represents a significant threat during Extravehicular Activity (EVA), where the margin for mishap is extremely narrow. Suit failure, accidental puncture, or collision of hypervelocity micrometeoroid debris may result in catastrophic loss of pressure in the Extravehicular Mobility Unit (EMU) space suit. The EMU operates at 4.3 psi using 100% oxygen. If the EMU suit pressure drops below 3.9 psi, the EMU secondary oxygen pack switches to a purge mode to maintain a survivable internal pressure. This pressure can be maintained for up to 30 min with a hole less than 4 mm diameter, allowing for translation back to the airlock. A hole greater than 4 mm diameter is considered critical, as the ability of EMU life support systems to maintain pressure is overwhelmed. Orbital debris objects greater than 0.35 mm in size traveling at 10 km/s will penetrate the EMU suit, and particles over 1.5 mm will likely produce a critical leak. Due to the relatively small cross-sectional area of a suited EVA crewmember and the limited time period for EVA sorties, the risk of a collision

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resulting in a critical penetration is relatively small. Based on orbital debris flux in LEO and the orbital altitude of ISS, the Bumper model has predicted penetration rates during EVA operations of 1 in 3500 for a single 6-h EVA, and 1 in 8 over the projected 2,700 h of EVA during the life of ISS. Odds of a critical leak scenario (>4 mm) are estimated at 1 in 16,800 for a single 6-h EVA and 1 in 38 over the 2,700 h of EVA during the life of ISS. In examining the possible kinetic energy of the impacting particle (1/2 mass times velocity squared), a 1 mm object traveling at 10 km/s would deliver 80 J and may impart an incapacitating injury, and a 1.7 mm particle at 10 km/s would deliver 400 J, potentially causing fatal injuries.

Physical Factors of Decompression Events Decompression may be slow or rapid depending on the inciting event. A slow decompression can occur when a leak develops in a pressure seal between modules. A slow leak may be below the threshold for pressure sensor detection, typically 0.01 psi/min. In such a case, a slow leak would be evidenced by a measured increase over time in consumable gas supplies used to maintain vehicle pressure. If undetected and allowed to progress, a slow leak could result in insidious hypoxia. Rapid decompressions are more dangerous, resulting from a perforation of the pressure vessel or failure of a port, valve, or hatch. In a rapid decompression, occupants are exposed to risk of hypoxia, decompression sickness, ebullism syndrome, gastrointestinal gas expansion, and hypothermia. High velocity and turbulent winds create the possibility of injury by flying debris, impact with cabin structures, or extraction through the breach in the pressure vessel. Factors that influence crew survivability include rate of decompression (hole size), time of useful consciousness (cabin pressure), crew injury or loss at time of decompression, crew reaction time, and crew distribution with respect to hole and escape route. Consequences of rapid cabin depressurization include noise, fogging, temperature change, and flying debris. Rapid air mass movement to a vacuum results in noise ranging from a hiss to a loud explosive bang, hence the term explosive decompression. Sudden decreases in temperature or pressure, or both, reduce the amount of water vapor the air can hold; during rapid decompression water vapor may instantly condense out of the air, appearing as fog. Rapid decompression results in temperature drop, which for an aircraft in the upper atmosphere is followed by equilibration with the colder outside air temperature. Upon decompression, airflow velocity increases as it approaches the hull breach, often with such force that dislodged items are extracted through the opening. Inter-module hatch position may influence crew survival in a cabin depressurization. Hatches on isolatable modules typically remain open on the ISS to allow ease of access during normal operations and rapid egress during a contingency. An open hatch prolongs the decompression time for a given platform by exposing the entire habitable volume to the leak,

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allowing greater mobility in responding to the situation but increasing the duration of venting and subsequent thrusting of the spacecraft. Closed hatches significantly reduce crew efficiency during normal operations and may impede rescue efforts. With catastrophic hull breach however, closed hatches allow improved chance for survival for those in the pressurized segments. The critical issue is the time between inciting event and subsequent decompression to a pressure that is no longer survivable and compared with the time for the crew to respond with emergency procedures. Crew response to a depressurization event centers on isolation of the leaking segment and rescue of injured crew. Two basic rescue strategies are available to the crew of a large space platform. In the heroic rescue, all efforts are expended to recover the injured until the rescuers succumb. In the greater good strategy, efforts continue until the rescuers are jeopardized and the hatches are closed to preserve a survivable atmosphere. Based on computer simulations, the best approach for reducing crew loss from depressurization is leaving hatches open and distributing crew in different modules during sleep. Leak isolation procedures for the ISS are based on a planned hatch closure sequence and monitoring of the rate of pressure change. The decision to abandon or remain on board the spacecraft is based on success of leak isolation efforts and reserve time (time available for crew to respond to troubleshooting the leak). For ISS, evacuation would be initiated when the atmosphere reaches 9.5 psia or the reserve time is less than 15 min. In the course of the initial leak isolation of the Mir station’s Spektr module during the 1997 collision and depressurization event, astronaut Mike Foale roughly determined initial depressurization rate by monitoring his own sensation of Eustachian tube popping. Crewmembers may also use the sound and feel of rushing air to determine leak location and hasten leak isolation.

Factors Controlling the Rate and Time of Decompression The principal factors that govern the total time of decompression for a given breach include the cabin volume, size of the opening, the pressure ratio, and the pressure differential. The decompression time within a larger cabin volume will be longer than that of a smaller cabin. For a given cabin volume, the cross-sectional area of the opening dictates the decompression rate and time. In spacecraft operations, the change in pressure per unit time or rate of pressure change (dP/dt) obtained from downlinked information available in the Mission Control Center (MCC) is used to estimate how long it takes for the cabin to reach a certain pressure. A simple estimate of this time is given by the equation below. This method gives only a close approximation because pressure change is not a linear function from one atmosphere to vacuum, and flow may be influenced by fluid dynamics particular to the shape of the hole.

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Time to reach P2 (minutes) = (P1 − P2)/(dP / dt( (P1 + P2) / 2 × P1) ) P1 (psia) = Initial Cabin Pressure P2 (psia) = Target Cabin Pressure dP/dt (psi/min) = Rate of Pressure Change (at the initial cabin pressure) The pressure of stabilization (POS) is the pressure that can be maintained with a given leak; POS is reached when air mass flow into the habitable volume is equal to air mass flow out. The POS is dependant upon the amount of gas able to flow into the cabin with the pressure regulators and is ultimately limited by the amount of gas available: POS(psia) = (dP / dtin × P1)/(dP / dtout) Where P1 (psia) = Initial Cabin Pressure, dP/dtout (psi/min) = Rate of Pressure Change at Initial Cabin Pressure, and dP/dtin is determined by the combined mass flow of O2 and N2 into the cabin.

Physiological Effects of Rapid Decompression Hypoxia Hypoxia is the dominant physiological hazard associated with loss of pressure from a habitable volume. The primary concerns with hypoxia are performance decrements with partial depressurization, and eventual catastrophic failure of oxygen exchange with complete depressurization to vacuum. Rapid reduction of ambient pressure produces a corresponding drop in the partial pressure of oxygen and reduces the alveolar oxygen tension. An accentuated effect of hypoxia after decompression is due to (1) a reversal in the direction of oxygen flow in the lung; (2) diminished ventilation (prolonged exhalation); (3) decreased cardiac output (impaired venous return). Hypoxia is discussed in detail in Chap. 22.

Hypothermia The cabin temperature drop associated with decompression may result in hypothermia-related injuries, with the extent and severity dependent on final temperature and associated injuries following decompression. For example, with rapid decompression from sea level to 50,000 ft (15,240 m), the temperature transiently drops from 68°F (20°C) to −76°F (−60°C). Hypothermia exacerbates the effects of hypoxia.

Evolved and Trapped Gas Disorders A major threat from atmospheric pressure reduction is the development of evolved gas disorders (decompression sickness and ebullism) and trapped gas disorders (pulmonary over-inflation syndromes and barotrauma). Decompression sickness is an illness that follows reduction in environmental pressures sufficient

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to cause formation of bubbles from gases dissolved in body tissues. Evolved and trapped gas disorders can occur together when associated with severe pressure reduction. A man accidentally decompressed to an equivalent altitude of 74,000 ft (22,555 m) for 3–5 min in an industrial vacuum chamber sustained a ruptured lung, massive decompression sickness, and ebullism. Five hours following the accident he was still unconscious; he was treated with a modified U.S. Navy Treatment Table 6A (see Figure 11.2) in a hyperbaric recompression chamber. He eventually made a full recovery. Serum levels of the enzyme creatine phosphokinase (CPK) peaked at 8,000 units 2 days after the accident, suggesting substantial soft tissue barotrauma [4]. In another instance of exposure to physiologic vacuum (pressure less than 47 mmHg), a NASA technician evaluating an EVA suit sustained a rapid decompression to hard vacuum in an environmental space simulation chamber. Prior to losing consciousness, he first noted bubbling on his tongue and eyes as the fluid on these mucus surfaces sublimated. He was recompressed to sea level within seconds and suffered no untoward sequelae.

Pulmonary Over-inflation Syndromes The pulmonary over-inflation syndromes are disorders caused by gas expanding within the lung, resulting in alveolar rupture. These syndromes include arterial gas embolism, pneumothorax, mediastinal emphysema, subcutaneous emphysema, and pneumopericardium. The lungs are one of the most vulnerable organs during rapid decompression. Whenever a rapid decompression exceeds the inherent capability of the lungs to evacuate gas, a transient positive pressure will temporarily build up in the lungs relative to the ambient atmosphere. If the escape of air from the lungs is blocked or seriously impeded during a sudden drop in cabin pressure, intrapulmonary pressure can rise rapidly enough to rupture lung tissues and capillaries. Intrapulmonary pressure differential of 1.5–1.9 psi or 80–100 mmHg (109–136 cm H2O) over 0.1–0.2 s has resulted in alveolar rupture in animal studies [5]. Human cadaver studies have shown that a gradient of only 70–81 mmHg (95–110 cm H2O) is needed to rupture the lung [6]. Alveolar rupture may result if the rapid depressurization occurs during momentary breath holding, as during swallowing or yawning, or if there is localized pulmonary obstruction, as from asthma or secretions, and may recur in susceptible individuals [7]. Pulmonary bullae are particularly susceptible to alveolar rupture because of reduced alveolar wall surface tension. Large pulmonary bullae and asthma are screened out in primary astronaut selection. Expanding gas trapped in the lung may enter tissue spaces, causing mediastinal emphysema, subcutaneous emphysema, pneumothorax, and pneumopericardium. Gas escaping into and accumulating in the pleural or pericardial spaces can result in emergent conditions. Tension pneumothorax may be life threatening and require urgent thoracostomy as well as administration of 100% O2. Diagnosis of tension pneumothorax in the space environment would be based primarily on exam and clinical symptoms as X-ray capability is currently not available

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on orbit. Preliminary experiments with a portable ultrasound device used during parabolic flight have shown that it is possible to detect pneumothorax by loss of movement between the visceral and parietal pleura [8]. A diagnostic ultrasound flown on ISS as part of the Human Research Facility could be used to evaluate pneumothorax. Crew Medical Officers, crewmembers specially trained to respond to inflight medical events using onboard systems and hardware, are trained to perform needle thoracostomy based on clinical indications. Pneumopericardium is rare and is usually detected only with radiographs. The presence of subcutaneous emphysema, typically noted by palpable crepitus over the site, should lead to a search for underlying over-inflation conditions. Arterial gas embolism (AGE) is caused by trapped air forced through ruptured blood vessels in the lungs and passing directly into the arterial circulation. Onset of AGE is usually sudden and dramatic following depressurization. The heart and brain with their high perfusion requirements are the organs most susceptible to life-threatening arterial gas embolism. Cerebral arterial gas embolism presents with significant neurological signs and symptoms, including unconsciousness, dizziness, paralysis or weakness, sensory loss, blurry vision, or convulsions.

Trapped Gas Barotrauma Exposure to decreasing ambient pressure causes the gas present in body cavities to expand. Impediments to expansion of trapped gas in air spaces in the middle ears, sinuses, teeth, and gastrointestinal tract result in earache, sinus pain, toothache, or abdominal pain. Essential conditions for barotrauma include a gas-containing enclosed space, particularly if walled with rigid bony structure, and ambient pressure reduction at a rate beyond the capacity of the enclosed space to equalize with the changing atmosphere. Boyle’s Law states that with a constant temperature the volume of a gas is inversely proportional to the pressure exerted upon it, as seen in the following equation: P1 × V1 = P2 × V2 According to Boyle’s Law, gases trapped in body cavities tend to expand as pressure decreases and contract as pressure increases. The potential for barotrauma is more likely early in pressure reduction from sea level or one atmosphere absolute (ATA), where the greatest fractional pressure excursions occur. Pain is more likely to occur during a rapid cabin pressure loss than during a slow decompression. Factors encountered in the space environment, such as oxygen-enriched gas mixtures and microgravity-associated fluid shifts, may also influence inner ear barotrauma. The major barotrauma syndromes are discussed below.

Gastrointestinal Tract Barotrauma The gastrointestinal (GI) tract normally contains gas at a pressure equivalent to the surrounding atmospheric pressure. The stomach and large intestine contain considerably more

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gas than the small intestine. Most GI gas comes from swallowed air and, to a lesser degree, from digestive processes (fermentation, decomposition). Digestion of vegetables and fruit commonly produces gas. Chewing food thoroughly can reduce air swallowed during meals. Relief from trapped GI gas is obtained by belching or passing flatus. GI tract gas is primarily nitrogen, with lesser percentages of oxygen, carbon dioxide, hydrogen, methane, and hydrogen sulfide. Discomfort from gas expansion within the digestive tract is frequently experienced with rapid decrease in atmospheric pressure and may produce severe pain if distension is significant. Abdominal distress from expansion of trapped gases within the GI tract is a potential danger during very rapid or explosive decompression. Rapid decompression might be accompanied by sudden emesis, as the gastric bubble seeks pressure relief. An altered level of consciousness (e.g. from accompanying hypoxia) could predispose to aspiration and chemical pneumonitis. Displacement of the diaphragm by expanding stomach gas may impede respiratory movements. Distention of abdominal organs may stimulate the vagus nerve, resulting in cardiovascular depression, reduction in blood pressure, and even shock.

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may effectively lock the natural ostia, resulting in buildup of pressure and barotrauma. Sinus blocks among aviators most often occur in the frontal sinus (70%), followed by the maxillary sinus. Maxillary sinusitis may produce pain referred to the upper teeth and may be mistaken for toothache. Sinus problems are usually preventable by frequently performing an equalization maneuver during repressurization and avoiding pressure changes if congested. If a sinus block occurs during repressurization, the repressurization should be stopped and a forceful Valsalva maneuver (closing the mouth, pinching the nose shut, and blowing gently) should be attempted. If this does not clear the sinus the individual should return to a lower pressure and perform normal Valsalva maneuvers during repressurization; the subsequent repressurization rate should be slowed. Individuals with a relatively large volume of air in the mastoid sinuses are usually less tolerant to pressure changes. Treatment for acute sinus barotrauma, whether on the ground or in space, is based on decongestants and antibiotics [9]. Repeated barotrauma should be evaluated with computed tomography (CT) scan of the sinuses when available. Functional Endoscopic Sinus Surgery (FESS) may be useful in evaluation of repeated sinus barotrauma in aviators and astronauts.

Barodontalgia The onset of toothache associated with pressure change, barodontalgia, usually occurs during initial ambient pressure reduction from 14.7 psi to 12–8 psi. Pain is invariably relieved upon repressurization, which distinguishes it from pain in the upper jaw due to maxillary barosinusitis, which worsens with repressurization. Barodontalgia is usually associated with preexisting dental pathology, such as imperfect fillings, pulpitis, and carious teeth; completely normal teeth are not affected. Expansion of trapped air under restorations in the absence of underlying pathology is responsible for only a very small proportion of barodontalgia cases.

Sinus Barotrauma The paranasal sinuses are air filled, relatively rigid, bony cavities lined with mucous membranes that connect with the nose by small openings (ostia). If the sinus openings are obstructed by swelling of the mucous membrane lining (congestion, infection, or allergic condition), polyps, or redundant pharyngeal tissue, pressure equalization becomes difficult or impossible. The opening to a sinus cavity is small compared to the Eustachian tube and unless the pressure is equalized during pressure excursions, extreme pain may result. In about 90% of cases, pain develops during repressurization, hence for space operations is more likely following an EVA as a crewmember repressurizes from the low operating pressure of the suit to a 14.3 psi sea level equivalent cabin atmosphere. During depressurization the expanding air usually forces its way out past the obstruction. During repressurization, however, the relative negative pressure within the sinus cavities

Ear Barotrauma (Barotitis) Eustachian Tube Function The eustachian tube (ET) is ~37 mm long and connects the middle ear with the nasopharynx. The lateral or tympanic end of the ET is bony and usually open, whereas the medial or pharyngeal end is cartilaginous, slit-like, and closed when relaxed, acting like a one-way flutter valve. Opening of the ET occurs with contraction of the palate lifters (the levator palatini) and palate tensor muscles (tensor palatini) during acts of chewing, swallowing, or yawning and by direct air pressure. The cartilaginous and bony portions meet at an obtuse angle in the narrowest portion of the tube. The most common cause of acute ET dysfunction is edema or tissue hypertrophy from infection, inflammation, or allergy. Chronic dysfunction is usually associated with anatomic abnormalities, such as scarring and chronic disease. An acute, unexplained unilateral dysfunction in an older person could be due to a tumor in the nasopharynx. The nasopharynx soft tissues surrounding the membranous ET are influenced by gravity. An upright posture aids tubal patency while a recumbent position can compromise a marginally patent ET, and a head down attitude can result in positional obstruction. In space flight ET function may be compromised by head congestion from cephalad fluid shifts during the early phase of the mission. Once fluid shifts associated with early adaptation to microgravity have resolved, ET function should not be adversely affected. Symptoms of ET dysfunction are generally fullness in the ear, mild intermittent discomfort or pain, and a mild decrease

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in hearing. On otoscopic examination, the tympanic membrane (TM) shows some retraction with either a normal appearance or slight hyperemia of the vascular strip. The short process of the malleus is prominent or foreshortened, and the malleus may angle more posteriorly than usual. In chronic cases, there is a “dimple” or retraction of the pars flaccida of the TM, indicating negative pressure. Silent or undiagnosed sinusitis can be associated with ET dysfunction, and barotitis media is directly related to ET dysfunction. As the outside pressure decreases, greater relative middle ear pressure forces open the “flutter valve” at the pharyngeal end of the ET every 0.3 psi to 3.5 psi (15–180 mmHg) relative differential. During repressurization, the collapsed pharyngeal end prevents air from entering the ET. Increasingly negative middle ear pressure builds and holds soft tissues together. Active opening of the ET must be accomplished before the differential pressure reaches 1.5–1.75 psi (80–90 mmHg), or muscular action cannot overcome the suction effect on the closed ET, and the tube is locked. Relative negative pressure retracts the TM and pulls on the delicate mucosal lining, leading to effusion and hemorrhage. Pain may be severe, with nausea and occasionally vertigo. On rare occasions rupture of the TM has resulted in syncope or shock.

Evaluation of Eustachian Tube Function The act of swallowing often causes a clicking or crackling sound, which is made when the moist tissues of the ET pop open. This sound can be heard by the person or ascultated with a stethoscope placed on the ear and listening for a crackling sound when the person swallows. Astronauts have used this ear popping as a subjective measure of pressure changes, such as during the depressurization following collision between the Progress resupply vessel and the Mir space station. The risk of barotrauma increases with a history of nasal or middle ear disease, otologic surgery, upper respiratory infection (URI), perforation, cholesteatoma, chronic use of decongestant nasal sprays, and previous barotrauma. Middle ear pathology, which varies with the rate and magnitude of pressure change, is associated with negative pressure and includes mucosal hemorrhage and congestion, edema, serous and hemorrhagic effusion, and leukocyte infiltration within the middle ear mucosa. The inwardly displaced TM also undergoes vascular congestion followed by vessel rupture and interstitial hemorrhage or formation of bullae. Pressure differentials as low as 0.6 psi (30 mmHg) have been shown to cause minor barotrauma. TM rupture most commonly occurs in the anterior portion, over the middle ear orifice of the ET. Significant force may also cause an annulus rupture. Otoscopic appearance can range from TM retraction with backward displacement of the malleus, a prominent short process, and anterior and posterior folds, to hyperemia or hemorrhage of the tympanic membrane with varying amounts of

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serous and sanguineous fluid visible behind the membrane. The Teed barotrauma classification scheme stages the clinical observations and quantifies sequential damage [10]. Grade 0 – no visible damage Grade 1 – congestion redness around umbo (2 psi/100 mmHg differential) Grade 2 – diffuse congestion redness of TM (2–3 psi/100– 155 mmHg differential) Grade 3 – hemorrhage within the TM Grade 4 – extensive middle ear hemorrhage with blood and bubbles (air/fluid level) behind TM Grade 5 – entire middle ear filled with dark blood Optimally, evaluation techniques would allow identification of susceptible individuals prior to exposure to potentially damaging pressure excursions. Static acoustic impedance tympanometry prior to altitude exposure did not identify individuals who developed otic barotrauma during flight but was useful in confirming barotrauma following flight, although no more useful than taking a history and performing an ear examination [11]. Assessment of TM impedance just before and after diving showed a transient but significant increase in middle ear compliance for dives to different depths, suggesting a reversible impairment of the recoiling capacity of the TM elastic fibrils [12]. Prelaunch examinations will detect acute or chronic disorders. For long duration space flight (over 30 days), the onboard crew medical officer is trained to perform ear examinations prior to EVA.

Ear Barotrauma Syndromes Pressure-Related Ear Block An ear block may occur when middle ear pressure is unable to equalize with ambient air pressure. This normally occurs because the lower orifice of the ET, which operates as a oneway flutter valve, fails to function adequately. Swelling of the ostia from an upper respiratory infection or the cephalad fluid shift that occurs in microgravity may also contribute to ET dysfunction. The difference in pressure will cause the TM to bulge outward as ambient pressure decreases and bulge inward as ambient pressure increases. An ear block is much more likely to occur as ambient pressure increases because the ET’s valve-like action allows gas to pass more readily out of the inner ear than into it. When the ambient pressure is reduced, middle ear pressure increases, and the eardrum bulges outward until an excess pressure of ∼0.2–0.3 psi (12– 15 mmHg) is reached and there is a sensation of ear fullness. A small amount of air is forced out of the middle ear into the ET, and the TM resumes its normal position. As the pressure is released, there is often a click or pop audible to the individual. Variability in ET lumen size and muscular activity, along with pharyngeal inflammation or mass effects, may result in widely varying ET opening times.

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

Symptoms of an ear block include ear fullness, pain, muffled hearing, dizziness, or tinnitus. Middle ear pressure equalizes naturally with swallowing, yawning, or tensing the oropharyngeal muscles that open the ET orifice. If relief is not obtained by this method, a Valsalva maneuver forces air through the closed ET into the middle ear and equalizes the pressure. If a pressure differential of 1.5–1.75 psi (80–90 mmHg) develops across the middle ear, voluntary maneuvers may be unsuccessful in equalizing middle ear pressure. Relief can be obtained by return to a lower pressure followed by a slower repressurization.

Post Oxygen Exposure Delayed Ear Block Crewmembers who have breathed O2 enriched air or 100% O2 during a prebreathe prior to staged decompression, during an EVA, or following extended oxygen mask use as protection against atmosphere contamination may develop an earache several hours after O2 use, even though they can clear their ears adequately. The high O2 concentration largely replaces air in the middle ear. Cells lining the middle ear gradually absorb oxygen due to its diffusion properties, which partially reduces middle ear pressure if there is not a widely patent ET. While awake an individual relieves the pressure differential by periodic swallowing, which opens the ET, and equilibrates middle ear pressure with ambient pressure. During sleep the middle ear may not be ventilated sufficiently to keep the pressure equalized. Ear pain may awaken an individual from sleep or may be noticed upon awakening. The symptoms sometimes include a sensation of ear fullness, pain, and bubbling sounds from accumulation of fluid in the middle ear. The condition is usually self-limiting and relieved by an autoinflation maneuver. Prevention of post-oxygen exposure ear block includes performing an equalization maneuver like the Valsalva frequently during the first 2 h after O2 use to lower the O2 concentration by flushing the middle ear with ambient air. EVA crewmembers are specifically briefed on this concern.

End of Day Barotrauma Repeated asymptomatic mild barotrauma may result in ET swelling that eventually progresses to symptomatic barotrauma as ET function worsens. Although unlikely in space flight, this may affect astronauts during ground activities such as water immersion EVA training.

External Auditory Canal (EAC) Barotrauma Obstruction of the external auditory canal by foreign body, cerumen, a tight-fitting cap, or an earplug may result in barotrauma to the EAC during a pressure change. The isolated space in the EAC develops relative negative pressure with an increase in ambient pressure, which can result in canal and or TM edema and hemorrhage. Outward displacement of the TM with decrease in ambient pressure can also result in TM trauma. Treatment for EAC barotrauma is the same as for otitis externa, with antibiotic drops and systemic treatment if warranted.

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Alternobaric Facial Paralysis Transient facial paralysis is a rare complication associated with acute middle ear barotrauma, such as would occur with rapid or explosive cabin depressurization. The likely mechanism is injury to the dehiscent tympanic portion of the facial nerve from direct pressure or bubbles that transit through the chorda fenestrum following overpressurization of the middle ear space. Alternobaric facial paralysis usually resolves spontaneously. Return to flight duties would be contingent on resolution of muscle function, particularly the protective eye blink and ability to purse the lips required to perform a Valsalva maneuver.

Caloric Vertigo A dramatic and common cause of vertigo underwater is a transient effect due to unequal caloric stimulation of the two labyrinths from water entering the external canal asymmetrically [13]. Such a syndrome would not be expected during spaceflight operations but may complicate water immersion EVA training, scuba, and water survival activities.

Alternobaric Vertigo (ABV) A number of vestibular conditions resulting in vertigo may be related to diving and space operations, including optokinetic illusions, asymmetric vestibular stimulation, inner ear barotrauma, decompression sickness, breathing gas toxicity, high pressure neurological syndrome, sea or space motion sickness, and noise-induced vestibular stimulation [14]. Lundgren first coined the name alternobaric vertigo after he found that 26% of Swedish sport divers surveyed had experienced pressure related vertigo, most frequently during or immediately after ascent from diving [15]. He also reported a similar phenomenon in aviators [16]. Alternobaric vertigo is the sensation of initial unequal pressure in the ear followed by dizziness and vertigo during exposure to changing pressure. A pressure difference of 0.9 psi (45 mmHg) between the two ears will asymmetrically increase labyrinthine discharge and induce nystagmus and vertigo. Many individuals who reported alternobaric vertigo with diving could reproduce their symptoms by performing a Valsalva maneuver. Symptoms usually last a few seconds to 15 min. Symptoms may be managed by stopping the pressure change and utilizing equilibrating mechanisms until resolved. Loud tinnitus, vertigo, nystagmus, and bone conduction loss suggest labyrinthine window rupture. Alternobaric vertigo is usually transient and, other than momentary disorientation, would be unlikely to interfere with spaceflight activities.

Inner Ear Barotrauma (IEB) The inner ear, composed of semicircular canals, vestibule, and cochlea, is embedded within the dense, compact petrous temporal bone, or osseous labyrinth. Within the bony labyrinth is a membranous labyrinth that contains endolymph fluid similar

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in composition to intracellular fluid (high potassium). The perilymphatic fluid, similar in content to cerebrospinal fluid (high sodium), is outside of the membranous labyrinth. Figure 12.4 shows the normal anatomy of the ear. IEB should be suspected in cases of barotrauma associated with sensory neural hearing loss, tinnitus, or vertigo. IEB may persist and lead to perilymph fistula (PLF). IEB usually occurs during rapid pressure changes and associated equalization problems. IEB may be due to mechanical disruption of Reissner’s membrane, which separates the endolymphatic from perilymphatic space. Mechanisms for round and oval window rupture include rise in endolymphatic pressure (from increased intracranial pressure via the cochlear aqueduct) or increase in perilymphatic pressure. In the explosive mechanism, intralabyrinthine fluid pressure is greater than middle ear pressure. A Valsalva maneuver may increase the intralabyrinthine fluid pressure, via the cochlear aqueduct or the internal auditory canal, but fail to equilibrate the middle ear pressure and therefore increase the differential between the middle ear, perilymph,

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and endolymph. The implosive mechanism results from a rapid increase in middle ear pressure, with inward displacement of the stapes footplate, resulting in rupture of the round or oval window and perilymph fistula. The implosive injury mechanism is less common than the explosive injury. When perilymphatic fluid leaks into endolymphatic spaces, auditory and/or vestibular symptoms may develop. Symptoms of a PLF including sudden onset of postural vertigo with or without hearing loss persisting after barotrauma, positional nystagmus, gaze evoked nystagmus, and reduced speech discrimination and speech reception threshold [17]. Therapy for PLF includes bed rest and avoidance of straining or activities that could increase intracranial pressure. The anatomic location of PLF has been documented clinically from rupture of both the oval and round windows, and membranous tears within the cochlea have been described post-mortem [18,19]. A fourth source of perilymphatic leakage is the microfissure, the existence of which has been surgically confirmed [20]. The timing of exploratory tympanotomy for PLF is controversial. Some specialists recommend immediate exploration,

FIGURE 12.4. Simplified anatomy of the human ear, emphasizing in particular the structures vulnerable to pressure changes

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

although most would observe over 24–48 h for signs of worsening [21]. If no improvement occurred in four to five days, most recommend surgical exploration [22]. Exploratory tympanotomy for suspected PLF with surgical closure as indicated resulted in improved hearing in 49% (23% improved to serviceable range) [23]. Ninety-five percent of the patients had elimination or decrease in their vestibular symptoms to the extent that it no longer interfered with their daily activities. The high rate of postoperative PLF recurrence has been reduced with a new surgical technique for PLF closure using laser graft-site preparation, an autologous fibrin glue “buttress,” and a program of postoperative activity restriction, with recurrences dropping from 27% to 8%. Complete resolution or significant symptomatic improvement occurred in 89% of patients with vertigo and/or dizziness and in 84% with disequilibrium. IEB related hearing loss may result from impaired microcirculation of the auditory artery, resulting in inner ear neuroepithelium damage. Irreversible hearing loss from IEB depends on the extent of damage to the organ of Corti [18]. Vertigo associated with IEB or PLF may be more severe and prolonged than alternobaric vertigo and could be associated with nausea and vomiting; hence it is more of a concern for critical spaceflight operations, particularly EVA.

Inner Ear Decompression Sickness Inner ear decompression sickness (IE-DCS) and IEB can result in similar symptoms and lead to permanent severe vestibulocochlear deficiency and can occur together [24,25]. IE-DCS is related to the formation and growth of inert gas bubbles within microvessels and membranous labyrinth fluids following rapid pressure reduction leading to ischemia of the venous circulation, hemorrhage, and protein exudation. IE-DCS is usually associated with deep dives but can occur at shallow depths [26]. Although more common in diving operations, it is sometimes seen in the aerospace environment. Associated symptoms of IEB include equalization problems with forceful Valsalva, and pre-existing nasal or sinus complaints. IE-DCS is usually not associated with pressure equalization problems and is not associated with non-otologic neurologic findings. Treatment for IE-DCS and IEB is different, one treatment being harmful for the other condition. Recompression therapy is indicated as soon as the diagnosis of IE-DCS is made and is contraindicated in IEB [25].

Hearing Loss (Barotrauma Versus Decompression Sickness) Middle ear barotrauma (MEBT) and inner ear barotrauma (IEBT) may be caused by pressure excursions associated with aviation, EVA, and diving, and in fact are major causes of diving-induced hearing loss. MEBT should be treated by prevention and symptoms should be treated by limiting pressure changes and judicious use of decongestants. Otologic manifestations of decompression sickness (DCS) occur rarely

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but should be considered as a cause of pressure-related hearing loss. When hearing impairment with or without vestibular symptoms is an isolated manifestation of type II DCS, it may be difficult to distinguish from middle and inner ear barotrauma resulting in labyrinthine window fistula. Immediate recompression treatment with hyperbaric oxygen may result in complete recovery [27]. A perilymph fistula may cause IEBT. Although reports of IEBT are relatively few, this entity should be kept in mind and differentiated from other causes of diving-induced hearing loss [28].

Maneuvers to Equilibrate Middle Ear Pressure A number of equalization or autoinflation maneuvers have been developed to aid ET function. Individuals exposed to variable pressure environments can develop ET awareness by listening for the crackle and pop of the ET opening. Individuals can practice equalization or autoinflation maneuvers, although Shupak showed that successful autoinflation at sea level does not necessarily reflect middle ear pressure equalization ability during descent in a dive [29].

Valsalva Maneuver A common procedure for self-inflation of the middle ear space is the Valsalva maneuver. During the Valsalva maneuver, the nose and mouth are closed and the vocal cords are open. By exhaling against closed anatomical outlets, air is forced into the nasopharynx, with the increased pressure forcing open the ET and increasing the pressure in the middle ear space. This can be observed as a bulging of the tympanic membrane on otoscopic examination, especially in the posterior superior quadrant. Conditions that make the Valsalva maneuver less effective include flexion of the head forward, rotation of the head to one side, pressure on the jugular vein, and placement in the prone or head down position. Obstacles encountered during the Valsalva maneuver include straining so hard that venous congestion in the head prevents opening of the ET, and closing the vocal cords, which prevents pressure from reaching the pharynx. One method to prevent vocal cord closure is to close the nose with the fingers and attempt to blow the fingers off the nose. The buildup of pressure should be rapid and sustained for 1 s to prevent venous congestion that reduces the efficiency of ET function. The adequacy of pressurization can be assessed by observing the fleshy portion above the nares balloon outward above the pinched fingers. The cheek muscles should be kept tight and retracted, not puffed out. With this technique, gradients of 2.67–4.45 psi (140–230 mmHg) can be achieved. A rare complication of this method is round or oval window rupture.

Frenzel Maneuver The Frenzel maneuver, taught to Luftwaffe dive-bomber pilots during World War II, involves closing the glottis, mouth, and nose while simultaneously contracting the floor of the mouth and the superior constrictor muscles. This maneuver actually

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takes less pressure to open the ET but is more difficult to learn. To perform one must thrust the lower jaw anteriorly, close the lips, slightly open the jaw, move base of the tongue against the soft palate, which compresses air in the nasopharyngeal space. The nostrils are pinched closed and a “K” or “guh” sound is made. This maneuver raises the back of the tongue and elevates the larynx, effectively making a piston out of the back of the tongue and compressing air in the back of the throat. The “bobbing the Adams apple” technique may be practiced by watching the nose inflate and the larynx move up and down. This technique is quick, can be done anytime during the respiratory cycle, does not inhibit venous return to the heart, and can be repeated many times in rapid succession.

Toynbee Maneuver If there is no TM movement with Valsalva, a small, quick retraction movement of the TM may be accomplished by the Toynbee maneuver. The Toynbee maneuver involves swallowing with the nose pinched closed. Joseph Toynbee first identified the crackling sound one hears with opening of the ET during swallowing. An initially positive nasopharyngeal pressure rapidly becomes a negative pressure, which helps unlock the ET. The muscles in the back of the throat pull open the ET and allow air to equalize if a gradient is present. The swallowing necessary to effect this maneuver can be difficult while breathing dry air. This technique is not recommended for rapid pressure changes, as there is no margin for error if the ET does not equalize on first effort. If a middle ear squeeze is already occurring, it will be more difficult for the ET to be pulled open.

Beance Tubaire Voluntaire (BTV) Maneuver The French Navy developed a technique for middle ear equalization called voluntary tubal opening. This technique involves teaching an individual to contract the soft palate and upper throat muscles similar to a yawn. This technique only works during gradual and predictable pressure changes.

Edmonds Maneuver This technique is accomplished by combining pressurization (Valsalva or Frenzel maneuver) with jaw thrust or head tilt, which more effectively opens the ET.

Treatment of Middle Ear Barotrauma Treatment is directed toward equalization of pressure, relief of pain, and prevention or treatment of infection. Pressurization should be stopped and, if possible, the individual returned to a pressure where an equalization maneuver can be attempted, followed by a more gradual pressure change. If barotitis symptoms are present without otoscopic signs, pressure environments should be avoided until all symptoms are resolved, usually within a week. Individuals with symptoms and objective signs but no TM rupture may require a longer recuperation. Antibiotics are unnecessary unless purulence is noted in the nasopharynx

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or the patient notices a worsening of the pain or purulent otitis is evident by exam. Most cases of frank TM perforation heal spontaneously. Oral decongestants may be helpful. Antibiotics are used if clear signs of upper respiratory infection are present. Ototoxic antibiotic drops (aminoglycoside antibiotics) should not be used, as there is a possibility of round or oval window rupture. Antibiotics should be used for 7–10 days. Politzerization or tubal insufflation may be necessary in cases of thick effusion and ET dysfunction or inability to perform an equalization maneuver. Politzerization is the mechanical inflation of the middle ear performed for treatment of acute ear and sinus blocks, chronic ET dysfunction, or middle ear disease. An autoinflation device (Otovent®) improved negative middle ear pressure after flight. Seventy-three percent of adults and 69% of children with an unsuccessful Valsalva maneuver showed improved or normalized middle ear pressure by inflating the device [30]. The politzerization procedure requires a source of pressure from an air pump, pressurized air supply, or rubber bag with a one-way valve. A rubber Politzer bag is useful where a pressurized air supply is not available. An air pump should have a variable control of the pressure and pressure gauge. If no gauge is present, the starting pressure should just be sufficient to blow off a lightly applied finger. When a pressure gauge is available, initial attempts should be made with 10 psi or less (500 mmHg). A metal or plastic tip is used to seal and deliver the pressure into the nose. If the patient has a very thin TM, lower pressure must be tried first. An explanation to the patient is important to ensure cooperation and prevent sudden movements that could injure the nose. The politzerization tip should be inserted into a nostril far enough to afford a good seal without striking the vestibule or septal walls. The opposite naris is occluded, and the patient is instructed to repeat K-K-K-K-K loudly and sharply as a 1-s burst of air is delivered. A characteristic soft palate flutter sound is heard if the procedure is performed correctly. If no results are obtained with this technique, the patient is instructed to swallow: as the thyroid notch rises up, air pressure is again applied in the nose. For people who have trouble with a dry swallow, a sip of water may be given. With the water technique, prolonged or high pressure might cause damage to the tympanic membrane, and there is a remote possibility of round window and inner ear damage. The patient’s TM should be assessed before and after inflation to determine the success of the procedure. Although not usually recommended, if symptoms have not resolved after 2 or 3 weeks of intensive therapy, persistent serous fluid may be removed by needle aspiration, and thick mucous or organized blood can be removed by myringotomy.

Return to Duty Mild middle ear barotrauma symptoms should subside within 1–2 weeks. When equalization function has returned, no abnormal bubbling sounds are heard, and hearing is normal, a return to a variable pressure environment can be safely

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

accomplished. Decongestants may help relieve mild to moderate barotrauma symptoms. The occasional use of inhaled decongestants, like oxymetazalone (Afrin) spray, may be used for prevention or treatment of mild congestion, but a spray should not be used more than three consecutive days, to prevent rebound nasal congestion. In one observational study, twenty patients who suffered IEB while scuba diving but continued to dive against medical advice were assessed on an interim basis for 1–12 years. All patients were instructed on methods of maximizing ET function, and no further deterioration of auditory or vestibular function was noted. Based on these preliminary results, recommending that no further diving after IEB may be unnecessarily restrictive [31]. Upper respiratory infections and allergic rhinitis increase the risk of barotrauma in the changing pressure environment. Crewmembers with persistent inner ear symptoms, difficulty with ear clearing, or persistent nasal or sinus complaints should not return to variable pressure environments [32].

Altitude Sickness Altitude sickness occurs in non-acclimatized individuals above 3050 m (10,000 feet) and represents a spectrum of pathologic states initiated by an exaggerated vascular response to hypoxia. Major discernible syndromes include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), highaltitude retinal hemorrhage, and noncardiogenic high-altitude pulmonary edema (HAPE). With the exception of retinopathy, gradual ascent to allow acclimatization can lessen or prevent symptoms of high-altitude illness [33]. A number of thorough reviews of the pathophysiology of acute mountain sickness, high altitude pulmonary edema, high altitude cerebral edema, and high altitude retinal hemorrhage are available in the literature [34–39]. The potential for AMS in space operations exists during staged decompression prior to EVA or following inadvertent pressure reduction due to partial loss of spacecraft atmosphere. There has been concern about altitude sickness during shuttle depressurization to 10.2 psi for planned EVA operations due to a seeming increase in the frequency of reported headaches among crewmembers during this lower pressure period. This was addressed on a recent Shuttle mission (STS 103), when a portable pulse oximeter was used to evaluate the crew. Arterial oxygen saturations remained in the mid 90% range during the lower pressure stage; hence it is unlikely these headaches stem from altitude sickness. The increased incidence of headaches seen during the 10.2 psi phase raises speculation on other potential causes, such as a change in the atmosphere control system or increased offgassing of volatile materials due to the lower pressure.

Acute Mountain Sickness Acute mountain sickness (AMS) affects otherwise healthy individuals who ascend rapidly to high altitude where the partial

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pressure of oxygen (pO2) in the air is reduced. The pathophysiology of acute mountain sickness (AMS) may stem from both hypoxia and hypobaria of high altitude. AMS is reproduced in an altitude chamber, demonstrating that rarefied atmosphere is the etiology. Normal effects of altitude exposure include exertional dyspnea, spontaneous diuresis, nocturnal periodic breathing (Cheyne-Stokes respirations), frequent awakening at night, and weird or vivid dreams. The symptoms of AMS include headache, poor appetite, nausea and vomiting, lightheadedness or dizziness, fatigue, weakness, and poor sleep, resulting from disturbances in fluid balance brought about by tissue hypoxia. Hypoxia is often accompanied by an increase in ventilation (hypoxic ventilatory response), which lowers CO2 and results in cerebral vasoconstriction and reduced cerebral blood flow. The increased ventilation results in greater oxygen saturation and delivery. Cognitive deficits may be due to hypoxic effects on sympathetic neurotransmitter function, and depletion of acetylcholine may contribute to fatigue [40]. The exact incidence of AMS is unknown, although approximately 25% of lowland visitors to moderate-elevation ski areas suffer at least mild AMS. There is no race or sex predilection, but age has a small effect, with younger adults slightly more susceptible than older adults. Carbon monoxide (CO) poisoning may mimic the signs and symptoms of altitude illness and must be considered if circumstances allow for this possibility [41]. In a small percentage of patients, AMS can lead to highaltitude pulmonary edema (HAPE) or high-altitude cerebral edema (HACE). AMS can be prevented by a sufficiently gradual pressure reduction, which is the best method. However, if time is a limiting factor, there are several drug therapies that provide relatively good protection.

Scoring Acute Mountain Sickness Various systems have been devised to quantify AMS. Scoring systems include both questionnaires (Hackett AMS questionnaire, Lake Louise AMS self-report questionnaire, Environmental Symptoms Questionnaire ESQ II and ESQ IV) and clinical investigation (Lake Louise AMS clinical and functional AMS assessment). The Environmental Symptoms Questionnaire (ESQ) contains nine symptom groups, with two factors representing AMS. The first factor contains symptoms indicative of cerebral hypoxia and is labeled AMS-C. The second reflects respiratory distress and is called AMS-R [42]. The AMS scores range between 0 and 9 for the Hackett AMS score 0 and 38 for the Hackett ESQ II AMS score, and 0 and 13.7 for the Hackett ESQ IV AMS score. The AMS scores range between 0 and 10 for the Lake Louise AMS self-report, and 0 and 2 for both the Lake Louise AMS clinical assessment score and the Lake Louise functional score. At moderate altitude (2,940 m), oxygen saturation correlated inversely with Hackett’s AMS score but there was no significant correlation with the Lake Louise AMS score, and the Lake Louise AMS score overestimated AMS incidence at moderate altitudes. Hackett’s AMS score, along with a structured interview and

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physical examination, remains the gold standard for evaluating AMS incidence [43]. Savourney et al evaluated the correlation of several acute mountain sickness (AMS) scoring systems. AMS was scored following a 9-h hypoxia exposure in a hypobaric chamber (altitude 4,500–5,500 m) that led to the development of AMS. In this study, AMS questionnaire scoring systems were without significant differences between them and were highly correlated to the clinical AMS assessment score [44]. The sensitivity and specificity of the Lake Louise score over 4 points was 78% and 93%, respectively [45]. The Lake Louise AMS scoring system, used to assess AMS, correlated with maximal self-report score observed at altitude as well as the functional report and clinical assessment scores in both laboratory and field conditions [46]. An AMS worksheet has been developed for space flight, which is essentially a modification of the Lake Louise AMD self-report questionnaire and clinical and functional assessment (Table 12.1). This was conceived to support Space Shuttle flights involving staged decompression in anticipation of extravehicular activity (EVA). Because there is little actual experience with altitude sickness during space flight, and because some of the basic AMS-associated symptoms such as headache and fatigue are common during space flight independent of cabin pressure changes, scoring of these symptoms is not directly transferable. However, determining a numerical score is useful for initial assessment and monitoring treatment and resolution. This is discussed further in the final section of this chapter.

Acclimatization Strategies to prevent AMS include allowing 2 days of acclimatization before engaging in strenuous exercise at high altitudes, avoiding alcohol, and increasing fluid intake. Physical conditioning exercise for patients older than 35 years is also recommended before departure. A high-carbohydrate, low-fat, low-salt diet was thought to aid in preventing onset of AMS, although in one study a high carbohydrate (68% CHO) diet for 4 days did not reduce symptoms of AMS in subjects exposed to 8 h of 10% normobaric oxygen [47]. A study assessing cardiovascular and respiratory physiological responses and AMS symptoms following induction to high altitude at 3,500 m (11,483 ft) then to 4,200 m (13,780 ft) compared symptom onset and resolution with the time of altitude acclimatization. The acutely inducted group was transported by aircraft to 3,500 m within 1 h, whereas the gradually inducted group was transported by road over a period of 4 days. After 15 days at 3,500 m, the subjects were transported to 4,200 m by road. Physiological responses at 3,500 m were stable by day three in the gradually inducted group, whereas it took 5 days for the acutely inducted group. Acclimatization schedules of 3 days for the gradually inducted group and 5 days for the acutely inducted group are essential to avoid high-altitude illness at 3,500 m. Both the gradual and rapid induction groups took 3 days at 4,200 m to achieve acclimatization [48].

J.B. Clark TABLE 12.1. Space AMS worksheet. Mission elapsed time (MET)/Cabin pressure Symptoms: 1. Headache: 0 No headache 1 Mild headache 2 Moderate headache 3 Severe, incapacitating headache 2. GI: 0 No GI symptoms 1 Poor appetite or nausea 2 Moderate nausea/vomiting 3 Severe nausea/vomiting, incapacitating 3. Fatigue/weakness: 0 Not tired or weak 1 Mild fatigue/weakness 2 Moderate fatigue/weakness 3 Severe fatigue/weakness, incapacitating 4. Dizziness/lightheadedness: 0 Not dizzy 1 Mild dizziness 2 Moderate dizziness 3 Severe, incapacitating dizziness 5. Difficulty sleeping: 0 Slept well as usual 1 Did not sleep as well as usual 2 Woke many times, poor night’s sleep 3 Could not sleep at all Total symptom score: Clinical assessment: 6. Change in mental status: 0 No change 1 Lethargy, lassitude 2 Disoriented/confused 3 Stupor/consciousness 7. Gaze/Eye movements: 0 Normal 1 Mild nystagmus; quickly remits/one direction 2 Moderate nystagmus; quickly remits/ > one direction 3 Severe nystagmus; sustained/any direction 8. Facial edema: 1 Mild edema 2 Moderate edema 3 Severe edema Total clinical assessment score: Meds used in past 6 h:

Physical Conditioning The effect of previous physical conditioning on acquiring acute mountain sickness at 3,000 m (9,840 ft) after 48 h was determined in a study by Honigman et al. Sea-level physical activity (SLPA) was measured with a validated questionnaire assessing patterns of work, sporting, and leisure activities. Acute mountain sickness defined as three or more of the following symptoms (headache, dyspnea, anorexia, fatigue, insomnia, dizziness, or vomiting) developed in 28%. No statistically significant difference in mean SLPA scores was found between those with and without acute mountain sickness, or in individual SLPA indices (work, sport, or leisure). Habitual sea level physical activity does not appear to play a role in the development of altitude illness at moderate altitude in a

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

general tourist group [49]. In two French high altitude expeditions (4,800 m/15,748 ft and 6,542 m/21,463 ft), there was a positive correlation between periodic breathing and individual hypoxic ventilatory drive; the periodic breathing latency decreased and sleep improved with acclimatization [50]. In a study of retention of acclimatization, lowlanders acclimatized at 4,300 m for 16 days returned to sea level and after 8 days were re-exposed to 4,300 m in a hypobaric chamber for 30 h. Retention of acclimatization after 8 days at low altitude was sufficient to attenuate the incidence and severity of AMS upon re-induction to high altitude [51].

Susceptibility Variability in sensitivity to AMS among individuals is a wellknown phenomenon. A hypoxia challenge test (abnormal cardiac or respiratory response to hypoxia, especially during exercise) may identify the most clinically susceptible subjects, who should be advised to increase acclimatization time and consider taking prophylactic medication [52]. The measurement of cardiac and respiratory responses to hypoxia (inspired O2 fraction = 0.115) at rest and during exercise at a level of 50% maximum oxygen consumption (VO2 max) allows the detection of subjects more likely to suffer from high altitude diseases. Monitoring of arterial oxygen saturation (SaO2%) with non-invasive oximetry provides a simple, specific indicator of inadequate acclimatization to high altitudes and may differentiate AMSresistant individuals from those with impending AMS. Likely mechanisms involved in AMS susceptibility include hypoventilation relative to normally acclimatizing individuals and abnormalities of gas exchange [53]. A low hypoxic ventilatory drive and an increased pulmonary vascular response to hypoxia may be predisposing factors to AMS and high altitude pulmonary edema. A low ventilatory response to hypoxia is associated with an increased risk for high altitude pulmonary edema, while susceptibility to acute mountain sickness may be associated with a high or low ventilatory response to hypoxia [54]. Individuals susceptible to high altitude pulmonary edema also show increased hypoxia induced vasoconstriction of pulmonary arterioles [55]. In addition, AMS susceptible individuals frequently lack the spontaneous diuresis normally seen at altitude. In subjects who traveled to 4,500 m (14,763 ft), hypoxic ventilatory response, alveolar carbon dioxide tension (PACO2), and VO2max showed no correlation with AMS scores [56]. Susceptibility to AMS appears to be independent of endurance training, but determined by the sensitivity of carotid chemoreceptors to hypoxemia and the induced hyperventilation and tachycardia. Exercising at high altitude is impeded during the first days of exposure to altitude hypoxia by the symptoms of AMS. Richalet et al investigated cardiac rate response at an equivalent altitude of 4,800 m (15,750 ft) in subjects both at rest and during 5 min of exercise at 50% VO2 max. Cardiac response to hypoxia at rest is lower in climbers with severe AMS than in those subjects without severe AMS, and similar differences were observed during exercise [57].

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Hypoxia and Simulated Microgravity Loeppky et al. conducted a study of altitude illness in subjects lying at 5 degrees head down bed rest (HDBR) to simulate the fluid shifts and responses of microgravity. Subjects who lived at 1,646 m (5,400 ft) were studied with and without HDBR during 8 days at an actual altitude of 3,255 m (10,678 ft). Plasma volume (PV) decreased with altitude-related hypoxia in both groups but further decreased with HDBR. There were no differences in electrolytes between HDBR and controls. Diuresis occurred in both groups but was greater with HDBR than controls. A rise in catecholamines was seen in controls and HDBR, but only HDBR showed a significant rise in atrial natriuretic peptide (ANP), which could account for the enhanced diuresis and decreased PV seen with HDBR [58]. AMS symptoms of headache, lightheadedness, insomnia, and anorexia were slightly more prevalent with HDBR, while arterial oxygenation was not seriously effected by HDBR [59]. The VO2 max increased by 9% without HDBR, but fell 3% after HDBR, which was significant, but could be accounted for by inactivity. At altitude the heart rate increase was enhanced and mean blood pressure was lower in response to an orthostatic stress (60 degree head-up tilt for 20 min) following HDBR, than head-up tilt without HDBR. Head-down bed rest did not significantly impact the ability to acclimatize to hypoxia in terms of pulmonary mechanics, gas exchange, circulatory or mental function, nor was pulmonary interstitial edema or congestion noted during HDBR.

Oxygen Prebreathe and Hydration Effects AMS may be related to reduced diuresis but not to increased water intake. In a study of water balance and acute mountain sickness (AMS), subjects developing AMS over a 4-day exposure at 4,350 m (14,272 ft) demonstrated reduced energy and water intake, increase in total body water (TBW) and a reduction in total water loss. Subjects with AMS showed the biggest shifts (at least 1 L) in extracellular water relative to TBW and did not show increased urine output expected as compensation for the reduced evaporative water loss at altitude [60]. In a study of positive water balance during acute altitude exposure, no significant difference in cardiovascular and ventilatory parameters were seen between normal and overhydrated subjects exposed to 4,570 m (14,993 ft) for 2 h. Prior O2 breathing reduced the hyperventilatory and alkalotic responses to altitude, mitigated the tachycardia response, and led to a drop in blood pressure despite a similar arterial desaturation in the non-prebreathe group. Reduced urine flow and increased urine osmolality observed in two subjects at 4,570 m were not seen in the same subjects at 4,570 m after O2 prebreathe [61].

Normobaric Hypoxia Versus. Hypobaric Hypoxia Hypoxia can occur without pressure change, as would occur if oxygen concentration fell below 20%, and normobaric hypoxia (1 atm) may be different than hypobaric hypoxia.

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Subjects exposed to normobaric hypoxia (14% O2) had the same degree of arterial desaturation but a significantly greater hyperventilatory response than with hypobaric hypoxia [61]. AMS symptom scores were higher with hypobaric hypoxia at a simulated 4,564 m altitude for 9 h compared with either normobaric hypoxia or normoxic hypobaria at equivalent simulated altitudes [62].

Respiratory Effects Respiratory effects occur at altitude but do not appear to correlate with AMS. In studies of pulmonary function at altitude, forced vital capacity fell significantly during the first 2 days of ascent and returned to normal after 3 or 4 days of stay at 4,600 m (15,092 ft). Forced expiratory volume in 1 s (FEV1) did not change in any period. However, maximal expiratory flow and maximal mid-expiratory flow rate significantly increased and remained elevated during the 4-day stay. No correlation was found between acute mountain sickness symptoms and changes in ventilatory function [63].

Diurnal Effects In subjects exposed to 79 h of hypoxia at 4,350 m (14,272 ft) AMS scores showed remarkable diurnal variations, paralleling plasma cortisol and red green color vision, with maximum variations seen in the early morning. Cortisol diurnal rhythm was maintained in hypoxia, although mean morning cortisol concentrations were higher than in normoxia [64].

Cerebral Blood Flow Decreased arterial partial oxygen pressure (PaO2) below a certain level presents a strong stimulus for increasing cerebral blood flow. Cerebral vasodilatation and an increase in cerebral blood flow are associated with acute mountain sickness (AMS). Using transcranial Doppler (TCD), mean middle cerebral artery velocity (MCA-V) showed a significant increase while vasomotor reactivity (VMR) decreased at 2,440 m (8,000 ft) [65]. Regional cerebral blood flow during short-term exposure to hypoxia at simulated altitudes of 3,000 and 4,500 m for 20 min showed only the hypothalamus had increased blood flow, and this at 4,500 m but not at 3,000 m [66]. Middle cerebral artery velocity was assessed by transcranial Doppler sonography (TCD) in subjects at 490 m, after rapid ascent to 4,559 m, and daily during a 72 h stay at 4,559 m. Relative change of MCA-V at high altitude was expressed as percentage of low altitude values. After ascent to 4,559 m, overall MCA-V increased in subjects with and without AMS, but the increase was higher in subjects with AMS and reached statistical significance on day one and two compared to healthy subjects. The rise of MCA-V correlated inversely with arterial PO2 on days 2, 3, and 4. MCA-V did not correlate with blood pressure, arterial PCO2 or hemoglobin [67].

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Intracranial Pressure Serial measurements of intracranial pressure have been made indirectly by assessing changes in tympanic membrane displacement on rapid ascent to 5,200 m. Acute hypoxia at 3,440 m was associated with a rise in intracranial pressure, but no further difference was found at 4,120 or 5,200 m in subjects with or without symptoms of AMS. Raised intracranial pressure, though temporarily associated with acute hypoxia, is not a feature of AMS with mild or moderate symptoms [68]. Hypoxia may alter cerebrospinal fluid (CSF) pressure compliance, resulting in a greater increase in CSF pressure for a given change in volume [40]. This may result in intracranial hypertension with supine posture.

Biochemical Markers Mechanical or inflammatory injury to pulmonary endothelial cells may cause impaired pulmonary gas exchange in AMS and high altitude pulmonary edema (HAPE). A marker of endothelial cell activation, E-selectin, which is produced only by endothelial cells, is increased after ascent to high altitude (4,200 m) in hypoxemic climbers with AMS and non-cardiogenic HAPE [69]. Serum concentrations of interleukin-6 (IL-6), increased during altitude hypoxia while other pro-inflammatory cytokines, including IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-6, tumor necrosis factor (TNF) alpha, and C-reactive protein (CRP) levels remained unchanged at sea level and during 4 days of altitude hypoxia (4,350 m). The serum IL-6 increases were related to arterial blood oxygen saturation but not to heart rate or AMS scores. The major role of IL-6 during altitude hypoxia may not be to mediate inflammation but rather to stimulate erythropoiesis at altitude [70]. Exposure to altitude hypoxia elicits changes in glucose homeostasis in the first few days at altitude. Insulin action decreases markedly in the first 2 days but improves with prolonged exposure. Glucose, cortisol, and noradrenaline concentrations increased at altitude, while adrenaline, glucagon, and growth hormone remained unchanged [71]. Aldosterone levels were elevated on the first day, and atrial natriuretic peptide levels were higher on both altitude days in subjects at 4,300 m. Altitude and the exercise on ascent resulted in a marked decrease in 24-h urine volume and sodium excretion. Aldosterone levels tended to be lowest in subjects with low symptom scores and higher sodium excretion. Atrial natriuretic peptide levels at low altitude showed a significant inverse correlation with acute mountain sickness symptom scores on ascent. No correlation was found between changes in hemoglobin concentration, packed red blood cell volume, 24-h urine volume, or body weight and acute mountain sickness symptom score [72]. Hypoxia has a suppressive effect on the renin-aldosterone system; however, beta-adrenergic mechanisms do not appear to be responsible for inhibition of renin secretion at high altitude. The renin-aldosterone system may be depressed in subjects exercising at high altitude, thereby preventing excessive

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

angiotensin I and aldosterone levels, which could favor the onset of acute mountain sickness. Subjects performed a standardized maximal bicycle ergometer exercise with and without pindolol, a nonselective beta-blocker (15 mg/day) at sea level, as well as during a 5-day period at high altitude (4,350 m, barometric pressure 450 mmHg). During sealevel exercise, pindolol caused a reduction in plasma renin activity (PRA), an increase in plasma alpha-atrial natriuretic factor (alpha-ANF) level, and no change in plasma aldosterone. Compared with sea-level values, PRA and plasma aldosterone were significantly lower during exercise at high altitude. Alpha-ANF was not affected by hypoxia. With beta-blockade at high altitude, exercise-induced elevation in PRA was completely abolished, but no additional decline in plasma aldosterone occurred [73]. Although acclimatization to environmental hypoxia is necessary to achieve optimal physical performance at altitude, scientific evidence to support the beneficial effects after return to sea level is equivocal. Unfavorable physiological responses to physical exercise at moderate altitude exposure include decreased plasma volume, depression of hemopoiesis, increased hemolysis, increased sympathetically mediated glycogen depletion, increased respiratory muscle work, and hypoxia mediated immunosuppression [74]. Hypoxia also generates inducible nitrogen oxide synthase, leading to generation of potentially damaging free radicals [75].

Associated Infectious Disease In a study of AMS and infection in hikers walking to Mount Everest base camp at 5,300 m (17,388 ft), 57% of subjects developed AMS, and 87% experienced at least one symptom of infectious disease. Coryza (75%), cough (42%), sore throat (39%), and diarrhea (36%) were especially prevalent. The incidence of AMS was greater among those with more symptoms of infection, and the number of symptoms of infection experienced was positively correlated with AMS score [76]. There was a 50% increase in the frequency of upper respiratory and gastrointestinal tract infections during altitude sojourns in high performance athletes assigned to a 4-week altitude training camp at 1,500–2,000 m [77]. Inflammationproducing illnesses such as viral respiratory tract infections contribute to development of high-attitude pulmonary edema in children but not adults. Release of inflammatory mediators associated with these illnesses may be tolerated at sea level but may predispose children to increased capillary permeability when superimposed on hypoxia and, possibly, cold and exercise [78].

High Altitude Pulmonary Edema High altitude pulmonary edema (HAPE), a severe form of altitude illness that can occur in young healthy individuals, is a noncardiogenic pulmonary edema that usually occurs within 2–5 days of acute exposure to altitudes above 2,500–3,000 m.

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Hypoxia constricts pulmonary vessels, resulting in an increase in pulmonary vascular resistance. Hypoxic pulmonary hypertension is generally moderate but may become severe during HAPE and may be associated with right heart failure. Subjects susceptible to high-altitude pulmonary edema present with a slight increase in pulmonary vascular resistance at rest and at exercise and may demonstrate enhanced pulmonary vascular reactivity to hypoxia [79]. Periodic breathing (PB) at high altitude is slightly more frequent and arterial oxygen desaturation more severe during sleep in subjects developing HAPE during the first night spent at 4,559 m altitude. The significantly lower arterial oxygen saturation in the HAPE group is secondary to diminished gas exchange rather than ventilation [80]. Pulmonary capillary wedge pressure is normal at rest, and there is an excessive rise in pulmonary artery pressure (PAP) that precedes edema formation. Recent observations of high PAP in HAPE-susceptible subjects who did not develop pulmonary edema after rapid ascent to high altitude suggest that the inflammatory response is a primary cause of HAPE rather than a consequence of edema formation [34,81]. HAPE is often related to AMS. In a study of pulmonary function and HAPE after 4 h of simulated altitude exposure (4,400 m), three of four HAPE-susceptible subjects developed acute mountain sickness (AMS) and two of the three with AMS developed mild pulmonary edema [82]. Rapid ascent without prior acclimatization may result in HAPE even in subjects with excellent tolerance to high altitude. Although the hyperventilation response to hypoxia is beneficial, HAPE can occur in susceptible individuals despite the presence of a normal or high ventilatory response to hypoxia [82]. Those with HAPE showed a small decrease in forced vital capacity (FVC) and greater decrease in forced expiratory volume over 1 s (FEV1) and forced expiratory fraction (FEF25–75) after arrival at high altitude, with rales or wheezing noted on physical examination. High ventilatory responses to acute hypoxia occurred in two HAPE subjects. The six non-HAPE subjects had minimal spirometry changes and did not develop signs of lung edema. HAPE is associated with high concentrations of proteins and cells in bronchoalveolar lavage fluid, with both large (immunoglobulin M) and small (albumin) molecular-weight proteins present [83]. An inflammatory response and/or a decreased fluid clearance from the lung is likely, as bronchoalveolar lavage in advanced HAPE patients shows an inflammatory response with increased capillary permeability. An increase in capillary permeability may be a consequence rather than the cause of high-altitude pulmonary edema [84]. HAPE-susceptible individuals react to acute altitude exposure with increased secretion of norepinephrine, epinephrine, renin, angiotensin, aldosterone, and atrial natriuretic peptide. This results in sodium and water retention, reduction of urine output, increase in body weight, and development of peripheral edema. The hypoxic pulmonary vascular response is enhanced in HAPE-susceptible subjects, favoring severe pulmonary hypertension on exposure to high altitude. Susceptible

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individuals can avoid HAPE by ascending slowly, less than 300–350 meters per day above 2,500 m. Supplemental oxygen and immediate descent are the primary treatment modalities, but if descent is delayed and supplemental oxygen is not available, treatment with the calcium channel blocker nifedipine is recommended until descent is possible. The prophylactic administration of nifedipine prevents the exaggerated pulmonary hypertension of HAPE-susceptible subjects and thus prevents HAPE in most cases. Treatment of HAPE with nifedipine results in a reduction of pulmonary artery pressure, clinical improvement, increased oxygenation, decrease of the alveolar arterial oxygen gradient and progressive clearing of pulmonary edema on chest x-ray. The primary treatment of HAPE is descent, evacuation, and administration of oxygen.

High Altitude Cerebral Edema High altitude cerebral edema (HACE) is probably due to hypoxiainduced changes in blood-brain barrier permeability, resulting in vasogenic brain edema. HACE manifests a diverse array of generalized and localized neurological symptoms and signs, such as headache and impaired consciousness (confusion, lassitude, mental status changes) [85]. HACE occurs above 4,500 m during acclimatization, and at extreme altitudes above 7,500 m it is often fatal [86]. AMS is a subacute form of the frank brain edema seen in HACE, and differentiating between these two syndromes can be difficult. AMS may be partially related to cerebral edema secondary to hypoxic cerebral vasodilatation and elevated cerebral capillary hydrostatic pressure, resulting in reduced brain compliance and compression of intracranial structures. These primary intracranial events may elevate peripheral sympathetic activity neurogenically in the lung and in the kidney [87]. The edema in HACE is primarily intracellular cytotoxic edema but may also have a component of vasogenic edema from leaking across the blood brain barrier [40]. HACE is estimated to occur in about 1% of those persons at risk. HACE should be suspected in a patient with symptoms of AMS who develops gait ataxia (cannot walk heel-toe in a straight line) or mental status changes. A combination of both ataxia and mental status changes strongly suggests HACE. Houston and Dickinson recognized a severe form of altitude illness as cerebral edema where neurological signs and symptoms dominated the clinical picture and recommended rapid descent, intravenous dexamethasone or betamethasone, hydration, pharmacological diuresis (furosemide), and hyperosmolar agents [88].

Treatment of Altitude Sickness Carbonic Anhydrase Inhibitors Acetazolamide is currently the drug of choice for prevention of AMS, and numerous studies have demonstrated its effectiveness when started 12–24 h before ascent. Acetazolamide can

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also be used to treat acute mountain sickness, and improvement has correlated with increased arterial oxygen concentration. Acetazolamide (250 mg twice daily or 500 mg once daily of a slow release preparation), taken before and during ascent is probably the treatment of choice for AMS; it improves gas exchange and exercise performance and reduces AMS symptoms. Acetazolamide (125 mg two or three times daily or once at bedtime) has also been shown to reduce susceptibility to AMS and the incidence of HAPE and HACE. Twelve climbers attempting an ascent of Mt. McKinley (summit, 6,150 m) who presented to the medical research station at 4,200 m altitude with acute mountain sickness were randomly assigned to receive acetazolamide, 250 mg orally, or placebo and again at 8 h. After 24 h, five of six climbers treated with acetazolamide were healthy, whereas all climbers who received placebo still had acute mountain sickness. The alveolar to arterial oxygen pressure difference (PAO2–PaO2 difference) decreased slightly over 24 h in the acetazolamide group but increased in the placebo group. Acetazolamide improved PaO2 over 24 h when compared with placebo [89]. Acetazolamide is indicated for established AMS, although faster acting carbonic anhydrase inhibitors such as methazolamide may be preferable. There is not extensive evidence of the effectiveness of acetazolamide in combination with other drugs such as steroids and calcium channel blocking drugs used for treating acute mountain sickness. Drug combinations could have additive beneficial effects [90]. Acetazolamide (250 mg oral) was administered to subjects at sea level and then on the day after arrival at high altitude (4,360 m), and acetazolamide concentrations were measured in whole blood, plasma, and plasma water. The elimination rate constant (lambda z) and clearance uncorrected for bioavailability were significantly increased, while apparent volume of distribution, mean residence time, and extent of protein binding, were significantly decreased at altitude [91]. In a double-blind study, the combination of sustainedrelease acetazolamide (500 mg once daily) and low-dose 4 mg dexamethasone twice daily was more effective than sustained-release acetazolamide alone in ameliorating the symptoms of AMS after rapid ascent to high altitude (2 days at 3,698 m followed by two more days at 5334 m). Oxygen saturation decreased in both groups, but the decrease was greater in the acetazolamide-placebo group [92].

Glucocorticosteroids Dexamethasone (4 mg, four times a day) may be used for short-term treatment or prevention of AMS but should not be used for more than 2–3 days [93]. Dexamethasone may prophylactically reduce symptoms of AMS, in part due to its euphoric effect. Dexamethasone offers an alternative to acetazolamide for those with sulfa intolerance [94]. Although effective in treating cerebral symptoms of AMS, dexamethasone is not routinely recommended as a prophylactic agent [95]. Dexamethasone effectively reduces AMS symptoms

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

but does not improve objective physiologic abnormalities related to exposure to high altitudes and should only be used when descent is impossible or to facilitate evacuation. Six male subjects were exposed to a simulated altitude of 3,700 m (barometric pressure 481 mmHg) in a hypobaric chamber for 48 h on two occasions to assess the efficacy of dexamethasone in the treatment of established acute mountain sickness. Dexamethasone (4 mg every 6 h) or placebo was given in a randomized, double blind, crossover fashion after diagnosis of acute mountain sickness. Dexamethasone reduced AMS symptoms by 63%, compared to 23% reduction by placebo. In spite of this response, one subject developed mild cerebral edema on brain CT after both placebo and dexamethasone. Dexamethasone had no effect on fluid shift, oxygenation, sleep apnea, urinary catecholamine levels, the appearance of chest radiographs or perfusion scans, serum electrolyte levels, hematological profiles, or the results of psychometric tests. Dexamethasone treatment was complicated by mild hyperglycemia in all subjects [96]. Although dexamethasone has shown demonstrated effectiveness against AMS, illness may recur with abrupt discontinuation of the drug. In a randomized, double blind study, 2 mg of dexamethasone given orally every 6 h, starting 1 h before a 1-hour helicopter flight from sea level to 4,400 m (400 mmHg), did not prevent AMS. Subjects with moderate to severe AMS treated with 4 mg of dexamethasone every 6 h orally or intramuscularly for 24 h all showed marked improvement at 12 h, but if the drug was stopped symptoms increased 24 h after discontinuation [97]. In a double-blind, randomized trial comparing acetazolamide 250 mg, dexamethasone 4 mg, and placebo every 8 h as prophylaxis for AMS during rapid, active ascent (elevation 4,392 m), the group taking dexamethasone reported less headache, tiredness, dizziness, nausea, clumsiness, and a greater sense of feeling refreshed, and reported fewer symptoms unrelated to AMS (runny nose and feeling cold). The acetazolamide group differed significantly from other groups at low elevations (1,300–1,600 m) in that they experienced more nausea and tiredness and were less refreshed. Prophylaxis with dexamethasone can reduce AMS symptoms during active ascent, and acetazolamide side effects may limit its effectiveness as prophylaxis against AMS [98].

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different between groups at high altitude [99]. Symptomatic HAPE subjects at 4,559 m treated with nifedipine were able to continue exercise at altitude without supplementary oxygen and exhibited clinical improvement [100]. Prophylactic application of slow release nifedipine, 20 mg every 8 h, prevented HAPE in nine out of ten subjects following rapid ascent and stay at 4,559 m. Seven of 11 subjects who received placebo developed pulmonary edema at 4,559 m. Nifedipine lowered pulmonary artery pressure and resulted in clinical improvement in subjects suffering from radiographically documented HAPE [101].

Hyperbaric Recompression A number of portable recompression chambers, such as the Gamow bag, have been developed for use in high altitude operations, and AMS has been successfully treated with portable pressure chambers. Early pressurization to 150 mmHg for 3 h of unacclimatized subjects who climbed from 1,030 to 4,360 m within 12 h did delay the onset of AMS slightly but did not prevent or attenuate its severity. AMS score decreased and SaO2 increased in the treatment group 15 min after leaving the pressure chamber, whereas the control group had unchanged AMS score and SaO2. The next morning, AMS score, HR, and SaO2 were similar for both treatment and control groups [102]. Climbers with AMS at 4,559 m above sea level were randomly assigned to portable hyperbaric chamber treatment for 1 h at 145 mmHg or dexamethasone (8 mg orally then 4 mg every 6 h). AMS symptoms (Lake Louise score, clinical score, and AMS-C score) were assessed 1 h and 11 h after beginning the different treatments. One hour of compression caused a significantly greater relief of symptoms of AMS than dexamethasone. In contrast, after about 11 h subjects treated with dexamethasone had significantly less severe AMS than those treated with compression. One hour of compression at 145 mmHg, corresponding to a descent of 2,250 m, led to short-term improvement but no long-term benefit. Treatment with dexamethasone (oral dose of 8 mg followed by 4 mg every 6 h) resulted in a longer-term clinical improvement. Optimal efficacy should combine the two methods if descent or evacuation is not possible [103].

Operational Approach to Acute Mountain Sickness in Space The calcium channel blocker nifedipine is effective for preCalcium Channel Blockers

vention and treatment of HAPE, but nifedipine is not recommended for prevention of AMS. In a double-blind study of subjects receiving nifedipine or placebo during rapid ascent to 4,559 m and a 3-day stay at altitude, lowering pulmonary artery pressure (PAP) had no beneficial effect on gas exchange and symptoms of AMS in subjects not susceptible to HAPE. Pulmonary artery pressures (PAP) estimated by Doppler echocardiography were significantly lower with nifedipine, but arterial PO2, oxygen saturation, alveolar-arterial oxygen gradient, and AMS symptoms were not significantly

Although AMS has not been documented in space, a protocol has been developed to implement during contingency cabin depressurizations and to manage the AMS like symptoms that have been associated with planned depressurization to 10.2 psia, seen during staged decompression prior to EVAs performed from the Space Shuttle and ISS airlock. Pressure reduction from sea level to 10.2 psi is accompanied by increased oxygen concentration, usually 24–25%, and is hence a normoxic hypobaric exposure. Examining the Longitudinal Study of Astronaut Health (LSAH) database for the

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first 89 Space Shuttle flights, 67% of crew experiencing this lower pressure reported headache. Headache and fatigue are often experienced during reduced cabin pressure operation on board the shuttle. Headaches at the lower pressure may be due to less effective air cleaning, offgassing from powered avionics, residual space motion sickness, or stress associated with workload preparing for an EVA. The procedure for AMS in space, outlined in Table 12.2, was developed particularly for EVA intensive shuttle missions, such as ISS assembly flights and Hubble Space Telescope servicing missions. This protocol uses a modified symptom scoring system (Table 12.1), replacing ataxia, which cannot be measured in space, with an analog measure of vestibular cerebellar function that can be tested in microgravity. Oxygen saturation is measured with a peripheral O2 saturation monitor. The only medication for the management of AMS in space is the carbonic anhydrase inhibitor acetazolamide. The potential for side effects has raised concerns about its use in space. Acetazolamide increases sodium and bicarbonate excretion, decreasing extracellular bicarbonate resulting in hyperchloremia and metabolic acidosis. Carbonic anhydrase inhibitors are sulfonamide derivatives and may cause crystalluria, sulfonamide-like nephrotoxicity, hematuria, dysuria, and oliguria. A significant concern is an increase in calcium excretion, which may increase risk for nephrolithiasis (renal calculi). Hyperuricemia can develop with acetazolamide and precipitate gout. Adverse central nervous system side effects of acetazolamide include drowsiness, seizures, irritability, vertigo, confusion, and paresthesias. Paresthesias occur frequently and are manifested as numbness, tingling, or burning in the distal extremities and mucous membranes. Adverse GI effects with acetazolamide include nausea, vomiting, diarrhea, excessive thirst, and anorexia. Very uncommon but severe side effects of acetazolamide include aplastic anemia and Stevens-Johnson

TABLE 12.2. Space AMS protocol. I. Crew complains of AMS-like symptoms following cabin depressurization below 14.7 psia. II. AMS Worksheet (Table 12.1) is used to assess AMS Score (symptom and clinical assessment). III. If symptoms score is ≥5 or has worsened by 2 or more points when compared to baseline at 14.7 psia and clinical assessment score is ≥3 or has worsened by 1 point, measure SaO2 using pulse oximeter. A. SaO2 > 94% Not likely altitude sickness. B. SaO2 < 94% and changed by ≥4 points. Consider trial of O2 via personal oxygen supply mask. 1). Symptoms do not improve on O2 after 15–20 min. a. Not likely altitude sickness. 2). Symptoms improve on O2. a. Continue O2 for total of 1 h. b. Remove O2 after 1 h and observe. 3). Symptoms do not return. a. Continue to observe. 4). Symptoms return. a. Consider acetazolamide 125 mg to 250 mg every 8–12 h. b. Continue acetazolamide for 1–2 days and reassess.

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syndrome. Generally, these adverse effects occur infrequently enough to warrant the use of acetazolamide terrestrially for AMS with a favorable risk-to-benefit ratio. For space crews, typically with no physician onsite, the diagnosis would have to be made remotely and occurs in a setting with multiple other potential causes of symptomology. The worksheet in Table 12.1 would be carefully applied in such circumstances.

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12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness 18. Nakashima T, Kaida M, Yanagita N. Round window membrane rupture and inner ear damage due to barotrauma. Acta Otolaryngol Suppl (Stockh) 1992; 493:57–62. 19. Antonelli PJ, Parell GJ, Becker GD, Paparella MM. Temporal bone pathology in scuba diving deaths. Otolaryngol Head Neck Surg 1993; 109:514–521. 20. Kamerer DB, Sando I, Hirsch B, Takagi A. Perilymph fistula resulting from microfissures. Am J Otol 1987; 8:489–494. 21. Ashton DH, Watson LA. Inner ear barotrauma: A case for exploratory tympanotomy. Aviat Space Environ Med 1992; 63:612–615. 22. Black FO, Pesznecker S, Norton T, et al. Surgical management of perilymphatic fistulas: A Portland experience. Am J Otol 1992; 13:254–262. 23. Seltzer S, McCabe BF. Perilymph fistula: The Iowa experience. Laryngoscope 1986; 96:37–49. 24. Adkisson GH, Meredith AP. Inner ear decompression sickness combined with a fistula of the round window. Case report. Ann Otol Rhinol Laryngol 1990; 99:733–737. 25. Shupak A, Doweck I, Greenberg E, Gordon CR, Spitzer O, Melamed Y, Meyer WS. Diving-related inner ear injuries. Laryngoscope 1991; 101:173–179. 26. Reissman P, Shupak A, Nachum Z, Melamed Y. Inner ear decompression sickness following a shallow scuba dive. Aviat Space Environ Med 1990; 61:563–566. 27. Talmi YP, Finkelstein Y, Zohar Y. Barotrauma-induced hearing loss. Scand Audiol 1991; 20:1–9. 28. Talmi YP, Finkelstein Y, Zohar Y. Decompression sickness induced hearing loss. A review. Scand Audiol 1991; 20:25–28. 29. Shupak A. Inner ear decompression sickness combined with a fistula of the round window (letter). Ann Otol Rhinol Laryngol 1991; 100:788. 30. Stangerup S-E, Tjernstrom Ö, Klokker M, Harcourt J, and Stokholm J. Point prevalence of barotitis in children and adults after flight, and effect of autoinflation. Aviat Space Environ Med 1998; 69:45–49. 31. Parell GJ, Becker GD. Inner ear barotrauma in scuba divers. A long-term follow-up after continued diving. Arch Otolaryngol Head Neck Surg 1993; 119:455–457. 32. Davenport NA. Predictors of barotrauma events in the Navy altitude chamber. Aviat Space Environ Med 1997; 68:61–65. 33. Meehan RT, Zavala DC. The pathophysiology of acute high-altitude illness. Am J Med 1982; 73:395–403. 34. Bärtsch P. High altitude pulmonary edema. Med Sci Sports Exerc 1999; 31(1 Suppl.):S23–S27. 35. Hackett PH. High altitude cerebral edema and acute mountain sickness: A pathophysiology update. Adv Exp Med Biol 1999; 474:23. 36. Hultgren HN. High-altitude pulmonary edema: Current concepts. Annu Rev Med 1996; 47:267. 37. Sutton JR. Mountain sickness. Neurol Clin 1992; 10:1015–1030. 38. Tso E. High-altitude illness. Emerg Med Clin North Am 1992; 10:231–247. 39. Ward MP, Milledge JS, West JB. High Altitude Medicine and Physiology. London: Chapman and Hall Medical; 1995. 40. Hackett PH. The cerebral etiology of high-altitude cerebral edema and acute mountain sickness. Wilderness Environ Med 1999; 10:97–109. 41. Foutch RG, Henrichs W. Carbon monoxide poisoning at high altitudes. Am J Emerg Med 1988; 6:596–598. 42. Sampson JB, Cymerman A, Burse RL, Maher JT, Rock PB. Procedures for the measurement of acute mountain sickness. Aviat Space Environ Med 1983; 54:1063–1073.

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43. Roeggla G, Roeggla M, Podolsky A, Wagner A, Laggner AN. How can acute mountain sickness be quantified at moderate altitude? J R Soc Med 1996; 89:141–143. 44. Savourey G, Guinet A, Besnard Y, Garcia N, Hanniquet AM, Bittel J. Evaluation of the Lake Louise acute mountain sickness scoring system in a hypobaric chamber. Aviat Space Environ Med 1995; 66:963–967. 45. Maggiorini M, Muller A, Hofstetter D, Bärtsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in the Swiss Alps. Aviat Space Environ Med 1998; 69:1186–1192. 46. Savourey G, Guinet A, Besnard Y, Garcia N, Hanniquet A-M, Bittel J. Are the laboratory and field conditions observations of acute mountain sickness related? Aviat Space Environ Med 1997; 68:895–899. 47. Swenson ER, MacDonald A, Vatheuer MI, Maks C, Treadwell A, Allen R, Schoene RB. Acute mountain sickness is not altered by a high carbohydrate diet nor associated with elevated circulating cytokines. Aviat Space Environ Med 1997; 68:499–503. 48. Purkayastha SS, Ray US, Arora BS, Chhabra PC, Thakur L, Bandopadhyay P, Selvamurthy W. Acclimatization at high altitude in gradual and acute induction. J Appl Physiol 1995; 79:487–492. 49. Honigman B, Read M, Lezotte D, Roach RC. Sea-level physical activity and acute mountain sickness at moderate altitude. West J Med 1995; 163:117–121. 50. Goldenberg F, Richalet JP, Onnen I, Antezana AM. Sleep apneas and high altitude newcomers. Int J Sports Med 1992; 13: S34–S36. 51. Lyons TP, Muza SR, Rock PB, Cymerman A. The effect of altitude pre-acclimatization on acute mountain sickness during reexposure. Aviat Space Environ Med 1995; 66:957–962. 52. Rathat C, Richalet JP, Herry JP, Larmignat P. Detection of highrisk subjects for high altitude diseases. Int J Sports Med 1992; 13:S76–S78. 53. Roach RC, Greene ER, Schoene RB, Hackett PH. Arterial oxygen saturation for prediction of acute mountain sickness. Aviat Space Environ Med 1998; 69:1182–1185. 54. Hohenhaus E, Paul A, McCullough RE, Kucherer H, Bärtsch P. Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary edema. Eur Respir J 1995; 8:1825–1833. 55. Bärtsch P. Who gets altitude sickness? Schweiz Med Wochenschr 1992; 122:307–314. 56. Milledge JS, Beeley JM, Broome J, Luff N, Pelling M, Smith D. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J 1991; 4:1000–1003. 57. Richalet JP, Keromes A, Carillion A, Mehdioui H, Larmignat P, Rathat C. Cardiac response to hypoxia and susceptibility to mountain sickness. Arch Mal Coeur Vaiss 1989; 82:49–54. 58. Loeppky JA, Roach RC, Selland MA, Scotto P, Luft FC, Luft UC. Body fluid alterations during head-down bed rest in men at moderate altitude. Aviat Space Environ Med 1993; 64:265–274. 59. Loeppky JA, Roach RC, Selland MA, Scotto P, Greene ER, Luft UC. Effects of prolonged head-down bed rest on physiological responses to moderate hypoxia. Aviat Space Environ Med 1993; 64:275–286 60. Westerterp KR, Robach P, Wouters L, Richalet JP. Water balance and acute mountain sickness before and after arrival at high altitude of 4,350 m. J Appl Physiol 1996; 80:1968–1972. 61. Tucker A, Reeves JT, Robertshaw D, Grover RF. Cardiopulmonary response to acute altitude exposure: Water loading and denitrogenation. Respir Physiol 1983; 54:363–380.

270 62. Roach RC, Loeppky JA, Icenogle MV. Acute mountain sickness: Increased severity during simulated altitude compared with normobaric hypoxia. J Appl Physiol 1996; 81:1908–1910. 63. Saldias F, Beroiza T, Lisboa C. Acute altitude sickness and ventilatory function in subjects intermittently exposed to hypobaric hypoxia. Rev Med Chil 1995; 123:44–50. 64. Richalet JP, Rutgers V, Bouchet P, Rymer JC, Keromes A, DuvalArnould G, Rathat C. Diurnal variations of acute mountain sickness, color vision, and plasma cortisol and ACTH at high altitude. Aviat Space Environ Med 1989; 60:105–111. 65. Otis SM, Rossman ME, Schneider PA, Rush MP, Ringelstein EB. Relationship of cerebral blood flow regulation to acute mountain sickness. J Ultrasound Med 1989; 8:143–148. 66. Buck A, Schirlo C, Jasinksy V, et al. Changes of cerebral blood flow during short-term exposure to normobaric hypoxia. J Cereb Blood Flow Metab 1998; 18:906–910. 67. Baumgartner RW, Bärtsch P, Maggiorini M, Waber U, Oelz O. Enhanced cerebral blood flow in acute mountain sickness. Aviat Space Environ Med 1994; 65:726–729. 68. Wright AD, Imray CH, Morrissey MS, Marchbanks RJ, Bradwell AR. Intracranial pressure at high altitude and acute mountain sickness. Clin Sci (Colch) 1995; 89:201–204. 69. Grissom CK, Zimmerman GA, Whatley RE. Endothelial selectins in acute mountain sickness and high-altitude pulmonary edema. Chest 1997; 112:1572–1578. 70. Klausen T, Olsen NV, Poulsen TD, Richalet JP, Pedersen BK. Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol 1997; 76:480–482. 71. Larsen JJ, Hansen JM, Olsen NV, Galbo H, Dela F. The effect of altitude hypoxia on glucose homeostasis in men. J Physiol (London) 1997; 504:241–249. 72. Milledge JS, Beeley JM, McArthur S, Morice AH. Atrial natriuretic peptide, altitude and acute mountain sickness. Clin Sci 1989; 77:509–514. 73. Bouissou P, Richalet JP, Galen FX, et al. Effect of beta-adrenoceptor blockade on renin-aldosterone and alpha-ANF during exercise at altitude. J Appl Physiol 1989; 67:141–146. 74. Bailey DM, Davies B. Physiological implications of altitude training for endurance performance at sea level: A review. Br J Sports Med 1997; 31:183–190. 75. Clark I. Can excessive iNOS induction explain much of the illness of acute mountain sickness? In Roach R. Wagner P. Hackett P. (eds.), Hypoxia: Into the Next Millennium. New York, NY: Kluwer Academic/Plenum Press; 1999. 76. Murdoch DR. Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal. Aviat Space Environ Med 1995; 66:148–151. 77. Bailey DM, Davies B, Romer L, Castell L, Newsholme E, Gandy G. Implications of moderate altitude training for sea-level endurance in elite distance runners. Eur J Appl Physiol 1998; 78:360–368. 78. Durmowicz AG, Noordeweir E, Nicholas R, Reeves JT. Inflammatory processes may predispose children to high-altitude pulmonary edema. J Pediatr 1997; 130:838–840. 79. Naeije R. Pulmonary circulation at high altitude. Respiration 1997; 64:429–434. 80. Eichenberger U, Weiss E, Riemann D, Oelz O, Bärtsch P. Nocturnal periodic breathing and the development of acute high altitude illness. Am J Respir Crit Care Med 1996; 154:1748–1754.

J.B. Clark 81. Bärtsch P. High altitude pulmonary edema. Respiration 1997; 64:435–443. 82. Selland MA, Stelzner TJ, Stevens T, Mazzeo RS, McCullough RE, Reeves JT. Pulmonary function and hypoxic ventilatory response in subjects susceptible to high-altitude pulmonary edema. Chest 1993 Jan.; 103(1):111–116. 83. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ Jr, Henderson WR Jr, Martin TR. The lung at high altitude: Bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 1988; 64:2605–2613. 84. Kleger GR, Bärtsch P, Vock P, Heilig B, Roberts LJ 2nd, Ballmer PE. Evidence against an increase in capillary permeability in subjects exposed to high altitude. J Appl Physiol 1996; 81:1917–1923. 85. Hamilton AJ, Cymmerman A, Black PM. High altitude cerebral edema. Neurosurgery 1986; 19:841–849. 86. Clarke C. High altitude cerebral oedema. Int J Sports Med 1988 Apr.; 9:170–174. 87. Krasney JA. A neurogenic basis for acute altitude illness. Med Sci Sports Exerc 1994; 26:195–208. 88. Houston CS, Dickinson J. Cerebral form of high-altitude illness. Lancet 1975 Oct. 18; 2(7938):758–761. 89. Grissom CK, Roach RC, Sarnquist FH, Hackett PH. Acetazolamide in the treatment of acute mountain sickness: Clinical efficacy and effect on gas exchange. Ann Intern Med 1992; 116:461–465. 90. Bradwell AR, Wright AD, Winterborn M, Imray C. Acetazolamide and high altitude diseases. Int J Sports Med 1992; 13: S63–S64. 91. Ritschel WA, Paulos C, Arancibia A, Agrawal MA, Wetzelsberger KM, Lucker PW. Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude. J Clin Pharmacol 1998; 38:533–539. 92. Bernhard WN, Schalick LM, Delaney PA, Bernhard TM, Barnas GM. Acetazolamide plus low-dose dexamethasone is better than acetazolamide alone to ameliorate symptoms of acute mountain sickness. Aviat Space Environ Med 1998; 69:883–886. 93. Coote JH. Medicine and mechanisms in altitude sickness. Recommendations. Sports Med 1995; 20:148–159. 94. Hackett PH, Roach RC. Medical therapy of altitude illness. Ann Emerg Med 1987; 16:980–986. 95. Porcelli MJ, Gugelchuk GM. A trek to the top: A review of acute mountain sickness. J Am Osteopath Assoc 1995; 95:718–720. 96. Levine BD, Yoshimura K, Kobayashi T, Fukushima M, Shibamoto T, Ueda G. Dexamethasone in the treatment of acute mountain sickness. N Engl J Med 1989; 321:1707–1713. 97. Hackett PH, Roach RC, Wood RA, Foutch RG, Meehan RT, Rennie D, Mills WJ Jr. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med 1988; 59:950–954. 98. Ellsworth AJ, Larson EB, Strickland D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. Am J Med 1987; 83:1024–1030. 99. Hohenhaus E, Niroomand F, Goerre S, Vock P, Oelz O, Bärtsch P. Nifedipine does not prevent acute mountain sickness. Am J Respir Crit Care Med 1994; 150:857–860.

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13 Renal and Genitourinary Concerns Jeffrey A. Jones, Robert A. Pietrzyk, and Peggy A. Whitson

Genitourinary (GU) disorders are pervasive in the adult population and broadly include the diagnoses of 15–20% of patients who are discharged from hospitals in the United States. The percentage is higher for ambulatory visits. Along with susceptibility to the common disorders of the general population, the GU system of astronauts is additionally vulnerable to spaceflight-related stresses, both in flight as well as immediately preflight and postflight. These stresses may include rigorous exercise, microgravity, dietary changes, limited availability of drinking water, thermal stress, effects of other spaceflightrelated disorders such as space motion sickness, and influence of medications used to treat other spaceflight-related disorders. Some of these conditions may increase the risk of occurrence of genitourinary disorders or complicate their presentation. Exposure to microgravity causes a number of metabolic and physiological changes. Fluid volume, electrolyte levels, and bone and muscle undergo changes as the human body adapts to weightlessness. Changes in urinary chemical composition occurring as a part of this adaptation process may lead to the potentially serious consequences of renal stone formation. With the length of human exposure to microgravity extending as we maintain a permanent presence on the International Space Station (ISS), the probability of GU-related illnesses such as renal stones or infections will undoubtedly increase. Exploration-class lunar missions for long-duration settlement and missions to Mars will pose even greater challenges for GU diagnosis and management as immediate return to Earth will not be possible. This chapter reviews spaceflight influences on GU function and disorders that might arise involving this system and describes treatment methods and countermeasures.

Spaceflight Factors Influencing the Genitourinary System

adaptive changes most affecting the GU system involve fluid and electrolyte balance as these systems are “reset” toward new homeostatic set points. These changes are described in more detail in Chap. 27. The first few days of space flight have much in common with bed rest on Earth. The loss of the constant 9.8-m/s2 (32 ft/ s2) force of gravity found on Earth results in a redistribution of body fluids toward the head and central circulation. The body’s volume sensors perceive the resulting shift of fluids, a consequence of redistribution, as an overload. Facial puffiness and nasal stuffiness are common outward manifestations of this fluid shift. During the early accommodation to microgravity, crews experience varying degrees of space motion sickness (SMS), which lowers their fluid intake—either due to nausea and vomiting or diminished thirst [1]. The combination of fluid redistribution and decreased fluid intake contributes to: (1) a diminished plasma volume (on average, about 12% less than normal) [2] and (2) reduced urine output 72 h after arriving in weightlessness. Reduced urine output often persists throughout the mission, placing crews at risk of urinary calculus formation due to increased urinary solute concentrations and osmolality [3]. Renal function was assessed during the 9-day Spacelab Life Sciences-1 mission (STS-40, June 1991) and the preceding three longer-duration Skylab missions (May 1973– February 1974). Measurement of creatinine clearance as an indicator of glomerular filtration rate (GFR) showed a probable but slight overall increase from 6% to 18% early in flight. Long-duration flight GFR measurements showed only a few percent gain over preflight levels. Renal plasma flow is felt to be increased on landing day, likely due to constriction in efferent arterioles in the renal cortex resulting from high levels of angiotensin I [2].

Body Fluid Balance The dominant factor governing the physiological changes associated with human space flight is microgravity, also known as weightlessness. As might be expected, those

Bone Mineral Loss Bed rest has been shown to be a reasonable analog to space flight with regard to bone physiology and calcium kinetics. 273

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Bed-rest subjects, as well as quadriplegics, show losses in bone mineral density over time as their gravity-resistant muscular actions are put to rest. Multiple bed-rest studies have demonstrated consistent demineralization of key regions of bone. Those key regions also show changes in space flight, though often to a slightly greater rate and magnitude than have been recorded in bed-rest studies [4–7]. The bone loss observed during and following space flight occurs despite vigorous in-flight exercise programs required by all crewmembers. Bed-rest studies have played a key role in developing countermeasures for musculoskeletal degradation during long-duration space flight, including performance of physical exercise and evaluation of pharmacologic agents such as bisphosphonates. Biomedical results of long-duration missions, notably those conducted on Skylab and Mir, provide limited but valuable information to apply toward the development of countermeasure regimes for the ISS. Calcium balance studies conducted on Skylab showed that 200–300 mg/day of calcium were lost by astronauts due to both urinary and fecal excretion [2,8]. Plasma parathyroid hormone levels were measured as normal during flight, and there have not been consistent results in the in-flight calcitonin measurements. The main etiology of observed net increases in urinary calcium losses during space flight appears to be leaching of bone calcium from the skeletal system due to diminished bone loading in microgravity. The Skylab calcium balance studies showed individual variation, but there was a generally consistent rate of daily calcium loss in the 28-day (Skylab 2) and 59-day (Skylab 3) flights, and no suggestion of decline in the rate of loss in the longer 84-day (Skylab 4) flight. Phosphorous loss varied from 222 to 400 mg/day in Skylab 2 and 4, mainly from the urinary route. The loss rate in Skylab 3 was much lower for unexplained reasons [7,9]. Although physiological findings from the joint Shuttle-Mir flights showed significant individual variability in the amount of bone mineral density loss in key regions such as the greater trochanter, femoral neck, lumbar spine, and calcaneus, overall there was a consistent 1.3–1.5% monthly loss in bone mineral density. Metabolic investigations showed negative calcium balance in flight due to decreased intestinal absorption and increased urinary calcium loss. Postflight, there was rapid return to zero balance. Additionally, there were inflight increases in other markers for bone resorption such as collagen cross links occurring in parallel with the increased losses of calcium [10].

Voiding Challenges Various operational factors may predispose some individuals to GU conditions during space flight. One of these is the mission schedule, especially during docked operations, which is often filled with crew activities. Frequently because of an intense operational timeline, basic needs such as eating,

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drinking, and voiding are delayed or skipped. Periods of inadequate fluid intake and subsequent relative dehydration, especially when the workload is high, predispose crewmembers to increased urinary solute concentration, thereby increasing the risk of forming renal stones. Delays in voiding because of schedule constraints can also predispose crewmembers to infection, bladder calculi, and urinary retention due to urinary stasis in the lower tracts. Two factors may significantly influence voiding in the immediate prelaunch timeframe. These are the long period during which a crew may need to wear a launch and entry suit, and the semi-recumbent position assumed by Space Shuttle crewmembers on the launch pad. Under these circumstances crewmembers must be able to void spontaneously without being concerned about the migration of urine to other locations in the suit, especially in the cephalad direction. Therefore, adult absorbent garments (pullup diapers) are worn beneath the liquid cooling garment. These pull-up diapers have a 1–2 L capacity. In spite of these absorbent garments, crewmembers often report difficulty voiding due to the prelaunch position and the confines of the suit. While participating in extravehicular activities (EVAs), a crewmember is maintained within the life support system of the extravehicular mobility unit. EVAs can be nominally scheduled for 6.5 h. This means a crewmember may be inside an EVA suit for as many as 8 h when taking into account pre-EVA preparation, suit checks, and nitrogen elimination prebreathe protocols. An EVA astronaut therefore wears a maximum absorbent garment or an adult diaper when performing an EVA. This same garment is worn during water immersion EVA training prior to launch. Urinary retention has been reported early in flight, and is most likely due to changes in autonomic function and other microgravity effects. In addition, finding privacy on a vehicle such as the Space Shuttle is difficult. Since up to seven crewmembers share the one small “bathroom area” that houses the waste collection system (WCS), the crew may experience a delay in access to the WCS. This may contribute to a risk for urinary retention and infection. Crew coordination for even these basic human needs is essential for overall health. Further attempts to maintain hygiene include: (1) assignment of a separate funnel adapter for each crewmember in which to collect liquid waste in the WCS (Figure 13.1), (2) biocidal wipes in the WCS area to clean the surfaces of equipment between uses, and (3) a hygiene shower hose that connects to the Shuttle galley to use with wet and dry wipes to cleanse and dry the perineum during flight. The thermal load on the crew during nominal operations on the Shuttle or ISS is minimal. However, physical demands or loss of environmental control can lead to undue heat stress. During the NASA-Mir Program the temperature on the Russian space station Mir often rose to over 85°F (29.5°C) and humidity occasionally exceeded 75%. This produced periods when the crewmembers’ clothing was moist, especially in

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as needed. Solid waste is dehydrated to some degree but is left in the WCS to be retrieved after flight. Activated charcoal beds minimize dispersion of solid waste odor throughout the Shuttle cabin. Aboard the ISS, a similar system is used for waste management in the Russian Segment. It also makes use of a urine collection hose, but there is a single funnel interface that is cleaned after each use. The Russian Elektron device, which was originally developed for Mir and is now used on the ISS, generates oxygen from urine using electrolysis to split water into its components— hydrogen and oxygen. Oxygen is used for breathing, and the hydrogen is vented overboard. In the current ISS configuration, atmospheric condensate water is being reclaimed and processed to become drinking and hygiene water. Eventually, it is planned to incorporate a more capable and robust water reclamation and recycling system that will process both urine and condensate to potable water. FIGURE 13.1. Urinary conduit and personalized funnel adapter, part of the Space Shuttle’s waste containment system (WCS). The hose attaches to a vacuum system that draws urine into a waste fluids tank, which is periodically dumped overboard

the perineum, increasing the likelihood of developing fungal infections such as Candida (Monilia) and urinary tract infections (UTIs). Several rashes were observed during this period, and fungal species were felt to be contributory.

Waste Management Systems During the early years of the U.S. and Russian space programs, astronauts and cosmonauts did not have a waste collection and storage system. Instead, individuals voided and defecated into collection bags. The urine collection bags, known popularly as “Apollo bags,” used a condom-like appliance to interface with the crewmen’s genitalia. (There were no women astronauts in the early years of the U.S. space program, the first flew on the Space Shuttle in 1983.) Today, the so-called “Apollo-bags” are still flown aboard space vehicles in the U.S. space program as a backup capability in case of WCS failure. The Space Shuttle has a single WCS that is used to collect urinary and fecal waste. It is located in the aft middeck area and has a privacy curtain. The Shuttle WCS has a corrugated tube that transports urine from the crewmember to the phase separator. Each crewmember has his or her own funnel adapter to interface between the urethral meatus and the tubing. When the WCS is activated, negative pressure is generated on the storage tank side of the WCS, thereby effectively aspirating the urine into the phase separator. Due to volume and weight constraints, only one funnel is flown per crewmember, each of whom is responsible for cleaning and drying the funnel between uses. A stowage rack in the WCS area houses the funnels. Liquid waste undergoes phase separation (air and fluid) in the negative pressure stream of collection before it is stored in a wastewater tank. Wastewater can be dumped overboard

Urine Collecting Devices The ability to efficiently collect quantified urine samples is fundamental to many investigational studies and operational monitoring and evaluation methods. However, the weightless environment adds complexity to this activity, primarily due to difficulty in fluid handling and air-fluid separation. Many different sampling devices have been developed over the years, with varying degrees of success. The first use of a newly designed polyethylene bag was on board Mir. For this first flight, the bags were launched to Mir from Russia as part of a series of inflight metabolic experiments. An improvement over the previous white vinyl bags in several ways, the new bag had a flat-lying one-way valve that allowed for a greater volume of urine flow than did the valves of the commercially available vinyl bags. This design helped reduce the backpressure felt by crewmembers when voiding and was also able to accommodate the lithium chloride concentration method of volume measurement, which was first done using this bag (previous vinyl bags tended to absorb the lithium chloride). After several years of use, a polyethylene bag was developed with an even wider valve to allow more urine to pass. This new bag also has a sample port that replaces the old one taken from the Shuttle drink bag port. The new port and valve are three times greater in diameter than the old port and valve, thereby allowing for much faster emptying of the bag. The new device first flew on Shuttle mission STS-97 in November 2000, with a good degree of success. In the past, only a commercially available, external, condomtype latex catheter was used to make the interface between the male astronaut and the bag. The catheter has earned mixed reviews from crewmembers, ranging from total dislike to “worked just fine.” Enough complaints were voiced to warrant finding an alternative. One option employs a condom with an inflatable collar to place around the glans. Another alternative, the BioDerm wafer, was first flown on STS-96 (May 27 to June 6, 1999) as a hardware evaluation experiment rather

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than for sample collection. It has been rated as the best possible means of collecting urine by all of the male crewmembers that tried it. The medical-grade adhesive on the back of the wafer allows the BioDerm wafer to attach directly to the penis, providing an easier-to-install, nearly leak-proof, handsfree method of collection. It is also designed to be worn for as many as 3 days and has been shown to work well for the 24-h period of wear necessary for most science experiments. The condom catheter remains an available option, with the latex being replaced by silicone to avoid risk of allergic reactions. In the past twenty years, women have comprised a gradually increasing fraction of space crews. Initially, female crewmembers collected urine by using a metal ring inside the condom catheter to press against the perineum. Although this method allowed for urine capture, there was often leakage or spillage around the ring, requiring multiple dry wipes to contain the liquid. Multiple alternative female interfaces were studied in microgravity during parabolic flight aboard the KC-135 aircraft and during actual Shuttle flights. Devices that fit over the labia majora or inside the labia minora inserted into the vaginal introitus, or inflated onto the perineum were all evaluated. The ease of one-handed application was a key consideration in design. Results varied by size and shape of the perineum, as well as personal preference. Most female crewmembers selected the silicone periurethral device with introitus locator insert as providing the best urine seal with ease of use. However, several sizes of the condom-ring system are made available for those female crewmembers that prefer alternatives. A device that fulfills stringent science requirements for urinary volume measurement and sampling of specific analytes has been developed to fly in the Human Research Facility rack during the final stages of ISS assembly. This will facilitate life science research without largely impacting crew time. This urinary monitoring system should also eliminate the cumbersome task of whole urine volume collection for ground sampling, which is required to complete research objectives.

Clinical Genitourinary Issues in Space Flight History Multiple genitourinary conditions have manifested in space flight crews dating back to the beginning of the first suborbital flights in both the U.S. and Russian programs. Initial problems were due to containment of urine while on the launch pad and subsequently while in microgravity in an enclosed pressure suit. Genitourinary tract infections began to appear in the Russian Salyut and U.S. Apollo eras. In one instance a case of cystourethritis with Pseudomonas aeruginosa occurred due to prolonged use of a condom catheter urine collection system in microgravity. More recently, a case of prostatitis progressing to urosepsis resulted in the premature deorbit of a crew from the Mir space station. Several episodes of urinary

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retention have occurred that were multifactorial in origin, some requiring urethral catheterization for relief. Cases of retention in non-infected female crewmembers with no terrestrial history of retention appear to have a microgravity-unique mechanism, perhaps with a psychosomatic component. An additional factor contributing to urinary retention may be the use of prophylactic and therapeutic medications to treat SMS that have anticholinergic side effects. Performance of urinary catheterization by crewmembers in microgravity has thus far not been problematic.

Nephrolithiasis Urinary calculi are both ancient and prevalent. The medical impact of urinary stones dates to antiquity, with the oldest known case in a 7,000-year-old Egyptian mummy. [11] Approximately 5% of the U.S. population will develop clinically significant urinary calculi in their lifetime, with a much greater percentage having sub-clinical calculi by autopsy incidence. More than 1 million patients will seek medical attention for urinary stones annually in the United States alone, with the incidence being greater in males than in females by a margin of 3:1 and highest in Caucasians than other ethnic groups. [12] The peak incidence is in the third through fifth decades, which embraces the vast majority of the active career astronaut corps. The time required to form stones varies from individual to individual, and the minimal time to form stones during space flight is not known. Patients immobilized due to orthopedic injury have an increased rate of stone formation, with time to stone symptoms in this cohort varying from a minimum of 74–76 days to a maximum of 622–1200 days, and averaging 276–362 days, depending on the study group [13,14]. Recurrence following a first episode is common. In the absence of any underlying medical condition, Earth-based clinical studies have shown an approximate 75% recurrence rate for stoneformers within 5 years following formation of the first renal stone. Dietary modifications, increased fluid intake, or pharmacological treatments can significantly lower these rates in patients [15,16]. Accordingly, it is NASA’s aim to understand the physiologic changes that occur when humans are exposed to microgravity and to minimize the potential for renal stone development in spaceflight crews. Various types of urinary calculi are found in the general population. These can be classified by composition into five basic groups: (1) calcium, (2) uric acid, (3) struvite, 4) cystine, and 5) miscellaneous stones. Calcium stones account for almost 80% of all urinary calculi, and can be further classified into calcium oxalate (65–75%) and calcium phosphate (< 5%) composition, with the majority being mixed calcium stones; only 30% of stones contain a single component. Approximately 50–60% of these patients show elevated calcium excretion in the urine (hypercalciuria). The next most common type of stone is struvite, otherwise known as magnesium ammonium phosphate (triple phosphate), comprising

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about 15% of all urinary stones and occurring exclusively in patients with recurrent or persistent urinary infections with urease-producing organisms, producing a urinary pH of greater than 7.2. Uric acid stones make up 6–8% of the total and are more common in patients suffering from gout. Following the first gout attack, 1% of gout patients per year will develop uric acid stones, with the prevalence being 20% of the gouty population. Cystine stones are rare, comprising only 1% of the total. These stones occur only in patients with cystinuria, which is a genetic disorder of amino acid metabolism. Miscellaneous stones include the remaining rare urinary calculi such as xanthine, silicate and triamterene stones of diverse etiologic mechanisms.

Factors in Stone Formation With normal anatomy, crystals form when the urine is supersaturated with minerals; i.e., when the concentration of stoneforming salt exceeds the solubility of the salt in solution and the solubility product exceeds the threshold for precipitation. It should be noted that although urine of non-stone-formers is also commonly supersaturated with respect to calcium oxalate, precipitation does not occur because of other factors such as urine flow and the presence of inhibitors such as citrate and pyrophosphate. Factors that promote precipitation include increased concentration of stone constituents (from reduced urine flow or increased excretion of constituents), and the presence of a physical substrate on which crystallization may initiate, such as damage from prior infections or the presence of a foreign body. Commonly, conditions involving the increased excretion of calcium into the urine, or hypercalciuria, underlie stone formation. Genetic predisposition to stone formation often involves familiar hypercalciura syndromes. Absorptive hypercalciuria, where excessive calcium is absorbed from the gastrointestinal tract, may result from excess dietary calcium. Resorptive hypercalciuria involves excess demineralization of bone mass, releasing free calcium onto the vascular system with subsequent renal loss. This is a particular concern in weightlessness. In nephrogenic or renal hypercalciuria, the kidneys filter out calcium from the blood but do not allow reabsorption of the calcium back into the blood from the renal tubules. Medications and supplements may induce hypercalciuria by increasing intestinal absorption (vitamin D), adding directly to the calcium load (antacids, calcium supplements), or enhancing renal calcium excretion (acetazolamide) [17,18]. Other factors will also bring about this condition. These include recurrent urinary tract infection, indwelling foreign bodies in the urinary tract (including catheters), a sedentary lifestyle or bed rest, and long-term dehydration—the latter often due to inadequate intake of fluids and the resulting concentration of urine. Clinical renal stone disease is associated with living in hot, arid climates, which induces sweating and loss of fluids, and frequent physical activity increasing heat loads and dehydration.

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Certain dietary factors predispose an individual to stone formation. Among these are diets rich in contributors (e.g., calcium, purine, dairy excess, oxalate, and sodium), and low fluid intake. An excess of calcium oxalate or other minerals in the diet may be due to local geographic factors such as water or soil conditions. Ironically, a diet that is too low in calcium may also promote calcium oxalate stone formation. Normally, a large fraction of intestinal oxalate is bound to calcium and undergoes fecal loss. With inadequate dietary calcium, hyperoxaluria may result from the absorption of unbound oxalate from the intestine. Urinary acidity also influences stone formation and type; low pH promotes the formation of calcium phosphate, cystine, and uric acid stones, which precipitate out of solution below 5.6 pH, whereas a high pH promotes the formation of struvite and calcium apatite stones. Anatomical factors found in stone formation include medullary sponge kidney, polycystic kidney disease, and bladder outlet obstruction, all of which produce increased particle retention. Most anatomical abnormalities would be screened out during astronaut medical selection. Underlying illness may also contribute to stone formation. Among these are sarcoidosis, hyperparathyroidism, cancer, gout, distal renal tubular acidosis, and myeloproliferative diseases. Primary and secondary errors of metabolism may also increase the concentration of stone contributors but again are expected to be screened out during astronaut medical selection. In the following paragraphs, we will discuss further the factors that lead to the formation of stones. We will address issues relevant to human space flight, including stone etiology, anatomical factors, disease states and related operational aspects of crew training and actual space flight.

Inhibitory Factors Many urinary substances have been shown to display properties that inhibit the phases of crystal nucleation, aggregation, and growth. These include ions such as citrate, magnesium, and phosphate, which bond to form soluble complexes with urinary calcium and decrease the amount of ionic calcium available to bond with oxalate. Other inhibitors include Tamm-Horsfall protein, nephrocalcin, uropontin, chondroitin-4-sulfate, heparin, and glycoaminoglycans. These primarily adhere to the surface of crystals, preventing or slowing their growth and allowing small crystals to be removed from the body with each urine void. Inhibitor compounds can be further classified as natural or exogenous. Natural inhibitor compounds are inorganic (e.g., pyrophosphate and magnesium) or organic (e.g., citrate, TammHorsfall protein, uropontin, nephrocalcin, uronic acid-rich protein, glycosaminoglycans, and prothrombin F1 peptide). Exogenous inhibitor compounds include potassium citrate or potassium-magnesium citrate, magnesium salt (usually oxide), allopurinol, thiazide diuretics, and neutral phosphates. These lead to therapeutic modalities that may prevent stone occurrence or recurrence. Inhibitory conditions to stone formation

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thus include a diet low in contributors and high in inhibitors as well as high fluid intake [19,20].

Flight Operations Astronaut training and spaceflight preparation involve several activities associated with long periods in environments that make it difficult to void or access fluids. High performance aircraft flying is known to be associated with an increased risk of stone formation. For U.S. astronauts, aircraft include the T-38 and Shuttle Training Aircraft, a modified Gulfstream jet, typically flown by astronauts as part of their training cycle. Most U.S. training occurs in the relatively warm climates of Texas and Florida, and along with flight duties vigorous physical training is required. Specific spaceflight operations that may contribute to renal stone risk include the use of full pressure suits, which may involve long periods of urinary storage without voiding and possible intentional or unintentional fluid restriction. These include launch and entry suits such as the U.S. Advanced Crew Escape Suit and the Russian Sokol, as well as extravehicular suits such as the U.S. Extravehicular Mobility Unit (EMU) and the Russian Orlan. U.S. suits are worn with an absorbent garment to accommodate voiding, but voiding is often consciously avoided by crewmembers for comfort and hygiene reasons. A drink bag is incorporated into the EMU, providing about 32 oz of water for an EVA sortie. It is not unusual to lose 1–2 kg of body mass during a 6-h EVA due to perspiration and insensible fluid loss. All of this naturally contributes to stone formation. Fluid intake can be demonstrated to decrease during flight for the reasons mentioned above, resulting in reduced urine output. Figures 13.2 and 13.3 show fluid intake and output in both short and long duration flight crewmembers [21,22].

Classic Symptoms and Signs of Stone Formation There are classic symptoms of stone formation that help in diagnosing this condition. One of the most common symptoms is agonizing pain in the lower back, occurring just below the ribs and spreading around to the front of the abdomen. The severity and character of pain associated with the presence of calculus varies by location. A calculus in the calyx, infundibulum, or pelvis of the kidney can produce discomfort that ranges from minimal to moderate. Calculi that pass into the ureter cause severe to incapacitating pain; this is usually due to complete or partial obstruction and acute distension of the collecting system. Pain may extend into the groin area when a stone passes into the ureter, often in a constant fashion; however it also may come in waves as the stone is induced to move through the ureter. In this case, the patient will feel colicky, due to episodic obstruction and subsequent distension of the ureter and mucosal irritation inducing hyperperistalsis. The pain may be nonspecific and mimic other intra-abdominal

FIGURE 13.2. Dietary fluid intake and urinary output in six astronauts during short duration space shuttle flights. BDC (baseline data collection) represents the preflight period 10 days prior to launch. E-flt is in-flight day 3–4, L-flt is in-flight day 12–13, R0-2 is landing day though 2 days post landing and R7-10 is 7–10 days post landing. Data represent the means and SEM. * p < 0.05

FIGURE 13.3. Dietary fluid intake and urinary output in 11 astronauts and cosmonauts during long duration Shuttle-Mir missions. BDC (baseline data collection) represents the preflight period. E-flt is in-flight day < 60, L-flt is in-flight day > 100. R+ day is the numbers of days post landing. Data represent the means and SEM. * p < 0.05

processes. Stones in the calices and renal pelvis may be only minimally symptomatic or asymptomatic. Sites of stone obstruction of the collecting system include the most common, the ureterovesical junction (UVJ); the second most common, the ureteropelvic junction (UPJ); and the third most common, the mid-ureter where it crosses the iliac vessels at the pelvic inlet. Obstruction at the UPJ tends to cause pain in the back radiating to the flank. Obstruction in the mid-ureter causes pain in the flank radiating into the lower quadrants of the abdomen, which can be confused with appendicitis or sigmoid diverticular disease, or in the inguinal region into the testicle or labia. Obstruction at the UVJ, in addition to groin pain, produces lower urinary tract symptoms typical of cystitis, namely, urgency, frequency, and possibly dysuria.

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On physical examination, the costovertebral angle, lower abdomen or lower back may be painful to palpation and percussion on the side ipsilateral of the stone. Bilateral pain suggests another process, such as infection. Peritoneal signs should not be present, except with the occasional forniceal rupture and associated urinoma, but then the signs are typically still focal. Pain is commonly referred to the ipsilateral groin and gonad, but these regions are non-tender to direct examination. The rectal examination should be non-tender as well. Vital signs often reflect adrenergic hyperactivity such as tachycardia and systolic hypertension, possibly shallow, rapid respirations, and diaphoresis. Skin may be pale and clammy. The presence of fever suggests associated infection. Hypotension can occur from a pain-induced vasovagal response or from dehydration associated with protracted nausea and vomiting. Sometimes gross hematuria occurs, but more commonly it is only microscopic.

Aeromedical Significance The formation of a renal stone during space flight affects not only the health and well-being of the afflicted individual, but may also jeopardize the success of the mission. The severity of the pain may be significant enough that the crewmember may not be able to successfully perform duties, such as piloting an aircraft or spacecraft or operating onboard systems. The relative remoteness of the spaceflight environment renders complications particularly worrisome. Specifically, the issues for space flight also include (1) the potential for forniceal rupture that may temporarily relieve the severe colic but causes a retroperitoneal urinoma subject to infection and diffuse ileus; (2) infection behind the level of obstruction that, due to increased pressure, increases the risk for urosepsis; and (3) a crewmember’s inability to maintain oral hydration due to the ileus. Any of these issues could lead to early mission termination.

History of Urinary Evaluation and Calculi in Space Flight Aside from the environmental risks noted above, space flight is associated with known biochemical alterations associated with microgravity adaptation and earth readaptation that are known to promote stone formation [21,22]. Table 13.1 shows urinary data accumulated from 332 astronauts during short duration Space Shuttle flights. Twenty-four hour urine collections were taken and analyzed as single samples 10 days prior to launch and on landing day. Data are the percent fraction of astronauts exhibiting increased risk for stone formation in the urinary factors shown. Hypercalciuria is defined as urinary calcium > 250 mg/day, hypocitraturia < 320 mg/day, hypomagnesia < 60 mg/day, and supersaturation values for calcium oxalate and uric acid are defined as >2.0. As is seen, the immediate post landing period, with its altered chemistries and relative dehydration, represents a vulnerable time with respect to renal stone formation.

279 TABLE 13.1. Urinary chemistries influencing renal stone risk, before and after space shuttle flight. Analyte Hypercalcuria Hypocitaturia Hypomagnesuria Supersaturation CaOx Uric Acid

Preflight

Postflight

20.8 6.9 6.0

38.9 14.6 15.8

25.6 32.6

46.2 48.6

Abbreviation: CaOx, calcium oxalate, n = 332. Data represent the percent fraction of crewmembers that exceed established risk thresholds for these analytes.

In the history of the U.S. space program, 14 renal calculus events in 12 astronauts have been recorded out of a total of 332 flown astronauts. Four of these occurred before flight (not associated with space flight), and ten occurred within 2 years postflight; two crewmembers have experienced multiple renal stone episodes. Six of these events occurred prior to 1990, and eight since 1990. In the history of the Russian space program, three cosmonauts have been identified with postflight urinary calculi. None of these were symptomatic preflight or inflight, and the stones were not detected before space flight. Subsequent evaluation of these cosmonauts revealed no anatomic or metabolic abnormalities to account for the formation of the calculi. One cosmonaut developed a presumed renal stone during a long duration mission that caused severe pain and significantly impacted the inflight timeline. This apparently passed spontaneously over a period of days, and the mission was completed. Metabolic investigations during the three Skylab missions in the 1970s showed a significant decrease in both fluid intake and daily urine volume during the first 6 days of the mission, followed by a return to preflight values in the nine crewmembers who were studied. Additional inflight changes in the urinary biochemistry included an increase in osmolality and excretion of calcium, sodium, potassium, chloride, phosphorus, and magnesium. Significant decreases in uric acid levels were observed. These changes may be critical in the development of renal stones due to the increase in concentration of the stone-forming salts in a decreased daily urine volume. Postflight results during the first 6 days showed some contrasting results to inflight data, including a significant decrease in the urinary excretion of sodium, potassium, chloride, phosphorus, magnesium, and uric acid. Urinary calcium levels continued to exceed preflight values. No changes in urinary creatinine values were detected [3]. The postflight changes may reflect a physiological adaptation to gravity and may be influenced by the ingestion of a saline solution taken before landing to minimize orthostatic intolerance. With the exception of urinary sodium, all of these urinary components returned to preflight levels 14–18 days following landing. [7,9] As noted in Table 13.1, data collected after space flight, within the first few hours of landing, indicate changes in the urine chemistry favoring increased risk of calcium oxalate

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and uric acid stone formation. Preflight and postflight data specifically targeting renal stone risk have further shown that crewmembers increase the concentration of salts in urine, decrease some urinary inhibitors of renal stone development, and increase the risk of calcium oxalate and calcium phosphate (brushite) stone formation. Table 13.2 compares values for renal stone risk parameters measured in 24-h urine collections obtained preflight (10 days prior to launch) and postflight (beginning at landing). It is possible that different mechanisms may increase the risk for renal stone development during different stages of space flight, namely exposure to the microgravity environment and readaptation to gravity following space flight. Various factors may account for this increased risk, although actual quantitative inflight data are limited. These factors include the decrease in daily urine output as a result of lower fluid intake arising from decreased appetite and increased workload schedules during the flight, as well as from space motion sickness during the first few flight days. Microgravity exposure associated with space flight causes the bones to lose calcium and the excess calcium to excrete as urinary waste (resorptive hypercalciuria). Given that ∼ 70% of kidney stones are calcium containing, the increased load of calcium into the urine increases the risk of calcium stone formation. It has been shown that the urine of astronauts is saturated with calcium salts. Similarly, citrate, an inhibitor of renal stone formation, has been shown to decrease during early space flight and immediately postflight at landing, thereby increasing the risk of renal stone formation [21,22]. Table 13.3 compares preflight, inflight, and postflight values of key urinary analytes TABLE 13.2. Renal stone risk assessment before and after spaceflight. Analyte Total volume (L/day) pH Calcium (mg/day) Phosphate (mg/day) Oxalate (mg/day) Sodium (mEq/day) Potassium (mEq/day) Magnesium (mg/day) Citrate (mg/day) Sulfate (mmol/day) Uric Acid (mg/day) Creatinine (mg/day)

Preflight 2.08 (0.06) 6.02 (0.02) 188.4 (5.34) 1043.8 (24.56) 36.7 (0.92) 163.1 (3.56) 67.1 (1.28) 114.3 (2.36) 707.9 (16.46) 22.4 (0.41) 655.0 (12.20) 1724.0 (23.2)

Postflight

p value

1.98 (0.06) 5.71 (0.03) 236.5 (6.48) 868.4 (18.53) 35.8 (0.87) 119.6 (3.63) 52.7 (1.10) 100.8 (2.18) 623.2 (17.66) 24.9 (0.48) 570.7 (13.56) 1769.3 (28.81)

0.076 <0.001 <0.001 <0.001 0.365 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.106

2.26 (0.08) 0.98 (0.06) 1.48 (0.08) 0.60 (0.08) 2.54 (0.10)

<0.001 <0.001 <0.001 <0.001 <0.001

Relative urinary supersaturation Calcium oxalate Brushite Sodium urate Struvite Uric acid saturation

1.56 (0.06) 1.30 (0.07) 2.62 (0.13) 2.27 (0.49) 1.88 (0.09)

These data show significant changes in parameters known to influence renal stone formation for postflight values compared with preflight values for Shuttle missions less than 18 days in duration. Data represent the means (+/− SEM) before flight and on landing day. Statistical analysis by paired t-test, n = 330, except oxalate and calcium oxalate, n = 329.

for a single crewmember of a long duration flight. Further study is ongoing to bolster these data, but the trend toward increased renal stone risk is evident. Through both space-related research and Earth-based clinical research, NASA has amassed a large database for studying risks and countermeasures for renal stone formation. The most obvious and easily implemented reduction in risk could be obtained primarily by increasing the fluid intake to increase the daily urine output to 2 L/day. In this way, the excess salts in the urine may remain in solution, crystals will not form, and a renal stone will not develop. However, without addressing the underlying calcium excretion due to bone loss, this treats the symptoms and not the cause of the increased urinary salts. Additionally, because of the space motion sickness experienced by many astronauts early in flight, increasing fluid intake may not be possible due to decreased appetite and nausea. A retained urinary crystal formed during these early days may grow to a renal stone during the remaining stay in microgravity.

Countermeasures and Risk Assessment Dietary modification and promising pharmacologic treatments may be used to reduce the potential risk for renal stone formation. Diets low in oxalate content and reduced animal proteins may be advised. Some of the inhibitor substances are being considered for higher risk spaceflight crewmembers. Potassium citrate is used clinically to minimize the development of crystals and the growth of renal stones. Possible side effects, although uncommon, include minor gastrointestinal complaints—e.g., abdominal discomfort, vomiting, diarrhea or nausea, upper gastrointestinal lesions—estimated at 1 per 100,000 patient-years; and hyperkalemia, which may occur in subjects with renal disease (a potentiality that has been screened out in astronaut population) or with potassiumsparing diuretic ingestion or acute dehydration. These risks may be minimized by providing slow-release wax matrix tablets, ingesting the dose with meals, ingesting the tablet whole without chewing, crushing or sucking the tablet, limiting additional salt intake, and encouraging high fluid intake. Currently a study is being conducted at NASA Johnson Space Center to look at the efficacy of potassium citrate as a prophylactic countermeasure for space flight. This agent has been used prophylactically during space flight in known stone formers who received a medical waiver for short duration missions. Potassium-magnesium citrate is also under clinical study and may soon be approved as perhaps an even more robust inhibitor of stone formation [23–27]. Inhibiting bone resorption associated with microgravity should also diminish the risk of renal stone formation. In theory, this could be accomplished by physical loading (exercise countermeasures) or pharmaceutical agents. Bisphosphonates are a class of drugs that has demonstrated efficacy in treating elderly patients with osteoporosis by inhibiting the loss of bone. These agents could potentially prevent the bone loss observed in astronauts and thereby avert the stone promoting

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TABLE 13.3. Urinary parameters (analytes, volume, pH, and supersaturation) influencing renal stone risk in a single crewmember throughout a long duration flight. Parameter

PRE

FD < 20

FD < 30

FD < 100

FD > 100

R+0

R+7

R+10–14

TV Ca Ox UA Cit pH Na SO4 P Mg K Cr

1.79 211 35.7 676 691 5.93 221 25.0 802 139 79 1701

1.043 255 13.1 376 610 6.14 141 25.6 881 175 80 1841

0.973 245 17.7 632 962 5.97 183 22.4 1110 132 73 1910

1.109 436 38.6 659 1119 5.49 269 34.3 1409 199 96 2160

1.038 338 39.9 571 765 5.34 158 25.4 1163 169 80 1946

0.54 224 20.5 355 618 5.22 136 23.5 544 109 64 1408

0.73 113 27.2 523 895 6.18 211 14.6 797 87 57 1507

1.85 161 35.5 518 1043 6.28 119 10.3 694 142 101 1717

1.24 4.14 1.11

1.61 3.44 2.77

4.02 2.59 5.48

4.53 1.57 6.11

4.46 1.25 8.31

1.69 2.20 2.02

1.19 0.97 0.67

L/day mg/day mg/day mg/day mg/day mEq/day mmol/day mg/day mg/day mEq/day mg/day

Relative supersaturation CaOx CaP UAS

1.60 1.09 2.66

Abbreviations: PRE, preflight; FD, flight day; R, return day; TV, total volume; Ca, calcium; Ox, oxalate; UA, uric acid; Cit, citrate; Na, sodium; SO4, sulfate; P, phosphorus; Mg, magnesium; K, potassium; Cr, creatinine; CaOx, calcium oxalate; CaP, calcium phosphate; UAS, uric acid saturation.

resorptive hypercalciuria. Studies are planned for the ISS to answer the question of efficacy of bisphosphonates in reducing renal stone risk.

Renal Stone Risk Assessment U.S. crewmembers are assessed with the renal stone risk profile (Mission Pharmacal, University of Texas Southwest Laboratories). Although the urinary risk profile does not directly predict the formation of renal stones, it illustrates to the flight surgeon and crewmember the current urine chemistry environment [28–31]. Figures 13.4 and 13.5 show preflight and postflight renal stone risk profile graphics for an individual. The graphic provides a convenient and easily interpretable risk profile understood by flight surgeons and crewmembers. In our retrospective review of cases and from our review of the postflight renal stone risk index assessment (RSRI), we found a 93% correlation between known stone formers and a high RSRI. All but one case were found to have significant abnormalities; the one case had minor abnormalities. There were some false positives in prospective cases, confounded by urine collection biases, but there were no false negatives. The risk profile considered in conjunction with the lifestyle and dietary habits of the individual can be a valuable monitoring and education tool. Individuals who are at an increased risk or have previously formed renal stones can be followed, patient compliance can be assessed, and the effectiveness of medical treatment can be determined with this profile. The renal stone risk profile has proven value in the clinical setting as a tool for classifying patients as to the etiology of the formation of their renal stones [17,27,30,32]. Table 13.4 shows the listed physician/patient information derived from the renal

stone risk profile, with guidelines for acting on significant findings. The relatively low cost of the renal stone risk profile makes this a cost-effective methodology, which may mitigate the potential for a mission impact if a crewmember is afflicted with a renal stone inflight. Clinical experience has shown that a program of monitoring the urinary environment and estimating the risk for renal stone development can lead to nearly total control of stone disease. The need for stone removal can be dramatically reduced by an effective prophylactic program. As applied to the U.S. space program, this health care monitoring program may provide several distinct advantages. Crewmembers experiencing an increased risk prior to space flight, who are then exposed to the microgravity environment and resultant bone loss, hypercalciuria, and increased urinary sodium, and decreased urinary output may have further increased their risk of renal stone formation. The RSRI evaluation would identify the risk prior to flight, generate appropriate medical intervention, and reduce the potential risk before, during, and after space flight. In implementing the schedule of RSRI measurement by 24-h urine collection, it was determined that all astronauts should have an annual examination—with another examination conducted preflight for Space Shuttle crews—only as indicated by a history of previous calculi or previously high risk index. The examination should be given postflight during the comprehensive medical examination performed 3 days following return in all crews. Pak et al [18]. concluded that for terrestrial stone formers, the reproducibility of urinary stone risk factor analyses is satisfactory in repeat urine samples and a single stone risk analysis is sufficient for a simplified medical evaluation of urolithiasis. The accuracy of

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FIGURE 13.4. Graphic representation of the renal stone risk profile derived from a 24-h urine collection in the preflight period before a Shuttle launch, typically obtained 10 days prior to launch. Reproduced with permission from the University of Texas Southwestern Medical Center at Dallas.

measuring urinary stone promoter and inhibitor substances is improved by including matrix components, uroproteins, uromucoid, and glycosaminoglycans in the analysis [20]. Other laboratory analysis for urinary stones include blood urea nitrogen, serum electrolytes, creatinine, calcium, uric acid, and phosphorous.

Treatment of Renal Stones Available treatment options for urinary calculi vary depending on the size, location, and composition of the calculus. The vast majority of stones will be calcium oxalate or mixed with a calcium oxalate component and are therefore easily visible on x-ray or fluoroscopy. Pure calcium phosphate stones

(brushite) are less common but very radiodense. Pure uric acid stones represent only 10–15% of the total and are completely radiolucent. They require ultrasound or computed tomography (CT) to detect on imaging. Stones that are less than 5 mm (0.2 in.) in diameter, smooth on the surface, and drop into the ureter will often pass spontaneously with hydration and analgesics and, therefore, will not require therapeutic intervention beyond pain management. Stones larger than 5 mm or possessing surface irregularities will usually not pass on their own and will require intervention for removal. Typically extracorporeal shock wave lithotripsy (ESWL) is the treatment of choice for radio-dense stones in the calices, renal pelvis, or upper ureter, although occasionally upper ureteral stones require retrograde manipulation to fragment well

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283

FIGURE 13.5. Renal stone risk profile for the same individual derived from a 24-h urine collection beginning in the immediate post-landing period. Multiple parameters show elevated risk as compared with preflight values. Reproduced with permission from the University of Texas Southwestern Medical Center at Dallas.

extracorporeally. Most ESWL devices require radiographic localization and so are not appropriate for uric acid stones, although ultrasound may be used to localize the stones. All stones that are large enough for ultrasound to detect (> 3 mm) can be treated with ESWL. Cystine and other stones resulting from metabolic disorders should have been screened out at the time of astronaut selection and, therefore, should not be an issue in a spaceflight crew. Calculi in the mid-ureter are often inaccessible to shockwave energy for treatment and require other modalities. Lower ureteral stones can be treated with some ESWL machines that treat in the prone position. ESWL can be performed without invasive procedures and, depending on the required energy and size and shape of the focusing reflector, using intravenous sedation with or without local anesthesia. If the stone

bulk is 1.5 cm or larger, most urologists will place a stent cystoscopically in the ureter prior to the ESWL to prevent a “Steinstrasse” (German for “street of stones”) obstruction of the ureter with a column of stone fragments. Large stones in the calyx or renal pelvis (partial or complete staghorn calculi) or stones associated with UPJ obstruction are often treated with percutaneous nephrolithotripsy with or without endopyelotomy. Stones that pass into the mid and lower (distal) ureter are often treated by ureteroscopy, which requires dilation of the UVJ followed by passage of a ureteroscope to the level of the stone. Here, under direct visualization, the stone can be placed in a basket and extracted or fragmented with any of several types of lithotrites—ultrasonic, electrohydraulic, and laser, Holmium being the current laser of choice [16].

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Management of Renal Stones in Astronauts After a stone has been diagnosed, a crewmember will be taken off flight status for both space flight and aviation. Should a stone arise in the final weeks prior to launch, the Aeromedical Board has the choice of recommending launch delay or the use of an alternate crewmember for flight. After treatment, a 3-month follow-up survey is conducted with x-ray examination of kidneys, ureter, and bladder and nephrotomograms or spiral CT to ensure clearance of all fragments. In addition, a comprehensive program is implemented to reduce the risk of recurrence. The crewmember is required to increase oral fluid intake (i.e., water, mineral water with bicarbonate, lemonade and other citrus fruit juices, and clear sodas); limit sodium intake, and make further dietary modifications based on the individual risk index. These can include a decrease in animal protein intake to reduce uric acid in the urine, and a decrease in oxalates-containing foods such as beets, spinach, chocolate, strawberries, coffee, Swiss chard, cola, tea, nuts, wheat bran, and rhubarb. Further, the crewmember usually receives a test dose of potassium citrate for determine tolerance to the medication. Other possible medications that might be considered include allopurinol for uric acid and gout, potassium citrate with magnesium, and thiazide diuretics for renal calcium leak. The crewmember is also advised to avoid caffeine-containing products such as coffee, tea, and colas. If a crewmember has been rendered stone-free, a metabolic stone work-up is performed, including a repeat 24-h urine collection for renal stone risk profile to rule out a treatable etiology for the stone disease. Due to the extensive screening at the time of selection, the vast majority of these stones will be found to be environmental. In these cases, the RSRI will help identify specific risk factors that may be addressed to prevent further stone episodes. In some instances, specific agents may require augmentation in the crewmember’s urine to prevent recurrence; e.g. supplementation of citrate or magnesium if these stone inhibitors are found to be low. If the crewmember is found to be persistently stone-free and has no latent metabolic condition, the Aeromedical Board reviews the case and considers a waiver for aviation operations and short-duration space flight, typically 2 weeks or less. Preflight tomograms obtained about twelve weeks prior to flight will ensure that the individual remains stone free and allow time for treatment options if small stones are found. For those astronauts with a history of environmental stones who are flying short duration flights, certain in-flight procedures are followed to prevent the formation of further stones. In addition, the flight surgeon ensures the crew medical officer (CMO) assigned to the flight, typically a non-physician, is proficient in performing onboard urinalysis and administering treatment in the event of inflight recurrence. Even in the case of a single environmental stone in the distal tract with no other predisposing factors, the individual is not eligible for long-duration space flight (greater than 30 days’ duration). Incidentally, all long

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duration crewmembers undergo screening ultrasound of the abdomen and pelvis about 6 weeks prior to flight.

Inflight Prevention and Management In flight, crewmembers follow procedures that prevent the growth of stones. Specifically, taking oral fluids in amounts sufficient to maintain adequate hydration is encouraged. If an astronaut is suffering from severe space motion sickness during early flight, intravenous fluids may be considered to guard against dehydration. Also, sodium consumption should be limited in flight. As noted earlier, potassium citrate or potassium-magnesium citrate may be useful countermeasures to stone formation in certain high-risk individuals. Imaging technology is unavailable to diagnose this condition in the crews of Shuttle flights, but ultrasound is available to the crews on the ISS. If stones occur in flight, spaceflight crews can take specific steps to respond and mitigate further risk. On orbit, the CMO with guidance from ground medical specialists would monitor an affected crewmember’s vital signs, hydration status, and clinical appearance. Also available to the CMO are the means to follow urine output, assess urine specific gravity and certain chemistries, and test for the presence of leukocytes and hemoglobin in the urine using colorimetric reagent dipsticks. Dehydration is addressed with oral fluids as a mainstay; intravenous fluids are available in limited quantities. It is also the CMO’s responsibility to administer medications as needed. Pain management will be paramount; available parenteral medications include meperidine, morphine, and ketorolac (Toradol). Oral medications include oxycodone, acetaminophen with and without codeine, and nonsteroidal anti-inflammatory agents. Other available medications that may be useful for stone management include antiemetics such as promethazine. Further, the CMO evaluates pain resolution, strains urine to capture a passed stone, and assesses the crewmember’s duty status. Ultrasound is available, on the ISS, allowing a CMO to perform an exam with real-time guidance from ground specialists. Such guided ultrasound has been performed and shown to provide adequate diagnostic imagery. Ultrasound may be used to show visible calculi in UPJ, UVJ, or renal pelvis. It may also show unilateral distension of the collecting system (either hydronephrosis or hydroureter) ipsilateral to the side of pain, if adequate time has passed to allow distention. Ultrasound may also show loss of ureteral jet in the bladder ipsilateral to the side of pain. It is expected that, in the course of pain management and hydration, most stones arising inflight would pass spontaneously. However, it is possible that complications such as obstruction with hydronephrosis, sepsis, or intractable nausea and emesis may prompt a medical evacuation. The basic steps of hydration and pain management would be required during entry and landing and may be dependent on the return vehicle. Following recovery from the U.S. Shuttle or Russian Soyuz, the crewmember would be transported to a medical facility for definitive treatment.

13. Renal and Genitourinary Concerns

Clinical Genitourinary Issues Examinations Many factors are taken into account when selecting candidates for human space flight. Obvious factors covering the genitourinary system include the astronaut’s health history, which includes family history (renal disease, tumors, and calculi), personal medical history (infections, nephropathies, and cancer), and personal surgical history (any urological, abdominal, or inguinal procedures). Astronaut applicants are also screened for certain symptoms or physical signs, such as pain or discomfort in the back, lower abdomen, genitals, or rectum or while voiding or defecating. Voiding symptoms address issues of urine volume, either decreased (oliguria) or increased (polyuria); irritative symptoms, including frequency, urgency, dysuria, and nocturia; obstructive symptoms, which include diminished force and caliber of urine stream, spraying of stream, hesitancy, dribbling, straining, and a sense of residual urine following voiding; and incontinence. Not surprisingly, astronaut candidates are subjected to an exhaustive physical examination that, in renal and genitourinary terms, includes an abdominal and inguinal examination and a genital examination. Laboratory tests are conducted on serum chemistries, including electrolytes, blood urea nitrogen, creatinine, uric acid, calcium, and phosphorous. Urinalysis is performed to test for pH, specific gravity, protein, glucose, leukocyte esterase, nitrites, hemoglobin, urobilinogen, and bilirubin. A cystine screen is also performed, supplemented by a cyanide nitroprusside test if the cystine level is greater than 75 mg/L or greater than 250 mg/24 h. Microscopic analysis for urinary crystals, red blood cells (RBCs), white blood cells (WBCs), casts, and transitional epithelial cells is performed routinely. Renal imaging is performed on prospective astronauts using ultrasonography. Some international space programs, for example Russia, also perform routine intravenous pyelogram (IVP) on initial selection. The potential crewmember must have two kidneys in normal anatomic location with normal parenchyma and collecting systems. Masses detected on ultrasound may require further imaging. Smooth, simple cysts require no further evaluation. Computed tomography is indicated for evaluation of solid masses or irregular cysts. Malformations, presence of urinary calculi, or hydronephrosis are causes for rejection. Further tests may be performed when evidence of abnormalities arises on standard evaluations that may or may not be disqualifying. Unexplained asymptomatic hematuria or pyuria is an occasional cause of such further evaluation. Functional anatomy of the renal system may be discerned by IVP or intravenous urogram. Voiding cystourethrography may be performed to rule out vesicoureteral reflux and urethral strictures. Combined nephrotomographic X-ray and IVP is the imaging approach of choice that is used by NASA physicians

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when clinical or first line diagnostic evidence suggests urinary calculi. However, from 10% to 12% of stones will be radiolucent and may be missed or show up as a filling defect on an IVP. More advanced imaging modalities may be employed to evaluate abnormalities in potential astronaut candidates. CT scanning provides higher anatomical detail for evaluation of renal masses as seen on IVP or found to be solid on ultrasound. Some CT scanners can provide high-quality axial, sagittal, and coronal views. Spiral CT images with fine cuts can be used to evaluate the kidneys for calculi, with the advantage of visualizing both radiolucent and radiopaque calculi in the absence of contrast media. Spiral CT also provides staging information for evaluation of genitourinary malignancies and can be used to evaluate multiple abdominal organs in the evaluation of abdominal pain of uncertain origin. Such CT scans may involve an ionizing radiation dose of 0.5 rem. Magnetic resonance imaging (MRI) may also be used to provide high anatomic detail in axial, sagittal, and coronal views without the use of ionizing radiation. Many MRI machines also allow 3-dimensional reconstruction of suspect areas. The application of T1 and T2 weighting allows differentiation of tissues within solid organs without the need for contrast, although gadolinium can be given to enhance the appearance of tumors. The powerful magnetic field that is produced by MRI can affect individuals who have implanted metallic devices; however, any retained metal bodies are cause for rejection into the astronaut program. Cystoscopy may be performed by a consulting urologist in the evaluation of hematuria, asymptomatic infection in male candidates, or intraurinary tract anatomic lesions noted on imaging studies. This procedure involves passing a lighted scope retrograde through the urethral meatus into the bladder. Cystoscopy can be performed on an outpatient basis under anesthesia when rigid instruments are used, or with local anesthesia when a flexible scope is used. Urodynamics studies to assess voiding function may be indicated; these include uroflowmetry, cystometrogram, and pressure-flow studies. Uroflowmetry measures the flow rate of urine as the subject voids into a calibrated flow meter toilet. A cystometrogram measures the pressure in the bladder as it fills. It requires a small indwelling catheter in the bladder during filling. The filling media can be water, contrast enhanced water, or carbon dioxide. Pressure-flow studies are a combination of uroflowmetry and a cystometrogram that differentiate outflow obstruction from detrusor (bladder muscle) dysfunction. When used by a consulting urologist, pressure-flow studies evaluate for either obstructive or irritative voiding symptoms or urinary incontinence. These studies allow an objective assessment of the subject’s voiding characteristics by quantifying urine flow and measuring voiding processes. In its most sophisticated form, testing combines all three of these methods under video recording and fluoroscopy for post-study review and anatomic and physiologic correlation.

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Annual Examination An astronaut’s annual examination involves a detailed intervening clinical history, a physical examination, and blood and urine laboratory tests. The clinical history specifically queries the subject concerning pain, voiding symptoms, infertility, and impotence. Physical examination entails surveillance and screening for tumors (prostate, renal, bladder, gonadal, cervical, and adrenal), sexually transmitted diseases and urinary tract infections, and for hernia in the inguinal canal. Annual examination also includes blood and urine chemistries and analysis similar to those on initial selection. Imaging studies and other more targeted laboratory studies may be performed if clinically indicated, such as in the workup of incidentally found hematuria or pyuria. Serum prostate specific antigen (PSA) is measured in men annually and has become more prominent in recent years as a screening modality. PSA is a protease secreted by the prostate as a constituent of seminal plasma that liquefies the viscous semen. PSA is stored in the lumen of prostate glandular ducts, and a small amount is released into the systemic circulation where it can be measured in serum. The PSA can be elevated from several conditions, such as BPH, prostatitis, prostatic infarction, vigorous manipulation (especially biopsy), and, most importantly, cancer. PSA levels slowly rise with age reflecting the age-related increase in prostatic size; as such, age-specific reference ranges must be used to determine if increased values warrant further diagnostic study [33]. Increased PSA density (the amount of PSA per volume of prostate tissue as measured on transrectal ultrasound), PSA velocity (rate of rise of PSA over 12 months, in which there is concern if the increase is greater than 0.75 ng/ml in a year), and ratio of free to bound PSA all increase the positive predictive value of prostatic tumor [34].

Glomerular Disease

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diagnosis is established, we recommend no attempt be made in definitive diagnosis for several reasons. In the typical incidental finding, there is no evidence of a more severe glomerulopathy. Usually this condition has been present for many years, with no evidence of progression or findings suggestive of renal insufficiency. No specific therapy is indicated, unless renal function begins to worsen. The crewmember will most likely not experience any health effects from this in his or her lifetime, much less within his or her career; and finally, performing a renal biopsy carries a not-insignificant risk. Instead, we recommend a program of monitoring be performed during which unrestricted training is allowed. IgA nephropathy is a slowly progressive condition, so that semiannual monitoring suffices to identify any development of renal insufficiency before a crewmember’s health is affected. Monitoring should involve a 24-h urine collection at each annual physical with action thresholds as noted in Table 13.4. In addition, a urinalysis should be performed every 6 months between annual exams. Although this test is less sensitive than the 24-h urine test, it would nevertheless detect any rapid worsening of renal function manifested by proteinuria, hematuria, or casts. A 24-h urine demonstrating no worsening of renal function is desirable no more than 1 year before the planned end of a space flight. If flight is delayed, it is recommended that another collection be obtained prior to the passage of another year. Also, a 24-h urine collection should be performed 1 month after returning from long duration flight. In this evaluation, we specifically look at blood urea nitrogen (BUN), creatinine, creatinine clearance, and total protein. With reference to a crewmember’s baseline, a urinalysis obtained 10 days prior to launch would not be considered abnormal unless it shows more than ten red blood cells per high power field or significant proteinuria. TABLE 13.4. Renal stone risk report, showing suggested actions based on parameters above the risk threshold. Renal stone risk assessment

Incidental hematuria is a not uncommon finding during routine health screening in the aeromedical population. In the evaluation of incidental hematuria, normal radiological and direct imaging studies may rule out pathology of the lower urinary tract. This would suggest a glomerular process. Nephropathies such as IgA nephropathy (Buerger’s disease) or idiopathic renal hematuria are the most common cause of recurrent glomerular hematuria, accounting for 10–40% of the glomerulonephritides. Fewer than 15% of individuals with IgA nephropathy develop progressive renal insufficiency over a 15year period, and 30–40% of individuals with IgA nephropathy develop renal insufficiency in their lifetimes. Indicators of a poor prognosis include increasing age, hypertension, preexisting renal insufficiency, male gender, and elevated urine protein (in the nephritic range). A definitive diagnosis is a finding of IgA deposits in glomerular mesangium on biopsy. For spaceflight crewmembers with normal renal function and apparent glomerular hematuria for which no definitive

Physician–patient information Evaluation should include patient history, predisposing medical conditions, medications, and lifestyle Urinary chemistry ® Hypercalciuriaa [>4 mg/kg/day or >250 mg/day in F and >300 mg/day in M] Preflight v Measure blood ionized calcium v If elevated, metabolic evaluation, incl. PTH v Increase fluid intakeb v Reduce sodium intake v Urinalysis-microscopic for crystals v Consider metabolic work-up, to include calcium load test(Pak) v Absorptive (type I or II – 50–60%) vs. renal leak – 5–10% v Treat according to Dxd (e.g. orthophospahte, thiazides, cellulose phosphate, diet) Postflight v Increase fluid intakeb v Reduce sodium intake v Follow up urinalysis – microscopic for crystals (continued)

13. Renal and Genitourinary Concerns TABLE 13.4. (continued) ® Hyperoxalauria [>45 mg/day] v Dietary counseling, reduce oxalate intakec v Greater than 100 mg/day, consider metabolic evaluation ® Hyperuricosuria [>600 mg/day in F and >750 mg/day in M] v Dietary counseling, lower purine (meat) intake v Increase urine volume v Blood uric acid level (possible allopurinol, KCit1) ® Hypocitraturia [<320 mg/day] v Increase dietary alkali intake (fruits/vegetables) v Increase urine volumeb v Consider potassium citrate tabletsd ® Hypomagnesiuria [<40 mg/day] v Increase dietary alkali intake (fruits/vegetables) v Supplement with Magnesium oxided ® Low urine volume v Increase fluid intakeb Urinary supersaturation ® High calcium oxalate/brushite (>2.0) v Increase fluid intakeb v Dietary counseling – avoid calcium excess, reduce sodium intaked v Consider magnesium oxide supplementationd v If CaOx is high, consider Kcit, KmgCit ® High urinary uric acid supersaturation (>2.0) v Increase fluid intakeb v Review protein ingestion, consider reduction if excessive [>12 oz. beef/pork/poultry per day] v Check urinary Ph (>7.0 predisposes for brushite,<5.5 predisposes for uric acid) Consider urinary alkalinization v (potassium citrate) v If serum uric acid is elevated, if have gouty symptoms or if having uric acid calculi v possible treatment with allopurinol Assess urinary chemistry and re-evaluate in 6 weeks ® High sodium urate (>2.0) v Dietary counseling, decrease sodium intake v Increase fluid intakeb ® High struvite (>75.0) v Check urinary pH (>7.00) v Evaluate for urinary tract infection and treat with appropriate Antibiotic or v possible acetohydroxamic acid v Increase fluid intakeb This information is used for preventive measures and crewmember counseling. All passed or extracted stones should be collected and analyzed. a Dietary calcium restriction is not advised due its influence on bone and oxalate absorption. 800–1000 mg/day is appropriate for all patients, from food sources, not supplements. b Minimum 2.5 L/day recommended urine volume. c A comprehensive list of food with oxalate contents is available upon request. d Treatment recommendations: KCit – 20 mEq bid to adjust urinary pH to 6.5. (KMg Cit is also recently being used clinically for prophylaxis). MgOx – 300–450 mg/day. Allopurinol – 300 mg/day. Orthophosphate – 1.5 g elemental P/day – divided doses. Hydrochlorohtiazide – 25 or 50 mg bid.

Should renal function begin to deteriorate, there are few general treatment options for progressive IgA nephropathy. The first treatment, immunosuppressive therapy with steroids or azothioprine (Immuran), can often arrest the progression of

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the condition and mitigate the need for further treatment. Failing this, renal dialysis, or in select cases, renal transplant offer further therapeutic options. Progressive nephropathy and all other nephropathies, with the exception of nil disease (minimal change), typically involve significant renal dysfunction. These are likely to require aggressive treatment and will most likely be disqualifying for future space flight (Table 13.5).

In-Flight Management of Genitourinary Problems In flight, the CMO—who is also an astronaut, a member of the crew, and may or may not be a physician but will, in any case, have basic medical training—should have knowledge of the other crewmembers’ relevant medical history. Further, the CMO should be trained to provide onsite treatment of infections, urinary obstructions and retention, urinary calculi, and other such problems that arise within the crew. An onboard medical checklist provides step-by-step guidance in treatment, and consultation with ground medical specialists is available at all times. Aside from renal stones and urinary retention, most genitourinary problems arising during a mission are expected to be infections. Some of the more common of these are discussed below.

Urethritis/Cystitis Infections Irritative voiding symptoms are the hallmark of cystitis, although the sufferer may have a honeymoon period of asymptomatic bacteriuria for a period prior to onset of symptoms. Dysuria is the most common complaint, but typically a patient will also suffer from urinary frequency, urgency, occasionally incontinence, and pain or discomfort in the suprapubic region, lower abdomen, or flank. Moreover, a patient will occasionally have gross hematuria, fever, or back pain. The suprapubic region or the area along the course of the urethra will be tender to palpation. Cloudy and foul-smelling urine are classic signs of this urinary tract infection, although early infections may exhibit neither. Cystitis is usually not associated with fever or leukocytosis. The presence of either of these is indicative of systemic toxins, most likely due to an ascending infection that will likely progress to pyelonephritis or lobar nephronia. Urinalysis is the most helpful and available immediate clinical indicator of cystitis, showing positive for leukocyte esterase and, possibly, nitrites on the urine reagent dipstick. It is not unusual for the hemoglobin test to be weakly positive, but this is not required for diagnosis. Leukocyte esterase is positive when the local immune response has been provoked and polymorphonuclear neutrophils (PMNs) are shed into the urine. Positive nitrites indicate the presence of a bacterium that can convert nitrates to nitrites, usually a gram-negative enteric species. Microscopic examination of the urine will

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TABLE 13.5. 24-h urine analysis regime for monitoring of IgA nephropathy. Parameter

Normal range

Off-nominal range

Abnormal range

Protein

< 1 g/24 h

1.5–2.5 g/24 h

> 2.5 g/24 h

CrCl (normalized to 1.3 M2BSA)

95–120 cc/min

< 80 cc/min

< 70 cc/min

Action

Continue monitoring

Repeat in 1 week to 1 month. If repeat is not in normal range, refer to nephrology

Immediate referral to nephrology

10–25 mmHg ∆ in SBP

> 25 mmHg SBP

Blood pressure Blood pressure reading

5–15 mmHg ∆ in DBP

> 15 mmHg DBP

Action

Continue monitoring

Repeat x3 days – consult Nephrology if persists

Immediate Nephrology Consult

Urinalysis # RBCs/HPF

0–3

3–10

> 10

Protein on dipstick

None

1–2+

3 + or >

Action at L-10

None

None. Considered consistent with known pathophysiology in this individual

Repeat in 24 h. If repeat is not in normal range, consider standard hematuria workup or 24 h collection at discretion of flight surgeon

Action at 6 month check

Continue monitoring

Continue monitoring. Considered consistent with known pathophysiology in this individual

Perform 24 h urine. If not in normal range, refer to nephrology.

Abbreviations: CrCl, chromium chloride; M2BSA, body surface area in square meters; SBP, systolic blood pressure; DBP, diastolic blood pressure; RBC, red blood cells; HPF, high power field. Source: Developed by J. Jones, T. Marshburn, NASA Johnson Space Center, Houston, TX.

often show increased urine sediment, including amorphous debris, PMNs, and bacteria. If the sample is fresh, the bacteria may demonstrate motility under microscopic analysis. The onboard CMO will have urinalysis dipsticks and in the future microscopic resources available to perform these tests. Organisms are likely to be simple community acquired species, including E. coli (79–90%), Klebsiella (5%), Enterobacter (2%), Staphylococcus saprophyticus or epidermidus (up to 10%), and Streptococcus faecalis (Enterococcus). Other nonbacterial organisms may also be present, including Chlamydia, unreaplasma, mycoplasma, Candida, and Adenovirus 11 and 21; both are associated with hemorrhagic cystitis. Upper tract infections will also include Proteus and Pseudomonas. Proteus mirablis and Klebsiella can contain ureases that split urea into ammonia, inducing an alkaline urinary pH. They may thus create a favorable milieu for the precipitation of magnesium ammonium phosphate (struvite) stones. The means to identify bacterial species inflight are not yet available on ISS; however, it is planned to add this capability in later stages of operations. Treatment of simple cystitis includes oral hydration with 2–3 L of water daily, oral antibiotics, and symptomatic relief with an agent such as pyridium. While pyridium provides local urinary analgesia, it also discolors the urine, turning it orange; the crewmember should be briefed about this effect prior to its use. For more severe symptoms, an antispasmodic agent (anticholinergic) may be considered, with careful attention to side

effects. Antibiotics of choice for treating cystitis include oral nitrofurantoin and combinations of sulfa and trimethoprim. Second-generation penicillins and cephalosporins are also effective but are more likely to adversely affect indigenous normal flora. Later-generation beta-lactams, aminoglycosides, and quinolones should be reserved for more complicated or refractory UTIs. Prophylaxis for a crewmember with a known history of UTIs may be advisable for the duration of a flight. This is best performed with a urinary antiseptic such as mandelamine mandelate, which is converted to formic acid in the urine, or a urinary-specific antimicrobial agent such as nitrofurantoin, which is less likely to produce side effects (e.g., diarrhea, vaginitis, or cutaneous drug reaction). Nitrofurantoin has a broad spectrum of action against community-acquired organisms and a low inherent resistance due to multiple sites of action. Neither of these medications is flown as a matter of course in the Space Shuttle or ISS medical kits, but either could be added to the manifest as needed. The sulfamethoxasole/trimethoprim combination, which is flown in the onboard kits, has a slightly higher but acceptable side effect profile.

Pyelonephritis Upper tract infections would represent a serious medical event during a space flight. Management would be highly dependent on the vehicle and mission setting. If the classic signs

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and symptoms are exhibited, including flank pain, fever, and shaking chills, immediate consultation with ground urology specialists is warranted. Treatment of preflight or postflight pyelonephritis would vary somewhat in light of the magnitude of systemic systems exhibited by the patient. If systematic symptoms are minimal and a close follow-up is possible, it may be appropriate to treat with oral hydration and high-dose oral bactericidal broadspectrum antibiotics such as quinolones. If systemic systems are moderate to severe, for instance to include toxemia (e.g., the patient’s temperature is higher than 38.5°C, the WBC is greater than 12.5 thousand or shows a significant left shift, or the patient is shaking with chills/rigors, etc.), the patient should be hospitalized, urology consulted, and the patient placed on IV fluids and antibiotics. A renal ultrasound should also be considered to rule out the possibility of urinary obstruction, calculus, or lobar nephronia. On the Shuttle, urine dipsticks may be used to confirm pyuria, but no laboratory diagnostic means beyond this are available. Antibiotic treatment options and intravenous fluids are limited, most likely necessitating an early mission termination to allow definitive treatment. Treatment of in-flight pyelonephritis on the ISS could be managed more aggressively than on the Shuttle, with the goal of preventing progression to urosepsis and mandatory evacuation. With appropriate ground consultation, a renal ultrasound could be conducted to rule out the possibility of urinary obstruction, calculus, or lobar nephronia. Treatment can include intravenous fluids and antibiotics, with choices including ceftriaxone, imipenem, and amikacin. Ciprofloxacin and quinolones are available as oral agents. A Foley catheter can be placed for a period of acute treatment, and close monitoring of fluid intake and outputs observed. Blood urea nitrogen, creatinine, and serum electrolytes can be assessed with onboard laboratory capabilities. At present the means to perform a white blood cell count is not available on the ISS, but an on-board analyzer is planned for later stages. Close monitoring of a crewmember would be required, with consideration for medical return if the condition does not resolve with available treatment or if obvious obstruction is noted on ultrasonography. Progression to urosepsis would require stabilization to the extent possible and earth return for definitive care and relief of any obstructive process.

Prostatitis As previously noted, prostatitis has occurred during a long duration mission, prompting an early crew return. Sufferers usually complain of a dull, heavy ache in the perineum or anterior rectum that often is worsened by defecation. The pain may be referred to the glans penis. A low-grade fever is typically present. The prostate will be tender and boggy on digital rectal exam. Some sufferers may have accompanying cystitis. Laboratory tests to support the diagnosis of prostatitis include urinalysis by urinary dipstick for leukocyte ester and nitrites. No imaging capability will be available on the

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Space Shuttle. However, on the ISS, an ultrasound exam may be performed with ground guidance to show post-void residual urine in the bladder and direct imaging of the prostate. If systemic symptoms are mild in flight, this condition can be managed with antibiotics, such as trimethoprim/sulfamethoxasole or ciprofloxacin given orally for 10 days. If the systemic symptoms are severe, intravenous fluids should be administered plus intramuscular ceftriaxone every 24 h or intravenous amikacin every 8 h. If the patient has accompanying retention problems, a Foley catheter should be inserted for 48–72 h. Additional symptomatic relief can be given with antipyretics, analgesics, and rest.

Bartholin’s Gland Infection Painful swelling in the labia majora, usually in the lower half signals Bartholin’s gland infection. The area is usually erythematous and may be warm, with possible palpable fluctuance of the gland. Neither laboratory tests nor imaging are indicated. If the gland is non-fluctuant and less than 3 cm, it can be treated with an oral antibiotic such as cefadroxil administered over a period of 7–10 days. If the gland is fluctuant and is greater than 3 cm (1.18 in.), it will require incisional drainage. For this, local anesthesia will be required. Drainage into the vaginal mucosa is preferred, leaving a temporary drain sutured in place for five or more days. ISS resources would support such treatment, with appropriate ground medical guidance.

Epididymitis Epididymitis typically involves a gradual onset of swelling and discomfort in the scrotum that is usually unilateral but can be bilateral. Prene’s maneuver, in which pain is relived by elevating the testes manually, may have little meaning in microgravity. Epididymitis can produce a fever, sometimes exceeding 38.5°C (101.3°F). Exquisite tenderness, which can be focal in either the testicular head or tail early, may extend into the spermatic cord, inguinal canal, or lower abdomen. The epididymis will be boggy and the spermatic cord thickened, occasionally with reactive hydrocoele that may be trans-illuminated. The common laboratory test is a dipstick that, when positive for leukocyte esterase, will show pyuria on microscopic urinalysis. Also, epididymitis can produce an elevated white blood cell count. On the ISS, ultrasound imaging may confirm the epididymis findings, as well as demonstrate increased Doppler detectable blood flow to the affected testis. Epididymitis must be carefully managed. If infectious and diagnosed early, it can be treated with a course of oral antibiotics, such as tetracyclines, cephalosporins, or amoxicillin with or without clavulinic acid. A late diagnosis, especially one with toxic systemic symptoms, may require the use of parenteral antibiotics. Chemical epididymitis may be induced by urine refluxed

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into the ejaculatory ducts, often due to elevated voiding pressure, such as may occur during voiding while performing the Valsalva maneuver. Rest and analgesics are indicated; pain can usually be managed with non-steroidal anti-inflammatory agents.

Urinary Obstruction/Retention Etiologies of obstruction include lower tract infections, BPH, urethral strictures, diverticula, caruncles, calculi, trauma, and cystourethroceles. Contributors to retention include obstruction, anticholinergic or sympathetic drugs, high emotional stress (increased adrenergic activity), advanced age or poor health. Medications with anticholinergic or sympathomimetic effects are frequently used when treating space motion sickness and may aggravate any emotional or psychological tendency for retention. The clinical presentation of urinary obstruction/ retention is a long period without voiding or overflow incontinence with dribbling or a weak stream. Physical examination of a crewmember suffering from obstruction or retention will reveal a distended suprapubic area or lower abdomen, which may be quite tender. There is no imaging ability available on the Space Shuttle to confirm the diagnosis. On the ISS, ultrasound may be performed and show an enlarged bladder with a volume greater than 400 cc, and it may show some bilateral ureteral distension and possibly bilateral hydronephrosis. Inflight management will require reassurance along with physical treatment. Although physical factors contribute heavily to cases of retention in space flight, there may also be an anxiety/psychological component that can be alleviated with reassurance and relaxation of the crewmember. Moreover, the crewmember should be assured that the CMO onboard the Shuttle or ISS can treat this difficulty if required. Treatment could entail the use of a urinary straight catheter, a Foley catheter, or percutaneous aspiration. Intermittent sterile catheterization is the preferred management form if it is practical to drain the bladder, minimizing the risk of infection. Each day a foreign body is left in the urinary system, the risk of urinary tract infection increases. At least three 14–16 French straight catheters should be flown in the medical kit along with two Foley catheters when retention is considered to be at an increased risk. With previous episodes of retention, planning and provision should include three catheters per day times the number of days of the mission. A Foley catheter may be indicated if the cause of retention is prostatitis or if there are more than 500 cc of urine retained in the bladder or significant hematuria after drainage. In the case of more than 500 cc urine or hematuria, the bladder has been acutely over-distended, thereby damaging elastic fibers in the bladder wall. The indwelling catheter will allow the bladder wall to heal without repeated stress until the underlying cause of the retention is treated. When used, a Foley catheter should be anchored and left in position. If the crewmember has a history of BPH, he is at additional risk and specialty straight and Foley catheters should accompany that crewmember (Coude tipped catheters).

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Percutaneous aspiration should only be attempted as a last resort to relieve urinary obstruction if the catheter cannot be passed from below. The means to perform this are provided on the Shuttle and ISS, although this has not been performed in space flight thus far. Careful preparation and sterilization of the suprapubic area would be required, most likely involving real-time guidance from ground specialists. Obstruction complicated by infection is a dangerous condition that can be fatal due to the elevated tissue pressure and transmigration of bacteria from the obstructed system into the venous system or lymphatics, leading to urosepsis. Management of urosepsis entails hydration and the administration of antibiotics, with fluids and analgesics as clinically indicated.

Testicular Torsion Testicular torsion occurs more commonly in men younger than 30 years old, with the peak occurring from the onset of puberty to 18 years of age. This means it is highly unlikely to occur in space flight given the current make-up of spaceflight crews. However, it remains possible. Signs and symptoms include acute onset of severe, unilateral testicular pain, often associated with epigastric pain and nausea. In these cases, the testes are commonly elevated with a shortened spermatic cord or have a horizontal orientation. Prene’s maneuver, again a one-G dependent maneuver, either makes the pain worse or leaves the pain unchanged. In laboratory tests, the urinalysis and white blood cell count are normal. With ultrasound imaging, decreased Doppler blood flow to the affected testis is seen. Following a spermatic cord block with local anesthetic, it is possible to de-torse the affected testis with gentle elevation and rotation. Failing this, immediate evacuation to Earth for open surgical de-torsion is required to salvage the testes and relieve pain.

Conclusions Genitourinary issues remain important considerations for human space missions. Some genitourinary clinical issues are closely tied to the effects of prolonged microgravity on the human body, such as increased bone resorption and renal stone risk. Rigorous development of physical and pharmacological countermeasures to mitigate the loss of bone mineral calcium and to prevent precipitation of stone mineral in the urine will be key to lessen the risk of urinary calculus in long-duration spaceflight missions. Imaging and minimally invasive management capabilities will also be important developments for future exploratory space missions in case of genitourinary contingency. Specific future technologies should provide improved onsite imaging with 3-dimensional ultrasound as well as a low-power CT or MRI device. Further, the means for onsite intervention for stones with a technique involving endoscopic stent placement with lithotripsy (i.e., miniaturized Holmium laser, endoscopic or extracorporeal lithotripsy) should be vigorously explored. In the event a crewmember is affected by nephrolithiasis when outbound for Mars, onboard treatment is the only option.

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The possibility of managing a non-passing stone must be considered carefully. One method of management in this scenario would be an endoscopic surgical technique, entailing placement of a ureteral stent from a retrograde approach through the bladder, using ultrasound guidance. This procedure has been successfully performed in microgravity in a porcine model in parabolic flight on the KC-135 aircraft [35].

Acknowledgments. The authors would like to acknowledge the following individuals for their contributions: Glenn Preminger, MD, Duke University; Donald Griffith, MD, Baylor College of Medicine; Y. Charles Pak Howard Heller, MD, University of Texas Southwestern; James Lingeman, MD, Indiana University Medical Center; Igor Gontcharov, Institute for Biomedical Problems; Jennifer Villareal, NASA JSC Engineering; Hubert Brasseaux, NASA Engineering; Laura Nichols, Lockheed Martin

References 1. Reschke MF, Harm DL, Parker DE, et al. Neurophysiologic aspects: Space motion sickness. In: Nicogossian AE, Huntoon CS, Pool SL (eds.), Space Physiology and Medicine 3rd edn. Philadelphia, PA: Lea and Febiger, Inc.; 1994, pp. 228–260. 2. Huntoon Charles JB, Bungo MW, Fortner GW. Cardiopulmonary function. In: Nicogossian AE, Huntoon CS, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea and Febiger, Inc.; 1994, pp. 286–304. 3. Huntoon CS, Cintron NM, Whitson PA. Endocrine and biochemical function. In: Nicogossian AE, Huntoon CS, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea and Febiger, Inc.; 1994, pp. 334–350. 4. Morukov B, et al. 120-day head-down tilted bed rest study with participation of female subjects: Tasks and protocols of the studies. Aviakosm Ekolog Med 1997; 31(1):40–47. 5. Zaichik Y, Morukov B. In vivo bone mineral studies on volunteers during a 370-day antiorthostatic hypokinesia test. Appl Radiat Isot 1998; 49(5–6):691–694. 6. Morukov B, et al. Changes in calcium metabolism and its regulation in humans during prolonged spaceflight. Fiziol Cheloveka 1998; 24(2):102–107. 7. Smith M, et al. Bone Mineral measurement experiment M078. In: Johnson RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC NASA SP-377; 1997, pp. 183–190. 8. Leblanc A, Shackleford L, Schneider V. Future human bone research in space. Bone 1998; 22(5 Suppl.):113S–116S. 9. Leach CS, Rambaut PC. Biomedical responses of the Skylab crewmen: An overview. In: Johnson RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC NASA SP-377; 1997, 204–216. 10. Smith SM, Wastney ME, Morukov BV, et al. Calcium metabolism before, during, and after a 3-month space flight: Kinetic and biochemical changes. Am J Physiol 1999; 277:R1–R10. 11. Salem ME, Eknoyan G. The kidney in ancient Egyptian medicine: Where does it stand? Am J Nephrol 1999; 19(2):140–147. 12. Manthey DE, Teichman J. Nephrolithiasis. Emerg Med Clin North Am 2001 Aug.; 19(3):633–654, viii.

291 13. Hwang TI, Hill K, Schneider V, Pak CY. Effect of prolonged bed rest on the propensity for renal stone formation. J Clin Endocrinol Metab 1988 Jan.; 66(1):109–-112. 14. Muller CE, Bianchetti M, Kaiser G. Immobilization, a risk factor for urinary tract stones in children. A case report. Eur J Pediatr Surg. 1994 Aug.; 4(4):201–204. 15. Pak CYC. Medical treatment of renal stone disease. Nephron 1999; 81(Suppl. 1):60–65. 16. Lingeman JE, Preminger GM. New treatment options for kidney stones. Fam Urol May 2001; 6(2):4–6. 17. Rivers K, et al. When and how to evaluate a patient with nephrolithiasis. Urol Clin North Am 2000; 27(2):203–213. 18. Pak CY, Peterson R, Poindexter JR. Adequacy of a single stone risk analysis in the medical evaluation of urolithiasis. J Urol 2001 Feb.; 165(2):378–381. 19. Pak CYC. Medical prevention of renal stone disease. Nephron 1991; 81(Suppl. 1):60–65. 20. Batinic D, et al. Value of the urinary stone promoters/inhibitors ratios in the estimation of the risk of urolithiasis. J Chem Inf Comput Sci 2000 May–Jun.; 40(3):607–610. 21. Whitson PA, Pietrzyk RA, Pak CYC, Cintron NM. Alterations in renal stone risk factors after spaceflight. J Urol 1993; 150:1–5. 22. Whitson PA, Pietrzyk RA, Pak CYC. Renal stone risk assessment during space shuttle flights. J Urol 1997; 158: 2305–2310. 23. Whalley NA, Meyers MN, Margolius LP. Long-term effects of potassium citrate therapy on the formation of new stones in groups of recurrent stone formers with hypocitraturia. Br J Urol 1996; 78(1):10–14. 24. Sakhaee K, Alpern R, Jacobson HR, Pak CYC. Contrasting effects of various potassium salts on renal citrate excretion. J Clin Endocrinol Metab 1991; 72(2):396–400. 25. Pak CYC, Fuller CF. Idiopathic hypocitrauric calcium-oxalate nephrolithiasis successfully treated with potassium citrate. Annals of Int Med 1996; 104:33–37. 26. Pak CYC. Citrate and renal calculi: An update. Miner Electrolyte Metab 1994; 20(6):371–377. 27. Grases F, et al. Chronopharmacological studies on potassium citrate treatment of oxalocalcic urolithiasis. Int Urol Nephrol 1997; 29(3):263–273. 28. Pak CY. Southwestern Internal Medicine Conference: Medical management of nephrolithiasis—a new, simplified approach for general practice. Am J Med Sci 1997; 313(4):215–219. 29. Pak CYC, Skurla C, Harvey J. Graphic display of urinary risk factors for renal stone formation. J Urol 1985; 134: 867–870. 30. Ryall RL, Marshall VR. The value of the 24-hour urine analysis in the assessment of stone-formers attending a general outpatient clinic. Br J Urol 1983; 55:1–5. 31. Yagisawa T, et al. Metabolic risk factors in patients with firsttime and recurrent stone formations as determined by comprehensive metabolic evaluation. Urology 1998; 52(5): 750–755. 32. Lifshitz DA, et al. Metabolic evaluation of stone disease patients: A practical approach. J Endourol 1999; 13(9):669–678. 33. Vashi AR, Oesterling JE. Percent free prostate-specific antigen: Entering a new era in the detection of prostate cancer. Mayo Clin Proc 1997; 72:337–344. 34. Overmyer M. Free PSA test granted FDA approval. Urology Times 1998; 26(4):498–501. 35. Jones JA, Johnston S, Campbell M, Billica R. Endoscopic surgery and telemedicine in microgravity, developing contingency procedures for exploratory class space flight. Urology 1999; 53(5):892–897.

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Selected Readings Gillenwater J, Grayhack J, Howards S, Duckett J. (eds.), Adult and Pediatric Urology. 2nd edn. St. Louis, MO: Mosby Yearbook; 1991. Hanno P, Wein A. (eds.), A Clinical Manual of Urology. Norwalk, CT: Appleton-Century-Crofts; 1987.

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Hesse A, Tiselius H-G, Jahnen A. (eds.), Urinary Stones: Diagnosis, Treatment and the Prevention of Recurrence. Basil: Karger; 1994. Lingeman J, et al. Urinary Calculi ESWL, Endourology, and Medical Therapy. Philadelphia, PA: Lea and Febiger, Inc.; 1989. Walsh P, Gittes R, Perlmutter A, Stamey T. (eds.), Campbell’s Urology. 5th edn. Philadelphia, PA: W.B. Saunders Co.; 1986.

14 Musculoskeletal Response to Space Flight Linda C. Shackelford

Locomotion on Earth is accomplished with techniques as varied as the creatures that move and the environments in which they move. Genetic design and the environment are integral in determining the locomotion methods and capabilities of animals and humans. The buoyant environment of the sea is home to the whale with its massive musculoskeletal system for propulsion as well as the jellyfish that moves about with the ocean currents with no rigid skeletal structure. Genotype provides the basic structure by which creatures locomote. Interaction with the environment further refines the locomotive structures, thereby influencing the phenotype. Environment and activity within that environment in turn modifies form. The musculoskeletal system of vertebrates, comprising a basically mechanical system integrating rigid articulating structure (bones) and contractile movement engines (muscles), both influences and is influenced by mechanical forces. Exertion of force by the musculoskeletal system, either for locomotion or determined effort and exercise, feeds back directly to alter shape and performance capability. The influence of specific exercises on muscle mass and body contours is easily recognized in humans. Weight lifters and distance runners have a distinct difference in body morphometry. The effects of exercise and activity on the skeletal system are less obvious to casual observers, except in the case of those who lack muscle activity in a limb at a young age. The paralyzed limbs of young polio victims, for example, fail to achieve the same length as normally functioning limbs. Less readily apparent are the narrow bones and the decreased bone mineral density in the affected limbs of persons stricken with polio as children. On the opposite end of the spectrum of skeletal loading and bone mass are competitive weight lifters. The world record holder in squat lifting has a spinal bone mineral density that is 13 standard deviations above normal [1]. The determinant of skeletal morphology and density, muscle mass and function, and soft tissue strength and organization is not a matter of locomotion versus no locomotion, ambulation versus suspension, or the presence or absence of gravity per se. The direct determinant of musculoskeletal strength, density, and morphology is the degree of musculoskeletal loading.

Thus, a new environment with different loading forces and factors is expected to change these parameters. Understanding this principle of relative loading is key to understanding the human musculoskeletal response to microgravity. Changes in mechanical loading during microgravity result in a cascade of biochemical, hormonal, and structural changes in bone, muscle, and connective tissues, each affecting and being affected by the other in a complex feedback loop as the system seeks an equilibrium in the new environment. The degree of change varies among individuals, among the different regions in the same individual, with the degree of change in activity compared with usual, and with the duration of the activity change, in this case spaceflight. For the spaceflight crewmember, just as the musculoskeletal system adapts to microgravity, upon return it must readapt to earth and the necessity of musculoskeletal activity to maintain upright posture and locomotion against the force of gravity. Changes in locomotor control that occur in the microgravity environment increase the risk of falls upon return to gravity, and microgravity-induced decreases in bone, muscle, and soft connective tissue strength can increase the risk of injury during readaptation to the terrestrial environment. With regard to the human, the dominant spaceflight factor influencing physiological changes is microgravity, or weightlessness. Given that functional loading is known to increase bone and muscle mass, loss of bone and muscle integrity are an expected consequence of space flight where such loading is diminished. Losses of muscle strength and volume have been measured after 5- to 16-day shuttle missions. Urinary excretion of calcium indicated increased bone resorption during short duration Gemini, Apollo, and Space Shuttle missions. Longer duration Skylab and Mir missions were required to detect changes in bone density. These observed changes raised early concern that muscle atrophy and bone loss could increase risks of long-term space flight to unacceptable levels unless adequate countermeasures were developed to prevent the losses. This chapter will focus on the effects of microgravity on the structural integrity of bone, muscle, and connective tissue, 293

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with an emphasis on the biomechanical changes, both as cause and effect. Countermeasures to these adverse effects will be discussed. Functional musculoskeletal disorders that occur as a result of adaptation to microgravity and subsequent return to Earth are also described. Further discussion of biochemical markers of bone and muscle turnover can be found in Chaps. 27 and 13.

Bone Structure, Function, and Physiology Bone is highly specialized tissue that comprises the vertebrate skeletal system and provides the structural framework that maintains the body’s shape. The skeletal system serves both protective and mechanical functions. From a static standpoint, bone forms a rigid shield to protect particularly vulnerable tissues such as the brain, chest, and pelvic organs. From a dynamic standpoint, bone provides a system of attachment points and moment arms to transmit forces of muscular contraction into expansion of lungs, movement of body parts, locomotion, and manipulation of external objects. It is a vital tissue that grows, undergoes self-repair, and adapts its shape and structural integrity in response to outside forces. Bone supplies the protective haven for the formation of blood cells. It also serves as the body’s main pool of minerals such as calcium (Ca) and phosphate (P), and supports a vast surface area for exchange of these minerals with circulating blood. A detailed treatise on the anatomy and physiology of bone is beyond the scope of this chapter. This section will review the basic aspects of bone structure and function to enable better understanding of observed spaceflight-associated changes.

Anatomy and Structure The human skeleton reflects the predominantly upright posture assumed for locomotion and load bearing, and may be grossly classified into axial (head, neck and trunk) and appendicular (limbs) divisions. Axial elements, such as the pelvis and spinal column, along with the lower extremities of the appendicular skeleton, logically bear the greatest gravitationally oriented loads, and so become the major focus for microgravity unloading. Bone must provide interfaces with muscle, tendons, and articular cartilage, and its structure and shape accommodates these based on anatomical region and function. The scapula comprises a broad, free-floating plate to anchor the large muscle masses controlling shoulder movement, while the long bones of the extremities are thick-walled hollow tubes suited to bearing axial loads and serving as lever arms. The shafts of the long bones are centrally narrowed compared with the ends, which flare to allow optimum load distribution in the articular cartilage surfaces of joints. A sheet of tough fibrous connective tissue, known as the periosteum, along with a thin layer of undifferentiated cells, cover the outer surface of most bone. An internal cellular layer known as the endosteum lines the central cavities of bone.

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Basic structural attributes of all bones include a smooth, dense exterior cortex and an interior network of cross-linking plates and trabeculae, which harbor blood and bone marrow. The relative thickness of the cortex as well as the mass of trabeculae vary considerably and are used as a basis for further classification. Bone can be divided into two basic types based on structural units; these are represented in all bone but in varying proportions. Compact, or cortical bone, comprising about 80% by mass of the human skeletal system, is strong and dense. The structural unit of compact bone is known as the osteon, or haversian system. These are cylindrical structures about 250 microns in diameter and a few mm long, containing a central canal for nerves and vessels and an extensive and intricate system of lacunae and canaliculi. These permeate the structure of concentric cylindrical layers known as lamellae about the central canal, providing a canalicular network with a surface area for nutrient and mineral exchange of from 1,000 to 5,000 m2 in adults. Bones that must assume a great deal of bending and shear forces, such as the long bones of the lower extremities, are primarily cortical. Figure 14.1 shows the basic anatomical and structural aspects of mature bone. Cancellous, or trabecular bone, comprises the remaining 20% by mass of the human skeleton and consists of a lattice of bony struts and plates arranged in an orderly pattern around lines of force and strain. This provides significant rigidity with a minimum amount of structural material, and provides a space for bone marrow, the site of hematopoietic activity. Bones that bear primarily axial compressive or tensile loads, such as the vertebrae, have a greater proportion of cancellous bone and utilize the trabecular structure to bear the loads. Mature bone tissue consists of a network of cells, primarily osteocytes, interspersed within an intercellular mineral matrix composed primarily of impure crystals of hydroxyapatite [Ca10(PO4)6(OH)2]. The hardness and compressive strength of bone are attributed largely to the structure of this crystal, but this material would be inherently brittle if not for the lattice of collagen fibers laid down by bone-forming cells, the osteoblasts. These fibers, along with an organic protein matrix known as osteoid, are expressed by osteocytes during bone formation and later mineralized. The resulting composite material combines the elasticity and tensile strength of the collagen fibers with the hardness and rigidity of the mineral to give bone its characteristic properties.

Physiology and Regulation Remodeling is the basic process by which mature bone tissue is repaired, renewed, and turned over in response to loads. It is an ongoing process involving both resorption (or breakdown) and formation, though not throughout all bone tissue simultaneously. In the adult skeleton, 80% of cancellous and cortical bone surfaces and 95% of intracortical surfaces are in a resting state at any give time, with no active remodeling. The process of resorption is undertaken by specialized giant cells known as osteoclasts, formed by the fusion of multiple blood

14. Musculoskeletal Response to Space Flight

FIGURE 14.1. Basic anatomy of mature bone. The long bone at left reflects the classic tubular shape of the lower extremities, which bear longitudinal, bending (shear), and torsional loads. It is about 90% cortical by mass, with the remainder cancellous at the ends. The lumbar vertebra at right bears primarily compressive loads and is about 60% cortical and 40% cancellous

monocytes. These sparsely populate the periosteal surface of cortical bone or the trabeculae of cancellous bone, forming resorptive units known as Howship’s lacunae. Focal bone resorption is followed by the influx of osteoblasts and the formation of new osteons. Following secretion of the osteoid, osteoblasts become surrounded by the progressively mineralized matrix and differentiate into resident osteocytes. The regulation of remodeling is multifactorial, comprising inputs from mechanical loads and blood-borne hormonal elements as well as local tissue factors. From a simplistic standpoint, greater loading, both in magnitude and duration of force, causes a net positive effect on bone density, while relative unloading causes the opposite effect. The mechanism of this process is not entirely clear but almost certainly involves localized electrical fields induced by piezoelectric effects resulting from shear forces within the bone crystal. Loads may be induced directly from outside forces, as in weight bearing, or by the pull of skeletal muscle. As such, bone density may be directly related to muscle mass. Normal age-related loss of bone mineral occurs partially in step with gradual loss of muscle mass. Hormonal mediators of bone and mineral metabolism are known to affect both rapid (Ca mobilization) and more longterm effects (remodeling). Parathyroid hormone (PTH), typically released in response to a hypocalcemic state, stimulates bone resorption and intestinal absorption of calcium. Blood calcium is increased to the system to restore normal levels, and any excess calcium is lost in the urine. Chronic elevation of PTH, as in primary hyperparathyroidism, is associated with undue loss of bone mineral. Hydroxy-cholecalciferol, also known as vitamin D, acts to stimulate intestinal absorption of calcium and phosphate. The active form of vitamin D (1,25-dihydroxyvitamin D) is

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formed in the kidney following stimulation by PTH. Calcitonin decreases blood calcium levels apparently by decreasing osteoclastic activity. Other hormonal mediators include testosterone, which stimulates formation of bone matrix, and glucocorticoids, which inhibit collagen synthesis and bone formation. Human bone mass plateaus in young adult life and begins to decline typically early in the fourth decade. A predictable loss of bone mineral is thus an index of aging, and any outside perturbations of remodeling must be viewed against this backdrop. A clinical aspect of bone loss is the risk of fractures associated with loss of structural strength; osteoporosis is a potential concern in advanced age among all populations. Efforts in the past few decades to measure this loss and provide metrics for countermeasures and treatment have produced several indices, the most common of which is from the World Health Organization (WHO). WHO recommends a definition of osteoporosis based on T-scores, representing standard deviations (SD) from the mean bone density of young adult Caucasian women. T-score changes are correlated with clinical data to reflect risk of fracture. Osteoporosis is present when areal BMD (aBMD) or aBMC (content) is over 2.5 SD below the mean (−2.5 T-score). The presence of fractures denotes severe osteoporosis. An aBMD or a BMC with T-scores between −1.0 and −2.5 SD is classified as osteopenia, a decrease in density in the absence of fractures. Individuals with osteopenia may not have increased fracture risk under normal activities, but may be at risk of developing osteoporosis in the future [2].

Bed Rest Studies In seeking to understand the effects of space flight upon the musculoskeletal system, bed rest has long been used as an analog for human space flight. In the 1940s physicians were concerned that prolonged bed rest used as a treatment for certain illnesses and injuries was possibly related to complications of the illnesses. Because it was difficult to separate the physiological effect of bed rest from the illness, studies were undertaken to characterize the effects of bed rest alone. In 1944 and 1945, four conscientious objectors volunteered for either a 2- or a 3-week bed rest study. In that study, a doubling of urinary calcium excretion and decrements in muscle strength and limb girth were documented [3]. Further investigations followed, and bed rest studies were used as an analogue to space flight in the 1960s, starting with the Gemini missions [4] and continuing to the present time. Even during bed rest, however, the body is not fully unloaded as in microgravity. There is an opposition force associated with movement in bed, and in pathological states the force required to lift a leg is sufficient to complete a partial stress fracture in the femoral neck. Because immobilization discourages muscle activity, bed rest studies with immobilization have been more effective in inducing bone loss than simple confinement to bed [3,5]. Patterns of bone and muscle loss at bed rest have been similar to that seen in space flight, though differing in degree of

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loss. Bone loss in 13 men and 6 women who were at horizontal bed rest for 17 weeks [6] was compared to that in 15 men and 2 women astronauts after 117- to 195-day (average 156 days) missions on Mir and International Space Station (ISS). Bed rest volunteers incurred about half the rate of bone loss in the hip, spine, and pelvis as astronauts. Conversely, bone loss from the calcaneus in space was about half the rate of bone loss seen in bed rest. The astronauts were required to exercise 6 days a week, while bed rest volunteers were required to remain sedentary, lying flat in bed. One study comparing crewmembers aboard the Mir station using Russian countermeasures to bed rested subjects demonstrated similar or slightly greater rates of bone loss inflight [7]. All bed rest subjects who did not use countermeasures (13 men, 5 women) demonstrated significant losses in at least one region of the spine and lower extremities. Although there are demonstrable differences in regional bone loss rates between bed rest subjects and astronauts, horizontal bed rest studies have been beneficial in testing efficacy of countermeasures [8–10].

Bone Loss in Space Flight Skeletal changes due to microgravity were first noted during the Gemini missions. Increases in urinary calcium excretion indicated that bone resorption was increased during space flight. At that time, means of measuring bone density were limited to single photon absorptiometry. Because absorption is related to the thickness of the material the radiation traverses as well as the absorption coefficient of the material, accurate measures of bone density change could only be determined in regions with little overlying soft tissue changes, such as the distal forearm and calcaneus. As such, measurements were restricted to the calcaneus, forearm, and wrist and hand for Gemini and Apollo missions. During the time of the Gemini and Apollo flights, variability in this technique was published as about 2%, comparable to the 1–1.5% error of measurement in current methods. In practice, preflight variability gave ranges of −2.6% to +1.5% from the mean of three preflight measures in the os calcis of one of the Skylab crewmembers [11]. Large bone loss in the calcaneus during the Gemini program raised concern that this would be a limiting factor in the duration of mission deemed safe [12]. Measurements of bone mineral density during the Apollo missions indicated that bone loss was much less severe than originally thought. Skylab studies indicated that calcium loss steadily increased for the initial month in flight and remained elevated for the duration of the mission, the longest of which was 84 days [13]. Bone mineral density of the calcaneus was decreased post flight in one of three astronauts after a 59-day mission (−7.4%) and in two of three Skylab astronauts after 84 days in space (−4.5% and −7.9%) [14]. The calcaneus had not fully recovered in the crew from the 84-day mission at 90 days post-flight. There had been no longitudinal studies of bone loss and recovery, and bone recovery was considered a long and indeterminate process [15].

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Later spaceflight studies used an improved method of assessing bone mineral density using dual energy X-ray absorptiometry (DEXA). DEXA scans are able to delineate soft tissue density from bone density by using two different x-ray energies that are differentially absorbed in soft and hard tissue. Use of DEXA scans has allowed accurate assessment of bone density with minimal radiation exposure in regions with overlying soft tissue such as the spine and hip. A typical radiation dose associated with a whole body DEXA scan gives an effective dose equivalent (EDE) of about 0.8 mrem to men and 1 mrem to women using an array scanner. The entire series of whole body, lumbar spine, both hips, heel and wrist scans performed on astronauts results in about 1.4 mrem EDE for men and 3.6 mrem EDE for women. In comparison, one chest x-ray is 5–10 mrem EDE and a CT scan about 100–500 mrem EDE. DEXA scans, Quantitative Computed Tomography (QCT), and peripheral QCT (pQCT) all have similar precision between 1% and 2% CV [16]. QCT and pQCT give 3D imaging as opposed to planar DEXA images. This allows structural analysis of bone. Structure is a significant determinant of strength and quality, and reversibility of architectural changes due to bone loss and the nature of bone loss with aging require 3D imaging to be fully addressed. QCT has the advantage of visualizing the bone architecture of lumbar spine and hip regions but carries a significant penalty of higher radiation doses. Lumbar QCT can give up to six times the radiation exposure of DEXA of the lumbar spine [17], but QCT radiation dose is significantly less than CT imaging. Because of its peripheral nature, pQCT radiation doses are in the range of about 0.1 mrem per slice of the tibial region (up to mid femur, depending on thigh volume, can be imaged with pQCT). In order to assess risks of weakened bone at tendon insertions and a potential avulsion fracture risk, 3D imaging through DEXA or MRI will be necessary. MRI is currently being investigated as a means to perform bone architectural analysis but still has significant artifacts and hence is not now used in standard practice for osteoporosis diagnosis and management. Russian studies performed during long duration Salyut and Mir missions showed that bone density measured by QCT decreased in the posterior spine. From 1990 until the end of the Mir program, cosmonauts flying four to six-month missions on Mir have received preflight and postflight DEXA scans to measure changes in bone density. It was found that the average loss in the trabecular regions of the lumbar spine, femoral neck and trochanter, and pelvis was 1.07%, 1.16%, 1.58%, and 1.35% respectively of the initial value for each month spent in space [18–20]. Variations among regions for different individuals and among regions within the same individual were quite large. No appreciable changes occurred in the upper extremities and skull. During a typical mission of about six month’s duration, the body lost about 1.4% overall bone mineral density, whereas the trabecular regions of the pelvis, lumbar spine, and femoral neck typically lost about12%, 6%, and 8% of the initial values respectively [21,22]. However, some individuals lost as much as 20% of the initial value in the femoral neck region. No individual maintained bone at initial values in all regions.

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Figure 14.2 illustrates the variability of bone loss within regions in 18 cosmonauts who completed 4- to 14-month missions on Mir. Eight bed rest control subjects exhibited similar losses. For any region, there is also considerable variability of loss within individuals. Cosmonaut recovery was estimated in repeat fliers by comparing preflight second mission values to preflight values for the first mission. Most cosmonauts recovered some of the bone lost, but few fully recovered bone mineral density in all regions. This raised the concern that the crew of long duration missions could present with early onset osteoporosis when bone losses due to space flight and aging were combined. Whether senescent and postmenopausal bone losses are independent of previous history of bone loss has not been determined, and assumption of additive effect as a worse case scenario gave concern that premature osteoporosis could be an occupational hazard of long duration space flight [23]. With seven U.S. astronauts having completed missions aboard the Mir station of 4–6 months’ duration, it was determined that incomplete recovery in all regions by 3 years postflight is the exception. Full bone mineral density recovery occurred anywhere from 6 months’ to 3 years postflight for the majority of astronauts. The few who lacked full recovery in one or two regions had partial recovery in those regions, with plateau after recovery less than 5% below preflight values. To assess aging of bone due to long duration space flight in those who failed to recover, the age of onset of osteoporosis predicted from normal aging curves using bone density measurements is utilized. Predicted age of onset assessed prior to long duration space flight was compared to a reassessment after up to five years postflight recovery period for the seven astronauts who served as Mir crew. Only one astronaut did not fully recover to within the range expected from pre-flight values. There was residual loss at three years in two regions. These femoral neck and femoral trochanter regions were predicted to become osteoporotic 6 years earlier, at age 97 as opposed to age103 predicted from preflight values, and 8

FIGURE 14.2. Changes in regional bone mineral density in 18 cosmonauts and five astronauts who completed missions of 4–14 months’ duration on Mir. Some data points are missing on crewmembers. Comparison is made with control subjects at bed rest for 17 weeks

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years earlier at age 125 compared to a preflight prediction of osteoporosis at age 133. (These predictions assume the rate of bone loss between age 75 and 85 as estimated by crosssectional studies remains constant with aging.) Bone density measurements in these regions were within normal bone density ranges preflight and post-recovery. The NASA Mir bone recovery study suggests that long-term risks of premature osteoporosis are much lower than originally feared. From the early ISS experience, results of the first 11 NASA astronauts, nine men and two women, have shown significantly less bone loss in the lumbar spine than in the previous Mir cosmonauts and significantly less loss in the femoral trochanter sub-region of the hip compared to NASA Mir astronauts and to Mir Cosmonauts and astronauts combined. These differences are present both from the standpoint of loss per mission and loss per day on orbit and may be attributable to enhanced resistance exercise initiated early in flight by NASA astronauts and continued throughout flight. The hip and lumbar spine have shown an insignificant trend toward less BMD loss in ISS astronauts than in ISS cosmonauts. Figure 14.3 depicts comparative bone loss between the first eight ISS missions and preceding Mir missions. When astronaut and cosmonaut data on ISS are combined, bone loss is similar to bone loss reported on Mir. It is noted that standard deviation of bone loss has been observed to be large in the cosmonauts who have flown on Mir. A report on 13 men and one woman who flew as Russian and U.S. crew on ISS Expeditions 2 through 6 notes no significant difference between ISS crew bone loss and Mir crew bone loss measured as a percent of the original bone density. Lumbar spine area BMD by DEXA is reported as 0.9% loss in the lumbar spine and 1.4–1.5% in the hip regions. Losses are similar by QCT, 0.9% in lumbar spine integral BMD and 1.2–1.6% for the hip integral BMD. Percent loss was largest in the trabecular regions of the hip (2.2–2.7%), though the largest actual loss came from cortical bone at the endosteal surface in the hip. Cortical losses were 0.4–0.5% of the original cortical bone density in the hip [24]. The results combine both U.S. and Russian crewmember data, and may be in part explained by the fact that resistance exercise was more utilized by NASA crewmembers. The Institute for Biomedical Problems in Russia has historically relied heavily upon treadmill exercise as a musculoskeletal countermeasure and continues to emphasize treadmill on ISS [25]. Change in T-score per mission for the lumbar spine averaged −0.33, for the femoral trochanter averaged −0.43, and for the femoral neck averaged −0.45. Mission duration averaged 171 days, ranging 128 to 195 for the first 11 astronauts on ISS on expeditions 1 through 8. When the ISS U.S. astronaut losses were normalized to time, BMD change expressed as T-score change in the femoral trochanter averaged −0.08, SD 0.04 per month, the femoral neck averaged −0.08, SD 0.04 per month, and the lumbar spine averaged −0.06, SD 0.04. Regional bone losses are not predictable for individuals. The population studied over the last decade has consisted of almost all men of European and Eurasian descent. As of this

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writing, one Russian and three American women have flown long duration missions ranging from 167 to 188 days duration. Their bone losses have been similar to that of the men. The longest duration Mir mission, 438 days, produced bone loss similar to the 4–6 month missions with exception of the femoral neck region, which had greater loss than average, but still showed equal or less loss than in two cosmonauts who flew 6.5- and 10-month missions. The amount of bone loss in a 6-month mission was not significantly different than that of a 4-month duration stay on Mir. Postflight bone mineral density (BMD) losses are treated with progressive increases in exercise load. In two instances of 20% loss BMD of the femoral neck, cosmonauts were cautioned to limit impact loading until sufficient bone had been recovered [26]. Specific exercises for regional losses have not been fully developed. Bed rest and ambulatory studies suggest that resistive exercises in the 5–11 repetition max load range are most effective in promoting bone formation [6,27–30]. Squat and dead lift exercises are used for increasing spinal BMD. Heel raises were proven highly effective in maintaining or increasing heel BMD during bed rest and are used as part of the post-flight exercise regimen. Appropriate bone-preserving hip exercises are less well established. It appears that maximal loading of the femoral trochanter is achieved through a shallow single-leg press with the foot centered under the body. This motion was effective in fatiguing the gluteus medius during a17-week bed rest study and minimized trochanteric losses. Though the number of bed rest subjects performing this exercise is too small to draw conclusions, both free body diagrams and trends of the bed rest study indicate the single shallow leg press with foot centered is most effective for the trochanter [31]. Squats have been shown in ambulatory studies to promote femoral neck bone formation and restore mineral density. Wide squats increase the lever arm effect on the femoral neck, providing more effective exercise for a given load. Sports activities involving jumping are associated

FIGURE 14.3. Changes in bone mineral density after spaceflight for the Mir and International Space Stations presented as absolute change per month of flight. ISS data are from U.S. crewmembers of the first eight missions

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with increased hip density and may be beneficial in postflight recovery [32].

Metabolic Aspects of Bone in Space Flight Though not a musculoskeletal disorder, renal stones may be related to metabolic changes associated with bone loss. Urinary calcium excretion has been elevated in all bed rest subjects, with a plateau loss rate at 3–4 weeks of bed rest. Similarly, urinary calcium excretion increases during space flight, leading to concerns that risk of renal stone formation may be increased. Postflight renal stones have been reported in space shuttle crew (see Chap. 13). Immediately postflight, calcium excretion is elevated. The relative hypovolemia seen in returning crewmembers in the immediate postflight period contributes to orthostatic intolerance and results in aldosterone secretion and scant urine production for several hours following landing, a condition also favoring stone formation. It is likely that the concentrated urine with hypercalcuria may result in renal stone nidus precipitation in the initial postflight hours. Symptomatic renal stones typically present days to weeks later. Calcium balance studies were initially the more reliable method of determining bone loss until the more accurate bone densitometers were developed but remain central to understanding this process. The net calcium balance is estimated from the difference between calcium excretion in the urine and feces and the calcium intake in the diet. Increased fecal excretion of calcium results from decreased calcium absorption in the intestines. Calcium balance and calcium metabolic modeling are useful for countermeasure development through elucidating the mechanisms of bone loss. Metabolic studies may indicate increased rates of bone loss before they are detected by bone densitometry. Calcium excretion in the urine is associated with increased bone resorption, which also results

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in increased collagen excretion. Deoxypyridinoline and pyridinoline cross links found in bone, muscle, and connective tissue as well as the bone specific collagen cross-link, n-telopeptides, are increased in space flight and bed rest [33–35].

Muscle Loss With strength trained and sprint athletes, muscle crosssectional area declines rapidly with inactivity. Force production declines along with electromyographic (EMG) activity, and eccentric force and sport specific power are impaired by inactivity [36]. Similarly, muscle mass, volume, and strength are diminished during space flight. Extensors are affected most rapidly, but both extensors and flexors may lose up to 30% of isokinetic torque during longer duration missions [37]. The type II fast fibers have greater loses in humans during space flight than their type I slow counterparts [38,39]. Increased urinary excretion of deoxypyridinoline and pyridinoline, metabolic markers for the muscle collagen loss, is associated with space flight muscle atrophy. Muscle strength losses in the antigravity, or postural muscles, have been measured postflight in short duration shuttle crewmembers as well as long duration astronauts and cosmonauts returning from Mir and the ISS. Shuttle crew experienced decreased concentric peak knee extensor torque (−12%) but no significant change in peak knee flexor torque during isokinetic testing at 60 degrees per second. Peak knee extensor torque decreased by 31% and peak flexor torque by 27% after Mir missions of 117–189 days [40]. Muscle volumes measured with MRI showed decreases from 4% in the psoas to 17% in the gastrocnemius and the soleus, with intermediate losses in the anterior leg, quadriceps, hamstrings, and intrinsic back muscles, reaching a new steady state at 4 months of space flight (as estimated by linear regression of 16- to 28week missions) and returning to normal 30 60 days postflight. Neck muscles had no volume loss [41]. Muscle soreness in the hamstrings, quadriceps, calves, and lumbar region is quite common in the postflight period, as these postural muscle groups are fully challenged following prolonged inactivity. Postflight lumbar pain from normal activity at home that was significant enough to postpone postflight isokinetic strength testing has been reported.

Other Musculoskeletal Disorders Other connective tissue changes noted have been increased spine length of 4–7 cm during space flight [42,43] and a 1 mm increase in single lumbar disc height on MRI with bed rest [44]. Increased disc height and postural changes, such as loss of lumbar lordosis, contribute to spinal lengthening. During the first few days of space flight, astronauts frequently report lumbar pain. Etiology of the back pain is unclear. One suggested cause is paraspinal muscle imbalance during the

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adaptation phase in microgravity with resulting mechanical low back pain (a condition frequently involving some degree of posterior facet overload or irritation). Another cause may relate to stretching of the posterior ligaments associated with spinal lengthening. The nucleus pulposis imbibes fluid when unloaded and increases in volume. This translates into increased disc height, which may produce pain due to connective tissue stretch. Similarly, bed rest subjects also experience low back pain during the first week of bed rest and have increased disc volume. There does not appear to be a higher than normal incidence of postflight bone or muscle injury. One cosmonaut fell down a hill and sustained a fracture during the postflight rehabilitation period, but Russian physicians did not feel bone loss was a contributing factor to the fracture considering the magnitude of the forces during the fall. However, soft connective tissue injuries have been reported in the feet and back. Astronauts have reported plantar fasciitis symptoms postflight, which resolve within a few days to weeks. This is similar to findings following bed rest studies in individuals who have had no exercise or standing for 17 weeks [6]. Incidence of herniated nucleus pulposus (HNP) in astronauts is increased in the astronaut population as a whole but has not been temporally linked to space flight [45]. One astronaut experienced acute onset of back pain when moving about the cabin prior to strapping into an entry seat after onset of gravity during shuttle descent for landing. This later proved to be a herniated nucleus pulposus. Sciatica has occurred inflight and postflight in more than one cosmonaut. One possible etiology of the higher than normal incidence of HNP in astronauts post flight is that the enlarged nucleus pulposis exerts unaccustomed strain on the annulus with subsequent reloading on return to earth. This increases the risk of rupture of the annulus during high lumbar disc loading activities such as bending and rotating.

Treatment of Pain Syndromes Postflight management of muscle pain consists of gradual increase in exercise intensity, post-exercise icing, and use of nonsteroidal anti-inflammatory agents. Tight hamstrings and calves are present in bed rest subjects and astronauts following space flight and may contribute to the sensation of muscle soreness. Stretching exercises for the back and lower extremities hasten recovery of flexibility. Low back pain in flight is commonly treated with postural adjustment. Periodically tucking into a tight fetal position for a period of a few seconds has been found to alleviate pain. Pain may also be relieved by tying the foot of the sleeping bag to prevent full extension during sleep or by strapping into one of the shuttle seats to sleep. Spaceflight veterans taught this technique to new astronauts long before it was recognized by flight surgeons as beneficial. Sciatica symptoms are treated with modification of activities to reduce spinal loading, physical therapy, and anti-inflammatory medications. Clinical

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motor strength and spinal reflex testing must be documented regularly in persons exhibiting signs and symptoms of sciatica at the onset of sciatica and continued until sciatica resolves, whether inflight or postflight. Diagnostic tests such as electromyography and nerve conduction velocity (EMG-NCV) studies may be useful in monitoring neurological changes. EMG changes typically lag neurologic insult by a couple of weeks, so it is important not to rely on EMG changes to diagnose a progressive motor deficit. Presence of a progressive motor deficit postflight is an indication for referral to a neurosurgeon. Any bowel or bladder symptoms are also cause for immediate referral. Plantar fasciitis is frequently observed in crewmembers and bed rest subjects and was present in several astronauts following long duration Mir missions. In a 17-week bed rest study, all subjects who did not exercise as well as about half of the resistive exercise group developed plantar fasciitis upon resuming ambulation. The exercising subjects recovered within a few days of reambulation and the non-exercisers within a week or two, although one non-exerciser required several weeks for recovery and one had a relapse about a month later. Two subjects in this study with persistent plantar fasciitis had aggravated the condition with walking several hours a day, one as a door-to-door salesman, the other on an international tour. Treatment in astronauts and research subjects reporting symptoms of plantar fasciitis consists of stretching the arches prior to walking and performing flexor digitorum brevis exercises by gathering a towel laid upon the floor into folds with the toes. Use of running shoes with good arch supports has proven highly beneficial in decreasing plantar fasciitis pain post-bed rest. Plantar fasciitis has not been reported in treadmill use on orbit and would not be anticipated given the lower than body weight loads exerted by the device during typical exercise. Muscle strength testing did not produce appreciable muscle soreness after 6 or more weeks exercise training while at bed rest. Overall musculoskeletal function following bed rest with exercise was near normal. One individual who was a sprinter prior to bed rest with exercise was able to sprint near his normal speed the first week out of bed rest. He tried out for a semiprofessional football team upon leaving the study two weeks after the end of bed rest and functioned at a level comparable to other players except in coordination testing. He reported he had difficulty negotiating the rope obstacle course at the same speed as the other players. Overuse injuries such as patellofemoral pain and low back pain, which were common to the alendronate and bed rest control groups, were not present following bed rest in the exercise group. Plantar fasciitis, which was present in all of the non-exercising bed rest volunteers, affected about half of the exercise group but resolved quickly and did not recur in those who exercised.

Physical Countermeasures The most obvious measure to prevent changes due to unloading in microgravity is to artificially load the bone. Artificial

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gravity has been proposed since long before the first human space flight, including by such revered pioneers as Russian visionary Konstantine Tsiolkovsky near the turn of the twentieth century. A force mimicking gravity alone is not sufficient, as bed rest occurs within a gravity field and results in bone loss. Active exercise that loads the bone in an overall magnitude and direction similar to that which modeled the bone is required to maintain mineral integrity. In a 1996 NASA study evaluating advanced life support systems for lunar and Mars missions conducted at the Johnson Space Center, four ambulatory subjects were confined to an enclosed chamber for 90 days and were found to have lost bone density in the femoral neck despite use of a bicycle ergometer and hydraulic exercise equipment. A subsequent chamber test in which a treadmill was used in addition to the cycle ergometer and hydraulic resistive device produced no bone density changes. Maintenance of musculoskeletal conditioning is dependent upon proper loading of the skeleton, which in this comparison, treadmill exercise apparently restored. Human space flight has seen an evolution of exercise devices and methods as experience in longer duration exposures to microgravity has accrued. The Skylab IV mission utilized a Teflon slip plate as a “treadmill”. The Mir station had a motorized treadmill that was used in the passive and active mode. Skylab and Mir both utilized resistance exercise in the form of a friction rope and 80 lbs bungee cords respectively; in spite of these, crewmembers from both stations showed increased urinary and fecal calcium and bone loss. The use of a rope pull apparatus for 80 min a day and that of longitudinal compression at 80% body weight during bed rest was found to be ineffective in mitigating bone loss [9]. Similarly, bone loss has occurred during flight despite use of bungee cord exercises and a full body-loading suit (penguin suit) utilizing bungee cords from the shoulders to the waist and waist to the thighs on Mir [21]. These findings contrast with the normal urinary calcium and preservation of bone mass during 17 weeks of bed rest with one to one and a half hours of exercise a day at high resistance [6]. Neither constant compression nor light to moderate resistance exercise appear to be effective in bed rest or space flight. A high net vector of load from ground reaction force (compressive forces) and muscle forces along the trabecular lines for the individual regions preserve the trabecular architecture and density and prevent bone loss. Rate of change in bone strain has also been proven a significant factor in maintaining or increasing bone density [46,47]. Hence, preservation of muscle strength is essential to preservation of bone, but is not sufficient alone. In space as well as on the ground, bone adaptation is governed by the three rules stated by C. H Turner: (1) It is driven by dynamic, rather than static loading. (2) Only a short duration of mechanical loading is necessary to initiate an adaptive response, and (3) Bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals [48].

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A 17-week bed rest study of resistance exercise as a countermeasure resulted in no bone loss in two of nine subjects and positive calcium balance in all subjects. The resistance exercise subjects preserved bone density through hypermetabolic state in which bone formation exceeded bone loss [31]. The 17 weeks of bed rest allows adequate time to detect bone changes in most regions. A series of bed rest studies conducted over a periods of 13 years in which subjects remained horizontal for durations of 5–36 weeks indicated that urinary excretion stabilized by the 17th week of bed rest [9]. Five weeks bed rest was not sufficient to produce a significant bone loss in the lumbar spine [5]. Subsequent studies conducted at JSC in the late 1980s using DEXA scans to detect bone changes were performed for 17 weeks [7]. This duration corresponds to the shortest Mir (115 days) and ISS (128 days) expeditions. It should be noted that bed rest corresponds to space flight in bone loss pattern but not degree of bone loss. Extrapolation of bed rest or spaceflight data beyond the period of time data has been measured has in the past been proven to be error prone. In the case of early Gemini and Apollo flights, missions beyond nine months were felt to risk serious impairment from bone loss [49]. Spaceflight exercise countermeasures have been limited according to the equipment available on Skylab, on Mir, on the space shuttle, and on ISS. Constraints of launch weight, volume, and loads imparted to the spacecraft all narrow the options for exercise hardware. Exercise countermeasures for shuttle missions (all less than 18 days duration) and Mir missions have included treadmill, rower and cycle ergometers. Treadmill exercise is felt to improve postflight gait through simulation of ground-based walking and gravity-like eccentric loads on the lower extremities [50]. Cycle ergometer as well as treadmill exercise have been used to preserve aerobic capacity. Elastic bungee cords were used to preserve muscle strength on Mir, as was a rope pulled through a resistive pulley (the “exergenie”) on Skylab. Neither device was beneficial in preventing calcium loss from the bones, with results overall similar to bed rest without countermeasures. The Russian system of countermeasures has consisted of cycle ergometry, treadmill running, and resistance exercise with bungee cords. Increased physical training occurs toward the end of the mission. In the first few months of a long duration mission, cosmonauts frequently missed or had shortened exercise sessions on the Mir station in order to meet the demanding schedule of station tending and scientific activities. Space flight with the Russian countermeasures has produced bone losses similar to or slightly greater than the bone loss measured in subjects undergoing 17 weeks of controlled bed rest [7]. The standard suite of capabilities—treadmill, cycle ergometer, and bungees—is available on ISS; however, due to compelling ground data with bed rest subjects, heavy resistive exercise capability has been added. A resistive device capable of producing 300 lbs of force and further augmented with bungee cords has been available for use by

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the ISS expedition crews since the first expedition (shown in Figures 14.4 and 14.5). Resistive exercises on orbit include squats, heel raises, and dead lifts as well as upper extremity exercises. The number of repetitions that can be performed per day is lower than desired due to hardware limitations. Therefore, increasing the number of repetitions to compensate for inadequate load has not been tested on orbit. In addition, frequent device failures have further limited effective consistent exercise. Despite such limitations of the equipment, resistive exercise appears to present a promising countermeasure that will be developed further with more robust successor devices capable of greater loading. Early initiation of exercise during 17 weeks bed rest allowed the muscle to maintain and increase strength to load the bone sufficient to maintain bone mineral density in an hour to an hour and a half of resistive exercise a day. Similarly, the

FIGURE 14.4. Astronaut Leroy Chiao preparing for a squat exercise on the interim resistive exercise device aboard the International Space Station. This requires a harness to distribute the force from two loading canisters over the shoulders and through the axial spine as the crewmember moves from a deep knee bend to a standing position (Photo courtesy of NASA)

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FIGURE 14.5. The classic dead lift exercise utilizes a rigid bar between the two loading canisters of the interim resistive exercise device (Photo courtesy of NASA)

improvements in ISS astronauts compared to Mir cosmonauts may be in part due to a more rigorously adhered to and earlier implemented exercise schedule as well as the increased intensity of resistive exercise in the former. The astronauts on ISS begin their intense training as soon as schedule permits and space motion sickness symptoms subside, usually during the first week of flight. These modest improvements have occurred during long duration ISS flights despite one half of the resistive exercise time having been missed due to scheduling constraints and equipment failures. In addition, restriction of load capabilities due to hardware failure to meet original design criteria have further limited effectiveness of resistance exercise [31]. Success of any resistance exercise program is dependent upon generating sufficient loads with proper biomechanics to load the affected regions. Elimination of body weight during exercises emulating lifting in microgravity increases the externally applied loads required to adequately train the musculoskeletal system. In the bed rest study, only one woman did not exceed 300 lbs in the horizontal leg press, and two men exceeded

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500 lbs during the 5 repetition maximal exercises at the end of the study. Numerous ambulatory studies of resistive exercise to improve bone mineral density have illustrated that bone formation requires loads of the 5–11 repetition maximal range for training. Lower loads of 15 repetitions or more to reach failure have not been successful in increasing bone density in young individuals. Also, regions with increased bone density during exercise programs vary between studies. This may be due to slight variations in the exercise regimens that can produce drastic differences in loading scenarios for individual regions. This was illustrated in the resistive exercise bed rest study in which individuals who added a slight hip flexion/extension movement to the single calf raise experienced little or no bone loss in the femoral trochanter, while those who held the hip straight had bone loss equivalent to bed rest controls. The exercise countermeasures used aboard Mir and Skylab did not prevent musculoskeletal wasting. Resumption of full activity was gradual, with rehabilitation carefully monitored by flight surgeons and exercise trainers. As noted above, injuries other than the higher than expected incidence of HNP in shuttle astronauts have not occurred. Full recovery of bone lost during long duration missions has occurred within 3 years in most of the astronauts who flew on Mir. From this standpoint of no injuries and full recovery during postflight rehabilitation in most astronauts, it can be argued that countermeasures are sufficient for long duration missions with the promise of return to a protective environment on earth. Possible compromise of ability to perform an emergency shuttle egress in the event of a landing mishap has caused some concern over muscle strength losses. However, not all astronauts can complete an emergency egress test preflight in the launch and entry suit. Muscle strength and bone density losses after shuttle and Mir missions have not had any mission impact or major health impact to date. However, exploration missions to Mars, which might involve transit times of six months or greater in microgravity, present a new challenge. If not prevented, musculoskeletal wasting on missions to Mars may limit mobility and ability to accomplish surface exploratory objectives. Geologic exploration is frequently most productive in areas with high relief due to the ability to observe and measure multiple sedimentary and volcanic strata without the necessity of drilling. One limitation of robotic exploration that human exploration may overcome is negotiation of difficult terrain. Failure to properly maintain musculoskeletal conditioning and cardiovascular endurance during four to six month flights to Mars may limit the advantages of manned exploration of Mars. A recent resurgence in interest in the use of artificial gravity as a countermeasure to the effects of space flight upon multiple physiologic functions includes predictions that exposure to mechanical forces integrated over time will preserve bone [51]. However, spacecraft design may have significant impact upon the efficacy of artificial gravity for the musculoskeletal system. If the spacecraft is designed with ergonomic

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efficiency to minimize work involved in maintaining and operating the spacecraft and in performing activities of daily living, the effect of artificial gravity will be nullified and bone and muscle strength may deteriorate unless exercise countermeasures are enforced. Development of exercise equipment capable of delivering loads of 500–600 lbs without imparting significant mechanical stress and vibration to the spacecraft frame is necessary to test musculoskeletal countermeasures that will enable astronauts to function as planetary explorers after 4–6 months confined to a spacecraft.

Pharmaceutical Countermeasures Because bisphosphonates inhibit osteoclastic resorption of bone, they have excellent potential to counter the resorption that occurs during weightlessness. This class of drug attaches to the hydroxyapatite crystal at the site calcium pyrophosphate is normally adsorbed and interferes with osteoclast activity. One of the first bisphosphonates marketed in the United States, etidronate, was tested during long duration bed rest and found effective at higher dosage [9]. The toxic dosage at which osteomalacic bone forms is very close to the therapeutic dosage, therefore the drug was not deemed suitable for space flight. Subsequently, clodronate was tested with good results other than large bone losses in the calcaneus in one bed rest volunteer [10,52]. Clodronate was withdrawn from the U.S. market by the manufacturer because of an adverse reaction during the clinical trial phase but continues to be marketed in Europe. The newest generation of bisphosphonates, including alendronate and risedronate, are aminobisphosphonates. The medications are the most effective oral antiresorptive agents currently marketed, with widespread clinical use in the prevention of osteoporosis related fractures. Results of studies in which bisphosphonates were given during bed rest were similar for the 1981 report of clodronate [53] and a more recent 17 week bed rest alendronate study completed in 2000 [52]. Overall calcium balance was positive, and regional losses were negligible except for the calcaneus. Research subjects taking alendronate preserved bone in a hypometabolic state in which bone resorption was decreased to a greater extent than bone formation. Although bisphosphonates decreased or prevented bone loss during bed rest, normal musculoskeletal functioning was not preserved. Slow unstable gait and limitation of walking distances were common to the five men and three women who used no countermeasure to bone loss at bed rest and to the nine men who used alendronate as a countermeasure. They also experienced muscle soreness in the calves, thighs, and lumbar regions upon reambulation. Maximum single-exertion (“one repetition”) strength testing resulted in muscle soreness for a day or two in the groups that did no strength training. In contrast, the nine exercise subjects walked with a normal gait except for some tendency to lose balance on turning around or cornering quickly. It is interesting to note that this same cornering imbalance has been noticed in astronauts post flight

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and attributed to a change in sensorimotor integration of vestibular signals due to microgravity exposure [54].

Skeletal Considerations for Exploration Missions With the recently renewed interest in manned exploration of the Moon and Mars, the influence of living and working in partial gravity on bone metabolism has become a concern of biomedical scientists performing risk assessments to define research and countermeasure needs for manned planetary exploration. At a recent conference of the National Space Biomedical Research Institute, physiologists and physicians with expertise in bone physiology and biomechanics identified the risk of developing osteoporosis due to losses in partial gravity added to losses during a weightless flight to and from Mars as the greatest concern related to the musculoskeletal system. Specifically, if losses are unabated during a 6-month weightless flight to Mars, one and a half years on the Martian surface, and 6 months return in weightlessness, there exists a possibility of bone loss to a density at which losses cannot be fully recovered due to bone architectural changes. These time periods reflect one of the dominant mission scenarios based on available propulsion methods and favorable planetary alignment. At present, there are insufficient data on missions over 8 months in duration to make valid assumptions about rate of change of bone loss for these longer periods. However, an estimate of worst case scenario would be bone loss during 400 days of weightlessness at the same rate experienced by astronauts on ISS, accounting for the out and back transit times. Bone loss on Mars, with partial gravity of 0.38 g coupled with physical loads of exercise and geologic exploration, would not be expected to be greater than bed rest on Earth with exercise, so a worst case scenario for Mars would be the bone change experienced in 117 days of bed rest, for which there are data, extrapolated to 547 days (1.5 years). Using this worst case scenario and adding in 1.7 times the standard deviation to give a 95% confidence interval in each situation, an estimate of the maximum T-score change expected in the lumbar spine would be −2.7, in the femoral neck −2.4 for men or 3.0 for women, and in the femoral trochanter −2.8 for men and −3.5 for women. (The database for men has a larger SD than that for women in the hip, hence different T-score changes from the same BMD loss estimate. Lumbar spine data bases for men and women have he same SD.) In terms of fracture risk, the threshold for fragility fractures is accepted as the BMD that is 2.5 SD below young normal for Caucasian females. It should be noted these values are highly speculative in that (1) they assume losses do not abate with time, contrary to ground-based evidence from spinal cord injury, (2) they assume continued losses due to disuse on Mars, which is unlikely with the provision of countermeasures and the loads associated with exploration, and (3) they incorporate

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the maximum bone loss within a 95% confidence interval based upon large SD values of bed rest subjects with exercise, as well as spaceflight crewmembers with current countermeasures that are inadequate and supply half of the load specified in the requirements for an inflight resistive exercise device. This worst case scenario does illustrate that the risk of irrecoverable or catastrophic bone loss is not an insurmountable obstacle for a mission to Mars. This risk would be further diminished by decreasing transit time in microgravity, such as might be afforded by advanced propulsion systems, and the expected ease of providing exercise countermeasures with full loads on the surface relative to the same in microgravity.

Conclusions In summary, spaceflight crewmembers utilizing exercise countermeasures available on Mir and Skylab experienced musculoskeletal decrements similar to those incurred during terrestrial bed rest studies with no countermeasures. Despite these changes, full recovery occurred in most astronauts and postflight injury rates have been minimal. One exception to the lack of injury is the small increased incidence of HNP in astronauts, which does not appear dependent upon the mission length. Currently, spaceflight of 4–6 months duration has not resulted in significant hazards to astronauts due to musculoskeletal deconditioning. However, the decrement of musculoskeletal strength and endurance following missions of 4–6 months in microgravity could prove severely limiting and possibly hazardous during geologic exploration of Mars. Preliminary results of ISS flights indicate some improvement in efficacy of bone countermeasures, as well as less limitation in immediate postflight physical activity as reported by flight surgeons, although loss of strength and muscle mass persist. Improvements in hardware and ISS exercise scheduling are required to fully assess and develop exercise countermeasures. Artificial gravity continues to remain an option to prevent musculoskeletal disuse and to preserve motor coordination, though no test platform for such an assessment exists at this time. Greater focus must be placed upon developing the physical training methods and equipment to ensure that astronauts arrive safely on the Martian surface with a musculoskeletal system trained and conditioned to meet the demands of geologic exploration of the hostile surface environment. It is the duty of the scientists, physicians, and engineers working with the space program to develop means to minimize risk of traumatic and overuse injuries that could inhibit or curtail useful scientific work while maximizing the benefits of manned exploration. Humans have performed geologic exploration of the lunar surface and have lived in space for durations equivalent to a trip to Mars. Safely accomplishing Martian exploration is an achievable goal. In accomplishing this goal, we have learned and will continue to learn about adaptation to the mechanical forces that act upon and are produced by that marvelous creation, the human musculoskeletal system.

L.C. Shackelford

References 1. Dickerman RD, Pertusi R, Smith GH. The upper range of lumbar spine bone mineral density? An examination of the current world record holder in the squat lift. Int J Sports Med 2000; 469–470. 2. WHO Study Group; Assessment of fracture risk and its application to screening for post-menopausal osteoporosis. WHO Technical Report Series 843, WHO, Geneva; 1994. 3. Dietrick J, Whedon G, Schor E. Effects of mobilization upon various metabolic and physiologic functions of normal men. Am J Med 1948; 4:3–36. 4. Mack PB, LaChance P. Effects of recumbency and space flight on bone density. Am J Clin Nutr 1967; 20(11):1194–1205. 5. LeBlanc A, Schneider V, Krebs J, Evans H, Jhingram S, Johnson P. Spinal bone mineral after 5 weeks of bed rest. Calcif Tissue Int 1987; 41:259–261. 6. Shackelford L, LeBlanc A, Driscoll T, Evans H, Rianon N, Smith S, Spector E, Feeback D, Lai D. Resistance exercise as a countermeasure to disuse-induced bone loss. J Appl Physiol 2004; 97(1):119–129. 7. LeBlanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks bed rest. J Bone Miner Res 1990; 5(8):843–850. 8. Hantman DA, Vogel JM, Donaldson CL, Friedman R, Goldsmith RS, Hulley SB. Attempts to prevent disuse osteoporosis by treatment with calcitonin, longitudinal compression and supplementary calcium and phosphate. J Clin Endocrinol Metab 1973; 36(5):845–858. 9. Schnieder V, McDonald J. Skeletal calcium homeostasis and countermeasures to prevent disuse osteoporosis. Calcif Tissue Int 1984; 36:S151–S154. 10. Schneider V, LeBlanc A, Huntoon C. Prevention of space flight induced soft tissue calcification and disuse osteoporosis. Acta Astronaut 1993; 29(2):139–140. 11. Tilton FE, Degioanni JC, Schneider VS. Long-term follow-up of Skylab bone demineralization. Aviat Space and Environ Med 1980; 11(Suppl.):1209–1213. 12. Rambaut PC, Smith MC, Mack PB, Vogel JM. Skeletal response. In: Richard S. Johnston, Lawrence F. Dietlein, and Charles A. Berry (eds.), Biomedical Results of Apollo. Chap. 7, pp.303–322, NASA SP-368; 1975. 13. Leach CS, Rambaut PC. Biochemical responses of the Skylab crewmen: An overview. In: Richard S. Johnston and Lawrence F. Dietlein. Biomedical Results from Skylab. Chap. 23, pp. 204–216, NASA SP-377; 1977. 14. Vogel JM, Whittle MW, Smith MC, Jr., Rambaut PC. Bone mineral measurement—Experiment M078. In: Richard S. Johnston and Lawrence F. Dietlein. Biomedical Results from Skylab. Chap. 23, pp. 183–190, NASA SP-377; 1977. 15. LeBlanc A, Schneider V. Can the adult skeleton recover lost bone? Esp Gerontol 1991; 26(2–3):189–201. 16. Sievanen H, Koskue V, Rauhio A, Kannus P, Heinonen A, Vuori I. Peripheral computed tomography in human long bones: Evaluation of in vitro and in vivo precision; J Bone Miner Res 1992; 13:871–882. 17. Njeh CF, Fuerst T, Hans D, Blake GM, Genant HK. Radiation exposure in bone density assessment. Appl Radiat Isot 1999; 50(1):215–236. 18. LeBlanc A, Schneider V, Shackelford L, West S, Oganov V, Bakulin A, Veronin L. Bone mineral and lean tissue loss after long duration spaceflight. J Bone Miner Res 1996; 11: S323 (abstract).

14. Musculoskeletal Response to Space Flight 19. LeBlanc A, Shackelford L, Schneider V. Future of bone research in space. Bone 1998; 22(5) Suppl.: 113S–116S. 20. Schneider V, Oganov V, LeBlanc A, Rakmonov A, Taggart L, Bakulin A, Huntoon C, Grigoriev A, and Veronin L. Bone and body mass changes during space flight. Acta Astronaut 1995; 36(8–12):463–466. 21. Oganov VS, Grigoriev AI, Veronin LI, Rakmonov AS, Bakulin AV, Schneider VS, LeBlanc A. Bone mineral density in cosmonauts after 4.5–6 month-long flights aboard orbital station Mir. Aero Environ Med 1992; 26(5–6):20–24. 22. Grigoriev AI, Oganov VS, Bakulin AV, Polyakov VV, Voronin LI, Morgun VV, Schneider VS, Marachko LM, Novikov, VE, LeBlanc AD, Shackelford LC. Clinicophysiological evaluation of bone changes in cosmonauts after long-term space missions. Aerosp Environ Med (Russia) 1998; 32(1):21–25. 23. Harm DL, Jennings RT, Meck JV, Powell MR, Putcha L, Sams CP, Schneider SM, Shackelford LC, Smith SM, Whitson PA. Genome and Hormones: Gender differences in physiology. Invited review: Gender issues related to spaceflight: A NASA Perspective. J Appl Physiol 2001; 91: 2374–2383. 24. Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone mineral loss from the spine and hip in long duration spaceflight. J Bone Miner Res 2004; 19(6):1006–1012. 25. Kozlovskaya IB, Grigoriev AI. Russian System of Countermeasures on Board the International Space Station (ISS). The First Results. American Institute of Aeronautics and Astronautics, Inc. 54th Annual Astronautical Congress of the International Astronautical Federation and the International Academy of Astronautics, and the International Institute of Space Law, Bremen, Germany; 29 Sept. to 3 Oct. 2003. 26. Oganov VS, Personal communication; 1996. 27. Dornemann TM, McMurray RG, Renner JB, Anderson JJB. Effects of high-intensity resistance exercise on bone mineral density and muscle strength of 40–50-year-old women. J Sports Med Phys Fitness 1997; 37:246–251. 28. Kerr D, Morton A, Dick I, Prince R. Exercise effects on bone mass in postmenopausal women are site-specific and load dependent. J Bone Miner Res 1996; 11:218–225. 29. Tsuzuku S, Shimokata H, Ikegami Y, Yabe K, Wasnich RD. Effects of high versus low-intensity resistance training on bone mineral density in young males. Calcif Tissue Int 2001; 68: 342–347. 30. Vincent KR, Braith RW. Resistance exercise and bone turnover in elderly men and women. Med Sci sports and Exerc 2002; 34(1):17–23. 31. Shackelford, LC, Feiveson A, Smith SM, Feeback D, and Greenisen M. Exercise countermeasure to disuse osteoporosis. J Bone Miner Res, 2001; 16(1):S485 (abstract). 32. Heinonen A, Sievanen H, Kyrolainen H, Perttunen J, and Kannus P. Mineral mass, size, and estimated mechanical strength of triple jumpers’ lower limb. Bone 2001; 29(3):279–285. 33. Smith SM, Nillen JL, LeBlanc AD, Lipton A, Demers LM, Lane HW, Leach CS. Collagen cross-link excretion during space flight and bed rest. J Clin Endocrinol Metab 1998; 83:3584–3591. 34. Smith SM, Heer M. Calcium and bone metabolism during space flight. Nutrition 2002; 18:849–852. 35. Smith SM, Wastney ME, O’Brien KO, Morukov BV, Larina IM, Abrams SA, Davis-Street JE, Oganov V, Shackelford LC. Bone markers, calcium metabolism, and calcium kinetics during extended-duration space flight on the Mir space station. J Bone Min Res 2005; 20(2):208–218.

305 36. Mujika I, Padilla S. Muscular characteristics of detraining in humans. Med Sci Sports Exerc 2001; 33(8):1297–1303. 37. Greenleaf JE, Bulblian R, Bernauer EM, Haskell WL, Moore T. Exercise training protocols for astronauts in microgravity. J Appl Physiol 1989; 67:2191–2204. 38. Fitts RH, Riley DR, Widrick JJ. Microgravity and skeletal muscle. J Applied Physiol 2000; 89:823–839. 39. Widrick JJ, Knuth ST, Norenberg KM, Romatowski JG, Bain JL, Riley DA, Karhanek M, Trappe SW, Trappe TA, Costill DL, Fitts RH. Effect of a 17 day spaceflight on contractile properties of human soleus muscle fibers. J Physiol. 1999; 516 (Pt. 3): 915–930. 40. Lee, S.M.C., M.E. Guilliams, S.F. Siconolfi, M.C. Greenisen, S.M. Schneider, and L.C. Shackelford. Concentric strength and endurance after long duration spaceflight. Med Sci Sports Exerc 2000; 32:S363. 41. LeBlanc A, Lin C, Shackelford L, Sinitsyn, V, Evans, H, Belichenko O, Shenkman B, Koslovsyaya I, Oganov V, Bakulin A, Hedrick T, Feeback D. Muscle volume, MRI relaxation times (T2), and body composition after space flight. J Appl Physiol 2000; 89(6):2158–2164. 42. Ledsome JR, Cole C, Gagnon F, Susak L. Wing, P; Long term stability of somatosensory evoked potentials and the effects of microgravity. Aviat Space Environ Med 1995; 66(7):641–644. 43. Hutchinson KJ, Watenpaugh DE, Murthy G, Convertino VA, Hargens AR. Back Pain during 6 degrees head down tilt approximates that during actual microgravity. Aviat Space Environ Med 1995; 66(3):256–259. 44. LeBlanc A, Evans HJ, Schneider VS, Wendt RE3rd, Hedrick TD. Changes in intervertebral disc cross-sectional area with bed rest and space flight. Spine 1994; 19(7):812–817. 45. Johnston SL, Wear ML, Birzele JA, and Hamm PB. Incidence of herniated nucleus pulposus among astronauts and other selected populations. Aviat Space Environ Med 1998; 69(3), abstract. 46. O’Conner JA, Lanyon LE. The influence of strain rate on adaptive remodeling. J Biomech 1982; 15:767–781. 47. Turner CH, Owan I, Takano Y. Mechanotransduction in bone: role of strain rate. Am J Physiol 1995; E438–E442. 48. Turner CH. Three rules for bone adaptation to mechanical stimuli. Bone 1998; 23(5):399–407. 49. Whedon GD, Lutwak L, Rambaut P, Whittle M, Leach C, Reid J, Smith M. Effect of weightlessness on mineral metabolism. Metabolic studies on Skylab orbital flights. Calcif Tissue Res 1976; 21(Suppl.):423–430. 50. Convertino VA, Sandler H. Exercise countermeasures for spaceflight. Acta Astronaut 1995; 35(4/5):253–270. 51. Lackner JR, DiZio P. Artificial Gravity as a Countermeasure in Long-duration Space Flight. J Neurosci Res 2000; 62:169–176. 52. LeBlanc, A. D., L. Shackelford, T. Driscoll. H. Evans, N. Rianon, S. Smith. Alendronate as a potential countermeasure to microgravity induced bone loss. J Bone Miner Res 2001; 16(1 Suppl.): S285. 53. Schneider VS, McDonald J. Prevention of disuse osteoporosis: Clodronate therapy. In: H.F. DeLuca, H.M. Frost, W.S. Lee, C.C. Johnston, and A.M. Parfitt (eds.), Osteoporosis—Recent advances in pathogenesis and treatment. Baltimore, MD: University Park Press; 1981: 491. 54. Black FO, Paloski WH, Reschke ME, Igarashi M, Guedry F, Andersen DJ. Disruption of postural readaptation by inertial stimuli following space flight. J Vestib Res 1999; 9(5):369–378.

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Suggested Readings Morey-Holton, WA, Meulen VD. The skeleton and its adaptation to gravity. In: Fregly MJ, Blatteis CM (eds.), Handbook of Physiology, Chapter 31. Section 4: Environmental Physiology, Volume I.

L.C. Shackelford Published by the American Physiological Society. New York, NY: Oxford University Press; 1996: 691–719. Webster SS Jee. Integrated bone tissue and physiology: Anatomy and physiology. In: Stephen C. Cowin (ed.), Bone Mechanics Handbook. 2nd edn. Boca Raton, FL: CRC Press; 2001: 1-1–1-68.

15 Immunologic Concerns Clarence F. Sams and Duane L. Pierson

Immune System Function and Significance for Space Flight The human immune system is composed of a complex set of specialized cells, chemicals, and organ systems that interact to protect the host from pathogenic challenge and aberrant tissue growth. The immune system consists of two major elements: innate immunity and acquired immunity. The innate or nonspecific immunity includes the phagocytes and natural killer cells as well as chemical factors (lysozyme, complement, etc.) that act to control extra-cellular pathogens. Resistance of this system to pathogenic entities is not adaptive and is not increased by repeated exposure. The acquired immune system itself consists of two functional components: humoral immunity and cell-mediated immunity. These elements adapt and become more responsive with repeated exposure to pathogens. Simplistically, the humoral immune system encompasses protein factors (antibodies) that bind and neutralize their antigen targets and the specific cells (B cells) that produce the antibodies. The cell-mediated immune system includes the T cells which regulate many aspects of overall immune response and directly provide self vs. non-self discrimination. This system is critical to the control of intracellular pathogens (such as viruses) and the containment and elimination of malignant cells. These elements interact to protect the host from a broad range of medical threats. Defects in immune function can result in three distinct failure modes: (1) immunodeficiency, where the immune system fails to contain infections, (2) autoimmunity, an inappropriate response to self antigens that damages the host, and (3) hypersensitivity, an over-reaction of the immune system to innocuous foreign antigens. Any of these failures can have a significant medical impact on crewmembers during space flight. Precise regulation of immune function is critical because an overly active immune system can be just as damaging as an unresponsive one. Finally, the interplay of immune changes and environmental exposures in space flight (e.g., radiation, chemical exposures) can also induce long-term health risks for the crewmember.

Immunologically mediated disorders can directly affect spaceflight crew operations, and the operational impact will depend upon the specific mission activities involved. Among the disorders that have potential mission impact are (1) infections, (2) allergic reactions, (3) autoimmune problems, (4) reactivation of latent viruses, and (5) increased risk for cancers. An added factor is that an illness that has minimal medical consequence in a terrestrial situation can have a major operational impact during space flight. Simple upper respiratory infections can cause delay of mission and incur significant programmatic costs. Illness can reduce crew comfort and wellbeing, adversely affect crew performance, cause the inability to complete critical mission tasks, result in early termination of the mission, or at an extreme, result in loss of life. Due to the potentially serious consequences of immunologic disorders, care must be taken to minimize these risks to the crew during all phases of mission operations.

Spacecraft-Related Risk Factors for Immunologic Diseases The crewmember risk for development of immunologically related diseases represents a balance between the challenges presented by the environment and the response of the immune system to those challenges. The spacecraft environment presents a number of unique characteristics that must be considered for the evaluation of crewmember medical risks, diagnosis, and treatment. These factors can increase frequency of insult, degree of exposure, route of exposure, and options for treatment. Spacecraft crew compartments are, without exception, closed ecosystems of limited volume. For example, Shuttle pressurized volume (crew quarters) is ∼2700 cu ft. However, the useable living space of the orbiter is considerably smaller. The middeck is 9 by 11 by 7 ft and flight deck area is about 7 to 8 by 11 by 6 ft with a curved ceiling that drops to about 3 to 4 ft on the outer edges. Additional space is lost to seats and stowage (lockers and equipment) located in this volume.

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Within this space, up to seven crewmembers must live, eat and work for 5 to 16 days at a time. The limited physical separation of galley and toilet facilities is a good example of the physical constraints imposed. Such cramped conditions may increase the risks of pathogen transmission by direct contact. Further, the limited volume exacerbates the potential for transmission by aerosols. The atmospheric restrictions of the spacecraft also exacerbate the consequences of chemical releases or combustion events. Such events may irritate mucosal membranes or expose the crewmember to potentially sensitizing chemicals or allergens. Because of this, a toxicologic assessment is performed on all items that are included in the pressurized volume. This limits the amounts and types of chemicals that can be carried. It also determines the level of containment that must be provided for the particular chemical agent during crew operations. As NASA moves to longer duration missions aboard the International Space Station (ISS), the issue of allergic sensitization of the crewmembers to compounds in the spacecraft atmosphere is beginning to be considered. Known sensitizing agents such as formaldehyde and nickel are present in the spacecraft atmosphere and water, respectively. Exposure to these agents for an extended time may result in the development of allergies to these compounds. Another obvious characteristic of the spacecraft environment is the lack of gravity. This has a number of physiological and operational impacts on the crewmembers, but a major issue relevant to immune-related disorders is the lack of sedimentation of larger particulates. Since gravity is absent, there is a greater exposure to particulates (especially large particulates >100 µm in size) than one would have in terrestrial settings where such particulates settle out of the air. These particulates can cause increased ocular and nasal irritation. This irritation may raise the potential for infections via the mucosal routes of exposure. The lack of sedimentation of aerosols, skin, and clothing particles may also result in new potential routes for transmission of disease. For example, if a crewmember developed a simple herpetic lesion during flight due to the reactivation of latent herpes, virus could be shed via spittle or direct sloughing of the lesion into the atmosphere. The virus, which is typically transmitted by direct contact, could potentially be transmitted to ocular or nasal sites via atmospheric routes. The potential consequences of an ocular herpes infection are quite serious and illustrate the additional complications of operating in the microgravity environment. Particulates are cleaned from the atmosphere by circulating the cabin air through a filter. Air and water must be recycled in the closed environment of long duration spacecraft such as the ISS or in exploration class vehicles. This results in significant constraints on the design of habitability systems and may have further impacts on crew health related to the approaches used or failures in atmospheric or potable water conditioning systems. Problems with life support equipment can result in significant environmental impacts to the crew. During the joint US–Russian NASA Mir missions, malfunctions in the life support systems resulted in cabin tem-

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peratures above 40°C and high humidity in the spacecraft. In addition to the increased stress on the crew from the heat load, growth of microorganisms such as fungi and molds were also increased. Release of spores or contact with fluids containing microorganisms during these events provides the increased potential for development of infections. The limitations of air and water systems also restrict the options for personal hygiene. Facilities for personal bathing and laundering of clothing are currently unavailable due to the impacts of microgravity on fluids handling, ability to recycle water, and power required. The result of these limitations is the use of sponge baths for personal hygiene and utilization of clothing for multiple days before discarding. This strategy increases the likelihood that minor skin irritation and rashes may occur. Rashes, abrasions, and other skin irritations are common during space flight, and dermatological ointments are among the more commonly used medications on orbit. While these are rarely a significant health threat, they may reduce crew comfort and productivity. The limited hygiene may contribute to the risk of infecting abrasions or other breaks in the skin and can exacerbate activities of special mission operations such as suited space walks. Special mission operations such as extravehicular activity (EVA) also have unique medical issues with respect to potential infectious insult. Crewmembers universally experience abrasions, blisters and other skin problems from contact with the suit during EVA. The characteristics of the pressurized suit result in numerous “hot spots” where hard points in the suits interact with crewmember movements. These abrasions can impact the ability to perform repeated EVAs. In addition, the requirement of the crews to constantly access stowed gear and perform routine maintenance activities increases the incidence of minor scrapes, cuts, and contusions on the hands during flight. Crewmembers anecdotally report that these minor cutaneous injuries are slow to heal during space flight, and this can increase the likelihood of developing an infection. While some antibiotics are available, the inability to culture and identify microorganisms during flight can limit diagnosis and treatment options. In some cases this can result in the application of an inappropriate treatment regimen due to a lack of the basic microbial information from the infected tissue. Due to the size and complexity of long duration spacecraft, there is a very real potential of establishing stable ecosystems within the habitable space. Variations in humidity and airflow at different locations in the vehicle can induce locally high humidity or condensation that is stable over time. This supports the establishment of microbial ecosystems that contain a variety of simple to complex microorganisms. The Mir Space Station had this specific problem when stable condensates from the atmosphere formed on cold water lines behind equipment. Although these condensates were routinely “mopped up” and cleared, they developed stable microbial colonies populated by a variety of uni- and multi-cellular organisms including algae, bacteria, ciliates, and protozoa (Table 15.1). The crew can be repeatedly exposed to these organisms during maintenance activities, and protective gear must be provided for

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TABLE 15.1. Microorganisms isolated from Mir surface condensate. Fungi Candida guilliermondii Candida lipolytica Cladosporium species Fusarium species Hansenula anomala Penicillium species Rhodotorula glutinis Rhodotorula rubra

Bacteria Alcaligenes faecalis Bacillus circulans Bacillus coagulans Bacillus licheniformis Bacillus pumilus Bacillus species CDC Group IVC2 Citrobacter brackii Citrobacter freundii Comamonas acidovorans Corynebacterium species Flavobacterium meningosepticum Presumptive Legionella species Pseudomonas fluorescens Serratia liquefaciens Serratia marcesens Unidentified gram-negative rods (3) Yersinia frederiksenii Yersinia intermedia

use when necessary to limit exposure. A further concern with stable microbial ecosystems in spacecraft is the potential for genetic mutation of microbes due to the continuous radiation exposure while in space. While this has not been documented in samples collected to date, the potential for alterations in virulence or other characteristics must be considered. The radiation inherent in the space flight environment results in significant exposure to the crewmembers over the course of a long duration mission. The biological response to continuous exposure to the energy spectrum experienced during flight in high inclination earth orbit or during missions outside the protective environment of the Van Allen belts is not currently known. However, the hematopoetic tissue is among the more radiation sensitive organ systems and one would expect changes in immune function and surveillance to occur in parallel with an increased incidence of genetic mutation at the cellular level in the crews. The combination may result in an increased risk of carcinogenesis over the course of an astronaut’s career. Acute exposure to solar events outside the Van Allen belts has the potential for catastrophic doses that could result in hematopoietic and immune system failure and an increase in morbidity and mortality. Overall, the physical and operational factors discussed above that are associated with space flight have a significant impact on the environmental challenges that the crewmember’s immune system must respond to. The spacecraft environment may also induce changes in the immune system itself, some of which may be unique to microgravity flight and others that are a result of general stresses to the human during adaptation to a novel environment.

Chronic Stress and Isolation Analog Population Studies Physical and psychological stresses are known to cause immune alterations, and these factors may be significant contributors to

the effects seen during space flight. Due to the limited numbers of individuals who have flown in space, analog studies have been useful to assess the potential impacts of stress-induced immune dysregulation. Data from studies of students during exam periods and military cadets during training indicate significant immune effects from psychological stress. Additional data from submarine crews, Antarctic expedition crews, and isolation chamber studies have made it clear that numerous factors associated with space flight, independent of the microgravity exposure, can and do cause immune alterations which can place the subjects at risk.

Cytokines and Immune Function The human immune response has been extensively studied in a variety of pathophysiologic conditions including acute and chronic stress. The components of immunity, cell-mediated (CMI) and humoral (HI), are designed to handle interactions between various forms of internal and external antigenic challenges. CMI, coordinated primarily by thymic-dependent (T) and natural killer (NK) cells, is primarily responsible for host defense against intracellular pathogens and neoplastic transformation. HI, coordinated by B cells that synthesize antigenspecific immunoglobulins, is primarily responsible for host defense against most extracellular pathogens. Thus, a person with an infection with improperly functioning CMI would have increased susceptibility to intracellular pathogens such as viruses, fungi, and mycobacteria, while an abnormal B cell function would increase susceptibility to extracellular pathogens such as bacteria and parasites. Both T cell and B cell functions are dependent upon a subset of T cells referred to as helper T cells (TH) that function by producing soluble glycopeptides called cytokines. These cytokines are largely responsible for the function of specific arms of the immune response (cellular vs. humoral). Type 1 help supports cellular responses and includes interleukin (IL)-2, IL-12 and interferon (IFN)-g while type 2 help supports humoral responses and includes IL-4, IL-5 and IL-10 (Figure 15.1) [1]. When an antigen is encountered and processed, the specific cytokines produced by TH cells influence the relative cellular vs. humoral response to that antigen. If a cellular response is needed for host defense to a pathogen (i.e. viral), a cytokine imbalance that favors a humoral response is clinically the same as a deficiency of total immune response. TH cells have recently been divided into subpopulations based upon differential cytokine production profiles. TH1 cells (T helper cells producing type 1 cytokines) support primarily CMI; TH2 cells promote HI. Clinically, this is important not only in infectious diseases but also in hypersensitivity diseases. Clinical hypersensitivity occurs when immune responses to a given antigen, although mechanically intact, create disease in the host. An easily recognized example is allergic rhinitis caused by allergen-specific IgE bound to mast cells. It has been established that an isotype switch from IgM to IgE in allergen-specific B cells is directed by type 2-specific cytokine control (i.e. IL-4) and antagonized by type 1 cytokines (i.e., IFN) [2]. Thus, this disease can be viewed as an immune dysfunction caused by abnormal

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FIGURE 15.2. An illustration of pathways associating space flight stress to the potential clinical outcomes with mission and crew health impacts. CRF = corticotropin releasing factor; ACTH = adrenocorticotropic releasing hormone FIGURE 15.1. Simplified representation of Type I and Type 2 cytokine balance and the regulation of different arms of the immune system. While the in vivo situation is considerably more complex than this simple representation, Type 1 cytokines generally support cellmediated immunity and type 2 cytokines favor B cell differentiation and humoral immune function. IL, interleukin; IFN, interferon; TNF, tumor necrosis factor

activity of one or both TH subpopulations in susceptible persons. The balance of cytokines produced is thus critical to the maintenance of appropriate immune system function, and dysregulation can result in adverse clinical outcomes. Though space flight provides an environment with unique stressors where astronauts live and work, it also includes stressors that are experienced in terrestrial settings. These stressors impact the central nervous system (CNS) resulting in neuroendocrine changes that alter the cytokine balance and induce differential expression of immune functions. Specific examples of such stressors include confinement, isolation, fear, anxiety, psychosocial stressors, sleep deprivation, and physical discomfort. Any one or combination of stressors may induce immune dysregulation due to the influence of the neuroendocrine changes on the immune system. This bidirectional communication between the CNS and immune systems has been well studied, and much is known about how physical and psychological stress affects the human immune response. The neuroendocrine regulation of the immune system occurs through both the glucocorticoid hormones of the hypothalamic-pituitary-adrenal (HPA) axis as well as the neurotransmitters of the sympathetic nervous system [3]. The glucocorticoids are potent anti-inflammatory agents and affect the production of specific cytokines and other proinflammatory agents (e.g., prostaglandins). Glucocorticoids inhibit the production of IFN-g, IL-1, IL-2, IL-6, IL-8, IL-12 and TNFA and GM-CSF, all proinflammatory cytokines associated with TH1 function. They also up-regulate the TH2 cytokines

IL-4 and IL10, effectively inducing a shift in TH1/TH2 cytokine balance. This shifts the immune system away from the differentiation of macrophages, natural killer (NK) cells, and cytotoxic T cells of the cell mediated immune system and toward differentiation of the eosinophils, mast cells, and B cells that support antibody-mediated response. Glucocorticoids also up-regulate the expression of B2-adrenergic receptors on lymphocytes. These receptors are the primary immune target for the sympathetic neurotransmitter noradrenaline. Noradrenaline is thought to suppress the function of lymphocytes via interaction with the B2 receptor, but these responses vary with immune cell type and tissue location. From the above discussion, it is apparent that the CNS modulates immune function via the action of glucocorticoid and sympathetic hormones while the immune system modulates itself and CNS function via the action of cytokines. This complex, bidirectional interplay provides a mechanism for tightly coupling immune response to neurologic function. This feedback system maintains the critical balance of immune function required to ensure optimal health. Disturbing this balance causing either over-stimulation or suppression of the immune system will have significant clinical consequences (Figure 15.2).

Closed Chamber Immune Studies An examination of in vivo cell-mediated immune function was recently performed in subjects during an extended test of a closed, atmospheric recycling system at the Johnson Space Center [4]. The subjects were sealed in a test chamber for 90 days during which atmospheric oxygen was generated from expired carbon dioxide (CO2) using recycling systems employing a mixed biological (plants) and chemical recycling system. The chamber subjects were required to maintain and repair hardware that was located within the test chamber. This chamber test was a test bed for systems that will eventually be utilized on ISS or exploration missions. Delayed-type hypersensitivity tests (DTH skin tests) were performed on the

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subjects shortly before entering the chamber. In addition, tests were performed 45 days into the chamber study and two days before chamber exit (day 88). Another test was performed 30 days after chamber exit. Several individuals who were working on the chamber system, but not confined to the chamber, were used as a control group. The DTH tests are scored by both the number of antigens that elicit a cutaneous response (minimum 2 mm induration) and by the area of the response. The chamber group exhibited a decrease in the number of antigens they responded to during the chamber confinement. This was not observed in the control subjects. When a composite score (CMI score) that factored in both the number and size of response was determined, the chamber subjects exhibited a unique decrease in DTH response after 90 days in the chamber (Figure 15.3). The sample size (n = 4 chamber and 4 control subjects) was not sufficient to reach statistical significance within the normal subject variability. However, from either the individual responses or the CMI score, it is evident that the chamber exposure down-regulated the cell-mediated immune function in all of the chamber participants. None of the control subjects exhibited this response. A potential consequence of the dysregulation of the immune system is the reactivation of latent viruses. The effects of both acute and chronic stress on the reactivation of EBV have been extensively studied [5]. EBV shedding patterns were followed in Antarctic expeditioners before, during, and after 8 to 9 months of isolation. Increased EBV shedding was accompanied by decreased cell-mediated immunity as measured by delayed-type hypersensitivity (DTH) skin testing [6]. Similar results have been obtained in a variety of stress models. Glaser et al demonstrated the proliferative response to Epstein Barr

FIGURE 15.3. Mean cell mediated immunity (CMI) Scores in 4 chamber and 4 control subjects by relative chamber day. C-30 is 30 days before chamber entry. C+45 and C+90 are 45 and 90 days in the chamber, respectively. E+30 represents 30 days after chamber exit. The mean CMI score for control subjects was relatively unchanged throughout the study period [4].

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virus polypeptide antigens was decreased during examination periods in healthy medical students [7]. Further studies during the examination and basic training period of military academy cadets demonstrated examination stress induced the reactivation of latent EBV without changes in latent herpes simplex virus (HSV)-1 or HSV-6 [8].

Immune Alterations and Medical Events During Space Flight Evidence suggests space flight causes a dysregulation of the immune system. U.S. and Russian space scientists have investigated human immune responsiveness following space flight since the late 1960s [9]. Russian scientists have reported reduced in vitro proliferative responses after 140-day missions that were associated with lymphopenia in crewmembers [10,11]. Reduced NK cytotoxicity and decreased in vitro interferon production after space flight have also been documented [10,11]. Further evidence of in vitro immune dysregulation was reported by French and Russian investigators from 5 cosmonauts who resided between 26 and 166 days on board the Russian space station Mir [12]. They reported reduced numbers of cells expressing IL-2 receptors 48 h after stimulation in culture, without changes in the number of T suppressor/cytotoxic (CD8+) or T helper/inducer (CD4+) cells. The supernatants from these cultures contained normal levels of IL-1 and increased amounts of IL-2. Taylor and Janney reported reduced delayed-type hypersensitivity responses to a panel of intra-dermally applied recall antigens on flight days 3, 5, or 10 from ten astronauts when compared to their preflight control values [13]. This demonstrates that alterations in cell-mediated immunity do occur in vivo and supports the hypothesis that the immune system is functionally altered during space flight. The immune changes associated with space flight have been postulated to increase the potential for infectious disease in crewmembers. Analysis of medical records during the early Apollo missions indicated that about 50% to 60% of the crewmembers experienced some symptoms of “infectious illness” during the preflight or in-flight time period. To minimize the mission impact of these incidents, the Health Stabilization Program (HSP) was implemented prior to Apollo 14 (discussed further below). The program limits exposure of the crew to potentially infectious individuals and significantly reduced the incidence of reported illnesses during subsequent Apollo missions. The HSP program remains an element of the current Shuttle and ISS medical support program and continues to minimize the incidence of illness in the crews. However, even with the HSP in place, a significant number of Shuttle missions have included reports consistent with infectious disease during the immediate preflight and in-flight time periods. This suggests a reduction in immune function is associated with the stress of preparing for and executing space missions.

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Postflight Crewmember Immunologic Assessment In a preliminary study, we have recently evaluated the cytokine production of various lymphocyte subpopulations in conjunction with serum and urine stress hormones before and immediately following space flight. Whole blood samples from 27 astronauts were collected at three time points (10 days preflight, landing day and 3 days postflight) surrounding four recent Space Shuttle missions. The duration of these missions ranged from 10 to 18 days. The assays performed included serum/urine stress hormones, comprehensive subset phenotyping, assessment of cellular activation markers, and intracellular cytokine production following mitogenic stimulation. Absolute levels of peripheral granulocytes were significantly elevated following space flight, but the levels of circulating lymphocytes and monocytes were unchanged. After three days of exposure to unit gravity, the percentages in most of the subjects had returned to near baseline. No significant alterations regarding levels of circulating monocytes were seen following space flight. Lymphocyte subset analysis demonstrated trends towards a decreased percentage of T cells and an increased percentage of B cells. Nearly all of the astronauts demonstrated an increased CD4:CD8 ratio, which was dramatic in some individuals [14]. Although no significant trends were seen in the expression of the cellular activation markers CD69 and CD25 following exposure to microgravity, significant alterations were seen in cytokine production in response to mitogenic activation for specific subsets. T cell (CD3+) production of IL-2 was significantly decreased on landing day, as was IL-2 production by both CD4+ and CD8+ T cell subsets for most subjects (Figure 15.4A). Production of IFNγ was not altered after flight in either T cells in general or in the CD8+ T cell subset. However, a decrease in IFNγ production in the CD4+ T cell subset was observed on landing day (Figure 15.4B). Serum and urine stress-hormone analysis indicated significant physiologic stresses in astronauts following space flight. Taken together, these results demonstrated alterations in the peripheral immune system of astronauts immediately after space flight of 10 to 18 days duration. However, due to the physical stresses of landing, postflight measurements are affected by confounding variables that make evaluations of space flight vs. reambulation effects difficult. Assays that will tolerate the delay of in-flight sampling, such as the ones posed here, will provide a true investigation of the effects of space flight on the human immune system.

Inflight Versus Postflight Changes in Circulating Immune Cell Populations It remains unclear whether the data collected from crewmembers immediately after space flight reflects the changes occurring during flight or an acute response to return to the unit gravity environment. It is apparent that reentry and reambulation are significant stressors on the flight crew due

FIGURE 15.4. Mean percentages of T cells (CD3+) and T cell subsets (CD4+ and CD8+) that respond to stimulation by producing cytokines (A) IL-2 and (B) IFN gamma. Samples were collected 10 days before launch (preflight), on landing day, and 3 days after landing (postflight). [13] *Significant differences (p < 0.05) and error is represented as standard error of the mean. IL; interleukin; IFN, interferon.

to the reduced orthostatic tolerance and other physiological changes. During the Mir 18/STS71 mission, during which three long-duration flyers were returned from a four-month mission on Mir, we examined the subpopulations of circulating white cells during flight (within 24 h prior to landing) and compared them with data obtained before flight and immediately after landing. The inflight samples were obtained by venipuncture and stained during flight using the Whole Blood Staining Device [15]. All ground samples were also stained using the same device. The data are limited to three subjects, in whom an apparent redistribution of white blood cell populations was uniquely observed on landing day (Figure 15.5). The circulating cells were not significantly altered during flight compared to the preflight samples. The circulating cells also returned to preflight distributions within 9 days after flight. These changes were observed in crewmembers that had been in orbit for 115 days. These data indicate that re-exposure to unit gravity has a significant impact on the crewmember immune cells and that this must be considered during interpretation of pre- and postflight immune studies relative to immune changes during flight. It is also apparent that the influence of this acute

15. Immunologic Concerns

FIGURE 15.5. Relative percentage of natural killer (NK) cells in circulating peripheral lymphocyte populations. Cells were identified as CD16/56 positive CD3 negative cells by flow cytometry. Data are expressed as the percentage of labeled cells over total lymphocytes. Samples were collected 150 and 35 days before launch (L-150 and L-35), ∼24 h before landing (FD-11), on landing day (R+0), and nine days after recovery (R+9)

response to unit gravity should be evaluated for its potential impact on crew health during the postflight period.

Viral Reactivation During Space Flight Another potential risk from immune dysregulation during space flight is the reactivation of latent viruses. Most individuals carry a variety of latent viruses that cannot be screened out by quarantine. These viruses can be reactivated and expressed during episodes of decreased immune function. For this reason, external advisory groups have identified latent viruses as an infectious disease risk in astronauts before, during, and after space flight. Eight herpes viruses have been identified that infect humans. This family of double stranded DNA viruses includes herpes simplex type-1 (HSV-1), herpes simplex type-2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), human herpesvirus-6 (HHV-6), human herpesvirus7 (HHV-7), and human herpesvirus-8 (HHV-8). Following a primary infection, these viruses are capable of establishing a lifelong relationship with their human host. Typically, they exist within the host in a latent state, undetected and with no symptoms. However, in response to various stressors and the subsequent diminishment of immune function (especially the cell-mediated immune system), these viruses may reactivate and be shed in saliva, urine, and other body fluids. Some of these viruses (e.g., VZV) may remain latent for decades before reactivating. An analysis of reactivation and shedding of latent Epstein Barr virus (EBV) during space flight was performed during

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recent Space Shuttle missions (n = 11) [16]. Saliva specimens were collected and the extracted DNA analyzed by a polymerase chain reaction (PCR) assay for specific herpes viruses. The frequency of EBV in daily saliva samples was 29% prior to flight (for a period of 1 month beginning at 6 months before launch), 16% during spaceflight, and 16% for the first two weeks following space flight. This compares with a 2% to 5% frequency of EBV shedding found in a control population. After the flight, IgG levels of EBV viral capsid antigen were significantly increased over preflight levels. To determine if EBV behaved similarly to other herpesviruses or was unique, Mehta and colleagues examined CMV shedding patterns in astronauts [17]. Seventy-one astronauts serving as crewmembers on space shuttle flights participated in the study. Fifty-five (75%) were seropositive to CMV. Approximately 25% of the urine specimens from the seropositive astronauts contained CMV DNA, whereas just 1 of 61 (1.6%) control subjects shed CMV in their urine. For the 55 seropositive astronauts, CMV IgG levels did not increase from the baseline collection point (∼22 months before launch) through the landing phase. However, the 15 CMV shedders exhibited significant increases in CMV antibody titers. Examination of VZV demonstrated increased reactivation and shedding in astronaut saliva specimens, whereas control subjects showed no evidence of reactivation of VZV. Shedding of VZV in astronauts occurred during and after flight but not during the preflight phase. No symptoms were associated with the VZV shedding. This is significant because subclinical shedding of VZV has not been previously reported. A rise in VZV IgG titers was also seen consistent with the VZV shedding data. HSV 1 and 2 exhibited no significant increase in reactivation and shedding in astronaut saliva. The observed increases in stress hormones, viral reactivation, and viral antibody titers indicate that stress associated with spaceflight phases (prior, during, and after) impacts the immune system through the hypothalamic-pituitary-adrenal (HPA) axis and allows latent viruses to reactivate, multiply, and be released in body fluids. Further, the number of copies of virus shed during the inflight episodes was greater than that observed during shedding episodes preflight or postflight (Figure 15.6). This suggests an altered ability of the immune system to control or contain the reactivation and shedding of the virus. The increase in viral shedding represents a potential crew health risk. Therefore, the changes in virus specific immune response must be examined in order to determine the mechanisms mediating the increase in viral release.

Infectious Disease Development of infectious disease represents interplay between exposure of the host and its ability to deal with the infectious challenge. A number of strategies are utilized with

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FIGURE 15.6. Epstein-Barr virus shedding associated with Space Shuttle flight, as measured during preflight, inflight, and postflight collection of samples for later analysis via polymerase chain reaction

astronauts to minimize the likelihood of exposure to pathogens and to maximize host defense. Crewmembers are selected as basically healthy individuals and have adequate host defense mechanisms under typical terrestrial exposures. Normal host defense mechanisms include the skin and mucosa found in the respiratory tract, GI tract, and GU tract. Unless damaged by trauma, puncture, or incisions, the skin is a most effective barrier to microorganisms. The mucosal membranes are coated with secretions containing lysozyme and immunoglobins, which also provide an effective barrier to microorganisms. In addition, healthy persons live symbiotically with their own microbial flora. This normal flora is composed of bacteria and fungi and also provides some protection against introduction of other pathogenic species. The crewmember’s host defense is furthered bolstered by appropriate vaccination against likely infectious pathogens. Management of immunization history, general crew health, and exposure mechanisms provides the best approach to minimize crew health risks during flight. The control of exposure mechanisms addresses a number of factors including the Health Stabilization Program, which limits exposure of the crew to potentially infectious individuals the week prior to launch, and numerous checks of the spacecraft to minimize environmental exposure of infectious agents to the crew. Bi-directional transfer of microorganisms between crewmembers and the spacecraft has been repeatedly documented, and establishment of stable microbial ecosystems on space stations such as Mir has been previously discussed. In order to manage this issue, regular sampling and cleaning of spacecraft environments is performed to monitor and manage microbial flora. In the Space Shuttle, air and surface sampling are done twice before each Shuttle flight: once about four weeks before launch and again at two days before launch. Samples are taken again at landing. Sometimes samples have been collected in

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flight. In general, microbial counts show moderate increases during a Shuttle flight and these flora typically reflect organisms originating from the humans on board. Water for crew consumption is produced by the fuel cells that react cryogenic hydrogen and oxygen to produce electricity and power the Shuttle. However, the water storage tanks are launched charged with water and tested four times before each flight. Water produced in-flight must pass through a microbial check valve, which contains an antimicrobial iodinated resin, before it can be considered potable. Recently, a second resin was added to extract the iodine from the purified water, in order to prevent iodine accumulation by the crewmembers. Similar strategies are utilized for ISS with regular sampling of air, surface, and water systems. The environmental monitoring, ongoing maintenance of crew health, and availability of inflight medications provides a system to manage the infectious risks that potentially occur during the mission. While all exposure cannot be eliminated, it is possible to utilize this strategy to minimize adverse effects on the crew and inflight operations.

Hypersensitivity and Allergic Reactions The strategy for controlling allergic, autoimmune, or hypersensitivity reactions during flight is very similar to the approach for infectious diseases. The first line of defense is prevention. Individuals with a history of clinically significant allergies, asthma, or autoimmune problems are eliminated during the astronaut selection process. The most common medications that are used by the crews are tested prior to flight to determine whether the crewmember will exhibit any idiosyncratic reactions, allergic responses or other intolerance. Food items and any compounds that the crewmembers must take internally for onboard experiments (via ingestion or injection) are tested before flight to ensure they are do not cause an adverse reaction. While these steps can minimize the likelihood that an allergic response will occur during flight, they cannot eliminate the possibility of an inflight event. Medications are provided for the inflight treatment of allergic disorders. However, it must be acknowledged that management of a significant allergic event (e.g., anaphylaxis) would be exceedingly difficult during space flight. During a recent experiment, an immunization with a pneumococcal vaccine was performed inflight. Approximately 30% of the flight subjects experienced significant injection site soreness with inflammation and redness compared to less that 5% of the control subjects reporting soreness alone (1 out of 21 subjects). No control subjects developed redness or noticeable inflammation at the injection site. The timeline of the response was consistent with an Arthus or immune complex reaction. While this has been reported as a possible response to this vaccine, it is striking that such dramatic responses were seen here almost exclusively in the flight subjects. It is possible that changes to tissue perfusion or immune regulation may contribute to this response.

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It is currently unclear whether the changes that occur in the immune system during flight alter crewmembers’ susceptibility to hypersensitivity reactions or allergic response. In terrestrial settings, it is observed that shifts in immune regulation can result in the alteration of clinical outcomes from other stimuli. The potential consequences of a hypersensitivity or allergic problem during flight can be quite serious. It is imperative that medical officers are aware of the potential for altered sensitivity to ingested or injected agents during flight in order to adequately prepare for any eventuality.

Conclusions While no illnesses or infections have been linked to altered immune response due to spaceflight, it is apparent that changes in immunity can potentially impact the crew during space flight. Neither the extent of space flight induced immunological changes nor their consequences to the crew can be fully determined at the present time. Factors such as the physical and psychological stressors associated with space flight appear to be the major contributors to the observed immune alterations, although direct effects of microgravity on cells of the immune system or their regulation cannot be ruled out. The complex interplay of these immune changes with the unique environmental challenges present in the spacecraft must be fully understood to minimize the impacts on flight operations. Experience suggests that the risks associated with immune system changes can be effectively managed during short duration flight, since there is little evidence of immune-related disorders causing significant crew distress on flight of less than 30 days. However, as mission durations increase and the interplay of adverse environmental factors, radiation, viral changes, and immune dysregulation extends over greater and greater intervals, it becomes more difficult to confidently predict the projected outcome. Much more study of immune factors during space flight and the fine balance between immune regulation and clinical response in healthy normal individuals will be required to make realistic projections of crewmember risks during and after extended space flight. The ground-based study of analogue populations and correlation of immune dysregulation and clinical events will shed more light on this scenario. This information will provide the basis for mission planners and flight surgeons to design systems that minimize the potential for adverse events and increase productivity, comfort, and safety of the crew during flight and upon return to Earth.

References 1. Mossman TR, Coffman RL. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989; 7:145. 2. Del Prete GF, De Carli M, D’Elios MM, Maestrelli P, Ricci M, Fabbri L, Romagnani S. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of

315 patients with allergic respiratory disorders. Eur J Immunol 1993; 23:1445–1449. 3. Webster JL, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annual Rev Immunol 2001; 20:125–163. 4. Sams CF, D’Aunno D, Feeback DL. The influence of environmental stress on cell mediated immune function. In: Lane HL, Saner RL, Feeback DL (eds.), In Isolation: NASA Experiments in Closed Environment Living. Advanced Human Life Support Enclosed System Final Report. San Diego, CA: American Astronautical Society; 2002; 357–368. 5. Glaser R, Pearson GR, Jones JF, Hillhouse J, Kennedy S, Mao HY, Kiecolt-Glaser JK. Stress-related activation of EpsteinBarr virus. Brain, Behavior and Immunity 1991; 52:219–232. 6. Mehta SK, Pierson DL, Cooley H, Dubow R, Lugg D. EpsteinBarr virus reactivation associated with diminished cell-mediated immunity in Antarctic expeditioners. J Med Virol 2000 Jun; 61(2):235–240. 7. Glaser R, Pearson GR, Bonneau RH, Esterling BA, Atkinson C, Kiecolt-Glaser JK. Stress and the memory T-cell response to the Epstein-Barr virus in healthy medical students. Health Psychol 1993 Nov; 12(6):435–442. 8. Glaser R, Friedman SB, Smyth J, Ader R, Bijur P, Brunell P, Cohen N, Krilov LR, Lifrak ST, Stone A, Toffler P. The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point. Brain Behav Immun 1999; 13(3):240–251. 9. Konstantinova IV. Problems of space biology. In The Immune System Under Extreme Conditions, Space Immunology Volume 59. Translated from Sistema V Eksytremai ‘Nykh Usloviyakh, Problemy Kosmicheskoy Biologiya Vol. 56. Washington, DC: Natl. Aero. Space Admin.; 1990. 10. Konstantinova IV, Antropova EN, Legen’kov VI, Zazhirey VD. Study of reactivity of blood lymphoid cells in crew members of the Soyuz-6, Soyuz-7, and Soyuz-8 spaceships before and after flight. Kosmi Biol Avikosmi Med 1973; 7:35. 11. Manie S, Konstantinova I, Breittmayer JP, Ferrua B, Schaffar L. Effects of long duration spaceflight on human T lymphocyte and monocyte activity. Aviat Space Environ Med 1991; 62(12):1153–1158. 12. Taylor GR, Janey RP. In vivo testing confirms a blunting of the human cell-mediated immune mechanism during space flight. J Leukoc Biol 1992; 51:129. 13. Crucian BE, Cubbage ML, Sams CF. Altered cytokine production by specific human peripheral blood cell subsets immediately following space flight. J Interferon Cytokine Res 2000; 20(6):547–556. 14. Sams CF Crucian B, Clift V, Meinelt E. Development of a whole blood staining device for use during Space Shuttle flights. Cytometry 1999; 37:74–80. 15. Payne DA, Mehta SK, Tyring SK, Stowe RP, Pierson DL. Incidence of Epstein-Barr virus in astronaut saliva during spaceflight. Aviat Space Environ Med 1999; 70(12): 1211–1213. 16. Mehta SK, Stowe RP, Feiveson AH, Tyring SK, Pierson DL. Reactivation and shedding of cytomegalovirus in astronauts during spaceflight. J Infect Dis 2000; 182(6):1761–1764. 17. Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL. Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 2004; 72(1):174–179.

16 Cardiovascular Disorders Douglas R. Hamilton

Long- and short-term exposure to microgravity significantly alters the cardiovascular system [1–9]. In this chapter, we describe the cardiovascular changes and the strategies used to manage problems in operational space medicine that arise as a consequence of those changes. Most descriptions of the effects of microgravity on the cardiovascular system have focused mainly on the physiological mechanisms that contribute to cardiovascular changes. Flight surgeons need to understand these important physiological effects on the human cardiovascular system so that they can place them within the operational context of a space mission. Crewmembers may also have subclinical cardiac abnormalities that could be exacerbated by the adaptive responses of the cardiovascular system to microgravity. To help readers of this text understand the cardiovascular issues facing space medicine flight surgeons, this chapter uses an operational approach and considers issues that arise during each phase of a space mission, beginning with crew selection and proceeding through launch, on-orbit activities, atmospheric reentry, and postflight recovery. Both the U.S. and the Russian space programs have implemented extensive research programs to understand the alterations in cardiovascular physiology that are induced by exposure to microgravity, changes that may eventually manifest themselves in the form of impaired cardiovascular performance such as postflight orthostatic intolerance, decreased exercise capacity, or on-orbit cardiac arrhythmias [8–10]. The current literature has devoted little attention to the various clinical complications and operational problems that can arise from the deleterious effects of microgravity on the cardiovascular system [11]. The focus here is on two of the primary goals of operational space medicine: (1) to prevent the occurrence of cardiovascular illness or impaired performance in space flight and (2) to rehabilitate or treat impaired cardiovascular function in a manner that minimizes the effect on the mission while maximizing crew health and performance. To date, operational space medicine experience has benefited from the clinical observation of crews on numerous missions and from the results of life science research in the area of

cardiovascular physiology [7,12]. This chapter addresses the challenges associated with determining how much overt cardiovascular pathology is acceptable in terms of the overall risk to a mission.

Risk of Cardiac Disease in Aviation Populations The primary goal of the flight surgeon is to maintain the cardiac health and performance of space travelers through prevention of cardiac disease. This goal is achieved by considering the prevalence of cardiac abnormalities in the astronaut cohort in the context of the positive and negative predictive value of tests used to screen and monitor their cardiac function. In this context, primary prevention refers to the means by which cardiovascular disease is prevented among those patients without prior manifestations of such disease. Secondary prevention refers to the means by which cardiovascular disease is mitigated among those patients with clinically manifested disease. In the case of the astronaut, cardiac disease requiring secondary prevention is usually grounds for removal from active duty. During space travel, several environmental and operational factors can affect the cardiovascular system. The signs and symptoms secondary to the presence of these factors must be distinguished from overt cardiac disease. The means with which to mitigate the effects of these risk factors are commonly referred to as countermeasures. Countermeasures have sometimes been referred to as secondary prevention even though overt disease is not necessarily present. In the earlier phases of human space flight, flight surgeons relied on provocative tests that had poor positive predictive value (PPV) for determining the risk of cardiac events in the astronaut cohort; risk factor assessment was the mainstay of prognostication for the purposes of developing preventive strategies. Unfortunately, substantial variations among the astronaut cohort (e.g., age, sex, race, occupation, nationality, culture, occupational exposures) prevent flight surgeons from deriving accurate data on the incidence and prevalence 317

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of cardiac abnormalities in that cohort, despite its relatively small size. Accordingly, risk data for the astronaut population must be extrapolated from the prevalence of cardiac disease in similar cohorts, such as military and civilian aviators. The clinical presentation of sudden cardiac death, myocardial infarction, unstable angina, and most ischemic arrhythmias will cause abrupt incapacitation or significant impairment of crewmember performance [13–15]. Coronary atherosclerosis or coronary artery disease (CAD) is the largest cause of morbidity and mortality in industrialized nations [13]. In the United States, CAD is responsible for more than 1,000,000 deaths per year, nearly half of which are sudden, unexpected, and the first manifestation of CAD [16–18]. Atherosclerosis usually begins to occur during the second and third decades of life [19], and a nonlinear correlation exists between the amount of coronary artery calcium and luminal narrowing found at the same anatomic site [20]. Coronary atherosclerosis is an insidious process that results in the intimal deposition of lipid- and calcium-laden plaques and is absent in normal arteries [21,22]. The primary mechanism leading to acute coronary syndromes (sudden death, myocardial infarction, unstable angina) is plaque rupture. The initiating event in an acute coronary syndrome (ACS) however is endothelial cell damage, followed by a pro-inflammatory response characterized by endothelial dysfunction, cell injury, leukocyte recruitment, increased monocyte adhesion, impaired nitricoxide relaxation, and plaque formation that eventually leads to rupture [23]. The endothelial activation by pro-inflammatory cytokines creates a tissue-factor-mediated prothrombotic setting, which further promotes the formation of clot upon plaque rupture [24–26]. Calcification within lipid-laden plaques may eventually lead to rupture, after which clots can form because of the release of highly thrombogenic material. In many cases, clots are lysed and reincorporated into the originating site of plaque. Plaque calcification may not occur until after lipid atherosclerosis is already significant. Surprisingly, many myocardial infarctions seem to occur from vessels with less than 50% stenosis [21], suggesting that plaque structure rather than narrowing of the lumen is a major factor in determining the probability of a clinical coronary event. In most cases, plaque rupture and healing is an ongoing process that promotes further narrowing of the arterial lumen. Plaque that is unstable and vulnerable to rupture has been characterized as having a large lipid core and thin fibrous cap; stable plaque, in contrast, has a small lipid core and is capped by a thick fibrous layer [21]. The relation of arterial calcification to the probability of plaque rupture secondary to “venerable” plaque is still unclear [27,28]. Significant evidence exists to relate the extent of coronary calcification to plaque burden, yet evidence of a strong correlation between either factor and venerable plaque is lacking [21,29]. The pathophysiological key to predicting acute coronary events is the identification of factors that result in an unstable or “vulnerable” plaque [30,31]. Recent data from Ridker et al. demonstrate the utility of measuring high sensitivity

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C-reactive protein (CRP) in the stratification of risk for primary prevention of cardiac events independent from Framingham risk scores [32–37]. Risk factors such as hypertension, lipid profiles, smoking, sex, age, and C-reactive Protein (CRP) levels may help to predict disease or to guide screening; however, the existence of coronary artery calcium in an astronaut should be considered to be abnormal. Atherosclerotic calcium is a harbinger of an insidious pathologic process that may take decades to manifest itself clinically. The Combined AlbanyFramingham Study revealed that of all cases of sudden cardiac death secondary to CAD, 50% were not preceded by warning symptoms [38]. The detection and prediction of atherosclerosis has changed considerably over the past few decades because of the increasing accuracy of noninvasive imaging of coronary calcium and simple blood tests [39]. Although the mortality rate from CAD has declined since 1970, the hospitalization rate from CAD increased by 25% from 1970 to 1986, indicating that improved early diagnosis and intervention can modify the outcome of this disease [40]. CAD in aviators is usually considered clinically significant (SCAD) if a single lesion narrows the diameter of the coronary artery by 50% or more. Minimal CAD (MCAD) is associated with lesions producing less than 50% stenosis. A long-term study by Proudfit and colleagues [41] showed that the rate of cardiac events among patients with MCAD ranged from 1.5% to 3.0% per year over a 10-year period and that positive findings on a treadmill stress test or a thallium scan did not predict future cardiac events or survival in that cohort. The ability to identify astronauts who will develop SCAD at some time during their career is very limited. A long-term study of patients with normal coronary anatomy (as determined by angiography) documented rates of cardiac events (e.g., sudden cardiac death, myocardial infarction, angina, and ischemic arrhythmias) as high as 0.65% per year over a 10-year follow-up period [41]. In that study, patients underwent the more invasive cardiac tests after experiencing positive findings on an exercise test [42] or experiencing symptoms [43] significant enough to convince a clinician to rule out abnormal coronary anatomy. Whether these patients had the same cardiac risk factor profile as the present U.S. astronaut cohort is unclear, but it can be assumed that neither cohort had significant comorbid conditions. Oswald and others [15] determined that cardiac event rates of 0.5% per year have been found in numerous U.S. population studies of healthy men aged 35–54 years, yet the annual rate for military aviators of the same age range is less than 0.15%. This significant difference in cardiac event rates among military aviators probably results from the comprehensive selection physical examination and annual medical evaluations that military aviators undergo throughout their careers [44], which may identify and subsequently control significant risk factors such as diabetes mellitus, gross obesity, hypertension, and tobacco use [45]. This reduction in cardiac rates for military aviators may also be due to their advanced level of education, which is associated with lower cardiac event rates. Frequent

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physical examinations ensure that military aviators are counseled on these risk factors more often than the general public. Also, military aviators are keenly aware that their health status is tied to their occupations. Determining the risk of an astronaut becoming incapacitated during a space mission because of a cardiac event is difficult because of the difficulty in extrapolating the unique aspects of space travel to aviation analog environments. The quantification of acceptable cardiac risk for space missions has not been clearly defined. Perhaps a starting point to bound the risk can be found in the in aviation community, where there is a broad consensus that the risk of professional pilots becoming incapacitated should not exceed the rate of mortality from cardiac causes for a 60-year-old man in Western Europe, that is, ~1% per year [14,46–49]. This guideline, the “1% rule,” provides a metric by which aviation medicine decisions regarding cardiovascular certification are often based. The rationale for the 1% rule is simple. A cardiovascular risk of 1% per year (10−2) for a pilot is equal to a risk of ~10−6 per hour, as each year consists of 8,760 h (i.e., <104 h). Because an average flight lasts roughly 100 min and because not more 10% of that time is regarded as critical, the risk of incapacitation of pilots aged 60–65 years at critical times (i.e., during takeoff and landing) is about 10−7 per hour of flight. These incidence rates decrease by a factor of ~10 for 45-year-old pilots and by a factor of 100 for 30-year-old pilots [14]. Although the desired individual cardiovascular risk of less than 10−9 per hour (for a 30-yearold pilot) is beyond the capability of humans of any age, it is still consistent with airworthiness standards for “extremely improbable” unanticipated catastrophic failures of any engine, system, or structure and for aircrew error or aircrew incapacitation [50]. A risk of 10−9 per hour can be obtained by adding a second aircrew member to the flight deck. Simulation studies have shown that monitoring pilots can lead to the detection and recovery of 99% of threatened crashes caused by sudden and subtle pilot incapacitation. For a 60-year-old pilot, such monitoring reduces the cardiovascular risk of a threatened fatal accident due to sudden incapacitation to 10−9 per hour for a 2-person crew. However, this failure risk model does not include all-cause mortality, which for some populations (60to 65-year-old male pilots from England or Wales) is twice (2.2% per year) the cardiovascular mortality rate of 1% per year [46]. The concepts of critical phases of flight in commercial and military aviation refer to those portions of a flight where pilot incapacitation would result in possible mission loss. In the Space Shuttle paradigm, mission loss can be interpreted as any significant cardiac event in any crewmember that requires a deorbit to a definitive treatment facility. Again, using a 1% rule for cardiac events, the chances of “mission loss” during a 16-day flight with a 6-person crew becomes 0.3% per flight [(1/(365 days/year) × (1-[1–0.01 annual risk of cardiac event/ year]6(crewmembers/mission)) × 16 days × 100 = 0.257%]. The worstcase risk of an incapacitating cardiovascular event for crews

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on the International Space Station (ISS) over a 1-year period is still 1% per person per year if all other space-related factors are ignored. This expected rate of critical medical events will need to be decreased for mission beyond low earth orbit. Cardiovascular selection standards for astronauts are based solely on the risk of cardiac events; hence such standards may be inappropriate if they are applied blindly to reduce overall mission risk. Pilot-related accident rates depend on flying experience and as such decline steadily with increasing experience up to age 60 years [51]. A small increase in accident rates has been observed among pilots older than 60 years, but 65-year-old pilots with normal experience still have lower accident rates than do 45-year-old pilots [51]. Therefore it is important to not presumptively remove experienced older pilots from spaceflight crews on the basis of these cardiovascular risk models unless overt and untreatable abnormalities have clearly been identified. The current model for ISS astronaut selection is based on the military and civilian aviation 1% rule [52]. However, medical support for long-duration space flights requires that missions be terminated in the event of any significant cardiac event. (Submarine crews, on the other hand, are selected and trained on the assumption that the mission will proceed regardless of the severity of any cardiac event in any crewmember.) Because current medical technology cannot effectively predict the occurrence of future cardiac events during long missions, current selection standards for astronauts, which rely on tests that are effective for evoking the 1% rule, may not be appropriate for long-duration ISS missions. Most cardiovascular abnormalities are grounds for disqualification from flight because they represent a significant risk to the safety of the affected crewmember and that of the crew and may well affect the success of the mission. Flight surgeons can serve as crew advocates helping crewmembers maintain their operational flight status. Nevertheless, flight surgeons are responsible for identifying cardiovascular abnormalities and for enforcing programmatic space medicine examination standards [44,53].

Prevalence of Cardiac Events in Aviation Populations CAD is the leading cause of permanent disqualification from flying status among aviators worldwide, and it is the leading cause of nonaccidental premature deaths in all military and civilian aircrews [54–57]. Autopsy studies of Korean War casualties by Enos and others [58] found gross atherosclerosis in 73% of hearts examined, at least 15.3% of which had at least 50% stenosis. McNamara and colleagues [59] performed autopsies on 105 soldiers who were killed in action in Vietnam (mean age, 22 years) and found gross evidence of CAD in at least 45% and SCAD in 5% of hearts examined. It should be noted that although these cohorts had clinically silent CAD, there was a very high incidence of cigarette smoking and they

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obviously did not receive the same level of selection screening as an aviator or the current astronaut corps. Pettyjohn and McKeen [60] reviewed 6,500 autopsies from records at the Armed Forces Institute of Pathology of deaths occurring in aircraft accidents or mishaps and found that 816 cases (13%) had been diagnosed with pre-existing heart disease at the time of the accident. Of these 816 cases (592 military and 135 civilian), 89.1% had CAD. This autopsy series compared the severity of CAD, year of death, and crew position within the military 5-year age groups. CAD was found in 86.6% of the 20- to 34-year-old military group. Moderate and severe CAD was present in 17.1%. Booze and Staggs [13] reviewed the autopsy reports of 710 commercial pilots who died in aviation accidents and found that 61% had some findings of coronary atherosclerosis, of which 2.5% were considered severe. Another study by Underwood-Ground [61] of 288 military, commercial, and private pilots killed in aviation mishaps and 132 healthy men aged 18–62 years who died accidentally revealed no significant difference in the prevalence of coronary artery disease between the aviators and the control group. The mean age in these four groups was less than 40 years, which is less than the mean age of the current U.S. astronaut population (44 years). Another study of apparently healthy U.S. Air Force aviators reported a rate of myocardial infarction, angina, and sudden cardiac death of 0.02% per year from 1988 to 1992; the mean age of the aviators who had a cardiac event was 44 years [15]. Notably, 61% of the events in that study were myocardial infarctions and 21% were sudden cardiac deaths. Angina, the most prominent presentation in ischemic heart disease, represented only 18% of the cardiac events. These findings suggest that denial or underreporting was of significant concern in this population [15]. Taneja et al reviewed 534 autopsies, performed from 1996 to1999 of deaths from fatal fixed-wing general aviation aircraft accidents (82% were older than 40 years) and found the prevalence of cardiovascular abnormalities in general and coronary artery stenosis in particular to be 43.82% and 37.64% respectively [62]. They also found that 41 of the 534 (7.6%) had severe atherosclerosis of the left coronary artery.” Nissen et al. [63] examined a series of transplant donors assessed by using Intravascular Coronary Ultrasound [64], and showed that coronary atheromas were found in 17% of those younger than 20 years, 37% of those aged 20–29 years, and 60% of those aged 30–39 years, whereas angiography results were negative in 97% of these donors. Necropsy data indicate a similar agerelated prevalence and suggest that atherosclerosis risk factors are mostly likely contributing to pathological changes at a very early age. Intravascular Coronary Ultrasound showed that CAD is characteristically diffuse and involves the entire arterial tree, with insidious progression to include the formation of multiple, potentially “rupture-prone” plaques that are not associated with vessel stenosis. [63] These findings indicate the need for aggressive and early systemic intervention that targets modifiable risk factors to reduce CAD in the astronaut population.

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Commercial pilots are routinely examined for disqualifying illness and injury by the civil aviation authorities of their respective countries. The requirements for these standards are published by the International Civil Aviation Organization and the European Joint Aviation Authorities. A recent study by Årva and Wagstaff [65] examined the permanent grounding of 275 Norwegian pilots over 20 years in a cohort representing 48,229 person years. Of the 275 groundings, 97 (35%) were for cardiovascular reasons with the majority occurring in the age range of 40–60 years, which is very close to the age range of our current astronaut corps. Of the 97 cardiac causes for grounding, 36 (36%) were for MI, 33 (34%) for CAD, 18 (19%) for arrhythmias, 3 (3%) for cardiomyopathy, and 7 (7%) for peripheral vascular disease. Data from Canadian [66], Russian [67], United States Air Force [68,69] and commercial pilots [70,71] also found that cardiovascular findings were the most common cause of permanent grounding. As noted earlier, the first manifestations of CAD can be arrhythmias with presyncope, syncope, or even sudden cardiac death, with potentially catastrophic aviation outcomes. Richardson and Celio [72] reviewed the cases of 430 patients (428 men; mean age, 40.3 years) who had been diagnosed with supraventricular tachycardia (SVT) and were evaluated 10 years later. Of these patients, 42 (10%) were found to have hemodynamically significant SVT, and 21 (5%) were found to have asymptomatic recurrent sustained SVT [72,73]. Although SVT characteristics, frequency, and occurrence in pairs were not predictive of future sustained SVT, the presence of reentrant tachyarrhythmias or recurrent sustained SVT were predictive of subsequent recurrent sustained SVT. Folarin and colleagues [74] studied 24-h Holter recordings from 303 patients (a subset of a group of 1,575 individuals with normal findings on cardiac catheterization) and found that only 36 individuals (12%) had no ectopy. Notable findings were the presence of isolated atrial (73%) and ventricular (41%) ectopy, atrial (14.5%) and ventricular (4%) pairs, nonsustained SVT (4%), and nonsustained VT (1–7 beats) (0.7%). Results from that study indicated that ectopy was very common, even among asymptomatic individuals with no evidence of cardiac disease (CAD, valvular, or conduction disorders). Another study in which patients with VT were followed by Holter monitoring showed that among 98 subjects with nonsustained VT, 92% had fewer than five runs of VT in a 24-h period, 63% had a 3-beat triplet, and 71% had only a single episode [72]. In a 10-year follow-up study of 193 aviators with asymptomatic nonsustained VT (more than two consecutive premature ventricular contractions [PVCs] at a rate of more than 100 beats per minute for less than 30 s), Gardener and others [75] found that 9 (5%) had hemodynamic symptoms— syncope in 1, presyncope in 5, and sudden death in 3. Of those 193 aviators, 103 had no evidence of cardiac disease (CAD, valve pathology, or cardiomyopathy) but were subsequently diagnosed with idiopathic nonsustained VT. These investigators concluded that cofactors such as caffeine ingestion, cholesterol levels, and VT characteristics were not predictive of VT

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and that the existence of nonsustained VT was not predictive of future sustained VT.

Occurrence of Cardiac Disease in Spaceflight Crews Over the past 40 years, the standard diagnostic tools for detecting CAD have evolved from noninvasive, provocative tests to include more definitive—but invasive—diagnostic imaging. Concurrent advances in noninvasive imaging and use of serum markers for estimating cardiovascular risk have made less-invasive techniques such as these more accurate for detecting cardiac abnormalities as well as better predictors of cardiac risk. Data on the incidence of CAD in early spaceflight crews are unreliable because of the poor sensitivity and specificity of the noninvasive diagnostic methods used at the time. An evidence-based cardiovascular risk model based on more recent incidence data is being developed to compare the relative cardiovascular risk for U.S. astronauts to that for analog populations such as commercial and military aviators, submarine crews, and others [76]. In the early phases of the U.S. space program, the presence of arrhythmias was taken as presumptive evidence of cardiac abnormality, and the first grounding of an astronaut for cardiac reasons was done because of an arrhythmia [1,5]. The incidence of arrhythmias during actual space flight can be assessed only for those intervals when a crew is being physiologically monitored. Use of electrocardiographic (ECG) monitoring is now restricted to periods of stressful or high-risk activities; however, monitoring on previous missions documented several types of arrhythmias in apparently healthy astronauts. The appearance of premature atrial contractions, PVCs, and ST-segment or T-wave changes was generally associated with strenuous activity during extravehicular activities (EVAs), exercise, and application of lower-body negative pressure (LBNP). Apollo 15 was the first U.S. space flight during which cardiac arrhythmias other than the occasional PVC were observed. At 178 h into the mission, shortly after the lunar module had returned from the moon and docked with the command module, the Apollo 15 lunar module pilot experienced five unifocal PVCs within a 30-s interval, a significant increase over the one or two PVCs per hour experienced during the translunar-coast phase of the mission. Approximately 1 h later, that same crewmember experienced a 22-beat run of nodal bigeminy. During the postflight debriefing, the crewmember recalled experiencing profound fatigue at the time of this bigeminal rhythm [6,77,78]. Postflight analysis of the medical data obtained during this mission indicated that the Apollo15 crewmembers may have been hypokalemic, and retrospective analysis found their lunar EVA workloads to be excessive. Twenty-one months after the Apollo 15 mission, the lunar module pilot experienced a myocardial infarction [6,77,79]. No evidence of CAD had been detected before flight by the noninvasive (exercise ECG) testing used during that era,

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and no invasive coronary diagnostic imaging information was available to determine the extent of CAD before flight. Testing associated with the Skylab Program also revealed significant arrhythmias in several crewmembers, including a 3-beat VT complex (triplet) occurring with exercise, an atrial-ventricular block during LBNP recovery, a junctional rhythm at rest after LBNP, and an episode of multifocal PVCs after an EVA [1]. During the first four flights of the Space Shuttle in the orbital flight test program, crews underwent continuous ECG monitoring during launch and landing. Nine of the 14 crewmembers had frequent PVCs, and two crewmembers had frequent PVCs during landing. One of these 14 crewmembers was noted to have occasional PVCs, never exceeding 2–3 ectopic beats per minute, during pretest altitude (chamber) and water immersion exposures. Despite having a normal serum electrolyte profile, this crewmember also experienced uniform PVCs after the onset of gravitational loading during reentry, with rates as high as 16 ectopic beats per minute [80]. Nevertheless, the benign nature of these arrhythmias, along with the logistics of providing monitoring for larger crews, did not warrant monitoring on subsequent Shuttle missions. Approximately one third of Shuttle crewmembers have exhibited PVCs during EVAs. One crewmember experienced sustained ventricular bigeminy for 10 min, and another had frequent premature atrial contractions. Analysis of ECG tracings from seven crewmembers and test subjects during simulated and actual EVAs from 1992 to 1995 showed no difference in the frequency of ectopy between astronauts and test subjects [81]. Although the number of subjects was too small to draw any significant conclusions, these results may imply that arrhythmias experienced during EVA were not due to microgravity per se and that the increased ectopy seen in earlier Shuttle flights could have been attributable to other factors. A retrospective Holter analysis of 160 EVAs over the last 20 years (104 from shuttle, 4 from ISS, and 52 from joint ISS STS missions) was performed by Hamilton et al. [82]. During the period from 1984 to 2002, NASA performed 160 EVAs averaging 300 ± 42 min duration (mean ± Standard Deviation), a cumulative length of 42 days, 16 h, and 54 min and 78% of this time was monitored by flight surgeons in mission control. The average ectopic beat per EVA was 0.31%, however some EVAs had ectopy greater than 10%. Remarkably, this study found 77 out of 160 (48%) EVAs showed a sinus arrhythmia compared to only 9 (5%) seen on preflight Holter reports. The causal relationship between space travel and this finding has not been elucidated, however down regulation of the sympathetic system with parasympathetic dominance has been hypothesized as one of many contributing factors [82]. The average heart rate for these EVAs was 82.9 beats per minute and the average age at EVA was 45.04 ± 17.63 years. A Shuttle based EVA was not extended to 8 h because of increasing bigeminy and trigeminy seen on during the first 6 h. Typically if the crew has finished all their planned tasks during an EVA, the crew surgeon can authorize an extension of the EVA based on the biophysical data they receive during the first 6 h.

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The Russian space program has also accumulated a great deal of ECG data [2,12,83], in part because the Russian program of health maintenance requires considerable routine monitoring. In addition to ECG monitoring during EVAs, all cosmonauts undergo ECG and respiratory-rate monitoring during launches and dockings of the Soyuz. On many longer Russian missions, ECG monitoring was conducted every 2–3 weeks at rest and during exercise, LBNP, EVA, and after flight [84,85]. In the Russian space program, the most common arrhythmias are extrasystoles, with supraventricular more common than ventricular [2,9,86]. The Russian space program has reported observing changes in R-, S-, and T-wave amplitude beginning in the second and third months of flight [87]. This increase may simply reflect microgravity-induced anatomic changes of the heart relative to other thoracic structures. The decrease in T-wave amplitude could also be due to changes in potassium metabolism, which could also be related to ventricular ectopy [87]. A crewmember during the Mir-2 mission in 1987 developed a persistent tachyarrhythmia during EVA that resulted in the mission duration being shortened from 11 months to 6 months; the crew returned safely in a Soyuz capsule [88]. A cosmonaut was reported to have suffered a massive myocardial infarction at the age of 49 years, just 2 years after his third short-duration flight [85]. Moreover, the Russian medical community reported to NASA having observed ~31 abnormal electrocardiograms, 75 arrhythmias, and 23 conduction disorders during the past 10 years of Mir operations. During the joint U.S.–Russian NASA–Mir Program, ambulatory ECG recordings (Holter recordings) were obtained from several crews. Significant abnormalities were found in one Mir cosmonaut who had no previous history of cardiovascular disease [89]. Preflight Holter recordings revealed ventricular couplets, multiform premature ventricular complexes, and a 5-beat episode of SVT with no episodes of ventricular tachyarrhythmias. A Holter recording made during the second month of orbit (Figure 16.1) revealed an asymptomatic, nonsustained, 14-beat run of VT [89]. We now know that a late diastolic PVC precipitated this event and that the peak rate of the arrhythmia was 215 beats per minute. Because those results were not available until after the flight, the cosmonaut who experienced this abnormality successfully completed the mission and was returned to Earth by the Space Shuttle as nominally scheduled. Unfortunately, this cosmonaut was diagnosed with CAD several months after this mission. Several studies in which healthy adult subjects have undergone Holter monitoring indicate that the prevalence of ectopy ranges from 40% to 93% and increases with age, suggesting that the regular use of Holter recordings on orbit might reveal more frequent arrhythmias [90]. U.S. astronauts are selected after an aggressive cardiac workup [53] that attempts to rule out any significant abnormalities, although angiography is not routinely performed. Nevertheless, the cardiovascular selection criteria for astronauts may not be entirely effective if the arrhythmias found by Holter recordings [74,75,77,90–92] are considered to be abnormal for this population.

D.R. Hamilton

Figure 16.1. Nonsustained ventricular tachycardia (VT) from a 2-channel Holter recording during long-duration spaceflight. The 14 beats of tachycardia were initiated by a late diastolic premature beat. Nonspecific ST elevations are evident after the event. (From FritschYelle, et al. [89] Used with permission.)

These cardiovascular close calls imply that our current screening tests used before missions are insufficient for ruling out the possibility of cardiac events on orbit. Most cardiovascular-risk stratifications in the military and civilian aviation communities focus on reducing the impact of cardiac events during the critical portions of flight. Other environments, such as missile submarine operations, may place mission success above the health of the individual crewmember suffering from a cardiac event. The cost and risk to the mission of a cardiac event outside these boundaries is tolerable to the military and civilian medical programs. This may not be the case for a permanent human presence in space, because the current program requirements dictate that an ISS crewmember suffering a cardiac event must be evacuated to Earth. If a Space Shuttle is not present at the station, the resulting deorbit aboard Soyuz could represent a $500 million cost to the space program. The question thus arises of whether space medicine flight surgeons should be applying cardiovascular selection and retention standards that are much more conservative than the current military standards if they are to mitigate this apparent gap between incidence of cardiac events on orbit and our ability to predict or prevent them.

Cardiovascular Risk—Mitigation Strategies for Spaceflight Crews Comprehensive cardiovascular medical care for spaceflight crews requires a balanced approach between prevention and treatment. The most effective means of delivering cardiovascular care in space to date has been through medical screening

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for cardiac abnormalities before selection and through using primary and secondary prevention and countermeasures [53,93] before, during, and after flight. This approach is expected to minimize the need for treatment and any medical interference with mission objectives. Yet despite the best attempts of flight surgeons to apply aggressive screening and countermeasures, episodes of cardiovascular abnormalities have occurred during or after space flight. Acquiring cardiovascular data, whether intended for operational or research use, in a manner that controls for the crew’s sleep, diet, mission-related activities, medications, exercise, and preflight and postflight activities without interfering with the primary mission objectives has proven difficult on most short-duration space flights. This problem was addressed during selected short-duration missions in which gathering operational and physiological data was the primary mission objective [1,7,93–95]. Results from these studies have proven useful in identifying causal relationships amidst the multitude of historical medical observations and descriptive studies dating back to Project Mercury and the Vostok Space Project. Cardiovascular events occurring during or after a mission can be considered in two categories—events that are a consequence of the expected cardiovascular physiological changes induced by space flight and events that are a consequence of preexisting subclinical cardiovascular abnormalities that may be exacerbated by space flight. Most studies of the cardiovascular system and space flight are of one of three types [7], namely (1) descriptive studies that report the cardiovascular response of a crewmember during or after a mission (usually either case reports of individual cardiovascular anomalies that may have been caused by space travel and may have operational implications in the future, or cohort studies [prospective or retrospective] of the risk or incidence of an observed cardiovascular anomaly caused by space travel in a significant number of space travelers); (2) mechanistic studies, which are usually structured to control many variables so that a causal relationship between space travel and the observed cardiovascular phenomenon can be explained by using a model of microgravity-based pathophysiology; and (3) prevention and countermeasure-validation studies, which are usually conducted after the mechanism responsible for the cardiovascular pathophysiology is understood well enough to form a cardiovascular risk-mitigation hypothesis. Using a methodical approach to mitigating cardiovascular medical events has proven useful in assessing causal relationships between space flight and observed changes to the cardiovascular system. The limited quality and quantity of medical data that can be collected during most spaceflight missions has made it difficult to establish an evidence-based approach [96] to on-orbit cardiovascular medical care. Consequently, flight surgeons have had to rely on limited experience and anecdotal data to implement on-orbit risk mitigation strategies and to make real-time clinical decisions [97,98]. Flight surgeons must be careful to balance the effect of changing an apparently successful cardiovascular risk-mitigation

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procedure or investigating a new procedure in light of the medical risk to the crew [99] and the potential effect on the overall mission. In attempts to protect deconditioned and possibly compromised crews during early space missions, scientists in the U.S. and Russian space programs implemented a set of countermeasures before the basic mechanisms underlying the human physiological response to microgravity were well understood. One example was the combined use of pharmacologic agents, fluid-loading, exercise (treadmill or cycle ergometry), and LBNP to prevent orthostasis upon landing. The success of these combined countermeasures is still unclear, and their simultaneous use may well interfere with the independent validation of individual countermeasures. Most of the clinical experience in applying effective cardiovascular countermeasures in the U.S. space program is currently limited to crews that complete landings considered nominal (i.e., those that satisfy the parameters established before flight by Agency planners) after brief exposures to microgravity and to the few long-duration exposures experienced during the Skylab, Shuttle-Mir, and ISS programs. It is hoped that when the ISS is complete, additional prospective controlled studies can be performed to help optimize countermeasure strategies [100] for microgravity and reduced-gravity exposures for missions to Mars (one-third g ravity), Earth’s moon (one-sixth gravity), or beyond.

Prevention of Cardiovascular Disease in Spaceflight Crews The primary means of minimizing the effect of medical events on the mission, in the space program and the military, is to use conservative selection and retention medical standards together with aggressive primary and secondary prevention programs. The medical resources aboard spacecraft are optimized to reduce the mass, power, and volume required. This factor, coupled with the limited expertise of the crew medical officers (CMOs), most of whom are not physicians, mandates that prevention, rather than treatment, be the focus of cardiovascular risk mitigation on orbit. Although the rates of mortality and morbidity from CAD have declined in the United States and other industrialized nations, CAD nevertheless remains the leading cause of death and disability in most industrialized nations. As discussed previously, heart disease can manifest initially as a suddenly incapacitating event (angina, myocardial infarction, arrhythmias, thromboembolic events, or syncope) or as sudden cardiac death with no prodromal symptoms. Approximately 25% of patients with premature CAD do not exhibit any of the classically recognized risk factors [101–103]. More than 200 new risk factors and markers (e.g., C-reactive protein, homocysteine [104], fibrinogen, and some infectious agents) have been identified and tested for their correlation with CAD [105–107]. Serum cholesterol and its fractional components also remain useful as surrogate risk factors. In a study of asymptomatic

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aviators with abnormal findings on noninvasive tests for CAD, analysis of 250 cardiac catheterizations showed that 4% of those without CAD and 88% with angiographically demonstrated CAD had a total cholesterol/high-density lipoprotein (HDL) ratio higher than 6.0 [40,108]. Of interest was the cholesterol measured in all female active astronauts in 2002 (average age = 44.0) being less than 165 (mg/dl) with the mean being 150. The cholesterol in all male active astronauts in the same year was greater than 164 (mg/dl) with 43% falling between 166 and 199 (mean cholesterol = 182, average age 39.8) and 57% having a cholesterol greater than 199 (mean cholesterol = 220, average age = 48.0). The average age of U.S. astronauts in 2002 was 44.0 ± 6.7 and 44.5 ± 5.6 for females and males respectively (Mean ± Standard Deviation). Since the first manned flight, the average age at selection was 35 ± 3.5 and 36 ± 3.5 and at discharge or death was 41.2 ± 3.8 and 44.3 ± 6.2 for females and males respectively. The average age of the retired astronauts is presently 48.7 ± 5.3 and 60.5 ± 9.3 for females and males respectively. Clearly the US female astronaut cohort has a lower cardiac risk based on Framingham risk scores. The 10-year risk of having a cardiac event in the 2002 active and 2002 retired astronaut corps as a function of age has been calculated using the prediction method of Wilson et al. [109,110] Of interest is the distribution of 10-year event risk Framingham risk scores (FRS) in the astronaut population as of the year 2002 where 40.1% of males and all females have a FRS of less than 3% with mean age of 39.6 and 44.0 respectively. The remaining corps has 51% of males in the FRS range of 5% to 9% (mean age 46.6) with 8% of males having a FRS greater than 10% (mean age 55.8). The risk of having a cardiac event of 5% or greater over the next 10 years in 59% of the males in the active corps may need to be reexamined if missions on the ISS get extended to one year or we engage in 3 year Exploration Class missions. Examining these risk data, it is evident that the current astronaut selection process seems to be effective in creating a cohort that has less cardiac risk than an age- and gendermatched cohort in the general population. Nonetheless, cardiac events have occurred in this astronaut cohort in close temporal proximity to missions. There is a general consensus that only about 50% of CAD events can be explained by the traditional Framingham risk factors. Approximately 85–90% of individuals dying of CAD and ~70% of individuals free of CAD related death over a 21–39 year follow-up have at least one traditional risk factor [111]. Traditional risk factors explain differential CHD rates across countries better than they do across individuals within a country. Framingham risk scores may not be a useful means of estimating CAD risk of individual astronauts but may be useful in examining the overall cardiac risk of the astronaut corps. Furthermore, using U.S. astronaut cohort and individual cardiac risk information to derive an international crew selection criterion for missions is difficult since these populations may not behave in a manner similar to Framingham data based on U.S. cohorts. Clearly,

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using risk factor analysis alone will not prevent disease from occurring during short- and long-duration space missions. After astronaut selection, modification of cardiac risk factors such as smoking, cholesterol levels (total lipoprotein, low-density lipoprotein [LDL], and HDL) [108,112], hypertension, obesity, sedentary lifestyle [113], and, for women, postmenopausal status [114] is addressed by a Cardiac Wellness program administered by the Flight Medicine Clinic at the Johnson Space Center [115]. Other risk factors such as hypercholesterolemia and hypertension are potentially disqualifying conditions that must be evaluated by the Aerospace Medicine Board. Many studies have been conducted to examine the costeffectiveness of lipid-reducing therapy and when such therapy should be initiated in various populations [116–121]. The Lipid Research Clinics Coronary Primary Preventive Trial reported that a 1% reduction in total cholesterol level reduced the risk of CAD by 2% [121]. These results should be considered in light of those of another study by Byington et al. [122], who found that angiographic changes observed during statin therapy did not predict reductions in cardiovascular events. Angiographic changes may not reflect a reduced intimal lipid burden in these individuals, which could serve to stabilize vulnerable plaque in an existing disease process [21,23,39,123]. A fully trained astronaut or cosmonaut is a significant asset and may warrant a preventive approach that is more aggressive than published risk-mitigation guidelines [124–126]. A study of 27,939 women by Ridker et al. [127] showed that the magnitude of risk reduction associated with random allocation to statin therapy is just as large for subjects with high CRP as it is for subjects with high lipids. Moreover, this study concluded that those with elevated CRP levels but low LDL levels (a group that includes almost 30 million Americans) may actually benefit from Statins just as much as did those with overt hyperlipidemia. More recent data push this concept even further; we now have evidence that CRP predicts vascular risk across a full spectrum of LDL levels and adds prognostic information at all levels of the Framingham Risk Score. Of significance is the challenge raised when an astronaut has a 5% 10-year Framingham risk score with a coronary artery calcium score of 200. Would a statin be appropriate for maintaining certification for long-duration space travel? CRP thresholds of less than 1 mg/L, 1–3 mg/L, and greater than 3 mg/L corresponding to low (<10%), medium (10–20%), and high (> 20%) risk for CAD respectively, have now been endorsed by both the American Heart Association and the Centers for Disease Control and Prevention [128,129]. These discrete CRP values approximate tertiles for an aggregate, asymptomatic population of over 40,000 persons. The high-risk subgroup has an associated CAD event relative risk of approximately twofold when compared to the low-risk tertile [128]. The CRP levels between 2 and 3 mg/L and above 3 mg/L, are 11% and 11% respectively, in the active astronaut population as of 2002. The CRP levels between 2 and 3 mg/L and above 3 mg/L, are 8.7% and 7.7%, respectively in the retired astronaut population. Given that 50% of all acute MIs occur in

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patients without hyperlipedmia, the improved predictive ability of adding CRP scores to overall cardiac risk assessment of the astronaut corps may help reduce mission risk and decrease the need for tertiary prevention strategies to become part of the mission design [129]. If the CRP threshold is breached, it would indicate a need for prompt preventive therapy such as HMG Co-A reductase inhibitor [130–132]. Finally, it should be remembered that CRP is an acute phase reactant produced by the liver during periods of stress. As such, it may be inaccurate during critical illness, infection, or liver dysfunction. In summary, military selection standards and countermeasures were used during the infancy of the U.S. and Russian space programs, and the modifications that were made were based primarily on hypothetical predictions as to the cardiovascular response to the unique environment of microgravity— predictions that later proved remarkably accurate [5]. Determining the threshold for acceptable risk of an incapacitating cardiac event in a healthy population of astronauts is difficult because no comparative cohort, nor any battery of tests, has adequate positive or negative predictive power to rule out a cardiac event from happening during a 5-month ISS mission or 3-year Mars exploration mission. Although there is a paucity of similar research in space medicine, a retrospective study performed by Hamilton et al. [133] compared derived 12-lead ECGs [134–144] collected as part of periodic fitness examinations (PFE) on the ISS to prelaunch exercise stress tests. A PFE is performed on a cycle ergometer which has a preprogrammed load profile prescribed by ground based exercise countermeasure experts. Data gathered from these 26 on-orbit PFEs lasting 20 min, and not exceeding 80% of the maximum aerobic capacity, showed no ECG anomalies including no ST or T-wave changes in any US astronauts. Another retrospective study by Hamilton et al. [145] of 295 astronauts illustrates the inadequacy of exercise treadmill tests (ETT) and Thallium treadmills (TT) as the predictor of ACS in a low-risk cohort. This was a longitudinal study that followed the incidence of cardiac events following 2,069 ETTs, and follow-up TT and cardiac catheterizations in the active and retired astronaut corps from 1977 through 2000. In the active astronaut ETTs (n = 1,330), 10 had positive tests (ECG findings only), 29 had borderline tests, 1 had an indeterminate test, and 1,289 had negative tests. No cardiac events were reported in the active group over the 23-year length of the study. In the retired astronaut ETTs (n = 739), there were 40 positive tests, 40 borderline tests, 7 indeterminate tests, and 652 negative tests. One cardiac death was seen within a year of ETT in the positive group (n = 40) and 4 cardiac events (3 sudden deaths and 1 MI) in the negative ETT cohort. When both active and retired astronaut groups are combined (n = 295, 2,240 person-years), they represent a follow-up time ranging from 1 to 23 years. Of 1,941 negative ETTs there were two cardiac events within 2 years and another two within 4 years of the test. Of the 51 positive ETTs there was one death within 1 year of the ETT. In this study, the gross incidence of cardiac events in the combined

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active and retired population is 0.22%/per person/year and all cardiac events occurred within 4 years of the last ETT with 80% of these ETTs being normal. Clearly the ability of ETT to predict cardiac events in the active or retired U.S. astronaut cohort is very poor.

Cardiovascular Selection Standards An astronaut selected by NASA for pilot or mission specialist training is initially screened for significant overt cardiovascular disease through a physical examination similar to the U.S. Air Force or Federal Aviation Administration class 3 physical examination [146]. This medical screening is then followed by NASA astronaut cardiovascular selection medical screening (Table 16.1), which has much in common with U.S. Air Force class 1 and class 2 physical examinations [44,53,92]. After selection, all spaceflight crewmembers undergo annual medical evaluations to evaluate and certify their cardiovascular fitness for flight. The scope of this examination is outlined in the NASA Astronaut Medical Evaluation Requirements Document [53].

Cardiovascular Screening Tests Modern evidence-based medical practice attempts to rule out overt cardiovascular disease by using screening tests that focus on a patient population with known cardiovascular risk factors. When cardiovascular diagnostic tests of known specificity and sensitivity are applied to a cohort of patients whose history or symptoms suggest possible cardiovascular disease, the positive and negative predictive value of these tests increases. However, when these tests are used to screen very healthy cohorts such as military pilots or spaceflight crews, their diagnostic and prognostic value diminishes [19]. Nevertheless, periodic evaluation facilitates the detection of serial changes that may reflect the development of a significant abnormality [19,147]. The cardiovascular portion of the astronaut selection physical examination is conducted as part of an overall comprehensive selection medical examination. These tests include 24-h Holter monitoring, resting echocardiography, standard 12-lead electrocardiography, and an treadmill exercise stress test conducted according to a Bruce protocol [148], which entails steady increases in treadmill grade and speed every 3 min until the test is terminated by the subject or test conductor.

Electrocardiography Taken alone, electrocardiography is very nonspecific for the detection of CAD [90,149] in healthy individuals, but it is still used routinely as a screening tool for military aviators and astronauts [44,53]. In a study by Joy and Trump of 16,000 electrocardiograms from 14,000 aviators and air traffic

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D.R. Hamilton

Table 16.1. Cardiovascular causes for rejection in section and retention examinations for U.S. astronauts. Examination type Rejection criteria Clinically significant hypertrophy or dilation of the heart or an ejection fraction of <50% at rest Recumbent untreated blood pressure: Systolic > 140 mmHg or Diastolic > 90 mmHg Recumbent treated blood pressure: Systolic > 140 mmHg or Diastolic > 90 mmHg Recurrent symptomatic orthostatic hypotension Pericarditis, myocarditis, or endocarditis or a history of these conditions requires further evaluation History of findings of major congenital abnormalities of the heart or the great vessels: • Uncomplicated dextrocardia and other asymptomatic abnormalities may be acceptable. • History of atrial or ventricular septal defect or patent ductus arteriosis that has been successfully repaired with a negative 1-year postoperative cardiac evaluation on a case-by-case basis Any clinical evidence of coronary artery disease, myocardial infarction, or angina pectoris at any time Electrocardiographic findings as follows: • Persistent tachycardia with supine resting pulse rate of more than 100 • Clinical evidence of cardiac arrhythmia, conduction defect, abnormalities on resting or Holter electrocardiography such as: • Atrial flutter or fibrillation and ventricular tachycardia or ventricular fibrillation History of single episode of atrial flutter or fibrillation with no evidence of underlying cardiac disease is evaluated on a case-by-case basis and may be disqualifying. Atrial tachycardia requires further evaluation and may be disqualifying. One episode of 3-beat ventricular tachycardia (triplet) with no evidence of underlying cardiac disease is evaluated on a case-by-case basis and may be disqualifying • Conduction defects such as first-degree A-V block, right bundle branch block, and second-degree block (Mobitz), unless occurring as isolated findings when evaluation reveals no cardiac disease • Left bundle branch block or second- or third-degree block • Paroxysmal supraventricular tachycardia • ECG evidence of old or recurrent myocardial infarction, ischemia at rest or after stress, or myocardial disease • Maximal exercise test that induces significant arrhythmias • Conduction defect or ECG abnormality requires further cardiac evaluation History of recurrent thrombophlebitis or of thrombophlebitis with persistent thrombus, Evidence of circulatory obstruction, or deep venous incompetence Varicose veins if more than mild in degree, or if associated with edema, skin ulceration, or scars from previous ulceration Peripheral vascular disease Cardiac tumors: • Cardiac tumors of any type • Cardiac tumors, unless benign and successfully resected without residual cardiac disease after 6 months, are reviewed on a case-by-case basis All valvular disorders of the heart, including mitral valve prolapse, require further evaluation and may be disqualifying Failure to meet NASA exercise stress-test standards

Selection

Annual

Ö Ö

Ö

Ö Ö

Ö Ö Ö

Ö

Ö

Ö

Ö

Ö

Ö

Ö

Ö

Ö

Ö

Ö Ö

Ö Ö

Ö Ö Ö Ö

Ö Ö

Source: From NASA, Space and Life Sciences Directorate [53].

controllers, 19 of 103 subjects with minor ST-segment and T-wave changes were found to have abnormal findings on exercise stress tests, and only five had SCAD [150]. A U.S. Air Force study found that among 147,571 resting electrocardiograms, 480 required additional evaluation by 24-h Holter monitoring because of ectopy [73,90]. Of these Holter recordings, 51% were found to be abnormal; 11% of those individuals with abnormalities on Holter recordings were returned to duty after an exercise treadmill test or stress echocardiography showed normal findings. Investigation of the other 40% of abnormal Holter recordings by the U.S. Air Force Aeromedical Consultation Service resulted in only 4% of individuals being permanently disqualified. The U.S. Air Force requires only that a resting electrocardiogram be obtained every 5 years for aircrew members who are older than 35 years [90]. The annual NASA astronaut examination does not require 24-h Holter monitoring, and

the exercise stress test is repeated only at ages 30, 35, and 40 years and then every other year until age 50. After age 50, the ETT is required annually. For those annual examinations when the Bruce protocol is not required, a submaximal cycle or treadmill test is conducted. This test is designed to screen out significant coronary heart disease and arrhythmias without imposing additional morbidity from the test itself. As a casefinding tool, the resting 12-lead electrocardiogram may reveal certain specific abnormalities such as Wolff-Parkinson-White syndrome, other conduction abnormalities, or hypertrophic cardiomyopathy [73, 90,91,151].

Exercise Testing Graded exercise testing with a treadmill or cycle ergometer and ECG analysis is a common means of screening for CAD. In aviators, treadmill exercise testing to rule out SCAD has

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a PPV of less than 25% [152,153]. An 8-year study of 548 military aviators found that graded exercise stress testing had a sensitivity of 16% and a PPV of 26% for clinically evident CAD [92,154]. A treadmill stress test study of 888 men and women over a 5-year period found that ST-segment depression in men older than 40 years had a PPV of 17% for CAD [155]. The PPV for ruling out SCAD by angiography or clinical findings in asymptomatic aviators or spaceflight crewmembers who have abnormal findings on a treadmill or cycle ergometer exercise stress test is probably in the range of 20–25% [92]. Nevertheless, a committee of experts from the American College of Cardiology and the American Heart Association has given the class 2 recommendation (i.e., for which there is conflicting evidence or lack of consensus within the committee) for screening men older than 40 years and women older than 50 years with electrocardiography and exercise stress testing who are engaged in occupations in which impairment may endanger public safety [154]. Patients with an intermediate or high probability of having CAD according to findings on an exercise stress test may benefit from further screening and stratification with diagnostic imaging methods that measure coronary artery calcium burden, such as electron-beam computed tomography (EBCT) [155–158].

Nuclide and Coronary Artery Calcium Imaging Stress radionuclide imaging is not considered a primary screening test, mostly because of its cost and inherent risk of significant morbidity. In a study of 845 asymptomatic young male aviators who underwent coronary angiography after positive findings on noninvasive tests, the PPV of an abnormal thallium exercise scintigram for SCAD was only 25% [159]. Information on more sensitive radionuclide imaging techniques applied to healthy aviator cohorts [160], such as single photon emission CT, is very limited at this time. Fitzsimmons and colleagues studied 759 military aviators with SCAD that had been diagnosed by coronary angiography and calculated the sensitivity, specificity, PPV, and negative predictive values for treadmill testing, thallium scanning, and coronary artery fluoroscopy (CAF) (Table 16.2) [161]. The 29.2% PPV for CAF in this cohort indicates that CAF is the best noninvasive diagnostic method currently used by the military to rule out SCAD. Loecker and colleagues [162] used CAF to screen 1,466 aviators, 613 of whom had undergone coronary angiography for abnormal findings on CAF, exercise treadmill testing, or exercise thallium scintigraphy. In that study, CAF was found to have a PPV of 68% for any measurable CAD. A study of 220 male aviators (mean age, 42.3 years) conducted from 1990 to 1995 by Smalley et al. [54] compared coronary angiography with graded exercise testing, thallium scintigraphy, and CAF and showed that CAF had a PPV of 81% for all CAD and 34% for SCAD. Although fluoroscopy can detect moderate to large calcifications, its ability to detect small calcific lesions is limited. In a study reported by Wexler et al. [28], only 52% of cal-

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cific lesions detected on EBCT could be seen by fluoroscopy, suggesting that EBCT is more sensitive but less specific than fluoroscopy for detecting calcific lesions. The CAF findings are clear that asymptomatic CAD is prevalent in these military cohorts despite the fact that these studies were not conducted as medical screening tests. Barnett et al. reviewed a database of 1,504 coronary angiograms obtained between 1979 and 1999 from asymptomatic military aviators [163]. Subjects were grouped into three categories: SCAD (n = 323), MCAD (n = 252), and normal (n = 929). The SCAD group was further divided into two subgroups, those showing 50–70% stenosis and those showing more than 70% stenosis [163]. Annual rates of cardiac events (cardiac death, nonfatal myocardial infarction, and coronary revascularization) were determined during the 2 years, 5 years, 10 years, and 15 years after the angiography. Notable were the annual cardiac event rates of 9.1% for those with SCAD and more than 70% stenosis and 6.0% for all individuals with SCAD during the first 2 years after the angiography (Table 16.3). During follow-up, only 24% of the SCAD group reported experiencing anginal symptoms—a finding that imposes a significant challenge to flight surgeons, who must detect disease and attempt to prevent cardiovascular-related mission-impact events [163]. The rate of cardiac events among those with asymptomatic SCAD ranged from 3.5% to 6.0% per year over the 15-year follow-up period, a rate comparable to that among symptomatic SCAD cohorts. Subjects with MCAD had annual event rates of 0.6% at 2 years, 0.4% at 5 years, and 1.1% at

Table 16.2. Predictive value of treadmill testing, thallium scan, and coronary artery fluoroscopy versus coronary angiography for detecting clinically significant coronary artery disease.

Test type Treadmill Thallium scan Coronary artery fluoroscopy

Sensitivity, % Specificity, % 54.5 55.1 67.6

Positive predictive value, %

Negative predictive value, %

15.9 20.5 29.2

85.8 88.6 92.5

48.8 62.0 70.9

Source: Adapted from Fitzsimmons et al. [161].

Table 16.3. Annual cardiac event rates (%/year/person) among aviators with minimal or significant coronary artery disease.

Time since diagnosis 2 years 5 years 10 years 15 years

Minimal CAD with <50% stenosis 0.6 0.4 1.1 1.9

Source: From Barnett et al. [163].

Clinically significant CAD with 50%–70% stenosis 1.2 2.5 2.6 4.6

Clinically significant CAD with >70% stenosis 9.1 4.7 4.0 4.6

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10 years [164]. The poor predictive value of these tests is of significant concern, considering that myocardial infarction in an asymptomatic nonmilitary cohort can be relatively common even when coronary vessels have only minimal evidence of disease [27]. The more difficult issue for flight surgeons is when asymptomatic MCAD is found in a trained and experienced crewmember. In another study, the progression of MCAD was followed serially in 44 of 252 military aviators with an angiographic diagnosis of asymptomatic MCAD [165]. Progression of MCAD to SCAD occurred in 11 (25%) of those 44 aviators; of those 11 aviators, 7 had had negative findings on noninvasive tests at the time of repeat catheterization, ~3 years later [166]. Notable in the group that progressed from MCAD to SCAD were the findings of higher total and LDL cholesterol levels and lower HDL cholesterol levels, suggesting that lipid-modifying medications should be considered for crewmembers with this type of abnormal lipid profile.

Electron-Beam Computed Tomography Schmermund et al. [167] used EBCT and angiography to evaluate 118 patients (mean age, 57 years) who had experienced unstable angina or an acute myocardial infarction. Of those 118 patients, 110 had angiographically proven SCAD and 106 had evidence of calcium deposits on EBCT. Of the 12 patients who had negative findings on EBCT, 9 had experienced a myocardial infarction; their mean age was 12 years younger than the group that had positive findings on EBCT and a myocardial infarction. Interestingly, the nine patients who experienced a myocardial infarction and had negative EBCT scores all had significantly increased LDL profiles and all were smokers. Coronary artery calcium can be detected directly and independently of the magnitude of stenosis causing ischemia [168]. Serial determinations of coronary calcium load may be a better predictor of CAD progression and long-term cardiovascular prognosis [39,54,169–172], and thus CAF and EBCT may turn out to be useful screening methods for selecting aviator and spaceflight crewmembers. However, both CAF and EBCT involve radiation exposure, which is a concern in screening a healthy astronaut or cosmonaut population. The possible role of EBCT as a screening tool in asymptomatic subjects has not been rigorously evaluated [20,39,173], and thus its greatest usefulness may be as a sensitive test for confirming the presence of CAD in aviators [172,174–177]. Coronary artery screening by EBCT is quite cost-effective compared with other diagnostic modalities, especially when the pretest probability or likelihood of disease is low to moderate [28,175]. It remains to be determined whether the mere presence of coronary artery calcium is a reasonable standard for “selecting out” on the basis of cardiovascular disease or whether some minimal level of calcium burden can be identified as being associated with an acceptable cardiovascular risk for the astronaut or the mission [29,176–182].

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Results from the 5-year Prospective Army Coronary Calcium Study, which was started in October 1998, should provide information regarding the utility of EBCT in predicting the occurrence of CAD and cardiac events in a young, asymptomatic population [172,180,183]. This study should also clarify the incidence [180] and progression of CAD and correlate calcium load with cardiac event risk. Interestingly, the presence of calcium detected by EBCT may be a reliable predictor of “soft events” such as coronary revascularization but a weak predictor of “hard events” such as death or myocardial infarction [184], in part because EBCT is much more sensitive for detecting presymptomatic CAD and facilitating intervention and because hard, fibrocalcific plaques may be more resistant to rupture than soft, minimally calcified, lipidrich plaques [172]. The immediate role of EBCT or carotid sonography for spaceflight crewmembers might be as a means of ruling out the presence of SCAD [185] or occult CAD in asymptomatic middle-aged men and women [39,178,186–189]. This capability might help flight surgeons select out astronaut or cosmonaut candidates with MCAD [189] and may provide temporary flight certification (with annual examinations) for specialized U.S. astronaut cohorts (e.g., payload specialists or non-Agency astronauts) with asymptomatic MCAD for short-duration flights within a 2- to 3-year period [190,191]. Most certainly, stress echocardiography, carotid sonography, CAF, and EBCT technologies should be monitored closely as future ways of screening candidates, following older astronauts or cosmonauts with suspected or proven asymptomatic MCAD, and selecting crews for lunar or planetary exploration-class missions.

Other Tests The sensitivity and specificity of stress echocardiography are superior to those of graded exercise stress testing and comparable to those of radionuclide imaging [192]. Although other noninvasive diagnostic imaging modalities expose crewmembers to radiation (a particular occupational concern in this cohort), stress echocardiography does not. Sonography of the carotid arteries to rule out gross atherosclerosis by measuring the intimal-medial thickness might also be used as a screening test for CAD. Several studies have been conducted to correlate the severity of carotid and coronary atherosclerosis [107,193], and at least one other study used carotid intimal thickening to predict the risk of cardiac events [194]. The ability to detect coronary calcifications with magnetic resonance imaging is limited because of the low signal intensity on both T1- and T2-weighted spin echo images, primarily because of the low density of mobile protons in calcified lesions [28].

Mission-Related Investigations Although most cardiovascular abnormalities revealed during the examinations for selection, annual evaluation, or mission

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readiness are disqualifying, some minor cardiovascular conditions can be waived by NASA’s Aerospace Medicine Board. This board must consider the risk of waiving a mild cardiovascular condition (e.g., an old borderline first-degree atrioventricular conduction block) versus the loss of a skilled astronaut whose training has incurred significant program expense. Even though our ability to apply prospective, evidence-based findings to career-affecting decisions such as these is quite limited, flight surgeons are nevertheless responsible for ensuring that a crew is medically ready for flight. From a cardiovascular perspective, the final test of a crew’s medical readiness for a long-duration space flight is determined 30 days before launch with resting and ambulatory electrocardiography, treadmill exercise testing, pulmonary function tests, and operational tilt tests. The operational tilt test involves 6 min in a supine position followed by 10 min at an upright position, representing an 80-degree tilt. In both positions, subjects are monitored with 2-dimensional echocardiography, Doppler sonography (to determine cardiac output and total peripheral resistance), 3-lead electrocardiography (including measurement of heart rate), manual blood pressure measurements every 1 min, and continuous noninvasive measurements of blood pressure. The tilt test is used for all first-time Space Shuttle flyers, those flying their first long-duration (>30 days) mission, and those who have shown functional orthostatic impairment on previous missions [53]. The cardiovascular examination conducted immediately after landing also involves a physical examination by the flight surgeon, an operational tilt test, and resting electrocardiography within hours of landing. Pulmonary function testing takes place within 3 days of landing, and another operational tilt test is conducted 10 days after landing. Additional tests are used for astronauts and cosmonauts returning from 3-month or longer tours aboard the ISS, who require more extensive long-term follow-up.

Cardiovascular Issues During Launch Before launch, crewmembers are acutely aware that they are sitting atop rockets that will accelerate them into space to an orbital speed of 17,500 miles per hour. Given their elevated adrenergic state and the position-induced central volume loading secondary to their near-supine posture in the vehicle, it is hardly surprising that crewmembers would experience increased heart rates during that time. Indeed, routine monitoring of U.S. and Russian spaceflight crews reveals that heart rates are typically highest during launch, entry into orbit, EVA, and reentry. Russian data from the Vostok and Voskhod launches indicated that cosmonauts’ heart rates during the launches were higher than during similar acceleration profiles in a centrifuge; specifically, heart rates were 39% higher than the centrifuge baseline as early as 10 min before launch and remained 52% higher than centrifuge-baseline rates through the first orbit [69].

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Thermal Loads From the flight surgeon’s perspective, a Space Shuttle launch starts when crewmembers don their advanced crew-escape suits (ACESs) 4–6 h before launch. The ACES rejects heat by means of a liquid-cooling garment composed of Capilene fabric lined with plastic tubing that circulates coolant water from an external portable individual cooling unit [195]. This cooling method eliminates the need for forced airflow through the suit, a design that was used in the Mercury, Gemini, Apollo, and early Space Shuttle programs. High cabin temperatures have at times overwhelmed the limited heat extraction capability of the individual cooling units. These units radiate their heat into the cabin, and their efficiency is less than 20%; thus, for a 70-kg man radiating 76 kcal/h (300 BTU/h) into the ACES, the individual cooling unit imposes more than 380 kcal/h (1,500 BTU/h) per crewmember on the cabin atmosphere’s cooling system. The total thermal load from the crew’s cooling units, in combination with the payload heat sources and the vehicle’s prolonged exposure to sunlight on the launch pad, may exceed the capacity of the cabin cooling systems before launch. Elevated cabin temperatures in turn degrade the performance of the individual cooling units, thereby diminishing their cooling capacity and raising the internal temperature of the ACESs. Crewmembers thus experience increased peripheral vasodilation and insensible fluid loss, possibly impairing their orthostatic tolerance in the event of an emergency egress from the vehicle. Flight surgeons must be aware of these factors and be prepared to advise launch management personnel regarding the ability of crewmembers to function in off-nominal cabin temperature conditions.

Launch Position Space Shuttle crews are placed in the vehicle ~2.5 h before the anticipated launch time. Depending on the temporal launch window for a successful launch and the duration of flexible pauses built into the countdown for troubleshooting of potential problems, crewmembers may be in the vehicle for as long as 4 h before the flight control team authorizes a launch or defers to another launch window. The launch seat configuration places the crew in a modified supine position, with an ~90-degree hip and knee flexion, to direct the launch acceleration forces in the +Gx (anteroposterior) direction. In the Russian Soyuz space capsule, its crewmembers are also in a +Gx orientation relative to acceleration for about 90 min before launch; however, the cosmonauts’ legs are folded more closely towards their chests than are the legs of Shuttle crewmembers. The Russian launch escape system does not rely on transatlantic abort landing sites; its use of a rocketpropelled capsule escape system facilitates crew emergency egress during system failures on the pad or during ascent. The combination of the vertically configured rockets and capsule and the lack of emergency return-to-launch site constraints

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makes Soyuz less sensitive to adverse weather conditions. This means that the Russian vehicle is much less prone to launch delays than is the U.S. Space Shuttle, and Soyuz crews typically spend less than 4 h in the launch position. With regard to cardiovascular system effects, maintaining the launch position for prolonged periods leads to significant venous blood volume being placed above the heart, thereby increasing the preload to the heart (i.e., central venous pressure [CVP] and ventricular end-diastolic volumes) and cardiac output [196]. The body interprets these physiological changes as an acute increase in intravascular volume and compensates by reducing intravascular volume though diuresis, reduced thirst, and insensible water loss. During the first 48 h on orbit, the intravascular volume lost through these compensatory mechanisms may be partially replaced by the vascular influx of extravasated fluid from the lower extremities. Spending 4 h in the legs-up launch posture can result in significant cephalad shifts of both intravascular and interstitial leg volume. Although the increase in cardiac preload upon exposure to microgravity may be partially mitigated by the posturally induced diuresis that occurs on the launch pad, volume changes induced by sustained time in this launch posture may impair the ability of the crewmembers to respond to an on-pad emergency because of potentially significant intravascular hypovolemia and the resultant orthostasis upon standing [197,198]. The series of complicated tasks that must be performed by the flight crew in the cabin to properly configure the Shuttle during countdown, the sealed nature of the ACES, the vehicle orientation, and the arrangement of the seats do not allow use of the Shuttle waste control system while the Shuttle is on the launch pad. Shuttle crewmembers therefore wear an undergarment containing a fluid-absorbent material that permits crewmembers to urinate inside the ACES if necessary. Crewmembers sometime prefer to restrict their fluid intake from 12 h to 24 h before launch and to “fly dry”; this self-induced preflight hypovolemia may exacerbate an existing orthostatic intolerance in susceptible crewmembers, and flight surgeons must be vigilant in confirming adequate volume status of all crewmembers before launch. The issue of orthostatic intolerance around launch times is not as crucial during Russian launch operations because, as noted earlier, launch delays are not common. The Soyuz does not expose crewmembers to significant Gz accelerations during launch-abort maneuvers, and crewmembers are not expected to exit the vehicle without assistance after landing. Russian flight surgeons occasionally administer a diuretic (e.g., furosemide) several hours before launch to decrease prelaunch volume and to help mitigate the expected cephalad fluid shifting process after arrival in microgravity.

Emergency Egress during Launch The limited fault prediction and mitigation capability of early propulsion systems, the reduced mobility of early launch

D.R. Hamilton

suits, and the extremely confined configuration of the capsule environment required that launch vehicles be designed to include crew escape systems capable of lifting the whole crew capsule to safety (e.g., the Mercury, Apollo, Salyut, and Soyuz launch vehicles) or propelling the individual crew members away from the failing vehicle with ejection seats (e.g., Gemini, Vostok, and Voshkod launch vehicles). The increased size of the Space Shuttle crew cabin and crew complement, however, made previous launch escape design philosophies prohibitively complex and expensive. As a result, Shuttle emergency egress plans call for the crew to escape through either the side hatch or the flight deck windows depending on whether the vehicle is in the launching or landing phase of the mission. A potentially confounding factor with regard to crew egress is the 41-kg ACES, which allows Shuttle crewmembers to breathe 100% O2 at 3.5 lbs per square inch (psi) in the event of cabin depressurization during a launch or landing. The Shuttle crew safety system requires that the crew be able to exit the vehicle quickly, whether it is on the launch pad or in stable flight [191]. After the crew has spent up to 4 h before launch in the supine position wearing an ACES, it is pertinent to ask whether members of that crew would be able to perform an emergency egress while the launch pad or from the Shuttle while in flight. When an emergency occurs on the pad at T minus 30 min, the crew must be able to exit the vehicle without help from ground personnel, as no one is allowed near the launch pad then. The crew, who will be wearing ACESs, must conduct an orderly, single-file exit through the Shuttle hatch and onto the launch tower via a walkway. After exiting the vehicle, the crew is to move rapidly to the opposite side of the launch tower and use the crew escape system, which consists of a large gondola that rapidly moves the crew away from the launch pad along a steep cable to a bunker or an armored personnel carrier. The crew must be able to perform an emergency egress for an abort as late as 3 s before liftoff and be able to ambulate 380 m upwind from the Shuttle [199]. The Space Shuttle can also prematurely separate from its central fuel tank and solid fuel boosters during a launch phase abort. During the initial portions of the launch phase, clearly some intervals exist in which crew escape is not an option; however, depending on when the mission departs from a nominal flight plan, the Shuttle may be able to glide back to the original launch site or to various trans-Atlantic contingency landing sites. In launch scenarios in which the vehicle does not have sufficient energy to reach these contingency sites, the crew must be able to exit the Shuttle during stable flight, through the side hatch, and parachute to safety [191]. Subjects wearing the ACES can complete simulations of Shuttle egress, but significant increases in mean in-suit CO2 concentration (4.5%) and heart rates (150 beats per minute) have been noted at the end of a 5-min period of walking at 5.6 km/h (3.5 miles/h) during such simulations [199,200]. Results from these studies indicate that the present ACES configuration is compatible

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with egress from the Shuttle if the crew is not experiencing any significant orthostatic intolerance. As noted, the current Russian Soyuz booster system uses a solid-rocket–powered launch escape system that lifts the crew compartment away from a disabled or an exploding launch vehicle. In this case, the cosmonaut crew does not need to exit the vehicle rapidly while the Soyuz is on the launch pad. This abort system was activated on the Soyuz T-10 mission during a fire that broke out while the Soyuz was still on the launch pad, requiring ignition of the emergency abort booster. Russian crewmembers Vladimir Titov and Gennadi Strekalov were exposed to 15–17 Gx but landed safely about 4 km downrange. In the event that future astronauts or cosmonauts experience an event like that on Soyuz T-10, flight surgeons must ensure that the crew has the cardiovascular capability to carry out an emergency egress. Aeromedical flight rules for the U.S. Space Shuttle [201] have been written to ensure that the crew cabin temperature and time spent in the launch position are restricted such that the crewmembers’ cardiovascular status will not impair their ability to perform an emergency egress during any aspect of nominal or off-nominal phases of launch.

Cardiovascular Issues During Orbital Flight The transition from Earth to a microgravity environment causes several short- and long-term changes in the crew’s cardiovascular system and may affect crewmember performance during orbital flight. Any space mission is operationally oriented, and brief spaceflights in particular have busy timelines and full schedules. Sometimes aggressive schedules may require that the crew devote the time nominally scheduled for cardiovascular countermeasures and personal activities to completing other mission-critical tasks. In the Russian experience, some crewmembers on long-duration missions have not complied with their prescribed cardiovascular countermeasures during the midportion of their missions, electing instead to use the time scheduled for countermeasures for other purposes and attempting to “catch up” with their physical conditioning later in the mission. On Earth, the normal activities of daily living require numerous rapid transitions between upright, sitting, and supine postures. Such transitions require that the heart and blood vessels be able to adjust quickly to a wide range of preload and afterload conditions. These frequent changes in posture demand exquisitely responsive cardiovascular control centers that can influence effector mechanisms to the heart and blood vessels on almost a beat-to-beat basis. This central cardiovascular control is provided by the medulla, and afferent input comes from neural receptors throughout the cardiovascular system. System output is provided by the efferent sympathetic and parasympathetic autonomic nervous systems [202]. In space flight, however, weightlessness removes the variance in gravitational stimuli to the system. As a consequence, feed-forward and feedback gains and set points are altered until a new hemodynamic

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homeostasis is established [203]. Flight surgeons must be able to determine when such alterations in cardiovascular control become maladaptive on orbit and upon return to Earth, when they may manifest as orthostatic intolerance.

Fluid Shifts On Earth, a large pressure gradient exists from our head to our feet when we are standing. The mean arterial pressure in a healthy human being is about 70 mmHg at the level of head, 100 mmHg at the level of the heart, and 200 mmHg at the level of the feet. The ankle veins sustain a pressure of~100 mmHg in a standing individual; this pressure decreases upon walking or sitting, but it never falls below 30 mmHg [204]. During normal activities of daily living, plasma volume is regulated to within 25 ml above or below the individual’s total volume (±0.8%) [205]. An immediate effect of the transition to microgravity is loss of the hydrostatic gradient in the venous vascular system, resulting in a cephalad shift [205] of roughly 1–2 L [206], an amount larger than the shifts involved in moving from an upright stance to a supine position or to a head-down-tilt posture on Earth [207]. This shift is thought to occur because the mechanisms that normally act to counter the pooling of blood in the lower extremities in humans continue to act even in the absence of gravity. The concept of a headward fluid shift was reinforced by a study that examined the effects of removing, by phlebotomy, 15% of the total blood volume of seated subjects who were immersed in water to the level of the suprasternal notch [208]. Water immersion causes an immediate cephalad intravascular fluid shift caused by loss of the venous and arterial hydrostatic gradients, with commensurate loss of venous pooling of blood in the lower extremities. Subjects who had not been subjected to phlebotomy experienced a 22% increase in cardiac output; those whose blood volume had been reduced by phlebotomy showed no such increase. Urine flow increased by 368% and sodium excretion by 200% in the normal blood-volume group as compared with increases of only 73% and 120%, respectively, in the phlebotomized group [208]. When a person is exposed to microgravity or is immersed in water, the venous volume is shifted toward the head, towards the primary volume sensors of the heart, which the body perceives as a volume overload even though the total body water and intravascular volumes are normal by terrestrial standards. Although these microgravity-induced changes in extracellular and plasma volumes may be appropriate adaptive responses during microgravity exposure, the resulting fluid redistribution and loss of blood volume can be considered profoundly hypovolemic by terrestrial standards. This spaceflight-induced loss of blood volume is thought to be the most significant contributor to postflight orthostatic intolerance [209]. Upon insertion into orbit, a crewmember is considered to be hypervolemic by microgravity standards. Displacement of intravascular fluid from the systemic capacitance vessels to

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the upper body stimulates neurohumoral activity and changes in vascular tone that result in a rapid reduction in intravascular volume through diuresis, reduced thirst, insensible losses, and sometimes space motion sickness [95,210–212]. Space motion sickness may be exacerbated by these fluid shifts [213]. Associated reductions in thirst and appetite, and possibly nausea and vomiting, may serve incidentally to correct the microgravity-induced volume “overload.” [210,212,213] The signs and symptoms resulting from fluid shifts in weightlessness were among the first physiological effects noted in humans during space flight [5,214,215]. Fluid shifts are readily visible as facial puffiness and enlargement of the external neck veins, with noticeable decreases in leg size [216]. Crewmembers have described such fluid shifts as feeling like “fullness in the head” or nasal stuffiness similar to chronic sinus congestion. As noted above, the intravascular volume lost through insensible losses and possibly through diuresis may be replaced by further intravasation of interstitial fluid from the lower extremities. The total loss of fluid from the vascular and tissue spaces of the lower extremities, 1–2 L, corresponds to a volume change of about 10% [217]. Apollo astronauts lost a mean of 4.6% of their body weight during 6- to 12-day missions [218], and Skylab astronauts lost from 1% to 4% of body mass during their first week in space [219]. Russian cosmonauts have lost from 4% to 8% of body weight after missions lasting 4–19 days [220]. Under normal terrestrial conditions, a 4% decrease in weight resulting from fluid loss constitutes significant clinical dehydration. If 50% of the weight loss experienced by crews of early Russian and U.S. space missions was from fluid loss, these crews were in fact clinically dehydrated according to terrestrial standards. More recent Russian findings obtained by using a radioisotope method during a 438-day flight revealed reductions in extracellular, vascular, and interstitial volumes by 9–10% on the fourth and fifth days of flight and reductions of 18% on the 434th day [12]. Intracellular fluid level was found to be unchanged during these experiments. Results from Spacelab Life Sciences (SLS) missions SLS1 and SLS-2 have shown, surprisingly, that total body water level, measured with an isotope-dilution technique [221], was unchanged despite decreases in extracellular fluid and plasma volumes [222]. During these missions, the total body water of crewmembers was found to be 57.2% of their body mass before flight and 57.1% of their body mass during flight. Such drastic shifts in lower-extremity extracellular and intravascular fluid as occur in microgravity were unexpected. Moreover, the proportion of extracellular fluid in these crewmembers was 41.1% of total body water before flight and 35% during flight [222]. These results imply that the 2 L of fluid lost in the vascular and interstitial compartments of the lower extremities [223] were lost to the body (with a resultant loss in total body mass) or were partially relocated in the intracellular space (with a resultant change in the distribution of water among the vascular, extracellular, and intracellular spaces).

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Volume reductions such as this would be caused mostly by the loss or transport of protein out of the vascular space and the movement of fluid into interstitial compartments that, because they are normally above the heart (i.e., the face and neck), do not normally experience any significant venous pressure. In humans, the capillary structures above the heart may be more permeable to plasma proteins, thus causing proteins to shift from the vascular space in the presence of extended periods of heightened venous pressures [224]. The results of the SLS-1 and SLS-2 experiments imply that loss of total circulating protein may account for the reduction in plasma volume through changes in oncotic pressures alone. After a reduction in blood volume (mostly through loss of plasma volume and red cell mass) [225–231], a crewmember will reach a new state of intravascular hydration that is euvolemic for microgravity but is profoundly hypovolemic for Earth-gravity conditions. It is currently unknown how the human will respond to acute exposures to 1/6 (Moon) and 1/3 (Mars) gravity after reaching microgravity euvolemia. The amount of diuresis during the first 2–3 days of space flight has been a topic of some debate, but findings from the SLS-1 and SLS-2 missions indicate that urinary output actually decreased during the first 2 days of space flight [222]. This decrease in urinary output was not caused by a decrease in glomerular filtration rate (which increased during the early in-flight period) and was consistent with the lack of significant reduction seen in serum antidiuretic hormone level. The physical and emotional stress of launch could possibly have prevented the central nervous system from inhibiting the release of antidiuretic hormone, despite the perceived volume overload from the volume sensors of the heart. An increase in the left ventricular (LV) cardiac chamber volume upon transition to microgravity has been well documented by echocardiography and is consistent with the observed fluid shifts [196,216]. The normalization of LV cardiac volume to near-preflight values occurs after the crewmember’s plasma volume is reduced to the new, microgravity-euvolemic state.

Volume Status and Central Venous Pressure An essential component of the bedside physical examination is determining the volume status of the cardiovascular system. This assessment is made by examining the extremities for edema or poor skin turgor; by measuring the jugular venous pressure (as an approximation of CVP), the aortic blood pressure and peripheral pulse contour and volume; and by pulmonary and cardiac auscultation. Exposure of an individual to microgravity greatly alters these physical findings. The typical bedside cardiovascular examination of patients in microgravity should be modified accordingly. This modification begins with a basic understanding of the altered physiology of healthy individuals. At the bedside, CVP is determined by observing the movement of the venous pulse in the external jugular vein. This simple bedside observation is useless in microgravity because

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the external jugular vein is continuously distended. Methods of measuring CVP in crewmembers in microgravity have used two types of pressure transducer technologies. The first involved use of an open-ended, polyurethane 4-French catheter connected to a differential pressure transducer, with the reference port positioned at the hydrostatic level of the midatrium [232]. Proper placement of the intravascular catheter tip was confirmed by anteroposterior and lateral fluoroscopy [196] just before launch. The second system used a fiberoptic central venous catheter with a pressure transducer placed at the catheter tip [233]. The distance between the transducer and the level of the midatrium was measured radiographically immediately after orbital insertion so that all pressures could be referenced to the same hydrostatic level. Interestingly, both of these techniques revealed that CVP decreased upon insertion into microgravity [196,233,234]. Assumption of the required supine legs-up posture before launch leads to an increase in CVP from 5–6 cm H2O to 10–12 cm H2O. During launch, CVP increases to 15–17 cm H2O, probably because of the 3.0 Gx hydrostatic loading of the venous system from the displaced vascular volume of the legs and the heightened adrenergic state caused by the crewmembers’ situational awareness of the unique circumstances surrounding rocket propulsion. At “main-engine cutoff” after insertion into orbit, crewmembers experience an abrupt transition from 3 Gx to microgravity, and the CVP decreases from 15 to 17 cm H2O to ~2.5–0 cm H2O [196,233].(The distention of the external jugular veins noted at main-engine cutoff and continuing throughout both short- and long-duration space flight, however, implies that CVP is always greater than 0 cm H2O.) During some microgravity measurements of CVP, the LV end-diastolic dimension was also measured by echocardiography and was found to increase from a mean of 4.60 cm to 4.97 cm within 48 h of exposure to microgravity. This result, combined with the simultaneous measurement of end-systolic dimensions, demonstrated that the LV stroke volume increased from 56 ml preflight to 77 ml during space flight [196]. Left atrial diameter was found to increase by ~13% during parabolic flight, which suggests that increased preload to the left ventricle is very rapid at the onset of microgravity [235]. This finding may seem surprising because increases in cardiac output and cardiac end-diastolic volumes on Earth are usually precipitated by an increase in CVP. Clinicians working on Earth have generally been able to imply a causal relationship between changes in cardiac preload and changes in CVP. During ground-based simulations of microgravity such as head-down bed rest, CVP increases by 3–4 cm H2O above that observed when a subject is supine [236,237]. Water immersion studies have shown that upon immersion, CVP increases immediately to a level 5 cm H2O above the pressures measured during head-down bed rest [238]. These CVP measurements differ remarkably from those experienced during parabolic flight [239] and space flight [196,233,240]. These results and the analysis of other cardiovascular variables [241] imply that ground-based car-

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diovascular microgravity analog models do not completely simulate the microgravity environment in space. The reduction in CVP of ~15 cm H2O in combination with increased cardiac output in space has been suggested to result from decreased intrathoracic pressure causing a decrease in external cardiac constraint greater than the decrease in CVP, which effectively increases cardiac chamber transmural pressure [233,242,243]. The role of pericardium in external cardiac constraint [244–247] has not been considered in the published discussions of these results. Nevertheless, the microgravityinduced changes in the position of the diaphragm [248] and its anatomic relation to the pericardium warrants investigation. This anatomic distinction is important because a fall in CVP with a simultaneous increase in LV end-diastolic dimension implies that either pulmonary venous pressure has increased or LV pericardial constraint has decreased. Terrestrial clinical studies have shown an increase in LV end-diastolic volumes with a commensurate fall in pulmonary wedge pressure when nitroglycerin is administered [245,249–251]. It has been proposed that the Gauer-Henry reflex (inhibition of antidiuretic hormone caused by atrial distension) [252] is diminished in microgravity because of a reduction in CVP, which implies a commensurate reduction in atrial distention [248]. The reduction in CVP upon transition to microgravity should bring about a reduction in right atrial transmural pressure; yet paradoxically, LV end-diastolic volume increases immediately upon insertion into microgravity. Typically, right atrial and ventricular end-diastolic transmural pressures parallel each other [244]; in combination with a reduced CVP, the observations are consistent with a decrease in overall ventricular pericardial constraint, resulting in an increased LV end-diastolic volume [247] and increased left atrial dimension [235,250]. This reasoning implies that the increase in LV end-diastolic dimensions measured during orbital flight may result from reduced LV pericardial constraint, which in turn could result from decreased CVP or from a microgravity-induced diaphragmatic rearrangement. Unfortunately, no echocardiographic evidence is available on whether right ventricular end-diastolic volumes change within 24 h of achieving orbit; such a finding might help to explain the paradox of increased cardiac output with reduced CVP. The transmural pressure of the human right ventricle that yields normal end-diastolic volumes is ~2 cm H2O when the CVP is ~10 cm H2O [244]. This relation implies that the decrease in CVP upon insertion into microgravity is very close to the decrease in right ventricular pericardial constraint, with right ventricular end-diastolic volumes decreasing only slightly. If reduced overall pericardial constraint permits the left ventricle to increase its end-diastolic volume at the same or even at lower end-diastolic pressure, then the right ventricular afterload would decrease, thus permitting the right ventricle to maintain its stroke volume at slightly lower end-diastolic volumes. Echocardiographic studies of the right ventricle upon insertion into microgravity would be needed to test this hypothesis [253].

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As a result of the decrease in blood volume associated with weightlessness, a crewmember who experiences hypovolemic shock in space may not be able to recruit pooled venous blood in the same manner as a patient in a terrestrial emergency, who would be placed in a Trendelenberg (head–down supine) position or supine with legs raised [198,254]. On the other hand, the increased capacitance of the venous system secondary to the microgravity-induced reduction in intravascular and interstitial volume after several days of space flight might allow a crewmember to tolerate a greater extent of left-to-right heart failure (e.g., as a complication of an acute myocardial infarction) than would be the case under terrestrial circumstances. It is important to understand that the apparent microgravity-induced change in venous capacitance may result from the venous system operating at smaller volumes. Nevertheless, it remains to be seen whether a crewmember with left-heart failure would be able to recruit any additional venous pooling reserve before manifesting symptoms of pulmonary edema.

Heart Rate and Blood Pressure Heart rates during space flight have been reported to be higher, lower, or unchanged from preflight values and can vary even in the same crewmember during the same flight [255]. Differences in the definition of baseline (i.e., before the experiment or during routine activities) and the combinations of countermeasure protocols and provocative cardiovascular research experiments undertaken during flight undoubtedly contribute to this variance. Variances in heart rate associated with different phases of sleep have also been shown to change during long-duration space flight [256]. In most crewmembers, the physiological and psychological stresses of launch lead to definite increases in heart rate [93]. Both the values of and variance in heart rate and diastolic pressure during orbital flight were reduced when measured during Space Shuttle missions that did not involve other provocative cardiovascular tests [255]. Diurnal variations in heart rate and diastolic pressure also were reduced during short-term space flight [255]. The fact that diastolic blood pressure and heart rate decrease [255] and cardiac output increases [257] implies that in microgravity the body is probably working with a reduced level of sympathetic activity and peripheral vascular resistance. These new set points in the cardiovascular control centers may contribute to an impaired response to orthostatic challenge upon return to Earth. The activities of daily living on Earth involve frequent shifts between supine, sitting, and standing postures. The bipedal human body is unique in that it exposes the cardiovascular system to a variety of preload and afterload conditions during changes in posture. Consequently, the cardiovascular regulatory centers are continually stimulated to adjust peripheral resistance, venous vascular capacitance, chronotropic and inotropic states, and vascular volume to counter the risk of syncope. Reduced variance in blood pressure during orbital flight may cause the central cardiovascular regulatory center itself to become deconditioned or “detuned.”

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Cardiac Rhythms The presence of arrhythmias in military aviators, unlike normal clinical populations, is not always associated with cardiac abnormalities. When monitored in ambulatory settings [74] or during mission simulations, ectopy is a common finding in apparently healthy aviators exposed to extreme accelerations and other induced stresses. Under these circumstances, flight surgeons are challenged to determine whether arrhythmias or ectopic beats are of occupational or pathologic origin. In the early U.S. and Russian space programs, ECG monitoring took place throughout the missions, and the results were visible in real time at the flight surgeon’s console. As mission durations increased and it became apparent that microgravity itself posed little risk of inducing arrhythmia or overtly abnormal heart rates, the requirement for ECG monitoring was limited to only the more stressful or mission-critical phases of space flight. Real-time ECG monitoring was performed continuously during the Mercury, Gemini, and Apollo spaceflight programs and during the launch and landing of the first four Space Shuttle missions. NASA has successfully completed more than 100 Shuttle missions without routinely monitoring the cardiovascular status of the crew during launch, nominal on-orbit operations, and landing. Real-time monitoring is required, however, during EVAs, LBNP procedures, any exercise that takes a crewmember above 85% of his or her predicted maximum oxygen consumption (VO2max), and other potentially hazardous investigational activities. Russian program flight rules also require that an adequate ECG signal must be received before Soyuz rendezvous/docking activities or any EVA involving an Orlan space suit can proceed. Although lack of adequate ECG information to the flight surgeon console does not preclude EVAs in the Space Shuttle program, it is required for EVAs that involve crewmembers who have been in space for more than 21 days (e.g., an ISS crew).

Periodic Cardiovascular Evaluations The cardiovascular fitness of crewmembers aboard the ISS is evaluated periodically by means of a cycle ergometer or a treadmill exercise evaluation with ECG and blood pressure monitoring. Before such evaluations, the crew is given an “exercise prescription” that is designed to prevent them from exceeding 85% of their predicted VO2max (maximal O2 uptake) during the exercise. The crew’s ECG tracings are recorded with four electrodes connected to a conversion network to provide the standard 10-electrode, 12-lead electrocardiogram. For simplification purposes, 4-lead EASI electrodes (leads E, A, and I of the Frank lead system plus an additional S lead positioned over the superior end of the sternum) [258–260] (Figure 16.2) are placed and the acquired data are stored and downlinked for retrospective analysis. A study by Drew et al. [261] in which 540 patients were tested with this 4lead system showed that the agreement with standard 12-lead electrocardiography was 100% for arrhythmias, 100% for

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Figure 16.2. EASI lead system used on the ISS for cardiac monitoring during periodic fitness exams. This system derives 10 signals for a 12-lead electrocardiogram from the Frank E, A and I electrodes and an addition sternal S lead. A converter device is used to reduce the patient electrodes to 5 from 10. This makes the setup and use of the electrocardiographic system easier and more reliable in microgravity. (Adapted from Drew BJ, et al. [261].)

acute infarction, 95% for angioplasty-induced ischemia, and 89% for transient ischemia. Although the 4-lead EASI electrode system has been used in terrestrial settings [261–268], correlation of the EASI 4- to 10-electrode electrical conversion for full 12-lead ECG monitoring under the conditions of microgravity-induced fluid and anatomic shifts has not been validated either at rest or during exercise.

Cardiovascular Issues During Reentry Adequate preparation of crewmembers whose cardiovascular systems are deconditioned for reentry, landing, and vehicle egress after exposure to microgravity is a serious concern for flight surgeons. Cardiovascular deconditioning comprises a spectrum of microgravity-adaptive changes that may become maladaptive upon return to earth; these include reduced blood volume, increased ectopy, reduced baroreceptor gain response, and cardiac atrophy, which alone or collectively can manifest as orthostatic intolerance and impaired exercise capacity. Flight surgeons supporting a long- or short-duration space mission strive to ensure that the crew is in the best possible condition to tolerate the cardiovascular stress of the transition between microgravity and Earth gravity. The transition includes reentry acceleration force profiles that involve exposures to 1.7–2.2 Gz for ~20 min on the Space Shuttle or 1.3–3.8 Gx for ~10 min on the Soyuz (Figure 16.3). For Soyuz spacecraft leaving the ISS, deorbit opportunities in which the capsule would arrive in Kazakhstan occur approximately every 21 h; forces experienced during nominal reentry profiles peak at ~4 Gx. For contingencies requiring immediate evacuation to the ground, emergency landing opportunities which

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Figure 16.3. Nominal Shuttle and Soyuz reentry acceleration profiles. Curves reflect acceleration in the vehicle +x axis; Soyuz crewmembers are recumbent while Shuttle crewmembers are seated upright. Orthostatic reentry acceleration (head to foot, +Gz) for Shuttle crewmembers increases steadily over a 20-min period to ~1.65 +Gz and declines to 1 G prior to the 1.36 +Gz to 1.5 +Gz experienced in the final turning maneuver one minute prior to touchdown. Trans-thoracic acceleration for crewmembers in the Soyuz increases steadily through early reentry, peaking at 4.43 +Gx at 200 s from the onset of acceleration forces

might utilize steeper trajectories are available within 45 min of Soyuz separation from ISS. However, this strategy might expose crewmembers to up to 8 +Gx during reentry to an emergency landing site that might not have adequate medical support capabilities in place. Moreover, high +Gx loads on a crewmember in the Soyuz during an emergency deorbit would certainly stress an already compromised cardiopulmonary system. Postflight findings from the 34-h flight of Mercury 9 revealed an increase in the astronaut’s heart rate from 132 beats per minute while supine in the capsule to 188 beats per minute, with presyncopal symptoms, after 1 min of standing upon return. The 2-man crew of Soyuz 9 were unable to exit the vehicle at landing after their 18-day mission, presumably because of cardiovascular deconditioning. The ability of crewmembers to ambulate after an emergency landing became a concern of the U.S. and Russian space programs after early astronauts and cosmonauts were noted to have problems with egress and postflight orthostatic intolerance. This concern was heightened when it was realized that changes made to the launch escape garments after the Space Shuttle Challenger accident increased the weight and thermal loads on Shuttle crews, which resulted in substantial increase in the incidence of orthostatic hypotension symptoms after flight (unpublished observation, RT Jennings, MD, 2000). As noted earlier in this chapter, the increase in thermal loading caused by the suit modifications may affect future crews by causing afterload reduction though vasodilatation, increased insensible fluid loss, and impaired vagal withdrawal to orthostatic challenge [269,270]. Introduction of the liquid-cooled ACES and more rigorous use of the gravity-suit pressure settings have reduced the thermal impact imposed by the heavy escape suit. Egress from

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the Shuttle after landing remains difficult, however, because the ACES and parachute together weigh 41 kg [199]. (The crew is not required to wear the parachute portion of the ACES during egress on the ground, which reduces the weight to 27 kg.) Egress may be further aggravated by the necessity for a rapid deorbit burn under emergency conditions, which may preclude completing fluid-loading countermeasures before reentry. In an emergency, the Shuttle may have to land at an emergency site in a country that does not have trained rescue personnel available to assist the crew in leaving the vehicle. Under these circumstances, the crew may have to exit the vehicle unaided by deploying a 20-kg inflatable slide from the side hatch or by climbing through the top window of the flight deck and rappelling down the side of the vehicle [195]. Finally, the crew may need to bail out of the vehicle during stable flight and descend to Earth by parachute. Crewmembers that have been on orbital flights for several months may not have the cardiovascular reserve for such activities while wearing a 41-kg pressurized suit. Maintaining cardiovascular fitness throughout space missions has been proposed as a means of mitigating the possibility of impaired performance during expedited emergency landing and other emergency scenarios. Current flight rules stipulate that anyone who has been in orbital flight for more than 30 days is required to be returned to Earth in the supine position (i.e., exposed to only +Gx acceleration) to reduce the chances of orthostatic intolerance during reentry and landing. This requirement raises concern over whether a crewmember could reasonably effect a self-egress from a recumbent seat system during an emergency after a long mission. In the event of an off-nominal landing, long-duration flight crews returning on the Shuttle may need to rely heavily on assistance from their shorter-duration and less deconditioned crewmates for egress. In a study by Lee et al. [199], healthy subjects who were not deconditioned performed simulated egress from the Shuttle while wearing the ACES; these subjects deemed the effort needed to walk 380 m, with the gravity-suit inflated to 1.5 psi (77.5 mmHg), difficult but not impossible. The orthostatic response of a deconditioned crewmember after a longduration space flight may be further impaired by an increase in core body temperature [269] resulting from impaired thermoregulation—a condition that has been documented after both long- [271] and short-duration [272] space flights. It seems reasonable to plan for a short-duration Shuttle crewmember to be available in the middeck area to assist any long-duration crewmembers in egressing the vehicle during emergency situations.

Orthostatic Intolerance Orthostatic intolerance during reentry, landing, and egress is one of the flight surgeon’s greatest concerns. Serious impairments in crew performance can happen to perfectly healthy and physically fit crewmembers. The ability to screen or test

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individuals for susceptibility to orthostatic intolerance has not been reliably established. Operational problems posed by orthostatic intolerance depend on the space vehicle flown and its mission profile. In the past, use of space vehicles that returned on ballistic flight paths while the crews were in a legs-up supine position during Gx acceleration did not pose significant concerns with regard to cardiovascular performance during reentry. Vehicle control during maximum Gx on such missions was mostly automatic, and the need for a crewmember to “fly” the vehicle occurred only four times, on Mercury 9, Voskhod 2, Soyuz 1, and Apollo 11. The Space Shuttle is a unique spacecraft in that its crew experiences reentry forces in the +Gz body vector as opposed to +Gx body vector common to all other spacecraft. This +Gzinduced loading, in combination with microgravity-induced cardiovascular deconditioning, can have deleterious effects, especially because the vehicle is controlled by the crew during critical landing phases. Use of inflatable anti-gravity garments and ingestion of isotonic fluids (fluid-loading) before reentry have been used to mitigate the risk of syncope during flight and upon assuming an upright posture after landing (Figure 16.4). To date, orthostatic intolerance has not manifested itself as a significant operational hazard to astronauts and cosmonauts during reentry and landing, largely because the landings have been nominal and ground support personnel have been immediately available at the primary landing sites. However, the ability of all astronauts in an ACES, or cosmonauts in a Sokol suit, to perform an autonomous emergency egress from the Shuttle or the Soyuz spacecraft continues to be a significant concern regardless of mission duration (Figure16.4). [199,273] Postflight orthostatic hypotension, with syncopal or presyncopal symptoms, has been noted in many returning Space

Figure 16.4. Heart rate response to entry and landing for crewmembers returning on the Shuttle. Comparison of short- and long-duration flights. The 34 short-duration spaceflight crewmembers (represented by the open circles) returned to Earth sitting upright, which loaded them in the +Gz axis while the three long-duration crewmembers (represented by the open squares) returned to Earth recumbent, which loaded them in the +Gx direction. Note the significant increase in the heart rates of recumbent crewmembers prior to standing

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Shuttle crews; this phenomenon, which reflects cerebral hypoperfusion similar to hypovolemic shock, is thought to result from a subject’s inability to recruit enough venous blood volume to mount an appropriate baroreflex-mediated sympathoexcitation and vagal withdrawal, which normally leads to cardiac acceleration and arteriolar and venous constriction [274]. Syncope and presyncope are caused by numerous factors [275–278], but the final manifestation is hypoperfusion [279,280] of the brain, which causes impairment of consciousness with a commensurate loss of postural tone. Eight to ten seconds’ loss of cerebral blood flow (< 30 ml/minute per 100 g of brain tissue) or arterial pressure (systolic pressure < 70 mmHg or mean atrial pressure < 40 mmHg) results in a loss of consciousness, with electroencephalographic inactivity ensuing 12–14 s later [278]. The ability of the cerebral circulation to autoregulate its vascular resistance to maintain parenchymal blood flow over a wide range of perfusion pressures has been well documented. Bed-rest studies by Zhang et al. [281] have shown that cerebral autoregulation may also be impaired after bed rest, and this impairment may further exacerbate orthostatic intolerance after exposure to microgravity. Although syncope certainly has deleterious effects, other side effects of cerebral hypoperfusion such as seizure and postsyncopal confusion could also profoundly affect a mission. Orthostatic intolerance is classified according to the changes observed in the subject’s heart rate and arterial pressure. In type 1 orthostatic intolerance, diastolic and systolic blood pressure decrease without an appropriate increase in heart rate. This presentation of symptoms may indicate an excessive blunting of the cardiac mechanoreceptors and baroreceptors to a hypotensive challenge. Type 2 orthostatic intolerance, on the other hand, presents as an increase in heart rate with normal or increased diastolic pressure. Sweating, palpitations, marked weakness, and an overall uncomfortable feeling indicative of a marked increase in sympathetic responsiveness may accompany these symptoms. Such an increase in sympathetic activity of the cardiovascular system is thought to be caused by excessive stimulation of the baroreceptor reflex induced by profound hypovolemia secondary to dependent venous pooling, which is further exacerbated by microgravity-induced reductions in blood volume. The appearance of these symptoms in crews returning to a 1-G upright posture after microgravity exposure implies that cardiac mechanoreceptor and baroreceptor function is present but that the sympathetic response may be blunted by the previous exposure to microgravity. These symptoms can be followed by a profound bradycardia and hypotension secondary to vagal stimulation of the heart (Bezold-Jarisch reflex), commonly referred to as vasovagal syncope. Orthostatic hypotension, with presyncope, has been observed in Space Shuttle crews after flights lasting as few as 4 days [282,283] and has been reported to occur in 15–20% of Shuttle crewmembers who flew between 1988 and 1990, before use of liquid-cooled garments became routine [284]. Investigations

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conducted by Fritsch-Yelle and colleagues found that 8 of 29 crewmembers observed after flight were unable to complete a 10-min stand test because of orthostatic intolerance; most of these crewmembers were female [285]. Subsequent observations of 91 crewmembers who flew on the Space Shuttle (17 women and 74 men) showed that 6 women (35%) and 5 men (7%) became presyncopal on landing day [285]. Waters and colleagues [286] studied the cardiovascular responses to standing in 35 Shuttle astronauts after 5- to 16-day missions. In that study, 100% of the women and 20% of the men experienced presyncopal symptoms in response to a stand test after landing. The authors attributed these findings to a combination of inherently low systemic vascular resistance, a strong dependence on volume status, and a hypoadrenergic response to orthostatic challenge. These investigators also found that the presence of high vascular resistance and hyperadrenergic activity was protective against presyncopal symptoms during a stand test. In another study, Buckey et al. [209] found that after 10–14 days of space flight, two thirds of crewmembers experienced orthostatic intolerance manifested by an inability to remain standing for 10 min when evaluated within 4 h of landing. One crewmember, who was observed after the landing of the SLS1 mission, demonstrated that orthostatic intolerance upon assuming an upright posture can occur without precipitous change in heart rate [275]. (The absence of gravity during short-term space flight [<16 days] led to a reduction in plasma volume [17%] and extracellular fluid [41–5% of total body water] within the first 24 h of flight [275], despite the fact that total body water was not significantly decreased.) [222,287] Cardiac pressure pulses are monitored by cardiopulmonary, aortic, and carotid baroreceptors; they elicit beat-to-beat changes in sympathetic and vagal cardiac efferent nervous activity. Cooke and colleagues [288] examined the spectral characteristics of electrocardiograms from three cosmonauts before, during, and after a 9-month mission and found reduced vagal-cardiac neural outflow and a blunted vagal baroreflex gain that did not return to normal until 2 weeks after the mission. Another common method of determining the gain of the carotid baroreceptor response is to impose external positive or negative pressure on the neck and subtract that pressure from the measured or calculated carotid artery pressure at the same hydrostatic level to derive a carotid transmural pressure. (The carotid transmural pressure is the distending pressure experienced by the carotid bodies that provide afferent signals to the baroreflex control centers.) Positive external neck pressure will decrease the carotid baroreceptor transmural pressure; this change elicits a homeostatic reflex mechanism that increases heart rate through efferent vagal withdrawal. A stimulus-response relationship can be derived when measurements collected with a neck chamber capable of delivering positive and negative external pressure are correlated with changes in heart rate (Figure 16.5) [255,283,289–293]. Studies conducted after head-down bed rest [236,237,294– 297] or after space flight [255,283] have shown that a minimal

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orthostatic challenge produces a blunted heart rate response to a given change in carotid body transmural pressure in many subjects. The diminished carotid baroreceptor response in spaceflight crewmembers manifests as reduced slope and reduced range of the R-R interval response to simulated changes in arterial pressure (Figure 16.5) [298,299]. Interestingly, carotid baroreceptors do not seem to significantly modify arterial vascular resistance when studied independently [298,299] or concomitantly [292] with volume-induced stimulation of the cardiopulmonary baroreceptors. These studies also revealed that arterial resistance in the forearms could be altered by acute changes in CVP despite stabilized aortic blood pressure, pulse pressure, and arterial dp/dt (rate of change in pressure with time). Thus, the control of blood pressure upon standing after exposure to microgravity may not depend on vascular volume status alone [292,298,300]. Studies of patients with congestive heart failure (CHF) in hypervolemic or euvolemic states have shown that impairments in the carotid baroreflex function [290,301,302] are responsible for many syncopal and presyncopal events in such patients. Blunted carotid baroreceptor response may be a significant contributor to the orthostatic intolerance seen after return from space [209]. Convertino [302] suggested that more effective orthostatic countermeasures for long-duration space flight may need to include ways of increasing baroreflex gain. If a crewmember’s baroreflex gain diminishes during orbital flight because of reduced central cardiovascular stimulation, interventions such as LBNP [216,241,303] or exercise [304,305] might impose baroreceptor challenges, with or

Figure 16.5. Effect of microgravity on the carotid baroreceptor response relationship. Diagrammatic representation of the effect of microgravity adaptation causing a rightward shift in the carotid baroreceptor response curve (the so-called microgravity effect). Microgravity deconditions baroreceptor response, resulting in larger changes in carotid transmural pressure needed to effect the same changes in heart rate (the so-called delta R-R interval response) compared to 1-gravity controls. Exercise and/or LBNP (the so-called exercise or LBNP effect) may provide a means of shifting the carotid response curve back to the 1-gravity control curve

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without changes in cardiac-vagal reflex gain (Figure 16.5), similar to the daily orthostatic challenges experienced during life on Earth [84]. Other investigations have addressed the role of catecholamines in postflight orthostatic tolerance. In one study [306], LBNP was delivered by means of the Russian “Chibis” space suit to a 52-year-old cosmonaut at 4 days after a 438-day mission, and epinephrine and norepinephrine levels were measured. Significant increases in catecholamine levels upon exposure to LBNP at that time returned to normal levels by 90 days after return. These case-study results seem to indicate a downregulation or impaired sensitivity to catecholamine hormone receptors after space flight. Results from the Extended Duration Orbiter Medical Project indicate that after missions lasting longer than 10 days, the neurohormonal response to postflight orthostatic challenge is blunted and manifests as a decreased ability to maintain arterial pressure and heart rate upon standing [7]. Postflight measurements of plasma norepinephrine and epinephrine, collected while the subjects were supine, were 34% and 65% higher than preflight control values; these values further increased to 65% and 91% above control values when the subjects stood [307]. Notably, the supine and standing epinephrine levels had returned to normal at 3 days after landing, but the norepinephrine levels remained elevated [285]. This study also showed that supine heart rate and systolic blood pressure were 18% and 9% higher than preflight control measurements, and standing heart rate and diastolic pressure were 38% and 19% higher than preflight control measurements. Of the 29 crewmembers studied, 8 were unable to complete a 10-min stand test on landing day because they became presyncopal and were forced to sit down to prevent syncopal collapse. Investigators observed that these 8 subjects displayed arterial pressure and heart rate responses that resembled those of partial adrenergic failure; also, the standing norepinephrine levels of the presyncopal group were significantly lower than those of crewmembers who were able to complete the stand test. Plasma volumes were no different in the groups, however, and thus the mechanism responsible for the presyncope was thought to be reduced peripheral vascular resistance secondary to impaired sympathetic release of norepinephrine. Reduced peripheral resistance also may have been due to receptor downregulation resulting in an impaired smooth muscle response to adrenergic stimulus, or possibly to changes in autonomic effector nerve function [300]. Before flight, supine and standing peripheral vascular resistance values were lower in the presyncopal group than in the nonpresyncopal group [285,286]. These findings might provide flight surgeons a way of identifying individuals who may benefit from more aggressive cardiovascular countermeasures before reentry. Midodrine, a peripheral alpha-1 agonist, may be useful for producing sufficient arterial and venous constriction to help crewmembers prone to orthostatic intolerance become less susceptible to presyncope when they stand after returning from space flight [308,309]. Drugs such as phenylephrine, ephed-

16. Cardiovascular Disorders

rine, pseudoephedrine, ergotamine, midodrine, and indomethacin have been tested in terrestrial settings for patients prone to orthostasis caused by autonomic disorders, and some of these drugs might have a role in mitigating orthostasis after space flight. On Earth, most of the blood stored in the lower limbs is in the deep venous structures, which have sparse sympathetic innervation and little smooth muscle [310]. Thus venous capacitance is significantly influenced by the passive compliance of the vessels combined with the external constraint of the surrounding muscle and interstitial structures and fluid. As such, changes in adrenergic tone may not invoke significant changes in the capacitance of the deep vascular venous space. The capacitance of the venous system in the lower extremities can be modified by external skeletal muscle mass and tone. Leg muscle atrophy and reduced tone secondary to disuse in microgravity may also contribute to increased venous capacitance and therefore to increased postflight orthostatic intolerance [311].

Impaired Exercise Capacity During the Gemini and early Soyuz programs, many crewmembers experienced a decline in exercise capacity after return, as determined by changes in their heart-rate responses and reductions in O2 consumption during a quantified workload. Measurements obtained before and after the Apollo 7 through Apollo 11 missions with a heart-rate–controlled cycle ergometer set to rates of 120, 140, and 160 beats per minute [312] revealed significant declines in exercise performance (specifically, workload tolerance, O2 consumption, systolic blood pressure, and diastolic blood pressure) at the 160 beats-perminute setting immediately after flight [206]. Skylab crewmembers similarly showed a decrease in exercise performance, with most of the cardiovascular responses returning to normal by ~3 weeks after return. In contrast to these findings, exercise studies conducted during flight proved that crewmembers could perform submaximal exercise (70% of preflight VO2max) with no significant changes relative to preflight values. In fact, some Skylab crewmembers showed a decrease in heart-rate response, implying that the astronaut could increase his exercise capacity on orbit. The Skylab findings are difficult to compare directly with other findings from long-duration microgravity exposures, however, because the atmospheric pressure in Skylab was 5.0 psi (258 mmHg) with an O2 concentration of 70%. The resulting partial pressure of oxygen prevented hypoxia, but the reduced atmospheric pressure may have reduced the ability of the crew to adequately thermoregulate during exercise. The Russian experience with exercise is somewhat different, showing significant decreases in exercise capacity depending on the mission duration. Cosmonaut crewmembers of the 140-day Salyut-6 and 237-day Salyut-7 missions demonstrated heart rates 17% higher and stroke volumes 30% lower than preflight values, despite daily 150-min exercise

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sessions toward the end of the missions [313–315]. Grigoriev and colleagues [12] reported similar results from 18 cosmonauts examined during Mir missions lasting as long as 366 days. Microgravity-induced intravascular hypovolemia has been implicated as a contributing cause of abnormal exercise capacity upon return to Earth gravity. A study of six astronauts during Space Shuttle missions SLS-1 and SLS-2 found no difference between VO2max measured during flight and that measured 2 weeks before flight; however, a 22% reduction in VO2max was found immediately after flight [9]. This reduction, which occurred after 9 days of space flight, was similar in magnitude to the decrease in VO2max noted after the 84-day Skylab mission. Ground-based studies using microgravity analog models have shown a direct relationship between reduction in VO2max and the percent reduction of plasma volume. Notably, one such experiment with 10 fit subjects demonstrated an average of 16% reduction in VO2max and plasma volume compared with only 6% reduction in VO2max and plasma volume with unfit subjects [223]. Levine and colleagues [146] noted significant reductions in plasma volume (17%), baseline pulmonary capillary wedge pressure (PCWP) (18%), stroke volume (12%), LV end-diastolic volume (16%), LV pressure–volume intercept (33%), and orthostatic tolerance (24%) in subjects after 2 weeks of head-down bed rest. The authors of that study concluded that a bed-rest-induced decline in ventricular compliance is a contributor to the impaired cardiac response to orthostatic stress after space flight. The 5% reduction in heart mass noted in combination with the reductions in PCWP, plasma volume, and stroke volume [146] is also consistent with the concept of a smaller heart operating within a less compliant portion of the pericardial pressure-volume relationship [247]. In another study, Perhonen and colleagues [316] challenged volunteers with simulated orthostatic G loads from LBNP or diuretics in a 14-day, head-down-tilt bed-rest study and documented a similar leftward shift in the LV end-diastolic function curve. The LV pressure–volume relationship of the heart is significantly influenced by the pericardial pressure–volume relationship. Assuming that LV transmural pressure is a function of PCWP alone, without considering the influence of the pericardium on the LV pressure–volume relationship, may lead to erroneous conclusions regarding shifts in LV transmural pressure–volume function curves [247] and commensurate Starling responses. Tyberg and colleagues [247] have shown that subtracting the mean right atrial pressure from PCWP is a better predictor of changes in LV transmural pressure and that LV transmural pressure is a better estimate of preload than PCWP alone. The studies by Levine et al. [146] and Perhonen et al. [316] used PCWP alone as a measurement of LV transmural pressure changes. Although these studies showed that the PCWP–LV end-diastolic volume relation shifted to the left, the true LV transmural end diastolic pressure–LV enddiastolic volume relation may not have shifted as significantly. The use of supine LBNP or acute diuresis to simulate orthostatic +Gz loading after flight may induce the same blood

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volume shifts seen in microgravity, but it remains to be seen whether the external constraint of the heart is altered in a similar manner. The mechanics of ventricular preload during an acute orthostatic challenge after bed rest or microgravity require further examination [253]. Lee and others [317] studied 30 crewmembers who performed various levels of exercise before and during flight missions lasting 9–16 days. They found that the group that performed moderate- to high-level exercise during flight had less orthostatic intolerance to a 10-min stand test after flight. Moreover, performing higher-level exercise during flight seemed to have had a protective effect on the increase in heart rate and the fall in pulse pressure that are experienced by all crewmembers upon return (Figure 16.6). Further research is needed to determine whether this effect was due to a change in the carotid-cardiac baroreflex set point [275,318], altered splanchnic vasoconstriction [319], increased plasma volume [315,320], or decreased venous capacitance caused by increases in lower-extremity muscle tone and interstitial volume [321,322]. Regardless, these results suggest that inflight exercise [317,323] may be an important component of a comprehensive orthostatic countermeasures program for both long- and short-duration missions [324]. One of the most significant operational workloads is the exertion associated with EVAs, when crewmembers may work

Figure 16.6. Space flight-induced change in physical work capacity with various exercise regimens during flight. The percent degradation in exercise capacity from preflight controls was measured on astronauts postflight and compared to the exercise they received on orbit. NONE = no on-orbit exercise; RUN C = exercising on treadmill regularly; RUN I = exercising on treadmill intermittently; BIKE I = exercising on a cycle ergometer intermittently; and ROW I = exercising on a rowing machine intermittently

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for 6 h or longer in a mechanically restrictive space suit, with mean metabolic expenditures of about 200 kcal/h (800 BTU/h) and 5- to 10-min peaks of more than 380 kcal/h (1,500 BTU/h). The current configuration of the U.S. extravehicular mobility unit (EMU) space suit, which is used to perform EVAs, allows a crewmember to drink 947 ml of fluid; the Russian Orlan space suit, which is also used to perform EVAs, has no supply of drinking water. Russian measurements of body mass before and after EVAs indicate that cosmonauts lose 0.7–2.2 kg of fluid during a typical EVA. EVA-induced dehydration, with its commensurate reduction in plasma volume, can exacerbate an existing decline in exercise capacity caused by long-duration exposure to microgravity. Thus flight surgeons should ensure that crews are well hydrated before undertaking an EVA.

Reentry Countermeasures Countermeasures such as fluid and salt loading have proven effective in reducing the incidence and severity of syncopal and presyncopal symptoms upon return from short-duration space missions [7,93]. A combination of pharmacologic [325] and mechanical [7,241] countermeasures may be more effective than mechanical countermeasures (e.g., LBNP, treadmill or cycle ergometry exercise, or use of a gravity suit) alone in preventing postflight orthostasis. Since the bioavailability, elimination half-life, volume of distribution, and clearance of drugs used for countermeasures are largely unknown [326,327], the use of several countermeasures simultaneously may interfere with the independent assessment of each individual countermeasure. Results from the Extended Duration Orbiter Medical Project suggest that most crewmembers are in a negative energy balance during short-duration space flight and that most weight loss is a result of reduced muscle mass [7]. The findings on electrolyte balance are quite variable, and no evidence exists to suggest that a well-hydrated and well-nourished crewmember would experience dangerous extremes in serum electrolyte levels. Unfortunately, in many circumstances crewmembers find themselves unable to drink or eat adequately. During the first several days of space flight, crewmembers may experience space motion sickness, which can manifest as malaise, fatigue, suppressed appetite, nausea, and vomiting. The crew activity schedule sometimes keeps crews from ingesting adequate amounts of fluid, which may exacerbate an already hypovolemic state relative to the terrestrial standard. Further, low urine volume and increased levels of calcium excreted in the urine from microgravity-induced musculoskeletal unloading are key risk factors in the development of nephrolithiasis [328–330]. Crewmembers are therefore encouraged to drink adequate amounts of fluids and to maintain a regular exercise schedule [328,331]. During handovers when the transport vehicle (Shuttle or Soyuz) is docked to the ISS, crewmembers returning from long-duration missions will be able to fully access all ISS exercise countermeasures facilities for daily use. Methods and

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opportunities for prescribed exercises will also be provided on the Space Shuttle for crews returning from long-duration space flights. At a minimum, equipment aboard the ISS for exercise countermeasures consists of a treadmill, a cycle ergometer, and a resistive exercise device. Other types of countermeasures available on board can include LBNP, whole-body elastic-loading suits (e.g., the Russian “Penguin” suit), thigh cuffs (e.g., the Russian “Brazlet” device), pharmacologic preparations, and electromyostimulator systems. At the end of an ISS mission, when the crew is returning home via the Space Shuttle, orthostatic countermeasure and exercise equipment include: fluid/salt-loading, anti-gravity garments (e.g., the pneumatic gravity suit, the Russian “Kentaver” elastic antigravity garment), active cooling (i.e., a liquid-cooling garment), recumbent seating (provided for crewmembers returning from flights longer than 30 days), and pharmacologic preparations.

In-Flight Exercise Regular exercise is part of the flight schedule on Space Shuttle and ISS missions to preserve physiologic function during entry and following landing. Space Shuttle Operational Flight Rules [201] require that the commander, pilot, and mission specialist (or flight engineer) who are supporting the landing exercise once every other day after being in flight for more than 3 days. Daily physical exercise (1.5 h of varying amounts of resistive and aerobic exercise) is also scheduled for ISS crewmembers. Exercise prescriptions are tailored to meet the needs of each crewmember, but all follow a basic schedule. Intense exercise (e.g., at levels > 85% of the preflight maximum VO2max) requires ECG telemetry and continuous air-to-ground voice communications during portions of the test and continuing throughout the recovery period. By definition, the recovery period lasts at least 5 min but it can be extended at the flight surgeon’s discretion. For space flights on which no trained physician is on board or real-time ECG monitoring capability is lost [332], exercise is to be limited to 85% of VO2max. When a trained physician crewmember is on board the ISS, he or she can continuously monitor a crewmember’s electrocardiogram during exercise above the 85% workload limit. Monitoring is required when vigorous exercise is part of a research protocol, but not for routine daily exercise. Intense monitored exercise, during programmed exercise sessions as part of a research protocol, or in the course of strenuous operational activities such as EVAs, is to be terminated if any the following cardiac rhythm disturbances occur: sustained abnormal SVT (defined as paroxysmal atrial tachycardia, atrial fibrillation, atrial flutter, or other SVT of unidentified etiology lasting longer than 10 s); VT; exercise-induced bundle branch block; R-on-T PVCs; unexplained inappropriate tachycardia; multifocal PVCs; onset of second- or third-degree heart block; increasing ventricular ectopy (in which more than 30% of the total beats are unifocal PVCs); maximum heart rate greater

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than explainable by exercise stimulus; chest pain, dizziness, or other symptoms of intolerance. Intense exercise is also to be terminated if the subject asks to stop.

Fluid Loading Early bed-rest studies revealed the usefulness of oral rehydration with saline solutions in the form of bouillon to protect test subjects from orthostatic stress by LBNP [303,333] or +Gz acceleration [334] by transiently expanding plasma volume. Oral rehydration with salt and water is considered a reentry countermeasure in both the U.S. and Russian space programs. Studies by Prisk and colleagues [242] showed that fluid loading prevented the sharp reduction in cardiac output and stroke volume observed during a stand test conducted after 17 days of head-down bed rest. Results from the SLS-1 Space Shuttle mission, on which no fluid load reentry countermeasures were performed, found that stroke volume and cardiac output decreased by 27% and 14%, respectively [242]. Results from the SLS-2 and Neurolab missions showed that fluid loading was effective in preventing the fall in cardiac output and stroke volume seen in crewmembers from the SLS-1 and D-2 missions [209]. Buckey and colleagues [209] noted that fluid loading alone may not be completely effective in preventing orthostatic intolerance and that an appropriate increase in cardiac afterload may also need to occur to protect against presyncope and syncope after flight. Because ionized compounds provide ~95% of plasma osmolality in humans, it seems logical to use oral fluids composed mostly of water and electrolytes to increase plasma volume [335]. The independent and combined effects of LBNP and oral fluid-loading with saline have been studied to determine the optimal means of expanding plasma volume. Oral rehydration alone was found to produce the largest increase in plasma volume [333]. Studies by Bungo and others [80,336] revealed that Shuttle crewmembers who ingested saline experienced a 29% reduction in the expected heart-rate response and a reversal in the fall of mean blood pressure when exposed to orthostatic stress after return from space flight. Greenleaf and colleagues [335] also found that in dehydrated subjects at rest, the cation content (e.g., sodium ions) of a fluid-loading solution is more effective than other ingredients (carbohydrate) that increase osmotic content for increasing plasma volume. Interestingly, in that study the final plasma volume after 70 min of exercise at 70% of peak VO2max was not affected by the osmotic or electrolyte content of the ingested fluid [335]. These results have led to the use of fluid-loading with normal (0.9%) saline as an operational countermeasure before reentry and landing. Experiments conducted by Frey and others [337] showed that 1.07% oral saline may be more effective than 0.9% saline in maintaining plasma volume after reentry (Figure 16.7), although use of the higher concentration has been associated with diarrhea [338]. The operational requirement in the Space Shuttle Program is a fluid load of 15 ml

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normal saline (0.9% NaCl) per kilogram of preflight body weight, to be ingested 1–2 h before landing. Basing the prescribed volume of isotonic solution on a crewmember’s preflight body mass helps to ensure that the fluid load is adequate for larger crewmembers and is not excessive for smaller crewmembers (Table 16.4). ASTROADE® and other flavored isotonic solutions provide plasma volume expansion similar to that of water and salt tablets and may be more palatable for some crewmembers. Flight surgeons must approve use of any alternative solutions before flight. Isotonic fluid-loading is required for all crewmembers before deorbit and is to be initiated no earlier than 1.5 h before the deorbit burn [201]. At that time, each crewmember must consume 8 oz of water and two salt tablets, or 8 oz of other approved solutions, every 15 min until the total prescribed dose is achieved. To prevent gastric irritation and an inappropriate increase in plasma osmolality, which may exacerbate dehydration, it is important that sufficient amounts of water be consumed with the salt tablets. Crewmembers are instructed before launch as to the proper amount of salt and fluid to ingest, and reminders are given during the private medical conference on the day of

Figure 16.7. Effect of oral fluid loading with various fluid types on changes in plasma volume as a function of time relative to landing. Water, normal saline (0.9%), or hypertonic saline (1.075%) was ingested in a quantity of ~910 ml (32 oz) 2 h prior to landing with plasma volume changes calculated by hemodilution. Table 16.4. Fluid loading requirements for astronauts returning to earth via the space shuttle. Fluid load

Preflight body weight lb (kg) <120 (<54) 120–155 (54–70) 155–190 (70–86) >190 (>86)

No. of 8-oz (237-ml) drink containers 3 4 5 6

+ + + +

No. of salt tablets 6 8 10 12

OR

Amount of approved alternative solution, oz (ml) 24 (710) 32 (946) 40 (1,183) 48 (1,420)

Source: Adapted from NASA National Space Transportation System [201].

landing. If a 1-orbit wave-off occurs (as is common because of weather problems at the landing site) and the fluid-loading protocol for deorbit has been completed, the protocol is repeated with half of the originally prescribed amount. If the delay extends beyond 1 orbit (i.e., more than 3 h), the entire fluid loading protocol must be repeated because renal clearance or loss of fluid to the interstitial spaces will have negated the effect of this countermeasure.

Gravity Suit Protocol The Space Shuttle reentry profile imposes a steadily increasing +Gz acceleration on the crew over a 20-min period, peaking at 1.65 Gz before rapidly declining to 1 G after the Shuttle has shed most of its kinetic energy. The crew also experiences a sharp increase in acceleration from 1.36 +Gz to 1.5 +Gz during the final turning maneuver, where the Shuttle, under manual control by the pilot, banks to align itself with the runway for the final approach and touchdown. Any presyncopal or syncopal events experienced by the pilot or commander at that time could be catastrophic. Space Shuttle commanders, pilots, and mission specialists have experience with flying high-performance aircraft and preventing +Gz-induced loss of consciousness. Present-day fighter pilots use a pressurized air bladder gravity suit [339] to help prevent these deleterious effects during high +Gz maneuvers, and all Shuttle crews use a similar 5-bladder gravity suit (the CSU-13B/P suit [195]) for reentry. Inflation of air bladders in the lower extremities of the suit prevents venous blood from pooling in the lower extremities and displaces blood toward the heart [339,340]. The onset of +Gz forces during Shuttle reentry is initially gradual (0.0012 Gz per second for ∼15 min) and typically reaches a plateau at ∼1.5 Gz for 5 min. In addition to using gravity suits, fighter pilots also use an antigravity straining maneuver, which is a repetitive modified Valsalva maneuver combined with isometric limb contractions to help maintain aortic root pressures and cerebral perfusion during high +Gz maneuvers. Prolonged use of the antigravity straining maneuver to prevent presyncopal symptoms or +Gz-induced loss of consciousness are not feasible for the longer-duration Shuttle reentry acceleration profiles. The Shuttle gravity suits take longer to inflate than those used in fighter aircraft (∼60 s to reach 1.5 psi [77.5 mmHg] vs. 1.5 s, respectively). A centrifuge study performed by Krutz and others [341] determined that inflating the Shuttle gravity suit to 1.5 psi (77.5 mmHg) 10 min before +Gz onset was effective in protecting dehydrated subjects exposed to a radial acceleration profile similar to a Shuttle +Gz reentry profile. These subjects were given a diuretic to simulate after-landing intravascular hypovolemia. This study also found that inflating the suit early maintained the eye-level blood pressure at a higher level and reduced the peak heart rates. Information gained during this study led to the Shuttle flight rule requiring all crewmembers to inflate their gravity suits before the reentry interface that marks the onset of acceleration forces on the vehicle.

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The anti-orthostatic protection provided by a gravity suit may diminish over time periods beyond 30 s, as manifested by the inability to maintain LV end-diastolic volume, when the gravity forces exceed 3.0 +Gz [342]. The air bladders in the Shuttle suit inflate in 0.5-psi (26-mmHg) increments to a maximum of 2.5 psi (130 mmHg) [195]. Space Shuttle Operational Flight Rules [201] require that the suits be inflated to 0.5 psi (26 mmHg) after entry interface and to at least 1.0 psi (50 mmHg) at 1 G during return from flights of more than 11 days. The gravity suits must remain inflated until the Shuttle wheels come to a stop. The suit must be inflated before the onset of symptoms; this is especially important to help prevent orthostatic problems after longerduration flights. Crewmembers can increase the pressure of the gravity suit during any portion of the reentry profile should they have symptoms that require it. Gradual deflation of the bladders after landing also minimizes symptoms by reducing blood pooling. If a crewmember elects to deflate the bladder before egress, deflation will be accomplished progressively over 10 min. As noted earlier in this chapter, crewmembers returning from long-duration flights in the shuttle do so in a recumbent seat system in which their feet are elevated into a middeck locker— a position not unlike the launch position. In this position, the abdominal bladder in the gravity suit may impose undue discomfort, especially when combined with a complete fluid load countermeasure. Under some circumstances, this pressure increases the risk of vomiting the fluid load before landing. Because this posture protects the crewmember from reentry +Gz stress, flight surgeons typically recommend that such crewmembers initially inflate the suit to 0.5 psig only—just enough inflation to remove the creases from the suit. The pressure can be increased as needed, but the crewmembers are forewarned about the abdominal discomfort that this can cause.

Lower-Body Negative Pressure LBNP refers to the application of pressure over the lower body that is below the ambient cabin pressure. Enclosing the subject below the level of the iliac crest in an airtight chamber achieves the desired configuration for lower-body decompression [84]. This decompression causes the intravascular volume to shift towards the lower extremities in a manner similar to the orthostatic load caused by assuming an upright posture in 1 G. LBNP has been used as both a countermeasure and as a method of screening for orthostatic intolerance before and during flight [304,343]. In the Russian space program, LBNP is delivered during space flights with a device called the Chibis, a set of corrugated pneumatic trousers that can develop a negative pressure of 1.0 psi (50 mmHg) [2,12,84,344,345]. The Chibis loads the body in a different manner than the LBNP devices used on Skylab and the Space Shuttle [84]. The Russian system includes a built-in foot support that requires a cosmonaut to “stand” in the device, which loads the pelvis with the feet sup-

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ported and loaded by airtight boots. The body support in the U.S. LBNP system, in contrast, is provided by a saddle or seat that lets the feet dangle, thereby mechanically unloading the lower extremities. If the intent of LBNP is to maximize the orthostatic challenge to the cardiovascular system, this system is probably more effective than the Russian system. However, if the intent is to mechanically load the musculoskeletal and cardiovascular system in a manner similar to postflight standing, the Russian Chibis is probably the more effective of the two [346]. Loading the lower extremities during LBNP leads to increased muscle tone and thus decreased venous compliance and capacitance, thus providing a protective effect against the caudal fluid shift induced by LBNP. The Russian experience with the Chibis device is extensive and has been used in all but one of the Salyut and Mir space station missions. As the crew usually returns to Earth on a Soyuz spacecraft and the time between the last use of the LBNP and landing is typically less than 24 h, Russian investigators have found in-flight LBNP to be an effective countermeasure against orthostatic intolerance. On the other hand, if the Space Shuttle is being used to return crewmembers from the ISS, the time between the last use of LBNP and landing can be several days depending on the mission plan after the Shuttle undocks from the ISS. Findings obtained from Extended Duration Orbiter Medical Project investigations with Shuttle crews suggest that LBNP may not be effective unless it is conducted within 4 h of landing [7]. The hope is that when ISS construction is complete, more prospective controlled studies will be performed to better understand operational protocols such as the “soak” countermeasure, which combines LBNP and fluid-loading. This countermeasure is mandatory for cosmonauts; however, it is optional for all remaining ISS crewmembers because it has yet to be standardized. Given the risk of LBNP to induce presyncope and syncope under nominal circumstances, ECG telemetry and continuous air-to-ground voice communications are required during portions of the LBNP ramp test when the decompression is less than about 0.5 psi (26–30 mmHg). A second crewmember is required to remain nearby during all LBNP operations while the first crewmember is in the LBNP device [201,347]. This second crewmember serves as the test operator, assisting his or her crewmate during depressurization and exit from the device as needed, e.g., during rapid egress or if the crewmate becomes incapacitated. If the ramping must be stopped because of reaching one or more termination criteria (Table 16.5), the LBNP device will be recompressed to ambient pressure. Both the Chibis and the U.S. LBNP device have a “dead-man” switch, held by the subject, which allows rapid repressurization to cabin atmosphere in the event of syncope. It is interesting to note the investigations of Convertino et al. [348–350] which found an increase in stroke volume on subjects undergoing LBNP (60 mmHg) using an “impedance threshold device” (ITD). The ITD acutely increases central blood volume by making the mean thoracic pressure negative with respect to the

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Table 16.5. Termination criteria for lower-body negative pressure ramp operations. Termination criteria g g g g

s s s

g

s s s

g

s

Drop in heart rate > 15 beats per minute in 1 min Drop in blood pressure (either a systolic drop > 25 mmHg or a diastolic drop > 15 mmHg in 1 min) Systolic blood pressure ≤ 70 mmHg Any of the following significant cardiac arrhythmias: • Heart rate < 40 bpm for person whose resting heart rate is > 50 bpm • Three or more beats in a row of supraventricular or ventricular tachycardia • Evidence of heart block other than first degree • Premature ventricular complexes (PVCs) that meet any of the following criteria: • ≥6 PVCs in 1 min • PVCs that are closely coupled (qr/qt < 0.85) • PVCs that fall on the T wave of the preceding beat (R on T phenomena) • PVCs that occur in pairs or in runs • Multiform PVCs Severe nausea, clammy skin, profuse sweating, lightheadedness, tingling, dizziness Subject request at any time Loss of ECG monitoring at the surgeon’s console or voice downlink during portions of ramp protocols below 30 mmHg of decompression (−40 mmHg and −50 mmHg) Resting heart rate greater than the maximum heart rate observed during preflight presyncopal LBNP testing

Abbreviations: g, ground initiated; s, subject initiated. Source: Adapted from National Space Transportation System [347].

local atmospheric pressure. This device uses a passive valve to control the inspiratory flow as a function of thoracic negative pressure. The ITD is being proposed as an acute treatment of hemorrhagic shock on Earth and a possible post-flight orthostatic countermeasure for long- and short-duration crews.

Treatment of Cardiovascular Illness in Low Earth Orbit As ISS assembly nears completion, medical planners are anticipating the next steps in exploring space beyond low Earth orbit. Cardiovascular events have consistently been ranked as posing one of the greatest risks for short and long-duration space travel based on the “probable incidence versus impact on mission and crew health.” [351,352,353] NASA’s Medical Policy Board, which considers cardiovascular abnormalities a medical problem likely to be encountered during exploration-class missions, has established a design requirement for stabilization and effective timely treatment in addition to the requirement for stabilization and evacuation of seriously ill or injured crewmembers [93,305]. This medical event management strategy is similar to the emergency medical support plans for injured workers on an offshore oil platform or other remote location that involves occupational environmental hazards. Acute myocardial infarction is considered the prototypic cardiovascular problem for which required medical capabilities are defined. On Earth, ~7% of patients admitted to a hospital with an acute myocardial infarction experience cardiogenic shock [354]; 50% of these patients are in shock at the time of admission, and the remainder develop symptoms within 48 h [355]. Cardiogenic shock after an acute myocardial infarction is usually precipitated by a reduction in LV function secondary

to infarction of the left ventricle (79%) or right ventricle (3%), papillary muscle dysfunction (7%), or ventricular septal rupture (4%) [355,356]. Randomized controlled trials of patients with acute myocardial infarction on Earth have shown that oral aspirin [357,358], thrombolytic therapy [359–361], angiotensin-converting enzyme inhibitors [362–364], early percutaneous transluminal coronary artery angioplasty [365,366], and beta-blocker therapy [367] can decrease mortality if applied emergently in a hospital setting. Studies have also shown that low-molecular-weight heparin and platelet glycoprotein IIB/ IIIA inhibitors have been effective for managing acute coronary syndromes [368–373]. Therapies such as these may be the only way of dealing effectively with ischemic syndromes and myocardial injury during orbital space flight because definitive therapy is currently impossible aboard those vehicles. A review of the equipment and procedures required to deliver this type of emergent health care on Earth is beyond the scope of this chapter; however, suffice it to say that this capability is not required in the current medical system on board the ISS. Outcome studies have shown that the risk of mortality from an acute myocardial infarction can be reduced if the patient is given therapies such as those noted above within 4–24 h [357–367]. If mitigation of cardiovascular mortality and morbidity risk is a requirement for crewmembers currently slated for ISS missions, then the prompt transport of these patients to a tertiary medical care facility on Earth within 24 h is the only means of accomplishing this. The medical resources aboard the ISS were designed to treat minor illness and to transport crewmembers that require advanced medical care. The current Integrated Medical System (IMedS) has two components, the U.S. segment Crew Health Care System and the Russian medical system. The IMedS was designed to include ways of resuscitating crewmembers through

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the use of procedures and hardware similar to those used in the American Heart Association’s Advanced Cardiac Life Support training. Most of the Advanced Cardiac Life Support capability comes from the Crew Health Care System portion of the IMedS, which contains a pacing defibrillator, a 100% O2-only transport ventilator, and an advanced life support pack that contains the cardiac drugs and equipment needed for resuscitation. With these resources, an unconscious crewmember could be intubated and external cardiac pacing administered as necessary; however, performing these procedures on a conscious patient in severe respiratory distress would be quite challenging for a CMO who is not a physician [374–380]. The unique environment of microgravity combined with the habitational design of the ISS require that affected crewmembers be electrically isolated from the vehicle with a crew medical restraint system before any defibrillating shock is delivered. This restraint system, described further in Chap. 4 (Space Flight Medical Systems), has been validated on the Space Shuttle and in parabolic flight aboard the KC-135; results of these tests indicate that non-physician crewmembers and test personnel can deploy and deliver the first defibrillation shock within 2 min of “calling a code.” Whether cardiac drugs in common use on Earth [381] would be effective during a resuscitation in space flight needs to be examined in light of the changes experienced by the cardiovascular and other physiological systems during space flight [325,326]. The decision to include aggressive life-saving measures in the IMedS design was based on findings from terrestrial paramedic and hospital-based advanced cardiac life support. On Earth, advanced cardiac life support capability is designed around the ability to transport a patient to a definitive care facility in time to deliver advanced emergency medical care [382]. Although the Crew Health Care System portion of the IMedS was designed to stabilize an acutely ill crewmember for transport to a definitive care facility within 24 h, the availability of a crew return vehicle that could support a patient in that condition is still to be determined. The design of a new crew return vehicle (still in the planning stages when this chapter was written) includes the ability to provide advanced life-support capability similar to that found in most terrestrial air transport ambulances. The current ISS “lifeboat” is the Russian Soyuz spacecraft, which was not designed to provide supplemental medical care during any phase of deorbit. The inability of the crew on board the Soyuz to provide pacemaker capability, to deliver supplemental O2, or to provide any ventilation support imposes serious limitations on the transport of a critically ill patient. Also of concern are the nominal peak reentry accelerations of up to 3.8 Gx, which would stress the cardiovascular and pulmonary reserves of a disabled crewmember. CMOs, under the guidance of the ground-based flight surgeon, would therefore need to wean a patient from 100% O2 in the ISS before that patient is transferred to the Soyuz for deorbit. In most cardiovascular emergencies, many aspects of a patient’s physical examination (e.g., circulatory volume status, vital signs, level of consciousness) are important. The abil-

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ity of the Mission Control-based flight surgeon to monitor an affected crewmember during the resuscitation and stabilization phases of a medical emergency is limited by the intermittent nature of communications to the ISS, which on average are available only 50% of the time [332]. This communication may be limited to a single air-to-ground voice loop and to the rhythm strip output of the defibrillator. Blood pressure, O2 saturation, and other important critical-care information will be unavailable to the flight surgeon unless crewmembers verbally relay this information to the flight surgeon on a voice loop. As discussed previously, evaluation of a patient’s circulatory volume status in space is complicated by the physiological alterations induced by microgravity and the lack of clinical experience and training of the CMOs. The absence of classical bedside findings (e.g., jugular venous pulsations, lower-extremity fluid shifts, and probable loss of dependent venous lung zones) makes determining volume status a challenge even for a critical care specialist at the microgravity bedside, let alone for a non-physician CMO with only 12 h of training in advanced cardiac life support. Thus flight surgeons must integrate their traditional medical training and experience in terrestrial medicine with the physiology and expected pathophysiology of space flight. For example, when the principles of terrestrial cardiac pathology are used in treating an acute myocardial infarction during flight, increased shortness of breath and the presence of diffuse pulmonary crackles can indicate extremely elevated pulmonary venous pressures and diastolic failure secondary to significant systolic failure or papillary muscle dysfunction. The concept of euvolemia is different in microgravity from that on Earth, and the physical findings indicative of abnormal volume status are currently unknown. The increase in venous capacitance secondary to microgravity exposure may allow the patient to “buffer” significant volumes of fluid before right-sided heart failure manifests itself. From a space-medicine clinical perspective, this may mean that the amount of central venous volume required to increase left atrial pressure to levels that induce pulmonary edema is greater in microgravity than on Earth, thereby possibly providing a protective effect on the lungs. This potential physiological advantage may be negated, however, by the fact that in microgravity, all regions of the lung may be susceptible to pulmonary edema at the same time because of the loss of dependent pulmonary venous zones. The ability to classify the severity of heart failure according to terrestrial categories such as Killip class, which is based on the degree of alveolar flooding (crackles) detected during pulmonary auscultation, may not be possible in microgravity. When patients on Earth have basilar crackles secondary to high-pressure pulmonary edema from CHF, the mid-lung pressure is ~20 cm H2O, which means that the pressure at the bases is about 30 cm H2O. Under microgravity conditions, pulmonary venous pressure will probably need to increase to 30 cm H2O to cause global alveolar flooding. However, when this occurs in microgravity, the auscultation of crackles anywhere in the thorax may be a harbinger of fulminant

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pulmonary edema that does not increase gradually with time, as would be the case on Earth, but rather may appear suddenly without warning. Detection of the early signs and symptoms of pulmonary edema may be essential to effective treatment in microgravity, given its potential to be acutely life-threatening [383–385]. The physical signs indicative of pulmonary venous pressures of 30 cm H2O in a patient in microgravity are unknown. The microgravity-induced cephalad fluid shifts and changes in lower-extremity intravascular volume may render use of a venodilator (e.g., nitroglycerin) ineffective in the immediate treatment of pulmonary edema [249,251]. Phlebotomy, LBNP, or thigh cuffs [215,386] to induce lower-extremity venous pooling and to reduce LV end-diastolic pressure may be more effective for treating CHF on orbit. The physical sign of CHF after several days of exposure to microgravity might be the appearance of non-edematous, volume-overloaded lower extremities that look normal by terrestrial standards but that are clearly larger than the normal “chicken legs” appearance in microgravity. In general a patient requiring cardiac critical care in microgravity should be considered to be similar to one on Earth in a critical care unit bed placed in 6 degree head down tilt [387]. Flight surgeons may need to assess acute changes in circulatory volume status by means of calf circumference measurements. A device that uses anthropometric landmarks at several points on the leg to measure calf circumference is manifested on the ISS. Calf circumference is usually measured every 2 weeks as a way of tracking calf muscle loss, but these measurements could also provide a baseline from which to follow acute changes in leg volume in the event of CHF. Changes in circulatory volume status might also be detected by measuring acute changes in body mass, which may reveal an unappreciated change in venous volume. A crewmember who must be returned to Earth after inflight treatment of respiratory distress secondary to an acute myocardial infarction may experience significant exacerbation of CHF during the reentry Gx acceleration experienced in the legs-up recumbent position in the Soyuz spacecraft. The CHF in such a crewmember may dramatically improve upon being given 100% O2 by mask and being placed in an upright seated position in a padded chair outside the spacecraft after landing. This simple maneuver alone may take advantage of the reduced intravascular volume incurred by long-duration microgravity exposure; that reduced volume should acutely drop the preload to the heart when the crewmember first stands despite the myocardial-infarction-induced CHF in microgravity. In this case, the cardiac deconditioning incurred by microgravity along with the terrestrial 1-Gz loading of the venous system may provide the same benefit as administering nitroglycerin and a mild beta blocker to a patient after a myocardial infarction on Earth. Flight surgeons must make real-time clinical decisions on the basis of limited telemetry data and unskilled observations

D.R. Hamilton

reported by the CMO. This information must then be used to guide the CMO in preparing the patient for transfer into the Soyuz escape vehicle and eventual deorbit. Flight surgeons must also be able to communicate the diagnosis and prognosis of the affected crewmember to the flight director and the mission management team. The ability to return a crewmember from the ISS to one of several possible primary landing sites in Kazakhstan or Russia with the Soyuz escape vehicle is limited to approximately three consecutive orbits every 24 h. Depending on the crewmember’s illness, it is questionable if enough onboard medical resources exist to stabilize a patient for this length of time. The timing of the next primary landing site opportunity could also require that a patient be transferred to the Soyuz rapidly, within 1 h from the onset of the initial emergency; otherwise, the next landing opportunity would be delayed by an additional 24 h. For a Soyuz landing, Mission Control in Moscow maintains control of vehicle operations. All communications are conducted with the very high frequencies that are not used by U.S. space-to-ground systems. Therefore, all medical communications will be handled by the Russian Medical Support Group. All medically relevant voice communications will need to be relayed by the Russian Medical Support Group to the lead flight surgeon in the U.S. Mission Control Center. Once the Soyuz has undocked from the ISS, it must “loiter” for two orbits (~3 h) before it re-enters and lands at a nominal landing and recovery site in Kazakhstan. While the Soyuz spacecraft is in orbit, the Russian ground medical officer will be able to communicate with the crew less than 20% of the time. If returning to the ground is time-critical, the Soyuz is capable of deorbiting within 45 min onto several emergency landing sites distributed throughout the world, including the continental U.S., but expedited deorbits such as these would expose the crews to gravity loads in excess of +8 Gx, which could strain an already seriously compromised cardiopulmonary system. Flight surgeons will need to decide whether an affected crewmember would be better served by exposure to 8 Gx in an expedited deorbit so as to reach a tertiary care facility within 8–12 h from the beginning of the cardiac event or by waiting as long as 24 h for a 3.8-Gx exposure and potentially deorbiting to a desolate part of Kazakhstan and incurring the increased risk of mortality during this time [388]. The parameters driving this decision are still more complex because the decision may need to be made in real time by the flight director, flight surgeon, and mission commander without the benefit of external expert consultation.

Treatment of Cardiovascular Illness on Exploration-Class Missions Crews on exploration-class missions will obviously be limited in their ability to transport an acutely ill crewmember

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to a definitive care facility on Earth. Another problem with the emergent treatment of acute cardiac disorders is the unpredictability of the outcome. On Earth, patients with potentially fatal yet treatable respiratory distress or a arrhythmia have been resuscitated successfully; thus aggressive resuscitation measures should always be considered for a disabled crewmember given the general excellent health of crewmembers as a group. Yet another problem in providing advanced cardiac and trauma critical care on very remote missions is the possibility that a patient-crewmember may require long-term and comprehensive care after surviving the initial medical emergency. The design of the medical facilities that will be needed to mitigate cardiovascular illness (and other medical contingencies as well) on an exploration-class mission thus must be based on the overall level of medical risk that the space program designers are willing to accept [76,389]. Obviously, prevention of illness should be the primary goal in selecting a crew for an exploration mission and maintaining the health of that crew. Nevertheless, treatment of chronic cardiovascular illness on an extended-duration mission may compromise the primary objectives of that mission. Designers of a medical care facility for an explorationclass mission must consider the resources needed to manage a chronically ill patient for the duration of a mission. Treatments for cardiovascular conditions that require acute therapy (thrombolytics [359–361,390], ventilator support, or others [391]) or chronic therapy (anticoagulation [357,358,392] or antihypertensives) [362–364,367,393,394] must be balanced against the mass, volume, and logistics that providing these treatments would require. The cardiovascular deconditioning and fluid loss associated with microgravity (and perhaps with one-third gravity or one-sixth gravity) may impair a crewmember’s response to a hypovolemic challenge such as hemorrhagic shock [254]. It is possible that the inability of the body to mount an appropriate response to shock may decrease survival under such extreme conditions even further. New concepts for the treatment of cardiogenic, hypovolemic, or septic shock need to be considered for these types of missions [198,254]. On the first planned long-duration mission to Mars, a crewmember experiencing an acute myocardial infarction who survived the initial event would probably be attended by a CMO and the remaining crewmembers, which could well prevent these individuals from performing payload activities or otherwise compromising the original mission objectives. Depending on the timeline, treatment in such circumstances may require a mission abort and an expedited return to Earth (not an option). If the risk is high that a certain cardiovascular event would require extensive treatment and crew resources, mission planners must decide to mitigate that risk or accept the possible consequences [389]. This decision process will establish the medical philosophy (e.g., necessary training for the flight surgeon and crew, selection standards) and mission

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resources (e.g., mass, volume, power) required to mitigate the potential effects of a cardiovascular problem on explorationclass missions. The cardiovascular selection criteria for a crew that will be assigned to an exploration-class mission must rule out existing abnormalities and minimize the risk of future abnormalities to the extent possible with current technology. This process represents a significant challenge for flight surgeons in terms of preventing and treating cardiovascular abnormalities. Most large-vessel coronary vascular diseases are not symptomatic until stenosis of the vessel reaches about 70% or 80%. How would a flight surgeon develop the criteria to determine what degree of coronary stenosis would disqualify a crewmember for a 3-year Mars mission that is launching 10 years from now—a determination that will be made at the time of final selection of the crew? An important factor to consider would be the risks associated with invasive screening and diagnostic procedures such as angiography. Should a flight surgeon suggest that a candidate for a particular crew be evaluated for atherosclerosis of other organs on the basis of coronary angiography findings? Would that flight surgeon use invasive tests such as these for selecting crewmembers for a lunar mission, where evacuation to Earth may take only 2 days but would incur significant cost and risk to others? Unless cardiovascular diagnostic and prognostic technology advances significantly during the next 10 years, flight surgeons will find it very difficult to rule out the possible appearance of cardiac disease in a crewmember slated for a mission in which expedited return to Earth is impossible and the mission is to last 3 years. Newer noninvasive technologies such electron-beam and fine-slice spiral CT may hold promise in that their PPVs are better than those of current invasive diagnostic methods for determining calcium burden and ruling out future significant cardiovascular abnormalities. In selecting a crew for an exploration-class mission, the question posed by the flight surgeon should focus on what constitutes a significant cardiovascular abnormality for the mission. Although new tests may be more sensitive in detecting coronary calcium load and possible stenosis, the process by which subclinical CAD progresses to an overt cardiac event remains unknown. If we decide to travel to Mars before 2015, our ability to prevent significant cardiovascular events during a 3-year mission may be no better than it is today unless more prospective data can be collected on subclinical cardiovascular abnormalities and their natural history. Cardiovascular selection and screening for a Mars mission will probably require a long-term approach. A cadre of Mars mission candidates may need to be selected several years in advance of the mission. Any minor cardiovascular abnormalities revealed during the selection process, if not immediately disqualifying, should be followed up over time. Because no data currently exist to guide flight surgeons in diagnostic dilemmas such as these, the natural history of the disease may need to be inferred on the basis of an invasive prospective

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diagnostic approach, which may precipitate medical complications that could disqualify a crewmember. Future advances in noninvasive diagnostic methods to prevent this from happening are fervently sought.

gravity on biological systems. One hopes that humankind will use this precious resource to unlock the gravitational enigma of the cardiovascular system before reaching out in earnest to explore beyond earth orbit [396].

Conclusions

Acknowledgment. I thank the following people who helped edit this manuscript: Drs. Alec Navinkov, Bojana Djordjevic, John Tyberg, John B. Charles, Kira Bacal, Jean-Marc Comtois, Gary Gray, P. Vernon McDonald, Victor Hurst, Smith L. Johnston, Andrew Kirkpatick, Hal Dorr, Thomas Marshburn, Jay Buckey; Mike Barratt; Mr. George Beck; Mr. Ben Voigt; and Ms. Genie Bopp.

Flight surgeons face real challenges in the prevention, detection, and treatment of cardiovascular disease in space crewmembers. The delivery of cardiovascular care in low Earth orbit and future exploration-class missions requires an aggressive preventive medicine approach [395]. As the international space programs move into a new era of interplanetary travel, diagnostic and treatment capabilities in space will be essential to mitigate the risks of extreme cardiovascular deconditioning, overt illness, or novel microgravity-induced cardiovascular abnormalities. Such medical problems are most likely to arise on long-duration space flights, which will invariably be characterized by less-predictable mission parameters, communications delays, and the impossibility of an emergency return to definitive care facilities on Earth. Subclinical, asymptomatic cardiovascular abnormalities that might be discovered in a spaceflight crew or aviator cohort do not seem to carry the same prognosis or natural history as in standard clinical populations. This disconnect imposes a significant responsibility on flight surgeons, who must strive to maintain the flight-readiness status of a limited number of extensively trained crews who may be candidates for low Earth orbit missions ranging from 10 to 100 days and for exploration class missions lasting 1,000 days. Given the limited positive and negative predictive value of present cardiovascular diagnostic technology, flight surgeons must apply very conservative standards for selection and continued flight-readiness status. Long-term studies that use future noninvasive cardiac screening methods for detecting subclinical abnormalities may provide solutions to the dilemma of having to be overly conservative with a very healthy cohort. The limited ability of current diagnostic technology to predict or prevent the occurrence of cardiovascular disease in this very specialized cohort before and during space flight requires that risk mitigation, in the form of treatment, be considered in the overall context of designing short- and long-duration missions. Requirements that define the means to treat only a select few cardiac events may not be enough to mitigate cardiovascular illness and to minimize the effects of such illness on the mission. Because the diagnosis, prognosis, and appropriate treatment of cardiovascular illness in space is not entirely predictable, the medical knowledge and systems used to treat patients in space may need to be applied in a creative fashion. Millions of years of evolution have led to the development of robust and highly adaptive cardiovascular systems for organisms living on Earth. The ISS provides a unique platform from which to observe the long-term effects of altered

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357 342. Tripp LD, Jennings TJ, Seaworth JF, et al. Long-duration +Gz acceleration on cardiac volumes determined by two dimensional echocardiography. J Clin Pharmacol 1994; 34:484– 488. 343. Güell A, Braal L, Gharib C. Cardiovascular deconditioning during weightlessness simulation and the use of lower body negative pressure as a countermeasure to orthostatic intolerance. Aviakosm Ekolog Med 1990; 33:S31–S33. 344. Egorov A, Anashkin O, Itsehovsky O, et al. Results of medical investigations obtained during a 125-day flight on Salyut-7/Mir Orbital Stations. Physiologist 1988; 31:S-1–S-3. 345. Gazenko OG, Shulzhenko EB, Turchaninova VF, et al. Central and regional hemodynamics in prolonged spaceflights. Acta Astronaut 1988; 17:173–179. 346. Watenpaugh DE, Ballard RE, Breit GA, et al. Self generated lower body negative pressure. Aviat Space Environ Med 1999; 70:522–526. 347. National Space Transportation System. ISS Generic Operational Flight Rules. Houston, TX: NASA–Johnson Space Center; 2000; 12820: B: Section 13, Aeromedical. 348. Convertino VA, Cooke WH, Lurie KG. Inspiratory resistance as a potential treatment for orthostatic intolerance and hemorrhagic shock. Aviat Space Environ Med 2005 Apr.; 76(4): 319–325. 349. Convertino VA, Ratliff DA, et al. Effects of inspiratory impedance on hemodynamic responses to a squat-stand test in human volunteers: Implications for treatment of orthostatic hypotension. Eur J Appl Physiol 2005; 94:392–399. 350. Convertino VA, Ratliff DA, et al. Hemodynamics associated with breathing through an inspiratory impedance threshold device in human volunteers. Crit Care Med 2004; 32(9 Suppl): S381–S386. 351. Billica RD, Simmons SC, Mathes KL, et al. Perception of medical risk of spaceflight. Aviat Space Environ Med 1996; 67:467–473. 352. Committee on Space Biology and Medicine Space Studies Board, National Research Council. (A Strategy for Space Biology and Medical Science.) Washington, DC: National Academy Press; 1987. 353. Task Group on Life Sciences, Space Studies Board, National Research Council. Space Science in the Twenty-First Century, Imperatives for the Decades 1995 to 2015.Washington, DC: National Academy Press; 1988. 354. Goldberg RJ, Samad MA, Yazebski J, et al. Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 1999; 340:1162–1168. 355. Hasdai JS, Califf RM, Thompson TD, et al. Predictors of cardiogenic shock after thrombolytic therapy for acute myocardial infarction. J Am Coll Cardiol 2000; 35:136–143. 356. Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction: Etiology, management and outcome: A report from the SHOCK Trial registry. J Am Coll Cardiol 2000; 36:1063–1070. 357. Mant J, Fitzmaurice D, Murray E, et al. Long term anticoagulation or antiplatelet treatment. inclusion criteria determine results of review. BMJ 2001; 323:233–234; discussion 235–236. 358. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 12:3A–13A.

358 359. French JK, Hyde TA, Patel H, et al. Survival 12 years after randomization to streptokinase: The influence of thrombolysis in myocardial infarction flow at three to four weeks. J Am Coll Cardiol 1999; 34:62–69. 360. Collins R, Peto R, Baigent C, et al. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 1997; 336:847–860. 361. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993; 329:673–682. 362. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: Systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998; 97:2202–2012. 363. Domanski MJ, Exner DV, Borkowf CB, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999; 33: 598–604. 364. Latini R, Tognoni G, Maggioni AP, et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: Systematic overview of individual data from 96,712 randomized patients. Angiotensin-Converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol 2000; 35:1801–1907. 365. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review. JAMA 1997; 278:2093–2098. 366. Cucherat M, Bonnefoy E, Tremeau G. Primary angioplasty versus intravenous thrombolysis for acute myocardial infarction. Cochrane Database Syst Rev 2000; 2:CD001560. 367. Freemantle N, Cleland J, Young P, et al. Beta blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ 1999; 318:1730–1737. 368. Cohen M, Blaber R, Demers C, et al. The Essence Trial: Efficacy and safety of subcutaneous enoxaparin in unstable angina and non-Q-wave MI: A double-blind, randomized, parallelgroup, multicenter study comparing enoxaparin and intravenous unfractionated heparin: Methods and design. J Thromb Thrombolysis 1997; 4:271–274. 369. Cohen M, Demers C, Gurfinkel EP, et al. Low-molecular-weight heparins in non-st-segment elevation ischemia: The ESSENCE Trial. Efficacy and safety of subcutaneous enoxaparin versus intravenous unfractionated heparin, in non-Q-wave coronary events. Am J Cardiol 1998; 82:19L–24L. 370. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events study group. N Engl J Med 1997; 337:447–452. 371. Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: One-year results of the ESSENCE study. Efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events. J Am Coll Cardiol 2000; 36:693–698. 372. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial

D.R. Hamilton Investigators. Platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy. N Engl J Med 1998; 339:436–443. 373. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) Study Investigators. N Engl J Med 1998; 338:1488–1497. 374. Beck G, Pettys R, Smith L. After Action Report. Evaluation of Endotracheal Intubation Methods in Microgravity. Unpublished report, NASA–Johnson Space Center, Houston, TX; 2001 May. 375. Keller C, Brimacombe J, Giampalmo M, et al. Airway management during spaceflight: A comparison of four airway devices in simulated microgravity. Anesthesiology 2000; 92:1237–1241. 376. Bishop MJ, Michalowski P, Hussey JD, et al. Recertification of respiratory therapist’s intubation skills one year after initial training: An analysis of skill retention and retraining. Respir Care 2001; 46:234–237. 377. LeJeune FE. Laryngeal problems in space. Aviat Space Environ Med 1978; 49:1347–1349. 378. Bradley JS, Billows GL, Olinger ML, et al. Prehospital oral endotracheal intubation by rural basic emergency medical technicians. Ann Emerg Med 1998; 32:26–32. 379. Li J, Murphy-Lavoie H, Bugas C, et al. Complications of emergency intubation with and without paralysis. Am J Emerg Med 1999; 17:141–143. 380. Sayre MR, Sakles JC, Mistler AF, et al. Field Trial of endotracheal intubation by basic EMTs. Ann Emerg Med 1999; 31:228–233. 381. Raymondos K, Panning B, Leuwer M, et al. Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease. Ann Intern Med 2000; 132:800–813. 382. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 382:2941–2947. 383. Pomerantz M, Baumgartner R, Lauridson J, et al. Transthoracic electrical impedance for the early detection of pulmonary edema. Surgery 1969; 66:260–268. 384. Ebert TJ, Smith JJ, Barney JA. The use of thoracic impedance for determining thoracic blood volume changes in man. Aviat Space Environ Med 1986; 57:49–53. 385. Gotshall RW, Davrath LR. Bioelectric impedance as an index of thoracic fluid. Aviat Space Environ Med 1999; 70:58–61. 386. Frey MA. Space research activities during missions of the past. Med Sci Sports Exerc 1996; 28:S3–S8. 387. Hamilton DR, Gloss D. Cases in space medicine. Aviat Space Environ Med 2004; 75(3):288–292. 388. Lauer MS. Primary angioplasty—time is of the essence. JAMA 2000; 283:2988–2989. 389. Williams DR, Bashshur RL, Pool SA, et al. A strategic vision for telemedicine and medical informatics in spaceflight. Telemed J E Health 2000; 6:441–448. 390. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction. JAMA 2000; 283:2686–2692. 391. Hochman JS, Sleeper LA, White HD, et al. One-year survival following early revascularization for cardiogenic shock. JAMA 2001; 285:190–192.

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359 394. Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001; 285:430–436. 395. Davis JR. Medical issues for a mission to Mars. Aviat Space Environ Med 1999; 70:162–168. 396. Barratt M. Medical support for the International Space Station. Aviat Space Environ Med 1998; 70:155–161.

17 Neurologic Concerns Jonathan B. Clark and Kira Bacal

Among other functions, the neurological and neurovestibular systems serve to support positional awareness and motor control. Because gravitational cues and visual references play a role in this support, it is not surprising that the spaceflight environment profoundly influences static and dynamic positional sense and subsequent motor function. Human adaptation to this unique environment is being investigated to understand how performance may be optimized in every flight phase. Proper neurovestibular function ensures spaceflight crew safety in the complex and unfamiliar visual and motion milieu of microgravity and because of reliance on mechanical display information, enhances ability to operate a vehicle safely. The neurovestibular system creates a consistent, conscious map of head and body orientation as well as an internal orientation reference that will correct for absent or erroneous visual and somatosensory systems. It primarily stabilizes the eyes (the visual system) by means of (1) the vestibular ocular reflex, which is related to maintaining a stable world during movement; and (2) the vestibular spinal reflex, which preserves body alignment and establishes an appropriate relationship between the head and body. The character of the vestibular and visual systems’ interaction depends on a specific task or relevant operational requirement. For example, whereas a crewmember depends on the visual vestibular ocular reflex to track a stationary target while turning, that same individual suppresses the vestibular ocular reflex when tracking a headfixed target, such as a head-mounted display, while turning. A person’s pursuit system (slow eye movement) is used to track and identify moving objects, and the saccade system (fast eye movement) is necessary to acquire objects in the peripheral visual field and scan instruments. Visually induced optokinetic nystagmus occurs when a person views a moving background. This adds to the optical data that generates a sense of speed over terrain. During initial adaptation to microgravity, spaceflight crewmembers experience conflict between the linear acceleration

detectors (otolith organs) and other sensory systems affected by position. Motion disrupts oculomotor control, which compromises the retina’s ability to hold an image still or to shift gaze to another object in a controlled fashion. This could potentially adversely affect crucial activities on orbit, such as rendezvous and docking, robotic arm operation, and extravehicular activities. Crucial activities during the landing phase of the Space Shuttle, which lands like a conventional aircraft, include switch throws, vehicle controller inputs, and acquisition of visual information from cockpit instruments and terrestrial landing aids. Oculomotor dysfunction could compromise these activities after prolonged space flight or while the crew is in a visually deficient environment when such problems are more likely to occur. The corrective eye movements (saccades) necessary to compensate for oculomotor disruption to reacquire the target can significantly delay reaction time. Prior spaceflight experience would be expected to reduce this effect based on the sensorimotor learning and the observation of reduced incidence and severity of motion sickness that occurs in veteran space flyers. Specific types of eye movement impairment related to spaceflight include alterations in eye-head coordination, target tracking, and optokinetic reflex function [1–3]. Sensory illusions include misperception of location and directional cues due to loss of spatial orientation and motion-generated spatial and temporal visual illusions [4]. Sensorimotor alterations include a postflight decrement in postural control and locomotion as well as disruption in the head-trunk coordination related to the modification of vestibulospinal reflex function and proprioceptive function [5]. Transition problems experienced by crews during readaptation to earth gravity (g) may manifest as a near-instantaneous return to the microgravity adaptive state, or “g state flashback”. This phenomenon could lead to sudden motor control dysfunction and increased visual dependency after gravity state transitions [6]. Specific operational problems associated with the neurological effects of spaceflight are discussed in the next section.

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Operational Concerns due to Neurologic Adaptation Manual Control of Spacecraft Reentry and Landing Alterations in eye-head coordination and the sensory illusions of crews in microgravity might lead to difficulty reading flight instruments and checklists, interpreting ground-based landing aids, estimating altitude, and making gaze transitions inside and outside the spacecraft cockpit. Analysis of Space Shuttle pilot landing performance following missions of 5 to 18 days’ duration has suggested an inverse correlation between mission duration and the accuracy of landing speed, position, or touchdown vertical velocity [7]. In a sensorimotor control study conducted on four mission specialists before and after a 14-day Shuttle flight, subjects were tasked with maintaining a normal upright position while they were seated in a modified Link aircraft trainer [8]. The trainer was configured with a motor that would tilt the cockpit as much as 12 degrees laterally left or right in the roll plane (1 degree-of-freedom) at up to 10 degrees per second at frequencies of 0.014 to 0.668 Hz. Manual corrective control inputs, which were made with a control wheel, were tested in the dark and with visual surround feedback. The crewmembers tested preflight showed no test session learning effect and were able to null motion at low frequencies (<0.25 Hz) in both dark and visual feedback conditions. Two crewmembers tested in the dark within hours after landing were unable to control tilt orientation as well as they had preflight (20% to 50% worse performance on normalized root mean square error). In this example, the first crewmember had returned to normal by one day after landing (R+1), and the second crewmember had returned to normal by two days after landing (R+2). When accurate visual cues were present, the crewmembers tested in the immediate postflight period were able to null low-frequency tilt and showed no decrements as compared to their preflight performance, demonstrating the heavy reliance on visual cues postflight. There is also concern about possible sensorimotor control problems associated with the interaction between neurovestibular effects and high workload with crew fatigue. This concern is subjectively corroborated by postflight debriefs of returning crewmembers. The profound fatigue associated with motion sickness has been termed Sopite syndrome.

Extravehicular Activity (EVA) Sensory illusions during EVA may cause outside suited crewmembers to become disoriented and provide incorrect inputs to the robotic arm (the remote manipulator system, or RMS) operators during joint EVA–RMS operations. Such complex operations—requiring high-level coordination between direct crew visual observations, camera views, and control system feedback—are common with International Space Station (ISS) assembly and maintenance tasks. EVA

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missions on planetary surfaces, i.e. within a gravitational field following a period of prolonged weightlessness during transit, would also be a potential problem, as the majority of crewmembers experience clumsiness in their movements in the postflight period following Earth return [9]. It may be prudent to delay surface EVAs for a few to several days following long periods in weightlessness until adequate adaptation has taken place.

Rendezvous and Docking, Robotic Operations Crewmembers who are performing rendezvous and docking between spacecraft and RMS operations rely on visual information to execute appropriate motor control inputs. Neurovestibular dysfunction may result in inappropriate commands and controller inputs, although these activities are performed frequently with success. Historically, neurovestibular dysfunction may have been partially implicated in the Russian space station Mir-Progress resupply vessel collision and in a satellite being bumped during a capture attempt by the Shuttle’s robotic arm.

Post-Bailout Motion Sickness Simulation exercises involving astronauts have been conducted to evaluate the emergency scenario of bailing out from the Space Shuttle during entry and landing, then awaiting recovery in life rafts on an open ocean for several hours. In these drills, some crewmembers become seasick even in mild sea swells. It is anticipated that when performing an over-water bailout after spaceflight, crewmembers who had been very recently adapted to a microgravity environment will experience motion sickness that could lead to decreased performance and efficiency in a survival situation. This might adversely affect survival (dehydration, electrolyte depletion, inability to perform self-rescue maneuvers), particularly if recovery is prolonged beyond several hours. The Apollo spacecraft landed in water on a parachute system. Nine of 25 Apollo crewmembers experienced seasickness post-egress or prior to egress during recovery. To reduce the incidence of motion sickness following landing, pharmacological interventions may prove useful, as they did for some Skylab crewmembers. Two of the 9 Skylab astronauts, on the first crewed flight, were seasick in their capsule after landing, and the last 6 Skylab crewmembers took anti-motion-sickness medication before landing [10]. After the 28-day Skylab 2 mission (May 25–June 22, 1973), the command module landed and remained upright in a heavy sea. None of these crewmembers took anti-motion-sickness drugs before entry. Although the commander experienced no seasickness, the pilot and scientist pilot experienced mild and severe symptoms, respectively. Prior to the splashdown of the 58-day Skylab 3 command module (July 28–September 25, 1973), the crew had taken anti-motion-sickness drugs (scopolamine/dextroamphetamine sulfate), and although the sea

17. Neurologic Concerns

state was twice as heavy as the one to which the Skylab 2 crew had been exposed, the symptoms did not occur. All of the Skylab 4 (November 16, 1973–February 8, 1974) crewmembers took the same anti-motion-sickness drugs and were symptom-free during recovery at sea [10]. This suggests that anti-motion sickness medications should be available to crews after an overwater bailout as part of the survival kit.

Unaided Vehicle Egress Decrements in postural and locomotor control, along with motion sickness, may lead to impaired egress ability, including difficulty in leaving the seat (getting out of restraints), moving to the hatch, and moving away from the Shuttle or Soyuz in an emergency or performing post-landing duties. Findings based on crew assessment by attending flight surgeons at Space Shuttle landings estimate that approximately 5% of crewmembers returning from short duration flights of 18 days or less would be unable to perform a nominal egress at the side hatch, in large part due to neurovestibular impairment. In an off-runway contingency where side hatch egress was unavailable, approximately 15% of crewmembers would be unable to perform the more difficult egress through the overhead emergency escape hatch. Along with neurovestibular factors, orthostatic intolerance and muscular strength issues may also contribute.

Neurological Dysfunction Associated with Spaceflight Adaptation Motion Disturbances The primary clinical manifestations associated with neurological changes during spaceflight are space motion sickness (SMS) and postflight neurovestibular symptoms. SMS, which is the form of motion sickness associated with microgravity, is a subset of space adaptation syndrome. Since SMS is only weakly correlated with the motion sickness associated with ship or air travel, or with symptoms upon exposure to rotation or parabolic flight, prediction of its occurrence in first-time flyers is difficult (Chapter 10). Experiencing SMS during spaceflight is not protective against or predictive for terrestrial motion sickness after flight, nor is it associated with presence (or absence) of postflight neurovestibular symptoms [9]. Spaceflight experience is somewhat protective against SMS on subsequent flights, as the incidence is less among repeat flyers than first time flyers. Nausea is a frequent component of in-flight SMS, as well as postflight symptomatology. Postflight nausea is seen more frequently in female crewmembers, but gender has not been found to be associated with any of the other neurovestibular symptoms seen after space flight, nor have age, mission duration, previous spaceflight experience, or in-flight SMS been associated with any postflight neurovestibular symptoms [9].

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SMS is a frequent occurrence during the early days of spaceflight, typically effecting only minor timeline changes. However, more significant consequences have been seen. SMS caused an EVA to be rescheduled during Apollo 9 (March 3 to 13, 1969), the first in-flight timeline change due to a medical cause. No SMS occurred on the lunar surface or in the return to microgravity after lunar exploration during the Apollo missions. The Apollo 15 (July 26 to August 7, 1971) lunar module pilot experienced delayed postflight symptoms following Earth return that persisted for seven days following recovery. He perceived a 30° head-down, tilted sensation when supine and persisted when he turned onto his side. The tilted sensation was not present when he was fully awake, regardless of postural position. Positional and caloric vestibular nystagmus tests, audiometry, and otolaryngology evaluation were normal 5 days postflight [11]. Symptoms most likely attributable to SMS occurred during one Shuttle EVA with nausea and vomiting occurring in the suit during airlock repressurization. Postflight neurovestibular symptoms have been described in a variety of ways in the literature. In one review, relative frequencies of several postflight symptoms were assessed via crewmember survey. These included: clumsiness in movements (69%, n = 410); difficulty walking straight line (66%, n = 403); persisting sensation aftereffects (60%, n = 324); vertigo while walking (32%, n = 393); vertigo while standing (29%, n = 397); nausea (14.7%, n = 346); difficulty concentrating (10%, n = 284); vomiting (8%, n = 347); dry heaves (3%, n = 291); blurred vision (<2%, n = 396) [9]. The majority of respondents in this study reported only mild symptoms, though 12% and 14% (respectively) used the term “moderate” to describe their clumsiness and difficulty walking a straight line.

Acute Performance Effects with Exaggerated Spacecraft Maneuvering Disorientation and vertigo can occur with spacecraft maneuvering and may produce acute performance effects in crewmembers. Vestibular stimulation can result in nystagmus, which adversely affects a crewmember’s visual acuity during the acceleration and deceleration phases of rotation. Tracking and visual acuity are more significantly impaired while rotating in the roll plane than in the pitch or yaw plane. Nystagmus is usually greater and visual acuity worse with acceleration than with deceleration [12]. On March 16, 1966, after pilot Neil Armstrong and copilot David Scott had rendezvoused and docked their Gemini VIII spacecraft with the Agena target vehicle, they experienced a disorienting event when an uncommanded thruster firing resulted in a high spin rate and a tumbling vehicle. The Gemini orbit attitude and maneuvering system engine had erroneously fired several times, resulting in a counterclockwise roll and left yaw motion. The 25-pound-thrust engine was capable of generating acceleration of 2.5 to 3.0 degrees/second [2]. Fourteen minutes after the initial rocket engine firing, the

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astronauts undocked the two vehicles in an attempt to stop the roll. This only resulted in an increased roll rate to more than 330 degrees/second for over a minute. During the next six minutes, Armstrong and Scott performed various actions, including disabling the maneuver electronics, disengaging circuit breakers, and firing the reentry control jets. They obtained partial control 20 min after the initial roll maneuver occurred, and recovered full control 3 min after that. Because the reentry control system had been fired, an immediate abort of the mission was required. The spacecraft splashed down safely but at a landing site far from the recovery forces. As a result, Armstrong and Scott had to remain on board their spacecraft for an additional three hours. In this case, disorientation and oculomotor disturbance, as well as SMS, could have seriously impaired performance, since the astronauts had to reach over their heads to disengage the maneuvering engine circuit breakers, a move traditionally provocative of spatial disorientation [13]. When this incident occurred, the Gemini VIII crew was undertaking a first-time activity of rendezvous and docking, never before performed in the human spaceflight program. Both astronauts were rookie space flyers who had experienced microgravity for only seven hours following launch. Anxiety could have been a factor in the disorienting event, since the men had not experienced simulation of roll in microgravity. The command pilot’s heart rate was reported to be 156 beats per minute for a sustained period that could be due to response to rotational g forces or anxiety [13]. In spite of this, the crew was able to regain control of their spacecraft. Similar to the aviation environment, deleterious effects of unanticipated and exaggerated spacecraft acceleration can include disorientation, dizziness, impaired vision, nausea, and anxiety. After this incident, new recommendations for spacecraft design were implemented and supplemental considerations for astronaut selection criteria and medical screening, as well as for astronaut conditioning, were proposed. Recommendations included designing instrument displays and controls so that left-right head rotations and up-down arm motions were minimized. A similar unanticipated thruster firing resulting in an unusual attitude event occurred on Apollo 10 (May 18 to 26, 1969) during initial checkout rendezvous and docking of the command module and the lunar excursion module. This resulted from a mission control center direction for an incorrect switch setting, but the crew quickly recognized the problem and recovered from this incident.

Perceptual Effects and Illusions of Space Flight In the absence of normal gravitational, proprioceptive, and postural cues, astronauts working in microgravity rely more on their vision to maintain spatial orientation and to establish the direction of “down” than do their earthbound counterparts

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[14]. Space flyers in the confines of the relatively small Soyuz, Mercury, Gemini, and Apollo capsules rarely encountered orientation problems, but astronauts in the larger volumes of the Skylab space station or the Space Shuttle have often reported disorientation—particularly when they are unrestrained or in visually unfamiliar orientations, such as when working “upside down” in the spacecraft or when viewing another crewmember who is upside down relative to the viewer. Visual reorientation illusions, in the absence of head movements, can trigger SMS during the first several days in weightlessness and may result in delayed recurrence of space sickness. For example, EVA crewmembers may feel uncomfortable working in the Space Shuttle payload bay when the payload bay faces the Earth. EVA crewmembers working far out on a structure have occasionally reported a sensation that they might “fall off” or “fall to Earth,” which has been termed EVA acrophobia. Disorientation could contribute to navigation difficulties for crews working inside a large, multi-axis space station. On both the Russian Mir space station and the ISS, some modules connect at 90-degree angles through central nodes, with hatches potentially located in the six cardinal directions. Visiting astronauts touring Mir occasionally reported experiencing difficulty with orientation, particularly when traversing the central node. Even after spending several months in space, some Mir crewmembers reported difficulty visualizing 3-dimensional spatial relationships among the modules. Orientation on the ISS after the station has been fully assembled may prove a significant challenge since the ISS will have as many as four multi-axis nodes and numerous modules. To optimize space use on modules, equipment is mounted on walls, ceilings, and floors where it may create multiple apparent visual verticals, depending on which workstation the astronaut is using. Locations that do not have obvious floors and ceilings, such as the tunnel connecting the Space Shuttle middeck with the Spacehab module in the payload bay, are even more likely to generate disorientation. To provide a local visual frame of reference on the ISS, the deck (floor) and overhead (ceiling) are painted different colors in a scheme that has been standardized for all of the modules. Disorientation and navigation difficulties are an operational concern to crewmembers, especially when traversing modules to respond to caution and warning events. This may pose a particular difficulty in an emergency evacuation to the crew return vehicle in the event of a depressurization or fire, where visual cues may be reduced or obscured. Preflight training in a water immersion facility for EVA crewmembers and a virtualreality lab for robotics operators may enhance visual orientation memory in conditions of unfamiliar visual cues. To aid escape to the return vehicle, particularly when a rapid egress is needed in darkness, lighted directional aids and emergency exit placards have been added. Ground-based studies of orientation have been conducted in the 2.4-m (8-ft) York Tumbling Room of York University, where the subject’s gravitoinertial vector and interior

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surroundings can be independently controlled [15]. The visual scene is sufficiently compelling that many supine subjects (with respect to the gravity vector) feel upright when the visual vertical is aligned with their body axis [16]. Animal studies have shown that the brain constructs an internal spatial representation of the environment for orientation and navigation, using information related to the body’s location in the environment as well as the head’s direction in the visual environment. Visual reorientation illusions increase as a function of age, possibly related to increased dependence on visual polarity [17]. About 80% of space flyers experience perceptual illusions during or after flight, and illusion intensity is increased with flight duration [18]. These may be of several different types. Illusory self-motion, the perception that occurs when viewing a moving visual scene, is known as vection. Vection may be perceived as linear or rotational motion [19]. Illusory motions of the surrounding or stationary objects include visual streaming (blurring), visual scene oscillation (oscillopsia), object position distortion, visual axis distortion (tilting or inversion), and platform stability illusion. Elevator illusion is described as a sensation of the floor dropping when doing a squat to stand, and levitation illusion is the sensation of things floating in space. During initial adaptation to microgravity, the perception of vertical vection appears as “inverted vection [20].” This may contribute to the inversion illusion, in which crewmembers experience a sense of being upside down early in space flight. For Space Shuttle astronauts, the perception of self motion or surround motion is greatest during entry, followed by wheel stop on the runway in the landing phase, and then by actual on-orbit experience. Illusions are more often associated with pitch or roll head movements than they are with yaw head movements. Roll head movements may be perceived as a lateral translation. Larger amplitude or faster head movements are more likely to produce illusions of self or surround motion. Perceptual illusions that affect gain disturbance include altered position, amplitude, or rate after movement. These are seen with an incidence of 40% of crewmembers inflight (n = 18) and 100% of postflight crewmembers (n = 24). The intensity and duration of perceived motion during entry and landing is related to mission duration (flight duration 10 or less days), prior spaceflight experience, and increased habitable volume (more maneuverability) [21]. Temporal distortion, where the self or surround motion lags behind actual motion, occurs with an incidence of 40% inflight and 90% postflight. Path disturbance, which is the phenomenon in which angular motion elicits a perception of linear motion, occurs with an incidence of 30% during flight and 70% after flight. Astronauts on the Skylab missions reported that, with eyes closed or lights out, they lost the sense of where everything was in relation to themselves. The central nervous system (CNS) may require an “up” and a “down” in space to create an external spatial map, a perceived image of the outside world. Proprioceptive mechanisms in joints, tendons, and

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muscles that normally provide positional sense on Earth may not provide accurate limb information in microgravity. This could contribute to a loss of the internal spatial map (a normal body image). Another possibility is that dysfunction of both external and internal spatial maps results in loss of spatial orientation. Detection thresholds for linear acceleration in all three body axes were assessed on the Spacelab-1 mission (STS-9, November 28 to December 8, 1983). Preflight motion perception thresholds were higher (less sensitive) in the Z axis (0.077 m/s2 (0.253 ft/s2) ) than in the X and Y axes (0.029 m/s2 (0.095 ft/s2) ). Inflight, three crewmembers exhibited greater thresholds (less sensitivity) than they exhibited preflight, with 4.3 times greater threshold in X and Y axes, and 1.5 times greater threshold in the Z axis [22]. An astronaut’s awareness of limb and body position may be altered by motion perception changes in microgravity. Astronauts have had difficulty in positioning their legs precisely during inflight “drop tests,” in which a subject is quickly pulled “downward” by an elastic cord. In-flight self-motion perception tests revealed that early inflight drops were perceived like those preflight. Drops late in-flight were described as sudden, fast, hard, and translational. Immediately postflight drops were perceived like those late in-flight. Astronauts reporting they did not feel they were falling but rather that the floor came up to meet them [23]. In a perception study astronauts secured by their feet to the Space Shuttle floor with eyes closed had difficulty knowing leg position with respect to their trunk by flight day 7 [23,24]. In an inflight study of pointing accuracy, subjects pointed to five remembered positions (center, up, down, left, and right) on a target screen with a handheld light, starting with the hand close to their chest [25]. The external spatial map was assessed by having the astronauts keep their eyes closed between each light pointer target session, whereas the perception of the internal spatial map was assessed by having the subjects open their eyes and memorize target positions. Eyes were kept closed during the light pointer target session only. Subjects in weightlessness exhibited a pronounced downward pointing bias for all five targets, but when the subjects were able to see the external world between each point, performance improved. Subjects also made greater errors after flight than before space flight, recovering to preflight performance level by the seventh postflight day. The primary factor influencing pointing errors in space flight is the loss of a subject’s external spatial map. Maintenance of a stable external spatial map depends on the presence of normal gravitational forces. The postflight recovery pattern suggests that both the otolith organs and the CNS may influence this phenomenon [25]. The operational implication of pointing errors would be critical during switch throws in a visually obscured environment, such as if there were smoke in the cabin. Crewmembers might be particularly vulnerable when using reach/grasp extension devices such as the Space Shuttle or Soyuz “swizzle stick” to make switch throws on panels out of reach due to suit and restraint systems.

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Rendezvous and docking operations constitute a high-risk phase of space flight during which the crew is vulnerable to perceptual illusions and sensorimotor control errors. Adverse effects of perceptual illusions during rendezvous and docking operations were likely contributing factors to an in-flight collision. This incident, which involved loss of crewmember situational awareness, occurred during the NASA-Mir Program Progress resupply ship’s docking. It clearly emphasizes how multiple factors can influence human performance. On June 25, 1997, an unmanned Russian Progress supply vehicle collided with the Russian Mir space station during a test of the Mir manual docking system. Typically, rendezvous and docking of the Progress used an automated system, with a manual system available as backup. When using the manual system, the Mir crew had to visually acquire the incoming vehicle and control the terminal rendezvous phase based on the Progress orientation, range, and closure rate using an external reference frame. During the actual docking phase, a crewmember had to virtually “fly” the Progress using visual input from a video camera with an internal reference frame located on Progress. In this instance, the Mir commander, who was guiding the Progress capsule to a manual docking using the tele-operated system in the Mir core module, reported to Mission Control that the Progress had come in very fast and could not be stopped. The Progress struck a solar array on the Spektr module and caused a depressurization of the module (and with it the station). The Spektr module was quickly isolated and sealed off, and its pressure eventually dropped to vacuum. During prior rendezvous events, crewmembers had reported experiencing difficulty with visually acquiring the incoming spacecraft, in part related to Mir solar arrays visually obscuring the arriving Progress ship and loss of visual reference with the background of Earth [26]. It is unlikely that a crewmember could accurately describe the position, velocity, and closure rate of a moving object in 3-dimensional space without having a reference point. Russian and U.S. neurovestibular experts also believe that the difficulties crewmembers had in establishing an accurate spatial coordinate reference frame of the different modules made it difficult for the crewmembers to know instinctively which window they should be looking out after moving between modules. During the first docking attempt, one crewmember described the crew as moving from one window to another in an attempt to find the incoming Progress. Following is that crewmember’s account of his experience [27]: The commander would pick his spot according to where he could best see the incoming Progress—something that none of us could predict with any confidence.… As lookouts, [we] began to survey the heavens, looking for the approaching spacecraft. Although I saw some fantastic views of the Himalayas on [Earth], I had not yet spotted the Progress. [The other crewmember] also reported no sighting.… Though I was moving from one Mir window to another, I could still not see the approaching spacecraft. We all began to worry.… More time passed. For some reason I was no longer hearing either [of my crewmembers] over my headset.… I floated back to

J.B. Clark and K. Bacal the base block to see what was happening.… [One crewmember] was flying frantically back and forth between his control station and the nearest porthole-sized window on the floor. I flew to a window that faced the same general direction as the window [that the other crewmembers] were using and did so just in time to see the Progress go screaming by us.

The following additional comments were made by another Mir crewmember about the incident: It was difficult to make out the [Progress]. It looked very similar to the clouds. Through the porthole, I could see the ship gliding below us. It was full of menace, like a shark.

Later, after an unsuccessful attempt to manually dock the incoming Progress, a crewmember recalled [27]: The only way I could determine whether [the commander] had done the right thing was by yelling to [the other crewmember]. He queried as to how the Progress was responding to his latest move. For [me], accurate description was an impossible task.

Disorientation was also a factor in the attempt to arrest the spin on the Mir space station following the Progress collision. Crewmembers fired the thrusters on the Soyuz docked on Mir and had difficulty determining the effect on spin rate. This was complicated by the multiaxial motion of the spacecraft.

Strategies for Spatial Orientation Firm body contact with a motionless surface can provide tactile cues and reduce illusions and SMS in the weightless environment. Adaptive strategies to microgravity and its associated altered orientation cues involve subjectively and cognitively deciding what is up and what is down [14]. For crewmembers who use the visual spatial strategy, the Earth is down or the vehicle floor is down. Forty-six percent of astronauts and 58% of cosmonauts seem to use this strategy. For crewmembers who are using the internal Z-axis strategy, their feet indicate “down.” This strategy is used by 46% of astronauts and 34% of cosmonauts. A mixed visual spatial-internal Z-axis strategy, which is a combination of both, is used by 8% of astronauts and 8% of cosmonauts. Astronauts who use the visual spatial strategy have noted that encountering another crewmember who is upside down with respect to the reference plan can result in sudden neurovestibular symptoms (disorientation or motion sickness) in flight [28]. It is not known whether the orientation strategy is the same over successive spaceflight experiences. One recommendation is to inform crewmembers that the use of the visual spatial strategy can result in adverse symptoms when presented with conflicting visual orientation cues.

Neuromotor Dysfunction and Assessment Neurosensory control of motor activities is disrupted after space flight. For most Space Shuttle crewmembers on shortduration missions lasting fewer than 16 days, recovery of

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normal (preflight) function requires four to eight days after return to Earth. The time course of recovery of normal function after long-duration (>30 days) missions has not been well characterized, but recovery does require a longer period (days to weeks). To ensure that crewmembers are sufficiently recovered to return to normal daily activities and duties, standard clinical neurological assessment techniques must be supplemented with more sensitive measures of sensorimotor control. A short battery of sensorimotor control tasks on long-duration crewmembers after flight has been proposed by NASA medical personnel to establish the characteristics of postflight recovery of neurological function—particularly of balance control, locomotor coordination, and eye-head coordination. Interaction of various nervous system components—which are responsible for visual image stability, balance, and gait control—is necessary for optimal performance of an astronaut or cosmonaut conducting planetary exploration and for ambulatory humans on Earth. Terrestrial patients with various clinical deficits will exhibit performance impairment that can lead to falls and an inability to see and avoid hazards. The same is true of returning astronauts and cosmonauts, who are otherwise healthy but whose microgravity adaptation has left them with clinically significant neurologic impairments during the readaptation period. Functional assessment tests should be applied that are (1) easily administered, scored, and interpreted; (2) adaptable to on-orbit use; (3) integrated with other tests to enhance or supplement diagnostic and predictive power; and (4) correlated with known clinical substrates. Other possible applications of these tests include assessment of fitness for duty (the ability to maintain acceptable performance) after a pharmaceutical countermeasure, assessment of injury risk during an exercise training session, and tracking of error potential during robotic operation after a virtual-reality training session. Functional assessment tests could evaluate the potentially adverse effects of countermeasures as well as optimal countermeasure use, including timing and duration. Currently within NASA, astronauts are evaluated according to medical requirements with mandatory established clinical assessment methods. Supplemental medical objectives may be required to evaluate the application of emerging technologies in clinical space medicine. The Functional Neurological Assessment Project is part of this integrated approach to a countermeasure validation and evaluation program. Determination of measures of performance will directly affect countermeasure development for future low Earth orbit operations and planetary exploration missions, as well as for possible technology transfer to terrestrial clinical populations. The Functional Neurological Assessment Project will obtain baseline data from a healthy normative population and from a clinical patient population; evaluate effects of gravitational variables (tilt, centrifugation, platform perturbation) and effects of operational constraints (EVA suit, terrestrial exploration vehicle); and will facilitate on-orbit assessment. Its three core subsections are gaze performance (oculomotor),

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ambulation (locomotion), and postural stability and balance. Specific oculomotor deficiencies may render pilots more susceptible to disorientation and motion sickness [29]. An operational vestibular test battery used by the U.S. Navy employs screening tests of vestibular function to rapidly assess vestibular performance and quantitative tests that comprehensively evaluate vestibulospinal and oculomotor function. These tests have been used on NASA crewmembers when clinically indicated. The screening tests include the Dynamic Visual Acuity Test (visual acuity during active head movement) and the Modified Sensory Organization Test (balance on an unstable platform while making head movements with eyes closed). Current applications of the operational vestibular test battery include assisting in the diagnosis and the disposition of flight personnel with vestibular disorders and in determining the timing of return-to-flight status after resolution of vestibular dysfunction. This experience is being applied by NASA to long-duration spaceflight crews in the form of a functional neurological assessment. Potential applications of the operational vestibular test battery include aid in the decision to return to terrestrial activities (e.g., exercise, driving, aircraft flight) after space flight, determining adequate adaptation after countermeasure and rehabilitation programs, and identifying medication that will not adversely affect spatial orientation performance. Preflight screening of astronauts and cosmonauts who are more susceptible to performance deficiencies (selecting out) and identification of aircrew with optimal or enhanced vestibular function (selecting in) have been discussed but remain controversial in the space medical community. Clear associations between demographic characteristics (such as age, gender, one-G piloting experience) and performance metrics (such as inflight SMS or postflight neurovestibular symptoms) remain elusive [9], and in their absence it is difficult to develop, let alone validate, appropriate select in criteria. Better assessment methods and predictive indices may make such screening worthwhile in the future.

Oculomotor Effects of Microgravity Gaze, which is coordinated eye-head movement in the direction of the ocular axis, is the sum of eye position with respect to the head, and head position with respect to space. A rapid movement of eyes from one fixation point to another is known as a saccade. When directed toward a target off the primary visual axis, gaze usually consists of a combined fast saccadic eye movement and vestibular ocular response that shifts the ocular axis onto the target. The oculomotor system that controls gaze undergoes constant recalibration and adjustment to ensure optimal stability of images on the retinal fovea. The fovea of the eye, which provides a high level of discriminative visual acuity, subtends a visual angle of 0.25 to 4.0 degrees. Gaze deviation of more than one degree off the foveal center results in a two- to threefold reduction of visual acuity. For optimal visual acuity, a target must be maintained within about

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0.5 degree of the foveal center. The time for a target to fall on the fovea depends on CNS control of head and eye movement, distance, and direction the head and eye must move to foveate (move the macular retina onto the optical axis of the target), as well as on the size of the target. Retinal image stability may be disrupted by nystagmus or fast eye movement deviations known as saccadic intrusions. When assessing eye movements, the gain of the eye movement refers to the velocity of the slow eye movement (slow phase velocity) compared to the stimulus velocity. This stimulus may be the target motion, subject motion, or visual field motion. Space flight is known to influence the oculomotor system. During changing gravitoinertial forces, compensatory eye movements may be inappropriate, leading to degradation of oculomotor function. The yaw vestibular ocular reflex (VOR) demonstrates minimal effects during or after flight. A Space Shuttle investigation showed a slight decrease in gain in flight, which returned to preflight level by flight day 7 [30]. Pitch VOR gain has been shown to increase during parabolic microgravity flight, decrease for the first 4 days of spaceflight, return to normal during flight on the Space Shuttle, increase 14 h after landing compared to in-flight values, and return to normal baseline values after flight. Optokinetic nystagmus (OKN) refers to the eye movements induced by a moving visual field (optical flow or background motion). The slow phase eye movement is normally in same direction of background motion. Compared to preflight, the optokinetic nystagmus gain resulting from horizontal (left or right) moving background decreases early in flight and returns to normal later in flight, while optokinetic nystagmus with vertical (up or down) moving background shows a downward drift or deviation during spaceflight and an upward drift after flight [1]. The downward ocular drift in microgravity may represent a loss of the tonic influence of gravity on the linear acceleration detectors (utricular sacculus of the inner ear), which provides neural stimulus to lift the limbs and eyes upward to compensate for the downward pull of gravity [1]. Saccades showed accuracy undershoots and velocity decreases during flight on the early Space Shuttle missions. Slow and inaccurate saccades and delayed saccade latency correlated with SMS susceptibility [31]. Visual-enhanced VOR gain increased postflight over preflight values in cosmonauts in all planes after long-duration spaceflight [32]. Pursuit amplitude decreased (undershot) in flight. VOR suppression was reduced on R+0, and difficulty with VOR suppression also correlated with susceptibility to SMS [33]. Postflight gaze showed significantly decreased gain in the horizontal and vertical planes with a greater reliance on fast eye movements (saccades). Smooth pursuit was also degraded postflight. Oculomotor dysfunction occurs during and after a gravitoinertial transition, such as from 1-G to microgravity or during reentry transition from microgravity to hypergravity and back to terrestrial gravity. The horizontal and vertical VOR, elicited by active yaw and roll head movement at 0.2 Hz, was studied in six cosmonauts during and after spaceflight. Changes

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in horizontal VOR evoked by yaw head movements during the adaptation to microgravity suggest central reprogramming. Horizontal and vertical eye movements were recorded during roll head movements that were not obvious preflight. One long-duration cosmonaut demonstrated unidirectional downbeat nystagmus, independent of head movement direction, lasting the entire mission. This may have been a result of reduced otolith influence on semicircular canal function. The “space” pattern of visual-vestibular interactions during postflight readaptation depended on the time spent in microgravity. The visually enhanced VOR (compensatory eye movement evoked by head movements with visual feedback) seems to dominate when a conflict arises between “space” and “terrestrial” patterns of sensory interactions [34]. Studies of neurovestibular effects in long-term microgravity demonstrate periodically abnormal spontaneous and induced oculomotor reactions interspersed with normal adaptive periods [35]. Changes in eye movements in microgravity occur primarily for pitch or roll head movements, which normally stimulate the otolith organs, although the relationship between eye movements and self-motion perception remains to be determined [3]. One perceptual model of spatial orientation incorporates our sense of where we are in the environment by linking vestibular, visual, and somatosensory information with experience of inertial and gravitational forces. On Earth, these relationships are established even in the absence of active behavior, while in microgravity these linkages must be actively established for stability in the environment, such as by grasping a handrail to traverse [36]. On Spacelab-1, caloric stimulation revealed that caloric nystagmus of the same direction as on Earth could be evoked in the weightless environment. This suggests a non-convective component to the normal thermal stimulation of the hair cells [37]. Visual input may be effective in reducing sensory conflict in microgravity [38]. In normal gravity, peak eye movements were slower than the visual display velocity when vertical head motion and optokinetic stimulation were in the same direction, and equal to the optokinetic display velocity when head motion and optokinetic stimulation were in opposite directions. In parabolic-flight microgravity, peak eye movement was about equal to the visual display when head rotation and optokinetic stimulation were in the same direction, and faster than display velocity when head rotation and optokinetic stimulation were in opposite directions. The interaction of vestibular and optokinetic nystagmus was nonlinear in microgravity, especially with downward optokinetic stimulation [2]. Neurosensory motor functions supporting three-dimensional orientation in space are disrupted or modified by sustained exposure to microgravity. This results in the degradation of the visual and visual-vestibular systems controlling smooth pursuit, visual scan, and the vestibular-assisted optokinetic system. Neural plasticity is the mechanism used to recalibrate sensory-motor systems and allow learning and adaptation. Plasticity in the spatial orientation system is distributed in the

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cerebellar cortex (floccular and parafloccular lobules) and to the brainstem nuclei (vestibular nuclei, olivary nuclei, nucleus prepositus hypoglossi, and interstitial nucleus of Cajal). The cerebellar cortex controls the timing of movement and guides learning in the brainstem nuclei and the gain of oculomotor systems via neurons within the neural integrator. End-gaze nystagmus is the hallmark of dysfunction of the neural integrator, which is the neural system that mathematically integrates velocity-coded signals (to move the eye off axis) into position signals (to hold the eye off axis). Measurements of gaze-holding nystagmus, holding gaze in an eccentric position, or rebound nystagmus, present in primary eye position after sustained eccentric gaze, are simple clinical tests of the neural integrator that provide a way to monitor neural plasticity and the effects of adaptation or readaptation to altered gravitoinertial environments. Extended Duration Orbiter Medical Project and Shuttle-Mir gaze-holding experiments indicate that the neural-integrator centers in the cerebellar cortex and brainstem nuclei, which maintain target acquisition, may occasionally be maladaptive and disrupt oculomotor stability (Figure 17.1). Monitoring the recovery time associated with the neural-integrator gain provides a means of quantitatively estimating when crewmembers have returned to a physiologically normal state postflight and are capable of engaging in the activities of daily living and standard crew duties. In the gaze-holding protocol, the subject views transiently displayed targets at ± 30 degrees in vertical and horizontal planes, and attempts to maintain gaze on the remembered location after the target disappears. The amount

Figure 17.1. Ocular stability with vertical head movement 10 days preflight (L-10) and on landing day (R + 0) following Shuttle flight. Pronounced ocular instability is demonstrated postflight

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of gaze drift is compared with preflight performance and is evaluated for specific abnormalities, such as eccentric gazeevoked nystagmus, rebound nystagmus, left-right or up-down asymmetry, and cross-plane eye movements. Oman et al. [28]. speculate that the CNS may respond to weightlessness by reducing the vestibular component driving CNS integration in favor of visual inputs.

Postural and Gait Effects of Microgravity Sensory-motor disturbances associated with microgravity are observed with postural responses to movement during space flight. A generalized loss of extensor muscle tone and increase in flexor muscle tone observed in flight resulted in a forward lean during running on the onboard treadmill as the flight progressed [39]. Postural stance in microgravity assumes the fetal-type posture immediately upon insertion into orbit, with an even greater degree of flexion noted with vision occluded and with previous spaceflight experience. Astronauts experiencing sudden “drops” with an elastic pull cord felt as if the floor was moving up, not as if they were moving down [23]. Using muscle vibration to stimulate the tonic vibratory response, preflight stimulation of the foot dorsiflexor muscles results in forward sway, while inflight the forward response is diminished [40]. Vestibulospinal reflexes in microgravity can be assessed with the tendon (T) reflex or Hoffman (H) reflex, which is the electrophysiological equivalent of the muscle stretch or deep tendon reflex. The T reflex was found to be potentiated postflight (increased amplitude) for Skylab crewmembers. On the Mir-Kvant 241-day expedition, the T reflex showed a fourfold increase in amplitude on R+6 days [41]. On the Spacelab-1 mission, H reflex potentiation was suppressed on flight day 6 and was increased early after flight, returning to normal by R+6 days [23]. Increased H reflex potentiation before and after flight correlated with SMS. The decrease in amplitude of the T or H reflex in-flight and the increase postflight indicate decreased vestibulospinal input in microgravity as well as increased vestibulospinal input after return from microgravity and correlates with deep tendon reflex changes inflight and postflight. Returning astronauts are found to be diffusely hyperreflexic on return day compared with preflight. This finding nearly normalizes by R+3 for Space Shuttle crews. Postflight ataxia and postural disequilibrium lasts from one to six days postflight for short-duration missions, and from a few to several weeks after long-duration missions. Factors related to postflight ataxia include initial severity of SMS and mission duration. Using the Fregly Rail Test for gait stability, the Apollo 16 crewmembers at R+4 days were all unstable with eyes closed. One Skylab astronaut at R+2 days was unstable even on a solid floor [42]. After the 48-day Skylab 2 mission, crewmember balance on the narrow rail with eyes open was affected until R + 7 days [43]. Gait effects postflight were related to spaceflight duration in the Soyuz series. Postflight gait effects persisted

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15 to 30 min for 2-day flights, 2 days for 6 to 8 day flights, 14 days for 16-day flights, and 25 days for 18-day flights [44]. Inflight exercise appears to be somewhat protective of postflight ataxia. After the 10-day Spacelab-1 mission, four astronauts, standing with eyes closed (Sharpened Romberg), were able to remain erect only 14% of their preflight stance time on landing day (R + 0) and only 21% of their preflight stance time on the first postflight day (R + 1) [45]. Stabilometry (static force plate), used by the Russian space program, consists of 1 to 2 min of balance assessment with eyes open or closed, in normal stance (Romberg) or with head tilt [46]. In the Soyuz series, stabilometry showed a postflight increase in sway amplitude, primarily in the pitch plane, and a decrease in sway frequency. Instability was related to length of flight, with stabilometry using calibrated perturbations measured at R+6 showing that recovery times were prolonged up to R + 11. Postflight postural testing revealed labile or under-dampened response to translations, indicating decreased ability of sensorimotor responses to external perturbations [41]. Sensorimotor responses to external perturbations recover within hours after landing. Following spaceflight, astronauts often report a sense of turning when they are attempting to walk in a straight line. They also experience disequilibrium when rounding corners. Vestibular inputs to the antigravity muscles result in a change in the distribution of tonic muscle activity, with an increase in ankle dorsiflexor and a decrease in ankle plantar flexor activity. Two levels of neural response, strategy and synergy, maintain our control of gait and balance. Strategy is the organizational principle applied to maintain balance in response to the magnitude of perturbation without regard to load. For small displacements, the ankle movement predominates. With larger displacements, the hip movement is used to maintain stability. Synergy is the neural program of response to the task and muscle loads. These two levels of neural response factor into the recovery of neurovestibular function after spaceflight. The majority of recovery occurs within hours, and full recovery occurs within days after short-duration spaceflight (Figure 17.2). Gait and balance effects are related to spaceflight duration and previous spaceflight experience (Figure 17.3). Postflight findings on spaceflight crews include affecting a wide-based gait, leaning toward the supporting leg; taking shorter, smaller steps while walking; and having a forward step accelerate at impact (stomping gait). Other gait effects noted among returning crews include the sensation of turning while walking a straight path; the lateral pulsion (pushing outward) sensation, as if being pushed by a giant hand while turning a corner; exaggerated pitch-roll sensation while walking; and the loss of orientation while in a visually deprived environment [47]. Altered vestibulospinal reflexes may make astronauts and cosmonauts more prone to musculoskeletal injuries immediately postflight due to altered muscle loading. Exposure to sensory visual vestibular conflict (e.g., walking on plush carpet in the dark, or on an escalator or a moving walkway) may result in postflight dizziness and ambulation

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Figure 17.2. Recovery of balance function following short duration (<18 days) space flight. The Normalized Equilibrium Score is based on maximum peak-to-peak anterior to posterior sway compared to the theoretical limit of postural sway of a normal subject (sensory organ condition 6—see text). A normalized preflight baseline is represented by 1.0. The 5th percentile is considered a threshold of clinical impairment

Figure 17.3. Postural equilibrium scores preflight and postflight in rookie astronauts and experienced astronauts with 1 or 2 previous missions. The Composite Equilibrium Score is a summation of six standard equilibrium tests in different sensory organ conditions (see text)

difficulties. On several occasions after Space Shuttle flights, astronauts reported transient significant disequilibrium that lasted for minutes and vertigo lasting seconds to minutes that occurred one to three weeks after landing and resolved without sequelae. These flashbacks were triggered by motion stimuli such as vehicle, platform, or head motion, presumably due to otolith stimulation. Following an eight-day Space Shuttle flight (International Microgravity Lab-1), four astronauts underwent yaw exposure

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on a rotating chair at R + 1. None reported any subjective change in postural equilibrium [48]. One astronaut had significant postural instability at R+0 but, as measured by computerized dynamic posturography, recovered normal balance function by R + 5. This astronaut then underwent exposure to eccentric pitch rotation followed immediately by posturography testing, which showed a decayed balance function similar to the R + 1 equilibrium score. The R + 1 equilibrium score was also significantly impaired compared to the astronaut’s normal preflight levels [48]. The rotation stimulus was brief and mild. It consisted of sinusoidal oscillation (0.05 to 0.8 Hz at 60 degrees per second, producing peak centripetal acceleration of 0.05 Gz and 0.27 Gx) and trapezoidal angular velocity (60-second ramps at 120 degrees per second, producing peak centripetal acceleration of 0.22 Gz and 0.1 Gx). This disruption of postural control after pitch rotation otolith stimulation could represent a reversion to a microgravity sensorimotor control paradigm. Four days after flight, another crewmember was riding on an escalator and developed acute disequilibrium due to the exaggerated perception of translation with the visual and motion environment. Yet another Space Shuttle crewmember, who was driving an automobile three weeks postflight on a curved highway overpass, experienced an excessive lateral translation perception that required pulling off the highway. In another instance, a Space Shuttle crew, three weeks postflight, was on a moving platform in a parade. Each time the platform motion started or stopped, the crewmembers noted persistent translation for several seconds. A mission specialist flying in a T-38 aircraft (rear cockpit) three weeks postflight noted an exaggerated roll perception after the pilot had initiated a roll break maneuver approaching to land. This maneuver typically results in a brief 2 to 4+Gz exposure and roll acceleration. One long-duration crewmember, two months postflight, reported transient vertigo and unsteadiness while standing in ocean waves on a beach. These flashbacks have been reported to be similar to the symptoms experienced in the immediate postflight period (R+0), and all occurred after readaptation to terrestrial gravity would be expected. These findings have implications for a safe return to daily activities and underscore the need for objective measures of fitness for duty. These findings also have operational significance for lunar and Mars missions. Since persisting sensation aftereffects are known to occur in the majority of crewmembers after exposure to microgravity [9], activities involving human control of complex systems, such as operation of rovers and robotic devices, should be delayed until after the crewmembers have had a chance to adequately adapt to their new environment.

Balance Assessment A standard and objective means of balance assessment is required to perform a functional neurological evaluation of returning spaceflight crews. The Neurocom Equitest dynamic

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platform posturography, a medical device that quantifies the functional status of balance, is used extensively in the terrestrial setting to clinically assess vestibular disorders. This device evaluates the interaction and integrity of the vestibular, somatosensory, and visual systems by assessing the response of these systems to specific sensory perturbations that degrade balance. Balance, the ability to maintain the body center of gravity over the base of support, is assessed by force transducers in the platform and is scored by a computer. The system includes a computer-controlled movable force plate platform and a full visual field surround. The Equilibrium Score is based on maximum peak-to-peak anterior to posterior sway compared to the theoretical limit of postural sway of comparable subject. The balance function score is expressed as a percentage between 0 and 100, where a score of 0 indicates a fall and 100 denotes perfect stability. A component of platform posturography, the sensory organization test (SOT), uses absent or conflicting somatosensory, vestibular, and visual stimuli during six different test conditions to evaluate the subject’s ability to organize dynamic visual, vestibular, and proprioceptive sensory input into useful information for maintaining balance. In SOT condition 1, the subject’s eyes are open and the platform and visual surround are stable. During SOT condition 2, the subject’s eyes are closed (no visual sensory input), fixed stable support is present (normal somatosensory input), and the integrity of the vestibular and somatosensory systems is evaluated concurrently. In SOT condition 3, the subject’s eyes are open, the platform is stable, and the visual surround moves with body motion (sway referenced), giving the subject inaccurate visual information. During SOT conditions 4, 5, and 6, the platform moves with the subject (sway-referenced). In SOT condition 4, the subject’s eyes are open, the platform moves (sway referenced), and the visual field is stable. In SOT condition 5, with the subject’s eyes closed and unstable platform support, the swayed reference provides inaccurate proprioceptive information and visual sensory input is absent; hence, the vestibular system is evaluated independent of proprioceptive and visual input. During SOT condition 6, the subject’s eyes are open and the platform and visual surround are both sway-referenced. SOT conditions 5 and 6 require an operationally functioning vestibular system to maintain balance. Normal subjects maintain their balance by ignoring inaccurate orientation information and are able to maintain their balance and not fall under all 6 SOT conditions, although their balance scores are generally lower and their body sway is greater under absent or conflicting sensory input. The pattern of abnormal balance scores may indicate a dysfunctional sensory system. Abnormalities on SOT conditions 3 and 6 indicate a preference for accurate visual information (visual predominance). When a subject is given erroneous visual cues, the subject who is visually dominant (visual preference) cannot suppress inaccurate information, which means balance is disrupted. Abnormalities on SOT conditions 5 and 6 indicate

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vestibular dysfunction, while abnormalities on SOT condition 2 indicate proprioceptive system involvement. The aphysiologic response is seen when equilibrium scores are not consistent with the expected decline in normal performance with more difficult tests. When a subject’s equilibrium scores are lower (worse) on easier tests with a stable platform and eyes open, than with harder tests with a sway-referenced platform and eyes closed, this indicates less than maximal performance on the part of the subject. The subject’s reduced performance may occur because of poor instruction or insufficient practice (training effect), fatigue, or voluntary reduced effort. The Neurocom Equitest computerized dynamic posturography system is an FDA approved medical device that is used by NASA to track the recovery of vestibulo-spinal integration and spatial orientation in crewmembers returning from spaceflight missions. For several days postflight, a crewmember may perform normally on test conditions with accurate visual, vestibular, and/or somatosensory inputs but may have significant degradation or even hazardous performance during sensory conflict situations such as walking on a moving sidewalk or an escalator. This clinical test battery can simulate sensory conflict situations that expose that crewmember to potential disorientation or fall potential [6]. Three randomized trials of 20 s each are performed on each of the six SOTs. Performance assessment is based on peak body sway during each condition. Interpretation is based on currently available normative population data, with the lower limit of normal defined as below the fifth percentile of the population. The population used is an asymptomatic normal population or active astronaut population. Failure on this test battery would be a score below the fifth percentile compared to the average general population. This approach is used in clinical practice in deciding when patients can return to driving after recovery from vestibular disorders [49]. Fitness to return to driving after events involving vestibular dysfunction is in part based on symptom recurrence and prognosis [50]. The ISS Program has implemented the postflight tests mentioned above to determine objective milestones for return to function for its crewmembers. Individual variability in readaptation timelines is seen in returning crewmembers, necessitating objective measures. One returning long-duration ISS crewmember, while riding as a passenger in a car 18 h after landing, reported experiencing a significant pitch down sensation when the car’s brakes were applied. By contrast, another returning ISS crewmember flew as a copilot in a light aircraft 20 days after spaceflight and reported no problems. Long-duration spaceflight crews are typically returned to flight status in high-performance aircraft after the 30-day postflight (R+30) examination. One long-duration crewmember expressed concern about returning to high-performance aircraft duties, so a posturography medical evaluation was performed on this crewmember while doing pitch and roll head movements at about the R+30 period. Test results were normal as compared to the population controls, and the crewmember returned to active flight status without difficulty.

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A road test has been recommended for evaluating chronic stable vestibular disorders [51] with regard to driving an automobile, and ocular stability has been suggested as a criterion to determine driving ability [52]. Astronauts returning from the ISS have gone back to driving five to seven days postflight without apparent problems, usually starting with driving in low-threat areas (empty parking lot), followed by more challenging city driving. Posturography is used to assess crewmembers at R+5 as a measure of visual vestibular integration. It is recommended that balance function should be better than the lower fifth percentile general population before return to driving [49].

Assessment of Locomotor Oculomotor Interaction During normal ambulation, gaze is stabilized from the top down with pitch head movements and vertical eye movements acting in a synergistic fashion. After space flight, astronauts and cosmonauts typically hold their heads fixed with relation to their trunks in order to resolve complex movements in their vestibular systems although this response might also be due in part to relative weakness in posterior neck antigravity musculature [47,53]. This head fixation strategy results in an alteration between pitch head movements and trunk translation. A locomotor coordination test battery has demonstrated alterations in head-trunk coordination during terrestrial locomotion after spaceflight. Change in head-trunk coordination disrupts gaze stabilization during ambulation and may lead to disorganization in locomotor control. Postflight alterations in lower-limb kinematics and in muscle activation patterns are observed, particularly at the gait heel-strike. These alterations are present for several days after short-duration spaceflight (< 30 days). The ability to maintain gaze stability during locomotion requires normal function and integration of a number of sensory and motor subsystems, including the vestibuloocular reflex, vestibulo- and cervico-colic reflexes, limb locomotor pattern generators, and heel-strike energy modulation systems. Disruption of any of these subsystems leads to altered dynamic visual acuity and impaired modulation of shock wave transmission to the head during locomotion and also serves as a global indicator of sensorimotor disintegration after space flight [53]. The performance outcome of locomotor disruption is the impairment of gaze stability while a subject is walking and the resultant increase in potential for musculoskeletal injury. Dynamic visual acuity during locomotion, which is a reliable and sensitive indicator of clinical vestibular function, is assessed during treadmill locomotion as the subject walks at 6.5 km/h(4 miles/h) and reads aloud numbers of varying sizes on a computer screen that is 2 m (6.56 ft) ahead at eye level. Performance is assessed based on the number of correct responses. To assess heel-strike, subjects walk at a freely chosen pace on a 6- to 8-m (19.69- to 26.25-ft) ground track with a built-in force plate that measures the relative amplitude of the shock wave, transmitted from the heel to the head.

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environment of space may directly affect synapses. On Space Shuttle missions Space Life Sciences-1 and -2, the number of synapses on macular hair cells increased both in flight and postflight [55]. Results of these flight experiments indicate that neurological adaptation to microgravity may not be limited to CNS phenomena. Peripheral plasticity of sensors may occur as compensation for loss of gravity bias. This has led to speculation about possible long-term secondary consequences to the CNS, such as premature neuronal death or apoptosis.

Vestibular Dysfunction

Figure 17.4. Recovery of visual function while ambulating following space flight. Solid square is mean, box is standard error of mean (S.E.M.) and line is standard deviation (S.D.). The number of subjects assessed is given below each data set

Eye-head coordination aids us in maintaining visual acuity while walking and moving and simplifies information transfer between the head and trunk for efficient control of movement. Dysfunction of eye-head coordination results in blurred vision during visual pursuit of a moving target and delay in visual target acquisition. Dynamic visual acuity, which is decreased to 70% of preflight dynamic visual acuity on landing day, does not return to normal for several days after a short-duration flight (Figure 17.4). Static visual acuity is not seen to change appreciably after spaceflight. (Transient reduced color vision and visual acuity have been reported during long-duration space flight immediately after the performance of squats on the resistive exercise device, presumably from Valsalva-related reduced retinal blood flow.)

Clinical Implications of Neurological Disorders in Space Flight General physical environmental alterations and hazards of the spaceflight environment include microgravity, pressure changes, toxic atmospheric conditions, vibration, noise, temperature, electromagnetic radiation, altered visual and vestibular cues, and orbital debris impact. Spaceflight has been associated with various problems affecting the central and peripheral nervous system inflight and postflight [54]. The microgravity

The altered gravitoinertial force that is associated with the microgravity of spaceflight and its effect on vestibular function has important implications for the diagnosis and treatment of vestibular disorders in humans on Earth as well [56]. Terrestrial neurovestibular dysfunction is manifested in similar ways to those seen on orbit: by perceptual symptoms of vertigo (spinning sensation); postural symptoms of disequilibrium or ataxia (unsteadiness or imbalance); oculomotor symptoms of oscillopsia (moving visual images); and vegetative symptoms of lethargy, stomach awareness, nausea, and vomiting. Thus neurovestibular symptoms are similar, whether due to altered physiological stimulation or pathological dysfunction. Physiological neurovestibular syndromes include spatial disorientation, vehicle-associated motion sickness (aircraft, car, boat), and visual motion sickness (simulator sickness). The causes of pathologic vestibular dysfunction include peripheral, central, and systemic etiologies. Peripheral vestibular dysfunction may occur with benign paroxysmal positional vertigo, vestibular neuronitis, perilymph fistula, Meniere’s disease (endolymphatic hydrops), alcoholic positional vertigo, and toxic vestibulopathies. Central causes of vestibular dysfunction include migraine disorders and lesions of the brainstem or the cerebellum. Migraine-associated vestibular dysfunction may be similar to space adaptation syndrome, particularly the postflight neurovestibular symptoms [57]. Vertigo is seen in 25% to 70% of migraine patients, and a history of motion sickness is seen in 25% to 60% of migraine patients. Any stimulation of the vestibular system (caloric irrigation) or visual system (moving stripes) can trigger migraine attack. Pharmacological treatment of vestibular migraine—such as calcium channel blockers, gamma-amino butyric acid agonists (gabapentin and sodium valproate), and carbonic anhydrase inhibitors (acetazolamide)—might be effective therapy (in addition to conventional measures such as benzodiazepines and vestibular suppressants) for postflight neurovestibular symptoms, particularly in the nearly one-third of crewmembers who report some vertigo [9,24,58]. In a study of the perception of self-orientation during microgravity vestibular investigations on a Space Shuttle Spacelab flight, four astronauts underwent passive whole-body rotation during a seven-day orbital mission. During pitch (Y-axis rotation with the otoliths at a 0.5-m (1.64-ft) radius), subjects experienced a constant force of −0.22 Gz at the otoliths and

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+ 0.36 Gz at the feet during the 60-s constant rotational velocity profiles. In these subjects, a −0.22-Gz otolith stimulus did not provide a vertical reference in the presence of a gradient of +Gz stimulation to the trunk and legs [59]. The peripheral and central vestibular system may influence autonomic function in normal subjects for whom vestibularinduced autonomic responses may be provoked during or after vestibular laboratory testing, vehicular motion, time spent in simulators, and exposure to microgravity, as well as in clinical patients [60]. In normal subjects, vestibulo-autonomic effects may impact the diagnostic testing, clinical diagnosis, and treatment of vestibular disorders. Vestibular control of cardiovascular function is evidenced by direct and indirect connections between the vestibular system and brainstem neurons that control heart rate, blood pressure and breathing [61,62]. In some patients with vestibular dysfunction, these vestibular-autonomic effects may lead to anxiety disorders, panic attacks, and agoraphobia, and may also play a role in vestibular-induced orthostatic intolerance [63]. Orthostatic intolerance postflight has been attributed to changes in lower-extremity hemodynamics, baroreceptor reflex alterations, diminished exercise tolerance and fitness, hypovolemia, and altered beta-adrenergic receptor sensitivity [64]. The otolith organs play an important role in regulating blood pressure during postural changes on Earth. Plasticity of the otolith organs during spaceflight may therefore also contribute to postflight orthostatic hypotension by imposing vestibular influences on cardiovascular control.

Cephalad Fluid Shift The microgravity-associated cephalic fluid shift might be associated with acute neurologic deterioration. This fact has raised concerns about an undetected brain tumor or an Arnold-Chiari malformation and brain herniation under similar circumstances and has caused consideration by the space medicine community of neurologic imaging of the brain as a screening criterion for space flight. Trans-cranial Doppler used to

study the middle cerebral artery showed an increase in middle cerebral artery velocity on flight day 1 in those with SMS compared to those who did not experience SMS. From flight day 2 through flight day 5, blood flow acceleration decreased, which is an index of vessel distensibility and an indication of changing cerebral resistance. The failure to increase cerebral vascular resistance may be related to SMS symptoms. Changes in intracranial fluid dynamics could affect a vascular tumor or an arteriovenous malformation. Fluid shifts may also contribute to neurovestibular effects via a patent cochlear aqueduct, which transmits intracranial pressure to the inner ear. Thus far, CNS imaging has not been implemented as a medical selection tool, primarily due to the limited clinical yield and chances of false positive findings (see Chapter 3).

Oculomotor Effects Since 1996, crew surgeons have performed a standardized clinical neurologic evaluation on Space Shuttle astronauts both preflight and postflight using a neurologic function rating scale. A summary of these results is found in Table 17.1. Oculomotor, gait, and postural effects are well known after space flight, although the performance correlates are not yet established. The potential exists for as yet undetected longterm effects on neurological function due to incomplete readaptation or maladaptation after spaceflight. In a review of postflight eye movement responses, spontaneous eye movements were observed in 7 of 19 cosmonauts after short-duration missions, and in 24 of 27 cosmonauts after long-duration missions compared to preflight oculomotor responses. Gaze fixation was impossible as eyes continued to oscillate, and typical jerk nystagmus developed into square wave jerks [65]. Gaze rebound nystagmus developed in 37% of cosmonauts postflight. Oculomotor findings returned to normal in most cosmonauts within 8 to 10 days after short-duration missions and by 14 days after long-duration missions, although 11 cosmonauts had not returned to normal by 75 days and 3 cosmonauts had not returned to normal after 3 to 4 years.

Table 17.1. Functional neurological assessment rating scale (112 astronauts 1996–2000)a. None

Headache Dizziness/Faintness Vertigo/Spinning Gaze/Ocular movements (nystagmus) Finger to nose (close eyes touch nose, open eyes touch finger) Drift (close eyes, extend arms, palms up) Rising from chair (without use of arms) Standing/Romberg (feet together, arms extended, close eyes) 30 s Leg lift/Hop (close eyes, lift leg, hop 3 times, alternate) Tandem/Heel-to-toe walk (5 m) Dynamic equilibrium (close eyes walk 9 m turn 180° and return)

Mild

R+0

R+3

R+0

R+3

94% 83% 88% 45% 81% 90% 86% 78% 60% 43% 53%

97% 98% 99% 93% 99% 99% 99% 97% 99% 98% 93%

3% 14% 9% 51% 19% 9% 11% 21% 26% 37% 41%

3% 2% 1% 7% 1% 1% 1% 3% 1% 1% 7%

Moderate R+0 2% 3% 2% 4% 0% 0% 1% 0% 9% 18% 3%

R, return day. Assessment performed on returning Shuttle crewmembers on landing day (R + 0) and three days following landing (R + 3).

a

Severe

R+3

R+0

R+3

0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%

1% 0% 1% 0% 1% 1% 2% 1% 3% 2% 4%

0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%

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Figure 17.5. Video Oculography (VOG) tracing of horizontal (H) on upper line, and vertical (V) eye movements on lower line demonstrating horizontal square wave jerks (SWJ) in a crewmember following long duration spaceflight. Although minimally present preflight, SWJ were magnified in postflight studies and persisted in this individual. This tracing was made five months postflight. Scale: 10 degree/block in y axis, 1 s/block in X axis

One long-duration astronaut exhibited frequent square wave jerks, which is an eye movement attributed to altered CNS function (Figure 17.5). A square wave jerk is a saccadic intrusion (fast eye movement deviation) that takes the eye off its original axis for about 200 milliseconds, is infrequent, and generally occurs with a frequency of less than 20 per minute in the dark [66]. Although in this case these square wave jerks were present before flight, they increased dramatically in number after flight, and remained more frequent more than four months after spaceflight. The crewmember remained asymptomatic and denied oscillopsia. The postural instability after spaceflight resembles mal de debarquement (debarkation sickness or land legs), which was first appreciated centuries ago, after crews had returned to land following long ocean voyages. Mal de debarquement is often a disabling condition [67].

Headache Headache is a common complaint in space flight. Data from the NASA Longitudinal Study of Astronaut Health, examining 89 Space Shuttle flights with 508 crewmembers over 4,443 flight days, revealed headache in 304 of 439 (69%) males and 38 of 69 (55%) females. Headache often occurs early after orbital insertion and has been attributed to cephalic fluid shifts. In this context, it is also thought to be a component of SMS. Other potential causes of headache in space flight include locally

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elevated carbon dioxide (CO2) levels, exposure to toxic fumes, and decompression sickness. Symptoms of headaches, nausea, and central vasodilatation occurred in some crewmembers on Mir and during docked Space Shuttle operations with the Mir or the ISS. This combination of symptoms (i.e., headaches, nausea, and central vasodilatation) is not typically known to occur on other Space Shuttle flights. Potential causes include localized CO2 increase, hypoxia, reemergence of SMS, excess heat and/or humidity, carbon monoxide (CO) or other contaminants, or a combination of factors. As an example, a crewmember experienced a headache while working in a fixed location in the SpaceHab module early during transfer operations to the Mir; symptoms progressed as work continued. This crewmember experienced nausea and vomiting as the headache worsened, and symptoms were relieved only when the crewmember took breaks in the Space Shuttle flight deck. Air samples obtained at that time showed no contaminants or accumulation of human metabolic products, though the sampling technique may have been flawed. These symptoms were different from the crewmember’s SMS symptoms, which were predominantly nausea and vomiting without a strong headache component. Crewmembers on other missions with docked operations had also noted occasional air hunger, breathlessness, and headaches during the docked phases of Shuttle-Mir flights. Symptoms were worse when all of the crewmembers were present in the aft base block of Mir, and resolved after short breaks in the Space Shuttle. No atmospheric abnormality unique to the Mir or the ISS has absolutely been implicated in this symptom complex, although a portable CO2 detector has been developed to rapidly assess local concentrations of CO2 to better characterize these events. Although hypercarbia symptoms exhibit some variability in character and intensity between individuals, the symptoms are usually consistent for each individual. ISS and EVA crews undergo controlled preflight CO2 exposures to familiarize them with their specific symptom complex. For a sea-level cabin, symptoms are usually not present at 1% or less CO2 (7.5 mmHg), although fatigue and headaches are possible above 2% CO2 (15 mmHg). Terrestrially, at 1 atmospheric pressure, CO2 percentage is normally 0.03% (0.2 mmHg), whereas normal human activity may result in CO2 levels of 0.13% (1 mmHg) in a typical room. Space Shuttle CO2 levels on average are about 0.26% (2 mmHg) during normal in-flight operations, though these may be higher in areas of inadequate air mixing (see Chapter 22). Headache is not a common initial presenting symptom of heat stress; sweating, nausea, and vomiting are more commonly associated with heat stress. Space Shuttle crewmembers who have experienced headache and other potentially CO2-related symptoms have noted that the ISS modules have not been uncomfortably warm. Other entities possible during space flight may also involve headache as a symptom. Acute hypoxia may include headache and be associated with fatigue, visual changes, and skin flushing. Symptoms of headache, nausea, and vomiting are

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seen in acute altitude sickness, and can occur within 24 h of exposure to a lower pressure but not usually within several hours. Symptoms of SMS rarely develop late in space flight unless crewmembers are exposed to a visual reorientation illusion or a significant gravito-inertial force, (e.g., a rotating chair experiment). It is conceivable that the gain of visual-enhanced VOR could change because of the proximity of the visual surround in enclosed spaces after a crewmember has adapted to more open habitable volumes, and this transition could induce SMS symptoms. The reemergence of SMS, although a possible cause of these symptoms, would require further study and may be diagnosed in part by exclusion.

Back Pain and Nerve Entrapment Back pain is commonly associated with space flight. It often manifests as a generalized axial skeletal ache that is significantly mitigated by flexing into the fetal position. Axial skeletal elongation is suspected, because crewmembers often grow in seated height from preflight by a few to several centimeters, although statistical correlation with back pain and postflight height increase has not yet been performed. Rarely crewmembers report sensory loss associated with spaceflight back pain. One crewmember developed upper-extremity numbness (proximal bilateral arms and chest in a cape-like distribution) in flight that persisted for weeks after a short-duration mission. This crewmember also flew on a long-duration mission and developed a large area of lower-extremity saddle anesthesia in flight. Symptoms persisted for several months postflight. An extensive work-up with neuroradiologic studies to evaluate for cranio-cervical junction abnormality, spinal cord syrinx, and tethered spinal cord revealed no pathology. Another long-duration crewmember developed bilateral distal finger and toe paresthesia and numbness that began several months into the mission. These symptoms correlated with postflight findings of reduced vibration and proprioceptive function in the affected extremities. Symptoms resolved several months postflight. A Space Shuttle crewmember reported a “pinsand-needles sensation” in the legs late in a short-duration spaceflight. During the mission, this crewmember had been exposed to unexpected 15-cm (5.9-in.) vertical falls (−Gz) using an elastic bungee harness that generated simulated gravity forces (0.33-, 0.67-, and 1-g) [68].

Neurologic Countermeasures A Vestibular Countermeasures Task Group of clinical and academic experts has been organized by NASA at the Johnson Space Center to assess the development and implementation of countermeasures to lessen or alleviate the adverse effects associated with neurological adaptation to spaceflight and return to Earth. Neurological countermeasures to optimize health and safety are required, but it is recognized that countermeasures to maintain or improve performance of one

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physiological system may cause or exacerbate problems in other physiological systems; as such, these countermeasures must be carefully developed. The countermeasure development process normally includes (1) basic science and laboratory research; (2) clinical efficacy research; (3) cost-effectiveness and risk versus benefit evaluation; (4) operational effectiveness evaluation; (5) assessment of interference with other countermeasures or spaceflight operations; and (6) eventual acceptance as an operational countermeasure after operational validation. Evaluation of countermeasures should establish the functional link between physiologic perturbations and operational performance deficits. The Vestibular Countermeasures Task Group has addressed and categorized several neurosensory disruptions that are caused by space flight: (1) SMS, (2) the “entry/landing syndrome,” and (3) severe disturbances after long-duration spaceflight. NASA countermeasures can be divided into those designated as currently accepted procedures and those in development, where research is incomplete or the efficacy is not yet established. Accepted countermeasures against SMS include (1) crew training, briefing, and timeline adjustment; (2) medication administration, with understanding of side effects and interactions; (3) development of individual outcome predictors; and (4) development of coping procedures. Countermeasures that address entry/landing syndrome include (1) crew briefings for education and awareness; (2) preflight training and in-flight landing task simulators, such as the portable in-flight landing operations trainer simulator; (3) operational landing requirements and procedures to create a best available “vestibular” environment; and (4) exercise protocols to prevent antigravity muscle loss. Countermeasures or which there is only anecdotal evidence include (1) crew briefing on risks versus benefits of head movements during entry and immediately post-landing, (2) egress training for ill or impaired crewmembers, (3) careful medication use and (4) dual-adaptation protocols using preflight adaptation training. For major neurosensory disturbances after long-duration missions, such as persistent sensation aftereffects, clumsiness, difficulty walking a straight line (ataxia), and vertigo, the only accepted countermeasure is assisted egress. Further analysis is under way to determine (1) contributions of pre-entry fluid loading to postflight vomiting; (2) relationships between in-flight exercise, preflight rotation tolerance, and post-landing postural control; (3) the neurological effects of recumbent positioning during entry; and (4) data from crew debriefs. Another area to be developed is analysis of the interactions between the different neurosensory disturbances, or normal readaptation time course and symptomatology. Ground-based programs, such as virtual-reality-based approaches that use projected or portable head-mounted virtual environment systems, could be developed to train crewmembers to orient and navigate through spacecraft without regard to their body orientation. A light, miniature, head-movement monitoring system was proposed as a future countermeasure

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to be used for crew training to adapt head movement strategies that minimize SMS, visual reorientation illusions, and reentry and postflight disorientation. Prediction of CNS sensorimotor patterns of response would allow appropriately trained astronauts and cosmonauts to maintain the dual-adaptive states that are appropriate for both the terrestrial and microgravity environment, thereby minimizing problems during landing and egress. Dual adaptation training could be performed in a terrestrial environment on a large-radius centrifuge, with visual displays that allow crewmembers to make active pitch and roll head movements in a microgravity field while minimizing or avoiding Coriolis and cross-coupling effects. A small-radius centrifuge on orbit, such as the Skylab M131 chair and the Space Shuttle Neurolab chair, might aid adaptation back to terrestrial environments. Crewmembers could use a modified space-based treadmill with proprioceptive and visual cues provided by tactile and virtual-reality devices to maintain posture and kinematic strategies appropriate for 1-G. Anecdotally, one ISS crewmember ran on the treadmillvibration isolation system for 1 to 2 h a day while viewing a digital video movie on a computer screen 1.5 to 2 m away. This provided a challenge to the ocular stabilizing function of the crewmember’s vestibular system that was similar to the dynamic visual acuity test performed on a treadmill. This crewmember, who usually suffers postflight neurovestibular symptoms, reported fewer symptoms after this flight and was able to egress the Space Shuttle unassisted after the long-duration ISS mission. Running on a treadmill while maintaining a visual fixation target may thus be an effective countermeasure for neurovestibular adaptation and deserves further evaluation, particularly in light of findings that in-flight exercise appears to have a protective effect against post-flight neurovestibular symptoms such as clumsiness and difficulty walking a straight line, while post-flight exercise is associated with a decrease in difficulty concentrating [9]. Spatial orientation is normally maintained by input from the visual, auditory, vestibular, and somatosensory systems that provide redundant and concordant information. The tactile situational awareness system has demonstrated that spatial orientation can be continuously maintained by providing proprioceptive orientation cues to a reference point, such as where down is to a pilot in an aircraft or where a hatch is to a diver underwater [69]. The system uses a harness worn over the body fitted with an array of “tactors,” small mechanical actuators, providing skin pressure or vibration cues that continuously update the crew with a haptic presentation of position and velocity information. Position and motion information could be provided to an EVA astronaut or cosmonaut over large structures such as the ISS, thereby reducing disorientation and illusions [70]. During a launch abort scenario, the Space Shuttle commander could have 3-dimensional situational awareness of the closest abort landing site or could be able to make a piloted reentry and landing without directly visualizing instrumentation. In the event of an emergency

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egress with reduced visibility (caused by smoke or water) or unusual attitude, Space Shuttle crewmembers could be aware of their orientation if provided such tactile directional cues to the escape path. A rotating artificial gravity device may be a viable countermeasure to prevent the physiological deconditioning associated with microgravity [71]. The ISS is devoted in part to investigating problems of human long-duration spaceflight and will eventually afford the opportunity to evaluate countermeasures that could be used for an exploration-class mission to Mars. The neurovestibular implications of rotational artificial gravity must be assessed, however, before this countermeasure can be accepted. A major consideration of artificial gravity is the trade-off between the radius and the rotation rate required to achieve a desired gravity level—a trade-off that influences rim velocity and gravity gradient (radius). If intermittent gravity is provided, e.g. on a short arm centrifuge, then there may be sensory problems related to shifting between gravitational and microgravity environments. In addition, a short radius implies a substantial gravity gradient along the rotational arm, with the outward body experiencing a greater centripetal force than further inward. Another fundamental task is determining what constitutes an adequate gravity level and whether to apply a given gravity level continuously or intermittently (i.e., exposure time). An adequate artificial gravity stimulus, combined with active head movements and locomotion, could potentially avoid reentry disorientation and post-landing postural instability if astronauts and cosmonauts could adopt a dual-adaptive state. Vestibular disturbances that are associated with cross-coupled Coriolis acceleration when making out-of-plane head movements are directly proportional to the rotation rate and can create sensory conflict leading to SMS. Rotation rates of 1 to 2 rpm are easily tolerated, and incremental adaptation can provide tolerance up to 6 rpm. In the microgravity environment, 10 rpm may be possible. At 10 rpm, a 10-m (32.8-ft) radius produces 1-G and a 5-m (16.4-ft) radius produces about 0.5-G. Intermittent exposure to artificial gravity may prevent deconditioning of otolith-ocular and vestibulo-sympathetic reflexes in microgravity. During the 1998 Space Shuttle Neurolab mission (STS-90, April 17 to May 3, 1998), four astronauts were exposed to centripetal accelerations with constant velocity centrifugation of 0.5-G and 1-G at the head during rotation on a short-arm (0.5 m radius) human centrifuge. Rotations were performed in two configurations; seated with the body vertical axis parallel to the axis of rotation and with the direction of motion through the chest (face or back first), or lying supine along the rotating arm with the axis of rotation approximately at the navel. Exposures were conducted both preflight and postflight as well as during the 16-day orbital spaceflight. Subjects were oriented either left or right ear-out (Gy centrifugation) or supine along the centrifuge arm with head off-axis (Gz centrifugation). Preflight centrifugation, which produced 0.5-G and 1-G along the Gy

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(interaural) axis, induced roll-tilt perceptions of 20 and 34 degrees for actual gravito-inertial acceleration vector tilts of 27 and 45 degrees. Preflight 0.5-G and 1-G Gz centrifugation generated perceptions of backward pitch of 5 and 15 degrees, respectively. Perception of tilt was underestimated early in flight during Gy centrifugation, but was close to the gravitoinertial acceleration after 16 days in orbit. In-flight roll-tilt perception during Gy centrifugation increased from 45 to 83 degrees at 1-G and from 42 to 48 degrees at 0.5-G. The difference of in-flight versus preflight tilt perception suggests that non-vestibular inputs, such as an internal body vertical and somatic sensation, may be used in perceiving tilt. Clément et al. have suggested that ambiguity of the otolith graviceptor response to linear acceleration in microgravity might result in tilt being perceived as translation. Since linear acceleration during in-flight centrifugation was always perceived as tilt, not translation, the findings do not support their Otolith Tilt Translation Reinterpretation hypothesis [72]. The gain of the ocular counter roll, which is a torsional (rotational) eye movement and one type of otolith-ocular orienting reflex, was maintained in flight and postflight, in contrast to previous postflight ocular counter roll studies that showed decreases in ocular counter roll gain. Intermittent exposure to artificial gravity (centripetal acceleration) was postulated as a countermeasure to deconditioning of the otolith-ocular orienting reflex during the spaceflight mission. In keeping with this proposed protective effect, all four rookie crewmembers on the Neurolab mission who participated in the experiment had normal postflight orthostatic tolerance, an unlikely occurrence given that orthostatic intolerance occurs in about 64% of returning rookie astronauts. This emphasizes the link between the neurovestibular system and the cardiovascular system’s influence on postflight orthostasis. Further studies to evaluate postflight otolith deconditioning and orthostatic intolerance are needed before intermittent centrifugation artificial gravity should be considered as a countermeasure in long-duration missions. Bed-rest deconditioning studies using a short-radius centrifuge could determine the radius, gravity level, and rotation rate most likely to provide an acceptable environment for intermittent stimulation in order to prevent bone, muscle, and cardiovascular deconditioning. Other studies using a slow rotating room will be necessary to assess human factors issues and the problems of adaptation schedules. After we have conducted ground-based studies, a small-diameter human centrifuge might be accommodated on the ISS to study intermittent gravity stimulation. If this yields promising results, definitive studies for longduration protection could be carried out with a large (1-km (0.62-mile) ) tethered Variable Gravity Research Facility in co-orbit with the ISS. A short-arm centrifuge could be an effective countermeasure to maintain dual adaptation by allowing adequate terrestrial sensory-motor functioning in space flight, while simultaneously allowing for adaptation to the microgravity

J.B. Clark and K. Bacal

environment. Entry/landing syndrome has been suspected when a Space Shuttle commander’s operational performance measures (touchdown velocity and vertical velocity at touchdown) have not correlated with preflight performance on the Space Shuttle landing simulator (the Shuttle training aircraft). This centrifuge might be effective in preventing the potentially devastating operational consequences of entry/landing syndrome resulting from spatial illusions and subsequent neurovestibular effects during manual landing. The shuttle has an autopilot feature that could be used to mitigate this risk.

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17. Neurologic Concerns 17. Howard IP. Visual reorientation illusions as a function of age. Aviat Space Environ Med 2000; 71(Suppl.):A87–A91. 18. Harm DL, Reschke MF, Parker DE. Visual-vestibular integration: Motion perception reporting. In: Sawin CF, Taylor GR, Smith WL (eds.), Extended Duration Orbiter Medical Project (Vol. NASA/SP-1999-534, pp. 5.2-1–5.2-12). Houston: NASA Johnson Space Center, 1999. 19. Held R, Dichgans J, Bauer J. Characteristics of moving visual areas influencing spatial orientation. Science 1975; 141: 722–723. 20. Muller C, Wiest G, Kornilova L, Deecke L. Visuo-vestibular interaction in determination of orientation behavior in weightlessness. Wien Med Wochenschr 1993; 143:630–632. 21. Reschke MF, Bloomberg JJ, Paloski WH, Harm DL, Parker DE. Neurophysiologic aspects: Sensory and sensorimotor function. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine, 3rd edn. Philadelphia: Lea & Febiger; 1994:261–285. 22. Benson AJ, Kass JR, Vogel H. European vestibular experiments on the Spacelab-1 mission: 4. Thresholds of perception of wholebody linear oscillation. Exp Brain Res 1986; 64:264–271. 23. Reschke MF, Anderson DJ, Homick JL. Vestibulospinal response modification as determined with the H reflex during the Spacelab 1 flight. Ex Brain Res 1986; 64:367–379. 24. Bikhazi P, Jackson C, Ruckenstein MJ. Efficacy of antimigrainous therapy in the treatment of migraine associated dizziness. Am J Otol 1997; 18:350–354. 25. Young LR, Oman CM, Merfeld D, Watt DGD, Roy S, Deluca C, et al. Spatial orientation and posture during and following weightlessness: Human experiments on Spacelab-Life-Sciences-1. J Vestib Res 1993; 3:231–240. 26. Morgan C. NASA-5 Mike Foale: Collision and Recovery. In: Shuttle—Mir NASA SP-2001-4225 NASA Johnson Space Center, Houston, Texas, 2001, pp. 104–117, and accompanying CD ROM: Foale CM. NASA Mir Oral History. Session 1, 16 June 1998; Session 2, 7 July 1998; Session 3, 31 July 1998. 27. BBC Television HORIZON. Mir Mortals segment, April 23, 1998, Random Postproductions, 1 Golden Square, London. 28. Oman CM, Lichtenberg BK, Money KE. Space motion sickness monitoring experiment: Spacelab 1. In: Crampton GH (ed.), Motion and Space Sickness. Boca Raton, FL: CRC Press; 1990:217–246. 29. Clark JB, Rupert AH. Spatial disorientation and dysfunction of orientation/equilibrium reflexes: Clinical evaluation and aeromedical considerations. Aviat Space Environ Med 1992; 63: 914–918. 30. Vieville T, Clement G, Lestienne F, Berthoz A. Adaptive modifications of the optokinetic vestibulo-ocular reflex in microgravity. In: Keller EL, Zee DS (eds.), Adaptive Processes in Visual and Oculomotor Systems. New York: Pergamon Press; 1986:111– 120. 31. Uri JJ, Linder BJ, Moore TP, Pool SL, Thornton WE. Saccadic Eye Movements during Space Flight. NASA TM-100475, NASA, Washington, DC; 1989. 32. Kornilova LN, Goncharenko AM, Godo G, Elkan K, Grigorova V, et al. Pathogenesis of Sensory Disorders in Microgravity. Physiologist 1991; 34:S36–S39. 33. Thornton WE, Uri JJ, Moore TP, Pool SL. Studies of the horizontal Vestibulo-ocular reflex in spaceflight. Arch Otolaryngol 1989; 115:943–949.

379 34. Kornilova LN, Grigorova V, Bodo G. Vestibular function and sensory interaction in space flight. J Vestib Res 1993; 3:219–230. 35. Kornilova LN, Grigorova V, Bodo F, Chernobyl’skii LM. Neurophysiological patterns of vestibular adaptation to microgravity. Aviakosm Ekolog Med 1995; 29:23–30. 36. Mergner T, Rosemeier T. Interaction of vestibular, somatosensory and visual signals for postural control and motion perception under terrestrial and microgravity conditions—a conceptual model. Brain Res Rev 1998; 28:118–135. 37. Von Baumgarten R, Benson A, Berthoz A, Brandt T, Brand U, et al. Effects of rectilinear acceleration and optokinetic and caloric stimulations in space. Science 1984; 225:208–212. 38. Oman CM, Balkwill MD. Horizontal angular VOR, nystagmus dumping, and sensation duration in Spacelab SLS-1 crew members. J Vestib Res 1993; 3:315–330. 39. Clement G, Lestienne F. Adaptive modifications of postural attitude in conditions of weightlessness. Exp Brain Res 1988; 72:381–389. 40. Lackner JR, Levine MS. Changes in apparent body orientation and sensory localization induced by vibration of postural muscles: Vibratory myesthetic illusions. Aviat Space Environ Med 1979; 50:346–354. 41. Grigoriev AI, Yegorov AD (eds.), Preliminary medical results of the 180 day flight of prime crew 6 on Space Station Mir. Presented at 4th meeting of the US USSR Joint Working Group on Space Biology and Medicine. San Francisco, CA; 16–20 Sept 1990. 42. Homick JL, Reschke MF. Postural equilibrium following weightless space flight. Acta Oto-Laryngol 1977; 83:455–464. 43. Kerwin JP. Skylab 2 Crew Observations and Summary. In: Johnston RS, Dietlein LF (eds.), The Proceedings of the Skylab Life Sciences Symposium, Vol. 1, Washington, DC: National Aeronautics and Space Administration; 1974:55–59. 44. Bryanov II, Yemel’yanov MD, Matveyev AD, Mantsev EI, Tarasov IK, Yakovleva IYa, Kakurin LI, Kozerenko OP, Myasnikov VI, Yeremin AV, Pervushin VI, Cherepakhin MA, Purakhin YuN, Rudometkin NM, Chekidra IV. Characteristics of statokinetic reactions. In: Gazenko OG, Kakurin LI, Kuznetsov AG (eds.), Space Flights in the Soyuz Spacecraft: Biomedical Research. Leo Kanner Associates, Redwood City, CA. Translation of Kosmicheskiye Polety na Korablyakh ‘Soyuz’ Biomeditsinskiye Issledovaniya. Moscow: Nauka Press; 1976:1–416. 45. Kenyon RV, Young LR. MIT/Canadian vestibular experiments on Spacelab-1 mission: 5. Postural responses following exposure to weightlessness. Exp Brain Res 1986; 64:335–346. 46. Kozlovskaya IB, Kreidich YuV, Oganov VS, Koserenko OP. Pathophysiology of Motor Functions in Prolonged Manned Space Flights. Acta Astronaut 1981; 8:1059–1072. 47. Paloski WH. Vestibulospinal adaptation to microgravity. Otolaryngol Head Neck Surg 1998; 118:S39–S44. 48. Black FO, Paloski WH, Reschke MF, Igarashi M, Guedry FE, et al. Disruption of postural readaptation by inertial stimuli following spaceflight. J Vestib Res 1999; 9:369–378. 49. Black FO. Personal communication, 2001. 50. Parnes LS, Sindwani R. Impact of vestibular disorders on fitness to drive: A consensus of the American Neurotology Society. Am J Otol 1997; 18:79–85. 51. Sindwani R, Parnes LS. Reporting of vestibular patients who are unfit to drive: Survey of Canadian Otolaryngologists. J Otolaryngol 1997; 26:104–111.

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J.B. Clark and K. Bacal 63. Furman JM, Jacob RG, Redfern MS. Clinical evidence that the vestibular system participates in autonomic control. J Vestib Res 1998; 8:27–34. 64. Yates BJ, Kerman IA. Post-spaceflight orthostatic intolerance: Possible relationship to microgravity-induced plasticity in the vestibular system. Brain Res Rev 1998; 28:73–82. 65. Reschke MF, Kornilova LN, Harm DL, Bloomberg JJ, Paloski WH. Neurosensory and sensory-motor function. In: Space Biology and Medicine, Chapter 7: Vol. III, Book 1: Humans in Spaceflight. Reston, VA: AIAA Press; 1998. 66. Shallo-Hoffman J, Petersen J, Muhlendyck H. How normal are “normal” Square Wave Jerks. Invest Ophthalmol Vis Sci 1989; 30:1009–1011. 67. Hain TC, Hanna PA, Rheinberger MA. Mal de Debarquement. Arch Otolaryngol Head Neck Surg 1999; 125:615–620. 68. Young LR, Oman CM, Watt DGD, Money KE, Lictenberg BK. Spatial orientation and weightlessness and readaptation to earth’s gravity. Science 1984; 225:205–208. 69. Rupert AH. Tactile Situation Awareness System: Proprioceptive prostheses for sensory deficiencies. Aviat Space Environ Med 2000; 71(Suppl.):A92–A99. 70. Rochilis JL, Newman DJ. A tactile display for International Space Station (ISS) Extravehicular Activity (EVA). Aviat Space Environ Med 2000; 71:571–588. 71. Sandler H. Artificial gravity. Acta Astronautica 1995; 35: 363–372. 72. Clément G, Moore ST, Raphan T, Cohen B. Perception of tilt (somatogravic illusion) in response to sustained linear acceleration during space flight. Exp Brain Res 2001; 138:410–418.

18 Gynecologic and Reproductive Concerns Richard T. Jennings and Ellen S. Baker

The seven U.S. Mercury astronauts, all of whom were male, were selected by NASA in 1959 to make the first human space flights. Nevertheless, the era of human space flight started not in the United States but in the Soviet Union with the single-orbit flight of a male cosmonaut, Yuri Gagarin, on Vostok 1 in April 1961. The Soviets also inaugurated female participation in space flight. The first woman to fly in space was Valentina Tereshkova, who spent 3 days on Vostok 6 in 1963. Nineteen years later another Soviet woman, Svetlana Savitskaya, ventured into space on the flight of Soyuz-T7 in August 1982. In June 1983, the first female U.S. astronaut, Sally Ride, joined this elite group of female spacefarers. The process by which the first astronauts were chosen for the U.S. space program was initiated in the late 1950s. The U.S. Government determined that the first groups from which astronauts were to be selected would be limited to military test pilots. Although several women were able to complete the medical selection examinations (the same ones given to the men), none of them qualified for the simple reason that all military test pilots at that time were men. This policy thus effectively delayed space flights by U.S. women for 2 decades [1]. The first U.S. astronaut class to include women was formed in 1978; of that class of 35, 6 were women. To date, more than 45 female career astronauts (pilots or mission specialists) have been selected for the U.S. space program. One female Canadian astronaut and three female payload specialists have flown on the shuttle. Dr. Sally Ride, the first female U.S. mission specialist to fly, launched in 1983 on Space Shuttle flight STS-7. Since Dr. Ride’s flight, more than 40 female mission specialists or pilots have orbited the Earth as astronauts in the U.S. space program. (When this book was written, 4 additional female payload specialists and 1 female cosmonaut had flown aboard the Space Shuttle.) The first woman to serve as a Space Shuttle pilot was Eileen Collins, who piloted the STS-63 mission in 1995. Collins also served as the first female commander of a Space Shuttle mission, STS-93 in 1999. Dr. Shannon Lucid, who is a member of the astronaut class of 1978, from 1996 until May 2002 previously held the record for the longest space flight by any U.S. astronaut. Dr. Lucid flew 75 million miles during her mission on board the Russian space station

Mir, a flight that lasted 188 days (from 22 March 1996 to 26 September 1996). She and 5 other female astronauts share the record for the greatest number of space flights completed by U.S. women. (Each has completed 5 flights.) More recently, Sunita Williams completed a 194 day mission aboard the ISS, and Peggy Whitson became the first woman ISS Commander. At the conclusion of her second ISS increment, Dr. Whitson will have accumulated more than 350 days in space. Despite the delay in admitting women to the U.S. space program, being female actually offers some advantages. The weightlessness that is part of life in microgravity negates some of the male advantages of size and strength. The closed environmental systems that are found on all spacecraft—with limited amounts of O2, water, and food, and with the need to process solid, liquid, and exhaled waste products—favor smaller individuals. Since the general implications for women participating in high-performance aircraft and in spacecraft have been reviewed elsewhere [2–5], they will not be addressed here in great detail. Suffice it to say that, although men and women differ in their ability to withstand extremes of hypoxia, decompression, temperature, acceleration, isolation, stress, and impact, these differences are generally small and often depend more on acclimation and individual variation than on sex. Regardless of the relative assets and liabilities of using men or women in future space crews, these crews will include people of both sexes. It is therefore prudent that the reproductive and gynecologic issues associated with selecting, training, and assigning female crewmembers to space missions be examined. This chapter addresses gynecologic medical standards and female astronaut selection, reproductive and operational gynecologic considerations during training and space flight, pregnancy after space flight, and gynecologic considerations for long-duration space flights.

Gynecologic Medical Standards and Female Astronaut Selection The prevention of gynecologic or other medical problems in space begins with the selection process and continues with aggressive preventive-medicine programs during the astronaut’s 381

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Earth-based career. The medical selection criteria for female Space Shuttle astronauts are generally identical to those for male Space Shuttle astronauts, except for reproductive-system standards and radiation-exposure limits. Radiation-exposure limits are based on guidelines issued by the National Council on Radiation Protection and Measurements. These limits allow a maximum lifetime increase in cancer risk of ~3% for all space crewmembers [6]. As the missions become longer and space crews travel greater distances from Earth, the radiation standards will have to be reviewed periodically and are likely to become even more conservative to maintain the maximum excess risk at 3%. Current career exposure limits for women at all ages are lower than those for men (see Chapter 23). Radiation standards, along with other medical selection standards for astronauts, are reviewed periodically; the difference in radiation limits for women and men essentially reflects the increased incidence of breast and thyroid cancer among exposed women relative to the incidence among exposed men. In addition, due to reduced risk of early death from cardiovascular disease, women live approximately 15 years longer than men, thus allowing more time for post-flight carcinogenesis. Gynecologic selection standards have evolved, and generally have been relaxed as spaceflight experience has progressed. For example, standards for the 1978 astronaut class disqualified women who had a history of endometriosis. This was done because microgravity was expected to increase the likelihood of retrograde menstruation, and exposure of the peritoneal cavity to menstrual products would further increase the risk of endometriosis [7–10]. Another concern, raised by studies of rhesus monkeys, was that exposure to space radiation could increase the risk of endometriosis [11–15]. A more recent concern regards the possible effect of space-induced immunosuppression on the incidence of endometriosis [16–18]. Current standards allow a history of endometriosis but disqualify candidates with endometriosis that results in severe dysmenorrhea, those with endometriomas, or those with extensive pelvic adhesive disease. Candidates with a history of surgically treated endometriosis are evaluated by the Johnson Space Center Aerospace Medicine Board on a case-by-case basis. Premenstrual syndrome must interfere with the performance of duties to disqualify a female candidate from the U.S. space program. Any gynecologic malignancy is disqualifying for selection and for space flight, except for successfully treated cervical carcinoma in situ. Many existing Space Shuttle or International Space Station (ISS) medical standards will probably become more stringent for exploration-class missions to the Moon or Mars given the reduction in treatment options afforded crews by mission length, remoteness from Earth, spacecraft treatment limitations, the inability to provide real-time medical consultation, and the inability to return to Earth in a timely fashion. Conversely, the medical standard for spaceflight participants or tourists on short flights to low Earth orbit will probably be less stringent than the standards for career astronauts. Astronauts who are already in training and who develop a disqualifying condition are often granted a waiver if the medi-

R.T. Jennings and E.S. Baker

cal threat is or can be eliminated or mitigated. For example, a woman with a history of corpora hemorrhagica who requires operative intervention might be given oral contraceptives and allowed to participate on a long-duration mission in low Earth orbit. Leiomyomata uteri that are symptomatic or cause menorrhagia may be successfully treated by surgery. It is possible that a female astronaut with a successfully treated gynecologic malignancy that has a high cure rate, such as well-differentiated endometrial cancer, could be granted a waiver for short-duration space flights; a waiver for a long-duration space flight, such as a mission to Mars, is unlikely, however. Decisions regarding waivers are usually made on a case-bycase basis by NASA and the ISS Multilateral Space Medicine Board after a thorough review of the condition, input from outside specialty consultants, successful therapeutic intervention, and a complete recovery. Waivers are not typically issued during astronaut candidate selection; in fact some candidates are deemed disqualified but surgically correctable (e.g., symptomatic leiomyomata, benign ovarian neoplasia, cholelithiasis, or inguinal hernias). Pending successful treatment, some disqualified candidates may become eligible for selection in that same cycle. As part of the extensive week-long astronaut selection medical evaluation and interview process, each female astronaut-candidate finalist undergoes pelvic and abdominal sonography, proctosigmoidoscopy, gynecologic examination, and Pap smear. Candidates aged 35 years or more undergo mammography. To date, the mean age for female astronaut-candidate finalists is 32 years. The gynecologic conditions found during the selection examinations are probably similar to those found in equally educated women of the same age in other professions. A review of gynecologic findings during the selection examinations in 1994, 1996, 1997, and 1999 showed that 20 of 90 women had a history of current or treated cervical dysplasia. The 88 female finalist candidates examined in 1991, 1994, 1995, and 1996 had a total of 5 ovarian masses that required further evaluation, and 9 had leiomyomata uteri. Endometriosis is a common finding during selection, and 3 of 21 astronaut-candidate finalists in 1999 had a history of surgical treatment of endometriosis. No female finalists have been disqualified because of a gynecologic condition found at the time of the selection examination. However, several applicants have been disqualified by the record review that takes place during the selection prescreening process. Several female astronaut-candidate finalists were required to undergo surgical procedures or biopsies to rule out disqualifying pathology or neoplasia in ovarian masses, breast masses, or breast microcalcifications. So effective is this preselection examination that, to date, no active female U.S. astronaut has been permanently grounded because of a gynecologic condition that developed after selection. A situation that causes difficulty in many selection cycles is a current pregnancy in female astronaut-candidate finalists. Pregnancy itself is not a disqualifying condition, but

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the selection examination cannot be completed during the pregnancy. Existing pregnancy has caused a few candidates to delay their selection examination or to postpone the entire selection process until a subsequent cycle.

Reproductive Considerations During Training Astronauts currently spend most of their time receiving generic training and performing leadership and support roles for the U.S. space program. Mission-specific training for either shortduration Space Shuttle or long-duration ISS flights usually begins from 1 to 2 years before an assigned mission. Astronauts are required to fly regularly in T-38 aircraft, maintain SCUBA qualification, undergo physiologic training in an altitude chamber, and practice planned extravehicular activities (EVAs) in underwater facilities such as those at the Sonny Carter Neutral Buoyancy Laboratory in Houston, Texas or the Hydrolab in Star City, Russia. In addition to the experience they accrue in the Neutral Buoyancy Laboratory, crewmembers assigned to perform EVAs are given additional experience in the U.S. extravehicular mobility units (EMU) or the Russian Orlan suits (space suits) inside a vacuum chamber. During their training, astronauts perform an in-suit 100% O2 “prebreathe” procedure at 70.3 kPa (10.2 psi) or 101.3 kPa (14.7 psi) before undergoing decompression in a vacuum chamber to an in-suit pressure of 29.6 kPa (4.3 psi). Pregnant astronauts are precluded from participating in this activity, among others, throughout the pregnancy. Since the T-38 training aircraft is equipped with an ejection seat, pregnant crewmembers are not allowed to fly in it after the first trimester. The cabin altitude in the pressurized T-38 may reach 5,490 m (18,000 ft), but all crewmembers breathe supplemental O2. Accidental decompression at altitude occurs occasionally; and since NASA T-38 operations are common up to 13,110 m (43,000 ft) altitude, this risk has to be considered. No astronaut has developed altitude decompression sickness from T-38 operations, but some episodes have occurred during training upon exposure to vacuum. This fact alone warrants the exclusion of pregnant astronauts from the vacuum chamber. Similarly, special precautions are taken to avoid decompression-related illness if underwater EVA or SCUBA training occurs before aircraft operations. Women who are known to be pregnant are not allowed to practice EVA in the Neutral Buoyancy Laboratory. The rationale for this preclusion involves the duration of the dives during EVA training, which last up to 8 h; the depth of the Neutral Buoyancy Laboratory, 12.2 m (40 ft); and the limited |information available about prolonged diving during pregnancy. In addition, oxygen-enriched air is used in the Neutral Buoyancy Laboratory, and very little data are available regarding the combination of use of this air, diving, and

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pregnancy. NASA’s restraint in this regard agrees with that of many authorities who suggest that for pregnant women, the risk of accidents, decompression sickness, or inadvertent exposure to teratogens and the requirement for high-partialpressure breathing gases usually outweigh any short-term training benefit [19]. NASA high-altitude physiologic training involves simulating ascents to 10,670 m (35,000 ft) cabin altitude and several minutes of exposure to hypoxia at 7,620 m (25,000 ft). Pregnant astronauts are prohibited from participating in these activities. In addition, EVA crewmembers are given hypercarbia experience with a rebreathing system starting with 100% O2 that results in brief exposures of up to 8% CO2 at sea level. Pregnant astronauts are precluded from this activity as well. Water survival courses, Space Shuttle emergency egress and escape slide training, and periodic parachute training are also not permitted during pregnancy. No pregnancy testing is currently performed before atrisk training activities, although this policy is periodically reviewed. Female astronauts are expected to self-report pregnancy. Pregnant astronauts are not usually allowed to train in parabolic flight because of the potential for trauma while flying unrestrained in the large cargo area. The effects on the fetus of repetitive flights with 40 to 60 parabolas involving free-fall simulations of microgravity and 2-gravity pullouts per flight—all of which are typically performed during KC135E or DC-9 training—are not known. In summary, the multiple constraints on training for female astronauts who are pregnant often result in planned delay of pregnancies until after the first or second space flight. These career considerations often lead to childbirth at relatively advanced maternal ages.

Operational Gynecologic Considerations Pregnancy and Contraception A few unique operational considerations are required for female crewmembers on current Space Shuttle and ISS flights. Pregnancy is disqualifying for space flight because of concerns regarding exposure to radiation and toxins, decompression sickness, the potential adverse effect of microgravity on early embryogenesis, and the risk of on-orbit pregnancy accidents such as spontaneous abortion, ectopic gestation, or preterm labor. Each female crewmember is tested for pregnancy during preflight medical examinations beginning 10 days before launch, and women who are found to be pregnant are removed from the flight. Although astronauts have used essentially every form of contraception, the disqualifying nature of pregnancy for space flight has led to an increase in the preflight use of contraceptive methods that have reported low method-related failure rates. Crewmembers are encouraged to continue their current contraceptive methods or methods during training and in flight. Most contraceptive methods (e.g., intrauterine devices, levonorgestrel implants, and oral

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contraceptives) have also been continued during Space Shuttle missions. No method-related incidents or complications have been experienced. For medical reasons, depot leuprolide acetate with estrogen/progesterone addback has also been used in space flight. Oral contraceptives on short-duration missions offer the opportunity to reduce the volume of menstrual efflux and to shift the menstrual cycle so as to avoid menses on orbit. On long-duration missions continuous menstrual suppression is often used. A pill-free week each month is not necessary while using low-dose oral contraceptives for suppression; indeed, continual therapy may offset some other problems associated with space flight such as hygiene and osteoporosis.

Menstruation and Hygiene Despite considerable initial concern about female crewmembers experiencing menstruation in space flight, menstruation has not presented a problem. Before the first U.S. female crewmembers flew in space, consultants met with the NASA Medical Operations group in Houston to discuss menstruation in microgravity. This group recommended that female crewmembers consider depot medroxyprogesterone acetate, oral contraceptives, or danazol to manage menstruation during space flight. Oral contraceptives with 30 to 35 µg of ethinyl estradiol were deemed most practical. Debrief data from the Space Shuttle Program have confirmed that menstrual efflux and required hygiene measures are similar to those experienced on Earth. There have been no reported symptoms that would suggest retrograde menstruation. Female astronauts on the Space Shuttle have access to multiple sanitary products for menstruation, including pads, minipads, and tampons in plain and deodorant versions. For launch, EVAs, and landing, crewmembers of both sexes have a maximum-absorbency garment available that can retain up to 2 L (4.23 pints) of urine, blood, or feces. These garments replace the absorbent material used in an adult diaper with the super-absorbent material found in urine containment devices. A unique area of difference for female crewmembers in space flight involves urination. Each crewmember has his or her own urine cup that can be integrated into the Space Shuttle waste collection system. The cups for women are shaped differently than those for men to accommodate anatomic differences. Nevertheless, several women have reported difficulty in drying after urination. This may be due to urine entering the vaginal orifice by surface tension or remaining in the distal urethra. Regardless of the cause, the small amount of wetness that occurs after urination is a minor annoyance noted by only a few women. Finally, crewmembers of both sexes have occasionally experienced difficulty initiating urine flow while on orbit, and the only cases of urinary retention requiring the use of a catheter have been in women.

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Pregnancy After Space Flight The vast majority of female finalists for astronaut candidate selection have not borne children. During the 5 astronaut selection cycles between 1989 and 1997, 99 female finalist candidates were examined. Only 18 of the 99 had given birth, and the total number of living children among this 18 was 24. As alluded to earlier in this chapter, the delay in childbearing is often the result of educational and career objectives that involve decisions about both marriage and children. Because of the constraints on training that pregnancy causes, many female astronauts prefer to delay their first pregnancy until after they complete 1 or 2 space flights. This decision, not surprisingly, has led to deliveries at relatively advanced maternal ages. The average maternal age at the time of delivery for the 15 children born to 13 U.S. female astronauts after flight is 41 years. The mean maternal age of the 12 postflight pregnancies that ended in spontaneous abortion is also 41 years. Because of the relatively advanced maternal age of female astronauts, there has been considerable need for infertility services and assisted reproductive technology (ART). The incidence of benign gynecologic disease also increases with age. The success rates for ART in female astronauts have been low but in keeping with those of other ART patients of similar age. The number of astronauts attempting ART is still too small to allow any further conclusions to be drawn except to state that the poor per-cycle fecundability is probably related to age rather than space flight.

Considerations for Long-Duration Space Flights Endometriosis The role that gravity plays in menstrual efflux is unknown, but considerable concern has been expressed about the potential risk of retrograde menstruation and the risk of endometriosis associated with radiation exposure. Many studies over the last half century have linked endometriosis to the peritoneal deposition of menstrual products [7–10]. However, debrief reports from the Space Shuttle Program have shown no evidence that women who menstruate in space flight have any increase in shoulder pain, abdominal symptoms, or reduction in their normal menstrual flow pattern that might suggest retrograde endometriosis. Long-term follow-up of rhesus monkeys that were exposed to high-dose single-energy protons, mixed-energy protons, x rays, and electrons has shown increased rates of endometriosis over the subsequent 2 decades as compared with controls. Most of the monkeys that developed endometriosis had massive disease, and increased mortality in individual monkeys was experienced before advanced diagnostic techniques were available [11–15]. Recent studies have associated endometriosis with abnormal immune function, and this

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could partly explain the increased risk of endometriosis after radiation exposure. Immune function seems to be depressed during space flight. The combination of radiation exposure, decreased immune function, and tendency to nulliparity in many female astronauts could theoretically place these astronauts at increased risk of developing endometriosis [16–18]. Human endometriosis is a benign condition that is medically manageable, and thus endometriosis would not be expected to develop rapidly or to cause sudden incapacitation. Exceptions to this would be the sudden rupture of a large endometrioma or bowel-related complications. With appropriate intervention, however, it is unlikely that endometriosis that develops on a long-duration mission would interfere with duties. Should endometriosis develop in a female crewmember during a long-duration mission, many nonsurgical treatment options are currently available to treat the condition. These treatment options include prescribing oral contraceptives, progesterone analogs, danacrine, and depot gonadatropinreleasing hormone (GnRH) agonists, perhaps combined with low-dose estrogen/progesterone addback.

Menstrual Cycling Because the longest Space Shuttle flights have been only 18 days, no studies of the effects of microgravity on menstrual cycling in female astronauts have been possible because the menstrual cycle is typically 28 days. Only 4 women had participated in long-duration space flights when this chapter was written (1 U.S. astronaut [Shannon Lucid] and 1 Russian cosmonaut [Elena Kondakova] flew on the Russian space station Mir, and two U.S. astronauts [Susan Helms and Peggy Whitson] flew on board the ISS). These missions were about 6 months in duration. The ISS, however, offers the opportunity to collect data from a cohort large enough to overcome privacy concerns. For a variety of reasons (discussed in the section on Prevention, Diagnosis, and Treatment), however, many female astronauts prefer to continue taking hormonal contraceptives while on orbit; therefore, accumulating information on spontaneous menstrual cycles in space is expected to require several years.

Reproductive Function and Osteoporosis Risk Loss of bone calcium associated with space flight is a major concern. Experience accrued from the Skylab, Shuttle-Mir, and ISS programs has shown that bone density is lost at a rate of about 1% per month, despite the use of existing physical countermeasures. Whether the loss will continue at this rate during longer exposure to microgravity is uncertain. Postmenopausal women have a greater risk of developing clinically significant osteoporosis than do men. Although osteoporosis is more common in women of certain ages on Earth, no spaceflight findings yet suggest that women of astronaut age are at greater risk of microgravity-related bone calcium loss than are men.

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Bone density in premenopausal women normally increases until the fourth decade of their life. Once a woman enters menopause, accelerated loss occurs unless estrogen is replaced exogenously [20–24] or bisphosphonates are employed. NASA recommends that hormone replacement therapy (specifically estrogen therapy) be used during long-duration space flights in postmenopausal female astronauts. Studies are ongoing regarding bisphosphonates for space flight. In addition to receiving adequate estrogen therapy and resistive exercise, consumption of calcium and vitamin D are also important in maintaining bone density. A lingering concern has been expressed that the strenuous exercise prescription necessary to prevent bone loss, muscle atrophy, and cardiovascular deconditioning in microgravity would result in anovulation, hypoestrogenemia, and accelerated bone loss in younger female astronauts [25–37]. Many factors are associated with this increased risk, including baseline hormonal functioning, nutritional status, body mass, stress, preflight fitness level, and duration, type, and intensity of the required exercise. The risks of anovulation, reduction in estrogen levels, loss of calcium, and increased incidence of fractures are well documented in women who have trained extensively for activities such as distance running or ballet. These risks are increased for individuals with nutritional deficiencies. Impact exercise, such as running, and resistive exercise may reduce calcium loss in hypoestrogenemic women as compared with other exercise programs, but hypoestrogenemic runners are still at increased risk of fractures. Female astronauts in this category who may be at increased risk can be identified before flight so that appropriate countermeasures are initiated early in training. The neurovestibular problems seen in astronauts after landing are manifested in part by gait abnormalities and motor coordination difficulties. These problems increase the risk of falls and fractures because of the astronauts’ reduced bone density. To address this issue, NASA has established a vigorous, well-supervised rehabilitation program for astronauts returning from long-duration space flight. This program is designed to accelerate the recovery of functional capabilities and to return crewmembers to baseline while minimizing the risk of injury. For female astronauts, the use of oral contraceptives, impact exercise, resistive exercise, and hormone replacement therapy is expected to mitigate most of this risk [38–41]. Studies of selective estrogen receptor modulators, calcitonin, and bisphosphonates such as alendronate are warranted to determine whether bone mass can be maintained as well with these or other compounds [42,43]. Selective estrogen receptor modulators may also offer the opportunity to reduce the risk of female crewmembers developing breast cancer while on long-duration missions, although only tamoxiphen is currently indicated for breast cancer prophylaxis. Similarly, other pharmaceutical agents offer a medical backup should any crewmember be unable to perform appropriate exercise countermeasures because of injury, hardware

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failure, or spacecraft environmental constraints. Even on short-duration Space Shuttle flights and on longer-duration Mir missions, constraints on performing exercise countermeasures are not infrequent. The possibility of encountering similar problems on an ISS or exploration-class missions is even greater because of the longer duration of such missions.

Prevention, Diagnosis, and Treatment Preventive Concepts Long-duration flights aboard the ISS or to the Moon or Mars present special problems because these missions will be much longer than those experienced previously, and ready return to Earth may not be possible. A mission to Mars will last ~3 years. In addition to the time required away from Earth, the gravitational force experienced by crewmembers during transit and on the planet surface will vary. Transit will most likely take place at microgravity, whereas the force on the planet surface will be 38% of the gravitational force on Earth [44]. Gravitational force on the Moon is one-sixth that on Earth, and the ISS will be at microgravity. The radiation exposure rate will be highest during transit to Mars, since the surface of Mars offers some radiation protection from galactic cosmic radiation and solar particle events because of its radiationblocking mass and CO2 atmosphere. From a gynecologic perspective, several concepts will be important for women on any of these long-duration missions. Concepts that also apply to male crewmembers include prevention of illness, conversion of surgical conditions to medically treatable conditions, and provision of surgical capability. Preventing pregnancy will be imperative during both the preflight and in-flight periods. The potential difficulties associated with pregnancy in space flight have been well documented [45–47], but for all practical purposes, the radiation dosage expected for a Mars mission will exceed 0.5 Sv (50 rem) per year, and the yearly radiation dose expected on the ISS is 0.25 to 0.4 Sv (25 to 40 rem). The National Council on Radiation Protection and Measurements recommends that the total radiation dose to which pregnant women are exposed should not exceed 0.005 Sv (0.5 rem) [48]. The International Council on Radiation Protection pregnancy limit is 0.002 Sv (0.2 rem). Exposures over 0.1 Sv (10 rem) may be associated with microcephaly and mental retardation [49–54]. In addition, the risk of toxic chemical exposure, reduced atmospheric pressure, altered breathing gas concentrations, and possible microgravity effect on early embryogenesis associated with normal and contingency operations preclude planned pregnancies. These factors thus make pregnancies during space flight very ill-advised at this stage of the program. Several animal reproduction studies have been conducted in microgravity; a few have been done on the Space Shuttle [55–59]. Although some of the problems noted in these studies may relate to factors such as launch vibration or experi-

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mental conditions rather than microgravity, several of these problems have raised concern about species-specific problems with early embryogenesis. At some time in the future and after extensive animal studies have been conducted, it may be possible to consider space-based human pregnancies—provided, of course, that adequate radiation shielding is established on the lunar or Martian surface, both for the pregnant woman and later for the growing child. Until the risks of pregnancy are more fully understood and we are able to deliver appropriate, fully implemented care, the prevention of unintended pregnancies in space flight will remain a more important focus. Any prevention program for long-duration space flights begins with selection standards and administering care on Earth. Each astronaut is examined annually with emphasis placed on prevention of illness. This examination includes a physical, extensive blood analysis, periodic exercise tolerance tests, mammography or breast MRI, colonoscopy, and bone density analysis. Great attention is given to appraisal of health risks, lifestyle counseling, and early medical intervention as indicated. For crews assigned to exploration-class missions, the flight-specific examinations will be much more thorough and spaced appropriately for the mission profile. Women will most likely be screened by using abdominal and pelvic sonography so that any abnormalities can be addressed early in the pre-launch timeline. Additional screening for renal stones and coronary artery disease is also likely to be done with crewmembers destined for long-duration space flight. Many Earth-based prevention concepts are appropriate for gynecologic care for women in space flight. As is true on Earth, the noncontraceptive benefits of oral contraceptives can be helpful; such benefits include reduction in menses and menses-related hygiene requirements, dysmenorrhea, mittelschmerz, and benign breast problems. The reduction in menstrual efflux may help minimize the loss of red blood cell mass and blood volume associated with space flight (typically about 10%). Women may take low-dose oral contraceptives in a continuous fashion and reduce the frequency of menses to 3 or 4 times per year. This practice provides significant benefit for several reasons, since women who are taking oral contraceptives are less likely to form ovarian cysts that could undergo torsion and are also less likely to experience other surgical conditions such as corpora hemorrhagica, upper genital tract abscess, or endometriosis. Oral contraceptives provide an effective way to manage dysfunctional bleeding and reduce the chance of either endometrial hyperplasia or menorrhagia. Finally, birth control pills also reduce the risk of ovarian cancer by 50%. Women who have completed their families can consider undergoing endometrial ablation before prolonged space flight. This evolving technology offers several office-based methods of safely ablating the endometrium with intrauterine therapy. Endometrial ablation provides several advantages over hysterectomy, including reduced risk of postoperative adhesions and subsequent bowel obstruction

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during flight. Finally, even though formation of a few adhesions is likely, elective laparoscopic appendectomies for both male and female astronauts may be indicated before prolonged lunar or Mars missions. The level of radiation exposure occasioned by a space flight to Mars poses a dilemma for astronauts who might later choose to produce children. Space flight involves exposure to galactic cosmic radiation, solar particle radiation, trapped radiation, and secondary radiation produced when high-energy particles are stopped by shielding material. Thus during spaceflight, crews are exposed to a combination of protons (charged H2 nuclei), alpha particles (charged He nuclei), neutrons, high linear energy transfer particles, gamma rays, and x rays, the effects of which on humans have not been modeled completely on Earth. The risk of acute gamete genetic damage is probably not overwhelming for women, and it is less likely than the risk for men because of the constant and relatively rapid division rate of spermatogonia. Additional information on the effects of radiation exposure is given in Chapter 23. Many questions remain about the long-term reproductive impact for individuals of either sex. Women who would like to become pregnant after a prolonged trip to the Moon or Mars will probably be offered the opportunity for preflight stimulation of ovarian cycles and cryopreservation of embryos, oocytes, or ovarian tissue. Since the success of ART, the rate of spontaneous abortion, and the rate of genetic defects in embryos depend considerably on the age of the female gamete at the time the embryos are collected, fecundability should be enhanced by cryopreservation of embryos in women who elect to delay pregnancy while their natural fertility potential is declining. Hopefully, cryopreservation of ova or ovarian tissue will advance to the point that women can preserve their gametes for future fertilization and transfer. However, when this chapter was written, the success rate for thawing multicell embryos is much better than that for thawing single-cell oocytes. Of course some of this discussion is moot, because many female crewmembers will either have completed their families or will not want to experience future pregnancies.

Avoiding Surgery on Long-Duration Space Flights Another important issue for long-duration space flight is the need to convert surgical conditions into medically treatable conditions, or at least mitigating surgical conditions so that they can be treated later after a return to Earth. For women, an excellent example of this is the successful treatment of early ectopic pregnancies with methotrexate. Previously, ectopic pregnancy was considered a surgical emergency; but with early diagnosis and medical therapy with methotrexate, many ectopic pregnancies can be managed medically on an outpatient basis. Another such therapy that is now available includes the use of GnRH agonists with estrogen/progesterone addback for leiomyomata uteri, endometriosis, adenomyosis, or dysfunctional uterine bleeding. In gynecologic practice, GnRH agonists have in the short term

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helped to reduce menorrhagia and uterine size, to convert cases requiring abdominal surgery into those in which vaginal procedures can be performed instead, and to increase hematocrit levels before surgery. For certain cases of menorrhagia that are resistant to hormonal management, placing a Foley catheter with a 30-ml balloon in the endometrial cavity could obviate dilation and curettage. In space flight, these and other options will be available to treat individuals or to delay definitive surgical procedures until a crewmember is returned to Earth. We believe that the development of alternative treatment methods for diagnosing and managing gynecological and other potential surgical problems should continue. We also hope that additional innovative treatment modalities that incorporate planned on-board medical equipment and supplies can be developed.

Diagnostic, Surgical, and Distant-Care Capabilities To date, no human beings have undergone surgery in space, but human surgical procedures have been accomplished during zero gravity parabolas in aircraft. Even with the use of preventive measures and minimizing the need for surgery, enabling technology will need to be developed for microgravity and reduced-gravity surgical intervention. Projections from analog environments with equally fit individuals who were isolated for 2 to 3 years suggest that surgery will not be required often in a crew of 4 to 8 healthy young astronauts. Nevertheless, trauma is a real risk in space flight, and minimally invasive surgery such as laparoscopy will be an important adjunct to abdominal sonography and laboratory analysis to manage severe blunt trauma in space [60–63]. Sonography and digital x ray are expected to be the principal modes of diagnostic imaging on a Mars mission or a lunar base, and it is imperative that we understand the effect that microgravity has on both normal and abnormal physical findings. In addition, the selection and training of crewmembers, including training in medical treatment, will be an integral part of the treatment options available for exploration-class missions. Microgravity surgical techniques are already under development, and several procedures have been conducted during parabolic flights on aircraft. Laparoscopy, laparotomy, thoracoscopy, advanced cardiac life support, advanced trauma life support, sonographic diagnostic imaging and percutaneous bladder puncture, and telemedicine procedures have all been accomplished in animal models during the repeated 20- to 25-s parabolas provided in the NASA Reduced Gravity Program [64–72]. Additional surgical experience was obtained on the Neurolab mission, flown on STS-90 in April and May 1998, which included performing the first on-orbit surgical procedure that the animals survived postoperatively. Use of zero gravity aircraft fosters the logical, stepwise development of surgical techniques for microgravity. The steps involved have included studying restraint systems, sterile technique, and fluid and blood control and performing laparotomy, laparoscopy, and thoracoscopy in animal models. During the development period, surgical isolation systems,

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surgical overhead canopies, restraint systems for both patients and surgeons, and techniques for scrubbing, gowning, gloving, and draping were tested. Results of these studies have been reassuring. Capillary and venous bleeding can be controlled by using local measures, and arterial bleeding may be associated with projectile dispersion of blood droplets. The canopies have been helpful with containing arterial bleeding, and we have found that direct pressure with an absorbent sponge can change a projectile arterial bleeder into a dome of blood. Since most bleeding areas form domes or coat body surfaces because of surface tension, blood or fluid is not usually released into the cabin atmosphere; however, these blood domes must be removed periodically to allow appropriate operative exposure. The zero gravity flights have demonstrated that traditional suction devices are not successful, and that dispersed blood droplets will occasionally form fragments, providing potential atmospheric contamination. Loose-weave sponges have been found to work better for blotting than tightweave sponges, and sponges should be applied gently to avoid fracturing or propelling droplets. Laparotomy has been accomplished on experimental animals without difficulty on the KC-135E. Although experimenters had no problem returning the abdominal contents to the abdomen, care was required in entering the peritoneal cavity since the intestines do not fall away from the incision when the tented peritoneum is entered. Laparoscopy has been performed repeatedly on porcine models on the KC-135E and DC-9; this procedure has produced favorable results in microgravity as compared with the same procedure at 1 gravity. Surgical balloon devices for creating operative abdominal space were used successfully during the KC-135E series, but the initial success with traditional laparoscopy made the balloon devices less desirable. However, in the KC-135E studies, a pneumoperitoneum was established at 1 gravity before flight. The initial pneumoperitoneum could be difficult to establish in microgravity, and an open technique of laparoscopy could be required. Direct trocar insertion is unlikely to be an acceptable surgical technique in microgravity because of the lack of gravitational separation of the viscera from the abdominal wall at the trocar insertion site. With the current experience base, it seems that laparoscopy for treatment of in-flight surgical intra-abdominal conditions and gynecologic problems in women offers many advantages, e.g., reduced requirement for anesthesia, containment of blood, debris, and fluids, and the use of minimally invasive surgical techniques. Laparoscopy also minimizes the size of the exposed incision and should lead to faster surgical recovery, a reduced chance of infected wounds, reduced need for analgesics, and reduced short-term disability. Incisional length and duration of exposure may be important factors in microgravity, where airborne particulate size and number are greatly increased over those encountered at 1 gravity. Video downlink available with laparoscopy provides the advantage of either real-time or store and forward second opinions from Earth-based consultants. Eventually, laparoscopy in low Earth orbit on the ISS or on a lunar base may be possible through the

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use of surgical telerobotics. However, the potential 1-way time delay of more than 20 min for a transmission to reach Mars will present a problem for real-time consultation and render telerobotic procedures unusable. Crew medical officers for exploration-class missions may not be physicians, and thus they must be trained to provide medical care independently of the ground and to use consultation services. Although considerable work lies ahead to develop laparoscopy as an enabling medical treatment technology for human space flight, early animal data suggest that laparoscopy will be a practical and effective way to approach surgical-gynecologic and other abdominal abnormalities. Moreover, continued development of smaller equipment with improved multifunctional capabilities and the potential for Earth-based experts to direct less-capable care providers makes endoscopy an ideal option for surgical care of gynecologic problems in space flight.

Conclusions The possibility of long-duration missions aboard the ISS and exploration-class missions to the Moon and Mars makes this potentially an even more challenging and exciting phase for space medicine than the past 46 years. Although space flight was initially seen to be a male preserve, women soon became involved integrally and have performed well. The medical data collected to date regarding women in space flight have been very reassuring. No medical or gynecologic problems have developed that cannot be addressed with current or planned intervention capabilities. Nevertheless, it is safe to assume that innovative and independent medical care capability will be required for exploration-class missions. Moreover, diagnostic, therapeutic, telemedicine, and robotic capabilities as well as crew training in the use of these capabilities will need to be enhanced for long-duration missions. Thus, there is a need to further develop and refine preventive measures and microgravity physiological countermeasures and to enable medical and surgical technologies. Mission success will require assurance that female crewmembers who develop medical, surgical, or gynecologic conditions can be successfully treated. With appropriate attention to planning, it is unlikely that medical problems will impede the participation of women in the exploration of space.

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18. Gynecologic and Reproductive Concerns 5. Rock JA, Fortney SM. Medical and surgical considerations for women in spaceflight. Obstet Gynecol Surv 1984; 39:525–535. 6. National Council on Radiation Protection and Measurements. Guidance on Radiation Received in Space Flight. NCRP Report No. 98, 1989. 7. Merrill JA. Endometrial induction of endometriosis across Millipore filters. Am J Obstet Gynecol 1966; 94:780–790. 8. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14:422. 9. Scott RB, Te Linde RW, Wharton LR. Further studies on experimental endometriosis. Am J Obstet Gynecol 1953; 66:1082. 10. Te Linde RW, Scott RB. Experimental endometriosis. Am J Obstet Gynecol 1950; 60:1147–1166. 11. Fanton JW, Golden JG. Radiation-induced endometriosis in Macaca mulatta. Radiat Res 1991; 126:141–146. 12. McClure HM, Ridley JH, Graham CE. Disseminated endometriosis in a Rhesus monkey. Histogenesis and possible relationship to irradiation exposure. J Med Assoc Ga 1971; 60:11–13. 13. Splitter GA, Kirk JH, Mac Kenzie WF, Rawlings CA. Endometriosis in four irradiated monkeys. Vet Pathol 1972; 9:249–262. 14. Wood DH. Long-term mortality and cancer risk in irradiated rhesus monkeys. Radiat Res 1991; 126:132–140. 15. Wood DH, Yochmowth MG, Salmon YL, Eason RL, Boster RA. Proton irradiation and endometriosis. Aviat Space Environ Med 1983; 54:718–724. 16. Braun DP, Dmowski WP. Endometriosis: abnormal endometrium and dysfunctional immune response. Curr Opin Obstet Gynecol 1998; 10:365–369. 17. Dmowski WP. Immunological aspects of endometriosis. Int J Gynaecol Obstet 1995; 50:S3–S10. 18. Taylor GR, Konstantinova I, Sonnenfeld G, Jennings RT. Changes in the immune system during and after space flight. In: Bonting SL (ed.), Advances in Space Biology and Medicine, Vol. 6. JAI Press Inc. 1997:1–32. 19. Taylor MB. Women in diving. In: Bove AA (ed.), Diving Medicine. 3rd ed. Philadelphia, PA: WB Saunders; 1997:89–107. 20. Andrews WC. What’s new in preventing and treating osteoporosis. Postgrad Med 1998; 104:89–97. 21. Kohrt WM, Snead DB, Slatopolsky E, Birge SJ. Additive effect of weight-bearing exercise and estrogen on bone mineral density in older women. J Bone Miner Res 1995; 9:1303–1311. 22. Naessen T, Persson I, Adami HO, et al. Hormone replacement therapy and the risk for first hip fracture. Ann Intern Med 1990; 113:95–103. 23. Notelovitz M. Estrogen therapy and osteoporosis: principles and practice. Am J Med Sci 1997; 313:2–12. 24. Prince RL, Smith M, Dick IM, et al. Prevention of postmenopausal osteoporosis. N Engl J Med 1991; 325:1189–1195. 25. Cann CE, Martin MC, Genant HK, et al. Decreased spinal mineral content in amenorrheic women. JAMA 1984; 251:626–629. 26. Drinkwater BL, Nilson K, Chesnut CH, et al. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984; 311:277–281. 27. Jones KP, Ravnikar VA, Tulchinsky D, et al. Comparison of bone density in amenorrheic women due to athletics, weight loss and premature menopause. Obstet Gynecol 1985; 66:5–8. 28. Lane N, Bloch DA, Jones HH, et al. Long distance running, bone density, and osteoarthritis. JAMA 1986; 255:1147–1151. 29. Lindberg JS. Exercise induced amenorrhea and bone density. Ann Intern Med 1984; 101:647–648.

389 30. Lloyd T, Myers C, Buchanan JR, et al. Collegiate women athletes with irregular menses during adolescence have decreased bone mineral density. Obstet Gynecol 1988; 72:639–642. 31. Lloyd T, Triantafyllou SJ, Baker ER, et al. Women athletes with menstrual irregularity have increased musculoskeletal injuries. Med Sci Sports Exerc 1986; 18:374–379. 32. Marcus R, Cann C, Madvig P, et al. Menstrual function and bone mass in elite women distance runners. Ann Intern Med 1985; 102:158–163. 33. Myburgh KH, Hutchins J, Fataar AB, et al. Low bone density is an etiologic factor in stress fractures in athletes. Ann Intern Med 1990; 113:754–759. 34. Prior JC, Cameron K, Yuen BH, et al. Menstrual cycle changes with marathon training: anovulation and short luteal phase. Can J Appl Sports Sci 1982; 7:173–177. 35. Russell JB, Mitchell D, Musey PI, et al. The relationship of exercise to anovulatory cycles in female athletes: hormonal and physical characteristics. Obstet Gynecol 1984; 63:452–456. 36. Shangold MM, Levine HS. The effect of marathon training upon menstrual function. Am J Obstet Gynecol 1982; 143: 862–869. 37. Shangold M, Rebar RW, Wentz AC, et al. Evaluation and management of menstrual dysfunction in athletes. JAMA 1990; 263:1665–1669. 38. Corson SL. Oral contraceptives for the prevention of osteoporosis. J Reprod Med 1993; 38:1015–1020. 39. Cummings DC. Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med 1996; 156:2193–2195. 40. DeCherney A. Bone-sparing properties of oral contraceptives. Am J Obstet Gynecol 1996; 174:15–20. 41. Lohman T, Going S, Pamenter R, et al. Effects of resistance training on regional and total bone mineral density in premenopausal women: a randomized prospective study. J Bone Miner Res 1995; 10:1015–1024. 42. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under age 60 years of age. N Engl J Med 1998; 338:485–492. 43. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641–1647. 44. Davis JR. Medical issues for a Mars mission. Texas Med 1998; 94:47–55. 45. Jennings RT, Santy PA. Reproduction in the space environment: Part II. Concerns for human reproduction. Obstet Gynecol Surv 1989; 45:7–17. 46. Santy PA, Jennings RT. Human reproductive issues in space. Adv Space Res 1992; 2:151–155. 47. Warren MP. Effects of space travel on reproduction. Obstet Gynecol Surv 1989; 44:85–88. 48. National Council on Radiation Protection and Measurement. Limitation of Exposure to Ionizing Radiation. Bethesda, MD: National Research Council; 1993. NCRP Report No. 116. 49. Mole RH. Consequences of pre-natal radiation exposure for post-natal development. A review. Int J Radiat Biol Relat Stud Phys Chem Med 1982; 42:1–12. 50. Mole RH. Radiation risks to the individual in utero. Report of a scientific symposium: Radiation risks to the developing nervous system. Int J Radiat Biol Relat Stud Phys Chem Med 1986; 49:183–189.

390 51. Otake M, Schull WJ. In utero exposure to A-bomb radiation and mental retardation; a reassessment. Br J Radiol 1984; 57:409– 414. 52. Otake M, Schull WJ, Lee S. Threshold for radiation-related severe mental retardation in prenatally exposed A-bomb survivors: a reanalysis. Int J Radiat Biol 1996; 70:755–763. 53. Reyners H, Gianfelic de Reyners E, Poortmans F, et al. Brain atrophy after foetal exposure to very low doses of ionizing radiation. Int J Radiat Biol 1992; 62:619–626. 54. Devi PU, Baskar R. Influence of gestational age at exposure on the prenatal effects of gamma radiation. Int J Radiat Biol 1996; 70:45–52. 55. Santy PA, Jennings RT, Craigie D. Reproduction in the space environment: Part 1. Animal reproductive studies. Obstet Gynecol Surv 1989; 45:1–17. 56. Snetkova E, Chelnaya N, Serova L, et al. Effects of space flight on Zenopus laevis larval development. J Exp Zool 1995; 273:21–32. 57. Suda T. Lessons from the space experiment SL-J/FMPT/L7: the effect of microgravity on chicken embryogenesis and bone formation. Bone 1998; 22:73S–78S. 58. Suda R, Abe E, Shinki T, et al. The role of gravity in chick embryogenesis. FEBS Lett 1994; 340:34–38. 59. Wong AM, DeSantis M. Rat gestation during spaceflight: outcomes for dams and their offspring born after return to earth. Integr Physiol Behav Sci 1997; 32:322–342. 60. Kirkpatrick AW, Campbell MR, Brenneman FD, et al. Trauma laparotomy in space: a discussion of the potential indications, conduct of operation, and technical support for the treatment of abdominal trauma during long-duration space exploration. Presented at the 28th International Conference of Environmental Systems, Danvers, MA, 13–16 July 1998. SAE Technical Paper Series 981601.

R.T. Jennings and E.S. Baker 61. Kirpatrick AW, Campbell MR, Novinkov OL, et al. Blunt trauma and operative care in microgravity: a review of microgravity physiological and surgical investigations with implications for critical care and operative treatment in space. J Am Coll Surg 1997; 184:441–445. 62. Smith RS, Fry WR, Morabito DJ, et al. Therapeutic laparoscopy in trauma. Am J Surg 1995; 170:632–637. 63. Townsend MC, Flanebaum L, Choban PS, et al. Diagnostic laparoscopy as and adjunct to selective conservative management of solid organ injuries after blunt abdominal trauma. J Trauma 1993; 35:647–651. 64. Campbell MR, Johnston SL. Surgical bleeding in microgravity. Surg Gynecol Obstet 1993; 177:121–125. 65. Campbell MR, Billica RD, Johnston SL. Animal surgery in microgravity. Aviat Space Environ Med 1993; 64:58–62. 66. Campbell MR, Billica RD, Jennings RT, et al. Laparoscopic surgery in weightlessness. Surg Endosc 1996; 10:111–117. 67. Campbell MR, Billica RD. A review of microgravity surgical investigations. Aviat Space Environ Med 1992; 63:524–528. 68. Markham SM, Rock JA. Deploying and testing an expandable surgical chamber in microgravity. Aviat Space Environ Med 1989; 60:76–79. 69. McCuaig K. Aseptic technique in microgravity. Surg Gynecol Obstet 1992; 175:466–476. 70. Rock JA, Hesla JS, Repke JT, et al. A surgical isolation system for gynecological and obstetrical surgery. Am J Gynecol Health 1989; 3:126–129. 71. Mutke HG. Equipment for surgical interventions and childbirth in weightlessness. Acta Astronautica 1981; 1:399–401. 72. Colvard M, Kuo P, Caleel R, et al. Laser surgical procedures in the operational KC-135E aviation environment. Aviat Space Environ Med 1992; 63:619–623.

19 Behavioral Health and Performance Support Christopher F. Flynn

This chapter reviews the stressors and countermeasures that affect crew behavioral health and performance during space flight. This review is based on the experiences of crewed space flight in both the Russian and U.S. programs, including Space Shuttle flights lasting from 1 to 3 weeks, Mir space station flights lasting longer than 1 year, and findings from analog environments that are similar in terms of isolation and other features to the in-flight environments on the Space Shuttle and on the Mir and International Space Stations (ISS). Significant physical and psychosocial stressors challenge crews during mission training, space flight, and mission recovery. In fact, at least one crew has been dissolved before a longduration flight because of incompatibility [1]. Severe stress experienced by crews during Mir and NASA-Mir flights probably contributed to mission-limiting cardiac dysrhythmias and the appearance of emotional symptoms among crewmembers [2,3]. Fatigue and overwork conditions have also affected longduration crews. Journalists have identified these conditions as important factors contributing to the depressurization accident on the Mir space station in 1997 [4]. Psychological stressors known to have affected long-duration crews include the death of a family member; significant interpersonal frictions, both between crewmembers and between space crews and ground crews; overwork and “underwork”; and life-threatening “nearevacuation” events on board a spacecraft, which to date have included fire, depressurization, and loss of power. Although Russian space mission aborts were officially related to diagnoses of intractable headaches, chronic prostatitis, and cardiac dysrhythmias, behavioral conditions were equally important in the early termination of these missions [5,6]. Both flight surgeons and crewmembers must be aware of these stressors and the countermeasures that need to be taken to maintain the behavioral health and mission performance of a crew. This chapter offers space medicine clinicians a focused approach to the known risks to behavioral health and performance by focusing primarily on the long-duration mission. An overview of likely problems with behavioral health (both psychiatric and psychological) and performance of long-duration crews is also provided, as is an outline of potentially helpful

countermeasures. Operational medicine experts who have reviewed pertinent space analog and spaceflight data agree that behavioral problems are one of the most significant influences on mission success [5,7]. After such a disorder has been identified, it must be aggressively treated to prevent the deterioration of crew health and mission performance.

Maintaining Crew Performance and Behavioral Health Role of the Flight Surgeon The relationship between flight surgeons and their crews is critical for addressing spaceflight factors that will affect crew performance. The great reluctance of professional aviators to being considered in less-than-optimal condition is a widely accepted psychological finding [8–11]. Professional aviators, astronauts, and cosmonauts generally are extremely self-sufficient, hardworking, and success driven [12–14]. Although these traits are of tremendous benefit to a crew that must complete its mission objectives under adverse conditions, the downside is the aversion of individual crewmembers to reporting any perceived “illness.” Indeed, crewmembers are likely to consider an admission of task saturation, over-fatigue, excessive stress, or concentration-impairing clinical depression as a personal failure. Rather than reporting these conditions to get help in dealing with them, it is far likelier that a crewmember will try to remain stoic about them, thereby retreating from appropriate help. The dilemma for flight surgeons is that they will not be able to help without first receiving the crewmember’s report. This is especially unfortunate because aggressive intervention is likely to produce a good outcome [15–19]. Thus flight surgeons must be prepared to listen to a crewmember’s report of distress in a manner markedly different from the way in which physicians would normally listen to a patient’s report. Humans display psychological distress by speaking about it, when they are more self-aware, or by demonstrating distress through a change in behavior, when they 391

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are less self-aware. Sometimes they use both methods [20]. For this reason, flight surgeons should pay close attention to both obvious and subtle characteristics of an interaction with a crewmember, because flight crewmembers can be so successful at “compartmentalizing” (i.e., denying the existence of) emotionally distracting thoughts and feelings that sometimes they may not be fully aware of their own significant level of stress. The wise flight surgeon would not ignore even an indirect hint of difficulties from a crewmember. However, this does not mean that the flight surgeon should aggressively question a crewmember, for aggressive questioning can generate a strong defensive reaction against “prying.” [17,21] Instead, flight surgeons should encourage further discussion. They should leave the door open to more visits and attempt to get a better understanding of the crewmember’s concerns, pay more attention to how that crewmember is doing at work and at rest, consult with a behavioral specialist when available and, when data are supportive of a conclusion, share this information with the crewmember and propose a solution. Astronauts, cosmonauts, and aviators all have a tremendous advantage over the general population in terms of correcting their behavioral health problems owing to their overall intelligence, adaptability, and problem-solving skills. Once a problem has been clearly identified by such individuals, it is highly likely that the problem will be corrected. One good example is the welldocumented treatment and occupational recovery of aviators treated for alcoholism [15,18,19]. The worst-case scenario is a crewmember who is reacting to emotional distress who does not seek help and is demonstrating a negative change in personality and behavior. Such a crewmember may well “act out” in excessive, perhaps riskseeking behaviors, as if needing to “prove something,” and has temporarily lost the ability to exercise good judgment. When questioned about it, the crewmember will deny any significant stressor, although collateral history will confirm the appearance of new behaviors that are the equivalent of a flashing neon sign giving warning. Aptly termed a “failing aviator,” such an individual is not going to “go quietly.” [22] Unfortunately, despite the need for help, this crewmember will typically push away those who wish to help until a powerful person in the crewmember’s life forces a change. This powerful person may be a supervisor, a spouse, a pastor—someone who will put a limit on destructive behaviors and demand intervention. In light of the physical and emotional demands of space flight, crew health will suffer unless flight surgeons can work successfully with all members of the crew to which he or she has been assigned. If a flight surgeon has been able to earn the trust of a crew and their close family members before flight, he or she can develop a partnership with that crew that encourages problem identification and problem solving. By using a supportive relationship, flight surgeons can learn about each crewmember’s usual response to stress as well as their typical coping skills. When stress begins to build later, the observant flight surgeon can identify changes in behavior early, without

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talking about stress, and can help redirect crewmembers to resume their typical coping measures. To maintain the wellbeing of a crew, flight surgeons must be aware of the physical and behavioral stressors of space flight and be able to build a supportive, trusting relationship with each crewmember.

Role of the Family Regardless of a crewmember’s self-sufficiency, family stability is understood to be a very important stress-coping factor in health and a significant factor in flight safety [23–26]. The pressures of space flight can strain even the best of family relationships, especially when preflight training deployments may take a crewmember away from home for as much as half the year. Deployments such as these are typically followed by total separation during a 4- to 6-month flight. Upon return to Earth, the crewmember’s expectant family, which has survived its own stresses and strains during the mission, welcomes home a physically limited and emotionally exhausted person, which creates an additional burden on the family. Flight surgeons must consider the stability of a family relationship when assessing an astronaut’s or cosmonaut’s preparation for a 4- to 6-month mission. Key issues to consider include an imminent divorce, an overwhelmed and angry spouse, a severely ill child, and the family’s and crewmember’s response to continued separation. In these situations, talking to a behavioral health consultant to identify mission risk would be advantageous to the flight surgeon.

Role of the Mission The isolated and confined environment of space flight, combined with the intensity of small-team operations, creates an environment that has its own unique and powerful stressors. The timeline of a short-duration mission keeps a crew scheduled to the minute, with a demanding and sometimes impossible workload. Even when interpersonal friction exists between crewmembers, time passes quickly because of the brief time spent on orbit and the high workload. Although the pressure to complete all tasks before return can greatly affect time for sleep and exercise, the shorter training time before flight and the brief physiologic recovery time after landing are relative advantages for short-duration crews. Long-duration crewmembers, on the other hand, typically experience 18–48 months of preflight training. Although this training takes place on Earth and typical coping techniques can be used, these crewmembers are often separated from their families and from other culturally familiar means of relaxation. Stress begins to build. Unless this stress is reduced, long-duration crewmembers will carry it on their rigorous and demanding missions. Once in orbit, crewmembers are isolated from their typical coping mechanisms, confined with their crewmates, and facing the inevitable physical deterioration from microgravity. On landing day, when relief might be expected, they face a legion of doctors and scientists who

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poke, prod, inject, collect, and analyze them before they can really be considered as having returned from space flight.

Approach to Maintaining Performance Flight surgeons must understand the behavioral problems that limit crew performance. At NASA’s Johnson Space Center, attention is focused on four key elements that support crew behavioral health and performance support. This approach is built from a simple model in which performance is defined as a two-step process—to think and to act. According to this model, crews first assimilate information cognitively and decide on a course of action based on previous training, current situational awareness, and anticipated threats to the mission (think). The crews must subsequently have the motivation, sense of purpose, and physical strength and coordination to carry out the course of action (act). When performance is considered from the behavioral perspective, several basic elements contribute to the ability to think and to act: sleep and circadian physiology; behavioral health; psychological adaptation; and the human-system interface in the on-orbit workplace. Sleep deficit and circadian “troughs” (periods in which alertness and concentration are at their nadir) significantly affect clarity of thought and psychomotor aptitude; these constitute issues of sleep and circadian health [27–33]. A healthy individual has a brain that is neither injured nor exposed to toxins and is not experiencing psychiatric illness (behavioral health). When this person is isolated from family and the usual coping skills, confinement and small-team operations require the use of countermeasures to maintain that person’s motivation to perform (psychological adaptation). These countermeasures are important in an environment where improper work schedules may not allow sufficient time for completing assigned work, where inappropriate task sequencing may hinder efficient completion of those tasks, where poor workplace design and environmental conditions may sap motivation, and where inadequate tools with which to maintain mission-critical skills throughout flight may be provided, thereby limiting effectiveness (humansystems interface issues). These four elements are closely interrelated. For example, inadequate sleep and circadian desynchrony (jet lag) can affect an individual’s concentration and mood. Depression decreases motivation. In the confined spaceflight environment, small-team operations must adapt accordingly; teamwork can help accomplish tasks more efficiently, decrease workload, and improve motivation. An overbooked work schedule will lead to extension of the working hours, which in turn creates sleep loss. Thus flight surgeons should consider each of these four elements—psychological adaptation, sleep and circadian rhythms, human-to-system interfaces, and behavioral health—in enabling crew performance to be maintained. Each element is described in further detail in the following section.

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Expected Behavioral Problems Arising from Space Missions Psychological Adaptation Problems Problems with psychosocial adaptation cause deterioration in crew cohesion and crewmember motivation. Such deterioration has been identified in both space analog studies (e.g., polar teams, submarine crews, and aviation operations) and observations of space flight crews, especially from the Russian cosmonaut medical care system. Important preflight stressors that can affect crews include family separation and cultural misunderstandings [2] as well as the risk of injury during rigorous physical activities, particularly survival training or extravehicular-activity training that could prevent a crewmember from being certified for flight. After flight, the crew’s readaptation to family living and the demands of the workplace requires significant awareness and effort. International space crews may encounter cultural differences in leadership style, communication, preflight training, identification of in-flight mission success criteria, and postflight differences in schedules, all of which may lead to friction [34]. Cultural differences in the workplace have the potential for producing nearly constant friction or irritation in interpersonal interactions that can break down team communication and coordination [35]. Despite the best intentions of crewmembers, unless cultural differences are recognized and accounted for during mission preparation, such differences have a high likelihood of negatively affecting mission success [35–38]. In one analog study in which measurements of stress were begun before the mission, scores did not drop significantly between preflight training and the first highly stressful weeks of the mission. This finding suggests that preflight stress is significant and must be managed to prevent launching an already exhausted crew [36]. Once a mission is under way, stress to the crew arises from isolation from the usual coping mechanisms, confinement, dependence on a very small team of colleagues for emotional and work support, physical deterioration, and increased reliance upon distant assistance or management teams, which limits personal autonomy. If not properly addressed, the stress on crewmembers, individually and as a group, can affect the beginning, the midpoint, or the “[third] quarter” of the mission [3,39–43]. Studies of stress experienced by isolated teams in space analog settings suggest that a range of common psychological adaptation complaints can flare at these times, including mild cognitive impairment, disturbances in time sense, motivational decline, sleep deprivation, psychosomatic symptoms, anger, anxiety, depression, social conflict, and social withdrawal [42,44–46]. An important distinction to be made is that between “symptoms” and “disorders.” Although teams preparing to “winter over” in Antarctica were screened psychologically and psychiatrically before their missions, ∼12% still experienced significant psychological adaptation symptoms, and 3% developed full psychiatric disorders

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[47]. In the U.S. experience during seven missions aboard the Russian space station Mir, which lasted from 115 to 188 days, only one astronaut reported experiencing significant in-flight depressive symptoms, thus reflecting a similar 14% incidence of problems [3]. Additional problems that commonly arise in isolated groups include interpersonal tension, the development of subgroups, and the tendency to restrict communication with distant support team personnel. If the group is multinational, subgroups may form along national lines in response to the commander or the external management. Isolation and confinement can worsen subgroup friction [46,48–50] and break down the subgroups further. Such breakdowns in crew cohesion have been noted in space flight as well [1,38]. In summary, findings from both space analog settings and spaceflight missions suggest that neither crewmember selection nor professionalism can prevent all of the problems that arise from the psychosocial stressors experienced by spaceflight crews.

Sleep and Circadian Problems Sleep deficit and circadian desynchrony occur in spaceflight crews when excessive workloads break the work-rest cycle, when emergencies interrupt normal sleep scheduling, and when mission requirements (e.g., extravehicular and docking activities) are scheduled during normal sleep periods. Events such as these can occur before, during, and after flight. Sleep and circadian stressors begin with the preflight training deployments that result in jet lag. Key problems associated with this are reduced ability to concentrate and changes in mood. In the course of landing, crews may return to a landing site that is not operating at on-orbit time; moreover, they may experience desynchrony again during a transoceanic flight home. Changes in the physiology of sleep are similar in spaceflight crews and in polar winter-over teams, as both environments involve loss of normal day - night cues. In a study of teams wintering over in Antarctica, subjects experienced a complete absence of stage IV sleep and sizable reductions in the amounts of stage III and rapid eye movement sleep [51]. Occasional use of sleep encephalographic recordings to document changes in sleep physiology in spaceflight crews has produced inconsistent findings. For example, a dramatic lessening of delta sleep (stages III and IV) was noted in one study but not in another, and rapid eye movement latency was found to have shortened more in one study than in another. However, other more consistent findings have been minimal circadian phase disruption and that, at present, the factors that reduce adequate sleep on orbit are workload, the effect of microgravity, and the discomforts of the spaceflight environment [52 –54]. Because of work demands, an average night’s sleep for a spaceflight crewmember, regardless of the duration of the mission, is slightly more than 6 h [55,56]. Flight surgeons therefore should recognize that moderate performance decrements and

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increased sleepiness have been noted in air traffic controllers (work that involves cognitive skills) after restriction to 5 h or less of sleep. Performance and levels of alertness are impaired after as little as 2 h of an individual’s normal sleep time is lost—and crewmembers’ normal sleep times are not measured before flight in the U.S. space program. Tasks involving cognition and vigilance are among the first to be affected when the amount of sleep is suboptimal. Most critically, a tired individual rarely recognizes that he or she has “dozed off” from excessive fatigue [27–33]. In brief, long- or short-duration spaceflight crews can be expected to incur substantial risks to performance because of expected problems with sleep deficit and circadian desynchrony.

Human-to-System Interface Problems This subsection outlines anticipated problems at the interface between the crewmembers, their environment, and their work schedules. This interface problem is made more complex by individual variation in the response to the spaceflight environment, such as the duration of space motion sickness symptoms; the adaptation time needed to demonstrate effective psychomotor skills in microgravity; the time needed to train, retrain, and sharpen mission critical skills; personal workload limits; task saturation; the physical “fit” to workstations and space suits; work relationships with ground management teams; the time required for physical and emotional postflight recovery; and variations between the crewmember’s and the space agency’s definitions of what constitutes mission success. Flight surgeons must remain alert to the ways in which a crew can be affected by these factors in the operational environment. Since each crewmember has a unique way of learning material before flight, crewmembers can benefit from individualized preparation and retraining materials. This benefit can translate into the mission itself where each crewmember, although part of a group, is likely to feel isolated in the alien atmosphere of space. Isolation negatively influences cognitive capabilities and task performance. In a study of 16 people who wintered over in an Antarctic station, expected improvements in complex task skills and a prospective memory task did not occur over the course of the mission [57,58]. Astronauts or cosmonauts thus need to understand how to retain missioncritical skills for long periods after their preflight training. Since many months can elapse between preflight training and completion of a task on orbit, the potential for in-flight error must be prevented to maintain optimal performance. Although work monotony creates stresses for the longduration crewmember, the extreme time pressure in a shorter flight also creates stresses as well [42,46]. Nominally, scheduling limits the workday to fewer than 8.5 h; but with exercise, meals, and hygiene activities, the workday easily stretches to 13 h. The history of crewed space flight suggests that despite the best effort of flight activities managers, ground schedules

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rarely reflect the on-orbit reality. This discrepancy is because flight schedules, which are based on terrestrial work times, are optimized before flight to fit as many operational tasks, projects, and experiments as possible into the crew schedule—not to satisfy an individual crewmember’s work limits, primarily because schedulers expect that fully trained crewmembers will be able to meet the operational expectations of the schedule, and not the other way around. On orbit, the reality is that equipment for planned use may be difficult to locate, and equipment malfunctions can lengthen the time needed to complete a task. Space motion sickness can negatively affect a crewmember’s efficiency, and contingencies will disrupt timelines. Crew performance suffers as workloads build and task saturation occurs, thus impairing a crew’s attention to detail and increasing the risk of error [42,43,50,59,60]. When time spent on a physically demanding task extends past the scheduled time, physical overuse injuries can result. Moreover, if a space agency’s definition of mission success requires completion of all scheduled tasks, the crewmembers may face an impossible dilemma—to continue to work with impaired performance or to reduce work and risk mission success. Differences in expectations of work completion have historically created tensions between ground managers and mission crews, adding to stress levels and hampering communications [39,48,61,62]. Poor performance by the support team in their preflight, in-flight, and postflight assistance to a mission crew can grind communications and teamwork to a halt. This is not only a psychological issue, but a workplace management issue as well. After flight, a lack of individual fit to the work schedule can lead to crew frustration and anger because many managers and some crewmembers consider the end of the flight to be the end of the mission. However, mission related tasks extend for months and, for some life science experiments, years after the end of the mission. This misconception that the crew is free once the spacecraft has landed tends to push the individual crewmember toward too early a reintegration into a space agency’s “ground-based” work responsibilities [34]. Despite the fact that the crewmember has just returned to Earth, physically debilitated from microgravity and emotionally distanced from family members, he or she begins to reorient to high workload expectations that are more appropriate to individuals who have never left Earth. Careful management and explicit support is required for the crew to successfully counteract the final mission problems of physical debilitation and emotional distancing from the family. Flight surgeons must therefore be strong advocates for crews to stay focused during this necessary part of the mission, which in the Russian system lasts for as long as 3–4 months after return to Earth.

Behavioral Health Problems Behavioral health problems that affect performance include psychiatric and cognitive disorders. Before, during, and after flight, problems with psychological adaptation, the human-system

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interface, and sleep or circadian stressors can, if sufficiently severe, lead to disorders that require healthcare intervention. Even without these stressors, the onset of a new behavioral illness in an astronaut or a cosmonaut is quite possible because of the natural occurrence of these disorders. A review of polar analog and submarine studies reveals that 1–4% of team members developed frank psychiatric illness during 4–8-month missions [47,63] despite careful psychiatric and psychological screening at the time they were selected. This finding underscores the importance of selection in reducing the impact of negative behavioral health events on the mission, even though the selection process does not completely prevent the occurrence of such events. Postflight readaptation is a significant stressor both for crewmembers and for their families, because both are dealing with the burdens of a mission that is continuing with postflight medical data collection, mission debriefings, and public affairs demands. Any family problems that were present before flight will not have evaporated, and new problems will have been experienced during the mission. Reconnecting between family members is stressful. Studies of readaptation in military families suggest that up to 5% of families developed significant problems during the 3 months after return and that these challenges may not lessen any sooner than that [2,64–67]. Behavioral health problems noted in analog populations have been primarily categorized as characterological (personality disorder) or emotional (mood, thought, psychosomatic, or anxiety disorders) [2,68]. In a review of 150 subjects participating in Soviet isolation experiments lasting from 7 to 365 days, Gushin et al. reported “apathy, anxiety, depression, illusions, [and] hallucinations” in subjects, although the report did not mention whether full disorders were present or whether any missions were terminated early because of these conditions [42]. Similarly, in-flight neurophysiological changes effected by microgravity have not been clearly characterized, although neurotransmitter effects are suspected from documented alterations in peripheral catecholamines and sleep [46,52–56] and from minor changes in cognition [42,58,69–71]. Although animal studies have demonstrated that stress-related neuronal changes can develop from the effects of space flight, limitations in on-orbit molecular-level study restrict the pertinence of this finding in humans [72]. In fact, Russian physicians believe that the cosmonauts are likely to develop “asthenia,” a condition described as “nervousness and mental weakness manifesting as tiredness, quick loss of strength, low sensation threshold, unstable mood, and sleep disturbance,” [46] during space missions that last 4 or more months [73]. Myasnikov and Zamaletdinov have also described other expected “states,” including euphoria, depression, neuroses, and accentuation of negative personality changes [46]. Whether these states occur simply as symptoms or as full behavioral health disorders is unclear, but anecdotal reports suggest that behavioral health problems have been severe enough to contribute to the early return of three long-duration mission crews (Soyuz-21 in 1976, Soyuz-T14, in 1985, and Soyuz-TM2 in 1987) [6].

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C.F. Flynn Table 19.1. Ages at which new psychological disorders typically appeara.

Changes in cognition must also be considered a threat to on-orbit crew performance. Recognized risks for neurologic or cognitive insults include exposure to toxic substances, traumatic head injuries, hypoxia, decompression, electrical injuries, and adverse reactions to medication. Anecdotal findings on cognitive effects during long-duration missions suggest that crews have experienced time and space distortions, decreased task performance over time, mental inertia, difficulty concentrating, memory problems, and slowing of intellectual activities [74]. However, objective measures obtained in the 1990s have shown only minor, albeit consistent cognitive changes such as increased response time to testing, reduced accuracy of response, impaired performance on dual-task tracking, and changes in visual-spatial recognition capability [69,75,76]. In one long-duration flight study, these alterations were more problematic in the first 10–20 days of flight and did not persist afterward [69,70,77]. Finally, flight surgeons must consider the risk of behavioral illness based on the incidence of illness in the crewmember’s country of origin. For example, during any 1 year in the United States, at least 8% of men and 13% of women will experience major depression [78], the third most frequent diagnosis in U.S. adults aged 25–64 years [79]. International differences must also be considered; for example, the annual rate of new cases of depression diagnosed in Taiwan is more than 3 times less than that in the United States and more than 6 times less than that in Alberta, Canada [80]. Nevertheless, major depression, manic depressive disorder, and obsessive-compulsive disorder are highly likely to develop for the first time in North American and Western European individuals aged 25–70 years (Table 19.1) [81]. The need to remain vigilant for behavioral illness after selection is underscored by findings that nearly half of all waivers for psychiatric disorders for U.S. Naval aviators were requested for those who were older than 30 years [16]; in another study, U.S. Air Force aviators who required psychiatric hospitalization ranged in age from 30 to 45 years [15]. Therefore, flight surgeons must recognize the continuing risk that a spaceflight crewmember may develop a new psychiatric disorder, even when no such history is present.

Alcohol Abuse/dependence

Countermeasures I: Monitoring and Prevention Strategies

Monitoring

After recognizing the multiple stressors that can affect a crew, a flight surgeon would be wise to enlist specialists to help in monitoring the behavioral health and performance of individual crewmembers to prevent any serious deterioration. At Johnson Space Center, the behavioral health and performance group that assists flight surgeons consists of individuals skilled in aerospace psychology, occupational and industrial psychology, occupational and aviation psychiatry, clinical psychology, and clinical psychiatry. This group also collaborates closely with specialists in human factors, professional training and development, and flight medicine. Although this psy-

Ranking: Age range Disorder

Men aged 25–64 years

Women aged 25–64 years

Major Depression

1: 25–29 4: 30–34 and 35–39

Bipolar (manic depression)

3: 25–29 and 55–59

2: 25–29 4: 30–34 5: 35–39 2: 25–29

4: 35–39, 45–49 and 60–64 Obsessive Compulsive

Panic

1: 35–39 2: 30–34 3: 25–29 4: 60–64 5: 40–44 and 50–54 1: 30–34 2: 40–44 4: 35–39 5: 25–29 3: 25–29 4: 30–34 and 35–39 5: 45–49

3: 30–34 and 35–39 4: 45–49 and 55–59 3: 25–29 4: 30–34 5: 50–54

1: 25–29 2: 30–34 4: 35–39 5: 40–44 3: 25–29 4: 30–34 5: 35–39

a The rankings shown are from life tables of individuals aged 25–64 years, the age range typical of the U.S. astronaut corps. Source: Data from Burke et al. [81].

chological support group was not modeled after the Russian psychological support group, the specialties represented in the 2 groups are very similar; both groups focus on improving the changeable aspects of a crewmember’s personal factors and work environment, namely knowledge, experience, capabilities, workload, work schedules, fatigue level, coping skills, mood, and motivation [82]. Long-duration mission crews require psychosocial support to maintain motivation and coping capabilities. In this respect, preventive countermeasures problems that need to be addressed include primarily selection, preflight training, and preflight/in-flight/postflight psychosocial support of crewmembers and their families.

In the U.S. program, monitoring a crew’s adaptation to the spaceflight environment is based largely on self-reports received from the crews. A crewmember can report a change in adaptation in several ways, e.g., through weekly scheduled private medical conferences with the flight surgeon, electronic correspondence, or twice-a-month scheduled private psychological conferences with a representative of the behavioral health and performance group. The Russian spaceflight program includes an additional step—analysis of communication between ground and space crews—that uses a psycholinguistic method to rate a cosmonaut’s adaptation to space flight.

19. Behavioral Health and Performance Support

Prevention Selecting-In During selection of astronaut applicants in the U.S. space program, the behavioral health and performance group works to identify individuals who bring well-developed teamwork and coping skills to the program (“select-in”), as well as to identify individuals who are at increased risk for behavioral illness stemming from the spaceflight environment (“select-out”) [12,25,83–85]. Generally, although use of psychological tests and specialist interviews is more similar than different among International Space Station partners, some partners also recommend use of rigorous computerized simulation, confinement in a test chamber, and field training exercises [39,86–88] in the evaluation process.

Training After being selected, U.S. astronaut-candidates’ psychological adaptation skills are sharpened through seminars and field exercises that teach the candidates about the challenges of isolation, confinement, cultural differences in team members, psychological self-awareness and self-regulation, small-team operations, leadership, and “followership.” [85–90] Recommended training includes having the astronaut-candidates work in small groups of 2–6 individuals with experts who have reviewed polar and spaceflight expeditions. Participation in field exercises in difficult and isolated environments (e.g., winter and water survival training, confined-chamber training) give these men and women the chance to experience their own reactions to challenging operations and offers them the opportunity to develop better self-awareness of the more challenging aspects of these environments and to learn new coping techniques or confirm the usefulness of seasoned coping techniques. Teamwork skills also can be developed [85,88]. Once a mission crew has been formed, mission training events may be observed to identify potential problems with crew compatibility [1,50,88,91]. If compatibility problems occur and cannot be remedied before flight, the crew should be dissolved—as has occurred at least once in international space flight [1].

Communication Communications with family remain a critical coping mechanism for deployed or on-orbit crews. Ensuring a crewmember’s ability to communicate with home is a central effort of psychosocial support. Astronauts and cosmonauts report that making connection with their families is one of the most enjoyable times in flight [2]. Cosmonaut Lyakhov, on his Salyut-7 mission, said, “For us the letter [from home] is an extraordinary event. We read [it] over and over many times.” In the same mission, Cosmonaut Aleksandrov stated, “I received a letter from [my wife] via Teletype. More joy…” [89] Weekly audio or video conferencing is available to deployed crews during preflight training, a capability that continues into the mission. Family communication time must be scheduled into

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the mission timeline, currently at a minimum of 15 min per week. Crewmembers also are launched with computer-based “family albums” that include electronic photos, video and audio clips, and special-event messages from family members to offer additional reminders of home. These help families communicate, even without two-way connections. E-mail has also become an important asset to maintain communication between the crewmember and his or her family, as well as facilitating in-flight communications between the crew and the ground support team.

“Active Rest” A leisure support plan is developed with each crew before flight with the goal of assembling as many items as possible to be sent into orbit with them. Leisure support may include favorite computer software, music on compact discs, electronic and paperback books, and films on videotapes or digital videodiscs. A leisure activity library on board the International Space Station includes electronic books and popular movies. Resupply vehicles also provide a means of delivering, about once every 3 months, ∼4.5 kg (10 lb) of special-request foods, videotapes, compact discs, and letters from Earth to crewmembers [86].

Family Support Families must not only endure preflight separations for training but also manage the normal fears and struggles of having a loved one in a distant and hostile environment. They must also be ready to give extra support when that family member returns to Earth. As much as crewmembers require support to maintain optimal performance, family members also benefit from communication with that crewmember and the Earth-based extended family and from learning about the stressors they can expect and the support they will receive to help them meet expected and unexpected family needs. The behavioral health and performance group works with crew families to maintain communication flow, to coordinate and provide education on cultural aspects of the crew (to help during crew and family gettogethers), and to provide information on stress points during long-duration missions. Before flight, the family actively participates with the psychosocial support staff in preparing the family album that goes into orbit with a crewmember, in planning communication events, and in supplying special surprises for resupply packages. These activities keep crew families involved in the mission and keep them aware of their own importance in maintaining a crew’s behavioral health and performance.

Monitoring and Preventing Sleep and Circadian Health Problems Monitoring The use of hypnotics for aiding sleep on orbit by nearly 30% of crewmembers [56,72,92] demonstrates that crews are

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concerned about getting sufficient sleep on orbit. The major issue confronting them is the degradation of performance from sleep deficit and from work being performed during circadian troughs. Experience shows that the hardware required to monitor sleep deficits and circadian problems can be aggravating to the point where a crewmember may be reluctant to gather data even when the tools are available. At present, sleep hours and circadian phases are monitered indirectly from the ground-based work-rest schedule. Not surprisingly, this method is inaccurate; the ground team may be unaware that a crewmember, after signing off for the night, has continued to work into his or her scheduled sleep time. Until crews have convenient objective monitors, self-reporting remains the only tool with which to monitor the sleep and circadian problems that crews experience. Advances in actigraphy, in which a wristwatch-sized activity monitor is worn on an individual’s nondominant wrist to monitor movement and sleep patterns, have advanced sleepmonitoring techniques and show promise for spaceflight application. Actigraphy is less cumbersome than having to assemble and wear monitoring electrodes, and except for downloading the data it does not add any work to an already full workload. Sleep studies of non-spaceflight workers wearing actigraphs or participating in sleep encephalography have revealed that motivated individuals report roughly 1 h of additional sleep than could be validated by objective measures [28]. In other words, the individual reports, in all sincerity, having slept an hour longer than was actually the case, and that individual also expects to be able to perform better than expected if too little sleep had been obtained. Thus even if a crewmember keeps logs of decreased sleep or circadian disruptions caused by working past a planned schedule, reporting these data to the flight surgeon may create another problem for both parties. If a crewmember reports that he or she is not following the schedule, then that crewmember may be reprimanded; however, without an accurate report, the ground support team will continue to expect more work to be accomplished than is possible within the timeline [93].

Prevention One of the best techniques to prevent sleep- and circadianrelated problems in space flight is to follow both on-orbit and postflight schedules. The work-rest schedule created for a crew is organized with the goal of maintaining adequate sleep and a regular circadian cycle, including appropriate sleepshifting schedules. The use of 1 h of the “presleep” period to relax is an excellent sleep-hygiene technique, as long as it is not interfered with by excessive workload. Other nonpharmacologic measures to reduce sleep disturbances include avoiding exercise for several hours before sleep, not consuming caffeinated beverages after the equivalent of 3 p.m., establishing a routine lights-out time each night, and maintaining a comfortable atmospheric temperature. The use of hypnotics can also be helpful. The decision of which hypnotic to prescribe is determined primarily by the period of sleep that is disrupted. Difficulty falling asleep or staying asleep early in the sleep period can be successfully treated with a hypnotic that has a short halflife. Alternatively, when sleep difficulties arise in the middle or the end of the sleep period, agents with longer half-lives may be more useful (Table 19.2). Prolonged use of hypnotics is of concern because of the potential for rebound insomnia, particularly when the use of shorter half-life agents is stopped [98]. Although hypnotics can benefit a crewmember who is suffering from sleep deficit, it is important to recall that hypnotics will not help reset the circadian phase. In other words, even if a crewmember may be getting sufficient sleep, work performed during the circadian trough will be at subotimal levels. Melatonin can be used both before and after flight to promote circadian shifting, but clinical studies have not shown it to be useful as a hypnotic [99]. Since onorbit power constraints preclude the use of light therapy for treating circadian-shift difficulties in crewmembers, scheduling their shifts during their usual sleep times is the primary countermeasure that can be used to optimize circadian influence on performance.

Table 19.2. Selected psychotropic medications for use on orbit. Class of medication Antipsychotic Sedative, antianxiety

Sedative/hypnotic Antidepressant

Hypnotic Nootropic

Provided on Russian missions Chlorpromazine Haloperidol Phenazepam Diazepam

Provided on US missions Haloperidol Diazepam Lorazepam Flurazepam

Amitryptiline Sertraline Nortryptiline Zolpidem Piracetam

Half-life (hours) Therapeutic dosage 3–40 15–30 10–18 20–90 10–20 50–160 9–46 26–66 18–56 2–3 5–7

25–2,000 mg 1–100 mg 0.5–1 mg 2–40 mg 1–6 mg 15–30 mg 100–300 mg/day 50–200 mg/day 50–150 mg/day 5–10 mg 400–800 mg

Abbreviation: BID, twice a day; TID, 3 times a day; QID, 4 times a day. Source: Data from Aleksandrovskiy and Novikov [94], Perry et al. [95], Albers et al. [96], and Jenkins and Hansen [97].

Dosing schedule Daily or BID Daily or BID BID or TID BID or TID TID or QID Daily Daily Daily Daily Daily BID or TID

19. Behavioral Health and Performance Support

Monitoring and Preventing Human-System Interface Problems Some human-system interface issues (e.g., the interior color of a space station, or the location of fixed equipment) cannot be changed, but other problems can be identified and corrected. During a 135-day simulation study, researchers noted that subjects began to allow small degradations to occur in noncritical tasks rather than sacrificing performance on primary tasks [59]. If the stress (e.g., overwork, isolation-confinement) had continued, the next step would have been to not perform noncritical tasks. This method of managing workload, task-shedding, is an effective way to reduce error in the primary task. However, this method can lead to problems on orbit when a crewmember is scheduled to perform multiple tasks that are all considered essential to the mission. The only alternatives then are to shed the task to another crewmember or to increase the individual level of effort in an attempt to maintain performance on all tasks, something that may be impossible for an already exhausted and overworked crewmember to achieve. These findings underscore the importance of recognizing that individual differences in reaching task saturation can be managed to reduce error in complex work environments. The development of flexible work schedules, the accurate prediction of workload, the effective maintenance and retraining of crewmembers to maintain efficiency in completing missioncritical skills, and the limiting of excessive noise, temperature, and off-nominal stowage are countermeasures that will decrease the energy drain on spaceflight crews. In reviewing more than 25 years of military aviation mishaps, researchers concluded that human error occurs not solely because of inadequate rest and circadian desynchrony, but because of a larger combination of problems. These problems, all of which are obstacles to optimal performance, include alterations in visual cues, attempting performance during circadian nadir, increases in cumulative fatigue levels, excessive focus on a single aspect of the work environment, and the inability to appropriately prioritize a sequence of required tasks [loss of situational awareness] [100,101]. Through development of monitoring tools and ways of training crewmembers to recognize and correctly react to these problems, crewmember performance can be maintained. Unfortunately, with regard to research into human-system interface problems, our knowledge and technology has not advanced apace with that in other areas of spaceflight research [51].

Monitoring The Workplace Environment Stowage is a critical issue with regard to monitoring the workplace environment, especially when stowed items interfere with rapid access to required equipment. A work timeline quickly becomes invalid if locating equipment is time-consuming. Problems with stowage may also create insufficient room to

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accomplish assigned tasks. Alexsandrov, during his 150-day Salyut-7 mission, remarked about this stowage problem: “[It] is getting increasingly difficult to move around the working compartment—cases of food and various equipment are everywhere. And we still haven’t taken out the containers with the additional solar batteries from the Kosmos [biosatellite] or more than 10 other large units.” [89] Currently, stowage monitoring is managed before flight by estimating the available volume on orbit. Monitoring of other environmental characteristics (e.g., noise and temperature) and the requisite responses are discussed elsewhere in this book (see chapters 24 and 22). Of importance to crew performance, however, is the effect of factors such as these on cognition and decision-making. Few definitive studies exist today to guide flight surgeons in preventing problems in these areas, other than studies that focus on physiologic injury and decreased stamina in individuals subjected to high levels of noise and temperature [12–104] — aspects of the workplace that can be monitored and adjusted.

Work Effectiveness Various methods are used to monitor work capability with the goal of preventing loss of crew effectiveness through work overload, task saturation, overuse injury, task sequence monotony with decreased attention, and atrophy or degradation of mission-critical skills [60,105]. One strategy involves monitoring the accuracy and timeliness of the completion of a work task (e.g., real-time monitoring of input reaction time or lapses of attention to the task). A considerable difficulty associated with such real-time assessments is the additional engineering required to monitor a crewmember’s current performance, to compare it to that crewmember’s nominal response on that task, and to override the current input if it is inaccurate. Another strategy is to predict work performance by periodically assessing changes in cognitive function scores [59,71] or reaction time [104] on a “representative task.” Problems associated with the representative-tasks method include the limits associated with predicting performance degradation using these tools and the addition of another timelined task into a crewmember’s already full workday [106]. Observing physiological changes (e.g., changes in speech parameters [107], blood pressure, skin resistance, heart rate, [104,108,109] eye activity, electroencephalogram findings [110], respiratory rate, and evoked potentials) [111] is another way of monitoring work effectiveness. This approach requires individualized calibration, has limits in its predictive value, adds hardware for a crew to wear and maintain, and requires baseline measurements on tasks that must be proven to be representative of anticipated mission tasks. Moreover, the microgravity environment also calls into question the validity of using preflight physiological baseline data as an effective on-orbit baseline [112–115]. Workload and work performance are primarily monitored through self-reporting, but this approach also has its limits. Individuals tend not to be able to accurately

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judge impairments in personal performance when they are overworked. In one review of workload assessment, aviators consistently rated their workload at 60–70% of capacity, even when they were task-saturated and their performance had significantly degraded [110]. The strengths and limits of these methods have led to disagreement as to how best to monitor workload and work performance in space flight [116].

require further development and validation, but they are definitely needed.

Prevention

Monitoring

Suggestions from Isolation Studies

In the U.S. space program, monitoring of behavioral health in the preflight, in-flight, and postflight phases of space flight depends largely on self-reporting. On Earth, physiologic measures have been investigated as potential indicators of current behavioral illness and as predictors of the onset of new illness [121–123]. However, these measures, which are not easily adapted to use on orbit, are not being used to screen crews [124]. Instead, flight surgeons are using self-report questionnaires from the crews, direct discussion with individual crewmembers, or evaluations of crew communication with the ground as monitoring tools [78,125]. The Russian space program has developed other methods of evaluating stress response, including analysis of voice harmonics, self-reports of mood change, observations of changes in facial expressions, changes in circulatory endocrine levels [86], and analysis of voice communications [46]. Currently on the ISS, crewmembers monitor their cognitive health with a computerized cognitive self-assessment tool. This tool, which relies on baseline scores obtained before flight, is used in monthly on-orbit testing to maintain a recent baseline in case of neurologic injury (from a physical mishap, toxic exposure, decompression event, hypoxia, and other causes). This cognitive assessment tool can also present a succinct summary of critical data immediately to the crewmember and crew commander for decision-making.

Current steps being taken to prevent the deterioration of work capability caused by human-system interface problems during space flight are based on findings from isolation studies. Recommended strategies include (1) clearly identifying mission success criteria before beginning operations; (2) identifying tasks that can be dropped during a mission because of contingency workload; (3) distributing the workload effectively among the crewmembers; (4) maintaining a flexible work schedule that can respond to changes in the mission; (5) enforcing regularly scheduled days off; (6) giving the crew a high degree of control over the schedule; (7) recognizing that postflight operations are a significant additional burden and are part of the mission; and (8) developing a close working relationship between the crew and ground support team so that individual crewmember requests will be answered quickly and accurately [42,58,88,117,118]. A point to reinforce is the need to schedule non-working days for recuperation. Enforced days off have been an important factor in sustaining performance in high-workload settings [50,119], because hard workers will work past their limits unless recuperation time is scheduled and enforced.

Suggestions from Space Flight Experience has taught that training crewmembers to recognize their own optimal level of stress for maintaining work performance has been considered advantageous by the Russian medical system. As some professional athletes do, crewmembers may be able to use sports psychology techniques to keep their task performance within an acceptable range. Self-regulation strategies for long-duration cosmonauts are taught by Russian specialists in addition to techniques that enhance awareness of the self and the body. Since this training is closely linked to Eastern-style yoga, with which U.S. astronauts are less familiar, Western-style sports psychology techniques may be a more workable concept for U.S. astronauts [50,120]. Ground-based work schedules are another vital part of improving work effectiveness by attempting to manage overwork and task monotony. Studies are needed, however, to validate just how accurately these schedules can predict work time on orbit and to minimize deficits in performance caused by monotony. Finally, retraining in mission skills needed on orbit might be improved if negative trends in performance can be identified early. Tools that could rapidly clarify such negative trends

Monitoring and Preventing Behavioral Illness

Prevention Selecting Out The natural history of behavioral illness suggests that biological (genetic and organic) as well as environmental (psychological and social) factors give rise to illness [126]. The prevention of behavioral illness in space flight, our first prevention strategy, is based primarily on two constructs, the first that psychiatric selection strategies attempt to reduce the likelihood of future illness by identifying past or current risk factors, and the second that behavioral health interventions are performed in an attempt to interrupt the progression from manageable to abnormal stress levels in crews [127]. The use of psychiatric selection for space flight is consistent with its use for choosing crews for winter-over tours in Antarctica. This method, after it was implemented in the late 1950s [128], was shown to reduce the number of untoward psychiatric events in polar teams, and it continues to be considered useful today by managers of isolated-confined team operations [51,129].

19. Behavioral Health and Performance Support

Internationally, psychiatric evaluation at the time of astronaut or cosmonaut selection has been successful in identifying and disqualifying, as appropriate, applicants who have a diagnosable psychiatric (axis I) condition (typically between 4% and 9% of the total applicant group) [13–133]. Over the past 30 years, this psychiatric “select-out” process has relied heavily on the clinical judgment of psychiatrists with extensive experience evaluating aviators or other operations-based personnel. Their psychiatric evaluation focuses on those personal qualities that would be expected to significantly interfere with performance or would indicate a low threshold for developing emotional distress and behavioral illness [25,134,135].

Heightened Self-Awareness A second set of prevention strategies builds on a crewmember’s personal coping resources, reduces the environmental stressors that are present, and establishes a preflight relationship with behavioral health specialists for later interventions on orbit as needed. Behavioral health specialists can help by teaching crewmembers how to identify symptoms of excessive stress, improve their personal self-awareness, and make optimal use of coping techniques. The perceived stress burden of crewmembers is occasionally monitored by specialists, but this method could be enhanced by objective measures of a crewmember’s mood and stress levels [86,94]. To remain mission-effective, a crew must maintain a balance between the burden of mission stressors and available energy for personal coping. When this balance falls too much toward stress, the risk for behavioral illness increases. A study supporting this concept demonstrated that most individuals who developed major depression exhibited a greater number of symptoms of depression during the year before diagnosis than did a group that did not develop depression. Moreover, individuals with an acute onset of depressive symptoms had a 4.4 times greater chance—and those with chronic depressive symptoms had a 5.5 times greater chance—of developing a major depression than did those who were not ill [136]. Therefore, new behavioral illness in spaceflight crews could be reduced by identifying symptoms of illness early and suppressing those symptoms by reducing accumulated stress or by increasing coping energy through rest, relaxation, exercise, talking with others, receiving counseling or pharmacologic treatment [137], maintaining good social connections to other crewmembers, and communicating with family and ground team members [138,139]. Helping crews develop effective strategies to combat the negative effects of overstress is a key function of the behavioral health and performance group.

Countermeasures II: Diagnosis and Treatment of Behavioral Illness Whether before, during, or after flight, the diagnosis of problems with behavioral health and performance can be aided by using the four-factor concept (Figure 19.1). The first step

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Four Primary Factor of Human Performance Low Fatigue

Healthy Brain and Mood

(Sufficient Sleep)

(No Behavioral Illness)

Alert

Focused Concentration

(Circadian Rhythm normalized)

(No Cognitive Impairment)

[Sleep/Circadian Assessment]

[Behavioral/Cognitive Healdth]

To Think + To Act = To Perform

Adapted to Workplace

Good Physical Interface to Workplace

(Adapted to Environment)

(Habirability, Workstation design)

Motivated

Sensible Approach to Workload

(Support During Flight)

(Work schedules, Work sequence, Personal limits)

[Psychological Adaptation]

[Human-to-System Interface]

Figure 19.1. Four primary factors of human performance.

in this concept is to assess how the factors of sleep/circadian rhythm, psychological adaptation, human–system interface, and behavioral health are being managed by a crewmember. When symptoms are present, the flight surgeon may need to make changes in one or more of these areas. Although adjustments may be needed in the other areas as well, our primary focus in this subsection is the diagnosis and response to behavioral illness in a crewmember. We anticipate that certain disorders are likelier than others to develop on orbit, including asthenia, mood disorders (mania and depression), psychotic disorders (thought disorders, organic disorders, and delirium), anxiety disorders, and adjustment disorders—including psychosomatic disorders and grief reactions [46,137]. The following sections cover diagnostic issues for these conditions and the countermeasures that are available on orbit. Table 19.2 provides an overview of psychotropic medications that have been considered the minimum to have available on extended-duration flights in low Earth orbit.

Challenges for Diagnosis Although findings from laboratory and physical examinations are important, the critical tool in psychiatric diagnosis is the focused interview, conducted by a skilled behavioral health specialist who is sitting with a patient. The standard method of organizing information is the mental status examination, the principal components of which are shown in Table 19.3. Reliable diagnosis of behavioral illness in a space-based crew is difficult for several reasons, chief among them being the inability of a behavioral health specialist to be physically present with the patient. Telemedicine techniques have been used as a diagnostic tool in terrestrial psychiatry, but under these circumstances another physician is present with the patient. Used as a single tool, telepsychiatry is inadequate for assessing and managing psychiatric emergencies such as psychosis or suicidal intent [140,141]. When a crew and a behavioral health specialist have established a good relationship before flight, however, telepsychiatry could

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Table 19.3. Components of a mental status examination. Component Alertness Orientation Speech Mood Affect Thought processes Concentration Attention Follows verbal commands (including repetition) Memory Reliability and insight Drawing

Normal response

Look for abnormality if…

Alert

Lethargy, variability of alertness over 24 h suggests delirium Consistently and correctly identifies self, location, Variability of response over 24 h suggests delirium and date Normal in rate, word choice, and content Pressured, rapid speech suggests mania Nonsensical speech suggests psychosis Even, stable Labile, excessive sadness, happiness, or anxiety Cooperative Fright or irritability could suggest psychosis, depression, anxiety Goal-directed Disrupted with psychosis, delirium, severe anxiety Can perform serial subtractions with fewer than Disrupted with psychosis, delirium, severe anxiety 2 errors Can repeat 6 numbers forward and backwards Disrupted with psychosis, delirium, severe anxiety Cooperative and accurate Disrupted in neurologic injury, psychosis Able to recall 3 objects at 0, 1, and 5 min as well Disrupted in delirium, severe anxiety as past events Logical reasoning intact Odd behavior or speech suggests psychosis Can draw a clock with requested time correctly Disrupted construction ability suggests neurologic without hints injury

Source: Modified from Kaplan and Sadock[124].

be a helpful diagnostic adjunct for both the flight surgeon and the on-board crew medical officer (CMO). Before or after flight, diagnoses can be made by ground-based behavioral health specialists; once a crew is on orbit, however, the CMO is the most vital asset for differential diagnosis and management. Although CMOs are currently trained to recognize psychiatric disorders, greater training and experience will be beneficial before exploration-class missions are begun. A second problem associated with reliable diagnosis of behavioral illness in space flight is that the on-orbit environment can create symptoms that mimic behavioral illness. Short-duration space flights typically induce symptoms of tension, sleep disturbance, and psychosensory discomfort in crews. The heavy workloads and high pressure of these flights can make crewmembers “scramble like a squirrel in a wheel.” [46] It is normal for crews during long-duration missions to experience symptoms such as asthenia, euphoria, depression, worsening of interpersonal relationships, sleep disturbance, accentuation of negative personality traits, anxiety, anger, boredom, mental slowing, and transcendental experiences [46,74,142,143]. Symptoms that worsen significantly, however, can reflect frank disorders, specific examples of which are described in the remainder of this section.

Specific Disorders: Their Form and Treatment Asthenia Asthenia or neurasthenia, which is produced by monotony and cumulative fatigue, refers to the development of weakness, lack of energy, irritability, problems with attention and memory,

unstable mood, and sleep disturbances. On space station missions, asthenia is thought to develop no sooner than the fourth month on orbit, and it requires intervention to prevent a chronic course [2,46,144]. Although neurasthenia is not a diagnosis currently used in the United States, it is well known and used in Eastern European psychiatry. Indeed, its use seems to significantly overlap U.S. research diagnostic criteria for major depressive disorder [144].

Treatment Russian medical specialists treat neurasthenia with nootropic medications such as piracetam and additional support measures [145,146]. These support measures include reducing difficult job tasks in the “evening” hours, reinforcing the workrest schedule with crewmembers, and increasing the ground support team’s focus on the personal requests of the affected cosmonaut [2,46,94].

Euphoria and the Development of Mania The Russian experience with long-duration missions suggests that episodes of elevated mood generally do not persist for more than 3 days after completion of a critical task of personal significance [46,94]. When a crewmember’s mood remains irritable and expansive, when that crewmember becomes resistant to recommendations from the ground team, or when he or she continues to overestimate how well things are going on the spacecraft, this crewmember’s condition is much closer to what would be considered hypomania. A worsening of this hypomanic state to include at least 3 symptoms such as grandiosity, racing thoughts, distractibility, loss of judgment in decision-making, pressured speech, hyperactivity, or lack of a

19. Behavioral Health and Performance Support

need for sleep for 4 or more days would indicate development of a manic state [147]. Mania has a lifetime prevalence of ∼1% in the U.S. population [80], and it occurs frequently as a new-onset disorder in the age ranges typical of spaceflight crews (Table 19.1). The differential diagnosis on orbit includes endocrine dysfunction, toxin exposure, central nervous system abnormalities, and abnormal mood occurring as a response to medications, especially steroids or antidepressants in people with undiagnosed bipolar disease [148].

Treatment According to Russian medical specialists, hypomanic crewmembers will benefit from brief but consistent information regarding job performance when combined with recommendations to strictly observe rest schedules [46,94]. The more severe mania requires medications to effectively control symptoms. The use of benzodiazepines to reduce psychomotor agitation and irritability can be very helpful initially [149,150]. Loss of reality-based thinking requires the addition of antipsychotic medication. More than one medication is usually required to treat mania, especially in the acute phases. First, a benzodiazepine helps to slow the manic patient. Second, an antipsychotic medication should be used to treat any hallucinations or extreme thought disturbances. Optimal management of mania requires longterm use of a mood-stabilizing agent, such as lithium, anticonvulsants, or long-acting benzodiazepines. Use of these medications, however, warrants thorough endocrine, cardiac, and blood-chemistry analyses before therapy is begun. Ongoing monitoring of medication levels is also required. Thus, given the level of medical assessment currently available on orbit, a crewmember with mania would require immediate return to Earth for more definitive treatment. A narrowed onorbit differential diagnosis of mania would include exposure to a toxic chemical or an aberrant reaction to medication, neoplasm, infection, or thyrotoxicosis [151].

Depression One of the difficulties associated with diagnosing depressive disorder in a long-duration crewmember during a mission is the presence of symptoms that are common to both longduration flight and the disorder. The lifetime prevalence of major depression in U.S. adults is roughly 5%; this disorder is twice as common in women as in men, and occurs frequently as a new disorder in the age range of spaceflight crews [80] (Table 19.1). Table 19.4 [46,80,152] compares the presence of symptoms typical of long-duration flight with those symptoms that occur across cultures in patients with major depressive disorder. Since so many symptoms are common to long space flight and depression, CMOs must decide whether a crewmember is experiencing a full depressive disorder or

403 Table 19.4. Comparison of symptoms common to long-duration. Spaceflight and depressiona.

Symptom Depressed mood Loss of normal interests and pleasures Loss of energy, fatigue Sleep disturbance Suicidal thoughts, hopelessness Poor concentration Significant feelings of worthlessness or guilt Poor appetite, weight loss Significant agitation or withdrawal

Usually present in crewmembers on longduration missions

Occurring in most patients with major depression in 8 crossnational study sites

Variably Yes

8 of 8 sites 0 of 8 sitesb

Yes Yes No

8 of 8 sites 8 of 8 sites 7 of 8 sites

Variably No

6 of 8 sites 5 of 8 sites

Yes No

3 of 8 sites 0 of 8 sitesc

a Symptoms needed for a diagnosis of major depression are 2 weeks’ of depressed mood or loss of normal interests and pleasures plus any 4 of the other symptoms listed here. b This symptom criterion, as phrased here, was not used in the cross-national study. c Withdrawal was not used as a symptom criterion in the cross-national study. Source: Data from Myasnikov and Zamaletdinov[46], Weissman et al. [80], and American Psychiatric Association [147].

whether the symptoms reflect a combination of lesser problems. The natural history of untreated depression suggests that only 50% of adults will recover at 12 months from the onset of the illness [152,153]. Tracking the persistence and severity of the symptoms that are present is the best method for CMOs and flight surgeons to establish a diagnosis of depressive disorder. A crewmember who has experienced depressed mood or loss of interests for 2 weeks plus 4 other symptoms, as noted in Table 19.4, would meet the terrestrial diagnostic criteria for the disorder. Grief is a special type of depressive symptom, but if a crewmember is experiencing the multiple, severe, and prolonged symptoms that meet the criteria for a depressive disorder, the diagnosis is warranted. The short list of differential diagnosis of major depression on orbit includes medication side effects, exposure to toxins, neoplasm, endocrine dysfunction, and vitamin deficiency [151].

Treatment Conservative measures to be used in treating a crewmember with depressive symptoms include maintaining a strict focus on workload and adequate rest. Another important technique is to regularly provide feedback with emphasis on positive evaluation of the quality and importance of work being performed. It is best not to repeatedly question the crewmember’s mood and general state [46,94], although tracking symptom severity with a simple numeric score would be useful.

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Use of medication is the next consideration. The problems associated with using medication to treat a crewmember, particularly one on a long-duration mission, are crewmember compliance with taking the medication and the potential risk to the crewmember from taking the medication. Antidepressant medication is effective in about 67% of patients; however, CMOs must monitor the affected crewmembers very carefully because of the the risk for self-injury, which increases as the depression starts to improve [155] but tends to wax and wane during the early recovery period [156]. Hence the CMO needs to assess whether the patient is tolerating and taking the medication. At least 2 antidepressant medications will be present on orbit to improve the chance for good compliance. With regard to the potential risk to the crewmember, the risk of self-injury must be considered. Once a depressed person begins taking medication, the risk of self-injury may increase because of the improvement in sleep and energy as the antidepressant medication starts to work. Unfortunately, although a depressed person may still feel hopeless, he or she is not helpless and may then have enough energy to carry out self-harm. Because 40–60% of people who have committed suicide had major depression [157], the CMO must ask frequently about suicidal ideation. Talking about suicide does not cause suicide. Rather, not talking about suicide is a more common problem. Indeed, 50% of individuals who commit suicide see a physician in the month preceding death, and 40% of those individuals had clearly communicated their intent to someone close to them [158–160]. All comments must therefore be taken seriously, and even a welcome change in reported suicidal intent can be misleading. In one study of hospitalized patients who committed suicide, 64% reported to staff members that they no longer had suicidal ideation in the period immediately preceding their death [156]. On Earth, an antidepressant may take nearly a month to produce the full effect; antidepressant use on orbit has not been documented. Therefore, monitoring to ensure that the crewmember is taking all prescribed doses of medication will be an important function of the CMO, as is increasing the dosage and managing the side effects until a therapeutic dosage is reached.

Psychotic Disorders, Including Organic Mental Disorders and Delirium The common thread in the diagnosis of psychotic disorders is the loss of ability to consistently maintain logical thought processes. Organic mental disorders and delirium may occur because of a severe mood disorder, a severe thought disorder, a toxic exposure, a severe medical injury, severe sleep deprivation, or a severe psychological maladaptation caused by stress or isolation and confinement [42,47,74,161]. Experience with isolated and confined teams and on-orbit crews has demonstrated risk for toxic exposures in space flight that can cause brain injury [7]; examples of this are the nitrogen tetroxide exposure during the Apollo space program and

C.F. Flynn

the ethylene glycol, smoke, and freon exposures during the NASA-Mir Program. Another risk is that of new-onset psychosis, types of which in the age range of spaceflight crews include mania, severe depression, or severe obsessive–compulsive disorder (Table 19.1). Whatever the etiology, a crewmember with psychosis cannot be trusted and must be closely supervised or even physically restrained. Psychosis should be recognized as an independent risk factor for self-harm regardless of whether the patient is depressed. Studies have shown that psychosis was present in 50% of hospitalized patients who later committed suicide [156]. New-onset psychosis is uncommon in older age groups, and delirium as a result of medical illness is a poor prognostic sign that indicates an increased risk of mortality [162]. Although psychosis could quite possibly occur, its diagnosis has not been documented in space medicine literature [143]. An important symptom to identify in psychotic individuals is hallucinations. Especially worrisome are command auditory hallucinations, because a person with this type of hallucination is at high risk of following those commands. Command hallucinations are typically verbal instructions to do something that involves extremely poor judgment or even destructiveness, e.g., hurting oneself or others, opening the door of the space station, etc. Additional symptoms indicative of psychosis include at least 24 h of confusion, emotional lability, disorganized speech, delusions, and disorganized behavior [147]. The CMO must have a high index of suspicion for hallucinations or psychosis in a crewmember whose behavior has dramatically changed, because psychotic individuals do not always express symptoms wildly. In one study of schizophrenic patients, 40% had poverty of speech, 88% were socially withdrawn, and not more than 34% demonstrated formal signs of thought disorder in verbal communications [160]. The CMO may need to ascertain psychosis by carefully observing an ill crewmember for nonsensical behaviors. Signs could include frequent distraction from a conversation, losing track of the conversation, poverty of speech, jumping from topic to topic during a conversation, mutism, poor eye contact, or inappropriate affect [164]. A special type of psychosis is delirium, the hallmark of which is the “coming and going” of confusion over 24 h. Visual hallucinations are more frequent in delirium than in other types of psychosis. Throughout the day, an individual with psychosis will show a wide range of symptoms, sometimes being completely confused in behavior and thinking and other times able to report fairly accurately in reality-based conversation. Typically, delirium is caused by a severe illness or injury, an abnormal reaction or a withdrawal from medication, a severe infection and fever, an endocrine dysfunction, a vitamin deficiency, an intracranial abnormality, or an exposure to a toxin [162]. Symptoms include reduced awareness of the environment, reduced ability to focus and sustain attention, cognitive deficits of memory, and disorientation to time, place, or person [147,162,165]. Insomnia is often a problem at “night,” whereas the person is unable to stay alert and awake

19. Behavioral Health and Performance Support

at periods of normal “daytime.” People who are delirious are usually agitated when they are confused. Organic mental disorders may present as delirium or psychosis, and exposure to a chemical can present as disrupted brain function. Some toxins can cause a rapid change in behavior or cognition (because of confusion and disorientation), whereas chronic exposures to chemicals such as mercury, copper, or lead can lead to slower changes in cognition. Ten percent of patients who have suffered a mild head injury have ongoing neurocognitive sequelae, including behavioral change [166].

Treatment Once a crewmember is recognized as having psychosis, physical restraint is necessary until pharmacologic control is successful. Medication must be used to improve the psychotic symptoms [46,132,161]. Antipsychotic drugs, which are available on orbit, are very effective at stopping psychosis, but they also have side effects that can require the use of additional medications. Anticholinergic side effects (e.g., blurred vision, dry mouth, tachycardia, constipation) are less prominent with highly potent agents such haloperidol, but extrapyramidal effects (e.g., parkinsonism, dystonia, akathisia) are more frequent, occurring in about 60% of patients receiving antipsychotic medications [167]. The potentially lethal side effect of neuroleptic malignant syndrome may develop in about 0.2% of patients treated with an antipsychotic medication. With its hallmark symptoms of hyperthermia (temperature higher than 38° C) in 98% of patients, muscular rigidity in 97% of patients, and worsening confusion in 97% of patients, this syndrome tends to develop within 1 month of starting to take the offending medication and develops rapidly over 24–72 h [168]. Antipsychotic medication should be given intramuscularly to treat hallucinations, agitation, and thought disorder. A longacting benzodiazepine may also be given intramuscularly for additional calming effects. Repeating the doses 60 min later may be considered if necessary, although this should be done cautiously, with consideration of the medication’s half-life (Table 19.2) and accumulation [96]. Treating the person with delirium or an organic mental disorder requires a different approach than treating a person with simple psychosis. The first step for the flight surgeon is to consider whether a toxin, a medication, or an illness is the underlying cause. If fever, high blood pressure or pulse rate, high white blood cell count, or abnormal bloodwork is present, the flight surgeon should begin treating the underlying problem as well as giving antipsychotic medication. For the delirious patient, it is also important to consider the patient’s ability to clear a dose of medication. An antipsychotic is still the drug of choice to stop hallucinations in patients, but small doses of a high-potency agent are best [161]. Use of a benzodiazepine in delirium is atypical, because any sedating medication may worsen the confusion, and therefore the agitation, of the delirious individual.

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Anxiety Disorders Symptoms of anxiety range from discomfort to disorder. The CMO must judge whether the level of anxiety experienced by a crewmember is within the scope of normal. For example, a severe level of anxiety in the face of a near-death event would be considered normal. However, such an experience may also lead the crewmember to develop a posttraumatic stress reaction that is both chronic and abnormal. The critical question for diagnosis is whether the observed reaction is comparable to a normal response. Anxiety symptoms are not the same as an anxiety disorder. To warrant a diagnosis of disorder, the patient must have experienced a sufficient number of symptoms for a specified period. The differential diagnosis for anxiety on orbit includes other mental disorders, medication effects (including withdrawal from a medication), exposure to toxins, endocrine dysfunction, or other general medical illness [169,170]. This subsection provides an overview of the anxiety disorders most likely to occur in the age range of spaceflight crews—panic disorder and obsessive–compulsive disorder. Panic disorder has a lifetime prevalence of 1.4% in U.S. adults, and occurs frequently as a new disorder in the age ranges typical of spaceflight crews (Table 19.1). The diagnosis of panic disorder requires recurrent panic attacks and worry or change in behavior because of the attacks for at least 1 month [147]. Panic attacks are discrete episodes of intense anxiety that have an abrupt onset and at least four additional symptoms such as palpitations, sweating, trembling, shortness of breath, a choking sensation, chest discomfort, nausea, dizziness/lightheadedness, feelings of unreality, fear of losing control, fear of dying, a sense of impending doom, paresthesias, chills, or hot flashes. [147] Panic disorder often goes undiagnosed for months or years because the affected individuals tend to fear that they are crazy and do not report symptoms to healthcare providers. Obsessive–compulsive disorder has a lifetime prevalence of 2.5% [79] and occurs frequently as a new disorder in the age range of astronauts and cosmonauts (Table 19.1). Individuals with this condition recognize that the fears and behaviors experienced are unreasonable but they are unable to overcome them. Obsessions are defined as intrusive, distressing recurrent thoughts or impulses that the person recognizes as being self-generated but cannot be controlled despite attempts to suppress them. Compulsions are repetitive behaviors that a person feels driven to perform to reduce distress over a dreaded outcome [147]. The classic example of obsessive–compulsive disorder is the person who fears death from infection and thus washes his or her hands so frequently that injury results.

Treatment Fortunately for the CMO, anxiety disorders respond quickly to benzodiazepines and sometimes to antidepressant medication. The primary consequence of using benzodiazepines for anxiety is the development of physiologic dependence and altered cognition. Although all anxiety conditions will respond to

406

benzodiazepines, antidepressants are also effective in treating panic disorder and obsessive–compulsive disorder [95,171]. Doses of benzodiazepines are typically based on the half-life of the medication, with doses overlapped so as to maintain the clinical effect. When used for treating anxiety disorders, antidepressants are administered at the same dosage level as for depression [46,94,96] (Table 19.2).

Adjustment Disorders Physical symptoms of severe stress reactions may include tachycardia, rapid breathing rate, diarrhea, nausea/vomiting, and sweating. Behavioral symptoms can also be recognized as part of a response to stress. The behavior of people suddenly caught in a catastrophe can be broadly characterized as 1 of 3 types—relative calm (10–20%), stunned (75%), and highly inappropriate (10–15%) [172]. When the physical symptoms of severe stress reactions create significant problems for an individual or are excessive in comparison to the precipitating stressful event, this defines an adjustment disorder [147]. CMOs must realize that a crewmember may not want to report suffering from the stressful event that occurred. Adjustment disorder is one of the most common psychiatric diagnosis and can occur at any age [173]. Some individuals will react to a calamity with depressive symptoms and a decrease in work motivation, whereas others may become more withdrawn or irritable. If the severely disruptive event is the loss of a loved one or a close friend, a grief reaction can be expected, as has happened in Salyut and NASA-Mir missions. Other individuals with depressive symptoms may develop new physical symptoms, or they may experience more physical discomforts than usual [137]. After a Russian Progress supply vessel collided with the Russian space station Mir on June 25, 1997, routine physical assessments of the crew commander demonstrated a new set of cardiac rhythm changes. The Russian medical group diagnosed this somatic change to be a result of severe psychological stress in the aftermath of the crash [2]. Clearly stress can induce somatic changes, not just alter an individual’s perception of illness. Accentuation of negative personality traits is also a hallmark of increased stress. The sign of this type of problem is a worsening of personality quirks that would be noted before flight, including impulsivity, subjective overestimation of one’s capabilities, the appearance of hostile interpersonal reactions with ground crew or other crewmembers, predominantly negative responses toward work rest schedules, and a labile mood. These negative reactions to stress will impair normal work capacity and interpersonal relationships and so can best be described, in U.S. diagnostic terminology, as adjustment disorders.

Treatment The Russian medical group responds to adjustment disorders by instituting a businesslike approach in communica-

C.F. Flynn

tion sessions with the crewmember, encouraging extensive use of psychological support measures, recommending strict compliance with work–rest schedules, and officially notifying the crewmember of inaccuracies, errors, and violations in their work [46,94]. Encouraging the crewmember to discuss the stressful experience and attempting to help that crewmember develop alternative strategies to the adversity are typical responses to these conditions as well. Talking to a ground-based behavioral health specialist may also help a crewmember, but the degree of help will depend on the relationship that was developed between the crewmember and the behavioral health specialist before flight [61].

Treatment of Psychiatric Emergencies Because about 40% of all patients who are seen in psychiatric emergency rooms require hospitalization [97], once a psychiatric condition has become problematic in flight, the CMO and the flight surgeon must remain vigilant to the possibility of a psychiatric emergency. Such an emergency can arise from the illness or from the side effects of therapeutic medications. The primary goal of the CMO in such a situation is to quickly gain control of the patient to prevent injury to the patient or to other crewmembers. However, before “rushing in,” the CMO should develop a plan of action to take control of the situation rather than risking injury to the rest of the crew by an unpredictable crewmember. Control may require physical restraint using duct tape around the crewmember’s arms and torso or legs. Table 19.5 [158,159,164–167,174] outlines possible responses to anticipated behavioral health emergencies that could occur on orbit [95,96,161,162,167,168].

Medical Disposition The disposition of a space-based crewmember with a behavioral health disorder is the primary decision point in determining whether to return the ill crewmember to Earth or to attempt treatment on orbit. Flight surgeons should work to optimize the four factors that influence behavioral health and human performance. Patients with inadequately treated psychiatric illness are moderately to severely dysfunctional in a work setting [175]. Since 50% of individuals with depressive disorder can be expected to recover in 6 months from the onset of treatment, crewmember response to antidepressant therapy will be a key factor in a “stay or return” decision [153]. Less severe anxiety disorders will respond quickly to treatment with benzodiazepines, whereas response to antidepressant can take 3–4 weeks. It is certain that while adapting to the medication used, the patient will not be an optimal crewmember.

19. Behavioral Health and Performance Support

407

Table 19.5. Responses to psychiatric emergencies. Presenting problem

Restraint required

Suicidal

Constant observation, at minimum

Violent

Chemical/physical

Dystonia (2–64% of patients given antipsychotics)

None

Akathisia (21–75% of patients given antipsychotics)

None

Neuroleptic Malignant Syndrome (∼0.2% of patients given antipsychotics)

Physical

Delirium Psychosis

Chemical/physical Chemical/physical

Severe Anxiety

As indicated by cooperativeness

Medication suggested Diazepam 2.5 mg po q 12 h for anxiety Begin antidepressant Haloperidol 5 mg IM q 12 h Diazepam 5 mg IM q 12 h Benadryl 50 mg IM Decrease antipsychotic dose (if possible) or switch Benadryl 25 mg po TID Propanolol 10 mg po TID Diazepam 2.5 mg po BID Decrease antipsychotic dose (if possible) or switch Normal saline 250 ml/h IV Diazepam 5 mg IM q 8 h Amantadine 100 mg po BID Stop neuroleptic Keep as cool as possible Haloperidol 1 mg IM q 8–12 h Diazepam 5 mg IM q 12 h Haloperidol 5 mg IM q 12 h Valium 2–5 mg IM q 8 h Diazepam 2.5 mg po q 12 h

Watch for… More energy = more danger Psychosis = more danger Look for medical illness, psychosis, toxic exposure Recurrence

Recurrence

Loss of urine output Continued hyperthermia

Medical illness, toxin Dystonia, akathisia, parkinsonism, neuroleptic malignant syndrome

Abbreviation: BID, twice a day; IM, intramuscular; IV, intravenous; po, by mouth; q, each; TID, 3 times a day. Source: From Kaplan and Sadock[161,162,167], Casey [168], Perry et al. [95], Albers et al. [96], and Jenkins and Hansen[174].

Another consideration is that space medical standards preclude certifying a crewmember taking psychoactive medication for flight. Therefore, a decision to continue the flight and certify the recovered crewmember for on-orbit duties is likely to require several steps. First, the other crewmembers must be able to assist or absorb the ill crewmember’s mission-critical tasks until full function has returned. Second, a good response to medication must have removed the illness symptoms. Finally, since means of assessing cognitive function is available on orbit, such means should be used to determine when the treated crewmember has returned to baseline mental capacity. Before flight, a condition that is self-limited and rapidly treated should not require removal of a crewmember from a mission. However, if that condition keeps a crewmember from completing the required training, removal from the flight is likely. A return-to-flight opportunity could be indicated after 6–24 months of good functioning off medications, depending on the disorder. Fortunately, the excellent problem-solving capabilities, superior adaptability, and motivation in astronauts and cosmonauts are very favorable assets in behavioral health treatment [176–178]. In a study of 7 years of outcome data from psychiatrically hospitalized military aviators, an encouraging 65% achieved return-to-flight status [15]. After flight, a delay in recertification for flight would be warranted until good prognosis is assured. By keeping in mind the 4 factors that can influence behavioral health and human performance,

flight surgeons can work to optimize these areas and create a positive outcome for a crewmember.

Conclusions This chapter provides a review of the important risks to maintaining a spaceflight crew’s behavioral health and performance, including the effects of expected spaceflight conditions; expected behavioral symptoms and behavioral health disorders; and prevention, monitoring, diagnosis, and treatment strategies for medical disposition. The four-factor model described gives flight surgeons an efficient approach for recognizing expected problems and for planning countermeasures for these problems. The 4 factors in this model—psychological adaptation, sleep and circadian rhythms, human system interface, and behavioral health issues—are considered as distinctly independent but at times overlapping elements required to maintain human performance for space missions. To improve and maintain a crew’s mission performance, better tools are needed to monitor changes in these four areas, and countermeasures need to be identified and validated. From this perspective, the ISS will be an excellent test bed in which to improve these capabilities. Experience on the station is a necessary next step because exploration-class missions will require much better tools to clarify diagnoses, use prophylactic measures, and institute treatment of deficits in the four factor areas.

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Despite the significant and cumulative negative stressors that are known to challenge spaceflight crews, this chapter would be incomplete if it ended without identifying a likely positive effect of space flight on a crewmember’s behavioral health. In one study of cosmonauts who participated in space flights lasting up to 1 year, analysis of data gathered 2–3 years after landing revealed a significant improvement in the cosmonauts’ emotional stability, self-confidence, self-assessment, and interpersonal problem-solving techniques [46]. Similar salutary effects have also been noted in Antarctic winter-over individuals, who in general had fewer first hospitalizations after deployment than did a control group and who also developed more independence and self-reliance after the mission [129]. By joining together early to prepare for known mission stressors, flight surgeons and spaceflight crewmembers can not only maintain behavioral health and mission performance on orbit but can also maximize any potential positive behavioral health effects of the space mission experience.

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20 Fatigue, Sleep, and Chronotherapy Lakshmi Putcha and Thomas H. Marshburn

Early in the history of human space flight, scientists realized that several factors in the space environment might adversely affect human function and performance. Potential disturbances in circadian rhythms and the consequences of such disturbances on performance efficiency and the well-being of space crewmembers were among the principal concerns expressed [1]. In addition to environmental changes—e.g., microgravity and ultrashort light-dark cycles—several operational reasons were cited for the possible development of sleep disturbances and fatigue during space flight [2,3], including an abnormally long working period (the high-workload effect), continuing deviations in the sleep-wake schedule duration (the “migrating day” effect), phase shifting of sleep periods relative to Earthbased sleep time (the shift-work effect), and cyclic noise disturbances. The safety hazards associated with sleepiness and fatigue may have serious consequences for astronauts and cosmonauts as well as their supporting ground crews. In the current space flight environment, imposed 24-h schedules often conflict with physiological and psychological rhythms of space crews, thereby changing their work-rest periods from their accustomed ground-based sleep-wake cycles. Although the consequences of this change remain largely unknown, this chapter is intended to provide a “snapshot” of trends in the assessment of sleep and fatigue, performance implications in space flight, and methods of monitoring and managing sleep and fatigue in operational settings. Also addressed are specific space flight issues related to risk assessment and to sleep and fatigue management strategies for current and future long-duration space flights.

Sleep Sleep is a vital physiological function. The 24-h sleep-wake cycle is a complex, active physiological state characterized by two distinct types of sleep—non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep [4]. In humans, NREM sleep can be further subdivided into four distinct stages, based primarily on electroencephalographic

(EEG) characteristics obtained through polysomnography. Sleep stages also reflect the depth of sleep, with stage 1 being the lightest and stage 4 being the deepest stage of sleep. The distribution of an individual’s sleep among these four stages can be affected by many factors, chief among them being age and developmental stage; other factors that influence the pattern of sleep stages within a nighttime sleep period include the use of drugs or alcohol, exercise, and specific sleep disorders. Sleep stages are most often characterized by measuring EEG patterns, but electrooculographic (eye movements) and electromyographic (muscle tone) patterns may also help in identifying sleep stages. Stage 1 sleep, the lightest phase of NREM sleep, is characterized by an EEG pattern called the alpha rhythm. Typical alpha waves occur rhythmically at 8– 13 cycles per second and indicate a state of relaxed wakefulness with eyes closed [5]. Stage 1 is normally considered the relaxed and transitional stage preceding sleep onset. Another characteristic of stage 1 sleep is the presence of slow, rolling eye movements. The appearance of distinct “sleep spindle” and “K complex” EEG waveforms characterizes stage 2 NREM sleep. Stage 2 sleep is generally free of eye movements and is distinguished from stage 1 sleep by a higher arousal threshold, meaning that a more intense stimulus is required for arousal from stage 2 sleep. Stage 3 and stage 4 NREM sleep are collectively called slow-wave sleep. The EEG pattern of stage 3 and stage 4 sleep is characterized by delta waves, which are of higher amplitude (> 75 mV) and slower frequency (0.5–2 cycles per sec) than those of stage 1 or 2 sleep. Slow-wave sleep is often considered the deepest sleep, and no eye movements are evident. More detailed descriptions of sleep and EEG characteristics can be found in the Encyclopedia of Sleep and Dreaming [6]. Many of the physiological changes that occur during NREM sleep are caused in part by a shift of the autonomic nervous system such that the parasympathetic system predominates; REM sleep, however, is accompanied by an increase in sympathetic activity. Systemic blood pressure has been shown 413

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to decrease by 5–15% during NREM sleep [7]. Analyses of heart rate variability during sleep in healthy male and female subjects have confirmed differences in autonomic nervous system activity between waking and sleeping and between NREM and REM sleep; specifically, REM sleep was characterized by increased sympathetic dominance secondary to vagal withdrawal [8]. Autonomic functioning during waking and sleep also varies according to sex, with men tending to show decreased vagal tone during waking and increased sympathetic dominance during REM sleep as compared with women. Other physiological functions affected by sleep include those of the respiratory, gastrointestinal, renal, endocrine, and immune systems along with changes in thermal regulation and memory formation [7]. The temporal structure of sleep and wakefulness is believed to have evolved to maximize flexibility and to ensure that transitions from one state to the other are smooth. Sleepiness shows a biphasic rhythm over 24-h periods, with a first and greatest level of sleepiness experienced between 3:00 a.m. and 5:00 a.m. and a second, less intense level of sleepiness between 3:00 p.m. and 5:00 p.m. Afternoon sleepiness occurs independent of food consumption, but its effect can be exacerbated by consuming a meal [9]. Most people require about 8 h of sleep to maintain physiological balance, and most adults report sleeping 7–7.5 h per 24-h day [10]. The recuperative value of sleep depends on its duration and continuity [11]. Both sleep requirements and sleep structure change with age. Younger individuals require more sleep than do their adult counterparts, and changes in sleep structure, such as experiencing more sleep interruptions, are common in older adults. Inadequate sleep is endemic in industrialized societies. Many of us are chronically sleep-deprived [12,13]. The monophasic sleep pattern, which implies a single sleep period per day and is characteristic of most industrial societies, is of purely social origin. The existence of a biphasic sleepiness rhythm implies that at least one additional period of sleepiness would be experienced per 24-h period. Growing evidence suggests that even adult humans can benefit from polyphasic sleep (i.e., multiple sleep periods over the course of a day) rather than the more typical monophasic sleep pattern [14]. In a recent survey conducted by the National Sleep Foundation [15], 75% of those questioned reported experiencing daytime sleepiness, and 32% reported that that sleepiness was severe. Although the 32% with severe daytime sleepiness reported that their sleepiness interfered with their daytime activities, 82% of all of the subjects surveyed believed that daytime sleepiness had a negative effect on their productivity. Some evidence points to the existence of a basic trait that determines the balance between sleep-promoting and wakefulnesspromoting mechanisms in an individual. Two distinct profile types of sleep characteristics (somnotypes) have been identified: the sleepy and the alert. People with the “sleepy” somnotype can fall asleep easily, whereas those with the “alert” somnotype find it more difficult to fall asleep and stay asleep. Considerable

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evidence exists to indicate that those who need less sleep to feel alert should sleep less at night and nap less during the day [16]. This dimension of individual difference is independent of “morning” and “evening” types [17]. The performance effects of “sleep stress,” that is, sleep deprivation or compromise, are complex. Sleep deprivation impairs alertness, cognitive performance, and mood [16]. Sleep-deprived people typically show declines in overall performance, particularly in mental operations that depend on the prefrontal cortex [18]; simple psychomotor performance and physical strength and endurance, however, seem to be unaffected by sleep deprivation [19]. Fragmented or brief sleep is thought to have little restorative value for individuals deprived of sleep, and indeed has effects similar to those of sleep deprivation [20]. Shift work is often associated with increased rates of cardiovascular disease and accidents [21]. Discordance between the circadian rhythms of stress-related biological variables and work-sleep schedules, particularly those of shift workers, could also reduce work efficiency. In one study, 24-h electrocardiographic (ECG) recordings from shift workers indicated that weekly changes in shift work (from first shift [6:00 a.m.–2:00 p.m.] to second shift [2:00 p.m.–10:00 p.m.] to third [10:00 p.m.–6:00 a.m.]) were associated with changes in the 24-h oscillation of cardiac sympathetic and vagal autonomic modulation [21]. The finding in that study that indices of cardiac sympathetic modulation were reduced during night work was thought to be related to the presence of sleepiness or diminished alertness, which in turn could result in errors and accidents [21]. This finding may also underlie the higher rate of cardiovascular diseases described in shift workers [22]. Sleep loss has practical implications for aerospace operations and is of concern to the Transportation Safety Board and the Aviation Safety Board. Loss of sleep—as determined by EEG, ECG, and subjective ratings—has led to high fatigue ratings among airline pilots, particularly those on long-haul or overnight flights [23,24]. Self-reports of fatigue have been accompanied by changes in EEG and ECG variables, particularly on flights involving long duty hours and consecutive night work, which may place excessive demands on mental and physiological capacity [25]. Although electroencephalography is the considered the “gold standard” for sleep monitoring, it is also expensive and time-consuming. Modified self-winding accelerometers known as “actigraphs,” usually worn on the test subject’s nondominant hand like a wristwatch, were introduced in the 1950s to measure human physical activity. Several actigraphs have been developed since that time and have been used to monitor sleep [26]. Actigraphy provides a continuous measurement of the motor component of behavior [26]. In principle, the technique involves transforming the physical attributes of body movements into analog signals that can be directly recorded or further transformed into digital counts and scored in electronic memory for prolonged periods [27]. The motion sensor of an actigraph

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generates a signal voltage each time it is moved. This signal can be filtered or amplified according to various selectable settings to measure changes in overt behavior reflected in actigraphy readings. When a person is awake there is movement of the arms and when a person is asleep, this movement is much less. So, actigraphy can be used as an indirect measure to determine and record when an individual is asleep and awake. Actigraphy is now used as a tool in sleep research, psychiatry, and chronobiology. One of the main uses of actigraphy has been the assessment of sleep [28]. Several automatic sleep-wake detection algorithms have been developed and refined for use with actigraphy that have been shown to correlate well with traditional EEG sleep assessments, although the strength of the correlation depends on which algorithm is used. Actigraphy has been used as an objective measure of sleep during space flight. A recent study showed high correlations between actigraphy and polysomnographic measurements for sleep duration and efficiency and for the number of minutes of wakefulness between bedtime and wake time [29]. However, the actigraph used in that study did not detect an instance of a long interval between going to bed and the onset of sleep.

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Figure 20.1. Sleep restraints and sleep quarters on the mid-deck of a Space Shuttle. (Photo courtesy of NASA)

Sleep in Space Substantial, albeit mostly anecdotal, evidence exists that sleep is often impaired in microgravity. Some crewmembers state that arousal from sleep is common and sleep quality is poor, so they use sedatives in attempts to promote sleep. This practice, which does not ensure restful sleep, can result in diminished efficiency during work time. Continuous reductions of sleep time and increases in sleep latency have been reported in earlier missions [30], and more pronounced sleep disturbances have been reported by dual-shift crews [31–33].

The Spacecraft and Spaceflight Environment A unique problem for spaceflight crews who would like to achieve restful sleep in microgravity is to assume a supine sleeping posture. To achieve this sleeping posture during a mission, crews use sleep restraints (Figure 20.1) that anchor them to the sleep area so as to prevent their floating. On dual-shift missions, astronauts and cosmonauts sleep in lightproof, noise attenuating bunk areas. On the International Space Station, crewmembers have sleep stations that can be used as a rest or break area in addition to serving as a sleep area (Figure 20.2). The environmental conditions most likely to disturb sleep and impair performance during space flight in low earth orbit are thought to be noise, the short light-dark cycle, temperature, confinement, and frequent changes in the sleep wake cycle. Results from a noise-monitoring study on a Space Shuttle mission indicate that mission operations were not significantly impacted by noise, but crewmembers had to use earplugs during sleep [34]. Crewmembers also experienced

Figure 20.2. Cosmonaut Yuri Usachev relaxes in a personal sleep compartment on the Russian segment of the International Space Station. (Photo courtesy of NASA)

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interference with their ability to concentrate, relax, sleep, and communicate verbally during that flight, and some of the crewmembers reported fatigue and headaches from the noise levels. The flight deck, the sound pressure level of which was 63 dBA, was considered the most acceptable of all three habitable areas during this flight (flight deck, middeck, and SpaceHab module). Crewmembers rated the noise level in the SpaceHab as unacceptable even under minimum background noise conditions [34]. These noise conditions, coupled with other environmental or physical aspects of the sleep quarters (e.g., heat, CO2 build-up, posture, bed comfort) often contribute to less-than-optimal sleep conditions in space. Results of a study of Spacelab mission sleep-activity schedules and a simulation of shifting work-rest periods showed distinct increases in awake time, decline of the sleep efficiency index, and desynchrony of circadian rhythms [35,36]. Based on these findings, the space medicine community has recommended that planning in-flight work-rest schedules must include consideration of circadian rhythmicity in order to prevent sleep disturbances [37]. On some Space Shuttle missions, the crew works in two teams, in which the work and sleep periods of each team are staggered by several hours in a dual-shift schedule, to increase productivity. In one analysis of sleep on Space Shuttle missions, Santy and colleagues reported shorter sleep duration and greater use of sleep medications during dual-shift missions than on singleshift missions [38]. In another study, Monk and colleagues measured sleep and circadian rhythms in four astronauts aboard an orbiting Space Shuttle [39]. Although the circadian rhythms of core body temperature, urinary melatonin sulfate, and cortisol did not significantly change in these four astronauts during the mission, the duration of both total sleep (mean, 6.1 h/day) and delta sleep was shorter during flight than before flight. Dijk and others reported similar decreases in sleep duration (to about 6.5 h/day) in five astronauts on two subsequent Space Shuttle missions [40]. Medical debriefing records from 239 astronauts on 44 different Space Shuttle missions of 3–17 days’ duration were recently evaluated with regard to work-rest schedules and sleep characteristics. On average, these astronauts slept for a mean of 6.19 h during each 24-h subjective “day” during missions. Crews worked on a single-shift schedule on 28 of these missions and a dual-shift schedule on the other 16 missions. The mean (± standard deviation) sleep durations were 6.23 ± 0.92 h on single-shift missions and 6.13 ± 0.97 h on dual-shift missions. Crewmembers on some of these missions underwent light-assisted sleep-shift entrainment before flight, which is discussed later in this chapter. All of these results point to the existence of a sleep debt that could result in fatigue and performance decrements during space flight. It should be borne in mind, however, that the complexity of in-flight sleep schedules and other confounding factors such as use of sleep medications, a noisy and suboptimal sleep environment, work demands, and preflight sleep

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entrainment protocols that vary from flight to flight have limited any meaningful assessments of sleep in space.

Fatigue Fatigue is a universal complaint that accompanies almost every illness, whether mental or physical, and often signals the occurrence of some abnormality [41]. Described as a perception arising from a complex interplay of somatic and psychological factors [42], fatigue is a subjective self-evaluation of sensations and is associated with discomfort, decreased motor and mental skills, and increased aversion to performing tasks [43]. Fatigue is considered to be a protective mechanism that alerts the individual to the need for rest. The assessment and management of fatigue in human beings involves a wide range of activities addressing physical, psychological, cognitive, and spiritual dimensions [41]. Fatigue can impair information processing and reaction time and can also result in errors that can lead to accidents [9,44]. Although identifying fatigue as a contributing factor in an accident can be difficult, estimates of the percentage of accidents involving fatigue have been made for different modes of transportation. These estimates vary from very low to as high as about one third of all accidents. For example, about 21% of aviation accidents, 3.6% of fatal highway accidents, and 33% of train accidents have been attributed to human factors, especially the general issue of fatigue [45]. The transportation industry recognizes fatigue as a major contributing factor in accidents; the aviation industry and the U.S. Air Force are undertaking systematic research to develop fatigue models that can predict performance failures [46]. In the operations world, fatigue is viewed as a simple condition that is related to the amount of time spent working on a given task [47]. However, recent knowledge suggests that fatigue results from a complex interplay among several factors, including the duration and quality of sleep, shift work, circadian rhythms, drug and alcohol consumption, and time of day. Indeed, sleep, waking performance, and alertness are all profoundly influenced by circadian rhythms [48–51]. Fatigue is believed to be a response to stress, but measures of energy expenditure (in caloric output) and impairment of performance often do not correlate with an individual’s perceived level of fatigue. A well-motivated person can compensate for a feeling of weariness [52]. The complexity of the relationship between stress and fatigue may reflect individual variations in temperament, coping styles, the ability to perform a task, and mental and physical fitness as well as environmental factors related to comfort, such as noise, light, temperature, and humidity [52,53]. Information collected from U.S. Air Force flight crews on acute and cumulative fatigue and other stressors during Operation Desert Shield emphasized that an individual’s sleep history, recent duty-day cycles, subjective fatigue level, scheduling patterns, nutrition, and billeting facilities

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all contributed to fatigue and low levels of alertness [54]. Part of that study also included collecting data on sleep, task load, fatigue, and stress of extended-range operations from pilots on long-haul routes involving two consecutive night flights with a short layover between them. Those pilots lost an average of 9.3 h of sleep, resulting in an increase in fatigue rating that reached critical levels during the return flight. Motor activity, brainwave activity, and heart rate measurements all indicated drowsiness and low states of vigilance and alertness during both night flights that was greater extent during the second flight. These results suggest that extended duty schedules may impose excessive demands on the mental and physiological capacity of crews [23]. Any study of fatigue must consider the conceptual distinctions among the measures of fatigue that are most appropriate to the goals of that study [55]. For example, physiological variables such as blood pressure, pulse, or hematologic measurements (e.g., complete blood count, sedimentation rate) are not good indicators of early fatigue; rather, measurement of heterophorias, use of questionnaires, or other subjective evaluations are more effective markers of early fatigue [56]. Operational flight surgeons are often responsible for determining the aeromedical readiness of aircrew members, whose accumulated flight time often exceeds standard limits. Fatigue surveillance and monitoring have been used to ensure operational safety in aircrews that must complete extended missions [56]. Measurements of body temperature, salivary melatonin and cortisol levels, motion (by actigraphy), and subjective measures have also been used to monitor fatigue and circadian cycles in pilots [57].

Fatigue During Space Flight Most of the information available on fatigue in space is anecdotal, as no systematic or scientific studies of fatigue in astronauts or cosmonauts have been conducted on either short-duration or long-duration space flights. In part, this gap results from the lack of sensitive measures or methods with which to estimate fatigue in space. Some investigators have suggested that the work demands on crews during extended space flights resemble those of lengthy sport trials in which athletes are stressed by confinement yet expected to maintain a high level of performance while staving off fatigue and performance decrements [58]. If so, then perhaps astronauts and cosmonauts could use coping strategies and recovery techniques analogous to those used by athletes to avoid serious functional impairments. Instances of overt, serious functional impairment of space flight crews caused by adverse psychological responses have not been documented in the U.S. space program to date. However, transient disorientation, spatial illusions and visual disturbances, sleep disturbances, and instances of substandard performance have been reported [59]. Operational experience accruing on the International Space Station will help in characterizing this important performance factor.

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Circadian Rhythms Many endogenous physiological functions undergo cyclical variations over time. The periodicity spectrum of biological functions includes ultradian rhythms, which have a period of less than 20 h; circadian rhythms, with a period of about 24 h; and infradian rhythms, with cycles lasting longer than 28 h [60]. Human circadian rhythms generally are synchronized to the 24-h day resulting from the Earth’s rotation. The photoperiod, defined as the ratio of daylight to darkness hours, is considered the primary external synchronizer (“zeitgeber”) of biological rhythms. The internal circadian pacemaker, located in the suprachiasmatic nucleus of the brain [51], synchronizes the various biological rhythms with each other. Each rhythm has a distinct waveform that can be characterized in terms of amplitude (the distance between the mean value and the peak [maximum] or trough [minimum]); phase (the time reference point of the rhythm); acrophase (the time of maximal or minimal value); and mesor (the mean value). A phase shift refers to an advance or a delay of the reference point of either the biological rhythm or the timing of the environmental cue, typically while maintaining the duration of the period. The consequences of circadian rhythm changes, whether resulting from shift work, transmeridian flight, or changes in the length of subjective day, have been called desynchronosis, dysrhythmia, dyschrony, jet lag, or jet syndrome [61].

Markers of Circadian Rhythms In addition to sleep and alertness, several vital physiologic functions show circadian rhythmicity, including gastrointestinal, cardiovascular, and immune functions; thermoregulation; and DNA synthesis (Table 20.1). Even birth and death seems to have circadian patterns that peak at night [45]. Figure 20.3 shows examples of physiological and biochemical markers that can be used to determine an individual’s circadian rhythms. For example, melatonin and core body temperature are the “hands” of the biological clock and can be used as markers for determining the phase and amplitude of circadian rhythms in humans [51]. Core body temperature is a common means of estimating internal clock times and is often measured continuously over several days to get a reliable determination of the minimum (“bathophase”) of temperature rhythm. The trough of the cyclic diurnal variation in core body temperature occurs between 3:00 a.m. and 5:00 a.m., a time when alertness, performance, and mood are also at their lowest levels. Most physiological systems tend to exhibit lower activity levels between 12:00 a.m. and 6:00 a.m. As means of collecting and measuring melatonin have become available, the rhythm of this pineal hormone has become an important marker of the endogenous human circadian system. The phase response curve of melatonin, although still not fully characterized, seems to be approximately oppo-

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Table 20.1. Organ systems and functions affected by circadian rhythms. System

Function

Kidneys

Urinary excretion of K+, Na+, Cl–, Ca++, Mg++, H2O, H+ Cortisol, growth hormone, insulin, rennin, aldosterone, prolactin, testosterone, thyrotropin, luteinizing hormone, gonadal steroids, melatonin Acid secretion, liver function Bronchoconstriction Blood pressure, cardiac output, heart rate, myocardial infarction, ischemia Leukocyte counts, hemostasis, clotting factors Immediate hypersensitivity, leukocyte function, detoxification of bacterial toxins Thermoregulation Metabolism of salicylates, amphetamines, sulfonamides, opiates, anesthetics, histamine, heparin, and other drugs DNA synthesis by bone marrow, intestinal tract cells Resistance and susceptibility to chemotherapy and radiotherapy

Endocrine systems

Gastrointestinal system Pulmonary System Cardiovascular system Hematologic system Immune system Other

Source: Modified from Kryger et al. [51].

Figure 20.3. Daily rhythms of key circadian markers. From Rhoades and Tanner [62]

site in phase to that of body temperature, i.e., the nocturnal decline of body temperature is the opposite of the rise in melatonin, and peak melatonin values are associated with the trough temperature values. This strict relationship is observed during light-induced phase shift [63] as well as under normal conditions. Melatonin measurements can be used to follow both chronic and acute effects of changes in the light-dark cycle on the human circadian system. Another common marker of circadian rhythmicity is cortisol level. Although cortisol rhythms show a series of pulses during the 24-h day, circulating cortisol levels have a consistent circadian rhythm in which the major peak occurs early in the morning (soon after rising), a smaller peak occurs in midafternoon, and the lowest levels occur in the early evening hours [64]. Measurements of cortisol levels, however, are easily confounded, as this stress hormone becomes elevated during stressful conditions [65].

Circadian Rhythms in Space Early investigations of the effects of the space environment on sleep-wake cycles and performance in primates indicated that circadian rhythms of the various parameters persisted, but the microgravity environment significantly influenced temperature regulation and circadian timing [66–68]. Ground-based space flight simulation studies with humans (e.g., bed rest, antiorthostatic bed rest, and isolation) have shown evidence of phase shifts of circadian rhythms [69–74]. In most of these studies, however, hypokinesia may have been the main factor contributing to the changes. To better understand the interaction of work-rest activity schedules and biological rhythms during confinement in a closed life support system, NASA conducted two separate studies in which 8 healthy subjects lived in an isolation chamber at the Johnson Space Center for 60 or 91 days. The work-time light intensity inside the chamber was lower (50– 100 lux) than baseline levels (1000–1500 lux). Although no significant differences in sleep variables were noted between baseline and chamber stay periods, melatonin acrophase was delayed by about 2–3 h during the chamber stay period as compared with baseline values. Both the lighting and circadian rhythm effects in this study were thought to be similar to those observed during space flight or other ground-based simulation studies [75]. Circadian rhythms of oral temperature and urinary calcium, potassium, and 17-hydroxycorticosteroid levels were measured in 2 astronauts before and after the 9-day Spacelab-1 mission (STS-9; November 28–December 8, 1983) [76]. As this mission was to be conducted in two shifts, with the study subjects working “nights” while two other astronauts worked during the subjective “day,” the study subjects underwent sleep-shift entrainment before launch. Preflight and postflight data were analyzed with a cosinor method to determine the acrophase (the time at which the study variable was at its peak) during each 24-h period. The acrophase for urinary calcium had shifted

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in both astronaut-subjects, and the acrophase for potassium excretion had shifted in one astronaut-subject, at the postflight measurement. The acrophase for steroids had not changed [76]. In addition to inducing circadian desynchrony, the dualshift work-rest schedule may have contributed to anecdotal reports of crew fatigue on this mission. A subsequent study involved use of a preflight time-shift protocol and preflight, in-flight, and postflight measurement of levels of adrenocorticotropin, cortisol, prolactin, and growth hormone in saliva in four astronauts [77]. The results indicated that the time-shift protocol prevented any major chronobiological disturbances from occurring during flight, and levels of all of the substances measured were maintained at reasonably low levels in flight. Further, no major changes were evident in the cortisol rhythm during flight. Dijk and colleagues [40] later reported that urinary cortisol levels seemed higher during Space Shuttle flight relative to preflight levels, but this increase was not statistically significant. No obvious changes in urinary cortisol levels were noted during the early days of this mission, but the cortisol rhythm seemed to be delayed relative to sleep schedule later in the flight. Normal cortisol rhythms were restored after landing. With regard to sleep, preflight patterns of non-REM and REM sleep were found to continue during the 1965 Gemini VII mission [78]. In one astronaut, in-flight measurements of core temperature and subjective alertness revealed a delayed rhythm during the 8-day space flight and a change in the structure of non-REM/REM cycles [79]. The latter finding was thought at the time to be evidence that sleep structure did not adapt to space flight conditions; however, the problems experienced by this crewmember (shorter sleep periods with disruptions) may have resulted from difficulty with thermal comfort and finding a comfortable sleeping position. In a more recent study of sleep and circadian rhythms, Gundel and colleagues [80] reported that the circadian phase of body temperature was delayed by about 2 h during a long-duration flight aboard the Russian space station Mir as compared with baseline findings. The authors concluded that observed disturbances in sleep did not seem to result from either the circadian phase delay or changes in sleep structure. Finally, results obtained from four astronauts on a 17-day space flight indicated that circadian rhythms in orbit were very similar in phase and amplitude to those on the ground and were appropriately aligned for the required work-rest schedules for that mission [39]. Similar trends were reflected in mood, alertness, and performance scores. No changes in these variables were noted between the early and later days of the mission. However, overall sleep duration and duration of slow-wave (delta) sleep were both shorter during flight than before.

Light and Circadian Rhythms Light has profound and multiple effects on human circadian rhythms and thus on sleep and performance. These effects can

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be elicited by sunlight or artificial light and depend on the timing and intensity of exposure. Daily exposure to light entrains rhythms to environmental cycles and also maintains internal synchrony among various physiological processes [50,81– 87]. Bright light is known to be a strong zeitgeber of circadian rhythms [81,85], but the contributions of other environmental cues to circadian rhythms are less clear. During the subjective night (the time a person perceives as being nighttime), exposure to light of sufficient intensity can shift the phase of free-running or entrained circadian rhythms. In addition to these “clock” effects, light has “masking” effects on overt circadian rhythms. For example, light exposure can acutely suppress nocturnal melatonin synthesis and attenuate nighttime declines in temperature and performance [56,88–92]. As a result, altered exposure to light can, directly or indirectly, disrupt circadian rhythms, sleep, performance, and well-being. Several situations on Earth disrupt circadian rhythms, in part because of changes in light. Traversing time zones, shifting one’s usual work schedule, or living in constant or unaccustomed lighting conditions (e.g., caves or the Arctic) all have documented effects on physiological rhythms and performance. Space flight could also be expected to have such effects because of the lack of a natural 24-h light-dark cycle. Most human space missions in low Earth orbit expose the crews to “sunrises” about every 90 min. Such unusual patterns of light exposure may have adverse medical and operational consequences, but few data have been collected to document the illumination conditions during Space Shuttle operations. Although a “free-running” circadian rhythm, similar to that found in human subjects in isolation, was speculated to occur in space [93], Gundel et al [80]. dismissed this idea after their investigations on Mir revealed that crewmembers’ circadian systems do not show a free-run pattern but rather a phase delay.

The Light Environment Aboard Spacecraft The daily alternation between light and darkness synchronizes human circadian rhythms to the 24-h day. A nonlinear relationship exists between the intensity of the light stimulus (measured in lux or foot candles) and the biological response it elicits. One lux of light is that emitted by a single candle (one international candela) viewed from a 1-meter distance; a typical dinner candle emits about 12 lux, a small artificial lamp, about 180 lux, and a 60-watt, white incandescent bulb, about 855 lux. The range of light intensity in work environments is quite large, typically ranging from 200–2,000 lux depending on work conditions. Light intensity outdoors on a sunny day can range from 10,000–100,000 lux depending on weather conditions and geographic location. During space flight, both the intensity and timing of illumination differ markedly from the patterns of light exposure on the ground. Space Shuttle crews are exposed to light from two sources: interior fixtures, which provide low-intensity artificial

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illumination, and direct or indirect sunlight, which comes through the heavily filtered windows of the flight deck and varies according to the spacecraft’s orbital path, altitude, and orientation (facing the Sun versus Earth). Although such unusual patterns of light exposure may have adverse medical and operational consequences, few data have been collected to document illumination during flight operations aboard the Space Shuttle. The single systematic study performed to date involved the use of Actillumes (Ambulatory Monitoring, Inc., Ardsley, NY), digital monitoring systems containing a linear accelerometer to record motion and a photometer to measure light. Two of these devices were mounted on the flight deck and middeck, and two astronauts wore wristwatch-style devices on their nondominant arm throughout the mission. Illumination on the flight deck consisted of infrequent, brief “spikes” of very high luminance on a low-illuminance background that cycled every 88 min (mean illuminance, 83.8 ± 432 lux; range, 0–18,479 lux). Although the high-intensity spikes probably accounted for most of the variability in light exposure, such spikes were very brief; during the 14,900 min of recording, luminance levels were 2,000 lux or more less than 0.4% of the time. On the middeck, luminance levels were lower but more consistent than those on the flight deck (mean, 11 ± 7 lux); at no time did middeck illuminance exceed 86 lux. The recorded 88-min periodicity was the same on the middeck and flight deck. As the Space Shuttle middeck has only one small window, the source of the periodicity on the middeck was probably the indirect illumination from the flight deck. The luminance measured by the actillume devices was higher than that measured by the fixed devices, but data from both the mobile and the fixed devices had the same periodicity. Finally, the mean work-time luminance levels were lower during flight than on the ground. Clearly, light exposure during space flight differs from that on Earth in both timing and intensity. Both mean light intensity and the time of exposure to high luminance levels were drastically lower in flight than on Earth. Decreased light exposure has been linked to sleep and mood disorders and to loss of circadian entrainment and coupling [94]. The observation that in-flight luminance levels were similar to those reported in a survey of natural light exposure among 40- to 64-year-old adults [95] led to speculation that circadian and sleep deficits during space flight might resemble age-related sleep changes [96]. The relatively common use of sleep medications during space flight [97] seems to support this speculation. Thus changes in the timing and intensity of illumination on the Space Shuttle flight deck and inadequate illumination in the middeck could disrupt the circadian rhythms, sleep, performance, and well-being of shuttle crews. On the other hand, illuminance patterns recorded during this single flight may or may not be typical of most Space Shuttle missions. In a recent investigation on two other Space Shuttle flights [40], subjective “daytime” illuminance aboard the spacecraft was reported to be very low,

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ranging from only 5.0 lux to about 79.4 lux. However, light exposure during missions could differ not only because of the orbital path and orientation of the spacecraft, but also because of specific mission activities. The lighting conditions on the Space Shuttle flight deck presumably differ from those in the Spacelab or other payload modules or aboard the International Space Station; certainly they would differ substantially from light exposure conditions during extravehicular activities. The minimum light intensity necessary for circadian entrainment or phase shifting is currently under investigation. A light stimulus as weak as that produced by ordinary artificial lamps (about 180 lux) can phase-shift the endogenous circadian rhythms of plasma melatonin and cortisol [98]. Although some information is available regarding the light intensities necessary to mask or change endogenous cycles such as these, little is known about the exposure duration necessary to achieve such effects; thus the high-luminance “spikes” recorded on the Space Shuttle flight deck may or may not affect endogenous circadian rhythmicity.

Strategies for Improving Sleep and Performance in Space Light therapy and pharmacologic countermeasures are now used in the U.S. space program to enhance the sleep and performance of astronauts scheduled for shiftwork aboard the Space Shuttle [38,96,99,100]. It is also accepted by the crew health providers at NASA that even astronauts who are not scheduled for shiftwork during a mission would benefit from similar interventions to reduce sleep disturbances and stabilize circadian rhythms during space flight. The limited information collected to date suggests that use of sleep-shift protocols before launch can prevent chronobiological disturbances [101]. Gundel and colleagues have suggested other improvements such as introducing a nap schedule, which has been shown to alleviate spontaneous sleepiness of civil aviation pilots in the cockpit [102]. Another means of improving sleep and performance in operational environments is the use of pharmacologic agents. Midazolam (for sedation) in combination with flumazenil (for recovery) is used to promote rest and maintain performance during U.S. military operations; this combination has been shown to eliminate performance impairment [103]. When sleep is not possible, the U.S. Army endorses the use of caffeine at doses of 300–600 mg to enhance alertness; this practice can improve performance for 10–12 h after 48 h of sleep loss [104,105]. In another study, dextroamphetamine was shown to improve helicopter pilot performance during short periods of sleep loss without producing adverse side effects [106]. This drug has also been effective in sustaining pilot performance and in reducing feelings of fatigue, confusion, and depression without significant side effects [107].

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Entrainment Strategies for Space Shuttle Crewmembers An objective of the preflight use of light-assisted schedule entrainment is to prepare crewmembers for launch activities as well as in-flight work-sleep schedules. Part of the current preflight protocols thus include the gradual adjustment of sleep schedules so as to support activity schedules during flight. Sleep schedules may be phase advanced, in which the new bedtime is moved earlier (similar to moving eastward across time zones) or phase delayed, in which the new bedtime is moved later (similar to moving westward across time zones). Phase delays are typically more effective in entraining new sleep schedules, but the success of either type of phase shifting can be enhanced with appropriate light therapy. Currently, no supplemental light treatments are administered during space flight. In an attempt to extend the time crews can work aboard the Space Shuttle, NASA adopted use of dual-shift missions, in which two teams of crewmembers work in two separate shift groups. To entrain crews for such schedules, a preflight period of sleep shifting, assisted by bright light treatment to shift endogenous circadian rhythms, is currently used beginning during the preflight quarantine period until the end of the mission (Figure 20.4). Approximately 28% of the 44 missions from STS-40 to STS-99 had dual-shift work schedules; the remaining flights had single-shift schedules. The phaseadvance times for all missions, both single- and dual-shift, ranged between 1.2 and 12.0 h, and the phase-delay times ranged between 0.3 and 14.5 h (Figure 20.5).

Figure 20.4. Diagram of a representative light-assisted sleep-shift entrainment protocol for a dual-shift Space Shuttle mission

Figure 20.5. Frequency distribution of sleep-shift phase advances and phase delays (both shown in hours) for Space Shuttle flights. The Y-axis refers to the number of Shuttle flights

The entrainment protocols are designed specifically for each mission to maintain in-flight activity schedules for that mission; no standard protocols for entrainment are available. The entrainment and phase-shift maintenance protocols practiced by the U.S. space program obviously differ from the shift-operations entrainment programs used for shift workers on Earth, in part because no real-time light maintenance treatment is provided on the Space Shuttle. Another unique aspect of these experimental shift protocols is that the entrainment protocols often include manipulation of sleep schedules during flight, again without supplemental light treatment. Concerns about the safety and effectiveness of using these complex protocols for promoting sleep and alleviating fatigue in space flight crews during missions point to the need for further studies to better quantify operational performance and fatigue levels during flight so that the most effective sleep adjustments can be planned and implemented. Limited information exists on the effectiveness of using these preflight sleep-shift protocols to promote sleep and enhance performance during space flight. Preliminary testing suggested that preflight sleep-shift protocols were effective

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Figure 20.6. Influence of phase advance and phase delay on sleep duration in space crewmembers

in preventing chronobiological disturbances [101]. Another group studied the effectiveness of preflight light-assisted sleep entrainment for astronauts on dual-shift missions by testing rates of excretion of melatonin sulfate and cortisol in urine and saliva as markers of circadian shift. Results from that study indicated that the sleep-shift protocol was successful in producing phase delays in melatonin and cortisol rhythms [108]. Some anecdotal evidence from crew medical debrief records is also available regarding the effectiveness of preflight sleep-shift protocols and in-flight adjustment of sleep schedules on space operations. Crewmembers on nine single-shift Space Shuttle missions underwent preflight sleep entrainment to delay their sleep schedules, and crewmembers on seven, single-shift flights underwent preflight entrainment to advance their sleep schedules. Crewmembers in the first (phase-delay) group slept an average of 6.61 ± 0.78 h per 24h period during their missions, whereas crewmembers in the other (phase-advance) group slept an average of 6.08 ± 0.81 h per 24-h period during flight (unpaired t test, P < 0.01) (Figure 20.6). Crewmembers who had not undergone entrainment reported sleeping an average of 6.06 ± 1.01 h per 24-h period. Thus, although preflight entrainment may be beneficial for delayed sleep schedules, it does not seem to improve sleep for crewmembers on advanced sleep schedules. Moreover, the amount of sleep obtained across all space flights, regardless of shift schedules or sleep shifts, seems consistently low, ranging between 6.1 and 6.5 h per 24-h period. Such sleep decrements have been observed regardless of whether crewmember circadian rhythms remain entrained and undisturbed during flight.

Conclusions For the immediate future, certain changes could be made to ensure that crewmembers’ sleep patterns, shifted or not, are undisturbed and remain entrained. Crewmembers scheduled to work the “night shift” on their missions could benefit from preflight phase-shifting so that their phase-response curve

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coincides with the planned in-flight work-rest schedule, which would enhance the quality of their sleep during flight. Confining light exposure to these crewmembers to their subjective night period during flight would minimize the potentially deleterious effects of changes in light-exposure patterns and intensity in space. Mission planners and medical personnel should design sleep schedules that are regular and capable of maintaining entrainment in addition to meeting the other scheduling requirements of missions. Improved in-flight lighting that affords more continuous bright light in both the middeck and the flight deck would be helpful in circadian entrainment, although this improvement would require equipment upgrades. Padding should be provided for sound dampening in sleeping quarters. In-flight pharmacologic interventions might benefit from a change in focus toward increasing alertness rather than attempts to induce sleep. Finally, interventions after landing may be useful in aiding postflight readjustment, which has occasionally been reported as difficult. In summary, our operationally significant observations documented to date are as follows. First, sleep onset and quality during flight in shift-work crews, even with the use of sleep medications, is less than optimal. Second, circadian rhythm delays, as indicated by melatonin acrophase measurements, are longer during flight than the values targeted during preflight light-assisted sleep-shift entrainment, and these shifts are maintained during flight. Third, circulating melatonin levels of shift-work crews during their subjective work time are higher during flight than before. Fourth, spacecraft lighting, especially in the Space Shuttle middeck and in ISS, is less than optimal in terms of both intensity and exposure pattern during flight. In conclusion, based on the limited information available on the sleep, light-exposure, and circadian rhythms of astronauts and cosmonauts during short-duration single-shift and dual-shift space flights, we propose the following operational recommendations, which may help to enhance crew health and performance during space flights: (1) Consistent in-flight sleep times should be maintained throughout the mission. (2) If shifting is needed, circadian rhythms should be delayed rather than advanced during flight. (3) Sleep shifting protocols and schedules should be standardized and the amount of shifting should be minimal. (4) In-flight lighting conditions should be improved. (5) Means of dampening sound (e.g., padding) should be provided in sleep quarters. (6) In-flight interventions to improve alertness should be provided, and use of sleep aids should be minimized. (7) Postflight intervention options for circadian retraining and enhancing rest should be provided as needed. Finally, additional research on sleep and fatigue in space may help in optimizing the above strategies and uncover nuances of space flight that may be further points of focus for countermeasures. This might include: (1) collection of comprehensive, real-time sleep data during space flights; (2) analysis of data from all flights – including short-duration and long-duration, single shift and dual shift schedules – for

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circadian rhythms and sleep variables; (3) testing and validation of intervention protocols to facilitate sleep and augment performance; (4) optimization and standardization of preflight entrainment protocols; and (5) supplementation of preflight programs with inflight entrainment protocols that can support crew activity schedules.

Acknowledgments. The authors appreciate the technical support of Drs. Stephen F. Sarabia and Chantal A. Rivera and the library research by Kim P. So and Janine C. Bolton.

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21 Health Effects of Atmospheric Contamination John T. James

Safe air for breathing is the most immediate resource required by spaceflight crews. Clearly, gross parameters of the breathing atmosphere, such as temperature, pressure, O2 tension, and water vapor content, must be maintained within physiologically acceptable ranges. Even if these properties are well controlled, exposure to the trace contaminants and particles in the atmosphere confers a significant health risk. This chapter describes strategies for minimizing toxicologic risks to crew health, outlines how toxic exposures can be recognized in the crew and the space environment, and describes how crews and their environment can be restored to healthy conditions after accidental exposure to a toxic compound.

General Principles of Managing Exposures to Toxic Compounds in a Spacecraft An axiom in spaceflight toxicology is that the risk of air contamination is managed first and the consequences of plausible failures managed second. Risk can be viewed as the probability that an unwanted event will occur multiplied by the seriousness of such an event when it occurs. For example, the risk from a rare, serious event may be comparable to the risk from a likely, inconsequential event. Human space flight is an inherently risky activity, and the risks associated with air contamination must be managed in this context. Health risks from air contamination cannot be controlled so as to eliminate all risk to the crew; however, such risks can be controlled to acceptable levels within the context of human space flight. Since certain defined failures (e.g., fire or smoke in the cabin, leaks from spacecraft systems, excess CO2 in the atmosphere, etc.) can be anticipated, the management of their consequences is guided by flight rules regarding atmospheric monitoring, protection of the crew from exposure, decontamination procedures, and treatment of exposure victims. Another axiom of spaceflight toxicology is that the human occupants of a space vehicle and the environment of the vehicle that they occupy must be viewed as an integrated

human-vehicle system. Thus the patient should be treated first, but the patient’s environment may need to be “treated” (decontaminated) as well. For example, if a crewmember discovers a foreign body in his or her eye, the flight surgeon, after immediately treating the patient, also must determine whether the environment needs to be treated to remove any additional particles. Air contamination in spacecraft is unique in that airborne particles, which would settle out of the atmosphere at Earth gravity, remain suspended indefinitely in microgravity. These particles could pose a lasting threat to the crew’s eyes and respiratory systems. Similarly, after a system leak, aerosols of low-volatility liquids (e.g., ethylene glycol) can accumulate rapidly on any cool surface. As the accumulated liquid slowly evaporates, its vapors can present a long-term health threat to the crew if the surfaces exposed to that liquid are not cleaned. Moreover, accumulated liquid can provide a substrate for microbial growth, which can produce toxic metabolites. If carbon monoxide (CO) enters the spacecraft atmosphere in high concentrations and is inhaled by the crew, both the crew and the environment must be treated to achieve a successful outcome.

Carbon Monoxide Sources A fire or smoldering combustion is one of the most feared events in a sealed environment, especially in a space vehicle, which invariably will have limited escape options. A major health threat from combustion in a sealed space is the production of highly toxic products that can have both immediate and delayed toxic effects on crewmembers. Although not the most toxic of combustion products, CO has proven to be one of the most hazardous because it is produced in large quantities in most fires. In microgravity, since convection does not renew O2 in the vicinity of a fire, less oxidation of the fuel occurs and a larger portion of CO is produced than in a comparable Earth-based fire. In addition, the magnitude of the fire 427

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can be misleading in terms of the amount of CO produced, an observation that has been well illustrated by the two fires that occurred on board the Russian space station Mir during the NASA-Mir Program. The more highly publicized fire that took place on Mir, which occurred in the solid-fuel O2 generator, was an immediate threat both to crew health and to the integrity of the station. On Mir, the solid-fuel O2 generator was used by the crew to provide backup O2 when the O2 tension dropped below 160 mm Hg. The generator produced O2 through controlled heating of a cartridge containing potassium, lithium, and magnesium perchlorate that was ignited at 400°C (750° F) [1]. For unknown reasons, one of the cartridges activated by a crewmember on 23 February 1997 caught fire and burned out of control for several minutes. (The length of time that the fire burned is disputed. Compounding this hazardous situation was the fact that 6 people were on board Mir at the time, and the fire was blocking the route to one of the Soyuz escape vehicles.) The occupants of the station quickly donned respirators, and approximately 3 h after the fire had been extinguished, air samples were taken in grab sample canisters. Several months elapsed before all of the canisters were returned to Earth and an analysis of their contents was completed. That analysis showed CO concentrations of 16–20 mg/ m3 (18–23 ppm), depending on where the sample was taken [2]. This CO level posed no immediate threat to crew health since the 24-h spacecraft maximum allowable concentration (SMAC) for this compound is 20 ppm [3]. A second less highly publicized fire on Mir, on 26 February 1998, led to the release of much higher concentrations of CO and caused symptoms in at least 1 crewmember. That fire was started by the low-temperature catalytic oxidizer. (The low-temperature catalytic oxidizer consisted of a frontend, replaceable charcoal filter; a pair of regenerable filters that could operate in the sorption mode to remove contaminants from the air or in the thermal desorption mode to remove contaminants from the filter beds; and a back-end catalytic oxidizer to oxidize H2 and CO.) The fire apparently started in the Kvant-1 module, when regenerated filters were switched into the flow stream before they were allowed to cool, thereby igniting paper filters in the unit. The crew observed a little smoke, but the fire was quickly contained and the incident was considered minor until readings from a portable monitor indicated CO concentrations of 400 ppm (i.e., 20 times the recommended safety level) (Figure 21.1) [4]. The decay profile suggested that the CO level in the station was elevated for at least 80 h. A canister sample, taken 28 h after the fire began and analyzed in a ground-based laboratory later, showed a CO concentration of 130 ppm when the CO sensor was reading 95 ppm, indicating that the true CO concentrations were higher than the readings given by the portable monitor. The crew seemed fine for several hours after the incident, but that evening and the next morning, at least one crewmember reported having a headache and nausea.

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Figure 21.1. Readings from the CO sensor after the lowtemperature catalytic oxidizer burned on Mir

Other less spectacular and more predictable sources of CO include human metabolism and a minor contribution from offgassing of materials. The catabolism of hemoglobin produces approximately 32 mg of CO per person per day [5]. For a space vehicle with 100 m3 (3,531 ft3) of free volume occupied by 3 people, this translates into a concentration accumulation of 1 mg/m3 per day, or roughly 1 ppm/day. A failure in the catalytic oxidizer that removes CO thus can result in potentially unhealthy concentrations (i.e., concentrations above 20 ppm) in approximately 20 days. The contribution from CO offgassing is very small, as documented in a 209-h test of the International Space Station (ISS) Node 1 module for contaminant accumulation in the absence of human occupants or air scrubbing. Throughout that test, CO was present at no more than trace levels [6]. In spacecraft, CO is controlled by catalytic oxidizers that convert it to CO2, which is removed by replaceable alkali canisters or by one of several regenerable sorbent beds. The capacity of these systems is ordinarily scaled with appropriate safety margins to maintain the CO concentration below 5 ppm at a nominal rate of CO generation. Unfortunately, these systems can be easily overwhelmed when a fire produces large concentrations of CO in the range of a few hundred ppm, as it did on Mir in 1998. Under these conditions, the crew must be isolated from the contaminated atmosphere, often for many hours, until the slow process of CO scrubbing is completed. Additional CO scrubbing capability is available on some spacecraft. Although respirators are available on all spacecraft, they may not offer prolonged protection from a CO-contaminated atmosphere.

Mechanism of Toxicity Inhaled CO displaces the O2 bound to hemoglobin and has an affinity for hemoglobin approximately 250 times that of O2. The resultant carboxyhemoglobin (COHb) molecule can severely reduce the delivery of O2 to body tissues, especially those tissues (i.e., the heart and the lung) with limited anastomotic development and high metabolic activity. So if the

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concentration of CO is only 0.08% (800 ppm), or 1/250th the normal concentration of O2 (21%), for example, 50% of the hemoglobin sites available for O2 binding are occupied by CO at equilibrium. CO not only competitively reduces the formation of oxyhemoglobin in the lungs, it also inhibits the release of O2 to the tissues by causing tighter binding between O2 and the hemoglobin. Since the rate at which CO binds to hemoglobin can be rather slow for a sedentary person, symptoms of toxicity can be delayed for several hours. The binding of CO to cytochrome oxidase and myoglobin may also contribute to the pathophysiology of CO poisoning.

429 Table 21.1. Symptoms of CO poisoning based on levels of COHb in nonsmokers. COHb

Poisoning

Symptoms

5–10%

Subclinical

20–30%

Mild

30–40%

Moderate

40–50% 50–60% >60%

Severe Extreme

Reduced exercise capacity, slower reaction time Headache, nausea, impaired dexterity and judgment Throbbing headache, nausea, vomiting, impaired dexterity and judgment As above plus possible syncope Convulsions and coma Death

Abbreviation: COHb, carboxyhemoglobin.

Warning Properties One of the most important aspects of CO toxicity is its complete lack of warning properties. CO is a colorless, odorless gas, the presence of which cannot be detected by human senses even in high concentrations. The onset of the symptoms of CO poisoning can be such that the victim is unaware of the accumulation of CO in the breathing atmosphere. This lack of a warning property has resulted in the severe poisoning of many persons who place themselves in semi-closed environments with a source of combustion [7,8].

Airborne Concentrations that Cause Toxic Effects The symptoms caused by CO exposure depend on a combination of the airborne concentration of CO, the activity level of the victim, and the length of the exposure. These factors can be combined in the Stewart equation to predict COHb concentrations in blood as an index of toxic effects resulting from short exposures: COHb(%) = 3.317 × 10−5 [CO]1.036 × RMV × t where [CO] is the atmospheric concentration of CO in ppm, RMV is the respiratory minute ventilation in L/minute, and t is the exposure time in minutes [9]. For exposures to high concentrations that last longer than 1 h, the Coburn-Foster-Kane equation is recommended [10], but this sort of exposure is unlikely on board current spacecraft because of CO monitoring and ready access to respirators. The Coburn-Foster-Kane equation takes into account the dynamics of CO uptake and release in the lungs as the blood and airborne concentrations approach equilibrium. However, neither the Stewart equation nor the Coburn-Foster-Kane equation provides an accurate estimate of COHb levels when a victim has been exposed to widely varying concentrations of CO. The symptoms associated with different levels of COHb are shown in Table 21.1. Since the correlation between toxic effects and COHb varies somewhat, the information given in Table 21.1 should be taken only as a rough guide. In a practical situation, COHb can be estimated by using the Stewart equation and the measurements that are immediately available to the flight surgeon. For example, if a crewmember is exposed to CO at a concentration of 1,000 ppm for 10 min

and is moderately active during that time (i.e., with an RMV of 15 L/min), the COHb can be calculated as follows: COHb(%) = 3.317 × 10−5 × 1,0001.036 × 15 × 10 = 6% According to Table 21.1, such an exposure would not be expected to elicit any obvious symptoms in the crewmember.

Clinical Presentation The characteristic ground-based presentation of a COpoisoned patient can include weakness, fatigue, confusion, impulsiveness, and incontinence. Abnormal motor and sensory findings may also be present [11]. In spaceflight crews, subtle effects of CO exposure (Table 21.1) may be difficult to distinguish from the effects associated with headward fluid shifts and space motion sickness. Among the symptoms of space motion sickness are impaired concentration, headache, nausea, and vomiting [12]. Space motion sickness is very common in crews of most space vehicles. Moderate to severe symptoms have been experienced by 30% of crewmembers on board early Space Shuttle flights [12]. Symptoms usually disappear within 2 days of orbital insertion, although they have lasted as long as 3 days into flight. Symptoms, such as those cited in Table 21.1, that occur later than 3 days into flight could suggest CO poisoning rather than space motion sickness. If CO originates from a fire, simultaneous exposures to other toxic compounds (e.g., hydrogen cyanide [HCN]) are likely. Some of these compounds can produce symptoms that are magnified beyond those associated with COHb formation. In addition, hypoxia due to the removal of O2 from the breathing atmosphere during combustion can also play a role. The combined effects of CO and HCN exposure seem to be no more than additive on a fractional-dose basis. The uptake of HCN and CO should be assumed to be increased in proportion to any increases in RMV caused by CO2 from the fire and from use of the CO2 fire extinguishers present on many space vehicles. Any narcosis induced by CO2 exposure should be independent of that induced by CO, HCN, or hypoxia [10]. At relatively low levels of CO, interaction with hypoxia seems to be unimportant; however, at exposures to high concentrations

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of CO, the effects of hypoxia are likely to be additive when combined with those from CO [10].

Differences in Individual Susceptibility Astronauts are generally in good health and the individual responses to CO exposure are unlikely to vary much unless the astronaut smokes. This is because people who smoke are much less susceptible to the central nervous system (CNS)depression effects of CO exposure than are people who do not smoke [13]. Exposures to CO at 111 ppm for 1–2 h led to COHb levels of approximately 7%—levels that impair the vigilance of nonsmokers but not of smokers. Persons with impaired lung function or with cardiovascular disease are much more likely to experience symptoms from exposure to a specific concentration of CO; however, such persons would not qualify as astronauts.

Sampling and Analysis Atmospheric CO can be measured in real time on board modern space vehicles, or archival canister methods can be used to sample the air for later ground-based analysis. Currently on the ISS, an electrochemical sensor is used in the compound– specific analyzer for combustion products to warn of CO accumulation or release from a fire. This commercial instrument (Industrial Scientific Corporation, Pittsburgh, PA) has a data logger and a downlink capability so that it can be used to manage CO pollution in spacecraft. (Additional sensors selected for the ISS compound specific–analyzer for combustion products include HCN, HCl, and O2.) The instrument was found to perform well in combustion atmospheres generated by hardware typical of that used in space vehicles [14]. An adapter called the CO breath sampler, which is available from the manufacturer but has not, as of this writing, been manifested for the ISS, permits indirect measurement of COHb by correlation with the CO concentration measured in the victim’s breath [15]. A confounding factor for space applications, and the reason the adapter has not been manifested for the ISS, is that the user must inhale a breath that is relatively free of CO, and this could only be done in a CO-polluted space vehicle if the victim’s breath was inspired from a respirator and expired into the sampling device. Detector tubes for CO are also available on board the ISS to assist in the measurement of CO if a fire occurs. A pump is used to aspirate air through a glass tube containing chemicals that produce a colored stain when they react with CO. (The length of the stain indicates CO concentration.) This method is totally independent of the electrochemical sensor. The availability of 2 methods to measure CO highlights the high risk associated with this compound. The probability of a fire on ISS during the lifetime of the station is high, and consequences of a fire could be catastrophic if appropriate preparations have not been made to manage those consequences.

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Archival samplers have been used for many years to obtain air samples for ground-based analysis. For the Space Shuttle and ISS crews, an evacuated SUMMA-treated canister that has a 350-mL volume is used to obtain an air sample. For the Space Shuttle, air samples are usually collected near the end of the mission. On board the ISS, canister samples are taken when the hatch to a new module is opened and the crew enters that module or when air pollution is suspected. These archival samples can be useful in understanding the magnitude of air pollution but only long after the event has been resolved.

Protection and Treatment after Exposure Only limited resources are available on board a space vehicle to treat a crewmember who is exhibiting symptoms of CO exposure. Since CO production will most likely be associated with a fire, the most important action is to ensure that a respirator has been donned as quickly as possible after the fire is detected and that the crew has been moved to the least polluted portion of the space vehicle. If the fire has been extinguished, closing the hatch between the module in which the fire occurred and the remainder of the space vehicle is desirable. (This action could preclude measurements of the CO concentration in the isolated module and could thus make planning to recover the module more difficult.) Unfortunately even the best precautions are no guarantee against a crewmember being exposed to high levels of CO. Inhalation treatment using 100% O2 will reduce the half-life of COHb from 5−6 h to 0.5–1 h, and the patient exposed to CO should be so treated until the blood COHb concentration has been reduced to 15–20% [11]. Obviously, the patient must also remain on the respirator regardless of COHb concentration if the concentration of CO in the cabin has not been reduced to safe levels. U.S. space vehicles use a portable breathing apparatus to provide immediate respiratory and eye protection in the event of CO exposure. Approximately 15 of O2 at a consumption rate of 15 L/min is available in a pressurized cylinder. With the arrival of the O2 tank on ISS mission 7A, the portable breathing apparatus was able to be connected to an O2 port. The portable breathing apparatus can be used in positive pressure mode or on demand mode. (It does not provide an adequate seal for crewmembers with beards, however.) The Russian segments of the ISS contain a rebreather type of gas mask that can provide protection for 20–120 min depending on ventilation rate [1]. The chemical reaction that produces the O2 in the Russian gas mask is activated by respiration, which means that there is a delay of 20–30 s after the mask is donned before the O2 becomes available.

Decontamination of the Environment Various types of catalytic oxidizers are used on spacecraft to control the nominal load of CO into the atmosphere, but the capacities of these oxidizers are insufficient to rapidly remove large amounts of CO from the atmosphere after a fire. In a

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well-mixed atmosphere, the level of pollutant will be reduced by at least 80% after two complete volumes have passed through a filter that maintains 100% sorption efficiency. The ambient temperature catalytic oxidizer that is used in the Space Shuttle consists of platinum-coated charcoal with a prefilter to remove other pollutants that could “poison” the catalyst in the primary filter. The flow through this filter is only 1.7 m3/h, however, and the Space Shuttle free volume is 65 m3, so 76 h would be required to make 2 complete volume passes through the filter. An option in the Space Shuttle is to replace one of the LiOH canisters—LiOH canisters scrub CO2 from the air on board the Space Shuttle—with the hydrazine adsorber element, a large ambient temperature catalytic oxidizer filter that is capable of scrubbing approximately 1 cabin volume in 1.5 h. The Russian service module of the ISS uses a palladium catalyst canister operated at ambient temperature and a flow of 20 m3/h [1]. Thus the service module, with its free volume of 100 m3, will require 10 h for two complete passes of air through the catalytic oxidizer. The U.S. modules of the ISS use a high-temperature catalytic oxidizer with a flow rate of 4.6 m3/h to remove CO [16,17]. With free volumes of 98 m3, the laboratory and habitation modules will each require about 43 h for a two-volume scrub of CO from the air. The ultimate solution under certain contingencies may be to depressurize the polluted module, assuming that the module has been isolated from the module in which the crew has sought refuge. Most space vehicles have provisions for at least a partial depressurization-repressurization cycle.

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in Houston, Texas—nearly caused an abort of the test [20]. This happened because the hardware had not been screened for off-gassing properties. Air samples that were taken during the first few days of the test showed rising formaldehyde levels, and eventually one of the crewmembers reported respiratory irritation. Approximately 15 days into the test, an effort was made to remove any material that could off-gas formaldehyde, after which the formaldehyde levels diminished significantly, the respiratory irritation disappeared, and the test was completed without further problems with formaldehyde (Figure 21.2). In an incident of formaldehyde exposure on board the Space Shuttle during STS-40, a motor in the Space Shuttle’s middeck refrigerator overheated and the motor housing, which was made of the formaldehyde polymer Delrin, had thermally degraded to produce quantities of formaldehyde that were both irritating and nauseating to the crew [21]. The crew was able to minimize exposure by staying out of the middeck as much as possible. The cause of the incident remained unknown until the refrigerator was disassembled on the ground (Figure 21.3). Finally, investigations of the catalytic oxidizer used in the 90day Lunar-Mars Life Support Test, after that test was complete, revealed that incomplete oxidation of methanol, possibly as a result of a poisoned catalyst, was resulting in the unit releasing formaldehyde into the effluent stream [22]. In summary, these four separate incidents indicate that formaldehyde can originate from numerous sources on board a space vehicle and that controlling the risk of crew exposure can be a challenge.

Formaldehyde Sources Formaldehyde is a highly irritating compound that can enter a space vehicle’s atmosphere through leakage of fixatives from payload experiments, off-gassing of hardware, thermodegradation of certain polymeric materials (e.g., Delrin), and incomplete oxidation of contaminants in the environmental control system. The hazard rating of formaldehyde solutions in payload experiments, which is based on its potential for eye irritation, is critical if the solutions are between 0.25% and 1.0%; it is catastrophic if the concentration is above 1.0% [18]. During the Mir-18 mission, while the crew was conducting fixation operations as part of the Fundamental Biology Experiment, several drops of paraformaldehyde solution were released into the environment. A postflight inspection of containment bags showed that the inner level of containment had been breached [19]. The crew suffered no known harm from this exposure, and measures were subsequently taken to minimize the risk of recurrence. In a potentially hazardous incident, formaldehyde offgassing of hardware during a ground-based test—part of the Lunar-Mars Life Support Test at the Johnson Space Center

Figure 21.2. Profile of formaldehyde accumulation in the groundbased Lunar Mars Life Support Test. Excess materials off-gassing caused the accumulation from day 1 to day 15. Reprinted with permission from SAE paper number 981738 ã 1998 Society of Automotive Engineers, Inc. 28th Conference on Environmental Systems; 13–16 July 1998; Danvers, MA

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J.T. James Table 21.2. Estimated toxic responses to acute exposures to formaldehyde vapor [11,25,27,28]. Formaldehyde concentration <0.25 ppm 0.25–0.5 ppm 0.5–1 ppm 1–3 ppm 4–5 ppm 5–30 ppm 50–100 ppm

Figure 21.3. The small motor in the refrigerator that generated formaldehyde when the Delrin was overheated

Mechanisms of Toxicity Formaldehyde is a highly reactive compound with 2 major toxicologic properties—it acts an irritant to the eyes and respiratory system; after prolonged exposure, it is carcinogenic in rodents and perhaps in humans. The compound irritates the upper respiratory system, where its stimulation of the olfactory and trigeminal nerve endings causes the affected person to try to hold his or her breath. When the breath can no longer be held, normal respiration resumes, and if the exposure concentration is sufficiently high and prolonged, tissue inflammation, tissue necrosis, and eventually cancer are possible. At moderate concentrations, inhaled formaldehyde is primarily captured in the nasal passages, where it binds to glutathione in the cytosol of nasal cells, is oxidized principally by formaldehyde dehydrogenase, and is then released from the glutathione by S-formyl glutathione hydrolase as formate and CO2 [23]. The molecular mechanism by which formaldehyde causes nasal irritation is unknown. If the amount of formaldehyde present exceeds that which the formaldehyde dehydrogenase can metabolize (> 6 ppm in rats), free formaldehyde can reach the nuclei of nasal cells, where it forms DNAprotein cross-links. These cross-links, and the cell replication subsequent to inflammation from tissue damage, are thought to lead eventually to nasal cancer, at least in rats [24]. Also, if concentrations are sufficiently high or minute ventilation is high, formaldehyde can reach deeper into the respiratory system and elicit pulmonary irritation.

Warning Properties The warning properties of formaldehyde can be considered adequate for most conditions of exposure. For most people, the odor threshold is from 0.5 to 1 ppm, and mild irritation is felt at 2–3 ppm [25]. Although controversy exists as to which levels of exposure humans can tolerate without increasing the

Effects to expect 10–20% of those exposed may have a respiratory response up to 20% of population finds exposures disagreeable Most persons sense the odor of formaldehyde Mild irritation in most people Many people find this intolerable for any length of time Lower airway and pulmonary effects such as cough, chest pain, dyspnea, wheezing Pulmonary edema, inflammation, pneumonia

risk of cancer, the concentration predicted to increase the cancer risk no more than 1 in 10,000, with 95% confidence for a 180-day exposure, was estimated to be about 1 ppm [26]. Hence, the odor of formaldehyde, and certainly any respiratory or eye irritation from it, can be considered a warning that the space vehicle atmosphere must undergo increased scrubbing or that a new source of formaldehyde must be identified and contained.

Airborne Concentrations that Cause Toxic Effects Target organs for formaldehyde are the eyes and respiratory system. Susceptibility to formaldehyde vapor varies considerably among individuals; however, Table 21.2 can be used as a general guideline for acute exposures lasting several minutes.

Clinical Presentation Relatively mild acute exposures to formaldehyde will result in burning and tearing of the eyes, upper airway irritation, rhinitis, and throat irritation. Since these symptoms are characteristic of any primary irritant, their presence by no means specifically suggests exposure to formaldehyde. Formaldehyde does tend to have a characteristic odor, however, and the irritant symptoms, along with crew identification of an aldehyde-like odor, are suggestive evidence of excess airborne formaldehyde. The crew of STS-40—as cited in transcripts of the STS-40 air-to-ground comments—indicated an aldehyde odor from the refrigerator when the Delrin polymer was apparently being pyrolized by overheating of the motor. The evidence is unclear whether olfactory fatigue will reduce a crew’s ability to sense the odor of formaldehyde or to experience the symptoms listed above. It seems reasonable to expect a crew to be less aware of an odor from a given airborne concentration of formaldehyde if the odor builds slowly rather than being suddenly present. Conversely, the irritant properties of formaldehyde do not seem to become more tolerable with prolonged exposure. In fact, there is some evidence that respiratory sensitization may be possible. According to

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one expert panel, “the role of formaldehyde as an irritant and potential allergen affecting … nasal mucous membranes is recognized… Some individuals may become highly responsive to low doses leading to debilitating… rhinitis, conjunctivitis, and asthma.” [29]

Differences in Individual Susceptibility Some concern has been expressed that in Earth-based populations, people with asthma could experience asthmatic symptoms as a result of formaldehyde exposures. In one investigation, of 230 asthmatic patients studied, eight displayed an immediate bronchial reaction when inhaling 2 ppm formaldehyde for 30 min [30]. At present, persons with asthma are disqualified by U.S. astronaut selection criteria; however the U.S. criterion could change in the future. Even among people who do not have asthma, a portion of the population is extremely sensitive to formaldehyde vapor. After reviewing the data on formaldehyde, the Threshold Limit Value Committee of the American Conference of Governmental Industrial Hygienists, Inc., noted “an unusually broad range of reported susceptibility of humans to the irritating properties of airborne formaldehyde.” The Committee concluded that “It is plausible that a similar portion (10–20%) who are more responsive may react acutely to formaldehyde at very low concentrations, <0.25 ppm.” If formaldehyde exposures are suspected on board a space vehicle, the reported level of symptoms may vary widely because of individual differences in susceptibility.

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eye protection. Symptoms of exposure disappear quickly once appropriate protection has been put in place. If the source of formaldehyde is a spilled liquid, goggles, respirator, and impermeable gloves should be worn as protection. Skin contact should be avoided, as skin sensitization is possible with all aqueous formaldehyde solutions. Repeated exposures must be avoided because they could lead to sensitization to formaldehyde. In fact, there is a report that after a 140-day and a 175-day Russian mission on board the Salyut space station, the Russian crews returned with a sensitivity to formaldehyde that they did not have before flight [32].

Decontamination of the Environment Formaldehyde can be removed from the environment by using charcoal filters and humidity condensers. The absorption efficiency of activated charcoal for formaldehyde is limited, but space vehicles with large charcoal filters can partially scrub the air by this means. In space vehicles where the humidity condensate is not recovered (e.g., the U.S. Space Shuttle), much of the formaldehyde can be condensed from the air along with the water vapor. Formaldehyde has been regularly found in the Space Shuttle humidity condensate, which indicates that a load of formaldehyde is entering the air and that condensation is an effective removal mechanism. In space vehicles in which the humidity condensate is recovered for purification and reuse by a crew, airborne formaldehyde can present a risk to water quality.

Ethylene Glycol Sampling and Analysis At present, no real-time analytical method exists that is suitable for use in a spacecraft and can quantify formaldehyde at the long-term SMAC of 0.04 ppm. (A revised value of 0.10 ppm has been approved recently.) Formaldehyde concentrations have been measured on the Space Shuttle, the Mir, and the ISS using sorbent badges to sample the air; later, groundbased colorimetric analysis by ultraviolet spectrophotometry is used to quantify the formaldehyde [31]. The badge can be placed on the uniform of a crewmember or located on a wall; however, it is essential that an adequate cross-flow of air be present or undersampling will result. Sample times can range from 8 to 24 h, and the limit of detection is 0.01–0.02 ppm, depending on sample time and dispersion in blank values. Although their small size and ease of use make the badges ideal for space flight, a real-time method is needed to assist the flight surgeon and environmental engineers in the event of a contingency involving formaldehyde.

Protection and Treatment after Exposure Given the irritating properties of formaldehyde, no crewmember would tolerate a toxic inhalation exposure to it unless he or she was unable to escape to a clean module or to don respiratory and

Sources Ethylene glycol (EG) is a colorless, odorless, water-soluble liquid that has a low vapor pressure and a sweet taste. It is familiar to most people as the major ingredient in the antifreeze used in the cooling systems of automobile engines. It was used in the Apollo space vehicle, where concern over its leakage into the cabin was sufficient that the Apollo astronauts were given training in detection of its presence in the atmosphere [33]. The only source of EG on board modern spacecraft is in heat-exchange loops, where it can be used in large quantities to redistribute heat. During the NASA-Mir Program, large amounts of EG escaped several times from the Mir cooling loops. The escaped material was difficult to clean up and at times elicited toxic symptoms including respiratory irritation and, when large drops were encountered, eye irritation. Airborne EG was also captured in the water-vapor condensation system; at times, this condensed water could not be purified to potable standards [34]. Thus, recycled water, which is used for drinking and to reconstitute food, can become a source of EG exposure for a spaceflight crew. Because of these toxicologic concerns, EG has been replaced with “triol” in the Russian segments of the ISS and is not used in any of the U.S. segments of the ISS. Triol

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consists of a 30–32% solution of glycerin in water that also includes up to 8% additives to control corrosion and microbial growth (personal communication from Valeri Ryumin to Frank Culbertson, 24 May 1999.) Future space habitats could see a return to the use of EG in applications where heat exchange is required.

J.T. James Table 21.3. Irritation caused by ethylene glycol vapor and aerosol. EG concentration (ppm [mg/m3]) 25 [60] 50 [130] 73 [190]

Mechanism of Toxicity EG is relatively low in toxicity, but it can be lethal to adults when it is ingested in quantities that exceed 100 mL. Since EG is most often ingested accidentally, considerable research has been dedicated to our understanding of EG toxicity by oral ingestion. However, oral ingestion is not considered a major route of exposure in spacecraft since the water will be monitored for changes in total organic carbon, which will reflect the presence of EG. The primary concern during space missions regards the inhalation by spaceflight crews of EG vapor or aerosol as well as skin or eye irritation during contact with large, free-floating drops formed after an EG release. When inhaled as a vapor or an aerosol, EG can irritate the upper respiratory tract. Once EG enters the body, the potential exists for CNS effects and renal toxicity. Respiratory irritation is apparently caused by the interaction of EG or its metabolites at receptors in the respiratory tract. CNS effects are caused by EG or an aldehyde that is formed by oxidative metabolism [35]. Oxalic acid, which is another of the metabolites of EG, is thought to increase the probability of calcium oxalate crystals forming in the kidneys and to contribute to EG-induced renal toxicity. The direct effects of EG metabolites on the tubular epithelium may also cause necrosis. EG can cause eye irritation when direct contact is made between the liquid and the surface of the eye. In animal models, the degree of irritation depends on the concentration of EG in solution and the length of exposure. Repeated topical exposures of rabbit eyes to EG caused a strong irritation response at a 40% concentration in balanced salt solution, a reduced response at 4% concentration in balanced salt solution, and no response at 0.4% in balanced salt solution [36]. Single administrations do not seem to elicit an irritation response [37]. This observation is consistent with reports that emerged during the NASA-Mir Program that crewmembers who repeatedly got airborne EG drops (∼40% in water) in their eyes experienced eye irritation.

Warning Properties The warning properties of EG by inhalation exposure are upper airway irritation and a sweet taste in the mouth. Inhaled EG has little acute toxicity. During brief exposures, the upper airway is irritated at concentrations that are unlikely to cause injury. If the exposure is prolonged, however, EG concentrations that are below the irritation or taste threshold can be sufficiently high to increase the risk of tissue injury. The irritation response to EG is summarized in Table 21.3. Exposures of up to 100 mg/m3 (about 40 ppm) could be undetected by crewmembers.

80 [200] 95 [250] 120 [300]

Response No effect Pharyngeal irritation and sweet taste common Subjects could tolerate exposure for 15 min Pain in tracheobronchial tree Tolerable for no more than 1–2 min Intolerable to breathe

Source: Modified from Wong [38].

Airborne Concentrations that Cause Toxic Effects It is estimated that prolonged exposures at or below 5 ppm to EG will not result in detectable CNS depression [38]. This estimate was based on the finding that no effects were found in a psychometric test of 20 men exposed to EG at 12 ppm for 30 days [39]. Likewise, no renal effects (as measured by urine specific gravity, serum urea nitrogen, serum creatinine, and creatinine clearance) were found in the same group of men; hence, exposure to up to 5 ppm EG for a prolonged period is unlikely to cause kidney injury. The 5 ppm limit is well below the 12-ppm, 30-day experimental exposures because of a statistical safety factor that takes into account that only 20 men were exposed. It is reasonable to expect that sensitive individuals may not have been represented in that numerically limited test population.

Clinical Presentation Ingestion of EG causes a series of clinical effects that can be grouped into 4 stages. At the first stage, which occurs with the first 12 h after ingestion, a victim of EG poisoning may have sufficient CNS depression to appear drunk. A second stage, which occurs 12–36 h after EG ingestion, entails cardiopulmonary effects such as tachypnea, tachycardia, hypotension, and cyanosis. A third stage involves renal failure characterized by proteinuria, blood cells in the urine, and calcium oxalate crystals in the urine. A fourth stage, which involves neurologic symptoms, has been suggested to occur in some victims approximately 2 weeks after the ingestion [40]. Such severe symptoms as appear in these four stages are extremely unlikely to occur after inhalation of EG vapor or aerosol. In the event of a major EG vapor or aerosol release that cannot be controlled, the flight surgeon should be cognizant of the possibility of minor CNS and renal effects in crewmembers.

Differences in Individual Susceptibility Although inter-individual differences have not been specifically documented in human susceptibility to EG poisoning, this issue has received little study. Initial metabolism of EG

21. Health Effects of Atmospheric Contamination

involves alcohol dehydrogenase and aldehyde dehydrogenase, each of which, from studies of ethanol metabolism, is known to vary widely in its catalytic activity in the human population. Reduced inherent aldehyde dehydrogenase activity, common in persons of Asian descent, could predispose such persons to a higher susceptibility to inhaled EG vapor. This higher susceptibility could be the result of the accumulation of aldehydes, which are thought to cause many of the toxic effects of EG. It should therefore be expected that certain persons may be unusually sensitive to the effects of EG exposure.

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Protection and Treatment after Exposure If a large amount of EG has been released into spacecraft air, eye and respiratory protection should be used until the spill has been cleaned up. A crewmember may be able to tolerate EG exposures up to 25 ppm for 24 h, but longer exposures should be limited to 5 ppm. Since EG does not spread rapidly in spacecraft atmospheres, movement of sensitive persons to an area in the spacecraft where lower EG concentrations are found may be an option. If the patient’s eyes have been repeatedly exposed to liquid EG, use of the eyewash station available on all U.S. vehicles may be necessary.

Sampling and Analysis The accepted exposure limits to EG for Earth-based workers are approximately half the vapor saturation concentration of 80 ppm at 20° C (68° F). An extremely stagnant, nearly closed environment is required to vaporize a liquid to half its saturation concentration; hence, unless aerosols are produced by mechanical means, there is little need to measure EG in the atmosphere on Earth on a real-time basis. For this reason, rapid analytical methods for EG in the air are not particularly well developed. One method for sampling and analyzing EG, among other substances, is the use of Draeger tubes. (This method was used on board the Mir space station during the Shuttle-Mir Program.) These devices were flown on Mir because of persistent leaks of EG from the station’s coolant loops and concerns about crew health from prolonged exposure to EG. Draeger tubes indicate EG concentration by the length of pink stain produced by a colorimetric reaction when air is drawn into the tube. Estimates of EG concentrations after a leak on Mir are shown in Figure 21.4.

Figure 21.4. Persistence of ethylene glycol in the Mir atmosphere (estimated with Draeger tubes). Concentrations are from the Kvant module (diamonds), where the leak occurred and from the Core module (squares), where the crew spent most of their time. Reprinted with permission from SAE paper number 981738 ã 1998 Society of Automotive Engineers, Inc. 28th Conference on Environmental Systems; 13–16 July 1998; Danvers, MA

Decontamination of the Environment EG is extremely persistent in a spacecraft’s environment. It readily condenses on cold surfaces or impinges on other surfaces, where it forms a reservoir for continuing release of EG into the air and for microbial growth in the condensed state. Absorbent towels should be used to remove obvious areas of EG contamination. When clearing areas of contamination, it would be wise for a crewmember to wear protective gloves as a precaution. (Some space vehicles have a handheld, wetdry vacuum that could be used to capture large drops of EG floating in the air.) In normal circumstances, much of the EG present in air will be removed by the water-vapor condensing system, where it will present a challenge to the water purification system [34].

Freons and Other Halocarbons Sources Freons and halocarbons have 3 major uses on modern space vehicles. Certain Freons are used preflight as hardware cleaning agents; others are used in heat-exchange loops; and Halon 1301 (bromotrifluoromethane) is used as a fire extinguishant in the Space Shuttle. Low concentrations of certain chlorofluoro hydrocarbons are found in the course of routine sampling of the Space Shuttle atmosphere as a result of hardware cleaning, but they do not have the potential to enter the air in high concentrations. In contrast, perfluoropropane, which is used in some ISS coolant loops, is normally not detected but has been found in high concentrations when accidentally released. Halon 1301 is available in large quantities inside the Space Shuttle and would be released in the event of a major fire. Traces of it are routinely found in the Space Shuttle air, but no accidental or fire-related releases have occurred since Space Shuttle flights began in 1981.

Mechanisms of Toxicity This group of halocarbons has very low toxicity and has never been suspected of inducing toxic effects in Space Shuttle crewmembers. The primary effect of this class of compounds

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is cardiac sensitization leading to rhythm disturbances; however, this effect is generally noted only at concentrations above 1%. Freons and halocarbons are thought to act by sensitizing the heart to epinephrine, so exposure in stressful conditions may be somewhat more risky than in sedentary conditions. Some Freons and halocarbons have been found to cause CNS depression but only at very high concentrations. Halon 1301, for example, has been shown to cause no more than a 5% CNS functional decrement in 2 of 13 performance measures in humans exposed for 24 h to a 1% concentration [41]. Freon 21 (dichlorofluoromethane), which is used in the external coolant loops of the Space Shuttle and could indirectly enter the spacecraft cabin, has been shown to cause hepatotoxicity after prolonged exposures; hence, its limits are much lower than the limits of other members of this class. This hepatotoxicity may be due to metabolism of Freon 21 in the liver to phosgene-like compounds that are very reactive [42]. Many members of this class of compounds have been shown to cause ozone depletion in Earth’s atmosphere, so their use on this planet is being phased out. Since Halon 1301 is intended to extinguish fires on the Space Shuttle, the question invariably arises as to the toxicity of its pyrolysis decomposition products. Upon exposure to flames or to surfaces at temperatures over 480° C (900° F), Halon 1301 decomposes to form hydrogen bromide and hydrogen fluoride (among other less important compounds), both of which are much more toxic than Halon 1301 [10]. The major toxic effect of these products is mucosal and respiratory irritation at very low concentrations. This effect, together with the acrid odor of these compounds, provides a built-in warning system that these compounds are present before their concentrations become truly hazardous. The presence of these products is generally an issue only for deep-seated fires that require a long time to be extinguished.

J.T. James Table 21.4. Halocarbon spacecraft maximum allowable concentrations. Common name Halon 1301 Freon 11 Freon 12 Freon 21 Freon 22 Freon 113 Freon 218

Chemical name Bromotrifluoromethane Trichlorofluoromethane Dichlorodifluoromethane Dichlorofluoromethane Chlorodifluoromethane 1,1,2-trifluoro-1,2,2-trichloroethane Octafluoropropane

180-day SMAC Effect to prevent 1,800 ppm 140 ppm 95 ppm 2 ppm 1,000 ppm 50 ppm

CNS depression Cardiac arrhythmia Cardiac arrhythmia Hepatotoxicity Cardiac arrhythmia CNS depression

11,000 ppm Cardiac arrhythmia CNS effects

Abbreviations: CNS, central nervous system; ppm, parts per million. Source: NASA JSC-20584, Spacecraft maximum allowable concentrations for airborne contaminants, June 28, 1999.

many Freons and will also be used periodically to quantify trace contaminants in the station atmosphere [43].

Treatment after Exposure and Decontamination of the Environment It is very unlikely that Freon compounds will escape into the atmosphere in concentrations that are sufficient to cause ill effects or symptoms, so crewmembers are unlikely to need treatment. Many Freons are extremely difficult to remove from the atmosphere with conventional environmental control and life support system designs. So the flight surgeon should expect to see a slow decline in airborne concentrations over several days or weeks as the Freon gradually disappears from the environment.

Airborne Carcinogens

Warning Properties and Toxicologic Guidelines

Sources

This class of compounds has no warning properties discernable at concentrations that can be toxic to the individual. Because toxic concentrations are high for most members of this group, control can be readily achieved by limiting the amount that could be released into the atmosphere. Table 21.4 shows the SMAC guidelines for several members of this group and the toxic effects that the guidelines were set to avoid. Often refrigerator cooling systems are designed to use an amount of Freon that would not present a toxic hazard even if all of the Freon were to be released into the spacecraft environment.

Although several carcinogens are found consistently in spacecraft air, only rarely do the combined effects of airborne chemical carcinogens exceed the 180-day exposure guidelines, which were set to keep the increased lifetime risk of cancer below 1 in 10,000. Some common carcinogens and their sources are given in Table 21.5. The steady-state concentrations of the pollutants listed are well controlled by the environmental control and life support system, but when certain materials become overheated or burn, the products can include the carcinogens benzene and furan.

Detection and Quantification of a Freon Leak

Mechanisms of Toxicity and Warning Properties

Medical support personnel should be aware that, if crewmembers are exposed to a Freon in the atmosphere, the most likely clue is a detectable decrease in pressure in the source system. The volatile organics analyzer, the use of which began on the ISS with flight 7A (launched on 12 July 2001), can quantify

Carcinogens are broadly classified as causing cancer by genetic or epigenetic mechanisms. Except for isoprene and furan, all of the compounds listed in Table 21.5 have been shown to react directly with DNA and to cause mutations. These compounds are genetic carcinogens, and the risk associated with exposure

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Table 21.5. Sources of carcinogens and their limits in spacecraft air. Compound Acetaldehyde Benzene 1,2-dichloroethane Furan

Isoprene

Source Human metabolism, materials off-gassing Materials off-gassing, polymer pyrolysis Hardware off-gassing Hardware off-gassing, heating of organic material Human metabolism, plants

180-day SMAC 2 ppm 0.07 ppm 0.2 ppm 0.025 ppm

1 ppm

Abbreviation: SMAC, Spacecraft maximum allowable concentration.

to known concentrations is calculated by using a linear model [44]. According to this model, the risk of cancer is kept constant if the exposure time is increased by some factor and the concentration is reduced by that same factor. For long exposures, the levels estimated with this model to attain an acceptable risk of cancer can be extremely low. Furan and isoprene cause cancer in rodents, but there is little evidence that either compound is carcinogenic in humans. The weight of evidence for furan suggests that it or a metabolite affects DNA through indirect mechanisms. This deduction leads to an approach to cancer risk that recognizes a threshold exposure concentration, below which—regardless of the time of exposure—there is no increased risk of cancer [42]. For different reasons, isoprene is also thought to be a threshold-type carcinogen. Genotoxicity data on isoprene are most consistent with aneugenic activity (such as spindle disruption during cell division). Isoprene is produced endogenously, and the cancer data in rodents suggest a threshold effect [45]. Of the carcinogens listed in Table 21.5, only acetaldehyde has a significant warning property. The SMAC in Table 21.5 for that compound was actually set to prevent mucosal irritation. If acetaldehyde did not have this irritant property, the SMAC for 180 days of continuous exposure would be 4 ppm to protect against the increased risk of nasal cancer [46]. Nasal tumors were observed in rodents that were exposed to high concentrations of acetaldehyde for many months. The SMACs for the other carcinogens in Table 21.5 are so low that no warning property exists, thus reinforcing the need for periodic monitoring of spacecraft atmospheres for compounds that could be carcinogenic to the crew if exposures were prolonged.

Differences in Individual Susceptibility Many important factors affect the susceptibility of humans to carcinogens. Genetically determined differences in the metabolism of carcinogens to active or inactive species can affect susceptibility. Differences in the ability to repair DNA lesions can also affect susceptibility. The very young are considered most susceptible to chemical carcinogens. Of particular interest to spaceflight risks is the potential for increased suscepti-

bility due to changes in host immune function and co-exposure of crewmembers to non-chemical carcinogens. Immune surveillance for non-host cells provides a protective mechanism against cancer, but spaceflight crewmembers have been known to experience changes in immune function (see Chap. 15). The relatively high radiation environment of space has resulted in the SMACs for benzene being set at lower concentrations than otherwise because of the possible interaction of radiation and benzene in inducing leukemia [47].

Protection of the Crew and Decontamination of the Environment Inspection of Table 21.5 indicates that most carcinogens originate from materials off-gassing; hence, the risk of exposure to carcinogens in space flight can be controlled by screening materials for carcinogen-causing compounds. This practice provides a high degree of protection for the crewmembers as well as the environment. Additional protection is afforded by the scrubbing capabilities of the air revitalization system. Even after the serious solid-fuel O2 generator fire on board Mir in 1997 (during Mir Expedition EO-23), the air revitalization system was able to scrub the benzene concentrations from a peak of approximately 0.2 ppm to 0.02 ppm in 32 h [2]. Donning respirators after a fire will provide individual protection until the vehicle atmosphere has been scrubbed to risk levels judged acceptable based on the SMACs.

Noxious Compounds: Sulfurous Compounds Sources As space missions last longer and are conducted farther from Earth, the problem of trash and waste management becomes critical. A typical rate at which trash is generated on Space Shuttle flights is 2.5 lbs (1.1 kg) per person per day, of which 27% is liquid [48]. When biological wastes are stored for long periods, bacterial action can produce extremely noxious compounds that can certainly affect the crew’s well-being if not their health. Bacteria can metabolize certain types of stored chemical wastes, stored human waste, and discarded food. Materials that initially have little or no odor can, after long-term storage, generate volatile, noxious compounds. Eventually, the management of waste and trash in space may involve incineration to volatile compounds and ash that can be recovered and used in a closed habitat. One of the challenges of building such a system is the removal of sulfur dioxide and other potentially toxic compounds [49]. Sulfur compounds are a major component of the gases that are generated from human metabolism. In one human study [5], dimethylsulfide was produced at about 0.1 mg/day by

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about a third of the participants, but almost all of the subjects produced large amounts of other sulfides. (These amounts averaged 6 mg per day.) If sulfur compounds are not scrubbed from the air, they can present a noxious odor within the cabin, especially for arriving crews that have not adapted to the odors.

Warning Properties of Noxious Compounds By definition, noxious compounds possess good warning properties at first exposure. Subsequent or continuing exposures, however, can lead to olfactory fatigue and to a loss of sensitivity to the detection of those compounds. Moreover, a slow accumulation of noxious compounds may go undetected by the crew.

Clinical Presentation and Individual Susceptibility Invariably, abrupt exposure to products from stored waste and trash will result in crew complaints about unpleasant odors. Individual thresholds for odor detection vary greatly and depend on whether the noxious compound enters the cabin suddenly or has accumulated slowly because of a small leak. Typically, a crew can determine approximately where the unpleasant odor is originating from and can minimize the time spent in the offending area.

Air Sampling and Analysis The human nose can be extremely sensitive to noxious compounds, so analytical methods may lack the sensitivity of the human nose to identify specific compounds — even when those compounds can be readily smelled. In Space Shuttle flights, in approximately half of the times when crews took an air sample because of a detectable odor in the spacecraft air, an analytical chemist was able to identify likely candidates for the cause of the smell. An example of this occurred on STS55 when the crew was using a contingency waste container to store biological wastes. After doing this for several days, crewmembers reported that the odor coming from the bag, which had to be periodically compressed for emptying into space, was overpowering. An air sample was taken from the area using a grab sample canister, and subsequent ground analysis by gas chromatography and mass spectrometry showed the presence of 3 noxious methyl sulfides. After the mission, a study of the contingency bag showed that the same sulfides and odors (as confirmed by crewmembers) could be produced when biological waste was stored in the bag. Although the bag was adequate to contain liquid waste, the volatile sulfides produced by bacterial action could readily penetrate its walls. Given this event and anecdotal reports of noxious air, it seems likely that odors will be a fact of life in space flight. Although resource limitations during space flight—weight limitations and storage limitations, among others—make it impractical to carry analytical means of detecting and identifying specific

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noxious compounds, a broad-spectrum analyzer such as a gas chromatograph/mass spectrometer (although not necessarily in orbit) would be capable of identifying and quantifying many noxious compounds.

Protection of the Crew and Decontamination of the Environment On the Space Shuttle, crewmembers are protected from exposure to odors by an acid-treated charcoal filter called the odor-bacteria filter. This filter, which is part of the waste management system, contains 2.3 kg of acidic charcoal and a 0.45-µm bacteria filter. A spare filter is carried in the event it is needed to augment the nominal scrubbing capability on board the spacecraft. Since sulfurous compounds can poison components of the air revitalization system, operation of these systems may need to be curtailed during a contingency. This naturally could delay the decontamination effort.

Ammonia Sources The primary source of ammonia inside a spacecraft is human metabolism. The amount of ammonia produced per person is expected to be in the range of 300 mg/day depending on the amount of sweating and the level of exercise performed [16,50]. Ammonia assists with heat exchange in some external coolant loops and could enter the internal compartments by leaking from the external loops to the internal loops, and then into the cabin atmosphere. In addition, if a crewmember became contaminated with ammonia during an extravehicular activity, some of the contaminant could reach the interior of the vehicle when the crewmember enters the airlock. The probability of this happening is considered very low, however.

Mechanism of Toxicity and Warning Properties Ammonia irritates mucous membranes and causes a burning sensation in the eyes, nose, and throat. Unfortunately, sensory fatigue develops with prolonged or repeated exposures [51]. In massive exposures, tissues are injured by the formation of ammonium hydroxide, which “dissolves” the tissues in the same way as an alkali burn would. Tissue is also injured by the heat released as the ammonia dissolves in the aqueous coatings of the mucous membranes [52]. The warning property of ammonia exposure is its odor and irritation of mucous membranes. In non-adapted, non-expert persons, the odor intensity and degree of irritation can provide a rough estimate of airborne ammonia concentration. These subjective responses are summarized in Table 21.6 [52–54]. The degree of irritation increases with time and would be substantially less in persons who are adapted to ammonia exposure [55].

21. Health Effects of Atmospheric Contamination Table 21.6. Sensation of odor and irritation from initial, brief exposures to ammonia [54]. Ammonia concentration 5 ppm 20–30 ppm 50 ppm

80 ppm 110 ppm 140 ppm

Degree of irritation Odor threshold in sensitive persons Some sense a slight irritation Odor threshold in non-sensitive persons, perceptible to moderate irritation Distinctively perceptible irritation Irritation is a nuisance Nuisance, offensive, and unbearable irritation

Sources: Data from Wong [52], World Health Organization [53], and Verberk [54].

Clinical Presentation and Differences in Individual Susceptibility Subtle ammonia exposures from excess accumulation of ammonia in the atmosphere may be difficult to identify. If concentrations increase slowly, crewmembers will adapt to these concentrations and will not exhibit clinical symptoms until levels are well above those indicated in Table 21.6. The most likely complaint from the crew will therefore be the odor of ammonia. In the absence of analytical detectors, the most plausible scenario is one in which an arriving crew opens the hatch to the atmosphere of the parent vehicle and reports an odor of ammonia. To avoid this, it was common practice on the Russian space station Mir to operate the air contaminant removal system more frequently than usual when a new crew was expected to arrive soon. Differences in individual susceptibilities are obvious from the study performed by Verberk [54]. In this study, people with no known history of exposure to ammonia were questioned after a single exposure. In the extremes, an “expert” subject reported no irritation at 140 ppm for 0.5 h, and a “non-expert” subject reported distinctly perceptible irritation at only 50 ppm for 0.5 h. In a spacecraft environment, a flight surgeon should expect differences in individual susceptibilities to be obscured by the loss of sensitivity as ammonia accumulates in the air.

Air Sampling and Analysis Ammonia is rarely monitored in spacecraft air because it has good warning properties and is not very toxic. On board the ISS, ammonia is periodically estimated with detector tubes provided by Russian environmental experts. Similarly, ammonia levels were monitored during a 90-day ground-based test of a sealed chamber containing a 4-person crew. In this test, ammonia was quantified by using a commercial electrochemical sensor that was calibrated at 6.4 ppm using a permeation tube. Ammonia concentrations in the chamber increased from undetectable (<0.1 ppm) at the start of the test to 1.2 ppm on day 87 of the test [56]. Although the instrument used in this

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ground-based test is far too large, heavy, and power-consuming to be used to monitor spacecraft air, a smaller electrochemicalsensor instrument is being considered for ISS.

Protection of the Crew and Decontamination of the Environment Ammonia is not highly absorbed by ordinary activated charcoal, but activated charcoal treated with 10% phosphoric acid effectively removes ammonia. This type of charcoal is used in the trace contaminant control filters of the ISS, but these charcoal filters cannot be thermally regenerated. Hence, such filters would be unable to control a large release of ammonia into the cabin.

Airborne Particles and Dust Sources Substantially more free-floating particles are present in the Space Shuttle atmosphere than in a typical home or office, especially particles larger than 100 µm [57]. High-efficiency particle air filters improve this condition on U.S. segments of the ISS by removing 99.97% of particles larger than 0.3 µm [1]. Nominally, sources of airborne particles include desquamation of skin cells, flaking of paint, release of lint from fabrics, and handling of food [58]. Particles from other sources can enter the atmosphere when containment fails. For example, brown “dust” has escaped from the Space Shuttle waste management system, LiOH dust has been released from CO2 removal canisters used on the Space Shuttle, and particulate material has escaped from animal containment facilities [50]. Smoke particles are also an important component of the products of pyrolysis of polymers, and this fact can be used to detect fires in spacecraft. Extremely toxic dusts or fumes from condensation of the metal vapors that are produced when alloys are heated in metal furnace experiments could escape only if their required three levels of containment were to fail [18]. The use of glass is carefully controlled on spacecraft to prevent broken glass particles from entering the atmosphere. When this chapter was written, NASA was considering a return to the lunar surface and possibly undertaking a human flight to Mars as well. Dust in the lunar landing vehicles created a nuisance during the Apollo program, especially when microgravity was reestablished after liftoff from the lunar surface. The Apollo 12 crew indicated that the dust made breathing difficult without their helmet visors down, and that their vision was affected by the density of floating particles [59]. This dust, which adheres readily to space suits, was brought into the vehicle’s interior by crewmembers—despite their attempts to brush off their suits before entering the lunar module [60]. Although such dust may not be an acute health hazard, prolonged inhalation while stationed in a lunar outpost could affect health. A Russian report concluded that lunar

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dust is moderately fibrogenic to rat lungs when administered by intratracheal instillation [61]. Recent studies of simulated lunar and martian dusts have shown that each has potential for fibrogenic activity in mouse lungs, but that the martian simulant was more active than the lunar simulant [62].

Mechanisms of Toxicity Particles can be hazardous to the crew because of their mechanical properties, their chemical properties, or their infectious nature. Since all particles “float” in spacecraft atmospheres, there is a much greater probability that particles will enter the eyes and respiratory systems of crewmembers. Large particles will generally elicit a blink response to protect the eye. Since particles larger than 10 µm do not penetrate the respiratory system beyond the upper airway, they do little damage. Lint particles in particular have been responsible for mechanical discomfort to the eyes. LiOH dust, which has been accidentally released from Space Shuttle CO2 removal canisters, is highly irritating to the eyes because of the caustic nature of the chemical in the particle. Brown dust arising from the waste management system may cause immediate discomfort, but there may also be an increased risk of eye infection if the material is not removed thoroughly and quickly.

Warning Properties and Clinical Presentation Crewmembers will be immediately aware if airborne particles are threatening to injure them or affect their health. A particle that can cause mechanical injury will be immediately detected if it lodges in the eye. Particles that cause chemical injury to the eye will be obvious because of the associated pain, which will occur as soon as the chemicals begin to dissolve in the topical fluid of the eye. If an unhealthy level of smoke is generated from a fire, the event will be obvious to the crew. Hence, crewmembers will have a warning that they should don respiratory and eye protection until the particles, and other toxic combustion products, are removed from the atmosphere.

Sampling and Analysis Although particles on board spacecraft have been experimentally characterized, the risk of health effects is sufficiently well controlled that routine monitoring of particles, except for smoke detection, is considered unnecessary. In experiments on board the Space Shuttle, a cascade impactor was used to separate particles according to size into four fractions [57]. The relative mass of each fraction was determined gravimetrically after the instrument was returned to a ground-based laboratory. A companion instrument, the Space Shuttle particle monitor, was used to count the number of particles passing through a light beam in real time; however, that instrument gave no indication of the size of the particles detected [57].

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Smoke detectors can provide an index of airborne particle concentrations under certain conditions. For example, on STS-28 when ∼5 (2 in) of a Teflon-sleeved teleprinter cable was burned by an electrical short, a smoke detector gave a rise from 114 to 180 µg/m3, but remained well below the alarm level of 2,000 µg/m3. The Space Shuttle smoke detector uses an aerodynamic flow stream to distinguish particles larger than 2 µm, so it responds entirely to respirable particles. Particles are counted according to their ability to acquire charges and reduce ion current to the detector [63]. The ISS smoke detectors detect particles of about 0.3 µm by measuring the ability of the particles to scatter light from an infrared laser diode light source. Smoke density is measured by a combination of light attenuation (obscuration) and light-scattering methods.

Protection and Treatment after Exposure Protection from airborne particles can be accomplished by wearing goggles and dust masks, which are readily available to all crewmembers. If particles do reach the eyes of a crewmember, however, the Space Shuttle and the ISS have eye-wash devices available to flush material from the eye. The devices look like swim goggles with tubing connecting each of the eyepiece cups, and tubing to deliver water to one cup and remove water from the other cup. These eye-wash devices are located near the galley, where they can be quickly connected to a water outlet that provides slightly pressurized water. Provisions are made for adaptation of the device to flush one eye [64].

Decontamination of the Environment to Remove Particles Airborne particles can be removed from spacecraft air by the environmental control and life support system particle filters, but the rate of removal and the size of particles removed vary considerably from one space vehicle to another. The key design parameters of these filters are the flow rate through the filter bed and the minimum particle filtration size. On the Space Shuttle, particles are removed by the cabin air filter, which has a mesh size of 40–70 µm and a flow of approximately 540 m3/h [50]. This means that relatively large particles can be rapidly scrubbed from the Space Shuttle’s free volume of 65 m3; however, particles in the respirable range (i.e., those smaller than 10 µm) will not be removed efficiently. The presence of nuisance particles in Space Shuttle air has resulted in the addition of an orbiter cabin air cleaner to reduce the amount of airborne dust [65]. This air cleaner, which is placed in an opening between the Space Shuttle flight deck and the middeck, is designed to create turbulence sufficient to produce flow through areas that were previously stagnant. The filter is made of 400 mesh (38.5-µm pore size) stainless steel with an effective area of 0.46 m3 and a flow of 200–600 ft3/min (7–21 m3/min). The orbiter cabin air cleaner is required to be carried on all Space Shuttle missions lasting 50 or more

21. Health Effects of Atmospheric Contamination

person-days [65]. In a contingency, the handheld vacuum could be used to capture large, floating particles. On the U.S. segment of the ISS, particle removal capability is more advanced than it is on board the Space Shuttle. The ISS requirement is to restrict the airborne concentration of particles to less than 0.05 mg/m3 (∼105 particles per cubic foot) for particles larger than 0.5 µm. Cabin air bacteria filters meet this requirement by scrubbing 99.97% of particles 0.3 µm and larger from the atmosphere. The filters, with a nominal flow of 70 ft3/min (2.5 m3/min), are composed of borosilicate fibers and are protected by a 20 × 20 mesh screen that is periodically vacuumed. Six filters are located in the U.S. Laboratory module, and 4 filters are located in Node 1.

Conclusions As human space missions reach deeper into space, crews must become more independent of ground controllers. With this in mind, future analytical instruments for air pollutants must provide data that are complete and that can be readily interpreted by onboard personnel who are neither toxicologists nor physicians. As environments reach 100% closure for distant missions, the challenges of managing air pollutants will increase. Moreover, the addition of new pollutant sources (e.g., plant growth chambers, waste incineration, and dust) on celestial bodies will demand new strategies for providing safe air for crewmembers to breathe.

References 1. Wieland PO. Living Together in Space: The Design and Operation of the Life Support Systems on the International Space Station. Volume I. NASA-Marshall Space Flight Center; 1998. NASA TM-206956. 2. James JT, Limero TF, Beck SW, et al. Toxicological investigation of Mir during NASA 4. Unpublished NASA-Johnson Space Center Memorandum SD2-97-543; September 1997. 3. Wong KL. Carbon monoxide. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 1. Washington, DC: National Academy Press; 1994:61–90. 4. James JT, Limero TF, Beck SW, et al. Toxicological investigation of Mir during NASA 7. Unpublished NASA-Johnson Space Center Memorandum SD2-99-500; January 1999. 5. Shimoda T, Oikawa T, Miyake A. Sampling and analysis of human metabolites. Presented at the 28th Conference on Environmental Systems; 13–16 July 1998; Danvers, MA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 981739. 6. James JT. Offgas test results from Node 1—Second test. Unpublished NASA-Johnson Space Center Memorandum SD2-98-551; October 1998a. 7. Hampson NB, Kramer CC, Dunford RG, et al. Carbon monoxide poisoning from indoor burning of charcoal briquets. JAMA 1994; 271:52–53. 8. Centers for Disease Control and Prevention. Carbon monoxide levels during indoor sporting events-Cincinnati, 1992–1993. JAMA 1994; 271:419.

441 9. Stewart RD, Peterson JE, Fisher TN, et al. Experimental human exposure to high concentrations of carbon monoxide. Arch Environ Health 1973; 26:1–7. 10. Purser DA. Toxicity assessment of combustion products. In: DiNenno PJ, Beyer CL (eds.), The SFPE Handbook of Fire Protection Engineering. Section 1. Quincy, MA: National Fire Protection Association; 1988:Ch 14. 11. Ellenhorn MJ. Respiratory toxicology. In: Ellenhorn’s Medical Toxicology. 2nd edn. Baltimore, MD: Williams & Wilkins; 1997:Ch 66. 12. Reschke MF, Harm DL, Parker DE, et al. Neurophysiologic aspects: Space motion sickness. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1994:228–260. 13. O’Hanlon JF. Preliminary studies of the effects of carbon monoxide on vigilance in man. In: Weiss B, Laties G (eds.), Behavioral Toxicology. New York, NY: Plenum Press; 1975:61–75. 14. Delgado RH, Davis DD. Evaluation of Compound Specific Analyzer-Combustion Products. NASA-White Sands Test Facility; May 1998. Document TR-915-001. 15. Stewart RD, Stewart RS, Stramm W, Seelan RP. Rapid estimation of carboxyhemoglobin in fire fighters. JAMA 1976; 235: 390–392. 16. Perry JL, Curtis RE, Alexandre KL, et al. Performance testing of a trace contaminant control subassembly for the International Space Station. Presented at the 28th International Conference on Environmental Systems; 13–16 July 1998; Danvers, MA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 981621. 17. Tatara JD, Perry JL, Franks GD. Overview of the International Space Station System-level trace contaminant injection test. Presented at the 28th International Conference on Environmental Systems; 13–16 July 1998; Danvers, MA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 981665. 18. Lam CW, Coleman ME, Garcia HD. Guidelines for Assessing the Toxic Hazard of Spacecraft Chemicals and Test Materials. Houston, TX: NASA-Johnson Space Center; 1997. JSC-268957. 19. Alexander RG. Mir-18 containment bag failure. Unpublished NASA-Johnson Space Center Memorandum NS2-95-180; September 1995. 20. James JT. Analysis of air during the 60-day Lunar Mars Life Support Test. Unpublished NASA-Johnson Space Center Memorandum SD2-97-536; August 1997. 21. Huntoon CL. Toxicological analysis of STS-40 atmosphere. Unpublished NASA-Johnson Space Center Memorandum NASA-JSC SD4/91-362; October 1991. 22. Graf J, Perry J, Wright J, et al. Systems upsets involving trace contaminant control systems. Presented at the 30th International Conference on Environmental Systems, 10–13 July 2000, Toulouse, France. 23. ATSDR. Toxicological Profile for Formaldehyde. Washington, DC: US Department of Health and Human Services; July 1999. 24. Morgan KT. A brief review of formaldehyde carcinogenesis in relation to rat nasal pathology and human risk assessment. Toxicol Pathol 997; 25:291–307. 25. Costa DL, Amdur MO. Air pollution. In: Klaassen CD (ed.), Cassarett & Doull’s Toxicology: The Basic Science of Poisons. 5th edn. New York,: McGraw-Hill; 1996:857–882. 26. Wong KL. Formaldehyde. In: Spacecraft Maximum Allowable Concentrations for selected Airborne Contaminants. Volume 1. Washington, DC: National Academy Press; 1994:91–120.

442 27. American Conference of Governmental Industrial Hygienists. Formaldehyde. In: Documentation of the TLVs and BEIs. Volume 1. Cincinnati, OH: ACGIH; 1992:664–688. 28. IARC. Formaldehyde. Volume 29. International Agency for Research on Cancer (IARC) monographs on the evaluation of carcinogenic risk of chemicals to humans. Lyon, France: World Health Organization; 1982. 29. Canadian Department of National Health and Welfare, Expert Advisory Panel Committee on Urea Foam Insulation. Final Report. Ottawa, Canada; 1981. 30. Nordman H, Keskinen H, Tuppurainen M. Formaldehyde asthma— rare or overlooked? J Allergy Clin Immunol 1985; 75:91–99. 31. Pierson DL, James JT, Russo D, et al. Environmental health. In: Sawin CF, Taylor GR, Smith WL (eds.), Extended Duration Orbiter Medical Project. Final Report 1989–1995. Houston, TX: NASAJohnson Space Center; 1999:4-1–4-12. NASA-SP-1999-534. 32. Petro PG. Results of Soviet-Hungarian Space Research. East Europe Report No. 699, 3 April 1981:4–12. Cited in: Bluth BJ, Helppie M. Soviet Space Stations as Analogs. 2nd edn. Unpublished document prepared for NASA Grant NAGW-659 by the Space Station Freedom Program Office, NASA Headquarters, Washington, DC; 1986. 33. Harris ES. Inhalation toxicity of ethylene glycol. In: Proceedings of the 5th Annual Conference on Atmospheric Contamination in Confined Spaces, Dayton, OH, 16–18 September 1969:99–104. 34. Pierre LM, Schultz JR, Sauer RL, et al. Chemical analysis of potable water and humidity condensate: Phase one final results and lessons learned. Presented at the 29th International Conference on Environmental Systems; 12–15 July 1999; Denver, CO. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 1999-01-2028. 35. Parry MF, Wallach R. Ethylene glycol poisoning. Am J Med 1974; 57:143–150. 36. McDonald TO, Roberts MD, Borgmann AR. Ocular toxicity of ethylene chlorohydrin and ethylene glycol in rabbit eyes. Toxicol Appl Pharmacol 1972; 21:143–150. 37. Cavender FL, Sowinski EJ. Glycols. In Clayton GD, Clayton FE (eds.), Patty’s Industrial Hygiene and Toxicology. Vol. II, Part F. 4th edn. New York,NY: Wiley; 1994:4645–4719. 38. Wong KL. Ethylene glycol. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 3. Washington, DC: National Academy Press; 1996:232–270. 39. Willis JH, Coulston F, Harris ES, et al. Inhalation of aerosolized ethylene glycol by man. Clin Toxicol 1974; 7:463–476. 40. Chung PK, Tsuo P. Cerebral computed tomography in a stage IV ethylene glycol intoxication. Conn Med 1989; 53:513–514. 41.Calkins DS, Degioanni JJ, Tan MN, et al. Human performance and physiological function during a 24-h exposure to 1% bromotrifluoromethane (Halon 1301). Fund Appl Toxicol 1993; 20:240–247. 42. Garcia HD. Chloroform. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 4. Washington, DC: National Academy Press; 2000:264–306. 43. Limero TF, Trowbridge J, Taraszewski S, et al. Results of the risk mitigation experiment for the volatile organic analyzer. Presented at the 28th International Conference on Environmental Systems; 13–16 July 1998; Danvers, MA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 981745. 44. National Research Council. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press; 1992.

J.T. James 45. James JT. Isoprene. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 4. Washington, DC: National Academy Press; 2000:89–118. 46. Wong KL. Acetaldehyde. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 1. Washington, DC: National Academy Press; 1994a:19–38. 47. James JT. Benzene. In: Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants. Volume 2. Washington, DC: National Academy Press; 1996:39–103. 48. Grounds P. STS-35 trash evaluation report. Unpublished NASAJohnson Space Center Memorandum NASA-JSC-SP-90-2; December 1990. 49. Fisher JW, Pisharody S, Wignarjah K, et al. Waste incineration for resource recovery in bioregenerative life support systems. Presented at the 28th International Conference on Environmental Systems; 13–16 July 1998; Danvers, MA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 981758. 50. James JT, Coleman ME. Toxicology of airborne gaseous and particulate contaminants. In: Life Support and Habitability. Vol. 2 of Space Biology and Medicine. Nicogossian AE, Mohler SR, Gazenko OG, Grigoryev AI, series eds. Reston, VA: American Institute of Aeronautics and Astronautics; 1994:37–60 51. Hatton DV, Leach CS, Beaudet AL, et al. Collagen breakdown and ammonia inhalation. Arch Environ Health 1979; 34:83–87. 52. Wong KL. Ammonia. In: Spacecraft Maximum Allowable Concentrations for selected Airborne Contaminants. Volume 1. Washington, DC: National Academy Press; 1994:39–59. 53. World Health Organization. Environmental Health Criteria. 54. Ammonia. Geneva, Switzerland: WHO; 1986. 54. Verberk MM. Effects of ammonia in volunteers. Int Arch Occup Environ Health 1977; 39:73–81. 55. Ferguson WS, Koch WC, Webster LB, et al. Human physiological response and adaptation to ammonia. J Occup Med 1977; 19:319–326. 56. James JT. Toxicological assessment of air quality during the lunar mars life support test: Phase III. Unpublished NASA-Johnson Space Center Memorandum SD2-98-522; May 1998b. 57. Liu BYH. Airborne particulate matter and spacecraft internal environments. Presented at the 21st International conference on Environmental Systems; 15–18 July 1991; San Francisco, CA. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 911476. 58. Matney ML, Boyd JF, Covington PA, et al. Air quality assessments for two recent space shuttle missions. Aviat Space Environ Med 1993; 64:992–999. 59. NASA. Apollo12 Preliminary Science Report. Washington, DC: Office of Technology Utilization; 1970. NASA SP-235. 60. Lee LH. Adhesion and cohesion mechanisms of lunar dust on the moon’s surface. J Adhes Sci Technol 1995; 9:1103–1124. 61. Belkin VV, Kustov MK, Kulakova, et al. Biological activity of lunar soil from the Sea of Fertility when injected intratracheally. Izv Akad Nauk Ser Biol 1983; 3:461–465. 62. Lam CW, James JT, McCluskey R, et al. Pulmonary toxicity of simulated lunar and Martian dusts in mice: I. Histopathology 7 and 90 days after intratracheal instillation. Inhal Toxicol 2002 Sep; 14(9):901–916. 63. Stesslinger HR, Hoy DM, McLin JA, et al. Comparison testing of the space shuttle orbiter and space station freedom smoke detectors. Presented at the 23rd International Conference on Environmental Systems; 12–15 July 1993; Colorado Springs,

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443 65. Marak RJ, Ouellette FA. Development, performance and flight test results of the cabin air cleaner for the shuttle orbiter. Presented at the 24th International Conference on Environmental Systems; 20–23 June 1994; Friedrichshafen, Germany. Warrendale, PA: Society of Automotive Engineers Technical Paper No. 941253.

22 Hypoxia, Hypercarbia, and Atmospheric Control Kira Bacal, George Beck, and Michael R. Barratt

Space is characterized by absence—absence of air, absence of pressure, and absence of radiation protection—all basic elements necessary to support life on Earth. The human crewmembers who are today venturing into space, arguably the most hostile environment into which humans have yet ventured, must carry with them not only their food and water but also artificial atmospheres—life support systems. The design of these life support systems is extraordinarily complex [1–3]. This chapter focuses on how spacecraft designers provide and maintain a breathable, Earthlike atmosphere in human space vehicles. Also addressed are the dominant physiologic effects that occur whenever contingency situations arise. As challenging as it is to attempt to reproduce an Earthlike atmosphere inside a spacecraft, the tasks before environmental control systems designers are more complex because they must balance operational requirements and constraints with human resource needs—some of which conflict with one another. Atmospheric pressure, composition, temperature, and humidity must all be selected and maintained within healthy limits for space flyers. Within these limits, a great deal of variability can remain. For example, if a lower habitable atmospheric pressure is selected for a spacecraft, a spacewalker incurs less risk of decompression sickness in decompressing to suit pressure (see Chapter 11). This lower atmospheric pressure also means that the spacecraft hull does need not to be strengthened to withstand a higher internal pressure and that smaller stores of gas (oxygen and nitrogen) are required. However, the artificial nature of such a lower habitable atmospheric pressure environment may compromise the usefulness and generalizability of certain experiments that are normally performed in the standard sea-level atmosphere. Moreover, the higher oxygen concentration required to maintain acceptable oxygen tension at a lower overall pressure could lead to an unacceptable fire risk. So, one of the most fundamental tasks for life support system designers is to assess the competing needs of different groups. How can a system provide a safe and comfortable living environment for the crew, facilitate safe spacewalks, permit good science, and yet prevent undue safety concerns? Answering

this question, a basic design challenge, establishes only a basis for nominal operating conditions; planning for systems mishaps requires another layer of consideration. Space operations may entail exposure to both hypoxic and hyperoxic gas mixtures as well as to hypobaric or hyperbaric ambient pressures. A mishap involving any of these conditions may be quite hazardous and may require immediate action by the crew—even as the physiologic changes associated with these conditions impair the crew’s ability to take action. Acute depressurization, or loss of pressure, has in fact already led to tragedy in the case of Soyuz 11 (June 1971), in which cosmonauts Georgi Dobrovolksy, Vladislav Volkov, and Viktor Patsayev died when a pressure equalization valve opened prematurely during early atmospheric reentry. To avoid similar tragedies, space medicine clinicians must be intimately familiar with the hazards of the space flight environment. They must prevent, anticipate, identify, and treat the conditions that are associated with disorders of atmospheric composition (such as hypoxia or hypercarbia). To do so, they must understand not only the inner workings of the human body but also the atmospheric standards that must be satisfied by the spacecraft life support system. This chapter reviews atmospheric standards with particular attention to pathophysiology and operational issues associated with pressure, temperature, humidity, and trace contaminants. Next follows a discussion of the physiologically relevant atmospheric gases oxygen and carbon dioxide along with their associated clinical conditions (e.g., hypoxia and hypercarbia). The chapter concludes with a review of the environmental control systems found on board past and present spacecraft.

Atmospheric Pressure and Its Control The International Civil Aviation Organization standard Earth atmosphere is characterized as dry air composed of 20.948% oxygen, 78.084% nitrogen, 0.0314% carbon dioxide (CO2), 0.934% argon, and other trace gases. Dry air comprises an atmospheric pressure at sea level of 760 mmHg (14.7 pounds 445

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per square inch [psi]) and an atmospheric density at sea level of 1.225 kg/m3, held by a constant acceleration due to gravity of 9.8 m/s2 (32.2 ft/s2), with a temperature at sea level of 15°C (59°F) [4]. The major gas constituents of physiologic concern that require monitoring for space travel are oxygen, nitrogen, CO2, and water vapor. Other gases, such as carbon monoxide (CO), are also monitored because of their hazardous nature. An artificial atmosphere control system must regulate the spacecraft temperature, pressure, humidity, and composition. It also must remove CO2, ensure sufficient amounts of oxygen, regulate pressure, and clear the air of trace contaminants. Respirable gases for cabin atmosphere replenishment may be transported to and stored on a space platform in 2 basic forms: as tanked air consisting of a sea-level mix of nitrogen and oxygen or as individual gaseous components. The former approach avoids potential problems with the need to mix gases and is more convenient for servicing a sea-level atmosphere. (Introducing a small amount of oxygen into the atmosphere as needed compensates for oxygen consumption by the crew.) Conversely, maintaining separate stores of tanked oxygen and nitrogen affords flexibility in controlling cabin atmospheric composition, which can vary with the cabin pressure. Such a system would allow the staged decompression of an entire crew cabin, as in the Space Shuttle, or an isolated module such as the International Space Station (ISS) airlock, in support of extravehicular activity (EVA) “prebreathe” operations. At an intermediate pressure, the oxygen concentration is increased as needed to provide a physiologically adequate partial pressure of oxygen (ppO2). Variable oxygen consumption and leak scenarios can also be more effectively managed with such a system than with a mixed-gas system. The Space Shuttle uses cryogenically stored oxygen and nitrogen, whereas the ISS makes use of both tanked air and separate oxygen and nitrogen reserves.

Ideal Gas Laws Dynamics of cabin atmosphere control are best understood within the framework of the ideal gas laws. As such, it is useful to be familiar with the relevant equations and their physiologic consequences. Boyle’s law (P2/ P1 = V1/ V2, where P = pressure and V = volume) describes how gas volumes vary with changes in ambient pressure. As a physiologic correlate, gas expansion associated with decreasing ambient pressure can lead to abdominal discomfort as enteric gas volume increases during rapid ascent to altitude. Charles’s law relates the volume and temperature of a gas held at a constant pressure (V1/V2 = T1/T2, where V1 and V2 are initial and final volumes, and T1 and T2 are initial and final absolute temperatures). As a corollary, for a gas held at a constant volume, pressure is proportional to absolute temperature. This relationship reflects the greater molecular movement and higher collision rate associated with increased

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temperature and underlies the temperature increase felt by the occupants of a hyperbaric chamber as pressure increases. Avogadro’s law states that equal volumes of all gases contain equal numbers of molecules, when pressure and temperature are held constant. A gram molecular weight (mole) of any gas occupies 22.4 L at atmospheric pressure and 0°C (32°F) and contains 6.02 × 1023 molecules (known as Avogadro’s number). This relationship serves to unite Boyle’s and Charles’ laws into the general gas law (PV = nRT, where P, V, and T are pressure, volume, and absolute temperature of a gas, n is the number of moles of the gas, and R is a derived gas constant). Dalton’s law (Pt = P1 + P2 + … + Pn,, where Pt = total pressure and P1, ….Pn are individual constituent gas partial pressures) describes the relationship of partial pressures in a mixture of gases and underlies the phenomenon of hypoxia at altitude. As overall ambient pressure drops, the pressure of the constituent gases falls as well. For example, at sea level pressure (760 mmHg) or (14.7 psi), ppO2 is 0.21 × 760 mmHg or 160 mmHg. At 5,486 m (18,000 ft), however, ppO2 is halved at 0.21 × 380 mmHg or 80 mmHg. Henry’s law relates the amount of gas dissolved in a liquid to its partial pressure (C1 = kP1, where C1 is the concentration of a gas in solution, k1 is a solubility factor, and P1 is the partial pressure of the gas in contact with the liquid). This law explains why exposure to altitude and decreased ambient pressure causes gas to come out of solution, facilitating the creation of nitrogen bubbles as seen in decompression sickness.

Pressure As described by the gas laws, as altitude increases through the stratosphere, atmospheric pressure decreases while the relative proportions of constituent gases remain the same. The change in barometric pressure is not a linear one, however. Pressure changes with altitude are most extreme at lower altitudes; (ascending from sea level to 2,440 m (8,000 ft), ambient pressure drops by a quarter from 1 atmosphere (1 ATA) at 760 mmHg (14.7 psi) to 0.75 ATA at 570 mmHg (11.0 psi). An additional 3,050 m (10,000 ft) of ascent is required for barometric pressure to decrease another quarter, occurring at an altitude of 5,486 m (18,000 ft). As a result, equivalent changes in altitude may yield different physiologic responses depending on the starting and ending ATA values. Just as the pressure exerted by the atmosphere decreases as one ascends from sea level toaltitude (Table 22.1), the ambient pressure increases as one goes deeper underwater. The greater density of seawater, roughly 1,000 times that of air, means that relatively small excursions in vertical distance result in much more significant pressure changes. The human requirement for a pressure environment may be defined by several distinct stages of physiologic effects. The saturated vapor pressure of water at body temperature is 47 mmHg (0.9 psi). At ambient pressures below this, body tissues undergo spontaneous boiling, a phenomenon known

22. Hypoxia, Hypercarbia, and Atmospheric Control

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Table 22.1. Pressure changes associated with altitude excursions. Altitude

Pressure

Meters

Feet

ATA

mmHg

mbar

psi

0 1524.0 3049.0 4573.0 6098.0 7622.0 9146.3

0.0 5,000 10,000 15,000 20,000 25,000 30,000

1.0 0.8 0.7 0.6 0.5 0.4 0.3

760 627 517 426 352 291 240

1013 835 689 568 469 388 320

14.7 12.1 10.0 8.2 6.8 5.6 4.6

Abbreviations: ATA atmospheres absolute, mbar millibars, psi pounds per square inch.

as ebullism (see Chapter 11), that leads to rapid cooling and the creation of gas cavities as well as massive damage to pulmonary and other tissues [5,6]. As a result, a minimum barometric pressure of at least 47 mmHg (0.9 psi) is required just to keep body fluids in solution. The altitude at which this pressure is reached is roughly 19,200 m (63,000 ft), which is known as Armstrong’s line. The atmosphere must also provide a breathable composition of gas with sufficient pressure for the alveolar exchange of oxygen and CO2. Thus the ambient or barometric pressure is integrally linked to the physiologic availability of oxygen. Along with the 47 mmHg of water vapor, a normal tension of 40 mmHg CO2 is present in the alveoli. Ambient pressure must exceed these combined pressures before further gas exchange can occur. Therefore, the threshold atmospheric pressure for any degree of alveolar gas exchange is 87 mmHg (1.68 psi), which is equivalent to an approximate altitude of 15,240 m (50,000 ft). Above this altitude, humans must wear a pressure suit to prevent hypoxia. At a lower altitude, around 10,668 m (35,000 ft), barometric pressure is 179 mmHg (3.46 psia); if pure oxygen is breathed, normal physiologic functions can be maintained. Ascending between these two altitudes requires that oxygen be delivered under progressively increasing positive pressure. Although loss of pressure is thought of as an “off-nominal” (i.e., unusual or unplanned) event, as occurred during a Progress cargo ship’s collision with the Mir space station in June 1997, it is important to note that the ambient pressure of any spacecraft will fall over time because of gas leakage unless the gas is replenished [7]. As the total pressure drops, so too will the partial pressure of each component gas. Thus vehicles must carry or create a supply of gas or gases by which, through judicious introduction into the environment, the vehicle crew can regulate their cabin pressure. For a dual oxygen-nitrogen environment, each gas must be present in its proper proportion. In practical terms, this means that the system must ensure that sufficient stores of oxygen are present to maintain an adequate alveolar oxygen tension (PAO2) and nitrogen supplies are used to regulate proper ambient pressure. It is easy to imagine how the improper use of either oxygen or nitrogen could lead to problems in the closed environment of a spacecraft. The release of too much oxygen would increase

the fire hazard, whereas inadvertent increases in nitrogen could lead to hypoxia or localized asphyxiation. The complexity that use of a second gas adds to the life support system is one of the factors that led to the use of single-gas environments in early U.S. crewed spacecraft. It is important to understand how the risk of decompression sickness affects the design of a spacecraft environmental system. For any mission whether one flown in low Earth orbit (e.g., those of the ISS or Space Shuttle) or to an extraterrestrial body, ready and convenient access to the outside of the spacecraft is desirable for assembly, maintenance, or scientific activities. Whether for routine exploration or unexpected repairs, the time required before the transition from the cabin environment to the vacuum of space should be as short as possible to minimize the overall operational overhead associated with EVA. Because current space suits operate at fairly low pressures (222 to 295 mmHg [4.3 to 5.7 psia]), a lower cabin pressure would minimize the nitrogen washout time. Minimizing the cabin pressure also decreases the required hull strength and overall weight of the vehicle, thereby requiring less propellant and less energy expenditure to deliver to an orbital or surface site. Concerns have also been expressed within the space medicine community that chronic exposure to low barometric pressures, particularly in combination with low ppO2, may have deleterious effects on the human body. Combining low ambient pressures with higher concentrations of oxygen to avoid insufficient oxygen tensions in the body also increases the risk of fire, as was demonstrated in the Apollo 1 tragedy in which three U.S. astronauts (Virgil Grissom, Edward White, and Roger Chaffee) perished in a fire during a pad exercise on January 27, 1967, when the Apollo capsule’s 100% oxygen atmosphere was pressurized to 827 mmHg (16 psia) for a preflight test.

Units of Pressure Familiarity with the various units used to measure pressures in different operations and environments is helpful in understanding barophysiology. The use of particular units has often been driven by historical precedent, operator preference, or convenience. Early physiologic experiments, for example, used mercury manometers developed to study atmospheric pressures; exposing a pressurized gas or liquid to a column of mercury in a glass tube and measuring the resultant change in linear height was easily accomplished. Early altitude experiments expressed pressure changes indirectly by equating phenomena to their altitudes, measured in feet or meters, rather than to the pressures at which the phenomena occurred. Similarly, the first underwater hyperbaric investigations were operationally oriented and expressed results in a practical unit relevant to their application—depth of seawater. It is important to note that physiologic calculations must be performed using absolute pressure, which includes the barometric pressure exerted in a system by the surrounding atmosphere. Gauge pressure, by contrast, is a relative pressure

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that does not account for atmospheric pressure. As an example, the units on pressure gauges commonly found on gas cylinders are shown as pounds per square inch gauge (psig), sometimes abbreviated to “psi.” When a gas cylinder is empty, its gauge reads zero despite the fact that the ambient pressure is not zero. The operational units of meters (or feet) of altitude and of seawater are also relative gauge pressures. The units typically used to express pressure in hypobaric, normobaric, and hyperbaric operations are millimeters of mercury (mmHg), psia, kiloPascals (kPa), bars, meters or feet of seawater (msw or fsw), and ATA. The mathematical relationship of these units is as follows: 1 ATA = 760 mmHg = 14.7 psia = 101.3 kPa = 10.1 msw (33 fsw), and 1 bar = 0.987 ATA = 100 kPa

For example, the absolute pressure experienced by a patient in a sea-level hyperbaric chamber pressurized to 18.3 msw (60 fsw) is [18.3 msw × (1 ATA/10 msw)] + 1 ATA (local atmospheric pressure) or 2.8 ATA.

Inspired Partial Pressure The amount of oxygen inhaled with each breath depends on both the percentage of oxygen in the inspired air (concentration) and the ambient pressure. From these two values, the physiologically significant absolute pressure or partial pressure of a gas is derived. Therefore, the partial pressure of an inspired gas (PIGas) is defined as the product of the fractional concentration of the inspired gas (FIGas) and the local barometric pressure (PB). PIGas = FIGas × PB

(1)

The fraction of inspired oxygen is expressed as FIO2, and the partial pressure of the inspired oxygen is denoted PIO2. The partial pressure of inspired nitrogen is PIN2 = FIN2 × PB. According to this equation, the inspired ppO2 (P1O2) at sea level, where PB is 760 mmHg (14.7 psi) and the concentration of oxygen in the air is 21% (FIO2 = 0.209), is calculated as (760 mmHg × 0.209) or 158.8 mmHg (3.1 psi). ISS flight rules state that the minimum pressure for any habitable element is 400 mmHg (7.7 psia), although a level as low as this would only be reached during a dire emergency such as a cabin leak. With the equation above and the recognition that flight rules allow the maximum emergency FIO2 to be 32.1% because of fire risk, the resulting partial pressure of inspired oxygen at this lower pressure would thus be 128 mmHg (2.47 psia). Table 22.2 shows ppO2 values, and hence PIO2 values, for atmospheric air associated with decreasing ambient pressures with increasing altitude. Although the percentage of oxygen in the atmosphere does not vary as the pressure decreases, the relative amount of oxygen diminishes as compared with its sea-level value. As such, measurements of oxygen concentration alone cannot be used to establish the safety of an area. If the

Table 22.2. Oxygen partial pressures of standard atmospheric air with increasing altitude. PB

PIO2

Equivalent

(feet)

Altitude

(mmHg)

(mmHg)

% O2 at sea level

0 5,000 10,000 15,000 20,000 25,000 30,000

760 627 517 426 352 291 240

159 131 108 89 74 61 50

20.9 17.4 14.4 11.8 9.6 7.8 6.2

Abbreviations: PB atmosphere pressure, PIO2 partial pressure of inspired oxygen.

barometric pressure is low enough, even an atmosphere of 100% oxygen cannot support life.

Alveolar Gas Equation By the time atmospheric gas reaches the alveoli during respiration, it has been warmed to body temperature and saturated with water vapor during its travel through the respiratory system. The ppO2 is further reduced from its inspired level by dilution as the inspired gas mixes with end-alveolar gas, which has higher levels of CO2. Therefore, the partial pressure of the oxygen that fills the alveoli during inspiration, PAO2 (where “A” represents alveolar), is a result of inspired gas mixing with water vapor and CO2. The equation governing this mixing, the alveolar gas equation, is: PAO2 (mmHg) = PIO2 – (PACO2/R) +{PACO2 × FIO2 × [(1 − R)/R]}

(2)

where PAO2 is the alveolar partial pressure of oxygen (alveolar oxygen tension), PIO2 is the inspired partial pressure of oxygen, PACO2 is the alveolar partial pressure of CO2, R is the respiratory exchange ratio (CO2 produced/oxygen consumed), and FIO2 is the fractional concentration of inspired oxygen. Although this equation is accurate, if we assume there is negligible CO2 in the inspired air, it has limited use outside of the laboratory. Operational crews and clinicians rarely have ready access to measurements of alveolar CO2 tension or R. However, the bracketed term in the above equation is a correction factor for R and is usually relatively small. Assuming average conditions and a body at rest, when R is typically 0.8, FIO2 is 0.21, and PACO2 is 40 mmHg (0.8 psi), alveolar CO2 levels are approximated by arterial PaCO2, and the term in the square brackets is never greater than 2 mmHg (0.04 psi) and can be ignored. The following more practical equation can then be derived: PAO2 = (PB – PH2O) × FIO2 – (PaCO2 × 1.25)

(3)

where PAO2 is the alveolar partial pressure of oxygen (alveolar oxygen tension), PB is the barometric pressure, PH2O is the water vapor pressure (47 mmHg or 0.9 psi at 37°C [98.6°F]) ), FIO2 is the fraction of inspired oxygen, PaCO2 is the arterial CO2, and 1.25 is the inverse of R, where R is assumed to be 0.8.

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This equation is convenient for determining alveolar oxygen at rest, where PaCO2 is assumed to be 40 mmHg (0.8 psi). During activities that might lead to hyperventilation, such as hypobaric operations, the PaCO2 will vary from 40 mmHg (0.8 psi) and the assumption is no longer valid. Further, during periods of physiologic stress, R will move toward 1 as the metabolic rate increases. Such conditions may occur in space operations, particularly during tasks that involve high metabolic rates (e.g., EVA).

Constituent Gases: Oxygen When ambient pressure decreases, such as during ascent to altitude, the ppO2 in the atmosphere, and subsequently the PAO2, falls as described by Dalton’s law. In most people, a normal PAO2 is generally accepted to be ∼100 mmHg, as is typical when the ppO2 is near 160 mmHg (3.1 psi), the ppO2 at sea level. For the average person who is living at or near sea level and is acclimated to that altitude, subtle physiologic decrements begin when PAO2 nears 80 mmHg (1.54 psi) and gradually worsen until consciousness is finally impaired at a PAO2 of ∼30 mmHg (0.58 psi) [8]. At a threshold altitude of 3,050 m (10,000 ft), the ambient pressure is 523 mmHg (10.1 psi), ppO2 is 109 mmHg (2.1 psi), and PAO2 is 60 mmHg (1.16 psi), a value that is no longer sufficient to oxygenate body tissues fully without adaptation responses [9]. At this PAO2, hyperventilation at rest is present even in healthy individuals and it is generally considered a threshold for hypoxia. The U.S. Air Force mandates the use of supplemental oxygen whenever cabin altitude exceeds 3,050 m (10,000 ft); under certain conditions, such as night flying, that limit may be even lower. Other organizations have slightly different threshold levels. The Federal Aviation Administration, for example, uses 3,810 m (12,500 ft) as its altitude criterion for use of supplemental oxygen. In the U.S. Space Shuttle Program, the crew compartment can undergo staged decompression from sea level to 527 mmHg (10.2 psi) to augment nitrogen washout in preparation for EVA. If the oxygen concentration is held constant at 0.21 during these times, the crew’s PAO2 would be 50.8 mmHg, as calculated using the alveolar gas equation: PAO2 = FI O2 (PB − PH2O) − (PaCO2 × 1.25) = 0.21(527 − 47) − (40 × 1.25) = 50.8 mm Hg However, NASA considers this PAO2 to be unacceptably low. As a result, the Space Shuttle’s atmospheric oxygen concentration is increased to 23.8% during operations at 527 mmHg (10.2 psi), yielding a PAO2 of 64.4 mmHg (1.25 psi), which is deemed acceptable. Aside from manipulating cabin atmosphere oxygen concentration, another way of maintaining a physiologically acceptable PAO2 at lower ambient pressure is with supplemental oxygen masks, such as those that aviators wear. Oxygen is not a benign substance, however, and its use must be controlled as carefully

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as that of any other biologically active drug. Although short-term use of increased FIO2 during an emergency is unlikely to cause medical problems, increasing the duration of exposure also increases the risk of oxygen “overdose” or toxicity. At sea-level pressures, breathing 100% oxygen has been shown to cause chest discomfort and atelectasis within a day [5,10]. However, like physiologically beneficial effects, the degree of oxygen toxicity depends directly on the ppO2 and the duration of the exposure. At low ambient pressures, such as 190 mmHg (3.7 psi), a pure oxygen atmosphere (FIO2 = 1) will maintain an acceptable PAO2: PA O2 = 1.0(190 − 47) − (40 × 1.25) = 93 mm Hg, which is close to normoxia. As described above, the physiologic consequences of hyperoxic environments depend on oxygen partial pressures. By contrast, high concentrations of oxygen carry an unacceptable fire risk. These two properties can act in combination, as was the case in the Apollo 1 fire. As noted earlier, that fire was due not only to the pure oxygen environment of the capsule, but also to the fact that the environment was pressurized to greater than sea level for the ground test. These two aspects— absolute partial pressure and concentration—exist in uneasy balance for the designers of environmental systems, driving a perpetual compromise between fire prevention and physiologic requirements.

Oxygen Transport and the Oxyhemoglobin Dissociation Curve In subjects with normal ventilation and gas exchange, the ppO2 in the lungs controls how much oxygen is delivered to the tissues. After crossing the alveolar-capillary interface, the oxygen from inspired air travels throughout the body via the circulatory system in two forms: dissolved in the plasma and bound to hemoglobin. The amount dissolved in the plasma is a function of the ppO2 in the alveoli, PAO2. The arterial partial pressure of oxygen (PaO2) is, in turn, proportional to the PAO2 and is tied to the diffusion constant for oxygen across the alveolar-capillary membrane. Blood plasma can hold 0.003 ml of dissolved oxygen per 100 ml. The other means by which oxygen is transported within the body is via hemoglobin. This method accounts for the vast majority of oxygen delivered to the tissues. Oxygen bonds reversibly with hemoglobin to create oxyhemoglobin. Each hemoglobin molecule can carry four oxygen molecules, which results in the transport of 1.39 ml of oxygen per gram of hemoglobin or 20.8 ml of oxygen per 100 ml of blood (assuming 15 grams of hemoglobin per 100 ml of blood). In addition to affording greater transport capacity, oxyhemoglobin has several other physiologic advantages that manifest in its dissociation curve (Figure 22.1). First, the plateau at high oxygen tensions ensures that small decrements in alveolar oxygen have little effect on the uptake of oxygen

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Figure 22.1. Oxygen—hemoglobin dissociation curve. CO2, carbon dioxide; DPG, diphosphoglycerate

by the blood. Thus minor increases in altitude, for example, do not cause a proportional decrease in oxygen transport. Without this trait, humans would be unable to leave coastal areas and settle in other regions; the adaptive benefit of such a property is obvious. Second, the steep portion of the curve demonstrates that a small drop in the ppO2, as occurs at the tissues, will be accompanied by a large amount of oxygen offloading. Where a great deal of oxygen is present (e.g., in the lungs), the oxyhemoglobin remains intact. Where little oxygen is present (e.g., in the tissues), the molecule dissociates and oxygen is made available to the active tissues. In this fashion, the ppO2 in the blood and thus the gradient driving diffusion of oxygen into the tissues are maintained. Although the curve’s basic shape does not change, its position can shift laterally in response to various homeostatic perturbations. Physiologically, this is equivalent to a change in the affinity between hemoglobin and oxygen. Blood levels of CO2 and hydrogen ions influence this affinity to the body’s advantage. A shift to the right is induced in the terminal vasculature, where higher CO2 levels reduce the affinity of the hemoglobin for oxygen and facilitate its dissociation from the heme groups at any given oxygen tension to supply the tissues. In the lungs, where blood CO2 levels are diminished as CO2 diffuses into the alveoli for exhalation, a leftward shift of the curve facilitates enhanced blood oxygenation. This shift in the blood oxyhemoglobin dissociation curve in response to altered blood levels of CO2 and hydrogen ions is known as the Bohr effect. Conversely, the binding of oxygen with hemoglobin causes displacement of CO2 and thus influences CO2 transport, a phenomenon known as the Haldane effect. Oxygen dissociation from hemoglobin in the terminal vasculature leads to increased CO2 binding; in the lungs, increased oxygenation induces CO2 release and subsequent ventilation. A rightward shift can also be caused by other conditions, such as higher temperature. In general, conditions such as

Figure 22.2. Relationship of barometric pressure, inspired oxygen tension (PIO2), and oxygen saturation (SaO2) with increasing altitude while breathing ambient air. The narrowing of the difference between PIO2 and SaO2 at increasing altitude results from increased ventilation. (Hackett PH, Roach RC [11].)

these are associated with increased tissue workload or metabolic rate, requiring an increased offloading of oxygen to the tissues to meet metabolic demands and an increased uptake of CO2. The biochemical modulating substance 2,3diphosphoglycerate (2,3-DPG) also shifts the oxygen dissociation curve to the right. 2,3-DPG is present in red blood cells, and its concentration increases in hypoxic conditions. Such an increase, as is found in humans and animals living at high altitude, shifts the curve, facilitating the release of oxygen to the hypoxic tissues. As described above, barometric pressure, percentage of oxygen, and available hemoglobin all interact to determine the actual oxygen content available to the tissues. A disruption in any of these parameters will impair the physiologic transport of oxygen according to the oxygen content equation. The content of oxygen in arterial blood (CaO2) is measured in ml of O2 per 100 ml blood and is often expressed as volume percent: CaO2 (vol%) = (Pa O2 × 0.003) + (hemoglobin × 1.39 × SaO2)

(4)

where CaO2 is the content of oxygen in the arterial blood, averaging 20.4 ml/100 ml blood (vol %), PaO2 is the partial pressure of oxygen dissolved in plasma (average value 80 to 100 mmHg), and SaO2 equals the fraction of hemoglobin saturated with oxygen, which typically ranges from 95% to 100%. Hemoglobin is expressed in units of grams of hemoglobin per 100 ml blood. The relationships between altitude, barometric pressure, PIO2, and SaO2 are shown in Figure 22.2.

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Types of Hypoxia

Acute Hypoxia This section addresses the physiologic results of breathing cabin atmospheres that contain inadequate oxygen, which could result from a cabin leak (resulting in hypobaric hypoxia) or an environmental control mishap in which cabin pressure is maintained but oxygen regulation is inadequately controlled (resulting in normobaric hypoxia). Hypoxia is a state of oxygen deficiency in the tissues and cells that is sufficient to cause impairment of function. Whether from exposure to altitude or breathing sea-level gases in which the FIO2 is less than 0.21, acute hypoxia is marked by immediate physiologic responses triggered by sensitive target tissues. The magnitude of these changes and their operational impact depend on the PIO2. To ensure adequate PAO2 on the ISS under normal conditions, flight rules require that the ppO2 in a habitable environment remain between 146 mmHg (2.82 psia) and 178 mmHg (3.44 psia). Assuming an ambient pressure of 734 to 770 mmHg (14.2 to 14.9 psia) during normal operations, the corresponding upper limits of oxygen concentration on the ISS are 24.1% for most of the structure and 30% for the joint airlock. The Space Shuttle has an upper limit of 30% depending on the ambient pressure. (Both the ISS airlock and the Space Shuttle can be decompressed to a pressure intermediate between sea level and the extravehicular mobility unit [EMU] space suit pressure of 222 mmHg (4.3 psia) to facilitate nitrogen washout before EVA. This intermediate pressure is usually 526 mmHg [10.2 psia].) In off-nominal situations, these limits are relaxed to accommodate the emergency, because PAO2 must be maintained, even under extreme conditions, to allow crewmembers to carry out their necessary tasks. As an example, if cabin pressure were to drop to 400 mmHg (7.7 psia), the oxygen concentration should then be increased to 32.1% to ensure that the ppO2 does not fall below 122 mmHg (2.35 psi). This value corresponds to a PAO2 of 63 mmHg (1.22 psia), which NASA considers adequate to permit the crew to function in an emergency. It is important to note that as barometric pressure decreases, the acceptable lower limits of ppO2 and oxygen concentration must rise to maintain PAO2 because of the saturation of breathing gases with water and their dilution with alveolar CO2. Table 22.3 lists the acceptable pressures and oxygen concentrations for the ISS under off-nominal conditions.

Table 22.3. Off-nominal International Space Station cabin atmosphere constraints. Ambient Pressure (mmHg [psi]) 760 [14.7] 490–527 [9.5–10.2] 400 [7.7]

Minimum ppO2 (mmHg [psi]) 120 [2.32] 122 [2.35] 128 [2.47]

O2 Concentration (%) 15.7 23–24.7 32.1

The four generally recognized physiologic classifications of hypoxia—hypoxic, hypemic, stagnant, and histotoxic—are based on the relative position of the insult in the chain of oxygen delivery to the tissues. Hypoxic hypoxia occurs when gas exchange at the alveolarcapillary interface is inadequate, such as from a diminished ppO2, an obstruction in the airway, a disease process in the lungs (such as pneumonia), or a ventilation/perfusion mismatch. In hypoxic hypoxia, the supply of oxygen to the blood is compromised in some way. This form of hypoxia is seen at altitudes greater than 3,050 m (10,000 ft), the lower level of the “physiologically deficient zone.” For some individuals, a much lower altitude may be sufficient to produce significant effects because of underlying conditions such as high carboxyhemoglobin levels from smoking, anemia, or cardiac insufficiency. Conversely, acclimatization to a lower ppO2 will increase the threshold altitude at which physiologic effects are seen. In general, the space medicine patient population will have few, if any, of these preexisting conditions. Hypemic or anemic hypoxia, by contrast, results from a reduction in the oxygen-carrying capacity of the blood. Anemia, hemorrhage, CO toxicity, and hemoglobinopathies are examples of conditions in which oxygen is available in the lungs but the blood is incapable of transporting it from the lungs to the tissues in sufficient quantities. In stagnant or ischemic hypoxia, as the name implies, the hypoxia results from inadequate circulation. Congestive heart failure, hypovolemia, venous pooling, occluded blood vessels, and acceleration forces (such as those in high-performance aircraft and spacecraft during launch and landing) are all causes of stagnant hypoxia because they diminish the body’s ability to transport oxygen-enriched blood from the lungs to the tissues. Finally, in histotoxic hypoxia, oxygen is available to the body, the blood is able to transport it, and the cardiovascular system can circulate the blood to the tissues, but the tissues are incapable of using the oxygen efficiently. Such cases result from the tissues having been poisoned by toxins such as cyanide or alcohol, leading to impairment of the cytochrome chain and therefore to the end use of oxygen at the cellular level. Although hypoxic hypoxia is the form most commonly seen in aerospace operations, multiple forms can be present simultaneously and can have additive effects. For example, in the event of a debris or micrometeorite penetration on a space platform, the module may be punctured, leading to leakage of the cabin atmosphere (hypoxic hypoxia). Simultaneously, a crewmember may be injured and suffer blood loss (anemic hypoxia). If a fire occurs, CO and other combustion by-products may be created, leading to hypemic and histotoxic hypoxia. As a result, aerospace medicine clinicians must maintain a high index of suspicion for all forms of hypoxia based on environmental circumstances.

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As noted above, hypoxic hypoxia occurs in the presence of an insufficient supply of oxygen across the alveolar-arteriolar interface, leading to a diminished PaO2. As the ambient ppO2 decreases, the oxygen gradient between deoxygenated hemoglobin and alveolar air is reduced, resulting in reduced diffusion from the alveoli to the bloodstream (Ficke’s equation). Hypoxic hypoxia is one of the major physiologic risks associated with aviation and space operations, which take place in environments involving risk of acute depressurization of the crew compartment or pressure suit. One such example was the Soyuz 11 tragedy, in which the Russian flight crew died when a small and inaccessible valve designed to equalize cabin and ambient pressures during the final stage of the descent was jolted open immediately after the deorbit burn. The cabin depressurized during descent at 168 km (104.4 miles), an altitude incompatible with life. At the time, Russian operating procedures did not call for the routine use of either pressure suits or supplemental oxygen. Similarly, before the Space Shuttle Challenger accident, U.S. Shuttle astronauts did not wear pressure suits during launch or landing. The use of closed-atmosphere control systems presents another risk of hypoxia during space operations. Closed systems generally add oxygen to the atmosphere based on metabolic demand, environmental feedback, or both while continuously removing CO2 from the air. If the system should fail to add oxygen, the FIO2 would fall continuously with metabolic consumption. Moreover, given the insidious nature of symptoms of hypoxia, affected individuals may not notice until they are too impaired to take corrective action. The situation is even more dangerous if the system continues to remove CO2 as the FIO2 diminishes, because no hypercarbic reaction would occur to alert the crew. Factors such as these drive the requirements for redundant and reliable monitoring systems in spacecraft.

Physiologic Effects of Acute Hypoxia Perhaps the most critical effects of acute hypoxia are those that affect the central nervous system. To maintain consciousness requires an adequate flow of oxygen to the brain. The brain, even at rest, has one of the highest oxygen consumption rates of all tissues. Unlike other tissues, such as muscle, the brain can only minimally increase from its resting state the number of open capillary beds or the volume of blood flow through it. As a result, it is particularly vulnerable to hypoxic effects. As the brain’s oxygen supply is impaired, increasing levels of hypoxia result in greater cognitive and motor impairment and the inability to perform useful work. The neurologic effects of hypoxia are believed to be mediated both directly, through effects on the neurons, and indirectly, through the chemoreceptors and reticular formation. Hypoxia produces characteristic changes in brain electrical activity on electroencephalography as well as two-phase response of the cerebral circulation. Below an equivalent altitude of 4,570 m (15,000 ft), equal to 429 mmHg of ambient

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pressure, diminished PaCO2 predominates because of secondary hyperventilation and cerebral vasoconstriction occurs, reducing blood flow to the brain. At altitudes above 4,880 m (16,000 ft), however, diminished PaO2 predominates and the vasculature dilates, increasing cerebral blood flow and oxygen delivery to the neural tissues. The magnitude of this response is limited by the increase in cerebral blood pressure, which can raise intracranial pressure and contribute (in chronic hypoxic states) to the development of altitude-related illnesses. Hypoxia is also associated with a modification of the blood-brain barrier permeability. As the brain’s capillary beds dilate in response to an increased capillary pressure, the barrier opens transiently and vasogenic edema develops [12]. The latent recovery from central hypoxia further suggests that hypoxia alters the uptake and release of both excitatory and inhibitory neuroeffectors, causing a net increase in inhibitory agents [13]. In severe hypoxia, this inhibition may have neuroprotective effects because it reduces the metabolic demands of the brain (and those of the organism as a whole) by reducing motor activity. Even before neurologic effects of hypoxia become evident, compensatory cardiopulmonary changes occur in response to the drop in alveolar oxygen levels. The decrease in PaO2 triggers the carotid body to stimulate the medulla’s central respiratory center, increasing respiratory rate and minute ventilation. This rise in ventilation, known as the hypoxic ventilatory response, is regulated by the carotid body and serves as the primary means by which the body seeks to maintain PaO2. The response also has the simultaneous effect of decreasing PaCO2 levels through increased ventilation. As might be expected, anything that blunts the hypoxic response (e.g., respiratory depressants or chronic hypoxia) will interfere with the body’s ability to compensate for acute hypoxic conditions. In the lungs, a decrease in alveolar ventilation causes pulmonary vasoconstriction, redistributing lung perfusion and shunting blood away from the unventilated hypoxic alveoli. Although this reflex has beneficial effects in the case of regional hypoxia, it is detrimental in a hypoxic environment such as at high altitude. In hypobaric hypoxia, because all of the alveoli are filled with hypoxic gas, the hypoxia-induced vasoconstriction occurs globally. This generalized alveolar vasoconstriction leads to increased pulmonary artery pressure. Simultaneously, in an effort to increase oxygen delivery to the tissues, the accompanying increase in heart rate raises cardiac output, although stroke volume initially drops slightly. Mean arterial pressure is generally unchanged despite the increase in sympathetic tone. These changes are magnified significantly when exercise is superimposed on the hypoxic event (Table 22.4). Hammond, Wagner, and colleagues studied the response of healthy men exposed to hypobaric hypoxia at 3,050 and 4,570 m (10,000 and 15,000 ft) during rest and rigorous cycle ergometry and demonstrated that the physiologic responses to hypoxia are similar for both hypobaric and normobaric hypoxia [14,15].

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Table 22.4. Cardiopulmonary performance during exercise (cycle ergometry) at sea level and “at altitude”. Altitude 10,000 ft (PB 523 mmHg) Sea level Physiologic Parameters . Ve, L/min HR, beats/min VO2, ml/min PaO2, mmHg PaCO2, mmHg

Workloads

15,000 ft (PB 429 mmHg)

Rest

60 W

120 W

180 W

Rest

60 W

120 W

180 W

Rest

60 W

120 W

180 W

10.7 89 380 95 34

28.5 121 1,170 98 36

49.1 146 1,950 97 37

76.5 165 2,660 94 34

10.7 91 370 56 32

31 131 1,160 48 34

52.9 153 1,800 47 33

86.5 173 2,530 48 29

12.7 102 370 39 30

35.3 143 1130 33 30

67.2 164 1750 34 28

101.9 172 2270 35 26

. Abbreviations: W watt, PB barometric pressure, Ve oxygen consumption, HR heart rate, VO2 volume of oxygen, PaO2 alveolar oxygen pressure, PaCO2 alveolar carbon dioxide pressure. Source: Data from Wagner PD, Gale GE, Moon RE, et al. [14]. Used with permission.

Maintenance of core body temperature (Tb) also plays a significant role in oxygen consumption. Cold exposure and decreased core temperature initially increase the hypoxic response because of the increase in metabolic rate. When the ambient temperature is below the thermoneutral range (24°C [75°F] in air, 28°C [82°F] in water), mammals shiver and perform other behaviors in an attempt to produce more heat and raise their .core temperature. For most animals, oxygen consumption (VO2, expressed in ml/min) increases by ∼11% for every degree Celsius that their core temperature drops. In addition to the additive effects of hypothermia on hypoxia, hypoxia alone can contribute to hypothermia because the resultant hyperventilation further cools the body [16]. Ample evidence shows that moderate hypothermia (Tb of 25–28°C) and profound hypothermia (Tb of 15–20°C) have neuroprotective effects during hypoxia. In highly specific conditions, such as certain surgeries, hypothermia is used to minimize the damaging effects of prolonged tissue hypoxia. This phenomenon is familiar through widely publicized cases of persons who made neurologic recoveries after prolonged immersion in icy waters. Unfortunately, the diminished vulnerability of the hypothermic human body to hypoxia is irrelevant for aerospace operations, as the effects of the hypothermia itself render the individual operationally useless.

Symptoms of Acute Hypoxia The clinical manifestations of these various physiologic responses to hypoxia are quite variable. Signs and symptoms of hypoxia can range from the subtle to the overt. Subjective sensations can be very broad and range from a vague sense of apprehension to frank air hunger, vision changes, numbness, or paresthesias. Nonspecific symptoms of acute hypoxia include fatigue, nausea, headache, dizziness, hot or cold flashes, and mood disturbances such as lethargy, euphoria, belligerence, and sleepiness. Also seen are decrements in color, night and peripheral vision, increased respiration rate and depth, loss of fine motor control, decreased muscular coordination, and cyanosis. Perhaps most dangerous to crewmembers in the

space flight environment are the mental changes that occur that may not be perceptible to the affected pilot or space flyer who is simultaneously called upon to recognize and remedy the situation. Such changes include poor concentration, mental confusion, poor judgment, lack of insight, deterioration in mental performance, short- and long-term memory loss, and eventually unconsciousness. Because none of these signs and symptoms is pathognomonic for hypoxia, crews and clinicians alike must maintain a high index of suspicion for hypoxic events. Unfortunately, confusion, poor insight, and other mental changes often predominate in acute hypoxia, making it even harder for affected individuals to realize their condition and placing even greater responsibility on the aerospace clinician to recognize these signs. Although the rate of onset varies depending on the acuity of the hypoxic insult, both rapid and gradual onsets of hypoxia can be dangerous. In rapidly occurring hypoxia, the crews may become incapacitated so quickly that they may have no opportunity to react. In hypoxia that occurs more slowly, symptoms may develop so gradually that the crew may not realize what is happening. Many case reports have described subjects being entirely unaware of their deteriorating mental state during the hypoxic event. Retrograde amnesia has also been reported in several investigations [17]. The clinical presentation of acute hypoxia can vary depending on the hypoxic insult and the concomitant circumstances. Many factors can compound the severity of the symptoms and resulting impairment, including increased physical activity, the ambient temperature, the presence of underlying illness, and the ingestion of drugs such as morphine and other neurodepressants or alcohol.

Effective Performance Time (Time of Useful Consciousness) An acute hypoxic exposure is an operational emergency. Immediate responsive action is often required, either to correct the situation or to effect an escape. The remedial actions necessary

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may require the operator to move about, work through a set of procedures, or develop a nonscripted solution. Inherent in all of these actions is the need to think clearly and to perform efficiently. However, as described above, hypoxia’s effects on the brain tend to prevent purposeful activities. In an attempt to understand these effects and plan appropriate responses for loss of pressure events, two specific operational indices have been developed. Effective performance time (EPT) or time of useful consciousness (TUC) refers to the period beginning with initial hypoxic exposure during which an afflicted crewmember may continue to perform operationally relevant duties. Reserve time (RT) is the period between the initial exposure to hypoxic conditions and complete loss of performance capacity. These indices relate operational considerations to the physiologic effects of an acute hypoxic insult by representing the length of time that a person can be expected to perform purposefully under various levels of hypoxia (Table 22.5). The EPT is the most specific and the most operationally useful measure for the purposes of training and for establishing preplanned responses. Although these indices provide a means by which altitude can be linked to general operational capabilities, significant shortcomings are associated with the current EPT tables with regard to spaceflight operations. The EPT differs among individuals for a given exposure and is also influenced by factors such as the speed of the depressurization (rapid or explosive depressurizations can reduce EPT by 50%), physical activity (which diminishes EPT), metabolic rate, and underlying physical condition (poor condition also reduces EPT). As is often the case in aerospace physiology, EPT tables were designed with data largely derived from healthy young military aviators seated at rest in altitude chambers. This fact is of particular interest to space medicine, because space flyers are often older than such subjects (tolerance to hypoxia decreases with age) and may be physically deconditioned after extended stays in a microgravity environment. These differences could lead to variations in the EPTs among the aerospace population. In addition, reversing the inciting event in the space environment usually requires performing active work, and the effect of such activities on EPT has not been well documented.

Table 22.5. Effective performance times with increasing altitude. Altitude 5,500 m [18,000 ft] 6,700 m [22,000 ft] 7,600 m [25,000 ft] 8,500 m [28,000 ft] 9,100 m [30,000 ft] 10,700 m [35,000 ft] 12,200 m [40,000 ft] Above 13,100 m [43,000 ft]

Effective performance timea 20–30 min 10 min 3–5 min 2–3 min 1–2 min 30–60 s 15–20 s 9–12 s

a Also known as time of useful consciousness; can be reduced by up to 50% by rapid decompression. Source: From Pickard [18]. Used with permission.

In the aviation environment, a depressurization rarely involves much physical activity on the part of the pilot: putting on an oxygen mask located within easy reach, initiating a rapid descent with the aircraft controls, issuing instructions to other crew or passengers, all of which are done within a small area. In contrast, a space crewmember confronted with a leaking space station may have to locate and switch to a supplemental oxygen supply, vacate and seal the leaking module or modules, establish communications with the ground, and perform complex troubleshooting procedures that may entail moving to several different workstations and locations. Although some tasks may be easier in a weightless environment (e.g., donning a portable breathing apparatus), other tasks (e.g., moving masses) may be significantly harder because of the need for body fixation. Finally, the physiologic changes associated with adaptation to microgravity may affect the EPT estimated from the current tables. In summary, space medicine clinicians must use caution when applying terrestrial EPT tables to design space flight-related limitations and operational guidelines. Until more is known, applying a conservative margin is prudent.

Hyperventilation Hyperventilation can mimic hypoxia in its symptoms and can occur simultaneously with hypoxia. Whether induced by hypoxia, stress, or faulty breathing equipment, hyperventilation can also lead to significant psychomotor impairment. Because the level of CO2 in the blood (PaCO2) exerts a powerful influence on the body’s respiratory drive, hyperventilation and its attendant elimination of excessive amounts of CO2 can have far-reaching effects. The primary influence of hyperventilation is mediated through acid–base disturbances. CO2 exists in equilibrium with blood bicarbonate, the dissociated form of carbonic acid. Reduction of CO2 levels via hyperventilation causes bicarbonate levels to decrease as the equilibrium shifts to favor the formation of CO2. The acute effect, before longerterm blood chemical buffering responses occur, is an elevation in arterial blood pH. Among other responses, the leftward shift in the oxygen-hemoglobin dissociation curve results in a decreased ability of hemoglobin to offload oxygen in the terminal vasculature (the Bohr effect). Cardiac output and blood pressure fall, as does peripheral vascular resistance. Cerebral vasoconstriction also induces a central stagnant hypoxia that leads to impaired cognitive performance and potentially loss of consciousness. Alkalosis also increases the sensitivity of the peripheral nerves. Muscle spasms of the limbs and face can occur at PaCO2 tensions of 15 to 20 mmHg. Clinical symptoms of hyperventilation resemble those of hypoxia: anxiety, dizziness, numbness, muscle tightening or tremors, tingling, faintness, cognitive and visual impairment, and nausea. Hyperventilation during ascent to altitude causes an approximately linear fall in PaCO2. At the summit of Mt. Everest, at 8,848 m (29,028 ft), the PaCO2 in a group of climbers was a surprisingly low 7.5 mmHg [19]. Individuals with both a good

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pulmonary system and hypoxic drive were able to maintain their PAO2 at about 35 mmHg despite being exposed to altitudes over 7,010 m (23,000 ft), resulting in an estimated pulmonary capillary oxygen tension of 28 mmHg. This calculated value was confirmed by actual measurements taken during a simulated Everest summit ascent [20]. As is true for recognizing hypoxia, crewmembers must have a high index of suspicion to recognize hyperventilation or any change in respiratory pattern and take appropriate action. When hypoxia or hyperventilation is suspected, remediation and treatment should begin immediately.

Recognition and Treatment of Acute Hypoxia Oxygen, in addition to being required for fundamental metabolism, can also be regarded as a drug. Accordingly, its applications should be guided by an understanding of its operational benefits and its physiologic effects. The greatest difficulty in treating acute hypoxia is early detection and recognition. Altitude chamber training, in which space flight crews are trained to recognize their own symptoms, can be helpful for becoming aware of and preparing for insidious events. Once hypoxia has been recognized, the treatment is simple: resolve the oxygen deficiency. The method for doing so will depend on the type of hypoxia being experienced. For hypoxic hypoxia resulting from exposure to altitude, use of supplemental oxygen may suffice. Histotoxic hypoxia due to cyanide poisoning requires significantly more intensive treatment and support. Certain aspects of aerospace operations and the means by which hypoxia can develop during flight are unique. For example, aviators need not worry about pockets of hypoxic gases in their environment, but this is a very real concern in space travel due to inadequate gas mixing and uneven cabin ventilation. Because of the potential for hypoxia in the training or space environment, astronauts and cosmonauts must undergo periodic altitude chamber training (annually for the Russian Space Agency, every 3 years for NASA personnel) to remain adept at recognizing their individual symptoms (Figure 22.3). Because of the insidious nature of the process by which hypoxia develops, recognizing it in other team members is emphasized as well, because an unaffected space flyer may realize what is happening before the hypoxic person can. Crewmembers are reminded to be cautious in unventilated or poorly ventilated modules and to be vigilant in monitoring each other for the signs or symptoms of hypoxia (e.g., tachypnea, poor concentration, repeated errors, or mood changes). On the ISS, a portable oxygen analyzer is used as a first-line check in poorly ventilated and potentially hypoxic atmospheric pockets. The analyzer is also to be deployed whenever a crewmember exhibits hypoxia-like symptoms. When a hypoxic atmosphere is confirmed to be present, the appropriate response depends on the vehicle involved. Crewmembers on the Space Shuttle are trained to use quickdon masks, which provide supplemental oxygen through hoses that connect to oxygen ports. In the event of a cabin

Figure 22.3. NASA Type II Altitude Chamber Profile used for altitude training and hypoxia demonstration for astronauts, pilots, and other flight crew. At 28,000 ft equivalent altitude, subjects remove oxygen masks and perform mathematics problems and other cognitive tasks until hypoxic symptoms are recognized and self-recovery (mask donning) is performed. (PIO2, inspired oxygen pressure.)

leak, pressurized launch and entry suits are to be donned as the next level of protection. Aboard the ISS, given its larger volume, both quick-don masks and “walkaround” bottles are used. Flight rules require the station crew to vacate and isolate an ISS module should its ppO2 drop below the equivalent of breathing air at 2,440 m (8,000 ft). The station itself must be evacuated if the overall ppO2 level drops to an oxygen equivalent altitude of 3,050 m (10,000 ft) for longer than 24 h. These levels were established by NASA to address concerns regarding the development of altitude sickness and high-altitude pulmonary edema in such situations.

Chronic Hypoxia Acute hypoxia is an inherent hazard of space operations. The results of exposure to slight hypoxia on a chronic basis, however, may not be as severe. When an individual is exposed to diminished oxygen tensions for periods longer than 2 weeks, that person’s body begins to adapt to the new condition—a process known as acclimatization. Previous research has demonstrated that humans can adapt to altitudes as high as 4,500 m (14,770 ft) and yet be able to perform relatively strenuous physical tasks at such altitudes [21]. The highest human habitations exist at 5,300 m (17,500 ft) above sea level, demonstrating the strength of this adaptation process.

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Adaptations generally assume two general forms: those that enhance metabolic use of oxygen at the end site, such as changes in the cytochrome system that improve the efficiency of mitochondrial utilization of oxygen, and those that increase oxygen-carrying capacity, including increased cardiac output, hyperventilation, increased pulmonary circulation, changes in cellular membranes that enhance oxygen diffusion across them, increases in red cell mass or the oxygen-binding affinity of hemoglobin, and capillary angiogenesis (particularly in tissues that are vulnerable to hypoxia). Some of these responses are apparent immediately, such as increased. heart rate, oxy. gen consumption (Ve), and cardiac output (Q), whereas other responses can take weeks to become manifest. Lambertsen further describes the factors involved in the complex adaptation to chronic hypoxia as (1) a sustained increase in respiratory drive and alveolar ventilation; (2) an adjustment of blood and central nervous system acid-base relationships; (3) an increase in the rates of hemoglobin and erythrocyte formation, which increase arterial oxygen-carrying capacity; and (4) an increase in cardiac output [22]. Details of these processes are given below. At the onset of hypoxia, acclimatization begins as a sustained increase in alveolar ventilation resulting from stimulation of the hypoxic chemoreflex. The increase in minute ventilation lowers PACO2 in the process of raising the PAO2 and subsequently the PaO2. The effectiveness of the reflex can be shown with the alveolar gas equation. The sustained increase in ventilation, with its resultant drop in CO2 and hydrogen ion levels in the arterial blood and tissues, leads to a respiratory alkalosis. In response, the renal excretion of bicarbonate increases so as to restore normal acid-base balance. As a result of the new, sustained decrease in bicarbonate buffering capacity, pH values eventually return to normal over the course of 4 to 7 days. The carbonic anhydrase inhibitor acetazolamide, used as a pharmacologic adjunct to altitude acclimatization, facilitates this process by increasing bicarbonate loss. The central chemoreceptors, driven by the arterial tension of CO2, eventually reset themselves to a lower PaCO2, providing a way of measuring the extent of acclimatization [23]. Simultaneous with these changes, the arterial oxygen-carrying capacity increases as a result of both the increase in hemoglobin levels and the leftward shift in the oxyhemoglobin dissociation curve brought about by the respiratory alkalosis. Increases in hemoglobin and red cell mass result from hypoxia’s rapid stimulation (within 2 h) of erythropoietin production [24]. Hypoxia also stimulates an increase in 2,3-DPG levels, which decreases hemoglobin’s affinity for oxygen (a shift of the oxyhemoglobin curve to the right), thus facilitating release of oxygen at the tissues and offsetting the leftward shift caused by the alkalosis. In addition to cardiovascular adaptation to chronic hypoxia, alterations can also occur in fluid balance and regulation. The ongoing loss of bicarbonate is accompanied by a general diuresis during initial adaptation. Upon exposure to altitude, peripheral vasoconstriction caused by hypocapnea appears,

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thus increasing central blood volume and leading the baroreceptors to suppress the release of antidiuretic hormone. As a result, plasma volume diminishes and osmolality rises, effects that contribute to the hemoconcentration characteristic of chronic hypoxic states. The time needed for adaptation is believed to be a function of the exposure altitude or level of hypoxic challenge [25]. Different body systems adapt at various rates, although some changes (such as increased resting ventilation) can be seen immediately whereas others (such as increased serum norepinephrine levels) occur within the first few days [25]. Among the changes that take place over a longer time are those mediated by growth factors and other chemical messengers [24]. Vascular oxygen sensors activate expression of vascular endothelial growth factor 1, which counters hypoxiainduced ischemia by promoting angiogenesis in the heart and brain, thereby improving perfusion in these organs. In the liver and the kidneys, hypoxic stress causes expression of erythropoietin, which increases red blood cell mass [26], and hemoglobin and hematocrit levels, thus enhancing the blood’s oxygen-carrying capacity. Bebout and others demonstrated an 11.3% increase in hemoglobin levels after a 2-week hypoxic normobaric exposure with PIO2 of 91 mmHg [27]. Hypoxia also induces enlargement of the heart, particularly the right ventricle; protein and nucleic acid synthesis increase in several organs (notably the heart and brain) and decrease in others (e.g., the reproductive organs) [2]. Other conditions associated with chronic hypoxia that are more maladaptive and seen at altitudes of 3,500 m (11,500 ft) and above include weight loss, poor sleep patterns with altered sleep stages, weakness, chronic headaches, malabsorption, diminished renal function, microcirculatory sludging due to polycythemia, and right heart strain due to pulmonary hypertension [28].

Implications of Hypoxic Acclimatization for Space Operations Selecting an operational environment for a space platform, whether an orbiting vessel, a surface habitat, or a space suit, requires balancing several operational factors. With these factors in mind and with the specific intent of preventing decompression sickness, some groups have proposed using a hypoxic environment in Martian habitats. For example, for the minimal Martian atmosphere (ambient pressure of 5 mmHg [∼0.6 kPa] and gaseous components of CO2 [95.7%], nitrogen [2.7%], and argon [1.6%]), Conkin suggested a 414-mmHg (8.0-psia) habitat atmosphere with an operational PAO2 of 77 mmHg [29]. The overall goal was to reduce the risk of decompression sickness associated with surface EVAs by minimizing the pressure differential between the habitat and the EVA suit. In addition to the potential use of nominally hypoxic atmospheres, contingency situations such as the loss of consumable gases or diluted environments resulting from fire or toxic gas release could arise that would force the prolonged use of

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Table 22.6. Twenty-four-hour minimum oxygen limits for the International Space Station. Ambient pressure 760 mmHg (14.7 psia) 527 mmHg (10.2 psia) 490 mmHg (9.5 psia) 400 mmHg (7.7 psia)

Partial pressure of oxygen 108 mmHg (2.09 psia) 111 mmHg (2.14 psia) 111 mmHg (2.14 psia) 114 mmHg (2.19 psia)

Oxygen concentration 14.2% 20.1% 22.5% 28.4%

hypoxic breathing mixtures. Because of the global nature of the long- and short-term adaptations to chronic hypoxia, few, if any, of the body’s organ systems are unaffected. The effect that such changes could have on the pursuit of aerospace operations depends on the operational scenario. ISS flight rules strictly limit the conditions under which crewmembers can be exposed to a hypoxic environment in a habitation module during a contingency situation. ISS crewmembers cannot be exposed to the environments shown in Table 22.6 for more than 24 h. If these minimum pressure and concentration levels cannot be maintained, appropriate action (from donning portable breathing apparatuses up to and including evacuation of the station) must be taken. An operational environment that intentionally exposes the crew to chronic hypoxic conditions may be useful but must be designed carefully. The potential operational benefits (lower ambient pressure, diminished fire risk) must be weighed against the resultant physiologic changes and the as-yet unstudied relationships between hypoxic acclimatization and adaptation to microgravity. Many questions still require answers, including how the composition of the blood would change in light of the increase in hemoglobin from hypoxia and the decreased red cell mass characteristic of microgravity adaptation and how the right heart would respond to the increase in pulmonary pressures. Finally, basic assumptions regarding long-duration space flight often ignore the effect that the inevitable minor illnesses and the possible major acute medical events that could have on such missions.

Hyperoxia Like hypoxia, hyperoxia does not depend on the concentration of oxygen to which the body is exposed, but rather its partial pressure. This is why at hypobaric pressures, a pure oxygen atmosphere will not cause oxygen toxicity but at a suitably hyperbaric pressure, even a concentration of oxygen well below the 21% normal for sea level will lead to oxygen toxicity syndromes. Breathing a gas mix with an FIO2 greater than 0.4 at sea level for an extended period can result in toxic side effects in less than a day. Hyperoxia should thus be thought of as elevated oxygen tensions, i.e., when the ppO2 is higher than 160 mmHg (3.1 psi) (the ppO2 at sea level) and corresponds to a PAO2 level above 100 mmHg. Other groups have defined hyperoxia in more operational terms, noting concerns for pulmonary oxygen toxicity at oxygen pressures from

0.5 to 2.5 ATM and central nervous system toxicity at oxygen pressures above 2.5 ATM [30]. Malkin assigned ppO2 ranges on the basis of target tissue effects: central nervous system effects at ppO2 1,500 to 2,000 mmHg; pulmonary effects at 400 to 1,500 mmHg; and effects on the respiratory, blood, and lymphatic systems at 280 to 400 mmHg [2]. Oxygen toxicity has also been categorized in broader terms as a pulmonary syndrome seen after long-term, moderate exposures (the Lorraine Smith effect) and a central nervous system syndrome associated with short-term, high-level exposures (the Paul Bert effect). The latter syndrome results from hyperbaric exposures, which are infrequent in normal space operations. The pulmonary syndrome, by contrast, can be seen with nominal therapeutic and operational oxygen levels that are simply maintained beyond appropriate durations. Cells generally require an intracellular oxygen tension of only 3 to 5 mmHg to convert adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which the cells then use as the basic substrate for creating cellular energy. Local tissue oxygen levels are the result of numerous factors, including arterial oxygen tension, local arteriolar and capillary flow, metabolic requirements of the tissue, and the diffusion distance from the capillary. Exposing the cells to additional oxygen beyond what is required for cellular respiration can lead to the formation of reactive oxygen molecules such as free radicals (superoxide, hydroxyl radicals) and activated molecular oxygen in the form of hydrogen peroxide or singlet oxygen molecules. These radicals can then alter cell membranes and inhibit the activity of intracellular enzymes, type I alveolar cells, neurotransmitters and the pyridine nucleotide system, leading to destruction of type I alveolar cells and proliferation of type II cells [31]. In aerospace operations, hyperoxia could be encountered through the use of different gas mixtures during the various phases of a space mission. The nominal atmospheres of the Space Shuttle, the Soyuz, and the ISS are dual-gas oxygennitrogen (21% oxygen and the balance nitrogen). However, numerous contingencies can lead to higher oxygen concentrations. In environmental contingencies such as fire, atmospheric contamination, or loss of cabin pressure, the crewmembers are to don portable breathing apparatuses, which supply 100% oxygen. An illness or injury might require an afflicted crewmember to breathe supplemental oxygen for an extended period, and that supplemental oxygen will be 100% oxygen unless an atmospheric entrainment or gas-blending system is available. Before routine EVAs, crewmembers breathe pure oxygen at cabin pressure to eliminate nitrogen from the tissues and thereby prevent decompression sickness. During the EVAs, crews continue to breathe 100% oxygen in the low-pressure, single-gas EMU (space suit) environment. In the event of decompression sickness, modest hyperbaric treatment pressures can be provided on orbit by overpressurizing the EMU to levels above its normal 222 mmHg (4.3 psig); such suit pressures would be in addition to the cabin’s ambient

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pressure and would provide a total pressure on the crewmember of ~1,140 mmHg (22 psia) of 100% oxygen. With time and increased partial pressure, no tissues are immune to the toxic effects of oxygen. As described below, the physiologic ramifications of oxygen toxicity can be classified according to whether the exposures take place at hypobaric, normobaric, or hyperbaric pressures relative to the sea-level equivalent.

Hypobaric Hyperoxia At reduced barometric pressures, healthy humans can breathe 100% oxygen, corresponding to a PAO2 of 171 mmHg, for as long as 4 weeks continuously without incurring ill effects [32]. Subjects in these early U.S. Air Force-NASA experiments did not develop atelectasis, underscoring the importance of partial pressure over oxygen concentration. These findings suggested that the pure oxygen atmospheres planned for U.S. spacecraft through Apollo would not be harmful to the crew. A project investigating high-pressure EVA suits also demonstrated that a pure oxygen environment at 429 mmHg (8.3 psia) for 8 h per day caused no physiologic decrements [30].

Normobaric Hyperoxia Although hypobaric hyperoxia can be relatively benign, breathing high concentrations of oxygen at sea-level pressure results in an initial decrease in ventilation and heart rate within a few minutes. As the hemoglobin becomes saturated with oxygen, the blood’s ability to carry CO2 is decreased (the Haldane effect). As CO2 is retained, hydrogen ion levels increase, leading to an increase in ventilation that depends directly on the PIO2 [33]. The increased oxygen tension produces cerebral vasoconstriction and dilation of the pulmonary vasculature. The eye is also affected by oxygen exposures lasting longer than 24 h, as evidenced by depression on electroretinography. In normobaric hyperoxia, the available oxygen has increased but the metabolic requirements for oxygen have not, and as a result pathologic oxygen species are formed. Cells have a finite ability to mitigate the toxic effects of oxygen through the use of free-radical scavengers and other protective mechanisms; prolonged (>12 h) exposure to 100% oxygen at sea level results in numerous deleterious effects in most individuals. The first reported symptom is often irritation of the trachea and bronchi, resulting in a dry cough and pain on deep inhalation [34]. Caldwell and colleagues documented progressive decreases in pulmonary function, vital capacity, alveolar-arterial differences, and diffusion capacity over a 6-day exposure [35]. By comparing studies of humans to studies of animals that included necropsies, Caldwell concluded that the observed decreases in vital capacity and diffusion capacity were probably caused by alveolar edema. Operationally, a hyperoxic exposure would likely arise from the use of supplemental oxygen because of atmospheric contamination or a medical contingency. Thus the flight surgeon,

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in addition to remaining vigilant about the toxicity associated with the operational uses of high oxygen pressures, should also be diligent in directing the administration of oxygen in clinical contingencies. The aim of the NASA exposure limits for normobaric oxygen breathing is to prevent pulmonary oxygen toxicity. Six hours of breathing pure oxygen in a sea-level environment is considered the minimum exposure needed to cause the physiologic changes typical of oxygen toxicity. As a result, crewmembers are not permitted to breathe 100% oxygen via quick-don masks or in a launch-and-entry suit for more than 6 h at pressures above 620 mmHg (12 psia), or for more than 12 h at pressures between 526 and 620 mmHg (10.2 to 12 psia). The same rules are used for both the Space Shuttle and the ISS, with the following exception: ISS rules also limit the monthly exposure to enriched cabin atmospheres to no more than 10 days per month when the ppO2 is 200 to 250 mmHg and no more than 1 day per month when the ppO2 is 250 to 300 mmHg. On both the ISS and the Shuttle, the current medical ventilator equipment, like field transport ventilators, can only deliver 100% oxygen to the patient. In subjects breathing 100% oxygen, the alveolar gas is a mixture of oxygen, CO2, and water vapor that readily diffuses into the surrounding tissue. This diffusion facilitates atelectasis and, in combination with hyperoxiainduced reduction in surfactant levels, promotes complete alveolar collapse. Pulmonary oxygen toxicity may also be associated with increased secretions. Any condition that requires mechanical ventilation (which presumably will take place at a nominal cabin pressure [760 mmHg or 14.7 psia]) for more than 12 h can be expected to incur some degree of pulmonary toxicity. It will thus be necessary to aggressively maintain pulmonary toilet and prevent the build-up of secretions in the airway. Retained secretions will block the flow of gas into and out of the alveoli, resulting in absorption atelectasis. The accumulation of secretions could be substantial depending on the underlying pathology. Inhalation of toxic gas and thermal pulmonary injuries are associated with significant production of secretions and require regular suctioning just to maintain the patency of the airway [36,37]. Although potentially lethal, the toxic effects of normobaric hyperoxia resolve quickly when normoxic gas is breathed, unless the exposure is long enough to lead to irreversible pathologic changes such as the induction of fibrosis.

Hyperbaric Hyperoxia Operational exposure to hyperbaric oxygen breathing during space flight missions is currently limited to short-term preparations for EVA before airlock depressurization, when the additive pressure of suit and cabin is 982 mmHg (19 psi) and to contingency treatment of decompression sickness, when the space suit is overpressurized to 1,140 mmHg (22 psi). Given the potential risk of decompression sickness, some clinicians argue that the ISS and any spacecraft to be flown beyond low

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Earth orbit should have definitive hyperbaric capability on board. The original design for Space Station Freedom included a chamber capable of pressures up to 6 ATA; however, these plans were not carried over to the ISS, in part because no decompression sickness events associated with EVA had ever been reported. However, aside from normal EVA-related pressure excursions, mishaps are also possible. As noted elsewhere in this chapter, oxygen pressure during hyperbaric operations is typically quantified in terms of ATAs; for example, an occupant of a hyperbaric chamber pressurized to 14.7 psig (29.4 psia) who is breathing 100% oxygen is actually breathing 2 ATA oxygen, and individuals at sea level are breathing 0.21 ATA oxygen. As ppO2 is increased above that at sea level conditions, the rate of onset and the severity of pulmonary symptoms increase. Visual effects become more pronounced, with significant decreases in electroretinogram activity and visual fields apparent after as few as 8 h at 2 ATA oxygen [30]. Operationally, the most significant toxicity occurs within the central nervous system and includes symptoms ranging from seizures to nausea, tinnitus, dizziness, lightheadedness, retching, paresthesias, and poor concentration. Treatment includes removal from the hyperbaric oxygen exposure and palliative care. Acute central nervous system effects of oxygen toxicity are generally reversible once the subject is returned to a normoxic environment.

Constituent Gases: Carbon Dioxide Production and Control On Earth, CO2 accounts for 0.03% of the air, at a partial pressure of about 0.228 mmHg at sea level, but even tenfold increases in environmental CO2 levels are not associated with physiologic decrements. However, if CO2 levels rise well beyond this, changes in acid-base balance, respiration, circulation, and central nervous system activity are noted [2]. In an attempt to balance operational realities with crew safety, NASA has identified 15 mmHg (i.e., 65 times the normal terrestrial levels) as the upper limit for “off-nominal” ppCO2 level and 20 mmHg as the “emergency” level. The average human produces ∼0.4 L of CO2 per min (600 L/day), although this rate varies widely with metabolic production and can range from 0.2 L/min at rest to 5 L/min during heavy physical activity. Most of the CO2 produced is excreted from the body in gaseous form through the lungs during respiration (∼1 kg/day), and a smaller amount is excreted as bicarbonate ions in the urine [5]. CO2 levels, as a product of respiration, will naturally increase in a closed system. The detrimental physiologic effects first became noticeable when levels exceed about 12 mmHg. Accordingly, the cabin environment of a spacecraft must be designed not only to support the demands for metabolic oxygen but also to remove the CO2 that is the product of respiration. In a closed environment, CO2 can be removed by

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use of a continuous purge (in which small amounts of gas are continually vented overboard) or a closed-loop removal system. For routine space operations, resource limitations make it impossible for crews to rely on atmospheric purging, so CO2 must be actively removed from the spacecraft environment. “Scrubbing” of the spacecraft air is usually accomplished by chemical means as the air is recirculated through the cabin. Space presents a further challenge to a CO2 removal system because of the lack of convection associated with microgravity. CO2 is heavier than air; in a gravitational field it will fall away from the face as it is exhaled, and gravitationally driven convective forces, local airflows and winds serve to further disperse it. In microgravity, a ventilation system is required to carry the CO2 away from the mouth and nose and to move air continuously through the cabin or space suit. As a result, the efficiency of CO2 scrubbers in a microgravity environment is highly dependent upon the ventilation system. Forced ventilation in a spacecraft is essential to ensure good mixing of the atmosphere components. Without well-blended air, CO2, water, heat, and trace contaminants cannot be efficiently removed. Circulation minimizes temperature variation, ensures a homogeneous gaseous composition, and facilitates early smoke detection [38]. Ventilation, as is true of other atmospheric parameters, is also closely tied to atmospheric pressurization. Less dense atmospheres require increased ventilation to achieve the same cooling capacity, a phenomenon related to mass flow of a surrounding gas. Ventilation systems for habitable modules generally operate with a flow velocity between 0.08 and 0.2 m/s to control the CO2 level [39]. If ventilation is poor, as it is behind a rack or within a closed space, atmospheric pockets of uneven gas distribution can develop. CO2 “bubbles,” for example, may form around the heads of stationary space crewmembers in such areas. If they are intent upon their task, crewmembers may not realize the problem until physiologic symptoms appear. In addition to unventilated areas, cramped or highly populated spaces also pose problems for the CO2 removal system. For example, if several crewmembers were to gather in a single module, the ventilation and CO2 removal systems would be more heavily burdened. As a result, systems must be flexible enough to accommodate changing crew operations. Although CO2, unlike CO, is not odorless, its characteristic scent and taste is undetectable to most people until it is present at fairly high concentrations. Most people, for example, will not choose to leave an area until the ppCO2 is above 23 mmHg, by which time work capacity has already decreased and ventilation increased [2]. For this reason, regulations regarding elevated CO2 rely more heavily on measured levels than on crew symptoms. The maximum length of time permitted in a station module that has lost ventilation either between or within modules depends on the number of crewmembers present, the volume of the affected module, and the assumption that the crewmembers will be performing no more than “moderate” work in the unventilated area. According to ISS flight rules, the

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ppCO2 is allowed to reach an average of 6 mmHg in an ISS module during the ventilation repair process. At ppCO2 levels of 10 to 15 mmHg, actions must be taken to reduce the CO2 level, e.g., increasing the atmospheric scrubbing. At levels above 20 mmHg, these tasks assume the highest priority because of the unacceptably high risk of adverse effects (e.g., headaches, tachypnea, or dyspnea). Flight rules also require oxygen masks be donned as protection against hypercarbia should crewmembers exhibit symptoms or if repairs require more time in the module than is permitted by the flight rule. Assuming that the ventilation is adequate, however, CO2 can be removed from the cabin air by any of several methods including absorption (a chemical reaction that uses a sorbent, such as lithium hydroxide [LiOH]), adsorption (physical attraction to a sorbent, such as zeolite), membrane separation, or biological consumption [1] from plant mass. Submarine life support systems, which are faced with this same problem, have made use of organic amines (e.g., monoethanol amine) to combine with CO2. Hydrogen-depolarized devices that use an electrochemical reaction to remove CO2 from the atmosphere can also be used, as can molecular sieves that make use of synthetic silicates to collect the gas. Earth’s ecology relies heavily on biological consumption, as plant life draws CO2 from the atmosphere and exchanges it for oxygen. In future long-duration missions and extraterrestrial colonies, plants may also have a critical role in CO2 removal. Up to this point, however, long-duration platforms such as Skylab, Mir, and the ISS have successfully used active, regenerable sorbent beds and short-duration spacecraft with missions on the order of several days have tended to use absorption reactions with LiOH. The latter method relies on the exothermic reaction of LiOH with CO2 to create Li2CO3 and water: 2LiOH + CO2 → Li2CO3 + H2O

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The theoretical CO2 binding capacity of LiOH is 0.92 kg CO2 per kg of LiOH, or, stated another way, 2 kg of LiOH can remove one person’s daily CO2 from the cabin environment [39]. LiOH is an attractive choice for space flight because of its high absorption capacity and the small amount of heat produced in the reaction. Disadvantages to the use of LiOH include the irreversibility of the chemical reaction, which requires periodic replacement of the canisters and thus represents a potential limit on the duration of a mission, and its considerable toxicity. For these reasons, plans for longerterm missions rely on other means to remove CO2 from the spacecraft environments. To avoid the need for resupplying LiOH, Skylab used a molecular sieve technology for CO2 removal. Its regenerable zeolite matrix had a crystalline structure with a very large surface area. The U.S. orbital segment of the ISS also uses a zeolite molecular sieve. ISS space suits use silver oxide (also known as metal oxide or “metox”) in the form of regenerable canisters to remove CO2, while the Shuttle space suits use LiOH. Future spacecraft environmental control systems may also regenerate oxygen from recaptured CO2—first through reduction

of the CO2 and then through electrolysis of the resultant water into hydrogen and oxygen. The Sabatier process, for example, involves the following reactions: CO2 + H2 → CO + H2O

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CO + 3H2 → CH4 + H2O

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CO2 + H2O → CO + O2 + H2

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Hypercarbia Unlike hypoxia, the onset of which is either gradual or immediate, hypercarbia is primarily insidious because of the steady metabolic production of CO2. (An exception would involve discharge of a CO2 fire extinguisher, but those circumstances would be obvious to all.) As a result, in microgravity, hypercarbia should be anticipated in any circumstance where ventilation is compromised, such as when active ventilation systems fail or are blocked, e.g., in enclosed spaces. During their mission to recover the Salyut 7 space station in 1985, cosmonauts Dzhanibekov and Savinikh were forced to work in a cold, unpowered platform with no active ventilation. They reported having headaches, lethargy, and sluggishness associated with the CO2 from their exhalations and that providing active ventilation as soon as possible mitigated this effect. Crew time in an unpowered module whether in the ISS or some other spacecraft is initially limited by lack of ventilation; moving air with portable fans extends the time crewmembers can remain in such modules for repair and recovery activities by dispersing exhaled CO2 and circulating whatever oxygen is available. Enclosed spaces and local decreases in ventilation typically lead to mild symptoms of hypercarbia during space flight. Often crewmembers must work behind panels or in tight quarters where multiple stowed items compromise airflow (Figure 22.4). Crewmembers sleeping in small, enclosed stations on the Space Shuttle have occasionally been awakened from sleep by headaches that can be mitigated by opening the compartment door to allow ventilation. As is true for hypoxia, hypercarbia is best prevented rather than treated. If the potential for hypercarbia is recognized, symptoms during work in confined spaces can be mitigated by taking frequent breaks in an actively ventilated area, by using small portable fans, or by routing flexible ventilation ducting into the space. Measures as simple as periodically fanning the area with procedure books have also been used. The relationship between the decrease in O2 and the buildup of CO2 for an individual at rest in an enclosed area is shown as a function of volume in Figure 22.5. In a volume of 100 L (3.5 ft3), CO2 levels can exceed the symptomatic threshold in less than 20 min. In the absence of gravitational convection forces and forced ventilation, such volume can be a virtual enclosed space; physical activity, of course, increases CO2 production and accelerates the development of symptoms.

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Exposure to atmospheres enriched in CO2 has predictable physiologic effects. The effects of CO2, like any drug, depend on the dose and duration of exposure and include respiratory stimulation and vasodilation, mediated through stimulation of the respiratory chemoreceptors in the carotid bodies and central receptors. In the blood, carbonic anhydrase catalyzes the hydration of CO2 and the dehydration of bicarbonate as follows: CO2 + H2O ←→ HCO3− + H+

Figure 22.4. Working in an enclosed, poorly ventilated area in microgravity can lead to symptomatic hypercarbia. (Photo courtesy of NASA)

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In this way, increased CO2 levels lead to the formation of additional hydrogen ions, thereby decreasing pH. Thus when hypercarbic gas mixtures are inhaled, the increased level of CO2 in the tissues and blood generates an acidosis, which prompts substantial increases in ventilation. Hypercarbia also influences hyperoxic effects. During hyperbaric oxygen exposures, hypercarbia has been associated with decreases in the seizure threshold thought to result from CO2-induced vasodilation and increased blood flow to the brain [41].

Signs and Symptoms of Hypercarbia Initial symptoms of hypercarbia vary somewhat among individuals, but generally include air hunger, shortness of breath, tachycardia, increased blood pressure, sweating, headache, lethargy, anxiety, dizziness, and nausea. Prolonged exposure to higher CO2 levels results in difficulty breathing, muscle spasms, tremors, visual effects, convulsions, loss of consciousness, respiratory failure, and death. These signs and symptoms, and their effects on physical and mental performance are summarized in Table 22.7.

Chronic Hypercapnia Figure 22.5. Oxygen decrease and carbon dioxide buildup associated with an individual breathing in an enclosed area. In microgravity, a “virtual” enclosed space of low equivalent volume may exist around a stationary crewmember without active ventilation. Source: Rahn H and Fenn WO [40] and Billings [5]

For these reasons, space flight crewmembers are taught to recognize symptoms of CO2 exposure. In a controlled training exercise, crewmembers are exposed by means of a rebreathing apparatus to CO2 beginning at ambient sea-level partial pressures and increasing gradually to a partial pressure of (~60 mmHg. Exposure is limited to several minutes, but participants are to take note of physiologic symptoms corresponding to specific CO2 levels. A portable CO2 detector developed to assess CO2 levels in local environments aboard ISS provides another level of safety in potentially unventilated areas and can help distinguish symptoms of hypercarbia from those of exposure to other toxins that could accumulate locally, such as pyrolysis products from an electrical fire, which could also be associated with the malfunction precipitating loss of ventilation.

Although CO2 levels in spacecraft are significantly (20 to 50 times) higher than the levels on Earth, no evidence exists to suggest that such high CO2 levels lead to any short- or longterm deficits. Studies in healthy subjects have demonstrated no residual effects from breathing low to moderate CO2 levels (<11 mmHg) for extended periods (30 to 40 days), although the consequences of exposure to higher levels, on either a sustained or an episodic basis, remain unclear [2]. Prolonged exposure to CO2 results in several physiological adaptations, including a compensatory metabolic alkalosis arising from the metabolic buffering with hydrogen carbonate (HCO3) and a respiratory acidosis that leads in turn to various electrolyte and metabolic alterations. Changes in calcium levels in blood and bone in particular can raise the risk of forming renal calculi [2], a particular concern for space operations. Three different syndromes, corresponding to different levels of hypercapnia, have been described. A ppCO2 between 4 to 6 mmHg produces few, if any, adaptational changes. Beginning at about 11 mmHg CO2, subtle changes in acid-base equilibrium,

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Table 22.7. Symptoms and performance effects of increased atmospheric CO2. PCO2 (mmHg)

Exposure Duration

≤7.5

3–4 months

<15

Up to 30 days

25–30

Up to 7 days

35–40

up to 15 h

< 50

up to 3–4 h

< 60 > 60, < 75

Up to 1 h None acceptable

Symptoms

Exercise performance

No unpleasant sensations, no functional impairments No perceived symptoms; some increase in respiratory minute volume; slight acidosis Discomfort; dyspnea, especially on exertion; respiratory minute volume elevated by 2–2.5 at rest; exposure up to 3 days leads to easily reversible changes in metabolism due to acidosis Dyspnea, even at rest, “heaviness” of head, vertigo; respiratory minute volume elevated by a factor of 3–4; parameters if cardiovascular function relatively stable; respiratory acidosis; impaired cerebral functioning; sleep disorders Dyspnea, headache, vertigo, visual impairments, sleep disorders; respiratory minute volume increased by a factor of 4–5, respiratory acidosis; marked changes in cardiovascular function; tachycardia, elevated blood pressure; disruption of central nervous system function Drastic worsening of symptoms Drastic worsening of symptoms

Mental performance

Possible (all levels)

Possible

Light and moderate; heavy is difficult

Possible

Light possible; moderate limited; heavy extremely difficult

Possible, if well learned

Light limited; moderate extremely difficult

Limited, even for familiar tasks

Light limited; moderate and heavy impossible

Difficult

All types impossible Precluded

Impossible Precluded

Source: Malkin [2]. Used with permission.

ventilation, and electrolyte balance are seen that although minor may become deleterious over times. Above 22 mmHg ppCO2, obvious abnormalities are noted, including decreased performance and subjective complaints. These findings have lead several groups to suggest that the ppCO2 in enclosed vessels—whether submarines, biospheres, or space stations—be maintained at levels below 4 mmHg and permitted to rise only for transient episodes [2]. NASA and its international partners have chosen to accept slightly higher levels than this for nominal operations, but flight rules described below ensure that potentially harmful levels are avoided.

Operational Limits The CO2 levels that are considered “normal” in space operations are surprisingly close to the threshold for toxic effects on Earth. On the Space Shuttle, for example, the current upper limit for normal CO2 levels is 7.6 mmHg (i.e., 33 times Earth-normal levels). If the atmospheric revitalization system cannot maintain the cabin ppCO2 below 15 mmHg, the shuttle crew must don portable oxygen masks and the Space Shuttle must deorbit at the next opportunity to arrive at a primary landing site. The ISS, like the Space Shuttle, also sets 7.6 mmHg as a level above which corrective actions must be taken. Above a ppCO2 of 20 mmHg, these actions take on high priority for a crew.

Specifically, the procedure for managing abnormally high CO2 levels calls for recovering ventilation, followed by increasing atmospheric gas flow through the CO2 absorption bed. If scrubbing is inadequate, procedures then require the use of personal breathing apparatus and evacuation of the affected area. Although early crewed U.S. missions made extensive use of pure oxygen environments, single-gas environments are currently limited to operations in EVA suits and launch and landing suits. Rules regarding CO2 limits for EVA suits differ somewhat from those of habitable modules because of the more significant isolation and lower failure tolerance associated with EVA and because the suit sensor system is less redundant than the spacecraft CO2 transducers. In addition, telemetered values of CO2 levels around the face may not be accurate owing to sensor placement in the helmet. As a result, self-recognition of hypercarbia symptoms takes on an even greater importance for EVA operations. ppCO2, along with heart rate, electrocardiogram, and temperature, are monitored in the current U.S. EVA suits. In the U.S. program, when ppCO2 levels reach 3 to 8 mmHg hypercarbic symptoms are present, the crewmember must return to the airlock, connect to the umbilical, and purge the suit with oxygen. When ppCO2 levels exceed 8 mmHg, the EVA must be terminated, even in the absence of symptoms. In the Russian Orlan space suit, however, operations are permitted for ppCO2 levels up to 10 mmHg while the

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crewmember is at rest or is not displaying any symptoms of hypercarbia. If that resting limit is exceeded, if symptoms are present, or if the ppCO2 rises above 20 mmHg upon exertion, the crewmember is to terminate the EVA and return to the airlock. These differences in CO2 limits reflect technologic variations between the Russian and U.S. space suits. Although the goal in both programs is to prevent crewmembers from being exposed to CO2 levels above 15 mmHg, the sensors used in the two space suits are slightly different. The placement and response time of the U.S. EMU sensor are such that a measured value of 8 mmHg likely means that the concentration in the helmet is closer to 15 mmHg. The Russian Orlan sensor is configured differently, and its measured value is closer to the actual helmet ppCO2, thereby allowing 10 mmHg (0.2 psi), rather than 8 mmHg, to be used as the threshold value.

Treatment of Hypercapnia Therapy for hypercapnia is similar to that for environmental exposures to other toxins, and starts with the removal of the exposed individual to a safe environment. Exposure to hypoxia is often associated with significant exposure to CO2, although hypercarbic symptoms typically appear first because of the exquisite sensitivity of the chemoreceptors. After prolonged exposure to elevated CO2 levels, nausea and vomiting often occur immediately after removal to a normoxic, normocarbic region. This “CO2 withdrawal” syndrome is not dangerous in itself and will resolve spontaneously with continued exposure to a normal atmosphere. However, the occurrence of this reaction within the close confines of an EVA suit could pose significant problems, as emesis in an EVA helmet could easily lead to aspiration or other complications.

Other Factors: Temperature, Humidity, and Trace Contaminants In addition to atmospheric pressure and gaseous composition, other factors play a role in creating and maintaining an acceptable artificial atmosphere. Temperature, humidity, and trace contaminants can also create challenges for environmental system designers.

Temperature Spacecraft must be designed to protect their occupants not only from the extreme temperatures outside the vehicle but also from the buildup of heat within it. Avionics and other equipment can produce high thermal loads, and task performance is known to decrease with uncomfortable ambient temperatures. Given the coldness of the surrounding space, it would not be unreasonable to assume that astronauts are at greater risk of exposure to cold than to heat; however, the reverse is generally

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true, although the risk depends on the attitude of the spacecraft with respect to the Sun. Notable exceptions have included the return of the crippled Apollo 13 spacecraft, where cabin temperatures fell to 9° to 13°C (49° to 55°F) because of low electrical power levels, and the salvage of the Salyut 7 space station, during which crewmembers conducted repair operations in subfreezing temperatures. Spacecraft must have a way of rejecting the heat from solar incident radiation and from onboard systems [6]; flight rules specifically address the issue of heat buildup. Crew cabin temperature limits on the Space Shuttle are specifically defined and must be kept below 24° to 27°C (75° to 80°F) depending on the phase of flight. Temperature limits during entry and landing are 3°C (5°F) cooler than other times because of uncomfortable increases in orthostatic hypotension associated with thermal stresses upon return to Earth. On the ISS, crewmembers must take actions, such as fluid loading (to avoid dehydration) and donning supplemental oxygen masks (to facilitate respiratory cooling) should the temperature and humidity throughout the entire station rise beyond 32°C (90°F) and 90%, respectively. As described below, life support designers have used different methods to control cabin temperature depending on spacecraft and mission parameters. In all cases, however, temperature control relies heavily upon circulation of cabin air, as does CO2 removal.

Humidity Humidity or water vapor is another atmospheric component of physiologic relevance. Humidity varies with temperature and the availability of free water. It can play a critical role in heat balance and the personal comfort of crewmembers. As temperature rises, humidity must fall to promote evaporative cooling, whereas at lower temperatures, higher humidity reduces evaporation and facilitates heat retention. Generally, humidity is less noticeable in comfortable ambient temperatures, but when ambient temperature strays outside normal ranges, relative humidity can play an important role in ensuring crew comfort. An example is the difference between desert heat and jungle heat: at equivalent temperatures, the humid, tropical heat will be more oppressive than the dry desert air. Humidity can be removed from cabin air either by use of a desiccant material or through condensation of atmospheric water vapor followed by the phase separation of moisture from air. The latter method has been more widely used in spacecraft because it permits the reclamation and further use of water. As warm cabin air is processed, it is cooled below its dew point on heat exchangers and the water is condensed from the humid air. The water droplets thus created are then separated from the air flow through either a wick condenser separator, which uses capillary action and surface tension to transfer the water, or a hydrophobic-hydrophilic separator, which deflects and directs droplets through use of hydrophobic and hydrophilic

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Figure 22.7. Relationship between temperature and humidity ratio, showing an optimal “comfort box” for sustaining human occupants. RH, relative humidity. Source: Wieland P [43].

Figure 22.6. Atmospheric gas flow requirement and heat load for humidity control. Source: Rousseau J [42] and Jones [1].

surfaces. The reclaimed water is then sent to the water management equipment [1]. Desiccant materials are more widely used in space suits, the short-term use of which makes reclamation unnecessary. To maintain lower relative humidity levels requires relatively higher airflow and cooling load (Figure 22.6), and thus from an engineering perspective a relatively high cabin humidity is preferable and a water vapor pressure of 10 to 14 mmHg (0.2 to 0.27 psi) is considered optimum. Higher (> 70%) humidity levels promote condensation and produce conditions that favor the growth of microorganisms and adverse physical effects such as corrosion. Low humidity (<25%) leads to chapped lips, dry eyes, and increased incidence of upper respiratory infections [8]. The comfort zone for humans in terms of relative humidity and ambient temperature is illustrated in Figure 22.7. An example of the difficulties created by the failure to control humidity was reported on the Russian space station Mir shortly after the cosmonauts began using the on-orbit shower. Complaints of insufficient water were attributed at first to less condensate being collected than predicted, but it was eventually determined that the materials in the habitable volume were

themselves absorbing water (in the form of humidity) from the atmosphere before the water reclamation system could do so. These conditions led to a temporary water shortage, affected temperature control (wet insulation cannot function properly), and promoted bacterial growth in the wet materials. Some of the microorganisms produced in turn created a green slime that contaminated the environment, while other microorganisms consumed the adhesive material used in the station construction, loosening materials and creating particulate debris [44]. This experience underscores the need not only to set temperature and humidity limits but also to select materials that will function properly and be compatible with other systems.

Trace Contaminants On Earth, gravity and weather remove most of the trace contaminants from the air, which are generally in the form of particles and gases. Because neither gravity nor “weather” exists on orbiting spacecraft, the environmental system is responsible for removing both particulate matter (such as dust) and gases (including CO, sulfur dioxide, ethanol, and butanol) [1] before they can become a source of irritation or toxicity. Sources of such contaminants in a spacecraft include their off-gassing from habitat materials, leaks or spills, food preparation, combustion products, crew metabolism (feces, urine, sweat), scientific experiments, and cleaning supplies. By the early 1970s, results from studies of closed-loop environments such as submarines and ground-based test chambers showed that trace contaminants could build up to significant levels over time. Before the Skylab Program, spacecraft had measured only CO levels and used LiOH canisters, filters, and absorbents in a somewhat blind approach to removing any and all possible contaminants [45]. No capability for on-orbit monitoring and analysis of trace contaminants aside from CO was included on Mercury, Gemini, Apollo, or the post-Skylab era Space Shuttle, in part because of the relatively short duration of those flights. Samples of the spacecraft atmospheres were obtained and archived for study after landing, but no on-orbit

22. Hypoxia, Hypercarbia, and Atmospheric Control

analyses were performed. For contingency events, chemical colorimetric tests have been available on the Space Shuttle for certain targeted substances; hydrazine, for example, can be detected by a “gold salt” method involving a color change on a coupon. Skylab, which supported the first long-duration U.S. missions, monitored a variety of contaminants through the use of various sensors. Since the Skylab era, researchers have used gas chromatography, mass spectrometry, ultraviolet and infrared spectroscopy, and sensors for individual contaminants (such as CO or hydrogen cyanide) to examine atmospheric samples for the presence of trace contaminants. Such substances are usually removed through the use of various physical barriers. Although careful selection of component material and other preventive measures by environmental control system designers can minimize off-gassing hazards, some contaminants are unavoidable, and the biological implications of such exposures remain unclear. Although classical consideration of trace contaminants have typically studied the accumulation of a single substance to high levels, attention has recently turned to the potential interactive effects of multiple substances at lower concentrations [4]. Some trace contamination can be expected as part of the normal life of a spacecraft, but off-nominal situations can greatly increase these levels. For example, when the Skylab micrometeoroid shield was lost during launch of the vehicle, the interior wall of the orbital workshop overheated, causing concern that its polyurethane foam insulation would off-gas unacceptable levels of toluene diisocyanate [46]. Activated charcoal filters were used to remove the contaminants from the cabin before the first crew entered, and subsequent investigation found no danger to crew health and safety. The most severe spacecraft event that generates toxic products is fire, as occurred on both the Salyut 1 and Mir space stations [7]. During and after a fire, the number and amounts of trace contaminants from pyrolysis rise exponentially. In addition to the smoke itself, combustion products such as hydrogen cyanide, hydrogen sulfide, and CO are likely to be generated, as well as particulate matter. Not all toxins after a fire will be airborne; surfaces will also be contaminated and will require careful cleanup. The fire suppression system can also contaminate the environment by introducing Halon or CO2 into the atmosphere. Although the Halon 1301 agent used as a fire suppressant on the Space Shuttle is highly effective and not overtly toxic, when combusted it produces cardiotoxic byproducts that are difficult to scrub from the atmosphere. CO2 requires a higher concentration than Halon to suppress a fire, but it is also more readily removed from the atmosphere. Russian firesuppressant systems use water in a foam or spray form that complicates the clean-up process after the fire but essentially eliminates any additive toxic constituents. A further option, depending on the severity of the fire and the damage it caused, is to seal off and vent the affected part of the spacecraft.

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Future missions may include time on other planetary bodies and thus will have to consider contamination of the atmosphere by unknown substances such as Martian soil or lunar dust. Toxicity hazards will remain high for the foreseeable future and will continue to pose a challenge for life support system designers and medical care providers alike.

Environment Control Systems The three major acute environmental threats to humans aboard a spacecraft or planetary habitat are loss of pressure (as occurred in the Soyuz 11 mission), fire (as occurred on the Apollo 1 ground test), and atmospheric toxicity from sudden contamination (as occurred during landing of the Apollo capsule after the joint Apollo-Soyuz mission). These threats can occur singly or in combination and constitute the three major atmospheric emergencies of space flight. All require not only immediate, focused action by the crew but also a supplemental breathing supply for the crew to protect them from diminished oxygen levels or dangerous atmospheric contaminants where they carry out the activities necessary to salvage the vehicle. As a result, emergency oxygen ports and portable oxygen bottles must be placed strategically throughout every space habitat to ensure crew protection and enable corrective actions. Simultaneously, scrubbing and other atmospheric purification systems must be highly redundant and sufficiently robust as to clean a contaminated environment. The provision of such multiple, interactive, reliable, and complex systems forms the foundation necessary for establishing and maintaining a human presence in space. In brief, the goals of a life support system (Table 22.8) are to maintain acceptable cabin pressure and atmospheric composition; to circulate the cabin air; to remove humidity, CO2, and contaminants from the air; and to return cooled, purified air to the cabin. CO2 can be processed or dumped Table 22.8. Goals of a life support system. Variable Adequate pressure Adequate pO2 Acceptable fire risk Structural mass constraint Availability of replenishment gases Atmospheric composition Acceptable relative humidity Acceptable temperature Acceptable ventilation Trace contaminant and odor removal system CO2 removal system Risk of decompression sickness

Goal Minimum of about 210 mmHg (for a pure O2 atmosphere) About 160 mmHg FiO2 < 0.3 Decreased P = Decreased Mass Tanked, Generated, etc. Single gas (O2) versus dual gas (O2 + N2) 25–70% 22–24°C (72–75°F) 0.08–0.2 m/s Maintain levels below SMACs Maintain levels below 15 mmHg ↓ cabin—suit ∆P to ↓ DCS risk

Abbreviations: SMAC spacecraft maximum allowable concentration, DP pressure differential, FiO2 inspired oxygen fraction.

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overboard depending upon the scrubbing system used; atmospheric water vapor can be recycled for drinking or technical use. Sufficient supplies of the atmospheric gas or gases must be available during the course of the mission to compensate for depressurizations, both mission-related, such as use of an airlock during EVAs, expected, such as nominal gas leakage, or unintentional, such as a hull breach. Last, the vehicle itself must be constructed with sufficient structural integrity to contain the pressurized atmosphere within it. These goals can be achieved in a variety of ways and the methods selected will naturally differ based on mission parameters, budget, weight constraints, acceptable levels of risk, safety, and reliability. Physiologic factors often compete with engineering or technical considerations. Atmospheric pressures, for example, must be chosen to ensure that gases are sufficiently dense to provide cooling to crewmembers and electronics while maintaining an acceptably low medical risk in the transition to lower pressures during EVAs. Previous spacecraft have used atmospheres pressurized from 259 to 760 mmHg (5 to 14.7 psi), with ppO2 as high as 260 mmHg (5 psi). The earliest space missions were brief, on the order of a few days, and involved only one crewmember, thus necessitating minimal reclamation systems. The long-duration missions supported by the ISS, by contrast, are vastly more complex. The number of people aboard the station fluctuates over time, as the ISS crew is joined by astronauts and cosmonauts from the Space Shuttle and Soyuz vehicles that dock for joint operations with combined crews and then leave again. ISS missions last several months, and the station’s mandate—to perform scientific research—often necessitates maintaining an atmosphere as close to Earth-normal as possible. For short-duration missions, spacecraft designers may find it more economical to carry only what the crew needs and to vent wastes as needed rather than investing resources in developing and maintaining a complex recycling system. The ISS does not have that luxury and must rely on reclamation systems whenever possible. To maintain a breathable atmosphere, a life support system must provide pressure and oxygen, remove CO2, and control trace contaminants. A more complex closed-loop environment also requires systems for recovering oxygen from CO2 (CO2 reduction) and for generating (not supplying) oxygen. To maximize crew comfort, temperature and humidity must be controlled and means provided to remove trace contaminants, particulates, and odors. Atmospheric composition can be controlled manually, automatically, or by a combination of both. Some form of “on-demand” method is usually available to counter leakage with the periodic injection of gas. The amount of such gas needed is calculated from measurements of cabin pressure and (in a two-gas system) of ppO2. Similarly, if the total pressure becomes too great on board, for example because of leakage of stored gas into the cabin, a means must be available for “dumping” or reducing pressure before structural integrity of the spacecraft is compromised.

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The gases needed to repressurize the spacecraft can be stored in high-pressure tanks (as was done on all U.S. spacecraft from Mercury through the Space Shuttle), as liquids in cryogenic storage (as on Gemini, Apollo, Shuttle, and ISS), or in other more novel forms. Nitrogen, for example, can be stored as hydrazine (N2H2), which also serves the more customary role as spacecraft propellant [47]. For long-term habitation, some gases (e.g., oxygen) may need to be regenerated to the extent possible rather than totally resupplied. In a dual-gas storage system, care must be taken to adequately diffuse and distribute the gas constituents to avoid pockets of enriched nitrogen, which may create local asphyxiation hazards, or of oxygen, which may be a fire hazard. Systems are generally designed to circumvent such situations, but objects may be inadvertently placed in the path of gas flow, thereby thwarting the expected diffusion. In addition to the introduction and diffusion of respirable gases, continued ventilation is vital to maintaining atmospheric homogeneity. Temperature and humidity control are closely tied to pressure control. If the pressures dip too low, the ability to cool the spacecraft is impaired. Temperature is also affected by the multiple heat sources within the vehicle, including electronics, lighting, solar heating, and metabolic heat (as produced by exercise). The Russian experience has suggested that the ideal temperatures for a working environment are from 22.2°C to 23.9°C (72°F to 75°F), whereas temperatures below 18.9°C (66°F) and relative humidity greater than 70% are perceived by crews as unpleasantly cold [48]. The atmospheric control systems used in past and present spacecraft are discussed in the remainder of this section.

Mercury Missions in Project Mercury were relatively brief, lasting from 15 min to 34 h, and involved only one astronaut in a bell-shaped volume of 1.56 m3 (55 ft3) [44]. Accordingly, the life support system could be relatively simple. A single system provided atmospheric control to both the cabin and the astronaut’s pressure suit. Requirements called for a 28-h flight capability, based on an oxygen consumption of 500 ml/min and a standard cabin leakage rate of 300 ml/min [49]. The Mercury spacecraft used a low cabin pressure (258 mmHg [5 psi]) and a single-gas atmosphere. The cabin pressure was chosen because it provided the needed PAO2, a small pressure differential with the ambient atmosphere in case of vessel decompression, and a low potential risk of decompression sickness [49]. NASA mission designers decided that the spacecraft environment would be closed to conserve oxygen and thus to diminish the necessary amount and weight. Four pounds of oxygen were required, but a supply of 8 lb of oxygen was flown to ensure sufficient amounts in case of emergency. A store of pressurized oxygen provided both ambient pressure and adequate ppO2. From an engineering standpoint, NASA decided to use a single-gas atmosphere because it was

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simple and reliable and required minimal weight. The pressure suit was designed to operate at 238 mmHg (4.6 psi) after a cabin depressurization. The environmental control system originally called for a pure oxygen environment in the pressure suit, but a cabin atmosphere consisting of 33% nitrogen and 66% oxygen (obtained by enriching the cabin atmosphere at launch with pure oxygen) was chosen because of concerns about the fire hazard. In early ground tests, problems were experienced with nitrogen concentrating in the pressure suit, and so the pure oxygen environment was extended to the cabin. Additional emphasis was then placed on the selection of fire-retardant materials to combat the increased risk. LiOH removed CO2, and a sublimate heat exchanger cooled the cabin based on an estimated metabolic heat production of 126 kcal/h (500 Btu/h) by the astronaut. In a foreshadowing of future closed-loop systems, the heat exchanger used condensate derived from the vehicle’s humidity-removal system. The pressure suit was considered a backup to the cabin environment. A battery-powered blower drove oxygen into the suit torso, providing cooling and producing a mixture of oxygen, CO2, and water vapor. This mixed gas then left the suit through a helmet connection and was processed by the suit’s environmental subsystem. Activated charcoal filtered odors, LiOH absorbed the CO2, and a water-evaporative heat exchanger cooled the air. Additional oxygen was fed into the suit by a demand regulator. The suit subsystem was designed to work with a CO2 production rate of up to 400 ml/min.

Gemini The Gemini spacecraft supported two crewmembers simultaneously in a larger capsule (volume 2.26 m3 [80 ft3]) during missions lasting nearly 10 times longer than the Mercury missions (i.e., 5 h to 14 days) [44]. The capability of the environmental control system had to advance accordingly. At the same time, the desire on the part of NASA engineers was to retain as much of Mercury’s technology as possible because of its proven record of success. As was true for Mercury, a 260 mmHg (5 psi) single-gas atmosphere was used in Gemini, although its primary oxygen source was liquid oxygen rather than gaseous oxygen. Initially, concerns were expressed about the effect of a pure oxygen environment for the duration of the planned missions, but ground-based research documented that exposure to the Gemini atmosphere for up to 2 weeks had no negative physiologic effects on test subjects, and the pure-oxygen system went ahead as planned [50]. Liquid oxygen was heated to gaseous form by a heat exchanger and passed through a pressure-reducing regulator before being delivered to the cabin through a cabin pressure regulator. As was true in the Mercury program, the astronaut’s pressure suit served as a backup in the event of cabin decompression. A LiOH canister removed CO2 and associated odors. The longer missions and the larger crew (two crewmembers rather than the single-crewmember Mercury missions)

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made the rudimentary temperature control system of Mercury insufficient to support Gemini, and a new fluid coolant and radiator system was used to control temperature. The suit heat exchanger transferred heat and moisture from the suit circuit oxygen to vehicle coolant flow. The coolant (a silicon ester fluid) then went to the adapter module skin and transmitted the heat into space [51]. As much as 375 kcal/h (1,500 BTU/h) could be handled in this fashion, with control provided by the amount of coolant flow to the radiator. A backup system also permitted additional cooling through the use of sublimated water. The Gemini spacecraft was also the first U.S. design to provide environmental control to an astronaut outside the vehicle. Life support was controlled through an umbilical connection that tethered the astronaut to the spacecraft.

Apollo Apollo life support systems were necessarily more complex than previous ones, as they involved separate systems for the command module and the lunar excursion module. Once again, however, technology from proven environmental control systems of Projects Mercury and Gemini was extensively used. The command module was a pressurized conical capsule (5.9 m3 [210 ft3]) suitable for a three-person crew. The life support system took up 0.25 m3 (9 ft3) and could operate for up to 14 days; the service module supplied potable water and oxygen. The lunar excursion module, by contrast, was designed to serve two astronauts in a pressurized vessel of 4.5 m3 (158.9 ft3) [44]. Missions in the Apollo Program lasted from 6 days (Apollo 13) to 12.5 days. In the original plans for the Apollo Program, concerns about oxygen toxicity and pulmonary atelectasis led to the call for a spacecraft atmosphere of 50% nitrogen and 50% oxygen at 362 mmHg (7 psi). However, because Project Gemini had successfully used a 100% oxygen atmosphere for up to 14 days, NASA engineers elected to continue with the single-gas environment at 260 mmHg. Apollo preflight checkout initially called for overpressurizing the command module to 827 mmHg (16 psia) before launch, which unfortunately contributed to the fire that killed the Apollo 1 crew during a launch pad simulation. After this tragedy, an atmosphere of 60% nitrogen and 40% oxygen was used at launch. Over the course of the Apollo missions, the cabin environment eventually became nearly pure oxygen, as leakage was exclusively replaced by oxygen during flight. A cryogenic store in the service module supplied oxygen, which remained the only gas available during flight to maintain pressurization. During lunar surface activities, astronauts wore suits that were pressurized to 200 mmHg (3.9 psi) and breathed 100% oxygen. In his memoir, Michael Collins described a probable decompression sickness event during Apollo 11. Although this was reported retrospectively, it remains the only such event known during the Apollo Program [52].

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Again, LiOH removed CO2 and humidity from the spacecraft atmosphere, and the ppCO2 was designed to remain near 3.8 mmHg, with maximum levels of 7.6 mmHg and an emergency limit of 15 mmHg [50]. Sensors located in the command and lunar modules recorded CO2 levels, which remained within design specifications at all times other than during the return of Apollo 13. On that mission, the CO2 absorption capability of the lunar module’s LiOH canister became exhausted after 83 h, and CO2 levels rose to 14.9 mmHg until the command module’s LiOH canisters could be retrofitted for use. Once the modifications were made and the new canisters were deployed, CO2 levels again fell to between 0.1 and 1.8 mmHg. A space radiator similar to that used on Gemini maintained the vehicle temperature between 21.1°C and 26.7°C (70°F and 80°F), with a relative humidity of 40% to 70% [10]. Coldplate wall radiators were used to control the temperature in the command module after a cabin gas heat exchanger proved to be too noisy and inefficient.

Skylab In contrast to previous vehicles, the Skylab station was the first U.S. long-duration space habitat and accordingly required a more elaborate environmental control system. Three separate crews supported missions of 28, 59, and 84 days in a volume of 361 m3 (12,750 ft3). Trace contaminant buildup, which was previously less of a concern because of the relatively short duration of the missions, became a major consideration, as did the need for recyclable and renewable consumables. In the end, however, Skylab’s life support system did not recycle all compounds, which greatly simplified the system design, albeit at the cost of requiring larger supplies of consumables. The Skylab atmosphere also differed from that of previous programs. In response to concerns about the possible toxic effects of chronic hyperoxic environments, a two-gas environment was used for the first time. The atmospheric pressure remained at 260 mmHg (5 psi), but the atmosphere was altered to a 30% nitrogen +70% oxygen mix. This system resulted in an inspired oxygen tension of 182 mmHg, which was slightly higher than on Earth. The mixture of the gases was controlled both automatically and manually. Between the crewed missions, the atmosphere was depressurized to 103 mmHg (2 psi) and allowed to deteriorate as far as 26 mmHg (0.5 psi) as a means of preventing fire and removing trace contaminants. CO2 was removed from the atmosphere not by the LiOH canisters used previously but rather by regenerable molecular sieves. These sieves trapped CO2 in pores but allowed oxygen and nitrogen to pass through. The zeolite matrix was periodically heated and exposed to vacuum to remove the trapped CO2 and regenerate the bed for further use. Two alternating beds were usually used. The sieve operated at a slightly higher CO2 level (5 mmHg) than did the LiOH canisters, with the end result that Skylab astronauts were exposed to greater CO2 tensions than were previous crews. The upper limit of 7.6 mmHg was maintained, however.

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Thermal control was generally provided with passive systems. One such system involved the use of surface paints of various reflectivities and emission patterns, thereby allowing solar heat to be reflected or absorbed according to regional heat requirements. After repairs were made to the surface panels that had been damaged at launch, the use of radiators or evaporators was rarely necessary [10]. As did Apollo crewmembers, Skylab astronauts used liquid-cooled garments and space suits pressurized to 200 mmHg (3.9 psi) during EVAs. Also like the Apollo crew, the Skylab crews were transported to Skylab in an Apollo spacecraft so that additional nitrogen washout occurred even before they reached Skylab’s 70/30 ATM.

Space Shuttle The Space Shuttle required the next generation in life support systems. Although the durations of its missions were similar to those in the Apollo program, the crew complement was significantly larger at up to eight astronauts. Other significant changes were also made in the composition and volume of the spacecraft atmosphere. The environmental control and life support system on the Space Shuttle contains several interlinked systems, including systems for atmospheric revitalization, pressure control, active thermal control, and water supply, and waste water management (Figure 22.8). Unlike previous U.S. vehicles, the pressure of the Space Shuttle’s 74 m3, (2,615 ft3) cabin is maintained at sea level (760 mmHg [14.7 psi]) and consists of a mixture of 80%

Figure 22.8. Schematic overview of Space Shuttle environmental control and life support system. (ARS = atmosphere revitalization system; ATCS = active thermal control system.)

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nitrogen and 20% oxygen. Oxygen is supplied to the system through cryogenic storage tanks. The Space Shuttle is unique among U.S. spacecraft in that it also has nitrogen supply tanks. This dual-gas system is significantly more advanced than the single-gas system used through the Apollo era. Gaseous nitrogen provides atmospheric pressurization to sea level and also pressurizes the water tanks to 879 mmHg (17 psi). Oxygen, derived from the same source as that of the orbiter fuel cells, also provides pressurization to sea level. Supplies of both gases, as well as positive- and negative-pressure relief valves, are regulated at a nitrogen/oxygen control panel. Normal daily losses of crew cabin gas from metabolism and leakage are calculated as up to 3.5 kg (7.7 lbs) of nitrogen and 4.1 kg (9 lbs) of oxygen. Caution and warning lights are activated whenever the following ranges are violated: cabin pressure 724 to 796 mmHg (14.0 to 15.4 psi), ppO2 145 to 186 mmHg (2.8 to 3.6 psi), or oxygen or nitrogen flow rates in excess of 2.27 kg/h (5 lbs/h). Caution and warning limits can be changed to reflect different cabin pressures such as the intermediate pressures to support EVA. A complex active thermal control system provides temperature control by means of Freon-21 coolant loops, cold plate networks, heat exchangers, and heat sinks. Different heat rejection systems are used at different stages of flight. For example, once the Space Shuttle has reached orbit, its payload bay doors are opened so that the radiator panels on the undersides of the doors can begin to radiate heat. A water flash evaporator serves as a backup during flight and as the primary system when the payload bay doors are closed during launch and landing. The atmosphere revitalization subsystem maintains cabin humidity levels between 30% and 75%, removes CO2 and CO, and provides ventilation and temperature control for both avionics and crew areas. The atmosphere revitalization subsystem circulates cabin air while picking up CO2, odors, heat, and moisture; debris is then removed by using one of two fans to draw cabin air through a 300-µm filter. The air is sent through two LiOH-activated charcoal canisters to absorb CO2 and odors. The canisters have a lifespan of 24 h, requiring that one canister be changed every 12 h. Cabin air then travels to the heat exchanger and is cooled by the water coolant loops. Humidity condensate is removed and separated from the air. Up to 1.8 kg (4 lbs) of water is removed per hour and sent to the waste water tank. Most of the revitalized air is meanwhile ducted back into the cabin, with a small fraction of the air sent to the CO removal unit. That unit converts CO into CO2, which the LiOH canisters can then remove. The entire volume of cabin air travels through the atmosphere revitalization subsystem ∼8.5 times every hour (330 ft3/min). Some cabin air bypasses the heat exchanger and mixes with the revitalized air to maintain the cabin temperature between 18.3°C and 27°C (65°F to 80°F). The same system cools the avionics units and the three inertial measurement units, although this air is carried on independent loops from the cabin air.

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The life support system on the Space Shuttle can also be extended to pressurized modules in the payload bay, such as Spacehab, and can partially depressurize and repressurize for EVAs. Because U.S. space suits operate at 222 mmHg (4.3 psi) during EVAs, concerns have been raised that the pressure differential between the vehicle and suit might lead to the development of decompression sickness. On previous missions with pure oxygen atmospheres, the risk of decompression sickness was greatest at launch, when cabin pressure changed from 760 mmHg to 260 mmHg (14.7 psi to 5 psi). Gemini and Apollo crews minimized this risk by breathing 100% oxygen for 3 h before launch. By the time the crews exited the vehicle, the risk of forming nitrogen bubbles was extremely low. Even Apollo astronauts, whose space suits were pressurized to 200 mmHg (3.9 psi), had been breathing a high-oxygen environment for several days before engaging in EVAs on the lunar surface, so the small change between the cabin pressure and space suit pressure reduced the risk even further. Space Shuttle crews, by contrast, are at the greater risk during the transition from their sea-level-equivalent cabin to their single-gas, 222-mmHg (4.3-psi) EMU. As a result, ∼12 to 24 h before performing an EVA, the entire crew compartment is depressurized from sea level to 527 mmHg (10.2 psi). The crewmembers who will actually be outside the vehicle in the EMUs also breathe 100% oxygen to purge their tissues of dissolved nitrogen. After these actions, they enter the 100%-oxygen, 222-mmHg (4.3-psi) EMU and exit the Space Shuttle. The EMU space suit is essentially a single-person spaceship that is suitable for missions lasting up to 8 h. As such, it has its own independent life support system. LiOH canisters are used to regulate CO2 levels below 0.15 psi (7.75 mmHg) or at 0.29 psi (15 mmHg) at metabolic rates that exceed 400 kcal/h (1,600 Btu/h) [13]. (For stationbased EVA, the LiOH canisters are replaced by regenerable metal oxide cartridges) A liquid cooling garment helps to combat thermal stresses caused by heat released by the suit machinery, the exothermic CO2 absorbing reaction, and metabolic workloads. As is true for the cabin environment, the EMU atmosphere must be adequately ventilated and rigorously monitored. Although the Space Shuttle is the first U.S. spacecraft to offer an Earth-normal atmosphere on orbit, Russian spacecraft have done so for many years. The next section constitutes a review of Russian contributions to environmental control systems.

The Russian Experience Although the early years of space exploration were influenced by Cold War competition, the last decades have seen an increasing number of joint space operations. The ISS Program has greatly increased cooperation between the Russian and U.S. space agencies, and much knowledge has been shared with regard to previous joint missions on the Shuttle and Mir station as well. The Russian Space Agency is quite experienced, particularly in the realm

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of long-duration space flight. Since 1971, eight Soviet/ Russian space stations have been flown (seven Salyut stations and Mir); other Russian spacecraft include the Vostok, Voskhod, and Soyuz vehicles. Both the Russian and U.S. space programs began with small vehicles with open-loop environmental support systems. The Vostok, which carried cosmonaut Yuri Gagarin into history as the first human in space, was a spherical craft with a volume of 2 to 3 m3 (71 to 106 ft3). Unlike NASA’s early spacecraft, the early on the Russian spacecraft involved use of an Earthlike atmosphere (80% nitrogen and 20% oxygen at 760 mmHg [14.7 psi]) [53]. The Vostok’s life support system was similar to those of early U.S. spacecraft. The Voskhod was an improved Vostok that housed three seated crewmembers in a shirtsleeve environment (i.e., pressure suits were not required). The Soyuz spacecraft, upgraded versions of which are still in use as transport and escape vehicles for the ISS, was first flown in 1967. It contains two pressurized compartments for three crewmembers, again in shirtsleeves. After all three cosmonauts aboard Soyuz 11 died in a spacecraft depressurization, the Soyuz crews were limited to two people in pressure suits. The vehicle was later modified into the Soyuz T to accommodate three suited crewmembers. In contrast to U.S. vehicles, the Soyuz was designed to allow no gas leakage. Its sea-level atmosphere is a mixture of oxygen and nitrogen, maintained at an ambient pressure of 708 to 847 mmHg (13.7 to 16.4 psi) with partial pressures of oxygen between 140 and 202 mmHg (2.7 to 3.9 psi). These differences between vehicle design in the Russian and U.S. programs led to some concerns during the ApolloSoyuz Test Program, during which the two spacecraft were to dock and allow contact between crewmembers. Russian engineers were concerned about the Apollo capsule’s normal leakage rate of 1 kg/day, and U.S. flight surgeons were concerned about the development of decompression sickness. In the Apollo-Soyuz Test Program, the atmosphere of the Apollo vehicle was 100% oxygen at 260 mmHg (5-psi) atmosphere and the Soyuz environment was a mixture of oxygen and nitrogen at 517 mmHg (10 psi). Despite these concerns, no episodes of decompression sickness were reported. The Soviet spacecraft also stored oxygen in solid form, as alkali metal superoxides, rather than the liquid and gaseous forms used by NASA. As these solid compounds absorb moisture, they liberate oxygen and form alkalis, which in turn absorb CO2. Life support systems planned for space stations were revised to accommodate the longer-term functionality required for weeks- or months-long missions. The first space station was the Salyut, designed to house up to five crewmembers in three modules with a total volume of ∼100 m3 (3,530 ft3). Seven Salyut stations were launched between 1971 and 1982. Oxygen was created on board by means of a potassium superoxide system, and both LiOH canisters and the oxygen regenerators removed CO2. The life support system on Salyut 6 was modified to include a water reclamation system.

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The Mir space station was the next generation beyond the Salyut 7 station. Mir was designed to house up to six crewmembers in a volume of 150 m3 (5,300 ft3) and, like its successor the ISS, modules could be added to its core structure. In addition to tanked stores and a hypochlorite generator system, oxygen on Mir was produced by water electrolysis. As was the case on Skylab, CO2 on Mir was removed through an absorbable system that vented to space.

International Space Station The ISS is international not only in name but also in components. Many of the station systems were created by partnerships between two or more countries; the Russian and U.S. orbital segments of the ISS often use different methods, even in the environmental control and life support system. The atmosphere control and supply system onboard the ISS is responsible for maintaining the pressure and composition of the station atmosphere, providing oxygen and nitrogen, and allowing pressure equalization and depressurization. The ISS, like the Russian space stations that preceded it, uses a 760 mmHg (14.7 psi), 80% nitrogen and 20% oxygen atmosphere. The Russian orbital segment is primarily responsible for atmosphere control and supply during the initial years of station operations. Progress resupply vehicles, equipped with tanks that can be filled with nitrogen, oxygen, or mixed air, can be accessed by ISS crews in the event of a drop in cabin pressure. Although the ISS was initially supplied with all respirable gases, oxygen can also be generated through the electrolysis of waste water with the Russian Elektron device. An oxygen generator is eventually planned for the U.S. orbital segment as well. As a backup, a solid fuel oxygen generator is present that relies on the exothermic production of oxygen from chemical cartridges. The atmosphere control and supply subsystem in the U.S. orbital segment (Figure 22.9) makes use of four high-pressure gas tanks, two oxygen and two nitrogen, located on the airlock exterior and connected by a system of pipes. The tanks can be refilled by the Space Shuttle, although a pressure differential between the Space Shuttle tanks and the ISS tanks mandates use of a transfer pump to ensure that the ISS tanks can be fully recharged. The external location was chosen to allow the tanks to be replaced by full ones if refilling is unavailable. A pressure control assembly is responsible for introducing gas or gases into the cabin environment, monitoring the station pressure, and permitting depressurization as needed. Manual pressure equalization values are provided to equalize pressure between closed modules. The atmosphere revitalization subsystem on the ISS maintains the safety of the breathing air by removing CO2 and other contaminants and by monitoring air quality with a mass spectrometer. The U.S. CO2 removal assembly and the Russian Vozdukh system use a series of reusable sorbent beds to remove CO2, which is then vented to space. For maximal efficiency, the

22. Hypoxia, Hypercarbia, and Atmospheric Control

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Figure 22.9. Atmospheric control and supply subsystem for the U.S. orbital segment of the International Space Station

systems require cool, dry air and are linked directly to the temperature and humidity control subsystem to receive processed air. LiOH canisters are also available as backup. Trace contaminants are controlled in both the Russian and U.S. segments by high-efficiency particulate air filters and catalyzation. When the ISS is completely assembled, CO2 scrubbing will allow reclamation of oxygen that would otherwise be lost. The Russian Sabatier reactor will eventually be used to conserve resources by combining hydrogen from the Elektron and CO2 from the atmosphere revitalization subsystem at relatively high temperatures (480°C to 650°C [900°F to 1,200°F]) to create water and then oxygen by hydrolysis. As is true for other spacecraft, ventilation is critical for temperature and humidity control on ISS. Air circulation takes place at three levels: within an individual rack, within an

individual module, and between two or more modules. Rack ventilation makes use of the avionics air assembly, cooling the air within a rack by using fans and noncondensing heat exchangers. The system is also linked with smoke detectors from the fire detection and suppression subsystem. Intramodule ventilation in contrast, is provided by the cabin air assembly. That assembly draws cabin air through a highefficiency particulate air filter and then removes moisture through a condensing heat exchanger. The water thus produced is sent to the water recovery and management subsystem, and the cool, dry air goes first to the CO2 removal assembly and then back into the cabin. In the Russian orbital segment, dragthrough flexible ducting and open hatches provides ventilation between modules, and the U.S. segment uses a series of fans, valves, and hard-plumbed ducts.

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Both the 222-mmHg (4.3-psi) U.S. space suit and the higher-pressure Russian Orlan suit (295 mmHg [5.7 psi]) are used for EVAs from the ISS. Although flight surgeons continue to be concerned about the risk of decompression sickness from the pressure differential between vessel and suit, to depress the entire ISS to an intermediate pressure stage before an EVA, as the Space Shuttle does, is not practical. The Space Shuttle’s smaller volume and shorter mission duration allow it to depressurize and repressurize its entire crew compartment. The ISS airlock can serve this function by being isolated from the remainder of the station and being partially decompressed, although new concerns have been raised about prolonged isolation of crewmembers. To mitigate this concern and further conserve ISS gas resources, a new EVA prebreathe procedure in which exercise is used to enhance nitrogen elimination and decrease the amount of oxygen prebreathe time has recently been developed and utilized from the ISS joint airlock.

Future Directions As the duration of orbital missions and the size of the crews increase and as plans are made for explorations beyond Earth’s orbit, the ability to provide space crews with a healthy and comfortable living environment grows ever more complex. Advanced environmental control systems will be needed for both planetary exploration missions and permanent settlements beyond Earth’s atmosphere. New technologies will be needed to enhance water reclamation, produce oxygen, and remove CO2. The primary requirements for such a system will be minimal power usage and volume, robust autonomous operation, and a closed-loop design that minimizes reliance on stored consumables. Once we venture beyond low-Earth orbit, the risks associated with radiation increase, the capability for frequent resupply diminishes, and medical assistance and evacuation become less available. Life support systems must become more “closed loop,” more robust, more efficient, more operationally simplified, more automated, and more reliable—while simultaneously requiring less energy-intensive, less massive, and less expensive technology. Although the ISS currently uses electrolysis of waste water to produce oxygen, oxygen can be generated by other means, such as electrolysis of CO2 or water vapor or use of plants. Not only waste water but solid wastes will be recycled in future habitats, and plants, grown from these recycled solids may come to form a critical link in the life support loop. Just as Earth is a spacecraft with a planetary ecology that forms its life support system, extraterrestrial human habitations will need to create their own ecologies, complete with biological air revitalization and water reclamation systems. It is also critical to point out that the location of any future missions will influence the design of the environmental control system. For example, hazards associated with lunar or Mars missions (dust, falls, potential microorganisms) do not exist in long-duration space station mis-

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sions in microgravity; however, additional resources may be available on lunar or Mars missions that may range from oxygen-containing soil to potential heat sinks or radiation barriers. All of these factors must be considered in the development of future life support systems.

References 1. Jones W, Ingelfinger A. Atmospheric control. In: Parker J, West V (eds.), Bioastronautics Data Book. 2nd edn. Washington, DC: National Aeronautics and Space Administration; 1973:807–846. NASA SP-3006. 2. Malkin V. Barometric pressure and gas composition of spacecraft cabin air. In: Sulzman FM, Genin AM (eds.), Life Support and Habitability, Vol. II. Washington, DC: American Institute of Aeronautics and Astronautics; 1993:1–36. Nicogossian A, Mohler S, Gazenko O, Grigoriev AI, series (eds.), Space Biology and Medicine: Joint U.S./ Russian Publication in Five Volumes. 3. Graf J, Finger B, Daues K. Life Support Systems for the Space Environment: Basic Tenets for Designers, Rev. A, June 27, 2002. Web page available at: http://advlifesupport.jsc.nasa.gov. Accessed October 11, 2002. 4. International Civil Aviation Organization. Manual of the ICAO Standard Atmosphere. 2nd edn. Montreal: ICAO; 1964. 5. Billings C. Barometric pressure. In: Parker J, West V (eds.), Bioastronautics Data Book. 2nd edn. Washington, DC: National Aeronautics and Space Administration; 1973:1–34. NASA SP3006. 6. Busby D. Space Clinical Medicine, A Prospective Look at Medical Problems From Hazards of Space Operations. Dordrecht, Holland: D. Reidel Publishing Company; 1968. 7. Harland D. The Mir Space Station: A Precursor to Space Colonization. Chichester, UK: John Wiley and Sons; 1997. 8. Waligora J, Powell M, Sauer R. Spacecraft life-support systems. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine, 3rd edn. Philadelphia: Lea & Febiger; 1994:109–127. 9. Ernsting J, Nicholsen A, Rainford D. Aviation Medicine. 3rd edn. Oxford, UK: Butterworth-Heinemann; 1999. 10. Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: Lea & Febiger; 1994. 11. Hackett PH, Roach RC. High-Altitude Medicine., In: Auerbach PS (ed.), Wilderness Medicine. 3rd edn. St. Louis, MO: Mosby Year Book; 1995:3. 12. Lataste X. The blood-brain barrier in hypoxia. Int J Sports Med 1992; 13:S45–S47. 13. Neubauer J, Melton J, Edelman N. Modulation of respiration during brain hypoxia. J Appl Physiol 1990; 68:441–451. 14. Hammond M, Gale GE, Kapitan K, et al. Pulmonary gas exchange in humans during normobaric hypoxic exercise. J Appl Physiol 1986; 16:1749–1757. 15. Wagner PD, Gale GE, Moon RE, et al. Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol 1986; 61:260–270. 16. Wood S. Interactions between hypoxia and hypothermia. Annu Rev Physiol 1991; 53:71–85. 17. Yoneda I, Tomoda M, Tokumaru O, et al. Time of useful consciousness determination in aircrew members with reference to

22. Hypoxia, Hypercarbia, and Atmospheric Control prior altitude chamber experience and age. Aviat Space Environ Med 2000; 71:72–76. 18. Pickard JS. The atmosphere and respiration. In: DeHart RL, Davis JR (eds.), Fundamentals of Aerospace Medicine. 3rd edn. Philadelphia, PA: Lippincott Williams and Wilkins; 2002; Table 2.7, p. 37. 19. West JB. Tolerance to severe hypoxia: lessons from Mt. Everest. Acta Anaesthesiol Scand Suppl. 1990; 34:18–23. 20. Sutton J, Reeves J, Wagner P, et al. Operation Everest II: oxygen transport during exercise at extreme hypoxia. J Appl Physiol 1988; 64:1309–1321. 21. Powell F, Huey K, Dwinell M. Central nervous system mechanisms of ventilatory acclimatization to hypoxia. Resp Physiol 2000; 121:223–236. 22. Lambertsen C. Hypoxia, altitude and acclimatization. In: Mountcastle V (ed.), Medical Physiology, 14th edn. St. Louis, MO: Mosby; 1980. 23. Hackett P, Rabold M. High-altitude medical problems. In: Tintinalli J, Ruiz E, Krome R (eds.), Emergency Medicine: A Comprehensive Study Guide. 4th edn. New York, NY: McGraw-Hill Company; 1996. 24. Scholz H, Schurek H, Eckardt K, Bauer C. Role of erythropoietin in adaptation to hypoxia. Experientia 1990; 46:1197–1201. 25. Young AJ, Young PM. Human acclimatization to high terrestrial altitude. In: Pandolf K, Sawka M, Gonzalez R (eds.), Human Performance Physiology and Environmental Medicine at Terrestrial Extremes. Carmel, IN: Cooper Publishing Group; 1988. 26. Hochachka P. Mechanism and evolution of hypoxia-tolerance in humans. J Exp Biol 1998; 201:1243–1254. 27. Bebout D, Story D, Roca J, et al. Effects of altitude acclimatization on pulmonary gas exchange during exercise. J Appl Physiol 1989; 67:2286–2295. 28. Appenzeller O, Martignoni E. The autonomic nervous system and hypoxia: mountain medicine. J Auton Nerv Syst 1996; 57:1–12. 29. Conkin J. The Mars Project: Avoiding Decompression Sickness on a Distant Planet. Houston, TX: NASA, Lyndon B. Johnson Space Center; 2000. NASA TM 2000-210188. 30. Waligora JM, Horrigan DJ, Nicogossian A. The physiology of spacecraft and space suit atmosphere selection. Acta Astronautica 1991; 23:171–177. 31. Fenton L, Beck G, Djali S, Robinson M. Hypothermia induced by hyperbaric oxygen is not blocked by serotonin antagonists. Pharmacol Biochem Behav 1993; 44:357–364. 32. Robertson W, Hargreaves J, Herlocher J, et al. Physiologic response to increased oxygen partial pressure II: respiratory studies. Aerospace Med 1964; 35:618–622. 33. Clark J. Therapeutic and toxic effects of hyperbaric oxygenation. In: Crystal R, West J, et al. (eds.), The Lung: Scientific Foundation. New York: Raven Press Ltd.; 1991:2123–2131. 34. Montgomery AB, Luce JM, Murray JF. Retrosternal pain is an early indicator of oxygen toxicity. Am Rev Respir Dis 1989; 139:1548–50. 35. Caldwell PR, Lee WL Jr, Schildkraut HS, et al. Changes in lung volume, diffusing capacity, and blood gases in men breathing oxygen. J Appl Physiol 1966; 21:1477–83. 36. Nakae H, Tanaka H, Inaba H. Failure to clear casts and secretions following inhalation injury can be dangerous: report of a case. Burns 2001; 27:189–91. 37. Robinson L, Miller RH. Smoke inhalation injuries. Am J Otolaryngol 1986; 7:375–80. 38. Mission Operations Directorate, Space Flight Training Division. International Space Station Familiarization Manual. Houston,

473 TX: National Aeronautics and Space Administration; 1998. NASA TD 9702A. 39. Eckart P. Spaceflight Life Support and Biospherics. Torrance, CA: Microcosm Press; 1996. 40. Rahn H, Fenn WO. The Oxygen—Carbon Dioxide Diagram. WADC-TR-53-255, Wright-Patterson Air Force Base, Ohio 1953. 41. Gelfand R, Lambertsen CJ, Beck G, et al. Dynamic responses of SaO2 and “CBF” to abrupt exposure to inhaled 10% O2/4% CO2 at rest, followed by 50 and 100 watts exercise. Undersea Hyperbaric Med 1995; 22(Supp.):70–71. 42. Rousseau J. Atmospheric Control Systems for Space Vehicles. Report No. ASD-TDR-62-527, AiResearch Manufacturing Division, Los Angeles California; March 1963. 43. Wieland P. Designing for Human Presence in Space: An Introduction to Environmental Control and Life Support Systems. NASA Marshall Space Flight Center, Huntsville, AL. NASA Scientific and Technical Information Program; 1994: Page 25. NASA RP-1324. 44. Wieland PO. Designing for Human Presence in Space: An Introduction to Environmental Control and Life Support Systems. Marshall Space Flight Center, AL: NASA Scientific and Technical Information Program; 1994: Chapter 5. NASA RP-1324. 45. Churchill SE (ed.), Fundamentals of Space Life Sciences. Malabar, FL: Krieger Publishing Co.; 1997. 46. Rippstein WJ, Schneider HJ. Toxicological aspects of the Skylab program. In: Johnson RS, Dietlein LF (eds.), Biomedical Results From Skylab. Washington, DC: U.S. Government Printing Office; 1977:70–73. NASA SP-377. 47. Wieland PO. Designing for Human Presence in Space: An Introduction to Environmental Control and Life Support Systems. Marshall Space Flight Center, AL: NASA Scientific and Technical Information Program; 1994: Appendix C, C.2. NASA RP-1324. 48. Wieland PO. Designing for Human Presence in Space: An Introduction to Environmental Control and Life Support Systems. Marshall Space Flight Center, AL: NASA Scientific and Technical Information Program; 1994; 2.3. NASA RP-1324. 49. Link MM. Space Medicine in Project Mercury. Washington, DC: NASA Scientific and Technical Information Division; 1965. NASA SP-4003. 50. Johnston RS, Dietlein LF, Berry CA (eds.), Biomedical Results of Apollo. Washington, DC: NASA Scientific and Technical Information Division; 1975. NASA SP-368. 51. Hacker BC, Grimwood, JM. On the Shoulders of Titans: A History of Project Gemini. Washington, DC: NASA Scientific and Technical Information Division; 1977. NASA SP-4203. 52. Collins M. Carrying the Fire: an Astronaut’s Journeys. New York, NY: Farrar, Straus, and Giroux, Inc.; 1974. 53. Ezell, EC, Ezell LN. The Partnership: A History of the ApolloSoyuz Test Project. Washington DC: NASA Scientific and Technical Information Division; 1978. NASA SP-4209.

Suggested Readings West JB. Respiratory Physiology—The Essentials. Baltimore, MD: Williams & Wilkins Company; 1974. Wieland PO. Living Together in Space: The Design and Operation of the Life Support Systems on the International Space Station. Marshall Space Flight Center, AL: NASA Scientific and Technical Information Program; 1998. NASA/TM-1998206956.

23 Radiation Disorders Jeffrey A. Jones and Fathi Karouia

Space presents a unique radiation environment to the intruding human; from a different viewpoint, Earth is a unique radiation haven in which humans live and flourish. Radiation exposure remains perhaps the single most important limiting factor for human exploration of space beyond low Earth orbit (LEO), primarily because of difficulties in providing adequate protection for the crew. Protection that would limit exposures to anywhere near terrestrial normal values would involve shielding of substantial mass. Moreover, considerable varieties of radiation types and energies are associated with space flight, many of which can have potentially adverse effects on biological and physical systems. Unlike Earth-based radiation exposures, space flight involves exposures from outside sources such as solar particle events or galactic cosmic rays rather than radioactive contamination, and most such exposures affect the entire body. The effects of radiation on the cell, the fundamental unit of a biological system, can be compared with its effects on the electronic system equivalent, the integrated circuit. In the terminology of electronics, incident radiation could cause a “single event upset” that might go completely unnoticed but could also trigger an undesirable software response, shut down that component, or devastate the hardware through a short circuit or power surge, depending on the location and activity of the component that was hit. The same is true of ionizing radiation events in the cell. The ionized molecule could be immediately neutralized by a cytoplasmic antioxidant molecule, or it could produce a nuclear DNA point mutation in a non-coding region of the genome. It could trigger a chain reaction of ionization events or a DNA single-strand break (SSB) that might lead to mutation or a double-strand break (DSB) leading to cell death. The uncertainties associated with the effects of ionizing radiation and its risks to human health are still quite high. This chapter will review how the space environment differs from that on the surface of Earth and review current knowledge of space radiation. Also included are descriptions of the key areas of research needed to reduce the level of uncertainty associated with space travel and strategies to mitigate the inherent risks associated with human exposure to space radiation.

Radiation Physics: A Brief Overview Definition of Terms Definitions of terms used to describe radiation quantity and quality are provided below. The electron volt (eV) is the common unit of measure for energy present in radiation and is often expressed in multiples of thousands (keV) or millions (MeV). One eV is the kinetic energy acquired by an electron accelerated in a vacuum through a potential difference of 1 v; 1eV = 1.6 × 10 −12 ergs = 1.6 × 10−19 joules. The radiation absorbed dose (rad) is the amount of energy that is absorbed from radiation per unit mass of material. The System International unit (SI) unit for absorbed dose is the gray (Gy); 1 Gy = 100 rad = 10,000 ergs/g. Relative biological effectiveness (RBE) is the ratio of a standard X-ray dose to that of another type of ionizing radiation that results in the same risk of a biological event. The RBE, as its name implies, is used to compare the biological effectiveness of different types of ionizing radiation. The dose-equivalent or biologically equivalent dose is expressed as roentgen-equivalents man (rem) and represents the absorbed dose adjusted for the biological effectiveness of the particular type of radiation. The SI unit for doseequivalent is the sievert (Sv); 100 rem = 1 Sv. Dose-equivalents are calculated as the product of the absorbed dose and a quality factor Q (see below). The quality factor (Q) is a function of a particle’s linear energy transfer (LET) (see below), which in turn is determined by the charge and energy of the radiation particles. Quality factors account for differences in the biological effectiveness of different particles and, as noted in the previous paragraph, they are used to convert absorbed doses into dose-equivalents. In terms of the traditional units, rem = rad x Q; in SI units, sievert = Gy x Q. Current values for Q range from 1 (for X rays) to 20 (Table 23.1) [1,2]. Quality factor values as high as 100 for certain highly damaging particles may be deemed appropriate as additional research continues. 475

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Linear energy transfer (LET) quantifies the amount of energy deposited by a radiation particle per unit length of the particle’s track. This factor increases with the square of the charge and is inversely proportional to the energy of the radiation particle. The influence of the electric force field depends on the velocity of the particle. Slower moving charged particles will produce more ionizations per unit path length than faster moving ones. LET accounts for all energy transfers along the particle’s path, regardless of the mechanism of those transfers. The biologically weighted dose-equivalent value (H) is the product of the absorbed dose, Q, and other dose-modifying factors. H is expressed in rem or Sv and is intended to encompass all aspects of a certain radiation exposure influencing a biological effect. The dose rate effectiveness factor (DREF) measures the differences between acute exposures (i.e., a single large exposure Table 23.1. Quality factors associated with various types of radiation. Radiation type and energy range

Quality factor (Q)

Photons, all energies Electrons and muons, all energiesa Neutrons, energy < 10 keV 10 keV to 100 keV 100 keV to 2 MeV 2 MeV to 20 MeV 20 MeV Protons (other than recoil protons) of energy > 2 MeV Alpha particles, fission fragments, heavy nuclei

1 1 5 10 20 10 5 2b 20

event) and chronic exposures (i.e., an exposure fractionated over time) of the same type of radiation at the same total dose. Like RBE, the DREF is expressed as a ratio and is a way of understanding the influence of dose rate on the biological effect. Practically, this term becomes a scaling factor whereby meaningful comparisons can be made between acute exposure events for which there is historical evidence linking dose and outcome, such as those experienced by atomic bomb survivors, and events such as long duration space flight that involve low dose rates. Flux is the density at which particles are incoming, measured in number of particles/cm2. Fluence is the rate at which particles are incoming, measured in number of particles/second. Stochastic or probabilistic effects are defined as effects that have some probability of occurring; that probability is a function of dose. Some somatic effects, particularly carcinogenesis, are regarded as being stochastic, as are hereditary effects. Deterministic or nonstochastic effects, on the other hand, are effects considered to be inevitable; deterministic effects are associated with some threshold dose above which the probability of their occurrence is expected to be 100%. In biological terms, most of the deterministic effects of radiation involve cell killing and can occur soon after (early effects) or later after the radiation exposure (late effects). An overview of types of radiation of interest, with their sources, penetration, and principal types of interactions, is given in Table 23.2 [3].

Electromagnetic Radiation

NOTE: All values relate to the radiation incident on the body or (for internal sources) emitted from the source. a Excluding auger electrons emitted from nuclei bound to DNA. b The Q value recommended by the International Commission on Radiological Protection for this type of radiation is 5. Sources: Adapted from National Council on Radiation Protection and Measurements [1] and Prasad [2].

The electromagnetic radiation environment aboard a space vehicle in LEO is determined by the contributions of electric fields, magnetic fields, and electromagnetic radiation from onboard sources; other contributors include extremely low frequency variations in the electromagnetic radiation from the motion of the spacecraft within the geomagnetic field.

Table 23.2. Types of radiation and the possible extent of hazard. Type of radiation X rays Gamma rays

Symbol χ γ

Neutrons

Usual source

Penetration of external radiation

Principal types of interaction

X-ray machines and accelerators Most radioisotopes emit γ rays after β decay

X and γ rays penetrate deeply, for only Ejected electron loses energy by causing a fraction of the rays interact with additional ionization; deflected X or γ each layer of tissue ray may interact again some distance away

Generally produced by critical assemblies, nuclear reactors, or accelerators

Neutrons penetrate deeply, for only a fraction of the neutrons interact with each layer of tissue

Deflected neutrons may interact some distance away; recoil proton loses energy by causing ionization

Beta particles

β

Most radioisotopes decay by emitting β particles, usually followed by emission of γ rays

Penetration depends on the energy of the β particle but is usually limited to less than 8 mm in tissue

Ejected electron loses energy by causing additional ionization; deflected electron or β particle causes additional ionization

Alpha particles

α

Many heavy radioactive elements (e.g., plutonium) decay by emitting α particles

Penetration is limited to about the thickness of the epidermis

Ejected electron loses energy by causing additional ionization; deflected α goes on to cause additional ionization

Energetic protons are found only near particle accelerators

Penetration depends on the energy of the proton

Deflected proton causes additional ionization; ejected electron loses energy by causing additional ionization.

Protons

Source: Andrews and Cloutier[3]. Used with permission, Heldref Publications.

23. Radiation Disorders

Spans of interest in the electromagnetic spectrum (Figure 23.1) include the radiofrequency range, the microwave range (300 MHz to 300 GHz), and the ultraviolet light range (750 THz to 3 PHz). An electromagnetic wave is emitted any time electrical charges (i.e., electrons) are made to accelerate. Once an electromagnetic wave is underway, a changing electric field creates a changing magnetic field. The electric field and magnetic field point in directions perpendicular to one another, and the electromagnetic wave propagates in a direction perpendicular to both. The separation between adjacent peaks or valleys of the wave is called the wavelength (λ) and the number of peaks or valleys observed per second at a fixed point in space is called the frequency (f ), expressed in Hertz (Hz; 1 Hz = 1

477

cycle per second). Because the peaks are λ apart and pass a point at the rate of f per second, the velocity v of the wave must be λ × f = v. This general expression is valid for any kind of wave. However, the speed of electromagnetic waves is so central to modern physical theory that it has its own symbol, c. Thus, for electromagnetic radiation, λ × f = c, where c = 3.00 × 108 m/second. The energy of an electromagnetic wave is proportional to its frequency; therefore long low-frequency waves have low energy, and short high-frequency waves have high energy.

Ionizing Electromagnetic Radiation X rays. At the atomic level, two processes produce X rays. One process involves the collision of accelerated electrons with orbital electrons in target atoms. If the energy imparted to the orbital electron is greater than the binding energy of the specific electron shell, the orbital electron is ejected and the atom becomes ionized. As other electrons move to replace the ejected electron (from the outer to the inner shells), characteristic X rays will be emitted and their energy will be the difference of the binding energies of the two different shells. X rays are given a quality factor of 1 and are the benchmark by which all other bioeffects of radiation are measured. In the other process, a continuous spectrum is produced when high-speed electrons encounter nuclei in target atoms. If an electron passes close to the atomic nucleus, it will be attracted by the strong positive charge of the nucleus and its direction of travel will be changed. This process causes a reduction in electron energy in which the energy is dissipated as X rays (the Bremsstrahlung effect). The greatest X ray energy is produced when the high-speed electrons occasionally collide with an atomic nucleus. In such cases, all of the electron energy is given up as X rays. Because any amount of energy may be lost by the electron (up to the maximum electron energy) and converted to X rays, the X rays produced in this process are not of a specific energy but rather are distributed in the form of a continuous spectrum. Gamma rays. Atoms can also be unstable and therefore radioactive because they possess an excess of energy. Gamma (γ) rays are produced during the radioactive decay of an excited nucleus just after a beta decay has occurred. Gamma rays belong to the electromagnetic spectrum and have a characteristic wavelike nature; they are highly penetrating into matter and they interact briefly with material (e.g., tissues) that they encounter. Their reactions are more readily understood if gamma rays are considered as small bundles of energy traveling at the speed of light. A bundle of such energy is called a quantum or a photon.

Nonionizing Electromagnetic Radiation

Figure 23.1. The electromagnetic spectrum

Because the energy of nonionizing radiation dissipates mainly in the form of heat, the chief effect of nonionizing radiation on its target is thermal. The thermal effect depends on

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J.A. Jones and F. Karouia

the intensity of the source, the distance between the source and the target, and the duration of exposure. Another factor is the composition of the target material, as different types of material can absorb incident nonionizing radiation to different extents. The major types of nonionizing radiation are ultraviolet radiation, visible light, and longer wavelength electromagnetic radiation. Ultraviolet (UV) radiation ranges in wavelength from about 100–400 nm. UV radiation of wavelengths shorter than 180 nm, the most biologically active component of UV radiation from the sun, is absorbed almost completely by Earth’s atmosphere. Most of the long-wave component of UV radiation (320–400 nm, known as UV-A) reaches the surface of the Earth and penetrates air, quartz, glass, and water; until recently, its biological effects were thought to be slight [4]. UV radiation of intermediate wavelengths (280–320 nm; UV-B) is completely transmitted through air and quartz but is partially absorbed by the atmospheric ozone layer and is completely absorbed by ordinary window (lime) glass. UV-B significantly influences both the biosphere and human tissues by producing actinic changes, free radicals, and dimerization. Short-wavelength UV radiation (100–280 nm; UV-C) is poorly transmitted through air and quartz and is not thought to be important in terrestrial human disease, although it is bactericidal and fungicidal. UV radiation of wavelengths shorter than 240 nm reacts with oxygen

and nitrogen oxides to produce ozone; UV radiation of wavelengths less than 180 nm can, in the presence of oxygen, oxidize hydrocarbons. Visible light (400–780 nm wavelength) is extremely important for life on Earth. Plants convert visible light to energy via photosynthesis by their chloroplasts. Visible light also constitutes the range of wavelengths that mammalian eyes can detect. Electromagnetic radiation of longer wavelengths is found throughout the universe and is detectable on Earth from all directions. Radiofrequency energies are used extensively on Earth for communications and other purposes such as radar and microwave heating.

Particulate Radiation In the several known atomic and subatomic particle species, the fundamental particles are classed broadly as photons, leptons, and hadrons (Table 23.3) [5]. A photon comprises a single quantum of energy; X and gamma rays are short-wavelength forms of photon or electromagnetic radiation. As noted previously, gamma rays originate from nuclear interactions, whereas X rays originate from electron or charged particle collisions. Photons move at the speed of light (c), are electrically neutral and have no mass, but do have momentum. Leptons consist of three families of particles and their antiparticles, including the electron and electron neutrino (e, νe, –e, and –νe);

Table 23.3. Classification and occurrences of fundamental [particle] elements relevant to space radiation. Class

Charge

Rest energy (MeV)

Lifetime

Typical reaction

Quality factor

Occurrence

Photons X-rays 5 MeV γ rays

0 0

0 0

stable stable

γ → e− + e+ H2O+γ → H⋅+OH⋅

1 0.5

Van Allen belts, solar radiation, electro magnetic cascade (pair production, Brems strahlung), scattered photons (Compton and photoelectric effect), annihilation photons

Leptons Electron/positron

+/−e0

0.511

stable

e− +H2O → H2O−

1.0

+/−e0

105.66

2.2.10–6 s

µ+ →e+ + νe + ν−µ

1.0

Van Allen belts, GCR, solar particle events, induced radioactivity, primary and secondary beams, forward shielding GCR, radiation belts, atmosphere

+e0

938.28

Stable

p → n + e+ + νe

2.0–10.0

0

939.57

925 s

n + 16O → 4 He

2.0–10.0

+/−e0

139.57

2.6 10–8 s

GCR + N, O

1.0

Atmosphere, secondary beams

>10.0

GCR, solar radiation

Positive/negative muon Hadrons Baryons Proton

Neutron Mesons Positive/ negative pion

Van Allen belts, GCR, solar particle events, primary and secondary (δ-ray) beams, radiation therapy Van Allen Belts, solar radiation, atmosphere, shielding leakage, radiation therapy

Atmospheric → n, µ, π HZE Z > 2 elements

Z.e0

A⋅931.5

stable

Fe + DNA → DSB

56

With elementary charge e0 = 1.602⋅10–19C and the atomic mass number A. Abbreviations: GCR, galactic cosmic radiation; DSB, double-stranded [DNA] break. Source: Modified from ICRP 28, 1978.

23. Radiation Disorders

the muon and muon neutrino (µ, νµ, –µ, and –νµ); and the tau and tau neutrino (τ, ντ, –τ, and –ντ). Hadrons are particles that can interact with each other by strong (nuclear) interaction or, at longer distances, through the electromagnetic interaction; two examples include the scattering of protons in traversing matter and energy loss by ionization. Weak interactions can also affect unstable hadrons, causing various relatively slow decay processes such as the beta-decay of radioactive nuclei. Hadrons can be divided into two subgroups, the baryons and the mesons. Baryons such as neutrons, protons, and hyperons are particles with a half spin and a rest mass equal to or greater than the proton. Mesons are a rather large group consisting of eight elements that are distinguished on the basis of their composition of quarks. Mesons consist of strongly interacting particles, e.g. pions, which have integral spin; particles of dosimetric significance have rest masses lower than that of protons. The following sections focus on particle species with biological effects and their dosimetric significance associated with human spaceflight exposures.

Photons The energy of a photon is related to its wavelength as follows: E = (hc) / l, where h = Planck’s constant = 6.6 × 10–7 joule seconds For example, X-ray photons have energy of 1 keV, and gamma rays have energy of 1 MeV. Photons can interact only through electromagnetic interaction. In interactions with matter, the energy of the photon is transferred by collision, usually with an orbital electron in an atom of the absorbing medium. Photons are lightly ionizing and highly penetrating and leave no persisting radioactivity in the irradiated material.

Protons The proton is the nucleus of a hydrogen (H) atom and carries a charge of 1 unit. The mass of a proton is 1,825 times that of an electron. The ionizing track of a proton is straight, as they are not deflected by the less-massive electrons with which they interact, but their direction can be radically altered by occasional interaction with atomic nuclei. The ionization density of protons, for equal energies, is somewhere between that of electrons and that of alpha particles. Photons typically penetrate to several centimeters in air and to tens of micrometers in aluminum at energies in the MeV range [6].

Neutrons Neutrons are of similar mass to protons, but neutrons have no charge (and thus no electromagnetic interaction) and consequently are difficult to stop. Neutrons are classified according to their energy as thermal (< 1 eV), intermediate, or fast (> 100 keV). Neutrons in equilibrium with the environment are called thermal neutrons.

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Pions The most important mesons in dosimetry are the pions. These key hadrons are produced copiously in high-energy interactions. Depending on the medium, pions can decay into muons (e.g., in air and in a vacuum) or simply come to rest (while interacting in condensed matter).

Beta Particles: Electrons and Positrons Beta particles are electrons and their antiparticles, the positrons. With their small size and charge, beta particles penetrate matter more easily than do alpha particles, but they are more easily deflected. Their high velocity (normally approaching that of light) means they are lightly ionizing. Incoming electrons approaching a target atom can interact with either the orbital electrons or the atomic nucleus. They can directly collide with or exert their electrical force on orbital electrons (usually displacing them from the orbit), lose energy, and undergo a change in their direction of flight. Interactions with the atomic nucleus are possible when the electron is near the nucleus; slowing of the electron represents a loss of energy from it, which is produced as X-ray photons. This X radiation has great penetration in tissue and can produce biological damage distant from the track of the electron. This process, in which radiation is emitted by an electron through its collision with an atomic nucleus (the Bremsstrahlung effect) is most important with high-speed electrons and absorbers with high atomic (Z) numbers. Because living tissues consist of mostly elements of low atomic number (hydrogen [H], oxygen [O], nitrogen [N], and carbon [C]), this process is not common in organisms. However, Bremsstrahlung is important in the space environment, where high-energy electrons collide and interact with spacecraft structural elements, which could include materials of higher atomic numbers. Because of the tortuous nature of the electron track, the actual penetration of the electron in matter will be less than the total track length. The distance penetrated is called the range and is measured as the linear distance of a charged particle from the point of origin to its extinction as a charged particle. Ranges in tissue vary from about 6 µm for the beta particle emitted by the 3H radionuclide to about 0.8 cm for the beta particle emitted by 32P.

Alpha Particles Alpha particles are helium (He) nuclei with an atomic mass of 4 and a charge of +2. Alpha particles are the product of radioactive decay of very heavy radionuclides such as radium. Normally of high energy (in the MeV range), alpha particles interact strongly with matter and are heavily ionizing. They give up all their energy in short, straight tracks of exceedingly high ion density. Their penetrance ranges from a few to several microns in soft tissue, and they deposit large amounts of energy over the short distances that they travel. Alpha particles are highly damaging to living cells, and thus their quality factor (Q) is 20.

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Heavy Nuclei So-called heavy nuclei are the nuclei of ordinary atoms of high atomic number whose electrons have been stripped away, thereby yielding a heavy, highly charged particle. Interaction of these nuclei with any absorbing material produces absorber nucleus fragments and secondary particles that are highly damaging to biological systems. In space, the major source of such high-Z, high-energy (HZE) particles is galactic cosmic rays, which produce particles of a charge greater than 2 and can penetrate at least 1 mm of aluminum shielding (the density of which is = 2.6997 grams per cubic centimeter). Iron is the most important of the HZE particles because of its relative contribution to the dose from galactic cosmic rays and because of its high LET value.

Interaction of Radiation with Target Atoms Incoming (incident) radiation can interact with the elements of the components of the space vehicle or the crewmember’s body parts in several ways. It can pass through unperturbed; it can interact with one of the atomic components (nucleus, electron cloud, or other) so as to destroy the incident radiation, the target, or both, which usually produces secondary radiation; or it can interact with atomic components so as to change the target atoms and lose energy as the first step in a chain reaction of radiation events. The processes important in energy deposition can involve three of the four known types of fundamental interactions: nuclear (strong); weak; electromagnetic; and gravitational. (The fourth type, gravitational interactions, has no significant role in ionizing radiation events.) Nuclear (strong) interactions occur only between hadrons. The strongest of the fundamental interactions, nuclear interactions are of extremely short range (10−13 cm) and are responsible for the binding of protons and neutrons in atomic nuclei. Particles decaying through strong interactions are usually the shortestlived, normally decaying in less than 10−20 s. Because of the huge amount of energy used to keep the core stable, nuclear interactions are an important aspect of the biological effects from space radiation. Weak interactions are most important in the decay of particles that have been produced in strong hadronic interactions. Decays caused by weak interactions are the slowest of the three interactions, generally being longer than 10−10 s. Weak interactions do not participate in the various processes resulting in biological damage. Electromagnetic interactions are somewhat better understood than either the nuclear or weak interactions. In the first type of electromagnetic interaction, direct interactions occur between particles with charge or magnetic moment and are of long range. The most important of such direct interactions results from the electromagnetic force between electrostatically charged particles (the Coulomb force). Sequential electromagnetic interactions of a moving charged particle with electrons and atoms in a medium result in the important process of

J.A. Jones and F. Karouia

ionization and excitation loss, in which the largest part of the incident energy is transferred to the absorber. The second type of electromagnetic interaction consists of interactions in which photons are emitted or absorbed. Decays caused by electromagnetic interactions are intermediate between those of strong and weak interactions and are generally on the order of 10−16 s. Details of the interaction of photons with matter are described below.

Photon Interactions In the interactions of photons with matter, the energy of the photons is transferred by collision, usually with orbital electrons in an atom of the absorbing medium. Of the 12 possible processes by which the electromagnetic field of a photon can interact with matter, the processes most relevant to space radiation are the photoelectric process, the Compton process, and the pair-production process. The photoelectric effect involves the collision of a lowenergy photon with an orbital electron. In the most likely event, the photon transfers all its energy to the electron and the photon disappears entirely or is “absorbed” by the electron. As the photon gives up its energy to the electron, some is used to overcome the binding energy of the electron and release it from the orbit and the remainder is imparted to the electron as kinetic energy of motion. As outer electrons fill the vacancy, this energy is released as X-rays. This energy change is balanced by the emission of a photon. In tissue, this type of photon emission has a low energy, typically 0.5 kV, and is of little biological consequence. The process cannot occur with the electron of a particular orbit if the photon energy is less than the binding energy of the orbit. In Compton scattering, in which photons of higher energy interact with matter, only a portion of the energy of the photon is absorbed in interacting with orbital electrons, and the photon is confined, for the most part, to interactions with outer, loosely bound electrons. Part of the energy of the photon is given to the electron as kinetic energy, and the lower energy photon is deflected from its original path. Hence the products of Compton interactions are a scattered, less energetic photon of reduced wavelength; a high-speed electron; and an ionized atom. The ejected electron will travel some distance in matter, producing ionizations along its track; in the course of this travel, the photon may undergo additional Compton collisions before finally expending all of its energy. Thus, photons in this energy range have their energy distributed through repeated Compton interactions (chain reaction) over a relatively large volume of matter and therefore may have significant biological effects. Photon energy can also be exchanged into matter by pair production, which differs from the other two processes in that it occurs exclusively with high-energy photons and in that the interactions are with the atomic nucleus and do not involve the ejection of orbital electrons. Photons with energy higher than 1.02 MeV may interact with the electric field of the highly charged nucleus so that the photon’s energy is converted to

23. Radiation Disorders

mass. The photon changes into two particles, a positron and an electron. Photon energy in excess of the threshold value will be shared as kinetic energy between the two newly formed particles. If no excess energy is present, then the two particles recombine (or annihilate each other) and are converted back to energy. When the threshold energy is exceeded, the positron-electron pair moves away from the point of formation and moves through matter while interacting with and ionizing other atoms in the substance until the excess kinetic energy is exhausted. In this way, energy is ultimately transferred from the photon to matter. Finally, the positrons interact with electrons from the target matter to annihilate and produce two photons, which generate further scattering processes before they leave the system. Which of these three ionization events (photoelectric effect, Compton scattering, or pair production) occurs is a function of the Z of the target nucleus and the energy of the incident photon [7]. In general, the photoelectric effect is dominant for low-energy photons, and pair production is more likely for high-energy photons. Compton scattering is the predominant mechanism for intermediate photon energies of all absorbers [8].

Track Structure Details regarding track structures remain a subject of intense research; agreed-upon conventions include the concepts of tracks having a core and a penumbra (Figure 23.2). Energy from a heavy ion is deposited along the core of the track, where the ionization events produced in glancing collisions are quite dense. The core can be as wide as a few nanometers. Surrounding the core is a penumbra of delta rays (electrons), where the density of ionization events is much less than that in the core but extends for considerable distances. These features allow even a single heavy ion particle to affect many cells in an irradiated tissue, which make the biological effects of

Figure 23.2. Track and energy deposition pattern representative of an HZE particle, such as may be associated with galactic cosmic radiation, compared with an equivalent dose of ionizing electromagnetic radiation

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heavy ions different from those of other radiation phenomena. Deterministic models for calculating the probability of a molecular “hit” along an HZE track, based on frequency distributions of the imparted energy, have been developed for DNA-sized molecules [9].

Neutron Interactions Interactions of neutrons, given their small and uncharged nature, depend on chance collisions with atoms in the materials through which they traverse. Neutrons can penetrate great distances into matter of all types. Fast neutrons lose their energy mainly through colliding with atomic nuclei, which results in ejection of a high-speed proton that is highly ionizing and has high LET. From the viewpoint of shielding, neutrons can be slowed most effectively by materials that include many hydrogen molecules, because fast neutrons transfer more of their energy to hydrogen nuclei than to any other nuclei. Water is an especially effective shield for neutrons [10]. Slow neutrons, in contrast, interact with matter chiefly through capture. Specifically, slow neutrons lose half their energy upon collision with hydrogen, eventually reaching thermal status (i.e., of energy < 1 eV). Thermal neutrons continue to scatter until they are captured by a hydrogen nucleus, forming a deuteron.

Natural Sources of Ionizing Radiation Natural sources of radiation exposures for space crewmembers can be of terrestrial or space-related origin. Natural terrestrial exposures include the background radiation that penetrates from space to the surface of the planet and the radioactive decay of unstable isotopes present in Earth’s crust (e.g., uranium, thorium, radium, and others). These exposures vary geographically and by altitude. Radon and its radioactive daughter products are a common source of radiation that can affect health [11,12]. High radon concentrations appear in clusters throughout Earth, tending to become concentrated in the air in enclosed spaces (e.g., those of basements in buildings with closed circulation). Although radon is not a significant source of radiation exposure in Houston, Texas, where U.S. crewmembers train, radon accounts for more than half the general population’s annual radiation exposure ( 2 mSv/year), with the remainder coming from cosmic, artificial, and other terrestrial sources. Radiation exposures are also higher among members of aircrews in high-altitude flights; the exposure amounts depend on altitude and routes flown. (Exposures from high-altitude terrestrial flight are included in the annual dose monitoring of space crewmembers.) Representative terrestrial radiation exposures and those associated with space flight are shown in Table 23.4. Space radiation sources consist of a variety of particles that have a wide range of energies and both temporal and spatial variations. These variations result from complex phenomena and interactions such as solar particle events and the existence

482

J.A. Jones and F. Karouia Table 23.4. Typical terrestrial and spaceflight–related radiation exposures. Event or limit Exposure from a typical chest X ray Exposure during a typical trans-Atlantic airline flight Skin dose aboard the ISS during solar maximum Skin dose aboard the ISS during solar mininum Exposure from living in Houston, Texas (sea level) Exposure from living in Denver, Colorado (1,524 m [5,000 ft] above sea level) Exposure for an average U.S. radiation worker Exposure from a mammogram Exposure during EVA with excessive South Atlantic Anomaly passes Exposure limit for the U.S. general public Skin dose to a Space Shuttle crewmember during the October 1989 SPE (no magnetic storm, no EVA) Exposure limit for Russian terrestrial radiation workers Dose estimated during the October 1989 magnetic storm, from crew dosimeters aboard Mir Exposure limit for U.S. terrestrial radiation workers Exposure limit for U.S. astronaut in any 1-month period Skin exposure during an EVA during a radiation belt enhancement Annual exposure limit for U.S. astronauts

Radiation dose level 0.0001 Sv (0.01 rem)/exposure 0.00012 Sv (0.012 rem)/exposure 0.0005 Sv (0.050 rem)/day 0.001 Sv (0.100 rem)/day 0.001 Sv (0.100 rem)/year 0.002 Sv (0.200 rem)/year 0.0021 Sv (0.210 rem)/year 0.0035 Sv (0.350 rem)/year 0.0045 Sv (0.450 rem)/event 0.005 Sv (0.500 rem)/year 0.01 Sv (1.0 rem)/event 0.02 Sv (2.0 rem)/year 0.03 Sv (3.0+ rem)/event 0.05 Sv (5.0 rem)/year 0.25 Sv (25 rem)/month 0.4 Sv (40.0 rem)/event 0.5 Sv (50 rem)/year

Values indicate approximate dose to the blood-forming organs unless otherwise noted. Abbreviation: ISS, International Space Station; SPE, solar particle event; EVA, extravehicular activity.

of planetary magnetic fields. For practical purposes, the space radiation environment can be considered in two distinct categories: LEO and deep space. For missions in LEO, such as those on the Space Shuttle, Mir, and the International Space Station (ISS), the two main sources of radiation exposure are galactic cosmic rays and geomagnetospheric (trapped belt) radiation, bands of geomagnetically trapped particles (the Van Allen belts) consisting of mostly protons and electrons. Earth’s geomagnetic field lines protect the planetary surface from incident cosmic and solar radiation by deflecting charged particles, but the belts themselves also create a local hazard for LEO missions. Deep space missions, such as lunar or interplanetary space flights, extend beyond the relative protection of the geomagnetic fields; the primary sources of exposure in deep space missions include galactic cosmic radiation and potential exposures from solar particle events. Secondary radiation can also be produced when the primary particles interact with the materials of the spacecraft, those of its human occupants, or the constituents of the rarefied upper atmosphere in LEO.

The Radiation Environment in Low Earth Orbit Geomagnetically Trapped (Van Allen Belt) Radiation The trapped radiation belts surrounding Earth were first measured in 1958 by large Geiger counters flown aboard Explorer I, the first U.S. satellite; their existence was confirmed by later

Figure 23.3. The Van Allen radiation belts, showing the distribution of trapped protons and electrons along Earth’s geomagnetic field.

measurements on Explorer III and first reported by Van Allen in 1960. The trapped radiation particles in the ionosphere have been used for years to transmit amplitude-modulated and ham radiowaves by reflection over great distances on the planetary surface. The Van Allen belts span two broad regions—the inner belt and the outer belt (Figure 23.3). The inner Van Allen belt begins at an altitude of roughly 300–1,200 km (about 1.5 Earth radii) depending on latitude. The outer belt begins at about 10,000 km (about 5.0 Earth radii) and the upper boundary depends on the activity of the sun; the cap for the main components is about 55,000 km, but trapped belt effects can be evident at altitudes as high as 75,000 km. The “slot” region between the

23. Radiation Disorders

483

belts is thought to be devoid of high-energy trapped particles and is filled with lower energy protons. The trapped particles consist mainly of protons and electrons, but other species (helium, carbon, oxygen) have been observed as well. The most plausible sources of high-energy protons and electrons at lower altitudes are the decay of albedo neutrons produced by nuclear reactions between galactic cosmic rays and constituents of Earth’s atmosphere, particles from the ionosphere, or solar wind. Neutrons that are freed from the nucleus of atoms are unstable and decay with a half-life of 10.6 min (rest) into a proton p, an electron e, and an antineutrino n : nÞp+e+n These protons and electrons are then trapped by Earth’s magnetic field and oscillate back and forth along the magnetic lines of force (Figure 23.4). In each zone, the particles spiral around the geomagnetic field lines, moving towards and away from the magnetic poles, i.e., bouncing between mirror points in the Northern and Southern hemispheres. At the same time, their charge leads the electrons to drift eastward and the protons and heavy ions to drift westward. Interactions of the inner belt with Earth’s upper atmosphere produce colorful aurorae that can be observed in high northern or southern latitudes where the horns of the geomagnetosphere converge. Diffuse luminous forms over large areas of the sky have been observed since ancient times in northern regions, between 15 and 30° from the magnetic pole; astronauts in LEO have also witnessed spectacular auroral phenomena. Auroral emissions result when low-energy electrons precipitate out of the inner radiation zone and, through collisions, excite and ionize atmospheric gases. Solar flares and geomagnetic storms can influence the occurrence and intensity of aurorae. Geomagnetic storms arising from solar events can cause surges in the trapped belts, with the “bowshock” from the solar radiation distorting the magnetosphere; the latitude of the geomagnetic cut-off changes with enhancement of the electron belts associated with these storms. Thus the geomagnetosphere is now known to be highly dynamic. Unfor-

Figure 23.4. The motion of a trapped charged particle along geomagnetic field lines [18]. Used with permission by IEEE

tunately, current means of estimating radiation doses from trapped radiation rely on static models of the geomagnetosphere; because the geomagnetosphere is now known to be highly dynamic, new models for predicting doses are needed to account for the frequent changes in geomagnetic field particle density. Both the altitude and the direction of orbital flight with respect to geomagnetic field lines affect the radiation exposure to vehicles in LEO. An east-west anisotropy of trapped particle fluxes results from particle motion along magnetic field lines. At the bottom of a helical path of a trapped proton, the proton is traveling eastward; at the top of the helix, it is traveling westward. Thus on a spacecraft traveling east, its trailing edge is struck by particles traveling east and its leading edge is struck by particles traveling west. Particles traveling west are emerging from a region where the atmospheric density is greater (lower altitude); the interaction of westward particles with the atmosphere results in a reduction in their flux. The differences in the flux of particles striking the leading vs trailing edges of a spacecraft can be considerable; for example, the doses to the Long-Duration Exposure Facility, an experimental platform that remained in orbit from April 1984 through January 1990, were 2.5 times higher on the trailing edge than those on the leading edge [13]. The bulk of radiation exposure from the Van Allen belts during activities in LEO (e.g., those aboard the Space Shuttle) occurs as the vehicle passes through a region called the South Atlantic anomaly. This region represents a discontinuity in geomagnetic field lines resulting from the roughly 500-km offset between Earth’s geomagnetic center and its geographic center (center of mass). This offset shifts the magnetic axis from the spin axis by 11°, and the subsequent offset of the magnetic field results in trapped particles dipping to lower altitudes relative to the Earth surface. At this mid-latitude location, which extends from about 0 to 60° west longitude (Figure 23.5) [14], the intensity of trapped protons of energies higher than 30 MeV at 161–322 km altitude is equivalent to the intensity found at 1,287 km altitude elsewhere. Measurements made aboard the Space Shuttle indicate that the location of the South Atlantic Anomaly is moving westward at 300 km, or about 0.32, per year and northward drift by 0.16 degrees per year [15]. Spacecraft in LEO make anywhere from 5 to 7 passes through the South Atlantic anomaly during a 24-h period, with each pass lasting 15–20 min. By far the greatest part of the radiation dose received by crewmembers on LEO missions occurs during passage through this region, even though the total time spent there is only about 10% of total orbital flight time [16] (Figure 23.6). The trajectories of low-altitude Shuttle flights generally do not pass through the zone of maximal intensity within the anomaly; high altitude flights do, but they usually spend less overall time in the anomaly [17].

484

Figure 23.5. The South Atlantic anomaly (SAA) is shown, along with the track of an orbiting spacecraft. The actual shape and area vary with altitude. Passage through the SAA accounts for a large fraction of the total radiation exposure in low earth orbit

Figure 23.6. Three dimensional graphic showing radiation absorbed dose as a function of position for 28.5° shuttle flight (STS-31). The effect of transit through the South Atlantic anomaly is clearly seen

Galactic Cosmic Rays In 1912, Hess was the first to identify galactic cosmic rays (GCR). The cosmic rays are present isotropically in space and provide a continuous, low flux component of the radiation environment. In spite of their common name, GCR are not rays per se, but high-energy charged particles moving at near-light speed with large kinetic energies. GCR consists of ions of all elements of the periodic table and are composed of 97–98% baryons and 2–3% electrons. The baryons consist of 83% protons, 13% alphas (4He ions), and 1% heavier particles with energies extending to several GeV (1020 eV) [18,16].). Figure 23.7 shows the abundance and the distribution in

J.A. Jones and F. Karouia

Figure 23.7. Relative abundance and ionizing power of some of the more biologically important HZE nuclei comprising galactic cosmic radiation. As the atomic number increases, it is seen that the relative abundance decreases considerably as compared to hydrogen (H) and helium (He). However, the relative ionizing power increases by several orders of magnitude, giving iron (Fe) a composite biological effect approaching that of the much more abundant H

energy of several important HZE nuclei. GCR originates from sources outside the solar system, most likely associated with supernovae remnants and galactic nuclear events, and consists of charged particles ranging in energy from around 10 MeV to 10 GeV per nucleon. Most of the dose from GCR can be accounted for by the contributions from hydrogen, helium, carbon, neon, oxygen, silicon, and iron. Iron is usually considered the most important of the heavier ions for biological effects because of its abundance and high LET. Iron ions are one thousandth as abundant as protons but have equal dose contribution owing to the Z2 dependence. The HZE particles have very high energies and charges, sufficient to penetrate many centimeters of tissue or other materials to contribute to significant biological or electronic damage. HZE particles are characterized by marked spatial and temporal concentrations of energy deposition around and along their tracks, thereby making the term “mean absorbed dose” inadequate to describe their biological effects [19]. The incoming GCR in our solar system is modulated by the sun’s magnetic field and varies with the solar cycle. The interplanetary (solar) magnetic field strength increases as solar activity increases and typically extends radially outward from the sun to a distance in excess of 10.5 billion kilometers (6.5 billion miles) or 70 times the mean distance between Earth and the sun. GCR entering the solar system are deflected by the more intense interplanetary magnetic fields, an effect that reduces the GCR intensities in the inner heliosphere, where the terrestrial planets like Earth and Mars orbit. The greatest effects are observed for ions of lowest energies. The difference between the extremes of the solar minimum and maximum fluence levels is approximately a factor 2 to 10 depending on the ion energy. For example, intensities of ions with ener-

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gies < 100 MeV/nucleon can vary by as much as a factor of 10, but those with energies > 10 GeV/nucleon typically vary less than 20%. In the inner heliosphere, GCR fluence is at its peak level during solar minimum and at its lowest level during solar maximum. The length of the GCR modulation cycle is now considered by many to be 22 years and not 11 years as previously thought [18]. The solar cycle is driven by changes in the solar dipole movement, which reverses every 10–11 years. The orientation of the solar dipole has a 22-year cycle but results in a bimodal modulation of the GCR (every 11 years). GCR are also deflected by Earth’s magnetic field, which reduces the intensity of galactic cosmic radiation inside the geomagnetosphere. The galactic cosmic radiation received on Earth varies substantially as a function of the level of solar activity and the location on Earth’s surface, with less protection being provided by the geomagnetosphere at the poles and higher altitudes. Figure 23.8 shows the galactic radiation received at varying altitudes up to 36,750 m (120,000 ft) during periods of solar maximum and minimum. This figure illustrates the modulating effect of the sun’s magnetic field on GCR dose. The two curves are based on estimated wholebody dose to an unshielded human at about 40 degrees north latitude. Measurements obtained by deep space probes show similar intensity, suggesting that the GCR component would be similar at other planets, such as Mars. The rigidity threshold for each point inside the magnetosphere, below which cosmic rays cannot penetrate, is called the geomagnetic cut-off. The value is lower for high inclination (high latitude) than for low inclination (low latitude) orbits, which means that space crews are protected more by the geomagnetosphere at the low inclination orbits [16].

Figure 23.8. Measured and calculated radiation dose rate vs altitude for solar minimum and maximum phases

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Solar Flares and Solar Particle Events Solar flares are a major source of radiation concern, possibly the most potent of the radiation hazards encountered in space flight beyond the geomagnetosphere. As noted above, the sun follows approximately an 11-year cycle of variance of emission (the solar cycle) as part of an overall 22-year cycle of solar magnetic activity. Studies of recent solar cycles have determined that the length of the solar cycle over the past 40 years has ranged from 9 to 13 years (mean, 11.5 years). For modeling purposes and for defining the environment for spacecraft missions, the solar cycle can be divided into a 7year maximum phase of high levels of activity and a relatively quiet 4-year minimum phase. The charged particle environment in near-Earth regions is dominated by the activity of the sun, which acts as both a source and a modulator. When solar activity approaches maximum, spectacular disturbances can occur on the solar surface. A solar flare is actually a solar magnetic storm. These storms build up over several hours and can last for several days. The most dramatic and energetic solar particle event (SPE) is called a coronal mass ejection (CME), which occurs in the layer of the sun outside of the photosphere, known as the chromosphere. CMEs are observed as large bubbles of gas and magnetic field, releasing large quantities of plasma into interplanetary space. CMEs lead to large increases in solar wind velocity. The shock wave of the plasma release is associated with particle acceleration and magnetic storms at the Earth. CMEs are poorly associated with flares but, in very large CMEs, both CMEs and flares occur together [20]. Although solar flares cannot be forecast, the physical evidence for an impending flare can be observed on the solar disc. As the flare builds, an increase in visible light first takes place, accompanied by disturbances in Earth’s ionosphere, which are probably due to solar X rays. The principal problem, though, arises from the high-energy particles (mostly protons) that are produced during the flare, which may generate an SPE. The energy of these protons can range from about 10 MeV–500 MeV per nucleon. The flux can be quite high, resulting in a potentially lethal dose for unprotected space crews outside LEO. The size of an SPE can vary by many orders of magnitude. The location of an SPE flare on the sun relative to the position of Earth or space vehicle is one factor that affects the magnitude of the exposure. Another factor is association of an SPE with a CME that will affect the particle distribution zone and thus the likelihood of interaction with the space vehicle trajectory. The mean rise time of the six largest SPEs in solar cycle 21 (1971–1987) was 40 h for particle energies ≥10 MeV; the minimum rise time was 10.5 h. One of the largest SPEs ever measured, that of August 4, 1972, had a time-integrated intensity of 5 × 109 particles/cm2 with energies ≥≥30 MeV and 1.1 × 1010 particles/cm2 with energies ≥10 MeV. SPEs can affect orbiting satellites, including telecommunications, navigation, and military assets, as well as the communications network for crew operations in LEO. Disruption of

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satellite services as well as hardware failures can be expected in extreme cases. Energy spectra of SPE can also vary considerably. In addition to protons and alpha particles (helium nuclei), ions with higher atomic numbers have been observed during SPEs. Their spectra are relatively soft and their intensities significantly lower. Some SPEs have protons with energies high enough to penetrate to the ground where they (or their secondaries) can be measured. The largest event ever observed by ground measurements took place on February 23, 1956, in which levels measured were 3600% above background [21]. The anomalously large solar flare of August 1972 occurred within the initial launch window considerations of Apollo 16 and 17. Calculations indicate that astronauts exposed to such a flare during flight might receive a depth doseequivalent of around 50 rem (0.5 Sv)—a dose sufficiently close to clinical thresholds for acute radiation exposures to raise major concern. On October 19, 1989, a solar event occurred at the end of Space Shuttle mission STS-34. Monitoring equipment aboard the shuttle confirmed an enhanced radiation environment and led to the discovery of a secondary belt formed by effects on Earth’s geomagnetosphere. Dose calculation from models in use at the time demonstrated the shortcomings inherent in these older tools; efforts are underway to improve the accuracy of models used for dose projection calculations. Estimates of organ doses from these events conclude that either could have been life-threatening to crews in interplanetary space (i.e., outside of the protective geomagnetic fields [22]. Four anomalously large events have taken place during the last three solar cycles that could have produced lethal exposures to crews in interplanetary space. In the worst-case scenario, doses as high as 10 Gy could have been received over a few days, which would result in death in a short interval [16]. These events underscore the need for careful monitoring of the space radiation environment during all aspects of crewed operations in LEO and beyond, and demonstrate the need to account for the influence of solar activity on mission planning. Exploration-class missions such as those to Mars will require that the spacecraft have monitoring equipment on board that can determine radiation exposure risks from solar activity autonomously from Earth because particles from the sun will travel in spiral trajectories along solar magnetic field lines and may impact the spacecraft without affecting Earth or vice versa. The detection and warning system should be robust enough to provide adequate warning to the crew for their protection and safety, allowing them to take refuge in a radiation-hardened storm shelter.

The Radiation Environment Outside Low Earth Orbit For crewed missions to the Moon, Mars, and Earth-moon and Earth-sun Lagrangian points, all beyond the protection of the geomagnetosphere, the major radiation component is exposure to

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the highly damaging GCR. Additional radiation beyond the normal background dose could be received during SPEs, which pose a greater threat further away from LEO. For the first time in the U.S. human space program, crewmembers on an exploration-class mission will be approaching a significant portion of their established career exposure limits during a single mission. Factors to consider when evaluating radiation exposure on other planetary surfaces during exploration-class missions include secondary shielding resulting from the planet’s mass, atmosphere, and geomagnetosphere as well as the incident radiation’s interaction with planetary regolith. In the case of the moons of the giants Jupiter and Saturn, the trapped particle radiation field produced by the planet itself can be even more important than the local geomagnetosphere around the individual moon.

Secondary Radiation One of the principal problems in developing effective shielding for the occupants of space vehicles concerns secondary radiation. Whenever primary particles strike a spacecraft’s shielding and structural material, secondary radiation is produced. Incident electrons and positrons are stopped by the vehicle wall, which subsequently emits secondary gamma rays (Bremsstrahlung). Protons and heavy ions may hit a target in the wall or within the cabin, or they may pass through the structures. Wherever a target is hit, these particles produce characteristic showers of secondary particles. When a primary particle with an energy of 300 meV or more hits a nucleus of target material, secondary particles and electromagnetic radiation are generated in great variety. Secondary radiation, most importantly neutrons, is also produced when the primary incident radiation strikes components of the human body directly. The secondaries produced from these interactions may have the greater contribution to the total dose owing to their significant biological effect, where Q ranges from 2 to 20.

Neutrons Neutrons, inherently unstable entities with a half-life of roughly 11 min, arise locally from interactions of charged particles with matter within the spacecraft or Earth’s atmosphere. The concern for crewed space flight is high-energy GCR interacting with spacecraft structural elements and producing secondary neutrons. As described above, neutrons are uncharged particles that affect nuclei by direct collision, with significant biomedical implications. Neutrons can penetrate deeply into matter, including biological tissues. Fast (high-energy) neutrons lose energy mainly via collisions, whereas slow (low energy) neutrons lose energy mainly via capture. In early human space flight programs, neutrons were not considered a significant component of the overall dose to crews. The passive detectors flown during previous crewed missions were relatively insensitive to high-energy neutrons,

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providing data only on low-LET charged particles. More recent calculations and occasional measurements onboard the Space Shuttle and Mir indicate that the contribution of secondary neutrons could be significant and should be included in assessing the radiation risk to astronauts. Badhwar and others [23–26] measured neutrons on several Space Shuttle and Mir missions with the use of metal foils, nuclear emulsions, thermal means, Bonner spheres, and bubble detectors. Estimates by Reitz and others of fast neutrons on the Space Shuttle and Mir [27–29] have since been confirmed by measurements from Japanese and European investigators using a variety of different instruments and form the basis for the belief that neutrons contribute 15–40% of the dose equivalent from charged particles. Because standard thermoluminescent detectors are inefficient for detecting high-energy neutrons, up to half of the dose may be unmeasured, making the true neutron contribution 30–85%. Tissue-equivalent proportionate counters efficiently measure low-energy neutrons. Highenergy (>1 MeV) neutrons account for most of the H, with almost 50% coming from > 10 MeV neutrons. Neutron H increases by a factor of 2 as shielding increases from 20 to 40 g/cm2 aluminum equivalent. Notably, the 1- to 14-MeV neutron-to-charged-particle ratio in the least shielded area of Mir at the height of the last solar maximum, occurring at the end of the 1990s, was 5–8%, whereas at solar minimum it varied from 14% to 60%. These findings again reflect the influence of increased GCR associated with solar minimum on overall radiation fluence [30]. New evidence regarding the relative contribution of secondary neutrons to astronaut equivalent dose rates has led to the development of new detectors and dosimetry methods to support ISS operations. Crew dosimeters sensitive to secondary neutrons in the 0.1 to 200 MeV energy range are being provided; CR-39 plastic track nuclear detectors are currently the best candidate for this task. Radiation transport models for estimating organ doses from secondary neutrons in complex spacecraft are also being developed and validated.

Nonionizing Radiation The entire electromagnetic spectrum emanates from the sun and is minimally filtered when encountering objects in LEO. Ultraviolet, other low-energy-spectra visible light, and infrared will strike the vehicle and crew for at least 45 min of each 90-min orbit. Heating from infrared requires that cooling systems be included in the vehicle and in the extravehicular activity (EVA) suits. Crewmembers can be exposed to ultraviolet light during EVAs through the visor assembly of the helmet or from solar rays penetrating the vehicle windows. A 1997 study [31] in which dosimeters were used to quantify the exposure of a Mir crew to ultraviolet light showed that the dose to the crewmembers was negligible–—except when they passed by one of the windows, as the dosimeter behind

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the quartz window received significant ultraviolet doses, predominantly from UVB and C.

Artificial Sources of Radiation in Space Low-level ionizing radiation may arise from medical, investigational, and operational sources. Astronauts are required to undergo certain radiographic procedures to rule out disease states as part of the routine monitoring of their health (e.g., mammography, dental bite wing X rays). Crewmembers may also undergo radiographic evaluation for medical conditions that arise during training. The doses associated with these procedures are tracked and maintained as part of the crewmembers’ medical records. Astronauts may also participate in science experiments that involve exposure to radioactive agents. Strict flight rules dictate that such agents be contained and shielded to the extent required to minimize possible exposures. Although some inflight studies of animal and plant physiology may involve use of radioactive tracers, studies of human physiology mostly use stable (nonemitting) isotopes. Several on-board instruments can contain small amounts of radiaoactive materials; examples include smoke detectors (61.2 µCi of 241Am) and hydrazine monitors (10 mCi of 63Ni). The Soyuz descent module uses a gamma ray altimeter with 8 µCi of 137Cesium for calculating altitudes and triggering the braking rockets during the final landing phase. Exposure to crew is minimal, at 0.001 Gy (0.1 rad)/day at the source, 0.0005 Gy (0.05 rad)/day at 1 m from the source, and < 0.0001 Gy (0.01 rad)/day at 2 m from the source; the average extra dose to Soyuz crewmembers is about 0.0005 Gy (0.05 rad)/day when they occupy that vehicle. Despite this low dose rate, crews are advised not to sleep in the Soyuz vehicle during normal operations, when the ISS is docked to the Soyuz. Finally, because astronauts actively participate in high-performance aircraft flights during their training, the time spent above 7,620 meters (25,000 ft) is also tracked. At present no crewed space vehicles use nuclear power for propulsion or for power generation. However, future exploration-class missions may require a nuclear power source for propulsion as well as for generating power on a planetary surface. The inclusion of nuclear power aboard spacecraft will require meticulous attention to shielding, crew dosimetry, and mission planning to maintain and operate such a system, as is the case for nuclear naval vessels. Although explosions from nuclear weapons at orbital altitudes are thought to be unlikely in the post Cold War era, this possibility has driven the inclusion of high-rate dosimeters aboard spacecraft since the early years of crewed space flights. Artificial sources of nonionizing radiation, e.g., from radiowaves and microwaves, are also a concern in current operations. Spacecraft use much of the electromagnetic radiation spectrum for communication, spacecraft navigation,

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reconnaissance, and scientific experimentation. The Space Shuttle and ISS use ultrahigh frequency systems for communications between vehicles or between EVA crewmembers and the vehicle. The main operating frequency of such systems is in the vicinity of 400 MHz, and their maximum power output is 6.76 W. The wireless instrumentation system transmits at 915 MHz, with a peak output of 0.316 W (25 dBm). S-band and Ku-band antennae are used in Space Shuttle and ISS communications by means of the Tracking Data and Relay Satellites network. The S-band antennae typically broadcast and receive in the range of 2,200–2,300 MHz, with peak power output of 40 W and power density of 10 mW/cm2; the Ku-band transmits and receives in the range from 15.25 to 17.25 GHz, with a power output of 20 W and power density of 10 mW/cm2 (240 V/ m). The possible consequences of exposure to these forms of nonionizing radiation are unknown at this time owing to the scarcity of high-quality dosimetry and the complexity of isolating and identifying environmental factors. Sources of artificial ultraviolet radiation that may be present aboard spacecraft include antibacterial lamps and forms of radiation treatments that might be used to compensate for vitamin D3 deficiencies. The chief concern in ensuring the safe use of ultraviolet radiation involves selecting radiation of spectral energy that maximizes the putative therapeutic effect while minimizing the risk of dangerous side effects. Finally, laser light sources are flown on space vehicles as components of scientific instruments and range-finding equipment. The relative danger of these radiation sources is a function of the power and energy densities of the laser source as well as the wavelength and frequency of the laser light, because different human tissues absorb various wavelengths to different extents. The main hazard from the kinds of lower-level laser radiation likely to be used onboard a space vehicle is to ocular structures.

Space Weather Space weather describes the processes, influences, and effects of the space radiation environment and is largely driven by solar activity. Space weather is every bit as dynamic and potentially violent as its atmospheric analog and is on a much more massive scale of distance and energy. Understanding the sun’s inherent activity as well as its influence on GCR and Earth’s trapped radiation belts is crucial for developing useful methods of space weather forecasting and prediction. The need to do so pertains to both human space flight and to the sensitive electronics aboard unmanned spacecraft. NASA flight rules define a geomagnetic storm as a change from normal levels in the horizontal component of the magnetic field at Earth’s surface, as measured by magnetometers at Boulder, Colorado. Space weather monitoring personnel stationed at Mission Control during crewed space flights notify the Crew Surgeon and Flight Director if defined thresholds for

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major X-ray flares, SPE, or geomagnetic storms are exceeded. Actions to be taken in the event of the ensuing radiation alert or contingency condition might include terminating or replanning an EVA, changing the flight orientation of the vehicle or platform, or, in a major event, directing the crew to take shelter in the most heavily shielded structural elements. The alert is terminated when three consecutive readings show a downward trend [18].

Biological Effects of Ionizing Radiation Most of the current knowledge of the biological effects of radiation on humans has been derived from four sources— occupational exposures in industry and research settings, exposures from the detonation of nuclear weapons, exposures from use of radiation as medical treatment, and studies of animal models. Both the Russian and U.S. space programs have undertaken long-term assessment of space crewmembers for evidence of stochastic and deterministic effects of space radiation, but relatively few findings have been obtained and the data are far from mature. The epidemiologic data from the first three of these sources have served as a starting point for assessing the risks associated with of space flight–acquired radiation exposure.

Occupational Exposures Both standard occupational exposures and mishaps have resulted in a wide range of doses and dose rates. During the early part of the 20th century, radium dial workers, who tipped brushes on their tongues and ingested 226Ra to a dose equivalent of 0.5 rem (0.005 Sv) per week, showed increased incidence of bone cancer. Uranium miners were shown to have increased mortality from pulmonary neoplasms and fibrosis from chronic inhalation of radon and radon daughter molecules [32]. The excess relative risk of leukemia per Sievert of exposure in U.S. and U.K. nuclear workers averages 1.7 (95% confidence interval [CI], 0.5–9.0) as compared with 6.2 (95% CI, 2.7–13.8) for male atomic-bomb survivors over the age of 20 [33]. Nuclear power accidents, such as those at JCO Tokaimura, Japan in September 1999 and Chernobyl, Ukraine in 1986 have resulted in population exposures that are being carefully followed. One study has concluded, for example, that the radioactive iodine generated in the Chernobyl accident has resulted in an increase in thyroid cancer among children in neighboring Belarus [34]. Major epidemiologic studies of large numbers of people exposed to radiation from various sources are ongoing and provide data that may be extrapolated to the space flight environment. Typically, however, such exposures involve radiation of a single type and energy spectrum; the space flight environment, by contrast, involves multiple types of radiation and a wide range of energy spectra.

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Nuclear Weapons

Exposure to radiation in utero causes developmental impairment. In addition to noted reductions in head growth, height, and body weight, radiation causes a dose-dependent decline in intelligence quotient of at least 5 points, with the most severe effects noted if the fetuses were irradiated between 8 and 15 weeks menstrual age. Otake and Schull [35] reported mental retardation rates of 40–50% per Gy (100 rad) among fetuses irradiated during this period, although they could not exclude a threshold in the 0.1- to 0.2-Gy (10- to 20-rad) range. The ICRP has taken the position that irradiation during this particularly sensitive period causes a linear reduction in intelligence quotient of 30 points per Gy [36]. Radiation-induced (excess) cancer risks for crewed space activities can be estimated based in part on results of followup studies of atomic bomb survivors [37]. Projected risks based on the Japanese data are appropriate for the fraction of total risk attributable to low-LET geomagnetically trapped protons because the Japanese experience primarily involved low-LET radiation exposure. An excess risk of leukemia was one of the earliest delayed effects of radiation exposure seen in the victims of the atomic bombs dropped on Hiroshima and Nagasaki in August 1945. Now, more than 50 years after these events, this excess is widely seen as the most apparent longterm effect of radiation. As of 1990, 176 of the 50,113 survivors in the Life Span Study who had had significant exposures (> 0.005 Gy [0.5 rad]) had died of leukemia, and about 90 of these deaths were attributable to radiation exposure. This excess was especially apparent because much of it occurred during the first 10–15 years after the exposures. Unlike the dose-response curves for other types of cancer, the leukemia dose-response curve seems to be nonlinear, with low doses being less effective than would be predicted by a simple linear dose response. With regard to other types of cancer, 4,687 people in the Life Span study had died of nonleukemic forms of cancer by 1990, which represents an excess of 381 deaths as compared with an estimated of 4,306 deaths in a population that had not been exposed [38]. A comparison of excess deaths in the Life Span Study population between 1950 and 1990 according to radiation dose is shown in Table 23.5; the numbers of deaths sorted by type of cancer are shown in Table 23.6 [38].

Although the use of atomic weapons constitutes a grim wartime event, the information available should be used to benefit those in radiation occupations or with inadvertent exposures. The Radiation Effects Research Foundation (formerly the Atomic Bomb Casualty Commission) is a binational organization formed to evaluate the medical effects of radiation on humans and on diseases affected by radiation. Laboratories in Hiroshima and Nagasaki are dedicated to studying the acute and chronic effects of the atomic detonations in those cities. Epidemiologic tracking of the survivors has allowed the relationship between estimated radiation dose and development of leukemias and solid tumors to be studied. The acute, annual, and career radiation exposure limits recommended by organizations such as the International Commission on Radiological Protection (ICRP) and the National Council for Radiation Protection and Measurement (NCRP) are largely based on findings from this cohort of acutely exposed individuals. Weapon-related exposures represent large single-point events and thus do not correlate directly with the more protracted exposures encountered in space flight. However, scaling factors and other corrective methods can be applied to make meaningful inferences with regard to spaceflight risk. The characteristic spectrum of symptoms after acute irradiation has been ascertained largely through interviewing more than 100,000 atomic-bomb survivors. The highly subjective nature of survivor recollections may have biased the recorded data regarding early effects. Nevertheless, among the acute radiation symptoms recalled by survivors, epilation (hair loss) is regarded as the most reliably reported as compared with other symptoms such as vomiting, bleeding from the gums, diarrhea, and purpura. In general, acute radiation symptoms do not appear at low-dose radiation exposures, giving support to a threshold dose concept (i.e., that of deterministic effects); that is, below a certain radiation dose, no acute symptoms occur. This is in contrast to the linear dose-response relationship demonstrated by malignant diseases, one of the most well-established late effects of radiation exposure. By examining the fate of family members who were in the same houses during atomic bomb explosions, it has been estimated that doses of 2.7–3.1 Gy (270–310 rad) to the bone marrow caused death within 2 months in some 50% of cases. Estimates of the LD50/60 (death of 50% of the exposed population within 60 days) generated by the United Nation’s Scientific Committee from information on atomic bomb survivors, accidental radiation exposure cases, and radiation therapy studies suggest that the LD50/60 is 2.5–3.2 Gy (250–320 rad) to the bone marrow when little medical assistance is available, and about 5 Gy (500 rad) when extensive medical care is provided. Animal studies have shown that administering various growth factors to stimulate surviving blood-forming stem cells in bone marrow facilitates more rapid recovery from radiation injury, and the lives of 100% of the exposed population can be saved after a whole-body dose of up to about 10 Gy (1000 rad).

Medical Exposures Radiation has been used for diagnostic and therapeutic purposes for many years, mostly in the form of 60Cobalt, linear accelerators, and injected and ingested radionuclides. Some of these therapeutic modalities turned out to be more hazardous than efficacious. As an example, patients with ankylosing spondylitis treated with external beam x rays were found to be at slightly increased risk (relative risk, 1.5–1.8) of developing lung cancer or other solid tumors between 8 and 20 years after therapy; surprisingly, the relative risk declined thereafter. Women given pelvic irradiation for metropathia hemorrhagica showed a greatly increased risk of developing bladder cancer

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Table 23.5. Cancer deaths between 1950 and 1990 among life span have an RBE of 1.0–1.1, similar to that of 2-MeV x- and study survivors according to dose. γ- rays. In long-term follow-up (at 20–24 years), these animals 0.005–0.2 Sv 0.2–0.5 Sv 0.5–1Sv >1 Sv No. deaths from leukemia Estimated excess deaths Percent attributable to radiation No. deaths from all other cancers Estimated excess deaths Percent attributable to radiation

70 10 14% 3,391 63 2%

27 13 48% 646 76 12%

23 17 74% 342 79 23%

56 47 84% 308 121 39%

Source: Modified from Pierce et al. [38]. Used with permission.

Table 23.6. Cancer deaths between 1950 and 1990 among life span study survivors according to cancer site. Type of cancer Stomach Lung Liver Uterus Colon Rectum Pancreas Esophagus Gallbladder Breast (female) Ovary Bladder Prostate Bone Other solid tumors Lymphoma Myeloma

Total No. deaths 2,529 939 753 476 347 298 297 234 228 211 120 118 80 32 948 162 51

Estimated excess deaths 65 67 30 9 23 7 3 14 12 37 10 10 2 3 47 1 6

Evidence for effect Strong Strong Strong Moderate Strong Weak Weak Strong Moderate Strong Strong Strong Weak Moderate Strong Weak Strong

Source: Modified from Pierce et al. [38]. Used with permission.

(relative risk, 3.02), but the vast majority of these cancers were not observed until more than 20 years after treatment [39]. The more recent use of conformal radiation treatment for malignancies has tipped the balance of the risk-benefit comparison to favor benefit; however, the risk of developing certain radiation-induced malignancies may be increased in long-term survivors.

Studies of Animal Models The response to radiation differs among species, as it does among cell types. Animal models used for studying the bioeffects of radiation have included rabbits, mice, rats, and other mammalian and nonmammalian species, including dogs and monkeys flown aboard the Russian Bion satellites. Many of the bioeffects are thought to be universal responses to radiation, whereas others are thought to be specific to cell type or species. Studies conducted jointly by the U.S. Air Force and NASA from 1963 to 1969 looked at the RBE of various types of space-associated radiation exposures on rhesus monkeys and mice [40]. High-energy protons (>138 MeV) were found to

showed significant numbers of lenticular opacities from 55MeV protons at 1.25 Gy (125 rad), but these findings were consistent with other studies of low-LET radiation. The same is true of the induction of solid tumors and leukemia, where the observed extent of life-shortening was similar to that resulting from similar doses of low-LET radiation and the extent of lifeshortening and cancer induction depended on dose and not on proton energy level. Other animal studies indicate that longterm exposures to penetrating low-LET radiation result in less risk of cancer than acute exposures. Animal studies have also been useful for determining the RBE of various heavy ions for producing deterministic effects such as cell killing in the gut, testis, and bone marrow. Such values range from 2 to 3 for cell killing, peaking at an LET of 100 to 200 keV/nucleon. Data on the peak RBE for inducing Harderian gland tumors in mice was 30 at 100 keV/nucleon, but no decline in effect was noted beyond an LET of 100. The RBE for cataract induction by heavy ions in rats may be much higher than for cell killing, perhaps as high as 40–50 [41–43]. Significant uncertainty still exists in the accuracy of extrapolating results of animal studies to humans.

Acute Cellular and Molecular Effects of Ionizing Radiation Cellular responses to radiation involve a broad spectrum of structural and biochemical changes. Cytoplasmic responses to radiation include swelling (increased free water), vacuolization, and disintegration of the mitochondria and endoplasmic reticulum. Nuclear changes include swelling and distortion of the nuclear membrane and disruption of the chromatin materials. Factors that that can influence the response of a cell to exogenous radiation exposure include the cellular environment, the presence or absence of radiation sensitizers or protectors, and the cell’s natural defense systems. A cell’s sensitivity to radiation is influenced by its stage in the cell cycle, its state, and the component of the cell that was exposed. With regard to cell-cycle stage, cells are generally most sensitive to reproductive death when irradiated during M phase (mitosis); to chromosomal damage and division delay when irradiated during G2; and to problems with DNA synthesis during early G1. The most resistant stages are during late S phase and during G0. The timing of the irradiation also affects the progression of the cell through the cell cycle in a way that reflects the normal rate of cell division; for example, low-dose radiation stops slowly dividing cells—but not rapidly dividing ones—in G1. With regard to cell state, cells irradiated in vitro are more radiosensitive than those irradiated in vivo [2]. Amplification of the expression of specific oncogenes (e.g., ras, especially when myc is co-expressed, or raf) or the presence of radiosensitive or radioprotective genes can confer radioresistance to cells [44]. With regard to cellular components, the nucleus is more sensitive to both low- and high-LET radiation

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than the cytoplasm. Redundancy in numbers of mitochondria may confer radioresistance; lymphocytes, for example, contain few mitochondria and are exquisitely sensitive to irradiation. Another factor affecting cell death or inactivation from radiation is the oxygen tension in the cellular environment; many cells are more sensitive to irradiation under normoxic conditions as compared with hypoxic environments [32].

Mechanisms of Damage from Ionizing Radiation The main cellular effects of ionizing radiation relate to specific ionization events that produce molecular alterations. Space radiation, as opposed to typical terrestrial sources, contains a much greater proportion of particulate radiation. Of most concern are HZE, high-LET radiation particles, which produce dense ionization tracks. Cells exposed to radiation have one of four fates: (1) complete recovery to the preradiation state; (2) partial recovery with repair of injury but with diminished functionality; (3) mutations caused by incomplete or erroneous repair; or (4) cell death. Incident radiation injures cells both directly and indirectly. Approximately one third of biological damage from low-LET radiation is thought to be from direct ionization, with the remainder incurred from indirect damage. The vast majority of damage from high-LET radiation results from direct ionization [2]. The following sections outline mechanisms by which radiation directly and indirectly induces genetic damage (i.e., damage to a cell’s DNA), followed by a brief review of mechanisms of additional, epigenetic damage.

Direct DNA Damage Ionizing radiation can penetrate the cytoplasm of a cell and interact with the molecularly rich cell nucleus, which is packed with DNA, histone proteins, and nuclear matrix. The severity of the injury depends on the track, the cross-section, and the LET of the particle. When electromagnetic or particle radiation strikes DNA and other macromolecules directly, molecular damage occurs in the form of ionization and possibly breaks. The hydrogen bonds (including hydrogen-hydrogen [H-H] and sulfhydryl [S-H]) are the weakest in the macromolecular structure and are therefore the most vulnerable to disruption by ionizing radiation. Breaks in these bonds lead to changes in secondary and tertiary structure of proteins and enzymes, which lead in turn to decreases or loss of functional activity. Cellular proteins may express alterations in their viscosity, conductivity, and other physical properties. The side chains of amino acids are the most radiosensitive portions of proteins. Large macromolecules with repeated identical units often show disruption in the same bond, suggesting that the energy absorbed in the molecule can be transmitted down the molecular chain to the weakest bond. Histone proteins may lose their associations with DNA, and the secondary and tertiary DNA structure may be altered with disruption of the hydrogen bond linkage between base pairs; both effects can lead to errors in transcription and translation.

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Molecular disruptions in the DNA molecule are characterized as strand breaks (single or double), apurination, or deamination. Strand breaks often occur between a sugar (ribose) and a phosphate, although these breaks often will rejoin if the broken end is not peroxidized by a reactive oxygen species. Radiation of energy as low as 30–40 eV can produce a break in one of the two strands of DNA (a single-strand break [SSB]), and an exposure of a cell to 0.01 Sv (1 rem) can be expected to produce 10–20 SSBs. Double-strand breaks (DSBs) can occur when two SSBs are juxtaposed or when a single densely ionizing particle (HZE with > 500 eV) produces a cluster of ionization within a span of about 20 Å. High-LET radiation, at a given energy, will induce more nonrejoining strand breaks than will low-LET radiation, and nonrejoining strand breaks are more likely to lead to cell death. Another mechanism of DNA damage is crosslinking, irreversible binding between chemically active loci produced in adjacent molecules or within the same molecule. Base-pair dimerization, a type of cross-linking from an ionizing exposure, can easily produce a downstream mutation. Radiation-induced SSBs between a sugar and the phosphate group of the nucleotide can readily be repaired with high fidelity, since the template for the nucleotide is preserved. Occasionally, if SSBs occur in adjacent sister chromatid regions, the nicked DNA segments undergo a process called sister chromatid exchange. However, when an ionization event leads to a DSB, the template is lost and errors in repair are much more likely, producing a point or segmental mutation. Such injuries or mutations can be lethal if the DNA damage is severe enough to cause the loss of function of one or several key proteins, or if repair is not possible and the chromosomal elements beyond the break are lost. Sometimes DSBs can be removed by a process similar to sister chromatid exchange that preserves the broken chromosome, but such repair may place genes under different control mechanisms (as can happen with genetic recombination), which also can lead to changes in cellular activity and phenotype. Single hits within chromosomes are more likely to be repairable by normal cellular mechanisms, but multiple hits in the same region of a chromosome may require more complex repair mechanisms or may not be repairable at all. Depending on the path of the ionizing particle, multiple damage sites can occur in proximity to one another. If the sites are located less than 20 Å apart, the ionization event is usually lethal to the cell, whereas sites separated by more than 80 Å are usually survivable but are likely to lead to mutations. HZE exposure tends to produce more complex nuclear biochemical events than those produced by low-LET radiation. The complex events can lead to “unfaithful” or nonrejoining strand breaks and clusters of injury (e.g., base damage, SSBs, DSBs). Specific postexposure chromosomal aberrations observed in cytogenetic analysis of lymphocytes include inversions, dicentrics, fragments, rings, and translocations (Figure 23.9). If the cell survives the damage event, several downstream effects may occur. Translation errors can be seen if a DSB occurred in a coding region of the DNA, leading to mutated

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Figure 23.9. Chromosomal aberrations resulting from radiation damage to DNA. Such changes are representative of lymphocyte gene anomalies assessed for radiation dosimetry

or truncated proteins with aberrant or lost function and subsequent alterations in phenotype. Mutations can also result in replication errors during mitosis. Errors in replication, if they occur in a sensitive region of the genome, can cause further mutations in daughter cells through rearrangements; such errors are the root of potential carcinogenesis in these cells. In addition to overt injury, incidental radiation exposure can induce genomic instability. This can be produced with as little as 0.20.3 Gy (20–30 rem) of high-LET radiation in mammary and other cell lines. [44,45] In one experiment, transplanted bronchial epithelial cells that were irradiated with 0.3 Gy of 56 Fe (< 1 particle/cell) and 6 months later irradiated with 1 Gy of X rays developed tumors upon implantation in 3 of 7 animals; no tumors formed when cells had been irradiated with either 0.3 Gy of 56Fe or 1 Gy of X rays immediately before transplantation [46]. These results imply that exposure to as little as a single HZE particle may render a cell genetically more sensitive or unstable for months and thus at greater risk for subsequent initiation events. The mechanism for highLET–induced genomic instability is unknown, but genetic instability may account for the carcinogenic side effect of such irradiation. This condition seems to persist for several generations of cellular offspring after exposure. However, cells transformed by high-LET radiation cannot be distinguished phenotypically from those transformed by low-LET radiation.

Indirect DNA Damage Ionizing radiation can interact with other parts of the cell besides the nucleus. The nucleus-to-cytoplasm ratio of cells

Figure 23.10. Molecular pathology associated with oxidizing species production

varies from 1:5 to less than 1:1 depending on the lineage of the cell. For the vast majority of cells, the probability of radiation interacting with cytoplasmic organelles and molecular species is statistically much larger than with nuclear species. Damage to either the cytoplasm or the nucleus from ionizing radiation can result not only from direct damage but also from secondary reactive species. Radiation exposure results in energy being released into cellular materials, causing excitation of electrons or secondary ionization. In addition to the formation of ions, radiation can cause the loss of an electron from an atom or molecule resulting in an unstable, highly reactive entity called a free radical. The unpaired outer shell electron of these electrically neutral radicals causes them to react very quickly with one another or with stable molecules. Because the human body consists of about 70% water, such events primarily involve aqueous products, particularly the highly reactive hydroxyl (OH*) and peroxy (HO2*) radicals. Reactive species such as the oxidizing agents OH* and HO2* and the reducing agent H* generated anywhere in the cell can propagate and disseminate, interacting with various parts of the cell such as cytosolic proteins and other macromolecules, membrane constituents such as lipids, and nuclear contents, including DNA (Figure 23.10). The base structures are particularly susceptible to direct damage by hydroxyl radicals, and the pyrimidine bases are almost twice as radiosensitive as are the purines. In macromolecules, radicals can cause hydrogen bond breakage, molecular degradation or breakage, and intra- and inter-molecular cross-linking [8]. Hydroxyl species produced

23. Radiation Disorders

by γ-irradiation can induce DNA–protein cross-links, which tend to occur mostly in areas of the genome that are being actively transcribed [47]. Components of these links, known as DNA adducts, can be quantified as an indication of DNA damage from chemical or radiation exposure.

Epigenetic Effects As noted above, reactive species can be generated anywhere in the cell and can propagate and disseminate, eventually interacting with chromosomal elements, including the DNA itself. Such interactions can create DNA adducts and methylation (hypo- or hyper-) events, which do not mutate the structure of the DNA but change the pattern of expression of the affected genes. Epigenetic effects arise from one of three mechanisms: (1) from modifications of nongenetic nuclear proteins (histones or nonhistones) that affect transcriptional or translational activities or prolong the activity of protein kinases; (2) from binding between carcinogens and tRNA, which can change amino acid codons, or between carcinogens and RNA polymerases, which can increase the expression of enzymatic proteins; and (3) from the action of cocarcinogens such as hormonal transcription factors. Membrane Damage Another source of cell damage from radiation is its effects on cell membranes, chiefly through lipid peroxidation. Reactive oxygen species and other radicals can attack the carboxyl, ester, amide and phosphate ends of membrane phospholipids, producing lipid peroxides and their by-products. Peroxidation reactions can induce lipid–lipid, lipid–protein, and protein– protein cross-linking in the membrane [8]. These molecularlevel effects can affect membrane permeability and ultimately, if the damage is severe enough, loss of membrane function and integrity. Peroxidation reactions can also activate phospholipase A2, which results in the release of arachidonic acid from the membrane and the production of prostaglandins, leukotrienes, and thromboxanes via cyclo- and lipoxygenases [48]. Lipid peroxidation probably does not result in significant cell killing, but perturbations in membrane function unquestionably affect cell physiology and reproduction. Studies have shown that lipid peroxidation can eventually lead to DNA damage through the formation of etheno-, propane- and malondialdehyde DNA adducts [49]. Empirical findings that support the importance of membrane damage in cell radiobiological effects include the following observations: membraneassociated enzymes are not directly inactivated by ionizing radiation but rather are indirectly inactivated through lipid peroxidation; DNA function is intimately associated with membrane connectivity; oxygen enhances radiation damage to membranes; and even sublethal doses of radiation can induce structural and functional changes in membranes. With regard to the timing of these effects, biochemical changes resulting from radiation exposure can be observed within seconds after the exposure. Depending on the mitotic

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and metabolic rate of the cell, cell division can be affected within hours of the exposure. Tissue-specific effects can be seen within hours to days, depending on the exposure dose and dose rate, as well as the relative radioresistance of the tissue. Dysfunction of the organ and fibrotic reactions such as occurs in the lung will be observed over days to weeks. The appearance of other tissue pathology such as neoplasms and cataracts, plus any birth defects attributable to lesions produced in the genetic material of the gonadal cells, will take years to be seen after the exposure.

DNA Repair Mechanisms DNA repair processes have been studied extensively in prokaryotic and eukaryotic cells, and much of the processes for mammalian cells has been inferred from the study of lower organisms. A human syndrome, ataxia telangiectasia, which is characterized by increased sensitivity to radiation-induced mutations and cell killing because of a defect in cell cycle control and defective activation of damage-inducible DNA repair, has also provided significant amounts of information on the repair process. Eukaryotes have developed complex repair processes, with specialized enzymes that become activated depending on the mechanism of damage (oxidative vs. nonoxidative) and the degree of injury (SSB vs DSB). The timing of the repair effort is critical to subsequent cellular downstream events. If the repair occurs before the cell enters S-phase, during which DNA is synthesized in preparation for cell division, then the chances of point mutations or errors in replication would be greatly reduced relative to repairs that occur after DNA synthesis or chromosomal separation. Simple base and sugar damage, such as that which occurs in SSBs, is repaired by DNA excision repair via two main mechanisms. In base excision repair, the damaged base is recognized and removed by DNA glycosolase; after that, an endonuclease removes the baseless sugar, and the gap is filled by DNA polymerase and sealed by DNA ligase. In nucleotide excision repair, an incision nuclease cuts the DNA phosphodiester backbone near the damaged nucleotide (unless the radiation break had already involved the backbone). A second endonuclease or an excision exonuclease then removes the damaged material, and the resultant gap is filled by and then sealed by DNA polymerase and DNA ligase. More complex damage, e.g., DSBs and DNA crosslinks, is repaired by other mechanisms including global and transcription-coupled repair, recombinatorial repair, and postreplication repair. Many of these repair processes involve proteins that are normally involved in cellular transcription or housekeeping activities such as cell cycle regulation. Complexes of specific proteins that first recognize damaged DNA and then recruit repair enzymes seem to be more efficient in the recognition and repair process in regions of the genome that are actively transcribed [50]. The time required to initiate and complete DNA repair depends on the type of cell, the phase of the cell cycle, the type

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and dose of radiation, and the timing of the repeated exposure, if any. Sufficient time must be allowed between exposures to allow repair to be completed, if the cell is to survive. Exposures can be categorized as sublethal, potentially lethal, and supralethal based on the quantity of radiation and the above factors. Some evidence exists to refute the original postulate that damage by high-LET radiation cannot be repaired, but the time required and the mechanisms underlying that type of repair may be different from repair of damage by low-LET radiation [2].

Acute Tissue- and Organ-Specific Effects from Whole-Body Irradiation The likelihood of a significant acute exposure that would lead to acute radiation symptoms while a crew is in LEO is very low. Such an exposure would require either an exoatmospheric detonation of a nuclear weapon (which has not occurred since 1964) or a very large SPE while the vehicle is in a high-altitude polar orbit or in combination with a geomagnetic storm that would significantly distort the magnetosphere shielding. The likelihood of an acute high-dose radiation exposure is higher for a crew traveling in interplanetary space in a minimally shielded vehicle. As previously mentioned, SPEs of sufficient intensity to breach clinical thresholds outside the geomagnetosphere (e.g., for travel to Mars) have been recorded in the recent past. Mishaps with a nuclear power system used for propulsion or for surface electricity could also lead to such an event. This section examines the effects of ionizing radiation on specific tissues; the section that follows considers wholebody exposures and clinical presentation. Tissue sensitivity depends on the cellular, extracellular, and stromal composition of the tissue. The number of stem cells and stem cell dependence of the tissue, the dividing transits, the transit pool, and the closed (static) cell populations will also influence a tissue’s resistance to radiation injury. In general, tissues that have large numbers of active stem cells, such as the bone marrow and intestinal crypts, are highly sensitive to radiation. Those tissues with mainly terminally differentiated, static cells (such as neurons) or with large amounts of supporting stroma and noncellular elements (such as cartilage and connective tissue) are relatively radioresistant.

Cardiovascular Effects Cardiovascular tissue is generally resistant to radiation damage, in part because of the large numbers of mitochondria in cardiac muscle. The main effects of high doses of ionizing radiation include intimal fibrosis, endothelial swelling, vascular sclerosis, pericarditis, and pericardial effusion. The aorta can rupture after exposure to doses of 50 Gy (5000 rad) experienced over less than a 2-month period. Arterioles and capillaries are much more sensitive to radiation and account for many of the effects seen in other tissues. Doses larger than 50 Gy (5000 rad) can affect myocardial cells directly, inducing loss of cross striations, homogenization of the sarcolemma, intimal thickening, and nuclear lysis.

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Respiratory Effects Respiratory tissue exhibits mixed sensitivity to ionizing radiation. The pulmonary cartilage and pleura are radioresistant, but the rich network of small vessels and lymphatics are sensitive. Early changes in hyaline membranes are evident after 20 Gy (2000 rad). Radiation pneumonitis, an acute inflammatory reaction characterized by alveolar fibrinous exudates, septal thickening, leukocyte infiltration, and cellular proliferation, results after doses between 30 and 40 Gy (3000 to 4000 rad). Recovery from doses less than 50 Gy is possible, but interstitial fibrosis can result from exposure to higher doses over a period of several months.

Gastrointestinal Effects Exposures as low as 1 Gy (100 rad) can diminish gastric motility (with delayed gastric emptying) and sometimes induce sphincter incompetence, and the duration of the change in motility depends on dose. Delayed suppression of gastric acid secretion and release of neurohumoral factors are also possible. The normally high turnover of intestinal mucosal cells renders the intestinal lining quite susceptible to massive injury; dividing intestinal mucosal cells are extremely vulnerable. Nondividing cells can survive and may resume mitosis after an exposure to less than 10 Gy (1000 rad). Histamine released within minutes after exposure contributes to diarrhea. Fluid and electrolyte loss manifests within 12 h of exposure from impaired absorption of sodium and water, possibly because of damage to the tight junctions at the apical epithelium, with subsequent net secretion of both water and electrolytes from the gastrointestinal tract. The entire epithelial lining becomes denuded by 4 days after a 5-Gy (500-rad) dose. Increased permeability to enteric microorganisms has a key role in gastrointestinal syndrome mortality [8].

Hepatic Effects The liver is relatively radioresistant except for regenerating liver cells, which are very sensitive. Doses of up to 30 Gy (3000 rad) do not damage mature liver tissue, but doses exceeding 40 Gy (4000 rad) cause damage in 75% of cases. Radiation hepatitis is characterized by sinusoidal congestion, hyperemia, central venous dilation, and central lobar cellular atrophy.

Skin Effects Skin sensitivity to direct ionizing radiation varies with the anatomic location and type of radiation. Radiosensitivity is roughly associated with level of keratinization; the anterior aspect of the neck, for example, is more sensitive than the palms and soles. Mucous membranes are particularly sensitive. Integumental substructures, including hair follicles and apocrine sweat glands, are also quite sensitive. Skin injury associated with space flight could take place even in LEO operations if crewmembers were outside the space vehicle performing an EVA during a large SPE or geomagnetic storm.

23. Radiation Disorders

Although the penetration capability of protons or electrons into the vehicle is low because of structural shielding, penetration through the relatively thin layers of EVA spacesuits, particularly to the skin, renders the occupants significantly more vulnerable. Skin erythema and possibly transient depilation are observed at acute doses of 7–20 Gy (700–2000 rad). A dose of 30 Gy (3000 rad) produces dry desquamation, but moist desquamation of the epidermis does not appear until acute doses of 40 Gy (4000 rad) [2]. In rodents, the doses required to impair wound healing are about 5 Gy (500 rad), but whether the impairment results from loss of tensile strength or extension of healing time and increased incidence of infection remains uncertain [51]. Because other factors may be operative that could impair wound healing (e.g., stress, microgravity) in addition to radiation exposures, vigorous treatment of radiation-associated skin injury in astronauts is warranted. The response of mucous membranes to radiation is similar to that of the skin, except that the mucosal effects appear more quickly and tend to resolve (or progress) more quickly as well. With regard to acute effects on the oral mucosa, doses of 20– 24 Gy produce patchy mucositis, dysphagia, impaired mastication, and diminished taste by the end of the second week. Doses of 30–36 Gy lead to edema of the tongue and throat, confluent mucositis, and thickened saliva by the end of the third week; doses of 40–48 Gy produce mucositis that extends onto the buccal mucosa by the end of the fourth week. Doses of 50–60 Gy result in severe mucositis with the appearance of pseudomembranes and superficial ulceration; the tongue may finally show injury by the end of the fifth week, and regeneration begins after 6 weeks. The radiosensitivity of mucous membranes in the head and neck region varies depending on their location; those in the soft palate and pillars are the most sensitive, followed in order of decreasing sensitivity by membranes in the posterior pharynx, tonsils, floor of mouth, anterior buccal mucosa, lower alveolar mucosa, epiglottis, tongue, and vocal cords.

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increases; therefore the threshold dose for cataract induction is lower for high-LET radiation than for low-LET radiation [43]. An interesting phenomenon, initially reported by Edwin “Buzz” Aldrin, the pilot of the Lunar Excursion Module on Apollo 11 and reported on all subsequent Apollo missions, is the perception of transient light flashes during space flight. Light flashes apparently are not noticed by the observer unless the eyes are dark-adapted and the observer’s attention is not distracted by other visual stimuli. The exact mechanism underlying the flashes has not been elucidated, but some theories implicate particle interaction with the retina or elsewhere along the optic pathway. Direct interaction between retinal or nerve cells and relativistic particles or their Cherenkov (secondary) radiation has also been postulated. Either way, the loss of ionization energy as the particle traverses the cell is thought to produce the perceived flash. Whether the affected cells survive the incident is not clear. Flashes observed during Skylab 4 are believed to have originated both from GCR sources as well as trapped radiation in the Van Allen belts. Crewmembers aboard Skylab reported increased frequency of flashes during transit through the SAA (Figure 23.11) [52], prompting the question of whether the proportion of heavy (Z > 2) particles in the trapped inner belt is higher than the originally posited 0.1% [52]. Crews aboard the ISS sleeping behind shielding of water bags and high-density polyethylene brick have not reported seeing any light flashes.

Eye Effects The lens is quite sensitive to radiation; the threshold for the formation of cataracts is 2–5 Gy (200–500 rad) for a single dose or 5–10 Gy (500–1000 rad) fractionated over time. The average latency period is 2–3 years but can range from 10 months to 35 years. The cornea and conjunctiva are particularly sensitive, but the optic nerve and sclera are resistant. The blood-aqueous barrier is highly radioresistant, requiring 20 Gy (2000 rad) to produce a breakdown. The main effects of radiation on the eye, aside from the lens, involve the microvasculature. The lens is devoid of vasculature and depends on the aqueous humor to receive nutrients and metabolic support. The proliferative cells in the germinal epithelium are radiosensitive. Irradiation produces initial mitotic arrest followed by production of fragmented nuclei and degenerated cells. As the LET of the incident radiation increases, the number of abnormal mitoses, micronuclei, and disordered meridional rows

Figure 23.11. Distribution of perceived light flash phenomena relative to orbital position and passage through the South Atlantic anomaly (SAA), correlated with objective dosimetry. A striking increase is noted in the SAA

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Endocrine/Exocrine Effects Endocrine glands are relatively radioresistant. Moderate radiation doses produce inflammation, and higher doses cause glandular dysfunction. In the salivary glands, for example, 25 Gy (2500 rad) causes swelling of acini and loss of secretion. In the pancreas, the islet cells are the most sensitive, with a threshold dose of 25–50 Gy. The LD50 for alpha cells is 50 Gy, and the LD50 for the beta cells is 20 Gy. Steroidogenesis occurring in the adrenals can remain normal after exposure doses of up to 35 Gy (3500 rad). In the thyroid, moderate doses may produce hypofunction years after exposure, but it has been estimated that 500 Gy (50,000 rad) is required to completely destroy all thyroid tissue [2].

Immune System and Bone Marrow Effects The bone marrow stem cells, which are actively dividing, are extremely radiosensitive; mature peripheral white cells are more resistant. Radiation-induced immune dysfunctions can arise through several mechanisms. Loss of innate resistance results from breakdown of the natural mechanical barriers to infection, impaired cellular defense, impaired clearance of infectious organisms from decreased respiratory cilia function, increased bowel permeability to microbes, and diminished bactericidal properties of serum. Antibody production may be diminished after as little as 3 Gy (300 rad), thereby curtailing normal antibody responses. Progenitor cells may be lost; marrow pluripotential stem cells are highly sensitive to radiation-induced mutation and cell death. Marrow stem cell depletion can lead to pancytopenia, which without vigorous medical support can be fatal. In fact, radiation injury to the bone marrow may be the most important acute biological effect of whole body radiation influencing survival of the organism.

Muscle and Bone Effects Morphologically, muscle is highly radioresistant, tolerating up to 45 Gy (4,500 rad) with only mild changes in histology. Bone and cartilage are resistant if they are mature; growing bones and cartilage are more sensitive. For low-energy photons, bone absorbs five to six times as much energy per gram as soft tissue; for medium-energy photons, bone absorbs the same energy per gram as soft tissue; and for high-energy photons, bone absorbs twice as much energy as soft tissue. Doses exceeding 50 Gy (5,000 rad) may produce delayed necrosis in bone and cartilage, presumably through injury to the small vasculature.

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and convoluted tubule ischemia produces chronic nephritis 6 months after exposure. Other changes include epithelial degeneration or desquamation, and damage to connective tissue, especially elastin fibers. Large doses can cause necrosis, which can lead to obstruction of the ureters and formation of fistulae. Infection increases the likelihood of fistulae. The bladder and ureters are more resistant, but injury to the bladder mucosa can produce radiation cystitis, which may further lead to hemorrhage, fibrosis, and fistula formation. Radiation cystitis is characterized by irritative voiding symptoms (dysuria, urgency, and frequency) and is caused by primary and secondary edema in the bladder mucosa 3–4 weeks after exposure.

Reproductive System Effects In males, the testis is extremely radiosensitive, whereas the accessory reproductive organs such as the prostate, seminal vesicles, penis, and urethra are radioresistant. A single dose of 0.15 Gy (15 rad) has been been reported to reduce sperm counts in some healthy men. In men, transient sterility occurs after doses of 0.5–4.0 Gy (50–400 rad), but generally a dose of at least 2 Gy (200 rad) is required to produce effects that last a year (Table 23.7). Susceptibility of spermatogonia to radiation may be enhanced by chronic low-dose exposures because of the cyclic nature of meiotic division in these stem cells. Human testes have a finite number of stem spermotagonia. Radiation above threshold doses impairs and disrupts stem cell mitosis and meiotic division and can be lethal to the stem cells, resulting in temporary or permanent oligospermia or azoospermia as well as spermatic dysfunction. Sublethal levels of radiation can induce a state of dormancy in the spermatogonia that can last 7–8 years, after which sperm counts and function may improve. The effects of radiation on testicular stem cells can be reduced by administering gonadotropin-releasing hormone (GnRH) for several weeks beginning at the time of radiation Table 23.7. Radiation effects on reproductive function. Sex Male

5–6 (500–600) Femalea All ages

Ages 15–40

Genitourinary Effects The kidney is moderately radiosensitive, manifesting nephritis as the predominant clinical entity. Most of the radiation effects on the kidney result from vascular injury. The first signs are hyperemia, increased permeability and interstitial edema; later findings may include slow vascular occlusion due to endothelial swelling, fibrosis, and thrombosis. Cortical

Dose, Gy (rad) 2.5 (250)

1.7 (170) 1.25–1.5 (125–150) 3.2–6.25 (320–625) 1.5–2.5 (150–250) 2.5–5 (250–500)

5–8 (500–800) >8 (>800) a

Effect Temporary sterility lasting about 12 months Permanent sterility Temporary sterility lasting 1–3 years Amenorrhea in 50% Permanent sterility Temporary amenorrhea Ovulatory suppression in 40–100% (permanent in 60%) Permament ovulatory suppression in 40–100% Permament ovulatory suppression in 100%

Dose needed to induce ovarian failure is age-dependent, with lower doses needed for women older than 40 years.

23. Radiation Disorders

exposure [53]. Radiation damage is not cumulative for males because gametogenesis continues into later years of life, and damaged cells can be eliminated. In females, the ovary is extremely radiosensitive. Radiationinduced cessation of hormone production (premature menopause) can lead to temporary or permanent infertility. The vagina is similar to other mucous membranes in terms of radiosensitivity, but the vulva, labia, and clitoris are more sensitive. The uterus is radioresistant. Transient sterility can occur after doses as low as 1.25 Gy (125 rad), although most report the threshold dose for temporary sterility as being 1.7 Gy (170 rad) [2]. The dose required for permanent sterility in women ranges from 3.5 to 20 Gy (350–2000 rad) (Table 23.7) [54]. Radiation damage to the female gonads is cumulative because gametogenesis essentially stops at the time of birth.

Central Nervous System Effects Mature neurons are highly radioresistant; glia and support cells are also resistant, with astrocytes being somewhat more sensitive. Neuroblasts are very radiosensitive, and exposure to radiation has significant negative effects on the learning capacity of a developing fetal or infant brain. White matter is more sensitive than gray matter, presumably because of injury to oligodendrocytes and subsequent demyelination. Doses of 40 Gy (4000 rad) to the brains of monkeys have produced demyelination at 18 weeks after exposure. Peripheral nerves are more resistant than central (CNS) neurons. If radiation doses are high, symptoms and signs in the acute clinical period (i.e., within the first 6 months after exposure) include headache, lethargy, nausea, vomiting, and papilledema, progressing to convulsions and coma. The acute response in the cerebrovascular system includes endolethial injury, capillary circulation impairment and increased permeability, interstitial edema, leukocytic infiltration, loosening of perivascular astrocytes and weakening of the blood-brain barrier, petechial hemorrhages, vasculitis, meningitis, and choroid plexitis. Neurons show no acute morphologic response other than some delayed cellular disorganization, pyknosis, and dendritic process reduction at 12 weeks. Oligodenrocytes show edema with the acute inflammatory reaction. In the subacute period (6–12 months), recovery may be complete or can be characterized by episodic partial or grand-mal seizures, ataxia, or impaired motor coordination caused by slow neural degeneration and progression of vascular lesions that can lead to necrosis [2]. Doses of less than 5 Gy (500 rad) increase levels of neurotransmitters such as acetylcholine and 5-hydroxytryptamine, whereas doses greater than 500 rad tend to decrease neurotransmitter levels [2]. Several investigations of rodents showed impaired regulation of dopamine-controlling motor function and CNS performance impairments after only 0.5 Gy (50 rad) from 0.6-GeV 56Fe particles, which persisted for at least 6 months. Specifically, the rat striatum was depleted of dopamine when exposed to 0.6 GeV 56Fe particles but not when exposed to 1.5–4.0 Gy (150–400 rad) of 0.25-GeV protons

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[55]. Nerve signal transduction is also affected because of uncoupling of membrane receptors and G-protein signal molecules [56]. Adult humans undergoing radiation therapy for cancer have shown no impairments in higher mental function, motor coordination, or strength, but this may not be true for children. However, doses of −6 Gy (300–600 rad) to adult rat brains resulted in diminution of complex task performance scores and behavior decrements in these animals [57]. Spatial learning and memory were impaired in rats exposed to 1.5 Gy (150 rad) of 0.6-GeV 56Fe but not to 4 Gy (400 rad) of 250MeV protons [58].

Chronic and Long-Term Effects of Ionizing Radiation Cancer Types of cancer observed after exposure to ionizing radiation include leukemias (primarily acute lymphoblastic and myeloblastic and chronic granulocytic), which arise 7–15 years after exposure, and solid tumors of the breast, lung, gastrointestinal tract, lymphoid system, and various sarcomas, which can appear several decades after exposure. Given these long latency periods, neoplasms such as these would not be expected to appear de novo during any crewed space mission within the foreseeable future. However, cancers that arise after exposure to ionizing radiation are morphologically indistinct from cancers that are not associated with radiation. What is known is that limiting the radiation dose to which one is exposed will mitigate the occurrence of such neoplasms later in life. Attempts to maintain delayed effects at an acceptable incidence are made by setting and following strict career exposure limits. Knowledge of the carcinogenic process is still somewhat limited and that process almost certainly varies according to the type of cancer. However, it seems clear that several steps are required to induce neoplasia in a cell. Cell and tissue culture models have yielded useful information as to the mechanisms of radiation-induced damage, but such models have been less helpful in predicting oncogenesis in humans. Animal studies have provided the bulk of knowledge regarding the bioeffects of HZE particles on tissues and have allowed some testing of the complex interaction of radiation with co-carcinogens and tumor promoters. However such studies are expensive, timeconsuming and opposed by numerous organizations. Questions have also been raised regarding variability in radiation sensitivity between species and the validity of extrapolating risks of cancer and other stochastic effects from rodents to humans. As noted earlier, human data have been derived primarily from accidental and therapeutic radiation exposures. Although diagnostic doses of radiation may induce tumors in the breast, thyroid, and bone marrow, other solid organs require therapeutic levels of radiation to induce tumors. Table 23.8 shows the risk of cancer after a single radiation exposure at the indicated threshold doses; Table 23.9 shows estimates of probability of excess cancer deaths associated with an exposure to 0.1 Sv (10 rem) over a 1-year period [59].

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Table 23.8. Relative risk of developing leukemia, breast, or thyroid cancer after a single exposure to a threshold dose. Type of cancer

Threshold dose, Gy (rad)

Relative risk (Cases per million/year/rad)

at this stage, healing is poor because of the inadequate vascular supply. Over the long term, chronic dermatitis may ensue, associated with increased incidence of neoplasia, especially squamous cell carcinoma [2].

Leukemia Breast Thyroid

0.2 (20) <0.01 (<1) 0.06–0.07 (6–7)

3.1 6.6–8.7 1.9–9.3

Cataracts

Table 23.9. Estimated excess cancer incidence and mortality, in percent, after an exposure to 0.1 Sv over a period of 1 year. Mortality

Morbidity

All All Solid tumors Leukemia cancers Solid tumors Leukemia cancers Age at exposure 35 years Male 0.19 0.666 Female 0.34 0.023 45 years Male 0.13 0.039 Female 0.24 0.032 55 years Male 0.10 0.028 Female 0.16 0.021

0.26 0.36

0.39 0.71

0.044 0.031

0.44 0.74

0.17 0.27

0.21 0.60

0.049 0.061

0.26 0.66

0.13 0.18

0.16 0.38

0.041 0.03

0.20 0.41

Risks to women are higher because of breast and ovarian cancer and higher incidence of lung cancer. Source: (Modified from NCRP, 1997).

Many cocarcinogens, immune system modulators, and antitumor agents can influence the development of tumors in humans. Current theories of carcinogenesis postulate that cancer arises only after the accumulation of a certain level of abnormally expressed cellular oncogenes (amplified) or tumor suppressor genes (deleted or mutated). Normal cells have multiple growth-control points that must be circumvented to allow a cell to become immortalized, and additional changes in gene expression are required before a cell can become invasive and subsequently metastatic. Even low-dose radiation can induce genetic instability in the progeny of cells, and that instability can persist for up to 50 generations. Mutation rates are elevated in the progeny, producing increasing numbers of transformed descendents. Cells that have sustained radiation to their cytoplasm are at increased risk of undergoing subsequent mutational events; the existence of a “bystander effect” can even lead to mutations in nearby (nonirradiated) cells, presumably through the production of a soluble radiation by-product molecule [60].

Skin Late effects of radiation skin damage include dermal atrophy and telangiectasia, occuring a minimum of 6–12 months after exposure [61]. In the 1- to 5-year period thereafter, atrophy, ulceration, and deep fibrosis can appear after high-dose exposure. Repeated exposures may produce epidermal hyperplasia and hyperkeratosis. Atrophic skin is smooth, thin and scaly, and is more susceptible to traumatic injury. If ulceration occurs

Radiation exposure is well known to cause cataract formation in humans and animals. However, cataracts are a common clinical entity seen with aging, and it becomes important to track radiation as an attributable risk factor. Radiation exposure to the eye causes partial opacity in the crystalline lens. Symptoms are usually observed after several months of latency after radiation exposure, with 2–3 years being average. Unlike senile cataract common in old age, few radiation cataracts advance, and visual impairment is infrequent. One aspect of radiation cataract that sets it apart from radiationrelated cancer is the possible existence of a “threshold,” a certain low-dose value below which no effect is observed. Characteristically, radiation-induced cataracts occur most commonly in the posterior subcapsular area [61]. They can progress to full cortical and even nuclear opacities. Energy deposition from GCR, gamma rays, or neutrons causes ionization of lens constituents, mainly water, which in turn leads to production of free hydroxyl and other radicals. This process may be compounded by decreases in antioxidant concentrations associated with age, which further increases vulnerability to oxidative damage. Opacities of the lens are typified by multiple vacuoles, a feathery appearance, and web-like fringes. Glare is a common initial complaint of posterior subcapsular cataracts [62]. The risk for humans of forming cataracts from space radiation exposure is difficult to extrapolate from animal experiments, in part because species vary in their sensitivity to radiation. In humans, acute single doses are known to be more cataractogenic than multiple protracted doses. The singledose threshold is 2 Gy (200 rad) for photons in humans, 4 Gy (400 rad) if the dose is delivered over 3 months, and 5.5 Gy (550 rad) if delivered over 3 years [63]. Findings from several investigators suggest that because lens epithelial activity eventually returns to normal despite HZE particulate exposure, the differences in cataract dose threshold from high-LET radiation is quantitative and not qualitative. Protons over a broad range of energies do not seem to be more cataractogenic than photons. However, the threshold for mixed gamma-ray and neutron radiation may be lower than 1 Gy (100 rad). The RBE of neutron exposure in atomic bomb victims has been calculated to be 32 and may even be higher at lower doses [64]. The RBE of heavy ions is by most accounts similar to that of neutrons, but may possibly be as high as 200. The practical applicability of using objective classification methods for assessing the presence and progression of clinical cataracts is being demonstrated by several studies. The LOCS II and III subjective classification systems have been compared to objective techniques, including digital camera image

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analysis of Scheimpflug and retroillumination images [65,66]. Several studies have demonstrated the value of this approach for posterior subcapsular cataracts [67]. These methods are currently being used to evaluate cataract incidence and character in astronauts as part of the Longitudinal Study of Astronaut Health at the Johnson Space Center. Preliminary findings indicate a trend toward a higher incidence of cataracts among crewmembers who have flown outside the geomagnetosphere (to the moon) or on high-altitude flights, thereby incurring higher HZE exposures (Figure 23.12) [68].

Nervous System Curtis and others [69] estimated that during interplanetary space flight, every nucleus in the CNS (estimated area 100 µm2 per nucleus) would be hit by a proton once every 3 days, by an alpha particle once a month, and by higher weight particles once a year. The National Academy of Sciences has expressed concern regarding damage to nonrenewable cell systems, especially the CNS, from HZE ions. Considerable uncertainty

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exists as to the long-term effects of radiation on neurons, but studies by Lett and others with rabbit retinas suggest that initial radiation-induced DNA lesions can be repaired, but DNA degeneration will accumulate with age because of the long-term effects of irradiation in the DNA repair processes [63]. Such degeneration, in extreme forms, could conceivably give rise to premature dementia and cerebellar dysfunction. Late degenerative damage to neurons and behavioral changes including accelerated aging has been seen in animal models. Over the medium term of 1–5 years, CNS radionecrosis can still occur through progression of vascular lesions, which can continue for up to 15 years after exposure. Seizures have been observed 7 years after irradiation. Diminished cognitive capacity and motor performance may follow the progression of vascular changes. Radiation myelitis of the brainstem and spinal cord has been observed 11–20 months after exposure to 45–60 Gy (4500–6000 rad). Malignant intracranial neoplasia has also been noted 5 or more years after exposure.

Interaction of Ionizing Radiation with Other Space Flight Health Factors Cellular and Immune Function

Figure 23.12. Probability and standard error of cataract formation versus time in NASA astronauts following first space mission for low dose group (lens doses below 8 mSv, average 4.7) and high dose group (lens doses above 8 mSv, average 45). A depicts data for all cataracts; B depicts data for non-trace cataracts only. Trace cataracts are defined as a small opacification with no apparent loss of visual acuity

Assessments of immune function during long-term stays in microgravity indicate that both cellular and humoral immune functions are affected (see Chapter 15). Isolation, stress, and diminished sleep may all contribute to these functional decrements [70]. However, the microgravity environment itself seems to induce a unique pattern of cellular genetic expression, at least as evaluated in in vitro conditions. During a Space Shuttle investigation, human renal cells were grown for 6 days in microgravity and were then fixed during flight and analyzed for changes in gene expression. The expression patterns of 914 genes had changed as a result of microgravity exposure; these included heat shock proteins and shear stress response genes. Increased expression of specific transcription factors, such as the Wilms tumor gene zinc-finger protein and the vitamin D receptor, was also noted [71]. These findings contrast with conclusions drawn from experiments flown on Gemini 11, from which the investigators concluded that microgravity had no synergistic effects with radiation during orbital space flight [72], and Skylab, which showed no significant differences in the growth curves of cultured Wistar38 human embryonic lung cells. Analysis techniques in the Skylab experiments included microspectrophotometry, phase microscopy, scanning and transmission electron microscopy, and chromosomal C- or G-banding between space flight and ground-based controls [73]. Several mechanisms have been postulated to explain microgravity-induced changes in function at the molecular, cellular, and tissue or organ levels. Changes in genetic expression, especially in terms of DNA repair and hormonal and cytokine production, are thought to be particularly important in the potential synergy between microgravity and ionizing

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radiation exposure [74–76]. Investigators on the European Space Agency’s Biorack experiments found more anomalies in fetal insect tissues exposed to an onboard ionizing radiation source than onboard controls that were not exposed; the conclusion from these experiments was that microgravity has synergistic effects with GCR [77]. In the late 1970s, Grigoriev and colleagues [78,79] reported a synergistic effect of radiation and microgravity in the production of chromosomal aberrations in lettuce seeds and in Artemia (brine shrimp) larvae; work on the Biosatellite II mission demonstrated time-dependent effects of space radiation on pupal and larval development of a beetle (Tribolium), a wasp (Habrobracon juglandis), and a fly (Drosophila melanogaster) [80]. If the differences in genetic expression noted during these inflight investigations are valid, they could significantly affect the cellular response and repair mechanisms normally activated by exposure to ionizing radiation. This presumption would be contrary to opinions on radiation sensitivity during early crewed space flight, in which microgravity was thought to have no significant role [81].

Toxic Vehicular Agents Many chemicals associated wih space flight have potentially injurious effects. Hypergolic fuels such as hydrazine and nitrogen tetroxide as well as their combustion by-products are quite toxic to human tissues as well as being carcinogenic; their effects may be additive in combination with ionizing radiation. Components of the interior vehicular structure will emit volatile compounds into the contained atmosphere (listed in Chapter 21. Control levels for many of these agents have been established in attempts to prevent their potentially toxic effects from overtly affecting the crew. However, some of these agents can produce cellular injury by increasing oxidative stress or diminishing the cell’s natural defense mechanisms to oxidative stress. Therefore coincident ionizing radiation may act synergistically with inhaled or absorbed airborne chemicals to produce cellular injury in target organs.

Acceleration and Vibration Exposure of space crews to acceleration forces is usually brief, lasting on the order of minutes during the launch and landing periods, and thus is not thought to be a major modifier of radiationinduced bioeffects. Only limited studies have been conducted to date on acceleration in combination with radiation exposure. Animal studies by Bender and colleagues focused on cellularlevel responses; those by Antipov and colleagues looked at whole-organism effects. Both modest synergy and antagonism were observed, depending on the timing and intensity of exposure. Slight increases in radiation resistance seen during the accelerated state were attributed to acceleration-induced hypoxia resulting in reduced oxidative stress [82]. Exposure to vibration during space flight is also brief, experienced mainly during launch and landing, and is not believed to modify radiation-induced bioeffects. Limited previous

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studies have shown vibration to have either synergistic or antagonistic effects depending on the timing and intensity of the exposure [82].

Planetary Surface Dust On lunar and Mars missions, crewmembers may be exposed to planetary surface dust particles. Presumably surface habitats will have an air scrubbing system for particulate matter, and that system will be aided by planetary gravity. However, such gravity fields will be lower than those of Earth and particles thus will be suspended for longer periods before settling, thereby increasing the chance of aspiration. Lunar regolith was found to be chemically inert, composed mainly of silica, but its angular shape and hardness made regolith particles abrasive, particularly to space suit components. Chronic inhalation of these dust particles could produce inflammatory changes in the alveoli. Remote measurements and analysis suggest that the Mars regolith is chemically reactive [83]. Oxidizing or reducing soil when inhaled into the pulmonary system carries its own risk of pulmonary injury, but the localized reaction, along with an induced chronic inflammatory reaction, may be synergistic to coincident ionizing radiation exposure to the lung.

Clinical Aspects of Acute Ionizing Radiation Exposure Manifestations of Exposure Although the most common acute radiation incident in industrial settings involves local skin exposure, acute events in the spaceflight environment will most likely involve whole body exposures from SPEs. For a LEO platform in a low inclination orbit, radiation from even a significant SPE may be barely detectable. However, a geosynchronous platform or a transplanetary spacecraft outside the geomagnetic field is highly exposed, and the dose to the crew will depend entirely on shielding. For an SPE such as the one that took place on 4 August 1972, which involved the largest particle fluence ever recorded, the annual and career exposure limits for the skin would be rapidly exceeded. During the peak intensity period, the average dose-equivalent behind 2 g/cm2 equivalent of aluminum shielding would have been 1.5 Sv/hour (150 rem/ h) [84]. The radiation dose to a crewmember conducting an EVA during this time would certainly have exceeded the threshold for deterministic clinical effects. Exposure to even a few Sieverts (several hundred rem) may go unnoticed; exposed individuals may be completely unaware and without symptoms for several hours afterward. In the very early phase of exposure, the diagnosis of radiation exposure equates to dosimetry. Specific responses to measured doses of ionizing radiation have been characterized according to total dose and time and are influenced by individual variability, level of treatment, and other factors. Preexisting illness, stress, immune compromise, infections, and dietary deficiencies all

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Table 23.10. Selected features of acute radiation syndromes after whole-body exposure. Principal cause of death Lethal dose (latency period) range, Gy

Underlying cellular event

Hematopoietic (2–3 weeks)

2.5–10 Necrosis of bone marrow cells

Gastrointestinal (3–7 days) Acute incapacitation (15 min–3 h)

10–50 50+

Characteristic signs and symptoms prodromal phase

Principal phase

Anorexia, nausea, vomiting

Petechia and purpura, bleed ing from mucous membranes, infection Necrosis and mitotic arrest of mucosal Anorexia, nausea, Fever, bloody diarrhea, loss of stem cells vomiting fluids and electrolytes Unknown; perhaps direct injury of Anorexia, nausea, Apathy, lethargy. endothelial cells, death of neurons vomiting, confusion, somnolence, tremors, and vasculitis at very high doses ataxia, anxiety convulsions, coma

Time of death (after exposure) 2–3 weeks

5–12 days 10–36 h

Source: From Fajardo et al.[61].

correlate negatively with survival. A combined injury scenario involving major trauma and acute radiation syndrome could be particularly severe. The radiation impairment of immune and fibroblastic cellular reponse will significantly delay traumainduced wound healing as well.

Acute Radiation Syndromes The predominant symptoms resulting from acute radiation exposures are predictable and depend on the dose received; exposure to 1–5 Gy (100–500 rad) produces the so-called hematopoietic syndrome; 5–20 Gy (500–2,000 rad), the gastrointestinal syndrome; and exposure to more than 20 Gy (2,000 rad) evokes the CNS syndrome. Table 23.10 summarizes the characteristic signs and symptoms based on the pathophysiologic mechanisms underlying each of these three syndromes [61].

Temporal Sequence of Acute Reponses to Whole-Body Radiation Exposure The transient prodromal phase generally lasts 48–72 h and is seen after low to moderate doses of acute ionizing radiation. For doses larger than 10 Gy (1,000 rad), the prodromal phase is almost nonexistent. During this phase, chemical mediators are released from damaged cells in the marrow, lymphoid tissues, and possibly the gastrointestinal tract. Release of these mediators peaks at 8–12 h; they are usually cleared by macrophages by 48 h after exposure. Doses of less than 10 Gy (1,000) typically produce fatigue, malaise, listlessness, apathy, and weakness. Neuromuscular symptoms include headache, insomnia, difficulty concentrating, occasional dizziness, or vertigo. Psychological symptoms can include depression, despair, and hopelessness. Gastrointestinal manifestations may include abnormal tastes and smells, stomach upset within 2 h, anorexia, and nausea leading to emesis by 5–8 h, which usually subsides by 12 h. Painful edema of the parotid glands is typical. Diarrhea, intestinal cramps, dehydration, and weight loss may develop within 3–7 days. Doses of 7.5–10 Gy (750–1,000 rad) are often associated with a drop in blood pressure and an increase in pulse rate because of circulatory hypovolemia; these effects can lead to early death in individuals

Table 23.11. Expected acute radiation effects for doses acquired over 24 h or less. Symptoms Anorexia Nausea Vomiting Diarrhea Erythema Desquamation

Effective doses, rad (Gy)a ED10 ED50 40 (0.4) 50 (0.5) 60 (0.6) 90 (0.9) 400 (4) 1,400 (14)

100 (1) 170 (1.7) 215 (2.15) 240 (2.4) 575 (5.75) 2,000 (20)

ED90 240 (2.4) 320 (3.2) 380 (3.8) 390 (3.9) 750 (7.5) 2,600 (26)

a Effective doses are those at which a specified dose would produce the effect in question in various percentages of the exposed population; ED10, for example, is the dose that would cause the given effect in 10% of the population exposed to that dose.

with coronary artery disease. Oral ulcerations appear at 3–4 days after exposure and are often associated with fungal overgrowth. Erythema of the skin becomes apparent 1–3 days after exposure. The predicted acute effects of radiation exposure acquired over less than 24 h, according to dose, are summarized in Table 23.11. The latency phase is relatively free of symptoms, representing the time between initial injury to cells and the manifestations of impaired cell repair and renewal; it typically lasts 3–20 days. At 7–10 days after exposure, loss of mitotic activity results in incomplete, temporary hair loss. The number of surviving stem cells determines the duration and magnitude of complications such as pancytopenia and infectious disorders, since these cells are the only source of renewal [damage repair] in mitotically active tissues. The recovery phase is characterized by stem-cell renewal of depleted and damaged cell populations in the bone marrow and the gastrointestinal crypts. Whether recovery occurs at all depends on the radiation dose and the availability of medical treatment (Table 23.12). At a minimum, treatment should include fluid and electrolyte support and palliative care. Hematopoietic syndromes will require more vigorous supportive care, including blood products, infectious isolation, and carefully targeted antibiotic therapy. Gastrointestinal syndromes may require oral or parenteral nutritional support. Advanced treatment may

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Table 23.12. Whole-body radiation dose lethal to half of the population (LD50) without and with treatment. Expected response in healthy adults Blood count changes Effective threshold for vomiting Effective threshold for mortality LD50 with minimal medical treatment LD50 with supportive medical treatment LD50 with advanced medical treatment

Dose 50 100 2 Gy (200 rad)a 3.5 Gy (350 rad) 5 Gy (500 rad; range, 4.8–5.4 Gy) 10 Gy (1,000 rad)

a (ED10 = 2 Gy; ED50 = 2.85 Gy; ED90 = 3.5 Gy). Source: (Victor Bond NCRP SC75 report).

Table 23.13. Correlation of lymphocyte counts with radiation dose level and clinical effects at 24 hafter an acute radiation exposure. Lymphocyte counts >1500/mm3 1000–1500/mm3

500–1000/mm3

<500/mm3

Undetectable

Dose level and expected clinical effects Insignificant dose; no treatment necessary Low dose; treatment may be necessary for moder ately suppressed polymorphonucleocyte and platelet counts at 3–4 weeks after exposure Moderate dose; treatment for moderate to severe injury will be required; hemorrhage or infection can develop at 2–3 weeks after exposure High dose; treatment for severe injury will be required; exposure can be lethal, pancytopenia will ensue at 2 weeks Very high dose; palliative treatment as needed; survival unlikely beyond 2 weeks

involve compatible bone marrow transplantation or immune cell stimulants such as granulocyte-macrophage colony stimulating factor. Differential diagnosis of a crewmember presenting with acute whole-body radiation exposure should not be problematic if the radiation detection equipment is functioning properly. However, if real-time dosimetery equipment is not located near the individual during exposure (e.g., during an EVA that takes place during an SPE), the clinical signs can give a rough indication of exposure. Vomiting within 3 h of exposure suggests a high dose. Prompt, explosive bloody diarrhea suggests a lethal exposure. An early drop in the lymphocyte count indicates injury to the blood-forming organs, but levels of platelets and polymorphonucleocytes (PMNs) later after exposure are the most important guides for therapy. The PMN count will initially increase as a result of inflammatory release from the marrow; PMNs are not as vulnerable as stem cells. Neutropenia develops 3–4 weeks after sublethal exposures as the granulocyte reserves become depleted. Lymphocyte counts 24 h after exposure are a rough indicator of overall dose and expected clinical sequelae (see Table 23.13); means of measuring lymphocyte counts during space flight are under development. Given the wide-ranging physiological changes induced by the weightless environment, including diminished red blood cell mass and immune function, it remains to be seen whether

the symptomatic thresholds and dose-response relationships are the same for long-duration space crewmembers as for the terrestrially exposed. The net physiological effects of space flight would not seem to be favorable; however, further investigation is clearly needed.

Clinical Case Management Adequate therapy for even one victim of whole-body radiation will require significant medical care resources, and consumables such as antibiotics and blood products in any remote medical facility will be rapidly depleted. Treatment modalities and adjuncts for acute radiation syndromes stretch any foreseeable spacecraft’s logistics, storage, and shelf-life constraints to extreme limits. Plans for equipping a space vehicle’s medical facility must account for the likelihood of whole-body exposure syndromes, the possibility of rendering aid onsite vs the need to return a patient or patients to Earth, and the level of risk deemed acceptable from an operations standpoint. The level of training for the crew medical officer will be a vital element; expecting an individual who is not a physician to administer the level of care required to support even a minor acute radiation exposure during space flight is hardly justifiable. Classifying the radiation injury broadly in terms of exposure may be useful for making triage decisions. In such a classification, an exposure to up to 2 Sv (200 rem) would be considered “mild”, with survival deemed probable; exposure to 2–7 Sv (200–700 rem) would be moderate, with survival possible; and exposure to more than 7 Sv (>700 rem) would be severe, with survival improbable. The primary determinant of survival for individuals sustaining significant radiation exposures will be the ability to manage the sequelae of pancytopenia, with attendant decreased antibody production and phagocytosis. Clinical problems include susceptibility to infection and sepsis from skin or mucosal injury and loss of gastrointestinal epithelial tight-junction integrity, as well as hemorrhage from thrombocytopenia. Survival to 5–6 weeks indicates that marrow recovery is underway.

Initial Treatment Until the bone marrow recovers, the greatest concern for initial treatment strategies is infection. The main endogenous bacterial flora to cover will be Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus, and fungi such as Candida albicans. Synergistic antibiotic combinations such as late-generation β-lactams with clavulanic acid or monobactam agents with an aminoglycoside should be given at the onset of granulocytopenic fever and continued for about 2 weeks or until the leukocyte counts exceed 5,000/µL. Antifungal agents such as fluconazole or amphotericin should be given to patients whose blood cultures test positive for fungi or whose fevers do not respond to antibacterial agents. Support of septic shock will also require parenteral steroids such as methylprednisolone. Platelet transfusions, if available, are indicated for patients with platelet counts of less than 50,000/µL who are actively

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bleeding; platelets should be given prophylactically when counts are less than 20,000/µL. Erythrocytes and plasma may be required as well. Nausea should be treated symptomatically with antiemetics such as prochlorperazine and promethazine. Treatment of gastrointestinal manifestations may require large amounts of intravenous fluids in addition to blood products, and possibly nutrition via peripheral or central intravenous lines. Radiation-induced skin injury would be treated as a thermal burn based on the degree and percentage surface area burned. Ringer’s lactate solution, topical antibacterial creams, and petrolatum gauze dressings to the areas of skin damage constitute an initial response like that in the terrestrial setting. Because a transplanetary spacecraft is unlikely to have room to carry sufficient intravenous fluids to support treatment in such a scenario, parenteral support will rely on the on-site manufacture of sterile fluids from potable water sources.

Advanced and Definitive Care The advanced therapies described here are at present far beyond the scope of any spacecraft medical facility that has been flown thus far. For patients exposed to more than 4 Gy (400 rad), bone marrow transplantation may be the only chance for survival and should be begun between 1 and 2 weeks after exposure. Autologous marrow is greatly preferred to heterologous marrow to avoid inducing graft-vs-host reactions. Preparations for missions in deep space should require collection of autologous marrow from all crewmembers before flight, and that marrow should be stored in a refrigerated, radiation-protected facility on board. Marrow stimulants such as recombinant erythropoietin for erythrocyte precursors, and granulocyte and granulocyte-macrophage colony-stimulating factors for leukocyte precursors, may be used. Immune modulators such as interleukin-2 and interleukin-3 may be also useful for stimulating granulopoiesis and immune function.

Current Spacecraft Medical Capabilities Currently operating crewed spacecraft are limited to LEO, where the chance of an acute clinical radiation syndrome is highly unlikely, as it would have to entail an EVA taking place during a major SPE. However, procedures are in place for dealing with such an event. The ambulatory and emergency medical packs on the Space Shuttle enable the crew medical officers to provide basic initial supportive care for an acute radiation injury (described in Chapter 5). These kits include limited supplies of intravenous fluids, parenteral antiemetic agents, containers for vomitus, and oral antidiarrheal agents. Also included are first aid supplies for skin injury, including ointments and bandages to protect erythematous regions and to prevent breakdown of injured epidermis. Actual desquamation ulcers will be treated like thermal burns with topical antibiotics and dressings. The selection of oral and parenteral antibiotics for infection management will be limited. The ISS

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medical kits include all of the drugs found in the Shuttle kit in greater amounts, as well as an expanded advanced life support capability that includes respiratory support and cardiac monitoring, defibrillation, and pacing. The current stock of medical supplies onboard the ISS allows medical stabilization of an acute significant illness, but it does not allow that support to be maintained for longer than about 48 h. A mainstay of medical decision-making in LEO involves evacuation to definitive care on Earth. A significant radiation exposure requiring medical treatment would prompt return of the crew as soon as is practical, depending on vehicle “safing” requirements (e.g., configuring the station to continue operation in an untended mode if required) and landing site opportunities, to facilitate definitive care. Under most circumstances, return to an Earth-based tertiary care facility from LEO may be expected within 24 h. This would not be true for exploratory missions. A lunar base may require more extensive safing, or the injury may require more local care before the crew could safely endure the 2- to 3-day return to Earth. Crews outbound for Mars may not have any abort option that would allow return to Earth in time to positively influence treatment of radiation syndromes. Treatment capabilities for explorationclass missions will necessarily be more robust than those for LEO missions.

Radiosensitizing and Radioprotective Agents Radiation sensitizers (factors that have synergistic effects with radiation) can include chemicals such as polycyclic aromatic hydrocarbons, aromatic amines, hydrazine/azo compounds, metals, butyric acid [which is produced naturally in the colon]), drugs (such as psoralens, purine and pyrimidine analogs, paclitaxel, actinomycin D, hydroxyurea, raxozane, and electroaffinic agents such as misonidazole), endogenous factors (hormones, epidermal growth factor, or the presence of infection, endotoxins, or hyperthermia), or space flight–related factors such as vibration, noise, nonionizing radiation, and possibly acceleration forces [16]. On the other hand, the presence of radioprotective agents at the time of exposure may lessen the initial ionizing events from radiation such as cell death and induction of mutations. Radioprotective agents have been studied in the context of military (nuclear warfare) and medical (radiation oncology) applications. In terms of effectiveness, the ideal radioprotective agent must be present at the time of exposure, close by the site of damage (and remain there until the damaging actions have stopped), and able to protect against injury or damage arising from multiple pathways [85–88]. In practical terms, the ideal agent would be deliverable orally or parenterally; it would be effective for days to weeks (or could be given repeatedly); it would have minimal effects on performance; it would have no cumulative toxicity and minimal side effects; it would be compatible with other drugs; and it must have a

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long (2- to 5-year) shelf life. Although hundreds of potential radioprotectants have been studied to date, the ideal agent has yet to be identified. Many chemoprotective compounds are present in natural sources (Table 23.14). Indeed, it is preferable to derive these agents from natural sources, both for palatability and for the quality of their biological activity. However, it is not always possible to provide fresh foods and vegetables for an entire mission (especially long-duration missions), and therefore other means of accessing these nutrients, particularly with regard to their chemoprotective qualities, must be developed. Many potentially chemoprotective agents have undergone extensive testing in preclinical and clinical trials for their anticancer or cancer-prevention properties; indeed, much of the clinical experience with radioprotective agents has come from radiation oncology [89,48]. Of the chemical agents, amifostine (WR-2721) has been relatively well studied in this context, [48,90–93,] as has misoprostol [48,94]. Antioxidant agents such as vitamin C, vitamin E, beta-carotene, selenium, N-acetyl cystine, and alpha-lipoic acid may be recommended as prophylactic agents for deep space missions. Because radiation causes damage at many levels, a combination of agents representing the major classes of prevention molecules may be added to a daily prophylactic regimen. Such a regimen might include one or more of the following agents: retinyl acetate, allylic sulfide, ellagic acid, tea polyphenols, terpenes, isoflavones, isothiocyanate, indoles, flavonoids, phytoestrogens, anti-inflammatories, and protease inhibitors. Several other radioprotective agents have also been studied for their anticataractogenic effects [66,95,96]. Tests of agents used to protect against the effects of HZE radiation have been more limited; the few studies conducted have focused on reducing the frequency of mutations in cells [97] or reducing the number of cancers in exposed animals [98–100].

Table 23.14. Natural sources of chemical radioprotective agents in plants. Compounds Allium and N-acetyl cysteine [diallyl sulfide] Sulphoranes, indoles, and isothio cyanates [dithiolthiones, indole3-carbinol] Isoflavones and phytoestrogens Terpenes and ascorbic acid [perillyl alcohol, limonene] Curcumins Carotinoids, lycopene, lutein, antioxidants Polyphenols and flavonoids [epigallocatechin gallate, thearubigens, theaflavins] [Phenolic acids- ellagic acid, ferulic acid]

Sources Onions, garlic, chives, scallions Cruciferous vegetables (e.g., broccoli, cauliflower, kale, cabbage) Soybeans (e.g., tofu, soy milk) Citrus fruits (esp. lemon peels), cherries, tomatoes Tumeric Yellow vegetables, fruits (e.g., carrots, tomatoes, squash) Green and black teas, fruits, wine

Whole grains, nuts, tomatoes, carrots, citrus fruits

Biological Effects of Nonionizing Radiation Higher organisms have developed effective shielding mechanisms for UV radiation, e.g., the stratum corneum and melanin skin layers, to protect their DNA from the biological effects of shorter wavelength UV radiation. The risk of biological damage is tied to the specific spectral region and the effective irradiance incident upon the exposed tissue [101]. Short-wavelength UV radiation does not penetrate into the cell nucleus but does damage the cell membrane. Longer wavelength (240–400 nm) UV radiation penetrates into the cell, where it causes protein photodestruction and dimerization of nucleic acids [102]. UV cell killing results mainly from nucleic acid alterations rather than protein inactivation, as originally suspected. The main UV-photo product, cyclobutane pyrimidine dimers, is highly disruptive to the normal processes of replication and transcription. UV has a particular propensity to produce cross-linking between identical DNA bases (dimerization) either within or between DNA molecules [8]. Cyclobutane pyrimidine dimers can be repaired by photoreactivation with light of 300–600 nm, which costs the cell no energy and is error-free; or excision repair, which requires cellular energy and can be inaccurate.

Eye Effects Unlike the skin, the outer layer of the cornea of the eye is composed of living cells. All three types of UV radiation can damage the cornea. This is one of the more significant concerns of space flight and deserves specific mention here. Photokeratitis and photoconjunctivitis, also known as “snowblindness,” can result within as few as 90 min, but usually occur after a 4- to 12-h symptom-free period after exposure without eye protection. In terms of photokeratitis, the eye is most sensitive to wavelengths of 270 nm. The action spectrum threshold for corneal reaction is 4–14 mJ/cm2. Symptoms include the sensation of “sand in the eyes,” photophobia, blurred vision, edema of the eyelids, lacrimation, and blepharospasm. Horizontal staining bands may be seen on fluorescein staining, and acute corneal ulcers can be seen on magnification. Acute symptoms last ∼24 h, and the discomfort usually disappears by 36–48 h after exposure. Treatment of photokeratitis involves examination and removal of any ocular foreign bodies, including contact lenses. An ocular anesthetic can be instilled to relieve pain, but dosing and repeat installation should be limited. If ciliary spasm is severe, a cycloplegic-mydriatic agent should be instilled. Antibiotic ointment should be applied, followed by an eye patch and shield, taped into position. The patch should be left in position for 12 h before re-examination and reapplication of antibiotic. Oral pain medications should be used if pain is severe and cannot be controlled with the above measures. Generally topical steroids are not indicated and may interfere

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with re-epithelialization. Except for full-thickness injury, the corneal epithelium will heal and regenerate within days to a week; full-thickness injuries may produce scarring. UV-A exposure (350–380 nm) can produce lenticular fluorescence that is not damaging but can produce an unusual haze sensation on the retina in the absence of visual light. Chronic or very high-dose exposures can result in lenticular opacities, especially in the posterior subcapsular region of the lens. [95,103–105] Cataracts in experimental rodents are produced by exposures to light of 295–320 nm wavelengths, at a threshold of 0.15–12.6 J/ cm2 depending on the incident wavelength. The eye possesses two focusing (refracting) mechanisms for incident light—the convex surface of the cornea and the dual convexity of the lens. The ocular media (aqueous and vitreous humor) are transparent and transmit the focused light to the retina such that the irradiance (radiant exposure) is greatly enhanced at the level of the retinal pigment epithelium. The nonregenerative properties of this epithelial layer increase the potential consequences of overexposure to nonionizing radiation. The retinal pigment epithelium is where the first histologic and probably ophthalmoscopic damage is detectable. Higher levels of exposure can also damage the choroids and neural retina, which can result in permanent visual field defects. Such defects can be especially serious if the fovea and macula are involved.

Estimating Risks Associated with Viewing Activities A favorite crew activity, both for Earth observation and for recreation, is looking out spacecraft windows. On an orbiting spacecraft, the solar spectrum is not attenuated by the Earth atmosphere and thus the hazards associated with exposure to direct solar irradiance are greater than exposure to atmospherically screened irradiance on Earth. Thus the light transmittance properties of spacecraft windows and protective eyewear for space crews require careful analysis to avoid exposing crews to harmful levels of electromagnetic radiation. The best current source of information on human exposure to nonionizing radiation is found in the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values and Biological Exposure Indices, which outlines a method for evaluating the effects of exposures according to four pathways: retinal thermal injury from exposure to a visible light source (region of interest, 400–1400 nm), retinal photochemical injury from chronic exposure to blue-light (region of interest, 400–700 nm), exposure of the unprotected skin or eye to ultraviolet radiation (region of interest, 180– 400 nm); and corneal or lenticular injury from exposure to an IR source (region of interest, 770–3000 nm). The ACGIH method involves evaluating a known spectral distribution and provides a method for calculating the amount of time that the source may be directly viewed, or the amount of time for direct exposure in the case of skin UV exposure, before measurable molecular effects accrue. This “look time” can be used to guide crewmembers as to appropriate exposure durations. Figure 23.13 illustrates the peaks in injury potential based on

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the wavelength of incident light and the spectral weighting functions for retinal light hazards [106]. Evaluating a given exposure requires consideration of several points. First, the ACGIH values are not to be taken as a fine line between safe and unsafe conditions. Rather, they should be used as a guide, bearing in mind that the error associated with the available statistics is large enough so that case-bycase analyses are necessary. Second, because of the statistical inadequacies in the available exposure database, a margin of error is taken into account in the limits. For the retinal thermal (visible) hazard, a “safety” factor of 10 is associated with the source term in the calculation; a safety factor also applies to permissible exposure limits for blue light exposure. For IR, there is at least this margin of safety because of the conditions implied by the hazard. For UV exposure to the skin or the eye, there is no safety margin, and the limits given are the levels at which molecular rearrangement would be expected. Third, it should be noted that the limits given are levels at which molecular damage is expected, and these levels are often well below clinically detectable damage. Finally, the calculated times should be weighed against the body’s own natural aversion response. For example, if a look time of 5 s is calculated with regard to the retinal thermal injury pathway for exposure to the sun, then the reality of directly viewing the solar disk for 5 s should be evaluated. In this case, the pain associated with direct viewing of the sun would probably cause an individual to look away before the limit was reached, even though the time itself may seem to be short. These considerations should be borne in mind in evaluating risks associated with each pathway. In evaluating a particular viewing condition, the risk of retinal thermal injury associated with viewing a visible light source should be evaluated in terms of look time, window

Figure 23.13. Retinal thermal injury potential from the solar output spectrum, based on the American Conference of Governmental Industrial Hygienists (ACGIH) blue light hazard function [106]

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Table 23.15. Permissible ISS window observation time to avoid eye injury. Light and damage pathway Ultraviolet Blue light (direct continuous vision) Retinal thermal Infrared (corneal)

Light wavelength

Time to injury without approved sunglasses

Time to injury with approved sunglasses

180–400 nm 400–700 nm

36 min 4.41 s

>8 h 30.35 s

400–1400 nm 770–3000 nnm

1.71 s 27 min

>1 h >8 h

transmittance, sun angle, and sun spectral irradiance. For exposures longer than 1,000 s (about 16 min), the exposure to humans should be limited to 10 mW/cm2. The calculated exposure from this portion of the solar spectrum is 5.9 mW/ cm2; thus the exposure is roughly half of the long-exposure limit and therefore is acceptable. Analysis of transmittance through the ISS windows reveals an ocular hazard to the retina and other elements of the eye such that damage to these elements may occur within a matter of seconds of exposure if appropriate eye protection is not used. The window materials (magnesium fluoride and borosilicate) provide some protection from UV and IR wavelengths but not other wavelengths. Various types of sunglasses have been tested for their ability to block or filter transmission of light in the wavelengths of greatest concern; those that provide adequate protection and have been approved allow less than 2% transmittance of light shorter than 400 nm, less than 10% of light in the 400- to 700nm range, and less than 30% of light longer than 700 nm. The permissible “look times” while wearing these sunglasses thus can be extended from seconds to minutes or hours of constant viewing through windows from which the scratch pane has been removed (Table 23.15). The VIPOR study A hazard analysis conducted for the Visual Investigation Program on Orbiter Operations (VIPOR) specifically addressed non-ionizing radiation hazards associated with window observations during space flight. According to this study, unprotected viewing of the sun through the side hatch window of the Space Shuttle (or, for an EVA crewmember, through the EMU helmet without the sun visor protection being in place) should be limited to less than 2 s because of potential injury from light at several wavelengths. The exposure time limit for blue light (Lblue) is 1.23 s, and that for exposure to actinic UV (200–315 nm) is 3.36 s. The time limits for exposure to visible to infrared (IR) light is 11.7 s, 2.6 s, and 0.4 s based on a respective pupillary size of 5, 6, and 7 mm. Because the human blink reflex occurs within 0.15–0.2 s, the risk of thermal injury to the retina is thought to be low. However, given the collective risk from all nonionizing-wavelength radiation, crewmembers are advised to wear additional eye protection (in the form of blue-blocking polarizing sunglasses) when the protective shroud is removed from the side hatch window of the Space Shuttle during times of direct sunlight exposure.

Skin Effects Exposure to UV-B and UV-C wavelengths produces a photochemical effect that depends on the wavelength and duration of the exposure as well as the presence of melanin or photosensitizers. Agents that sensitize skin to UV irradiation include antimicrobial agents such as topical fungicides, hexachlorophene, oral sulfa drugs and tetracycline; chlorpromazine; salicylate; psoralin; and oral contraceptive pills. Melanin can increase the minimal erythema dose (typically 6–30 mJ/ cm2) by an order of magnitude. Observed effects resemble those of terrestrial sunburn and include erythema (with a 4- to 8-h latency period), blistering (after 8–48 h) and desquamation (more than 48 h after exposure). Exposure to a combination of UV-A and UV-B intensifies the erythema response. Skin sensitivity is maximal at 295 nm, and longer-wavelength UV (295–315 nm) produces a more severe and persistent erythema response. Chronic exposure to UV radiation produces tough, wrinkled, darkened skin (“farmer’s skin” or “sailor’s skin”) characterized by thickening of the epidermis and actinic changes such as actinic and seborrheic keratoses. Exposure to UV radiation, especially UV-B, at early ages predisposes the skin to basal cell and squamous cell carcinoma and melanoma [107]. Individuals with defects in DNA repair (e.g., those with xeroderma pigmentosum) are particularly susceptible to skin cancer because of the inefficient repair of UV-induced cross-links. Epidemiologic studies have also shown higher rates of skin cancer among populations living at low latitudes or those living at high altitudes and those with low melanin content in the skin (e.g., individuals of Northern European origin). The main biological effect of IR radiation is thermal. High levels of IR-induced tissue excitation produce increased temperature in the tissue. Generally slight, short-lived increases in temperature are well tolerated and rapidly dissipated by the circulation. Prolonged continuous exposure to IR or other nonionizing radiation, however, can overwhelm heat dissipation mechanisms and elevate cellular temperatures, which in turn can lead to the release of heat shock proteins and the induction of apoptosis. The strategy for controlling skin effects of exposure to nonionizing radiation is to use topical sunblock creams (those with a sun protection factor [SPF] rating of 30). Crewmembers are required to use such skin creams when the exposure of uncovered skin through the windows in the Lab Module, the Japanese Experiment Module, or the Cupola is anticipated to exceed 45 min over the course of a 24-h period.

Whole-Body Effects from Electromagnetic Radiation When the human body is exposed to electromagnetic radiation in the radiofrequency wavelengths, some of the radiation is absorbed and some passes through depending on the frequency. Both the type of tissue and the frequency of the radiation affect

23. Radiation Disorders

the depth of energy penetration and degree of absorption. For frequencies below 150 MHz, the body acts like a cylindrical antenna. For a typical 1.7-meter human, the resonance frequency is 44 MHz on the ground and 88 MHz in free space; this means that humans in the path of 88 MHz electromagnetic radiation can incur significant heating and tissue effects. The carcinogenic potential of electromagnetic radiation is controversial. Despite highly sensationalized anecdotal reports of brain cancer in individuals who use cell telephones, or testicular cancer in policemen who use radar to monitor the speed of motorists, no clear evidence of any increase in risk, or any possible mechanism of induction, has ever been found. In a 1997 meta-analysis of 70 studies to examine whether electromagnetic radiation was associated with cancer incidence [108], the authors concluded that a very small elevation in cancer risk was associated with exposure to electromagnetic radiation exposure in the workplace (relative risks of 1.10 for brain cancer and 1.18 for leukemia). However biases may have affected conclusions drawn in the studies analyzed that could have influenced their results and the results of the meta-analysis.

Space Radiation Monitoring and Dosimetry As is true for any occupational radiation exposure, the radiation doses incurred during space flight must be meticulously measured and tracked to ensure that identified health limits are not exceeded. Space radiation dosimetry differs from other branches of radiation physics in that the energies of the radiation to be measured can extend over many orders of magnitude and the radiation can include particles of many different species, thus mandating the measurement of several types of variables. A variety of techniques and instruments have been developed for measuring absorbed dose, dose equivalents, particle flux and fluence, and linear energy transfer spectra as well as particle charge, mass, and energy distribution. Most of these variables vary temporally as well as spatially. The detectors used in space-based dosimetry include thermoluminescent dosimeters (TLDs), plastic nuclear track detectors, tissue equivalent proportional counters (TEPCs), and charged particle directional spectrometers. After each space mission, an integrated report detailing the radiation dose for each crewmember is developed and becomes part of that crewmember’s medical record. Space radiation dosimetry can be accomplished through the use of active or passive measurement systems. Active systems involve dosimeters whose data can be read during flight, either on board or after telemetry to Earth and near-real time processing. Passive systems, in contrast, are dosimeters that are read and analyzed after landing; two examples used in space radiation dosimetry are TLDs and plastic nuclear track detectors. In the absence of active monitoring and telemetry, the crew and flight control team must rely on exposure data collected from orbiting satellites and the use of models to calculate the projected dose to the crew at altitudes that are different from those of the detection satellites. One such satellite,

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the TIROS, orbits at 830–850 km from Earth; by comparison, the ISS orbits at 400 km from Earth.

Passive Dosimetry Several types of passive dosimeters are used to track radiation doses to the crew and to the space vehicle over time. The crew personal dosimeter devices are small (5.5 × 3 × 0.5 cm) Lexan badges containing TLD chips that are to be worn at all times; these devices track an individual’s accumulated dose throughout a mission. Crewmembers are asked to wear the dosimeters during launch and entry and EVAs, which necessitates transferring the devices from clothing to the space suits. Personal dosimeters are returned with the crewmembers, and their data are processed after landing. Another type of passive dosimeter are the area monitors, which also incorporate TLD chips and are deployed throughout the Space Shuttle and the ISS to measure radiation that accumulates over the course of a mission. Devices on board the ISS are retrieved and exchanged at each crew rotation. Doses to the area monitors vary according to their location on the spacecraft (and the associated structural shielding) and the spacecraft attitude; as such, they are strategically deployed so as to best characterize the radiation environment of the habitable volumes and to correlate with personal dosimetry. High-rate dosimeters are carried for contingency scenarios involving large radiation exposures, such as those arising from a massive SPE or the detonation of a nuclear weapon in space. These dosimeters consist of small, easily visualized ionization chambers that are designed to give rough estimates of radiation doses between 0 and 6 Gy (600 rad).

Active Dosimetry Real-time measurement of radiation exposures during space mission require the use of active dosimeters. A suite of such dosimeters is currently on board the ISS, and others are being developed to enable real-time insights into radiation doses that might prompt immediate crew action. Two types of active dosimeters, those focused on microdosimetry and measurement of particle types and spectra, are described below.

Microdosimetry: Tissue Equivalent Proportional Counters Microdosimetry is based on the principle of measuring the energy deposited in microscopic (1-µm3) volumes of simulated tissue. For measuring energy loss from charged particles, tissue volumes of about 0.3 µm3 to several µm3 can be replicated by using gas at low pressure. Since the physical basis of the RBE of different types of radiation is thought to result from differences in the spatial distribution of ionization along the particle track, physical quantities can be measured and related to biologically relevant quantities. Radiation experts now recommend that the quality factor Q be expressed in terms of LET, which can be measured directly by microdosimeters.

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The tissue-equivalent proportional counter (TEPC) is the microdosimeter currently flown in the U.S. space program. It has flown on the space shuttle, the Mir space station, and is flying aboard the International Space Station (ISS) with data continually fed to the ground via telemetry link. Tissue equivalent proportional counter devices are characterized by small, nearly spherical chambers filled with a lowpressure gas such as propane. The gain of such devices, created by applying a potential of 600–800 v to a wire that passes through the chamber, has been demonstrated to be stable for more than a year, and calibration tests using ion beams at a particle accelerator have verified the ability of such instruments to measure LET distribution accurately. The TEPC is relocated periodically to map the dose in various parts of the station.

LET-Spectrum Measurement: Particle Spectrometry Microdosimetry instruments such as the TEPC cannot distinguish among particle types, nor can they provide information on the arrival direction of the particles. Detecting the arrival direction of GCR is not crucial since their fluence is isotropic. However, trapped-belt protons are highly directional and energy dependent. Radiologic studies [9] indicate that inactivation or transformation cross-sections for cells are not a function of LET but rather of the nuclear charge Z and the velocity β of the particle, where β = v/c (velocity v is expressed in units of the velocity of light, c). The restricted energy-loss model predicts a dependence of these cross-sections on Z2/ β2. Knowing the particle charge and velocity thus provides a means of computing the relevant energy loss parameter in any medium. When a nonrelativistic particle of charge Z and velocity β comes to rest in a stack of detectors, the amount of energy that it deposits in a top thin layer of thickness ∆x is DE ~ (Z2 / b 2) Dx Detectors in a charged particle spectrometer can be stacked to allow discrimination of energies over a broad range. If the particle of mass m is stopped in the bottom detector, its residual kinetic energy E is

energy of these high-energy particles cannot be calculated. However, a different arrangement can be used that replaces the total E detector with a Cerenkov detector. The light output L, which can be measured with a photomultiplier tube, is L = KZ2 (1–b 20 / b 2) where K is a constant and βo is the cutoff velocity below which no Cerenkov light is generated. βo is related to the real part of the index of refraction n by βo = 1/n. UV-transparent Cerenkov materials provide cut-off energies as low as 160 MeV/ nucleon for solids and up to several tens of GeV/nucleon for gases. The charge and velocity of the particle can be determined from measurements of ∆E and L. Both the technique that measures E∆E and the one that measures L∆E can yield energies and nuclear charges of particles over a wide range. For the ISS, one such single-axis, charged particle directional spectrometer will be kept inside the vehicle and relocated about every 2 weeks to map the radiation levels in the entire station. A triple-axis device with three directed telescopes will be mounted outside the habitable volume on the truss structure. Differences between the spectrometer readings outside and inside the spacecraft can be used to calculate transport of charged particles into the vehicle.

Russian Active Monitors The active R-16 monitor system, manufactured by Moscow State University Scientific Research Institute for Nuclear Physics, measures the dose of cosmic radiation and depth dose. The radiation detector consists of an integrated pulse ion chamber with two independent chambers. One chamber is filled with only air and provides the physical dose. The other chamber has a piece of glass across the ostium, simulating a tissue-like equivalence. Real-time data are provided via 16-bit binary code telemetry. The anticipated lifetime of the R-16 system is 8 years (20,000 h of use.) A similar instrument was flown aboard Mir. Two other Russian devices are the DB-8, a large monitor that is hard-mounted aboard the ISS that measures energy deposited into silicon, and the Lyulin, a smaller portable silicon detector.

E = mb 2/2 and thus

Active Personal Dosimetry EDE ~ mZ2

Every isotope can be represented by a unique hyperbola proportional to the mass of the particle and the square of its nuclear charge. The measurement, therefore, of ∆E and E yields a measure of the kinetic energy per nucleon, particle charge, and isotopic mass. Care must be taken with such detector systems to limit the acceptance angle of the spectrometer so that the variations in the particle path length are minimized. One option is to use position-sensitive detectors that can provide the arrival direction of the particle and avoid these path length variations. As particle energy increases, it becomes impractical to increase the depth of total E detectors because of possible interactions of the particle in the detector material. The charge, mass, or

The current suite of instruments onboard the ISS does not include an active personal dosimeter, which would be used to characterize the local environment during intravehicular or extravehicular operations. However a prototype has been built that would provide instantaneous readings of absorbed dose rate, cumulative dose, dose equivalent rate, and cumulative dose equivalent, plus an alarm for high dose rates, to the crewmember. The current compact prototype, designed not to exceed 100 grams, would allow crewmembers to know immediately, in the case of lost communication to the ground from a SPE or geomagnetic storm, when their exposure is increasing and let them know if the area of the vehicle provides adequate shielding protection to reduce the dose rate to acceptably safe levels.

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Organ Dose Models Newer organ-dose models and detector assemblies have been designed in an attempt to better replicate the exposure a human body would receive from space radiation sources. One such model, the Computational Anatomic Male, developed by P. Kase, uses anthropometric and anatomic data to better quantify incoming radiation effects based on organ and body weight and different tissue types. The model is constructed of 1500 quadratic surfaces in a Cartesian coordinate system yielding about 2500 closed volumes. This modeling system can be translated into a three-dimensional detector array to better simulate human body exposures. Such an anatomically correct array of detectors co-located with an on-orbit crew would give more mature estimates of whole body dose equivalent or effective dose. The Phantom Torso experiment, which features just such an array, has been flown on the Shuttle and ISS. Russians investigators have flown a water-filled phantom on the Mir, from which they reported exposures of 29 µSv/ hour, with 3 µSv/hour coming from neutrons. Phantom Torso measurements have helped to confirm calculated dose to specific organs during space flight.

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Analyses of aberrations in metaphase chromosomes in crewmembers aboard the MIR and EUROMIR missions (flown in 1994–1996) showed increased numbers of aberrations in chromosomes, but not in chromatids, after space flight, suggesting that the detected lesions had been radiation-induced. The numbers of dicentric chromosomes were doubled after flight compared with before in crewmembers exposed to > 2.5 mGy from HZE particles of LET > 2.0 GeV/cm; the pooled frequencies of dicentrics were 3–5 times greater after flight. Estimates of total flux of HZE particles with LET > 2.0 GeV/cm was 510/cm2. Given that the geometric cross section of lymphocytes is 16 µm2, the fraction of cell nuclei hit was calculated to be 8.2 × 10−5. Rogue cells containing multiple discrete aberrations within the same nucleus have also been reported after exposure to HZE radiation [19]. Other biological measures that might be used to quantify the effects of radiation on the human body are being investigated as well.

Radiation Exposures Measured Aboard Crewed Spacecraft The U.S. space program has involved missions at diverse altitudes and inclinations in Earth orbit and in lunar space.

Biodosimetry Use of principles from biodosimetry allows a better understanding of how radiation, measured by physical dosimetry, affects space crewmembers. Because the RBE of space radiation is largely unknown, biodosimetry provides means of measuring of the biologically relevant adsorbed dose by examining actual end point damage. The biologically relevant dose obtained by biodosimetric analysis should correlate better with actual health risk than physical measurements of radiation. Quantification of chromosomal aberrations found in peripheral blood lymphocytes is currently the most widely used method for biodosimetry. In its standard application, metaphase chromosomes are analyzed for physical and chemical evidence of damage. However, this technique requires some degree of cell-cycle synchronization, which is complicated by microgravity and by delays in the cell cycle induced by high-LET radiation. Thus, an interphase method is used for space radiation biodosimetry. Assaying cells that are in interphase rather than metaphase greatly increases the number of cells available for analysis. Use of premature chromosomal condensation by fluorescence in-situ hybridization (FISH) has also helped to overcome the problems with metaphase cytogenetics and has lowered the dose-detection threshold [109]. Chromosomal translocations are particularly informative for biodosimetry because they are easily identified by FISH chromosome painting techniques, they often remain stable in the body for years, and because they are associated with genomic instability they can serve as a marker for cancer risk. Background levels of translocations must be controlled for by using preflight measurements to develop a calibration curve; examples of such curves for a group of long-duration crewmembers are shown in Figure 23.14 [110].

Mercury/Gemini Project Mercury flights were both brief and flown at low altitudes, and thus the radiation exposure to the crews was inconsequential. Data from Gemini 4 (duration 4.05 days at 32.5 degrees’ inclination) resulted in a mission dose of 0.46 mGy, whereas Gemini 6 (1.05 days at 28.9° degrees’ inclination) resulted in a mission dose of 0.25 mGy.

Figure 23.14. Chromosomal translocations measured in peripheral blood lymphocytes as an index of radiation exposure in a group of long—duration flight crewmembers, with missions ranging between four and six months. A calibration curve is shown along with actual astronaut data [109]

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Apollo

Shuttle/Mir Program

The highest dose received during an Apollo flight occurred on Apollo 14, with a mission dose of 11.40 mGy. Most of the total radiation exposure during Apollo missions 7 through 17 took place while the vehicle was within the Van Allen belts. The Apollo 14 trajectory, particularly the outbound portion, also took the spacecraft close to the heart of the trapped radiation belts. Because the mission took place during solar minimum, the cosmic ray flux was relatively higher than it had been during previous missions. The dose rate of 0.13 mGy [0.127 rad] per day (total dose of 1.14 mGy [1.14 rad] over the 216-h mission) was the highest measured in the space program until high-altitude LEO flights were undertaken in the Space Shuttle program. The Apollo missions also represented the first crewed flights outside the protective geomagnetosphere. A major flare such as that of October 1989 may have imparted a few to several tens of rems to blood-forming elements over a 2-day period in areas shielded to 5–10 g/cm2 aluminum equivalent. An unshielded crewmember, i.e., one outside the vehicle during the flare, would have been exposed to doses of a few Sieverts (or a few hundred rem) [111]. A worst-case exposure scenario would involve a lengthy EVA during such an event; given the minimal structural shielding of the space suit, such a dose, experienced over 1–3 days, would eventually be fatal to a significant percentage of crewmembers.

Data collected and analyzed over the life of the Mir station, which orbited at a 51-degree inclination, have been invaluable for radiation monitoring, modeling, and dosimetry. Scientists from the European Space Agency and NASA have flown radiation-monitoring devices on the MIR during its operational lifetime, and in conjunction with the data from the Russian R16 ionization chambers, the results from these devices have been helpful for predicting exposures to crews onboard the ISS. Absorbed doses and dose rates for cosmonauts aboard Mir from 1986 to 1997 are shown in Table 23.16[23]. Because the length of the missions varied, the best comparator is probably dose rate, which varied from 182 to 397 µGy/d. The quality factors (Q) of radiation assessed during solar minimum, as measured with a TEPC during the NASA/Mir program, were found to be 3.18 from GCR, 1.88 from trappedbelt radiation (2.51 total) within the Service Module vs. 3.38 from GCR and 1.66 from trapped-belt radiation (2.14 total) in the Kristal module [23]. These differences are assumed to have been due to variations in shielding and east-west asymmetry. Assuming an average Q of 2.5, the dose-equivalent rate for the cosmonauts ranged from 0.457 to 0.996 Sv/d. Factoring in inefficiencies inherent in TLDs for high-LET charged particles and contributions from high-energy neutrons (which could not be detected by TLDs or the TEPC), the true dose may have been as much as 25% higher.

Skylab Radiation doses received during each Skylab mission ranged from 15.96 mGy for the 28-day Skylab 2 mission to 77.40 mGy for the 84-day Skylab 4 mission.

Space Shuttle Space Shuttle flights to date have involved relatively low radiation doses because of their limited duration (1–3 weeks). Mission altitude has a significant influence on exposures received by Shuttle crews. The lowest dose rate encountered during Space Shuttle missions was on STS-38, which was flown at low altitude (110 nautical miles) at 28.5° inclination (about 0.0002 Sv [0.02 rem] per day for a total dose of about 0.001 Sv [0.1 rem]). The enhancing effect of altitude at the same 28.5-degree inclination was notable on the STS-31 mission (during which the Hubble Space Telescope was deployed); at an altitude of about 300 km, the total dose-equivalent was about 0.01 Sv (1.1 rem), with a dose rate of 0.016 Gy (1.642 rad) per day. The largest total exposure to date during a Space Shuttle mission has been 0.043 Gy (4.3 rad); the smallest has been 0.00006 Gy (0.006 rad) (mean, 0.00235 Gy [0.235 rad] per mission; median, 0.0012 Gy [0.122 rad] per mission). The highest dose rate ever observed in on a Space Shuttle at high altitude was 3.211 mGy/d.

Table 23.16. Average cosmonaut absorbed dose and dose rates aboard mir. Mission

Altitude Launch Date Duration (d) (km)

Dose rate Dose (cGy) (µGy/d)

Mir-01 Mir-02 Mir-03 Mir-04 Mir-05 Mir-06 Mir-07 Mir-08 Mir-09 Mir-10 Mir-11 Mir-12 Mir-13 Mir-14 Mir-15 Mir-16 Mir-17 Mir-18 Mir-19 Mir-20 Mir-21 Mir-22 Mir-23

3-13-86 2-06-87 12-26-87 11-26-88 9-06-89 2-11-90 8-01-90 12-02-90 5-18-90 10-02-91 3-17-92 7-27-92 1-26-93 7-01-93 1-08-94 7-01-94 10-04-94 3-15-95 6-27-95 9-03-95 2-21-96 8-17-96 2-10-97

4.53 3.95 8.18 3.70 4.73 3.74 2.89 4.63 — — 3.71 4.96 4.61 4.38 4.81 2.90 4.11 3.32 2.43 7.10 6.62 7.50 6.15

123 217 366 152 225 179 131 176 145 175 146 190 180 197 183 126 169 115 76 179 195 198 187

— — — — 403.8 396.7 397.7 390.2 398.0 402.2 405.8 414.5 405.0 403.7 405.6 410.0 406.6 393.7 394.9 393.3 389.8 382.3 386.8

Source: Data from Table 23.2, Badhwar [23].

368 182 223 243 210 209 220 263 — — 254 261 256 222 263 230 243 288 320 397 339 379 329

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International Space Station The ISS orbits in a 51-degree inclination, and its external radiation milieu is much like that of Mir. The altitude varies with boost phases between about 320 and 385 km (200 and 240 nautical miles). As is true for other LEO platforms, the major radiation components contributing to the total dose on the ISS are trapped protons from the SAA and GCR. The radiation experienced at a given point within the ISS depends strongly on the external radiation impinging on the structures of the spacecraft and on the amount and composition of the materials of those structures (e.g., spacecraft walls, furnishings, stowage, electronics) in the radiation path. Structural materials both attenuate the incident radiation and serve as a source of complex secondary radiation. Because of these manifold interactions, the radiation environment within ISS will be considerably more complex than the primary radiation incident upon it, and it will vary substantially over time because of the changing orientation of the structural materials and the varying incident radiation field. This complex multicomponent radiation field presents a unique and difficult measurement problem for any space radiation protection program. Estimates of the radiation exposure for crewmembers onboard the ISS are based on historic dose measurements of cosmonauts onboard Mir along with modeling of exposure based on current knowledge of ISS vehicle components, shielding, attitude, and altitude, as shown in Figure 23.15 [112].

Radiation Monitoring during Extravehicular Activities Doses likely to be experienced from radiation exposures during specific EVA sorties are estimated and analyzed before flight and during each mission by a space radiation analysis group. This group also provides recommendations as to the timing of the EVA relative to the orbital trajectory so as to minimize the dose to the EVA crewmembers. Dose penalties associated with beginning an EVA before the scheduled start time or extending beyond the scheduled terminate time are also calculated. Depending on the altitude and inclination of the vehicle as well as the state of the geomagnetosphere at the time of the EVA, the dose penalties for suboptimal and extended timing of EVAs can be substantial. Other considerations for timing EVAs include avoiding the SAA and the electron horn (low cut-off zone) regions. Contingency EVAs that must be done during an SPE with electron belt enhancement are assessed with the goal of avoiding the periods of peak flux. The attitude of the Shuttle vehicle can be adjusted so as to afford maximum structural protection to crewmembers outside the vehicle. Doses during EVAs that take place in LEO come mainly from trapped particle radiation. The radiation analysis group also provides recommendations to the flight surgeon and the flight director to prematurely terminate or delay an EVA on the basis of current space weather and projected dose rate during the EVA. Projected organ dose and

Figure 23.15. Predicted radiation dose rates to International Space Station (ISS) crewmembers relative to altitude. Figure A shows predicted altitude-dependent dose rates to the skin and to the blood— forming organs (BFO) as a function of solar cycle extremes [112]. Figure B shows the annual BFO dose vs altitude for varying levels of shielding.

the cumulative projected dose to date for each crewmember are also taken into account.

Limits and Medicolegal Aspects of Radiation Exposure Space flight unavoidably exposes crewmembers to ionizing radiation from natural sources, and any increase in radiation exposure increases the risk of cancer or genetic mutations. Because risk avoidance is equivalent to dose avoidance and because complete dose avoidance in space is not possible, levels of acceptable risk must be established. Research over the past decade has led to the cancer risk per dose-equivalent being revised upward, and the relative carcinogenic effectiveness of certain types of space radiation may be much higher than previously thought. Current U.S. and international annual

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limits for ISS crewmembers dictate that a space crewmember may not receive more than a depth-dose equivalent of 0.5 Sv (50 rem) per year. Calculations indicate that a 180-day stay aboard the ISS could result in a worst-case depth-dose of roughly 0.3 Sv (30 rem). A 180-day mission in a spacecraft more heavily shielded than the ISS (e.g., one shielded to 20 g/ cm2) in a nominal, constant atmospheric density orbit with a varying altitude would result in a depth-dose equivalent of roughly 0.1 Sv (10 rem), which is still twice the annual allowable dose-equivalent of 0.05 Sv (5 rem) for terrestrial radiation workers. Astronauts thus work under an annual limit that is ten times the allowed limit for terrestrial radiation workers. Crewmembers on long-duration missions thus normally incur a much greater absolute dose, and a much higher fraction of their allowable limits, than do their terrestrial counterparts. Uncertainties abound in many of the variables influencing radiation dose, including the initial charged-particle spectra, radiation transport calculation, risk coefficients for low-LET radiation (most of which reflect uncertainty in the dose and dose rate effectiveness factor), and the risk cross section for exposure to high-LET radiation. The overall uncertainty in the risk of radiation-induced cancer, at our present state of knowledge, has been estimated as being between 4 and 15 for a space crew in the galactic cosmic ray environment [69]. Additional experiments with phantom torsos combined with the suite of instruments planned for ISS may improve the organ-specific quality factor and dose estimations of the risk models [113]. During this time, a rigorous occupational health approach is being developed and implemented. Although limits for nonionizing electromagnetic radiation, based on frequency spectra and field strength, have been established for space operations, the remainder of this section focuses on ionizing radiation and cumulative exposure aspects.

Occupational Health Aspects In the United States, astronauts have been classified as radiation workers, and thus the U.S. Code of Federal Regulations dictates that a program must be in place to protect them from excessive radiation exposure. This program and its regulations are the responsibility of the Occupational Safety and Health Administration (OSHA) under the Department of Labor. OSHA established limits for the exposure of workers and the general public to ionizing radiation in 1971. Presidential Executive Order 12196 (Feb. 26, 1980) requires that all federal agencies, including NASA, comply with OSHA regulations related to ionizing radiation exposure. Although NASA is required to follow OSHA regulations, no OSHA standards exist for space flight. Terrestrial radiation exposure guidelines provided in the Code of Federal Regulations (29 CFR 1910.96) are too restrictive for space activities and therefore have been judged inappropriate. For these reasons, NASA is allowed to establish supplementary standards for appropriate control of radiation for astronauts in accordance with 29 CFR 1960.18, “Basic Program Elements for Federal Employees Occupational

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Health and Related Matters.” This regulation was updated by the Presidential document “Radiation Protection Guidance for Occupational Exposure: Recommendations Approved by the President” (Vol. 52 Jan. 1987). The following NASA requirements serve as a basis for implementation of this supplementary standard: that it be used only for a limited population (i.e., space crewmembers), that detailed exposure records are kept for flight crews, that hazards are assessed before every mission, that planned exposures are kept as low as reasonably achievable (the “ALARA” principle), that operational procedures and flight rules are maintained so as to minimize the chance of excessive exposure, and that any exposure to artificial onboard radiation sources complies with 29 CFR 1910.96, except where the NASA mission objectives cannot be accomplished otherwise. NASA has adopted the recommendations of the National Council on Radiation Protection and Measurements as presented in its Report 98, Guidance on Radiation Received in Space Activities [114], as the basis for its supplementary standard for spaceflight crew radiation exposures. Values are defined for maximum (career), 1-year, and monthly exposure limits. Whereas monthly and annual limits primarily exist to prevent the short-term physiological effects of exposure, career limits exist to contain radiation risk at a maximum of 3% increased lifetime cancer mortality. The defined limit of 3% excess cancer deaths originates from comparisons to other occupational injuries. In a subsequent report (Report 132) [112], the National Council on Radiation Protection recommended that a new radiation measurement unit, the Gy-equivalent, be used for calculating short-term limits. The Gy-equivalent is based on RBE instead of Qf, the factor used for estimating late effects and the calculation of career limits. Short-term limits have been established for three organ-specific sites: eye, skin, and blood-forming organs. The recommendations of the NCRP reports 98 [114] and 132 [115] apply to activities in LEO, such as those aboard the Shuttle or space stations. In addition to the revision of units for radiation risk assessment information from recent reevaluations of atomic bomb survivor data and other sources and has provided the impetus for further examination of the acceptable limits of astronaut radiation exposure. Recommendations from the NCRP based on evaluation of the new data suggest that even lower career limits for astronauts may be warranted, and the NCRP 132 report cites lower doses associated with 3% excess cancer mortality career limits. The new recommended space flight exposure limits from NCRP 132 are presented in Table 23.17. These recommendations were being considered for adoption by NASA when this chapter was written. NASA is also developing flight rules that account for action levels (which are one third the levels of acute and annual dose limits) to assist in operational implementation of the ALARA principle. As noted above, sufficient uncertainty exists in predicting the risk of cancer from a certain dose that a further degree of conservatism may be warranted. The current agency approach is to work toward a radiation dose associated with a

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Table 23.17. Recommended organ dose-equivalent limits from ionizing radiation for space crewmembers in low earth orbit. Limits

Skin (Sv or Gy-Eq)

Ocular Lens (Sv of Gy-Eq)

Blood-Forming Organs (Sv)

30-Day 1-Yeara Career

1.5 3.0 6.0

1.0 2.0 4.0

0.25 0.50 1.0–4.0b

Abbreviations: Gy-Eq, Gray-equivalent. a 1-year limits are not to be considered annual limits, i.e., not repeated year after year. b The limit for the dose to the blood-forming organs varies according to age and sex. Source: NCRP Report No. 98 and 132.

3% excess lifetime cancer mortality within a 95% confidence interval. This level will vary with radiation type, and crewmember age and sex; for individuals at higher risk, i.e. young female crewmembers, the level may approach that of a dose associated with a 1% excess mortality. For doses projected to breach the 95% confidence interval range, further risk/benefit analyses and informed consent procedures will be undertaken. Depending on the astronaut’s age and sex, two or three 180-day ISS missions may complete his or her long-duration career under this new limit. At NASA, radiation health officers are responsible for generating reports that summarize each astronaut’s occupational radiation exposure, including both terrestrial and spaceflight exposures. These reports include physical absorbed spaceflight doses, as measured by the personal passive dosimeters; estimates of whole body effective dose, which are based on the average quality factor measured by TEPC or similar devices; and modeled estimates of individual organ exposure. Exposure from medical procedures and experiments are also determined for each crewmember. Exposure calculations and the age and sex of the crewmember are used to generate estimates of the risk of developing fatal cancer. Crew flight surgeons review these reports with each crewmember once a year and before every flight.

Radiation Issues for Exploration and Habitation Missions Radiation Assessment for Lunar and Mars Missions Many variables must be considered in assessing the radiation profile associated with travel beyond Earth and its protective geomagnetic fields. This section considers aspects of human lunar and Mars exploration efforts, in which the spacecraft traverses the Van Allen belts and their trapped radiation, exiting the geomagnetic shield and becoming exposed to isotropic GCR and unencumbered SPEs. With current propulsion technologies, transit to Mars will involve very long periods in this deep space environment. The increasing remoteness of travel through deep

space renders medical return for in the event of acute radiation syndromes much less likely. As such, missions must be carefully planned to minimize the chances of exposures that might approach the threshold levels for deterministic effects. This elaborate planning process begins with analysis of celestial mechanics to minimize transit time and synchrony with the solar cycle. Notably, a 36-month mission beginning 4 years after solar minimum would result in a total incurred dose 45% lower than would be received on a mission beginning at solar minimum [116]. In addition, the acceptable risk for stochastic effects may differ from current NASA limits, which were designed for routine LEO operations rather than exploration efforts.

The Storm Shelter To optimize crewmember protection from the most dangerous aspects of SPEs, the concept of a radiation haven within the spacecraft has been proposed. Such a storm shelter would provide a “radiation-hardened” volume within which all crewmembers could take refuge during these unpredictable but short-lived events. One scenario for a 500-day Mars mission includes the assumptions that the vehicle has been designed to include a 20 g/cm2 aluminum storm shelter and that the crew will occupy the sleep station, which could be a modified storm shelter, for 8 h a day [117]. Calculations generated with an anatomical model and assuming exposure to two types of environments (GCR and solar flares) yield estimated cumulative dose equivalents for a 500-day mission of 0.6621 Sv (66.21 rem) to the skin, 0.6695 Sv (66.95 rem) to the eye, and 0.4892 Sv (48.92 rem) to the blood-forming organs. All predicted dose-equivalents in this calculation would be below the annual exposure limit for astronauts as currently defined for LEO activities. The storm shelter concept would apply for lunar and Mars transit as well as for surface activities, as described in the following paragraphs.

Lunar Mission The overall radiation dose for a 12-month mission on the lunar surface has been estimated as follows. Days are divided into three 8-h periods, the first of which is used for research and exploration activities on the surface. During that time, crewmembers would wear a Space Shuttle-type EVA suit considered to have shielding equivalent to 0.3 g/cm2 of aluminum (i.e., a suit that lacks the hard upper torso and portable life support system of the current Shuttle suit). During the second 8-h period, crewmembers would be in a pressurized habitat, the worst-case areal density of which will be equivalent to 5 g/cm2 of aluminum. Several meters of lunar regolith will cover the habitat to minimize the dose exposure. During the third 8-h period, crewmembers would be inside a storm shelter sleep station, equivalent to 10 g/cm2 aluminum, to reduce radiation exposure. This scenario also includes an additional three EVAs outside the habitat per week.

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The dose exposure from a 3-day round trip to the Moon inside a 2 g/cm2 aluminum-shielded vehicle will be 0.05 Sv (5 rem) [118]. The overall dose exposure for the mission, calculated considering the 1977 GCR, will be 0.42 Sv (42 rem) to the skin, 0.41 Sv (41 rem) to the eyes, and 0.32 Sv (32 rem) to the blood-forming organs [85]. The addition of one 1972-class SPE during the 1-year mission, with the crewmembers inside a 10 g/cm2 storm shelter, contributes another 0.11 Sv (110 rem) to the skin and eyes and another 0.24 Sv (24.3 rem) to the blood-forming organs [85]. Hence the total dose exposure during a 12-month mission on the Moon plus a 6-day round trip flight plus one 1972 class SPE while the crewmembers are on the surface will be 1.57 Sv (157 rem) to the skin and eyes and 0.71 Sv (71 rem) to the blood-forming organs.

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(1.6%). Although the pressure at ground level is less than 1% of that of Earth’s atmosphere, the Mars CO2 atmosphere will have a substantial protective effect from space radiation, with some studies estimating that at ground level, the density of the CO2 would be equivalent to 16–22 g/cm2 aluminum [122]. Hence the shielding effectiveness per unit of CO2 is greater than that of either aluminum or Martian regolith [123]. At ground level, assuming a 100% CO2 atmosphere and a 1-year exposure to GCR at solar minimum, the contribution to the dose to the blood-forming organs from elements with atomic number between 10 and 38 (HZE particles) drops to 50%. However, secondary radiation, assuming a 100% CO2 atmosphere, increases the contribution from neutrons by a factor of 3 and that from protons by a factor of 1.5 [124].

Martian and Lunar Regolith Mars Mission In a similar calculation, a mission to Mars (using conventional chemical rocket propulsion systems) would involve two 6-month transit periods. The overall dose-equivalent exposure, assuming a 1977 level of GCR, can be calculated by dividing the day into two parts: a 16-h period spent inside a 5 g/cm2-equipped room and an 8-h period spent inside a 10 g/cm2 sleeping area storm shelter. The corresponding doses for that 1-year mission will be 0.82 Sv (82 rem) to the skin, 0.81 Sv (81 rem) to the eyes, and 0.63 Sv (63 rem) to the blood-forming organs [119,120]. Notably, this dose-equivalent is twice that of a similar period spent on the lunar surface. Estimated annual dose equivalents from GCR at solar minimum during long-duration stays on the surface of Mars, considering protection from the 16 g/ cm2 CO2 atmosphere, will be 0.12 Sv (12 rem) to the skin and 0.11 Sv (11 rem) to the blood-forming organs [121]. Adding an event of 10 times the scale of the 1989 SPE, while crewmembers are inside a 10 g/cm2 storm shelter, results in additional dose equivalents of 0.33 Sv (33 rem) to the skin and eyes and 0.25 Sv (25 rem) to the blood-forming organs for crewmembers on the Martian surface [122]. Thus the overall dose during a 2-year mission to Mars from GCR plus two SPEs, one 10 times the intensity of the 1989 event on the Martian surface and one equal to the 1972 event during the transit phase, will be 2.4 Sv (237 rem) to the skin and 1.2 Sv (123 rem) to the blood-forming organs. As a point of reference, Letaw [16] calculated that in the absence of SPEs and with a vehicle and habitat shielding of 4 g/cm2, the dose equivalent during solar maximum would be 0.18 Sv (18 rem) per year and 0.45 Sv (45 rem) per year during solar minimum.

Planetary Surface Shielding Martian Atmosphere In contrast to the Moon, which has essentially no atmosphere, Mars has a rarefied atmosphere composed mainly of carbon dioxide (95.3% by volume), nitrogen (2.7%), and argon

The Martian and Lunar regolith are composed mainly of silicate and iron. The shielding properties of the lunar regolith are similar to those of aluminum because the mean molecular weight of all its components is comparable to the atomic weight of aluminum [123]. At 30 g/cm2, adding a layer of lunar regolith to any kind of habitation will decrease the dose to the blood-forming organs from atomic particles higher than 10 by a factor of 2 for a 1-year exposure (considering GCR at solar minimum). However, because of secondary interactions, the dose exposure from protons will increase by a factor of 2 and that from nucleons will increase by a factor of 4 [125]. In other words, for a regolith thickness of 30 g/cm2, 70% of the dose would result from nucleons (mostly from secondary radiation from protons and neutrons). However, because regolith shields primary radiation quite effectively, the dose to the blood-forming organs would be kept below the current NASA annual limits [114], even assuming one or two SPEs (a dose-equivalent of about 0.3 Sv); the maximum dose per SPE is estimated not to exceed 0.12 Sv (12 rem) to the blood-forming organs [126]. The density of the Martian regolith, on the other hand, is lower than that of aluminum, and thus it provides less primary protection from SPEs and from the incident GCR. However, it will result in fewer secondary radiation particles being produced than in the case of lunar regolith [127]. The location of the habitat will also affect the amount of radiation the crew receives while inside. Given the relatively smooth surface of the Moon, a lunar habitation module will offer at least full 2π steradian protection of the volume because of the planet’s mass. For a Mars habitat, the dose can be decreased by taking advantage of the surface features, for example by embedding a module in the side of a cliff. The reduction in dose exposure would correlate directly with the dimension of the terrain overhanging the habitat; for a habitat under a 10-m cliff, the dose to the blood-forming organs during a 1-year surface stay, from GCR and from one solar flare, will decrease by 0.045 Sv (4.5 rem) per year [127].

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– Radiation shielding and storm shelters that use improved, easy to implement shielding strategies – Active dosimetry and monitoring with real-time alarm capability – Improved SPE forecasting – High-energy neutron monitoring – Study of HZE-specific mechanism of genomic instability and carcinogenesis – Study of HZE effects on CNS, fertility, spermatogenesis, teratogenesis, and heritable lesions – Means of monitoring radiation bioeffects during missions, including biomarkers and cytogenetics – Further study of radioprotective molecules and chemoprevention agents

calibration curves, and thereby to standardize estimates of relative risk; assays to define “hot spots” in the genome that are particularly prone to injury or cross-linking as the site of carcinogenesis or oncogene activation; and assays for evaluating epigenetic mechanisms of carcinogenesis instead of focusing only on stable events occurring after irradiation. Our ability to develop improved countermeasures and treatments for radiation-induced bioeffects [128] would also be enhanced by the development of animal models for testing chemoprevention agents, which would facilitate translation of findings from both low-LET and high-LET radiation from cell cultures to organ systems to animals and to humans. Another useful tool would be nontoxic, easily administered radioprotectant agents of high bioavailability that could be given alone or in combination to ameliorate or prevent radiation damage. The pharmacokinetics and pharmacodynamics of such agents would need to be thoroughly characterized both under Earth-based conditions and in microgravity. Genetic engineering may be useful for rendering astronauts more radioresistant in the future. Stem cells might be genetically engineered for radioresistance; key genes in molecular-level protection from HZE radiation might be inserted into cells, which would then be introduced into gastrointestinal and bone marrow stem cells. Radiation was one of the first aspects of the spaceflight environment to be characterized as humans ventured away from Earth in the mid-20th century, and it remains the most limiting factor with regard to stay time and enduring health risk. GCR make space radiation a ubiquitous background entity and acute clinical syndromes may result from unpredictable solar flares. Radiation will always be a prominent factor in human spaceflight planning and operations, as it drives both vehicle design and mission architecture. Technological leaps may someday allow the generation of electrical power levels great enough to create artificial magnetic fields sufficient to deflect charged solar particles from spacecraft crew cabins, and advanced materials may afford better shielding-to-mass capabilities. For now, vigorous research continues in ground and Earth-orbiting laboratories to better characterize radiation bioeffects and monitoring technologies.

For remote exploration missions, a multifaceted radiation management program must assume autonomous operations. Many techniques currently available for Earth-based laboratory analysis for assessing cytogenetics, genetic polymorphisms, point mutations, apoptosis, and the like could be modified for in-flight use. Such technologies would best be tested on the ISS and validated before attempting to embark on transplanetary missions. ISS research should also include vigorous efforts to reduce the uncertainties associated with risk assessment for stochastic events. Our ability to understand the biological result of a given dose of space radiation would be greatly enhanced by development of the following capabilities: a standardized scoring system for fluorescence in-situ hybridizidation (FISH) techniques to detect aberrations, to allow development of

Acknowledgments. The author would like to note the following individuals for contributions to the field of space radiation and to this chapter: Michael Stanford, Ph.D., University of Houston; Frank Cucinotta, Ph.D., NASA/JSC; Lief Peterson, Ph.D., Baylor College of Medicine; and [the late] Gautam Badhwar, Ph.D., NASA/JSC. Acknowledgments to: Mark Weyland. Mike Golightly, Steve Johnson, Ph.D., Ed Semones, M.S., Neal Zapp, M.S., S. Vlahovich, M.D., Canadian Space Agency, Prem Seganti Ph.D., John Wilson, Ph.D., Mike Moyers, Ph.D., Linda Hewes, Ed Stasinopolous, Ph.D., Vincent Witt, Jennifer Jadwyck, and Francois Becker, Ph.D.

Conclusions With current technologies, radiation doses associated with exploration and habitation missions to the moon and Mars may well exceed the limits currently defined for LEO operations. Assessment of the radiation protection needed during interplanetary and remote planetary missions should include consideration of several key technologies, such as integrating structural radiation shielding into vehicle design. Mission planning should, of course, account for solar cycles in considering vehicular trajectories. Vehicle designs could maximize shielding of crew compartments by considering fuel and water storage tanks as components of that shielding. Development of advanced propulsion systems are expected to shorten the required transit time. Advanced warning systems for SPEs might be possible through the use of solar orbiting satellites. Shielding strategies for surface habitats should include consideration of materials (e.g., regolith) that would reduce exposure to primary radiation and not evoke significant doses from secondary radiation. Geographic variations in the natural terrain can be exploited to enhance habitat shielding. Development and use of personalized active dosimeters deserves particular attention, as does selection of EVA suit materials. Other important areas of development, applicable to all aspects of human space travel and operations, include the following:

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517 62. Tasman W, Jaeger EA. (eds.), Duane’s Clinical Ophthalmology. Philadelphia, PA: Lippencott-Raven; 1996:Chapter 73. 63. Lett JT, Cox AB, Lee AC. Selected examples of degenerative late effects caused by particulate radiations in normal tissues. In: McCormack PD, Swenberg CE, Bücker H (eds.), Terrestrial Space Radiation and Its Biological Effects. NATO ASI Series, Series A: Life Sciences, Vol. 154, New York, NY: Plenum Press; 1988: p 393–413. 64. Otake M, Schull WJ. Radiation-related posterior lenticular opacities in Hiroshima and Nagasaki atomic bomb survivors based on DS86 dosimetry system. Radiat Res 1990; 121:3–13. 65. Datiles MB, Magno BV, Freidlin V. Study of nuclear cataract progression using the National Eye Institute Scheimpflug system. Br J Ophthalmol 1995; 70:527–534. 66. Chylack LT Jr, Wolfe JK, Friend J, et al. Validation of methods for the assessment of cataract progression in the Roche European-American Anticataract Trial (REACT). Ophthalmic Epidemiol 1995; 2:59–74. 67. Lopez ML, Freidlin V, Datiles MB 3rd. Longitudinal study of posterior subcapsular opacities using the National Eye Institute compute planimetry system. Br J Ophthalmol 1995; 79:535– 540. 68. Cucinotta FA, Manuel FK, Jones JA, et al. Space radiation and cataracts in astronauts. Radiat Res 2001; 156:460–466. 69. Curtis SB, Nealy JE, Wilson JW. Risk cross sections and their application to risk estimation in the galactic cosmic ray environment. Radiat Res 1995; 141:57–65. 70. Todd P, Pecaut M, Fleshner M. Combined effects of spaceflight factors and radiation on humans. Mutat Res 1999; 430:211–219. 71. Hammond TG, Lewis FC, Goodwin TJ, et al. Gene expression in space. Nat Med 1999; 5:359. 72. Horneck G. Impact of spaceflight environment on radiation response. In: McCormack PD, Swenberg CE, Bücker H (eds.), Terrestrial Space Radiation and Its Biological Effects. NATO ASI Series, Series A: Life Sciences, Vol. 154, New York, NY: Plenum Press; 1988. 73. Montgomery PO Jr, Cook JE, Reynolds RC, et al. The response of single human cells to zero-gravity. In: Johnston RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC: US Government Printing Office; 1977:221–234. NASA SP-377. 74. Morrison DR. Cellular changes in microgravity and the design of space radiation experiments. Adv Space Res 1994; 14:1005– 1019. 75. Kiefer J, Pross HD. Space radiation effects and microgravity. Mutat Res 1999; 430:299–305. 76. Horneck G.Impact of microgravity on radiobiological processes and efficiency of DNA repair. Mutat Res 1999; 430:221–228. 77. Bucker H, Facius R, Horneck G, et al. Embryogenesis and organogenesis of Carausis morosus under spaceflight conditions. Adv Space Res 1986; 6:115–124. 78. Grigoriev YG, Miller AT, Nevzgodina LV, et al. Effect of weightlessness and of artificial gravity on irradiated lettuce seeds. Life Sci Space Res 1977; 15:285–289. 79. Grigoriev YG, Planel H, Delpoux M, et al. Radiobiological investigations in Cosmos 782 space flight (Biobloc SF1 experiment). Life Sci Space Res 1978; 16:137–142. 80. Buckhold B. Biosatellite II–physiological and somatic effects on insects. Life Sci Space Res 1969; 7:77–83. 81. Hagen U. Radiation biology in space: A critical review. Adv Space Res 1989; 9:3–8.

518 82. Horneck G. Radiobiological experiments in space: A review. Nucl Tracks Radiat Meas 1992; 20:185–205. 83. Benner SA, Derihe KG, Matreeva LN, Powell OH. The missing organic molecules on Mars. Proc National Academic Science USA 2000 March 14; 97(6):2425–2430 84. Wilson JW. Overview of Radiation Environments and Human Exposures. Presented at the 34th Annual Meeting of the National Council on Radiation Protection and Measurements: Cosmic Radiation Exposure of Airline Crews, Passengers and Astronauts, Washington, DC, April 1–2, 1998. Health Phys 2000; 79:470–494. 85. Sharma S, Stutzman JD, Kelloff GJ, et al. Screening of potential chemoprevention agents using biological markers of carcinogenesis. Cancer Res 1994; 54:5848–5855. 86. Kelloff G, Hawk E, Crowell JA, et al. Strategies for identification and clinical evaluation of promising chemopreventive agents. Oncology 1996; 10:1471–1488. 87. Kelloff GJ, Boone CW, Steele VE, et al. Mechanistic considerations in chemopreventive drug development. J Cell Biochem Suppl 1994; 20:1–24. 88. Giuliano A. Review of cancer chemoprevention. Oncology 1998; 12:1659–1660. 89. Capizzi RL. Clinical status and optimal use of amifostine. Oncology 1999; 13:47–59. 90. Liu T, Liu Y, He S, et al. Use of radiation with or without WR2721 in advanced rectal cancer. Cancer 1992; 69:2820–2825. 91. Brizel DM. Future directions in toxicity prevention. Semin Radiat Oncol 1998; 8:17–20. 92. Brizel DM. Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma. Semin Radiat Oncol 1998; 8:237–246. 93. Senzer NN. Clinical results of a phase III study of ethyol (amifostine). Managed Care and Cancer 1990; 2(1). 94. Hanson WR, Marks JE, Reddy SP, et al. Protection from radiation-induced oral mucositis by a mouth rinse containing the prostaglandin E1 analog, misoprostol: A placebo controlled double blind clinical trial. Adv Exp Med Biol 1997; 400B:811–818. 95. Taylor A. Role of nutrients in delaying cataracts. Ann NY Acad Sci 1992; 669:111–123. 96. Robertson JM, Donner AP, Trivithick JR. Vitamin E intake and the risk of cataracts in humans. Ann NY Acad Sci 1989; 570:372–382. 97. Waldren CA, Ueno A, Zhang Y, et al. Using non-toxic chemicals to reduce the mutagenicity of the kinds of radiation encountered in space travel. Presented at the Bioastronautics Investigators Workshop, Galveston, TX, 17–19 January 2001.Jan 2001. 98. Dicello JF, Cucinotta F, Gridley D, et al. NSBRI Radiationeffects core project: In-vivo studies. Presented at the Bioastronautics Investigators Workshop, Galveston, TX, 17–19 January 2001:325. 99. Huso DL, Mann J, Ricart-Albona, R, et al. Chemoprevention of radiation-induced neoplasms. Presented at the Bioastronautics Investigators Workshop, Galveston, TX, 17–19 January 2001:326. 100. Burns F. Alteration of the risk of skin tumors from single and multiple doses of 56Fe by dietary retinoid. Presented at the Bioastronautics Investigators Workshop, Galveston, TX, 17–19 January 2001:331. 101. Frank AL, Slesin L. Nonionizing Radiation. In: Public Health and Preventive Medicine; John M. Last and Robert B. Wallace (eds.), Appleton and Lange, 1992: pp.513–522.

J.A. Jones and F. Karouia 102. Oleinick N, Chiu S, Friedman LR, et al. DNA-protein crosslinks: New insights into their formation and repair in irradiated mammalian cells. In In: Simic MG, Grossman L, Uptn AC (eds.), Mechanisms of DNA Damage and Repair. New York, NY: Plenum Press; 1986:181–192. 103. Taylor HR, West SK, Rosenthal FS, et al. Effect of ultraviolet radiation on cataract formation. N Engl J Med 1988; 319:1429– 1433. 104. Taylor HR, West SK, Rosenthal FS, et al. The long-term effects of visible light on the eye. Arch Ophthalmol 1992; 110:99– 104. 105. Bochow TW, West SK, Azar A, et al. Ultraviolet exposure and risk of posterior subcapsular cataracts. Arch Ophthalmol 1989; 107:369–372. 106. Zapp N. Hazard report: IVA Crewmember Non-Ionizing Radiation Exposure through the USL Window. The Boeing Company Information, Space, and Defense Systems International Space Station, ISS-C&T-95-5A. 15 December 2000. 107. Weichselbaum RK, Hines HH. Review of Rosen, E.M. Biological Basis of Radiation Sensitivity, Part 2 Cellular and Molecular Determinants of Radiosensitivity. Oncology, May 2000; 14(5):758; Weinstock MA. Overview of ultraviolet radiation and cancer: What is the link? How are we doing? Environ Health Perspect 1995; 103:251–254. 108. Kheifets LI, Afifi AA, Buffler PA, et al. Occupational electrical and magnetic field exposure and leukemia. A meta-analysis. J Occup Environ Med 1997; 39:1074–1091. 119. Durante M, Kawata T, Nakano T, et al. Biodosimetry of heavy ions by interphase chromosome painting. Adv Space Res 1998; 22:1653–1662. 110. Edwards AA, Finnon P, Moguet JE, et al. The effectiveness of high energy neon ions in producing chromosonal aberrations in human lymphocytes. Radiat Prot Dosim 1994; 52:299–303. 111. Nicogossian AE, Robbins DE. Characteristics of the space environment. In: Nicogossian AE, Huntoon CL, Pool SL (eds.), Space Physiology and Medicine. 3rd edn. Philadelphia, PA: lea & Febiger; 1994:50–62. 112. McCormack PD. Radiation dose and shielding for the Space Station. Acta Astronaut 1988; 17(2):231–41. 113. Badhwar GD. Radiation measurements on the International Space Station. Physica Medica 2001; 17:1–5. 114. National Council on Radiation Protection. Guidance on Radiation Received in Space Activities. NCRP Report No, 98. Bethesda, MD: National Council on Radiation Protection and Measurements; 1989. 115. National Council on Radiation Protection. Radiation Protection Guidance for Activities in Low- Earth Orbit. NCRP Report No 132. Bethesda MD: National Council on Radiation Protection and Measurements; 2000. 116. Nealy JE, Simonsen LC, Townsend LW, et al. Deep space radiation exposure analysis for solar cycle XXI (1975–1986). Paper presented at the 20th Intersociety Conference on Environmental Systems; July 9–12, 1990; Williamsburg, VA. SAE Technical Paper Series No. 901347. 117. Nealy JE, Simonsen LC, Qualls GD. Radiation shielding design issues. In: Wilson JW, Miller J, Konradi A, Cucinotta FA (eds.), Shielding Strategies for Human Space Exploration. NASA CP-3360. Hampton, VA: NASA Langley Research Center; 1997:29–42. 118. Eckart P. The Lunar Base Handbook. New York, NY: McGrawHill; 2000.

23. Radiation Disorders 119. Wilson JW, Cucinotta FA, Thai H, et al. (eds.), Galactic and Solar Cosmic Ray Shielding in Deep Space. NASA TP-3682. Hampton, VA: NASA Langley Research Center; 1997. 120. Wilson JW, Cucinotta FA, Thibeault SA, et al. Radiation shielding design issues. In: Wilson JW, Miller J, Konradi A, Cucinotta FA (eds.), Shielding Strategies for Human Space Exploration. NASA CP-3360. Hampton, VA: NASA Langley Research Center; 1997:109–149. 121. Simonsen LC, Nealy JE. Mars Surface Exposure for Solar Maximun Conditions and 1989 Solar Proton Events. NASA TP-3300. NASA TP-3668. Hampton, VA: NASA Langley Research Center; 1993. 122. Simonsen LC. Analysis of lunar and Mars habitation modules for the space exploration initiative. In: Wilson JW, Miller J, Konradi A, Cucinotta FA (eds.), Shielding Strategies for Human Space Exploration. NASA CP-3360. Hampton, VA: NASA Langley Research Center; 1997:43–77. 123. Simonsen LC, Nealy JE. Radiation Protection for Human Mission to the Moon and Mars. NASA TP-3079. Hampton, VA: NASA Scientific and Technical Information Division; 1991.

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24 Acoustics Issues Jonathan B. Clark and Christopher S. Allen

Omnipresent with human habitation in artificial environments is background and operational noise. Inherent in almost any platform or craft that maintains a human crew in an enclosed cabin is the need for circulation of air to remove metabolic and other adverse waste products and to replenish consumed oxygen. Water and fluid coolants of thermal control systems may also require circulation, typically provided by motorized fans and pumps. Noise generated by such systems is an expected consequence for surface ships, submarines, aircraft, and spacecraft and adds to noise that may be produced by propulsion systems and other operational equipment. Noise in low Earth orbit spacecraft operations has been identified as a significant environmental hazard for human crews. This chapter examines the sources and character of background noise on board orbiting spacecraft, the morbidity and pathophysiology associated with such noise, and aspects of remediation and crew protection.

Mechanics of Hearing Hearing is the transduction of sound (mechanical energy) into neural impulses and the interpretation of those impulses by the central nervous system. Hearing loss can result from a defect at any point in this system. Loudness is quantified as sound pressure level (SPL) determined by the amplitude of pressure changes in the alternating compression and rarefaction of air and is expressed in decibels (dB) with a reference pressure fluctuation of 20 µPa, which is accepted as the threshold of hearing for a typical 18-year old human male. Pitch is quantified as frequency, determined by the number of pressure peaks encountered per second and is expressed in cycles per second or Hertz (Hz). The frequency of sound is often presented on a logarithmic frequency scale that is divided into standard octave or 1/3 octave bands [1]. In order to relate sound pressure levels to human physiology, it is necessary to take into account the response of the human auditory system. One of the most frequently used methods for this incorporates the A-weighted scale, which

approximates the response of human hearing to high noise levels. When applying the A-weighted scale, adjustments are made to the SPL of each frequency band and the SPL units are changed to dBA, referenced to 20 µPa. While the A-weighted SPL values of individual frequency bands are rarely stated, the most commonly used acoustic metric is the A-weighted overall sound pressure level, referred to as the noise level, in dBA. This noise level is the combination of A-weighted SPL bands over the frequency range of human hearing (typically 63 to 20,000 Hz). This metric is the standard output of sound level meters and is also used when calculating or measuring noise exposure. The subsequent discussion will relate exclusively to the A-weighted scale. The noise criterion, or NC, family of curves also takes into account the human response to noise and is typically used when designing working or living spaces by specifying a curve for the octave band SPLs to satisfy, e.g., NC-50. The NC curves are a function of SPL and frequency in octavebands from 63 to 8000 Hz [1]. The relationship between the NC curves and A-weighted scale is shown in Table 24.1, where the A-weighted scale has been applied to the specified NC curve, and the corresponding noise level of the curve has been calculated and is shown. Noise is unwanted, unpleasant, or bothersome sound that often interferes with tasks and may be perceived as harmful [2,3]. Even at the high noise level extreme, the energy sufficient to cause permanent hearing loss resulting from a single acute exposure is low, equivalent to 1/10,000 of a watt, which equates to 120 dB SPL. In addition, chronic health effects (physiological) and performance effects (psychological) may result from long-term exposure to continuous noise sources at even lower levels. Physiologic effects of noise include temporary and permanent hearing loss, cardiovascular system fluctuations, digestive changes, and immune system suppression [2]. Threshold shift, a change in hearing sensitivity (expressed in dB or µdB for a given frequency) usually induced by noise exposure, occurs as a function of sound pressure level and duration and may occur after exposure to acute high intensity noise or long term continuous noise at lower levels. Krebs 521

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J.B. Clark and C.S. Allen Table 24.1. A-Weighted overall sound pressure level as related to the NC (noise criterion) curve. NC curve 70 65 60 55 50 45 40 35 30 25 20 15

Sound level, dBA of NC curve 78 71 66 61 56 52 47 42 38 34 30 25

reported a greater than 10 dB average threshold shift across frequencies in subjects exposed for four days to 60 dBA continuous noise and 77 to 89 dBA intermittent noise. Exposure to levels of up to 75 dBA noise for 30 days resulted in a threshold shift that recovered after 50 h of noise rest. Occupational noise exposure assumes a rest period at reduced noise levels (e.g. at the end of the work day) to allow critical recovery time; this understanding is incorporated into industry regulations. Exposure to prolonged noise as low as 58 dBA in combination with ototoxic drugs (e.g., neomycin and streptomycin) has been proven to cause permanent hearing loss. Analogous scenarios may be found in industrial and aviation settings; however, the spacecraft environment adds a further factor in that the measure of noise exposure is not limited by the workday or sortie. Crew exposure to spacecraft cabin noise is continuous; although some regional distribution is expected, there is literally no place to go for complete ear rest. High noise levels can cause headaches, irritation, fatigue, impaired sleep, and tinnitus. High noise levels disrupt communication in the spacecraft environment and on occasion have resulted in an inability to hear alarms at a distance. Speech intelligibility may be more impaired for crew understanding, especially with regard to non-native language use in a noisy environment, a factor of particular relevance to international space efforts. Speech reception will be further compromised when crew are not aligned upright with respect to each other, which will limit ability to interpret nonauditory cues such as facial expressions and lip movement [4]. Crews communicating in noisy environments often complain of sore throat from talking loudly. Community based studies of high levels of environmental noise suggest associated mental health symptoms (depression and anxiety) but not impaired psychological functioning [5]. NASA is particularly concerned about crew health effects of sound on the International Space Station (ISS), the largest and most complex spacecraft to date. Acoustic specialists have been tasked with providing guidance for safe permissible sound exposure on the ISS, developing strategies to assess and reduce acute effect of sound on crew performance, and coordinating the approach to study acute, chronic, and

delayed effects of sound on ISS crewmembers. The medical guidance provided to spaceflight crew and management concerning biological effects of acoustic energy will be used to optimize crew performance and reduce or eliminate adverse health effects. Specific objectives include characterizing the sound environment in habitable areas using onboard noise measurement equipment, tracking of crew hearing including inflight via onboard hearing assessments, providing medical guidance for safe permissible exposure levels on ISS, and identifying loud systems and payloads that may be amenable to engineering mitigation procedures. The operational approach is to identify issues based on known crew impact and priorities, develop workaround options, obtain supporting data, review the weight of evidence, and establish recommendations. Four levels of impact and priority have been established in this approach. Flight safety is the highest priority impact. The next level is mission accomplishment, which is given a high priority; impact on mission effectiveness is given a medium priority. The lowest priority is assigned to the effect on longitudinal health. All are of concern from the perspective of human health.

Pathophysiology of Noise Acoustic damage to the cochlea depends on the type, frequency, level, and duration of noise and the potential presence of other auditory toxins. Noise type is characterized as continuous (engine noise), impulsive (rifle shot/hammer blow), or kurtotic (impulsive noise superimposed upon continuous noise). For a given energy level, kurtotic noise is the most damaging, impulse noise is moderately damaging, and continuous noise is the least damaging [6,7]. Acoustic energy damages auditory tissue in several ways. At high energy levels, delicate cochlear structures are physically disrupted [8]. Metabolic exhaustion, the most common mechanism, occurs when increased metabolic activity from acoustic energy results in glycogen depletion induced by cochlear ischemia [9]. Excessive stimulation overdrives the auditory system, generating reactive oxygen species and free radicals, which initiate protein oxidation and disrupt cell membrane phospholipid integrity and the actin filaments of hair cell stereocilia [10]. Oxidation of the cell membrane results in release of toxins, such as 4-hydroxy 2,3-nonenal (HNE), which disrupts cellular processes such as sodium/potassium pumping, glucose and excitatory neurotransmitter (glutamate) transport, and ion homeostasis, and can lead to accelerated programmed cell death (apoptosis). Minor damage may be repaired and is initially manifested as a temporary threshold shift (TTS), while more significant injury can result in permanent noise-induced sensorineural hearing loss or permanent threshold shift (PTS). Typical antioxidant defenses include vitamins C and E, and reduced glutathione (GSH). Enhancing inner ear antioxidants by increasing antioxidant enzyme activity, increasing inner ear GSH, or adding exogenous antioxidants can reduce

24. Acoustics Issues

permanent noise induced hearing loss (NIHL) [10]. Permanent damage to hair cells may occur days or weeks following noise exposure, and this critical interval allows a potential therapeutic window that could be initiated after noise exposure but before cell death [6]. The generation of reactive oxygen species may be an early event, followed by the generation of lipid peroxidation products, then mitochondrial injury and activation of cell termination programs. The onset of TTS may be asymptotic, meaning a maximum threshold shift or plateau is reached at a given sound level exposure and duration and remains constant regardless of further length of noise exposure. The concern is that repeated TTS could produce NIHL. In animals, noise sufficient to cause a reversible behavioral threshold shift is known to produce histologic damage to the outer hair cells. Intracellular metabolic exhaustion of the hair cells, swelling of the auditory nerve endings, and spiral artery vasoconstriction with resultant hair cell ischemia have been demonstrated [11]. Noise at 70 dB SPL at 1000 Hz may induce peripheral vasoconstriction, minor changes in heart rate, and increased cerebral blood flow. Finkleman demonstrated increased heart rate with the combination of physical activity and noise [12]. Exposure to continuous noise may produce changes in skeletal muscle tension, depth of breathing, galvanic skin response, and a decrease in gastrointestinal mobility. Falk investigated the noise effects on the adrenal medulla, observing changes in blood and urine concentrations of cortisol [11]. Stimulation of the pituitary adrenal axis by 68 to 70 dB at 1000 Hz resulted in a release of adrenocorticosteroids, epinephrine, and norepinephrine that showed no adaptation and persisted as long as noise was present [13]. Falk showed that noise stress lowered resistance to disease, presumably from a suppressed immune system [11]. The use of ototoxic drugs such as salicylates, diuretics, and antibiotics (streptomycin and neomycin) combined with continuous exposure in the 50 to 60 dBA range may result in permanent hearing loss [13]. It should be stated that the difference in effects between response to tonal and random broadband noise with the same energy has not yet been determined. It is intuitive that the tonal noise would cause more damage as the total energy is concentrated at a single frequency. However, this effect is expected to be highly frequency dependant and related to physical dimensions of an individual’s sensing organs. Vorobiov and Skrebnev studied the effects of continuous noise exposure on jet aircraft maintenance workers living near the airport and reported 69% of maintenance engineers had hearing problems, 20% being significant, especially in the 1 to 8 kHz range [14,15]. The National Institute of Health (NIH) consensus development conference of 1990 stated levels of less than 75 dBA were unlikely to cause NIHL and levels greater than 85 dBA for longer than 8 h will cause hearing loss over time [16]. The American Society for Testing and Materials (ASTM 1166) and Department of Defense military criteria standard (MIL-STD-1472) provides similar acceptable upper noise limits for human indoor environments [17,18]. The Environmental Protection Agency in

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1971 recommended 70 dBA as the acceptable outdoor exposure for 24 h, 45 dBA during the day and 35 dBA during the night for indoor exposure. The NATO Advisory Group for Aerospace Research and Development (AGARD) in 1975 recommended avoiding levels greater than 90 dBA and noted that exposures between 80 to 90 dBA are potentially hazardous, and asymptotic TTS greater that 40 dB may cause permanent hearing loss [19]. The US Coast Guard (USCG) stated “the minimum goal of any noise program is to ensure that an exposure is not so great that any Temporary Threshold Shift cannot be recovered during the following rest period.” The USCG limit for intermittent noise is 82 dBA for existing vessels and 77 dBA for new ships [20].

Noise and Performance The acoustic environment on board the International Space Station (ISS) is expected to contribute to negative psychological effects, which may be exacerbated by high workloads, diminished sleep, stress from family separation, and other aspects of environmental habitability. The acoustic environment may be acceptable from an operational standpoint if permanent hearing loss and negative communication and performance impacts are unlikely. The continuous noise levels anticipated on ISS for the duration of typical crewed missions (up to six months) are not expected to cause PTS. However, the psychological effect of continuous noise exposure at levels likely to be encountered on long-duration space station missions could result in performance degradation during critical tasks and emergency situations. The level of performance degradation is dependent on the level, variability, duration, intermittency, and periodicity of the source noise, as well as the type of task undertaken by a crewmember. Annoyance from noise depends on the source, meaning, level of disruption, and ability to control the noise [13]. Driskell and Salas reported that long term continuous noise results in narrowed attention, decreased search behavior, longer reaction time to peripheral cues, decreased vigilance and motivation, degraded problem solving, performance rigidity, and decreased ability to scan alternatives. Noise exposure was associated with loss of the team perspective, decreases in helping behavior, decreases in team performance, attention narrowing, negative affective state, a threefold increase in operational procedure errors, and a twofold increase in time necessary to complete manual tasks [2]. Continuous noise exposure may have a greater negative impact on tasks requiring a faster work pace, and individual variability may be a function of personality [21]. The ambient background noise level may create performance decrements for repetitive tasks [22]. Tasks requiring multiple information sources, information processing, and vigilance all show degradation under noise exposure while repetitive or practiced tasks or tasks that provide clear warnings or use visual stimuli are unaffected by noise [22]. NASA developed a standard battery of performance tests for the assessment of noise stress effects [23]. Fifty percent of people in an open office area where the ambient background

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sound levels ranged from 53 to 62 dBA found the noise to be “extremely annoying” or “unbearable” [24]. Continuous noise (50.0 to 86.6 dBA, mean 56.3 dBA) for 24 h resulted in decreased rapid eye movement (REM) sleep, reduced sleep efficiency (time asleep/time in bed), and sleep deprivation [25]. Kawada reported a decrease in REM sleep at 45 dBA and subjective degradation of sleep quality and awakening [26].

Clinical Hearing Assessment The standard hearing test performed annually and before and after space flight on all astronauts is the pure tone threshold audiogram. The test is administered in an acoustically isolated chamber where a series of low intensity tones are sent to either ear via headphones at frequencies between 500 and 8000 Hz (0.5 to 8 kHz). The threshold intensity, defined as the lowest intensity sound at which the patient consistently hears the tone, is determined for each frequency and each ear. Pure tone thresholds in the NASA Flight Medicine Clinic are typically measured by automated testing, where a change in intensity is marked by a push button switch in the astronaut’s hand. The tone begins at a normally audible intensity, and the subject presses the button until the tone falls off into the inaudible range. When the button is released, the intensity begins to increase until the astronaut presses the switch again. This series continues for several cycles; then the signal frequency is changed. The process continues for all frequencies in both ears. The advantage of automated testing is that multiple tests can be done simultaneously. The disadvantage is that automated testing can be overcome by pressing the button in a cyclic pattern. However, newer testing machines present the tones in a random non-rhythmic fashion and the subject presses and releases the button for each tone heard. Audiometer outputs are set to comply with the American National Standards Institute (ANSI) 1969 standards to allow comparison of audiometry data to facilitate longitudinal follow-up. Audiometer calibration is accomplished annually. A standard threshold shift (STS) is defined as a change in hearing threshold over the baseline audiogram of an average of 10 dBA or more at 2000, 3000, and 4000 Hz in either ear. If an STS is identified on the annual examination, the crewmember will be scheduled for a repeat exam within 30 days. The second exam is preceded by at least 14 h in a relatively noisefree environment (<72 dBA). If the STS is resolved on the first or second repeat audiogram, the individual is counseled on effects of excessive noise; methods of conservation and hearing protection devices (HPD) are discussed. If the STS is persistent, a PTS is documented in the medical record. A PTS of >25 dBA is considered an OSHA-reportable loss. Referral to an otolaryngologist is indicated for significant audiogram changes consistent with noise-induced hearing loss, such as an STS, accompanied by clinical signs or symptoms of other otologic pathology, or changes of a magnitude that result in

J.B. Clark and C.S. Allen

hearing acuity below the standards for retention of flight status. If persistent STS is documented in the medical record, the baseline is reset to the values reflected in the audiogram, permitting increased specificity of the STS. If data in the annual audiogram which suggest an auditory acuity better than that seen in the baseline audiogram, the baseline will be adjusted upwards to increase the sensitivity for detecting significant threshold shifts. Unaided hearing loss in either ear of less than 25 dB for 500, 1000 and 2000 Hz, 35 dB for 3000 Hz, and 45 dB for 4000 and 6000 Hz is considered normal over time. Unaided hearing loss in either ear greater than 30 dB average over 500, 1000, and 2000 Hz and/or with a single value greater than 35 dB for 500, 1000, and 2000 Hz and 45 dB for 3000 and 4000 Hz requires audiologic and ear, nose, and throat (ENT) evaluation, as does an asymmetric hearing loss (greater than 15 dB difference between the two ears at any frequency). Restriction from flying is not required during workup and the evaluation may be deferred until the first long flight physical for individuals with longstanding hearing loss in this range. Unaided hearing loss in either ear greater than or equal to 35 dB averaged over 500, 1000, and 2000 Hz requires ENT evaluation for continued flying and audiologic evaluation of fitness for continued active duty, during which time disqualification from flying is appropriate. Hearing loss sufficient to preclude safe and effective performance of duty regardless of level of pure tone hearing loss and despite use of hearing aids requires the intervention of the Aerospace Medical Board for waiver.

Long–Duration Noise Exposure In an animal model of exposure to moderate sound levels for nine days, PTS occurred in animals exposed to 85 dBA SPL or greater [27]. But in a study of human subjects, 72 h exposures of 72 to 74 dBA resulted in raised hearing thresholds of 15 to 20 dB that recovered to normal thresholds in 2 to 3 h [28]. In a second set of experiments, Yuganov et al. reported that 10- and 30-day exposures (using the same levels of noise exposure) resulted in threshold shifts of 20 to 25 and 25 to 30 dB with recovery taking place in 8–18 h and 48 to 50 h after exposure, respectively [28]. These threshold shifts and recovery times are summarized in Table 24.2. A characteristic feature distinguishing these investigations was the constant complaints throughout the experiment of the “irritant and fatiguing action Table 24.2. Threshold shift and recovery time for high-frequency noise (<3 kHz) exposures lasting 3–30 days. Duration 3 day 10 day 30 day

Level

Threshold shift

Recovery time

72–74 dBA 72–74 dBA 72–74 dBA

15–20 dB 20–25 dB 25–30 dB

2–3 h 8–18 h 48–50 h

Adapted from Yuganov et al. [28].

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of the noise.” Ward indicated that a 150-day continuous exposure of 82 dBA SPL caused permanent hearing loss as well as quantifiable hair cell loss in the chinchilla. Intermittent rest prevented permanent hearing loss and cochlear damage due to noise [29]. Rest periods longer than 18 h were no more effective in preventing hearing loss than the 18-h rest periods [30–33]. Little data were found for rest periods shorter than 8 h although one duty/rest cycle used for 144 days involved 15 min of rest for every 45 min of exposure.

Space Shuttle Experience The U.S. Space Transportation System specification for noise on the Space Shuttle during development was the noise criterion curve NC-50, corresponding to 56 dBA. This requirement was increased to 68 dBA due to hardware constraints in 1986. Space shuttle flight rules stipulate that when noise levels are at or above 74 dBA when measured over a 24-h period, the crew is required to wear hearing protection during sleep and to adjust the time line and equipment usage to reduce noise. Shuttle noise exposure limits are 76 to 80 dBA for five min, 81 to 85 dBA for 1 min, and noise at or above 86 dBA is not allowed. Acoustic dosimetry, which measures noise exposure, on one Shuttle mission (STS-40), revealed background levels of 73 dBA, with a maximum of 80 to 85 dBA during ergometer operations. There were significant effects on crew performance and communication [34]. For short-duration shuttle flights, standard hearing tests pre- and postflight have been adequate to measure changes in hearing. Neither temporary nor permanent threshold shifts have been observed in the U.S. Space Shuttle program. During the nine-day STS-40 mission, six of seven crewmembers reported that noise interfered with their ability to concentrate and relax and the six crewmembers who wore earplugs still had sleep disruptions [35]. The average background noise levels were 70 dBA in the SpaceLab module, 64 dBA on the shuttle middeck, and 62 dBA on the flight deck. The STS-40 crew reported that speech intelligibility was hampered by noise and that an acoustic level equivalent to NC-50 would only allow 80% of key words to be understood. The crew reported increased vocal effort was necessary to communicate with fellow crew if they were more than 2 ft apart on the flight deck, 1.6 ft apart on the middeck, and 0.65 ft apart in the SpaceLab and that this contributed to fatigue. No clinically significant hearing loss was documented, but average postflight thresholds increased 4 dB, from 9 dB preflight to 13 dB postflight, which was statistically significant (see Figure 24.1). The entire crew agreed that the noise levels experienced during that mission, would be unacceptable for long-duration missions. On the 13-day STS-50 mission 67% of the crew (four astronauts) expressed difficulty concentrating or relaxing with background noise levels of 64 dBA on the flight deck, 60 dBA on the middeck, and 61 dBA in the SpaceLab [36]. The same report also indicated that 60% of

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Figure 24.1. Average preflight and postflight audiometry results for the STS-40 crew. Increased hearing thresholds were noted in all frequencies

33 flown astronauts reported disturbed sleep, annoyance, or trouble with relaxation and speech intelligibility as a result of noise on orbit. Half of the STS-57 crew felt that noise levels during that mission would be unacceptable for a six month stay [37]. The sampling interval of acoustic data may also be a factor. On the STS-74 mission to the Mir space station, a 1 h and 50 min audio dosimetry measurement extrapolated to a 24 h exposure was not felt to be a reliable estimate of the noise environment [38]. In a ground-based study involving a Lunar-Mars habitat test chamber, participants reported that noise exposure “could result in communication difficulties and cause hearing damage; they could also be annoying or stressful and cause degradation in work performance.” [39]

Russian Space Experience Temporary and, in some cases, permanent hearing loss has been a demonstrated consequence of long-duration space flight [40]. Reports from the Salyut 6 space station note the highest postflight threshold shifts were at 4 to 6 kHz. A Russian summary of Salyut 6, Salyut 7, and Mir station data found changes in cosmonaut hearing in high frequencies (2 kHz and higher) on flights of seven days to one year. In one study, TTS has been reported in 100% of cosmonauts, and PTS has been identified in 27 of 33 cosmonauts. In 30 years of Russian long-duration space flight, 33 Soyuz, Salyut, and Mir civilian cosmonauts, (excluding military aviators) with normal hearing initially were followed. Five cosmonauts were disqualified from further space flight because of extreme NIHL (50 dB loss at 4 to 6 kHz), and 12 had 30 dB loss. The noise environment on Mir caused permanent hearing damage in one third of the long-duration crewmembers, and five cosmonauts were medically disqualified from subsequent flights as a result. The measured sound pressure levels on the Mir from expeditions 26 and 27 were 71 to 77 dBA during work periods. One Mir cosmonaut had a threshold shift 71 days after a 365-day space flight [40]. Hearing loss incurred during space flight typically affects the high frequency range (1 to 6 kHz) [41]. Nefedova in 1990 summarized that “while there are individual differences, changes in cosmonaut hearing may be described as involving

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Table 24.3. Postflight threshold shift (dB) of either ear compared to preflight audiometry in cosmonauts who consistently did or did not use hearing protection. Flight duration (days)

0.5 kHz

1 kHz

2 kHz

3 kHz 4 kHz

Hearing 6 kHz protection

7 7 25 150 150 241 365 365

6 19 0 0 0 0 0 20–45

19 4 0 0 0 0 0

8 4 15–20 0 0 0 20–40

1 −11

0 −5

−6 11

0 0 0

0 0 0

10–20 0 0

0

20–45

No No No Yes Yes Yes No No

Actual audiograms available for seven-day missions only; other data derived from compiled data and presented as ranges in merged cells.

Figure 24.2. Hearing acuity (dBA) as measured in left ear at 4 kHz in Skylab astronauts compared with non-Skylab astronauts and controls (LSAH comparisons) vs. age. (LSAH = longitudinal study of astronaut health.)

changes in auditory sensitivity in the area of high frequencies (2 kHz and higher) for flights of seven days to one year.” [42] Table 24.3 summarizes published Russian studies from Salyut 6, Salyut 7, and Mir missions on hearing assessments performed after space flight. Unresolved questions include what the background noise levels were and type of and compliance with hearing protection. These data suggest that aside from bone and muscle loss and radiation accumulation, hearing loss may also be a significant medical problem associated with long-duration space flight.

U.S. Long−Duration Spaceflight Experience The Skylab series of long-duration space flight included the 28-day Skylab 2 mission, the 59-day Skylab-3 mission, and the 84-day Skylab-4 mission, each of which involved a three-person crew. No changes in pure tone audiograms were observed on postflight testing after the 28-, 59-, and 84-day Skylab missions. Differences between the Skylab and Russian experiences could be attributed to larger habitable volumes in the Skylab with increased crew distance from noise-producing equipment and the fact that the cabin atmosphere was maintained at lower than sea level pressure (5 psi rather than 14.7 psi), which may have resulted in acoustic effects such as reduced radiation efficiency of noise sources, and possible changes in the hearing response of the crew. Hearing protection was not used on Skylab. Follow-up audiograms have shown decline in high frequency hearing function as the crewmembers have aged. At 20-year follow up examinations, Skylab crewmembers had 40 to 70 dB loss at 6 to 8 kHz and 30 to 50 dB loss at 3 to 4 kHz. Comparing Skylab audiograms to those of age-matched controls in the Longitudinal Study of Astronaut Health, the Skylab astronauts showed 5 to 10 dB more loss at 2 to 4 kHz after age 55, which parallels the nonSkylab astronauts’ hearing decline with age (see Figures 24.2 and 24.3). These changes may be related to jet noise exposure and not necessarily to the spaceflight experience.

Figure 24.3. Mean hearing acuity (dBA) measured in left ear for Skylab astronauts vs. age. Flight experience includes three missions of 28, 59, and 84 days duration shared among nine crewmembers

One of seven NASA-Mir astronauts experienced a TTS as a result of long-duration space flight without hearing protection, with subsequent resolution (no PTS). On the Mir space station the measured sound was a maximum of 73 dBA. One NASA-Mir astronaut gave his perspective of noise on longduration space flight. During his stay on Mir, he slept in the Priroda module near a massive fan. Using this structure for added radiation protection, the sound level in this location was 58 dBA. His acoustic dosimetry readings averaged from 62 to 68 dBA. The muff headsets were found to be too uncomfortable after 30 min. However, foam earplugs were used as protection against high frequency noise, and an active noise reduction headset was worn for low-frequency noise for his entire 8-h sleep shift. The active noise reduction headset did not interfere with hearing alarms. The high noise levels interfered with communications, and this crewmember had to press the headset to his ears to hear. Noise levels of 68 to 70 dBA caused headaches in the crew. The operational impact of high noise levels resulted in an inability to hear alarms more than 20 ft away. The treadmill operation was also noted to be very noisy, and the continuous noise was noted to be worse than intermittent noise.

24. Acoustics Issues

International Space Station Experience

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The International Space Station (ISS) is comprised primarily of components built by the United States and Russia, which together with other international partners establish specifications for habitation. The Russian Space Agency (RSA) specification for continuous noise on board spacecraft is 60 dBA, in addition to SPL requirements given in each octave band, when the crew is awake, and correspondingly 50 dBA when the crew is asleep. The U.S. Space Station Program (SSP) specification for continuous noise in ISS modules is the noise criterion curve NC-50 when the crew is awake and NC-40 when the crew is asleep (see Figure 24.4). In U.S. modules with payloads (science experiments), the complement of payloads is also allowed an allocation equivalent to NC-48 so that the total module plus payloads requirement is NC-48 + NC-50, which is approximately equivalent to the NC-52 noise criterion curve. In addition to continuous noise requirements, there are also intermittent noise requirements, which are based on the duration of the increased levels. These intermittent requirements are implemented differently in the Russian and U.S. segments. Finally, an impulsive noise limit of 140 dB (not dBA) for a noise with duration less than 1 s, and a hazard limit of 85 dBA (for noise durations longer than 1 s) are established. Caution and warning alarms, which project acoustic tones at 0.5 and 2 kHz, are required to be 20 dB louder than ambient noise levels. Detailed acoustics analyses and application of countermeasures have been described by Goodman and Allen [43,44]. In order to ensure a safe acoustic environment for the crew, noise levels in the ISS modules are routinely monitored. In the Service Module, the primary residence for ISS crews, noise levels have been measured at 69 dBA during ground testing, and 67 to 72 dBA on orbit. These noise levels in the Service

Module exceed specifications substantially, and work is currently underway to reduce these levels. The U.S. Lab module produces levels up to 60 to 64 dBA depending on location. In addition, the Node 1 module has been measured to produce levels of 50 to 57 dBA, and the Functional Cargo Block (Russian Acronym FGB) produces up to 58 to 66 dBA. Crew noise exposure levels on ISS, measured over a 24-h period, range typically from 65 to 71 dBA. These exposure levels are highly dependant on where the crew spent most of their time, what type of work was being performed, and where the crewmembers slept. Among the significant noise sources throughout the ISS are the life support system ventilation fans. The most significant acoustic contributions on the Service Module are the “Vozdukh” carbon dioxide removal system (+70 dBA), the refrigerators (70 dBA), air conditioning and ventilation fans (69 to 52 dBA), and the Thermal Control System pump (57 dBA). The U.S. supplied Treadmill and Vibration Isolation System (TVIS) is an intermittent noise contributor with measured levels of 77 dBA during ground assessments (see Figure 24.5). The ISS Safety Review Panel (SRP) reviews hazard reports and endorses them as approved, approved with modifications, or disapproved. Failure of the functional cargo block (Russian acronym FGB) and Service Module, for example, to meet the Russian acoustic requirements necessitated the submittal of a non-compliance report (NCR) for the Russian Segment, which outlined a staged risk mitigation implementation plan. The SRP conditionally accepted the NCR with the provision that additional controls be identified and implemented for 24h ISS occupation. The ISS Russian Segment acoustic requirements were modified from 60 to 73 dBA for the FGB work environment. Maximum noise levels on the FGB module were measured at 74 dBA on the first Shuttle mission to visit the ISS (STS-88). Acoustic hardware modifications, including air

Figure 24.4. Noise criterion (NC) curves and Russian specification for spacecraft. Limits are expressed in octave frequency bands

Figure 24.5. International Space Station Service Module sound pressure levels (SPL) as a function of frequency with and without treadmill operations (from ground test data) at one location compared with Russian spacecraft continuous noise specifications

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vent louvers, air duct mufflers, and fan base isolators, were made to the FGB in May to June 1999 during the STS-96 mission. These modifications reduced noise 0.5 to 5 dBA in the FGB but failed to reduce noise levels enough to meet requirements and contributed to negative air quality experienced by the STS 96 flight crew [45]. The SRP granted approval of the NCR concerning the FGB and Service Module acoustic hazards, conditional upon crew hearing protection availability and implementation of acoustic mitigation hardware modifications. The Implementation Plan was divided into high priority measures, measures implemented during Service Module habitation for Expedition 1, logistics issues, and operational modifications to crew schedule. High priority measures included noise-dampening covers for the carbon dioxide removal system, installation of soundabsorbing material on circulation fans, modification to refrigerator components, and gap closures, as well as the addition of noise abatement material to the Service Module interior. Lower priority measures after Service Module habitation included redesign of fans and thermal control pump components. Logistic items included noise level assessment and use of active noise cancellation headsets by the crew. Modifications to crew schedule included identification of equipment that could be operated intermittently or in sequence to minimize cumulative noise. Finally, flight rules for operation of noise producing hardware and for the wearing of hearing protection were developed. Individual hearing protection hardware is provided to all ISS crewmembers and must permit caution and warning (C&W) tones to be audible. Comfort, anthropometric accommodation, and ease of cleaning were considered in the certification and selection of hearing protection equipment. Guidelines for the applicability of Active Noise Reduction (ANR) headsets include noise attenuation as a function of frequency of the passive components, overall noise attenuation of the system including active components, and individual factors. ANR headsets are generally effective from 125 to 2000 Hz and most effective up to 800 Hz, while other passive hearing protection (foam plugs, plastic plugs, and molded plastic plugs) are effective at all ranges tested, particularly above 2000 Hz. ANR and passive hearing protection may also be used simultaneously. In a study of ANR headset effectiveness in helicopters, substantial low frequency noise attenuation was demonstrated, but when white noise from the communication system was introduced there was an increase in middle frequency noise [46]. Assessment of the acoustic environment aboard the ISS is made possible with on-orbit equipment capable of making real-time measurements of sound pressure levels [47]. Two devices are available; the ISS Sound Level Meter (SLM) and ISS Acoustic Dosimeter. The ISS SLM measures the equivalent SPL in each 1/3 octave band from 50 Hz through 10 kHz, averaged over a short time, nominally 15 s. Measurements are performed at many locations on the ISS as part of a survey with only the continuously operating hardware activated. Octave band SPLs are then calculated from the 1/3 octave

J.B. Clark and C.S. Allen

bands to compare with ISS continuous noise requirements. The ISS Acoustic Dosimeter measures equivalent A-weighted overall sound pressure levels, averaged over an extended time, typically 24 h. These measurements capture the intermittent noise in addition to the continuous noise, including noise from speech, and are either worn by the crew or placed at a specified location. Both types of measurements are performed approximately once every two months as well as at the crew’s discretion.

Hearing Assessment in Space Conventional pure tone audiometry requires a personal headset and heavy soundproof booth, which is impractical for space flight. Audiometry was performed as a flight experiment on Space Shuttle flights STS-6, 7, and 8 by astronauts under the direction of investigator Dr. Bill Thornton, who designed and built an audiometer that delivered sound by a headset. Although the procedures worked well in this experiment, results were questionable due to differences in background noise levels between the missions confounding the findings and causing apparent threshold shifts during the testing. Pure tone audiometry has also been performed in space as part of a joint Russian-German cooperative project. The audiometer, Elbe 2, was flown on a seven day Salyut 6 docking mission and was also used on Mir. Complete data have been published from the seven-day flight [48]. The in-flight data show clear threshold shifts, particularly at the lower frequencies, that are not present on the day following landing. These data suggest that ambient noise in the station may have interfered with the measurements, but the details on how the testing was performed were not provided in the published reports. An in-flight hearing test could monitor effectiveness of standard hearing protection countermeasures and provide the crew with a new capability to tailor hearing protection countermeasures to individual crewmembers. Otoacoustic emissions (OAE) measurement offers an attractive alternative to standard pure tone audiography for the spaceflight environment. OAE are physiologic signals that arise from vibration of outer hair cells (OHC) in the cochlea [49]. Mechanical energy travels from the OHC via the middle ear ossicles and tympanic membrane, where it is measured by a microphone in the ear canal. Outer hair cells are highly metabolically active and are damaged by ototoxic medications and agents, vascular disease, hypoxia, and high-energy noise exposure. OAE signals have been used extensively in screening neonatal hearing and in assessing cochlear function in infants and children [50]. Otoacoustic emissions may be spontaneously generated or evoked by various stimuli. Two types of evoked OAEs are the transient evoked otoacoustic emissions (TEOAE) and distortion-product otoacoustic emissions (DPOAE). Evoked OAEs are generated by using a small speaker to excite a mechanical response from the eardrum and use a microphone to detect

24. Acoustics Issues

the response of the OHC to the sound stimulus [51]. The approaches used to acquire evoked OAE signals include (1) keeping stimulus intensity constant while varying frequencies or (2) varying stimulus intensity while keeping frequency constant. Transient-evoked otoacoustic emissions are evoked by brief click stimuli and may be detected in people with hearing thresholds of 30 dB or better [52]. DPOAEs are elicited after the presentation of two pure tones closely spaced in frequency (f1 and f2, where f1 = 1.2–f2) and amplitude (where L1 = 55 dB and L2 = 65 dB). The cochlea produces distortion product harmonics of these tones, the most prominent of which is at 2f1-f2. DPOAE is more frequency specific and is detected in people with hearing thresholds of 50 dB or better [53]. Otoacoustic emissions are entering clinical use for the monitoring of noise-induced hearing loss [51]. Otoacoustic emissions provide insight into potential damage before changes in pure tone audiometry thresholds can be detected, and can be used to identify noise-susceptible individuals [54]. High-energy noise decreases emission amplitude and narrows the spectral band. The DPOAE in noise-induced hearing loss shows a characteristic notch around 4 kHz [55]. Reduction of DPOAE amplitude has been observed with short (hour) and long-term (years) noise exposure [56]. Middle-ear abnormalities such as otosclerosis or external ear blockage from cerumen can interfere with OAE signals, although it is not entirely understood how such abnormalities affect OAE transmission [57]. Although DPOAE performed on normal hearing subjects can predict normal or sensoryimpaired hearing with a high degree of accuracy, threshold estimation is still marginal [58]. OAEs have several advantages for space flight operations; they may be performed quickly by unskilled personnel, do not require a subjective or conscious response, and may be done in a noisy environment. The DPOAE signal has been recorded in high-noise environments using a standard passive hearing protection headset placed over the otoacoustic probe, but the signal is usually not detectable in a noisy environment without hearing protection as the increased background noise decreases the signal-to-noise ratio (Figure 24.6). The noise environment used in the testing was sound-recorded from the ISS Service Module in May 2000 while it was operating during ground tests prior to the 12 July 2000 launch. The noise was played at the sound level of 70 dBA measured in the Service Module at the time of recording. DPOAE were recorded on six subjects using the Etymotic EroScan ER-34 with and without the headsets while seated in a quiet environment or subjected to Space Station noise. The passive hearing protection headset has attenuation better than 20 dB above 200 Hz, which was adequate to shield ambient background noise and generate reliable otoacoustic emission signal to noise ratios, as seen in Figure 24.6. DPOAE were not adequate in a noisy environment without the use of a hearing protection headset but were adequate in the noise environment with hearing protection. A similar test under identical conditions was conducted on the Grason Stradler GSI 70 OAE screening device, which yielded similar results.

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Figure 24.6. Distortion product otoacoustic emission (DPOAE) under quiet and noise conditions with and without hearing protection. Noise source used for testing is representative of International Space Station background noise

The clinical utility of OAEs lies in screening, monitoring, and quantifying hearing loss and aiding in differential diagnosis. OAE may be practical for on-orbit hearing assessment because it is objective (no subject response required), selfcalibrating, and functional in the presence of background noise. DPOAEs have been performed in noise fields beyond 65 dBA. DPOAEs are consistently and reproducibly able to detect smaller differences than audiometry. A 3 dB change in OAEs is considered clinically meaningful, and a 6 dB change is very significant, whereas with conventional audiometry 5 dBA is significant. Drawbacks of OAEs include difficulty recording with middle ear pathology (stimulus and OAE response transmit energy via the middle ear), signal limitations due to cochlear hearing loss (30 dBA for TEOAE, 50 dBA for DPOAE), and inability to assess retrocochlear function. In addition, OAEs represent a young technology without ANSI standards in place; as such, inter-manufacturer variability exists in available equipment. Physiologic changes in the auditory system associated with microgravity may affect evoked stimulus propagation and OAE detection. More global physiologic changes associated with microgravity may alter OAEs, particularly headward fluid shifts. Intracranial pressure is increased in weightlessness compared with ground valves in seated and standing postures [59]. Although some studies show no effect on otoacoustic emissions with changes in body position and the accompanying changes in CSF pressure [60], others do show changes [61]. Future flight experiments will hopefully evaluate OAEs to evaluate this procedure in the space environment and establish this method as a useful onboard clinical tool. To assess hearing of the initial ISS increment crewmembers, a Minimum Audibility Test (EarQ Software™) with modified off-the-shelf software used by musicians and professional divers was flight certified for on-orbit hearing assessment. The software uses a laptop computer sound card to deliver tones of varying frequencies and calibrated intensities through high fidelity custom molded earphones which are part of the Acoustic Countermeasures Hardware. The Medical Equipment

530

Computer (MEC) is part of the Crew Health Care Systems (CHeCS) on board the ISS. The MEC’s primary purpose is to provide the user with information services for CHeCS. The MEC is an off-the-shelf, flight-certified portable computer that has the ability to display physiological data, maintain medical records, assess crew health, and permit two-way data exchange through the command and data handling system of ISS. Volume in the Minimum Audibility Test may be increased in 1 dB increments using the MEC keyboard. The subject increases the volume level until a hearing threshold is reached at each frequency (0.25, 0.5, 1, 2, 4, 6, 8, 10 kHz) in each ear. The results are sent to the ground during scheduled MEC downlink periods for assessment by the ground medical team. The program is small (~500 kB), the user interface very intuitive, involving limited procedures and training, and testing may be completed in under 10 min. Each session is displayed with regard to frequency intensity and compared to baseline or other prior sessions to provide immediate feedback to crewmembers. Session data files are archived and downlinked for further interpretation. Based on the results of the EarQ tests, the flight surgeon may ask that the crewmember take additional precautions such as donning ear plugs for a certain amount of time each day or minimizing time in proximity to noise-producing systems to help conserve the crewmember’s hearing. Other methods for monitoring hearing include crew’s subjective reports during periodic medical debriefs as well as quantitative tools for measuring actual on-orbit noise exposure (audio dosimeter and sound level meter).

Space Environment Interactions The combined effects of environmental factors (vibration, temperature, continuous noise, and physical exertion) associated with long-duration space flight are relatively unknown. A number of ototoxic agents such as carbon monoxide and solvents may synergistically interact with noise to produce hearing loss [62]. Exposure to simultaneous noise and vibration results in temporary and permanent threshold shifts and hair cell loss greater than with noise alone [63,64]. A human study examined combinations of noise (two categories: no noise and stable broadband A-weighted noise of 90 dBA), whole body vibration (three categories: no vibration, sinusoidal whole body vibration of 5 Hz, z-axis and stochastic whole body vibration of 2.8 to 11.2 Hz) and dynamic muscular work (three levels: 2W, 4W, 8W). Noise was the greatest single contributing factor for TTS. TTS increased further as a result of the combinations of noise plus vibration and noise plus muscular work. The combined effect of all three factors (noise, vibration, and work) on the TTS results was greatest when the vibration was stochastic and the dynamic muscular work was light (2W); by increasing the workload the measured TTS levels were attenuated. Light dynamic muscular work and cardiovascular activity may have enabled the interaction of noise and vibration, while strenuous muscular and cardiovascular activity in

J.B. Clark and C.S. Allen

some way negated the effects of noise and vibration [65]. Heat stress also appears to play a role; a 10°C ambient temperature increase resulted in 5 to 10 dB greater TTS when subjects were exposed to noise and whole body vibration [66]. The microgravity environment, dynamic workload, stress, continuous 24-h-a-day moderate noise exposure, electromagnetic radiation, and potential for toxic exposure all may lead to cochlear hair cell damage and greater than expected noiseinduced hearing loss. Electromagnetic energy may be transduced to acoustic energy by thermal expansion, electrostriction (volume contraction in protein solution due to formation of electrically charged particles), and surface radiation pressure. Microwave energy such as from radiating communications antennae can result in audible clicks and annoyance [67]. Such emitters are present on the ISS, although radiating zones exclude habitable areas and outside emission zones are avoided during extravehicular activities (EVAs). Carbon monoxide, a byproduct of combustion that has been detected in spacecraft combustion events, can increase high frequency noise-induced hearing loss [68]. High intensity low frequency noise may emanate from such sources as the life support system ventilation fans. The use of the A-weighted scale of sound measurement for assessing spacecraft noise levels may under-emphasize the intensity of low frequency noise, where the maximum energy is often found [32]. By A-weighting sound pressure levels, the low frequency levels are reduced by 0.8 dB at 800 Hz, 26 dB at 63 Hz, and 39 dB at 31.5 Hz. Burdick demonstrated that low frequency noise exposures (below 500 Hz) in animal models consistently produced their greatest threshold shifts and hair cell damage 3 to 7 octaves above the characteristic frequency, and above 500 Hz noise produced its maximum effects onehalf to one octave above the center frequency of the noise band [69]. Burdick further demonstrated that humans exposed to tones from 2 to 22 Hz at intensity levels of 119 to 144 dB SPL developed threshold shifts in the frequencies from 3000 to 8000 Hz. Exposure to 63 Hz at 110 and 120 dB SPL (84 and 94 dBA) resulted in the highest threshold shifts occurring between 1000 to 3000 Hz.

Countermeasures Countermeasures against spacecraft noise include design engineering controls, sound insulation materials, and hearing protection. Engineering and design controls to reduce noise should be the primary focus of any hearing conservation program, but this is not possible in all situations. Quiet fan technology exists but may exact a penalty in weight, power consumption. and circulation efficiency, all of which are crucial factors in spacecraft environmental controls. Advanced composite materials with excellent low frequency attenuation properties could be applied as a barrier protection around noisy equipment or used on personal protective equipment worn by the crew. Hearing protection countermeasures include foam ear inserts, passive muff headsets, and active noise reduction headsets. Hearing

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protection is recommended when the crewmembers’ 24-h equivalent noise exposure exceeds 65 dBA or when they are exposed to high levels of noise such as when exercising on the treadmill (TVIS). However, wearing hearing protection for long periods of time is not an optimal solution because of discomfort, increased risk of ear infections, difficulty with communications, and reduced effectiveness when removed frequently to communicate. Crewmembers should also be aware that playing music over personal headphones or speakers in an attempt to mask noise only increases risk of hearing loss. While noise levels on spacecraft are far below the 110 dBA SPL levels considered necessary for mechanical damage, the continuous nature of this sound environment may cause longterm metabolic exhaustion of the inner ear cochlear tissue. Periods of quiet rest are needed to allow the cochlea to recover from hearing fatigue [70]. Although most people are able to experience relatively long periods of quiet while sleeping, this was not possible in the environment found on the Mir, and even hearing protection offers only slight attenuation of low frequency noise due to persistent bone conduction, of which the levels were unknown. The standard occupational exposure to environmental noise assumes an 8-h exposure with 16 h of acoustic rest. Periods of relative quiet (less than 70 dB) have been suggested for treatment of very high levels of noise exposure, to allow hair cells to repair themselves [71]. The recovery time for TTS, a biological repair process, is roughly proportional to exposure time and intensity and seems to depend on frequency as well [72]. The time needed for repair of the damage may be as long as 24 to 48 h for an 8 to 24 h exposure. In the Yuganov study, 50 h of recovery was needed for a 75 dBA exposure, but animal data at 80 dBA suggests TTS recovery took five days after a 48 h exposure and was still incomplete after a 90 day exposure at 150 days after noise exposure [28,73]. Noise capable of causing a TTS is proportional to the intensity and time of exposure and is also frequency dependent. A general formula for TTS four minutes post-exposure (TTS4 min) is: TTS4 min = 1.7(SPL − A), where A = 47 dB for 4 kHz octave band noise and A = 65 dB for 0.5 kHz octave band noise [73,74]. This formula implies that noise rest should occur in an environment with an octave band background of less than 47 dB for high frequency noise and below 65 dB for low frequency noise. Reestablishing a “rest period” through engineering methods, e.g. as with sufficiently quiet sleep quarters or provision of pharmacological protection or repair enhancement may constitute effective countermeasures. In many pathological conditions, such as injury, aging, inflammation, and ischemia and subsequent reperfusion, excessive production of reactive oxygen species has been postulated to occur and cause cell damage. Evidence has been accumulating that indicates that reactive oxygen species play a substantial role in damaging the inner ear secondary to various toxins and noise. Continuous high-level noise is

associated with cochlear production of superoxide anion and the hydroxyl radical, both of which are capable of inducing cochlear damage and loss of function. Noise modulates the level and activity of key antioxidant compounds in the inner ear such as glutathione (GSH) and a variety of antioxidant enzymes. Supplanting or reducing inner ear GSH either ameliorates or intensifies noise induced permanent threshold shift (NIPTS), and a variety of strategies to augment cochlear antioxidant defenses have been shown experimentally to reduce noise related hearing loss. It has recently been shown that an antioxidant combination of L-N- acetyl cysteine and low dose salicylate was effective in reducing permanent hearing loss as well as hair cell loss in a chinchilla model, opening up the very real and exciting possibility of utilizing pharmacological agents to prevent NIPTS [10]. Future work includes understanding the role oxidative stress plays in NIHL and developing an effective pharmacological strategy to reduce cochlear damage in the spacecraft environment associated with moderate continuous noise.

Conclusions NASA is concerned about acute effects of spacecraft acoustic noise on crew performance and is developing strategies to assess and reduce the acute, chronic, and delayed effects of this noise. High noise levels can cause headaches, irritation, fatigue, impaired sleep, and tinnitus, all of which can impair performance. High noise levels have resulted in an inability to hear alarms, and speech intelligibility may be more impaired for crew hearing a non-native language in a noisy environment. Countermeasures include hearing protection and design–engineering controls. Advanced composite materials with excellent low frequency attenuation properties could be applied as a protective barrier around noisy equipment or used on personal protective equipment worn by the crew. Hearing protection countermeasures include foam ear inserts, passive muff headsets, and active noise reduction headsets, though wearing hearing protection for long periods may be problematic. Microgravity, vibration, toxic fumes, air quality and composition, stress, temperature, physical exertion or some combination of these may interact with moderate long-term noise exposure to cause significant hearing loss. Crewmembers should be aware that playing music over personal headphones in an attempt to mask noise increases risk of hearing loss. Future work includes determination of whether the dBA scale is adequate for estimating acoustic bioeffects and what sound level and duration are adequate for noise rest (quiet). The ability to perform hearing assessments in the noise environment of spacecraft is highly desirable but leaves other unanswered questions. If a threshold shift occurs in flight, what treatment is adequate, and what agents can be used for NIHL prevention or treatment in space? A significant concern is the interaction between noise, vibration, workload, and comorbidity factors, such as radiation, toxicology, microgravity

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effects (e.g. thoracic fluid shift), and aging, which may be involved with NIHL. Longitudinal studies will need to address which of these co-morbid factors might be involved with hearing loss. The basic science of noise induced hearing loss (NIHL) is essential in developing strategies for protection, rescue, and regeneration. Pharmacological modalities may prove useful in countering cell damage. Space medicine practitioners should remain active in formulating and enforcing noise standards in all aspects of human space flight; this includes hardware design and production, mission design, and activities planning. New technology such as OAE may well prove useful for in-flight acoustic monitoring and longitudinal baseline screening.

References 1. Beranek LL, Ver IL. Noise and Vibration Control Engineering. New York: John Wiley & Sons, Inc; 1992; 14:626–629. 2. Driskell JE, Salas E. Stress and Human Performance. Mahwah, NJ: Lawrence Erlbaum Associates; 1996. 3. Dimberg U. Perceived unpleasantness and facial reactions to auditory stimuli. Scand J Psychol 1990; 31:70–75. 4.Cohen MM. Perception of facial features and face-to-face communications in space. Aviat Space Environ Med 2000; 71:A51–57. 5. Stansfeld SA, Haines MM, Burr M, et al. A review of environmental noise and mental health. Noise Health 2000;8:1–8. 6. Hamernik RP, Henderson D. Impulse noise trauma. A study of histological susceptibility. Arch Otolaryngol 1974; 99: 118–121. 7. Henderson D, Hamernik RP. Impulse noise: Critical review. J Acoust Soc Am 1986; 80:569–584. 8. Henderson D, Hamernik RP. Biologic bases of noise-induced hearing loss. Occup Med 1995; 10:513–534. 9. Slepecky N. Overview of mechanical damage to the inner ear: Noise as a tool to probe cochlear function. Hear Res 1986; 22:307–321. 10. Kopke R, Allen KA, Henderson D, et al. A radical demise: Toxins and trauma share common pathways in hair cell death. Ann NY Acad Sci 1999; 884:171–191. 11. Falk SA, Woods NF. Hospital noise levels and potential health hazards. N Engl J Med 1973; 289:774–781. 12. Finkelman JM, Zeitlin LR, Romoff RA, et al. Conjoint effect of physical stress and noise stress on information processing performance and cardiac response. Hum Factors 1979; 21:1–6. 13. Baker C. Sensory overload and noise in the ICU: Sources of environmental stress. Critical Care Quarterly 1984; 6:66– 80. 14. Vorob’ev OA, Krylov IuV, Zaritskii VV, et al. Current aspects of the noise problem in aviation medicine. Voen Med Zh 1996; 317:56–60, 79. 15. Skrebnev SV, Krylov IV, Vorob’ev OA, et al. Problems of hearing loss in aviation engineers (professional and ecological aspects). Vestn Otorinolaringol 1997; 2:9–12. 16. National Institutes of Health. Consensus Development Conference Statement: Noise and Hearing Loss. NIH Consensus Statement 1990 Jan 22–24; 8(1):1–24. 17. Department of Defense Military Specifications for Human Engineering. American Society for Testing and Materials F1166–95a,

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24. Acoustics Issues 39. Foley T. Everyday noise, all day. Houston, TX: NASA-Johnson Space Center; JSC 981787, 1998. 40. Prohl W, Nefedova MV, Birke J. Temporary results of the examination of the audition of cosmonauts during a long-term flight in the space station MIR with the audiometer ELBE 2 (Experiment AUDIO 2). IAF/IAA Paper 90–519. Paris, France. International Astronautical Federation; 1990. 41. Yakovleva IYa, Nefedova MF. Sensory systems: Hearing. In: Gurovskiy NN (ed.), Results of Medical Research Performed on the “Salyut-6-Soyuz” Space Station Complex. Moscow: Nauka Press; 1986:165–168. 42. Nefedova MV. The effect of space flight factors on the auditory function of cosmonauts. Space Biology and Aerospace Medicine: 9th All-Union Conference, Kaluga, June 19–21, 1990. Moscow: Nauka; 1990. in Russian]. 43. Goodman JR. International Space Station Acoustics, The 2003 National Conference on Noise Controll Engineering, Paper # NC03–125, 2003. 44. Allen CS, Goodman JR. Preparing for Flight—The Process of Assessing the ISS Acoustic Environment. The 2003 National Conference on Noise Control Engineering, Paper # NC03–006, 2003. 45. Alibaruho K, Gentry G, Sang A. Flight 2A.1/STS-96 ISS Air Quality Issue Assessment and Recommendations for Flight 2A.2/STS-101, October 23, 1999, ISS Independent Assessment Report. 46. Wagstaff AS, Woxen OJ, Andersen HT. Effects of active noise reduction on noise levels at the tympanic membrane. Aviat Space Environ Med 1998; 69:539–544. 47. Pilkington GD. ISS Acoustics Mission Support, The 2003 National Conference on Noise Controll Engineering, Paper # NC03–021, 2003. 48. Prohl W, Mocker R, Yakovleva IYa, et al. Initial audiometric investigations in an orbital station. Zeitschr Militaermed 1981; 2:60–62. 49. Brownell WE. Outer hair cell electromotility and otoacoustic emissions. Ear Hear 1990; 11:82–92. 50. Kemp DT, Ryan S. Otoacoustic emission tests in neonatal screening programmes. Acta Otolaryngol Suppl 1991; 482:73–84. 51. Lonsbury-Martin BL, Martin GK, Telischi FF. Otoacoustic emissions in clinical practice. In: FE Musiek, WF Rintelmann (eds.), Contemporary Perspectives in Hearing Assessment. Boston, MA: Allyn and Bacon; 1999:167–195. 52. Probst R, Lonsbury-Martin BL, Martin GK, et al. Otoacoustic emissions in ears with hearing loss. Am J Otolaryngol 1987; 8:73–81. 53. Lonsbury-Martin BL, Martin GK. The clinical utility of distortionproduct otoacoustic emissions. Ear Hear 1990; 11:144–154. 54. Prasher D, Sulkowski W. The role of otoacoustic emissions in screening and evaluation of noise damage. Int J Occup Med Environ Health 1999; 12:183–192. 55. Sliwinska-Kowalska M, Kotylo P. The role of evoked and distortion product otoacoustic emissions in the diagnosis of occupational noise-induced hearing loss. J Audiol Med 1998; 7:29–45. 56. Namyslowski G, Morawaki K, Trybalska G, et al. Comparison of DPOAE in musicians, noise exposed workers and elderly with presbycusis. Med Sci Monit 1998; 4:314–320.

533 57. Hall JW, Baer JE, Chase PA, et al. Clinical application of otoacoustic emissions: What do we know about factors influencing measurement and analysis? Otolaryngol Head Neck Surg 1994; 110:22–38. 58. Kimberley BP. Applications of distortion-product emissions to an otological practice. Laryngoscope 1999; 109:1908–1918. 59. Draeger J, Schwartz R, Groenhoff S, et al. Self-tonometry under microgravity conditions. Aviat Space Environ Med 1995; 66:568–570. 60. Froehlich P, Ferber C, Remond J, et al. Lack of association between transiently evoked otoacoustic emission amplitude and experimentation linked-factors (repeated acoustic stimulation, cerebrospinal fluid pressure, supine and sitting positions, alertness level). Hear Res 1994; 75:184–190. 61. Buki B, Chomicki A, Dordain M, et al. Middle-ear influence on otoacoustic emissions. II: contributions of posture and intracranial pressure. Hear Res 2000; 140:202–211. 62. Boettcher FA, Henderson D, Gratton MA, et al. Synergistic interactions of noise and other ototraumatic agents. Ear Hear 1987; 8192–212. 63. Pekkarinen J. Noise, impulse noise and other physical factors: Combined effects on hearing. Occup Med 1995; 10:545–559. 64. Hamernik RP, Henderson D, Coling D, et al. Influence of vibration on asymptotic threshold shift produced by impulse noise. Audiology 1981; 20:259–269. 65. Manninen O. Bioresponses in men after repeated exposures to single and simultaneous sinusoidal or stochastic whole body vibrations of varying bandwidths and noise. Int Arch Occup Environ Health 1986; 57:267–295. 66. Manninen O. Cardiovascular changes and hearing threshold shifts in men under complex exposures to noise, whole body vibrations, temperatures and competition-type psychic load. Int Arch Occup Environ Health 1980; 56:251–274. 67. Lin JC. The microwave auditory phenomenon. Proc IEEE 1980; 68:67–73. 68. Young JS, Upchurch MB, Kaufman MJ, et al. Carbon monoxide exposure potentiates high-frequency hearing auditory threshold shifts induced by noise. Hear Res 1987; 26:37–43. 69. Burdick CK. Hearing loss from low-frequency noise. In: Hamernik RP, Henderson D, Salvi R, (eds.), New Perspectives in Noise-Induced Hearing Loss. New York: Raven Press; 1982:321–329. 70. Lataye R, Campo P. Applicability of the Leq as a damage risk criterion: An animal experiment. J Acoust Soc Am 1996; 99:1621– 1632. 71. Flottorp G. Treatment of noise induced hearing loss. Scand Audiol Suppl 1991; 34:123–130. 72. Mills JH, Osguthorpe JD, Burdick CK, et al. Temporary threshold shifts produced by exposure to low-frequency noises. J Acoustic Soc Am 1983; 73:918–923. 73. Mills JH, Gengel RW, Watson CS, et al. Temporary changes of the auditory system due to exposure to noise for one or two days. J Acoustic Soc Am 1970; 48:524–530. 74. Mills JH, Talo SA. Temporary threshold shifts produced by exposure to high-frequency noise. J Speech Hearing Res 1972; 15:624–631.

25 Ophthalmologic Concerns F. Keith Manuel and Thomas H. Mader

This chapter reviews ophthalmic issues associated with spaceflight operations. Current vision standards for space flight, methods of vision correction for spaceflight crewmembers, and vision demographics are discussed, followed by clinical conditions that could affect spaceflight duties and common ocular emergencies that could occur during space operations. The current medical selection and retention standards ensure that space crewmembers are generally healthy, free of significant chronic disease, and are not taking medication on a long-term basis. This chapter focuses primarily on ocular abnormalities that might be expected in healthy subjects during exposure to microgravity.

Vision Standards and Selection Testing Since 1959, more than 300 men and women have been selected for service in the U.S. space program as pilots, mission specialists, or payload specialists. In the early years of NASA’s history, all astronauts were military test pilots and as such were required to meet the rigorous vision standards of the military. As the effects of space flight on vision became better understood and as more astronauts became needed in the post-Apollo era, vision standards were relaxed. The current NASA selection process begins with an initial screening of several thousand applications. Information on the physical health of these applicants is provided by examiners from the Federal Aviation Administration (for civilian applicants) or by military flight surgeons (for military applicants). Between 120 and 140 astronaut candidates are selected from this pool and personally examined by NASA flight surgeons to further evaluate their medical status. Because vision is critical for astronaut function and survival, the eyes of astronaut candidates are evaluated in a detailed and systematic fashion, with standard and specialized ophthalmic equipment, in accordance with NASA directives [1–3]. Unaided and best-corrected distant visual acuity is measured by using a Landolt C system, in which the letter “C” is presented in various sizes and orientations. The test consists

of a random, timed presentation of single letters starting at a visual acuity level of 20/300 and ending at the 20/20 level, with 10 letters presented at each acuity level. The target, a high-contrast letter C, is presented on a standard video monitor (Mentor B-VAT system) for ~1 s followed by a 1.5-s pause until the next presentation. Each eye is tested separately at a distance of 20 ft (6 m) under controlled lighting. Selection and retention standards dictate that for pilot astronauts, unaided distant visual acuity must not exceed 20/100; the corresponding value for mission-specialist astronauts is 20/200 in either eye. Selection and retention standards for both pilots and mission specialists also require that vision be correctable to 20/20 in each eye. Standards for uncorrected distant vision have not been established for payload specialists, but vision in these individuals must be correctable to 20/30 in the better eye. No standard has been established for uncorrected near visual acuity in any applicant group, but near visual acuity must be correctable to 20/20 in each eye. Extraocular muscle function and range of motion are evaluated by gross observation, alternating cover-uncover testing, phorometry, and prism and red-lens testing. The results must indicate no evidence of microtropia or macrotropia, suppression, or diplopia. The presence of any tropia is disqualifying. Measurements exceeding 10 prism diopters of lateral phoria or 1.5 prism diopters of vertical phoria are disqualifying. Stereopsis is assessed at distance with a telebinocular instrument (Optec 2300, Stereo Optical, Chicago, IL). A series of 3-dimensional circles consisting of 6 groups (3 rows of 5 circles per group) are presented with various levels of stereoacuity down to 15 arc-seconds. Inability to achieve stereopsis at 25 arc-seconds is disqualifying. No alternative tests are allowed. Color vision is assessed in each eye with a 14-plate Dvorine pseudoisochromatic test under recommended lighting. A qualifying score is the correct identification of 10 of 14 plates, with no more than 5 s’ viewing time allowed per plate. Subjects who fail the pseudoisochromatic test can be retested with the Farnsworth Lantern Test, which consists of 9 paired presentations of red, green, or white light. A successful score on this test is the proper color identification of all 9 paired presentations. 535

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Manifest refractions are performed in standard fashion at 20 ft (6 m) with and without cycloplegia. End points are established for minimum correction to achieve 20/20 vision in each eye. Notably, a candidate’s refraction is not maximized in an attempt to achieve 20/15 or better during selection examinations. Refractive error exceeding ± 5.5 D, 3.0 D of cylinder in any meridian, or 2.0 D anisometropia (between the 2 eyes) is disqualifying. Intraocular pressure, measured by Goldmann applanation tonometry, cannot exceed 24 mmHg in each eye. A difference of 4 mmHg between eyes is also disqualifying. The cornea, anterior chamber, iris, and lens are examined by slit lamp biomicroscopy. Corneal topography is mapped by videokeratography. Binocular indirect ophthalmoscopy is used to examine the fundus while the pupil is dilated, and the fundus is photographed as well. Central and peripheral visual fields are assessed with computerized techniques. Listing all of the disqualifying findings is beyond the scope of this chapter; however, in general terms, any active or potentially debilitating finding in any ocular tissue would disqualify a candidate for selection. However, many findings that are disqualifying for selection may be considered acceptable for retention purposes.

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Figure 25.1. Mean spherical-equivalent refraction values for 44 pilots and 88 mission specialists in the U.S. Astronaut Corps

Vision Correction Space crewmembers must contend with demanding visual environments during space missions and during training for those missions. In space, these environments include rapid lighting changes from sunrise and sunset occurring every 45 min, vibration, head-movement limitations caused by the space suit helmet, and possibly changes in visual acuity related to microgravity exposure. Challenges during training involve positional constraints and need to wear specialized headgear during flights aboard the T-38 aircraft and during underwater training activities. Environmental demands such as these, especially for individuals who require visual correction for presbyopia or other conditions, necessitate a vision support system that incorporates many forms of correction. Experience has demonstrated a need not only for standard-design bifocals, trifocals, double bifocals, and progressive addition lenses but for many other specialty lenses and frames as well. The following paragraphs give a brief overview of the vision demographics among the current active U.S. Astronaut Corps is given, followed by descriptions of special visual correction systems designed for use during training and space flight activities.

Vision Demographics The distribution and extent of refractive error among a current group of pilots and mission specialists in the U.S. Astronaut Corps are shown in Figure 25.1. The magnitude of refractive error reflects the stringent vision standards described previously. As the figure indicates, the data are distributed normally; the notable absence of individuals with emmetropia (i.e., those

Figure 25.2. Vision-correction modalities used by 135 pilots and mission specialists in the U.S. Astronaut Corps

with no refractive error) probably reflects the age of the population. According to the ongoing Longitudinal Study of Astronaut Health at Johnson Space Center, currently 59% of pilot astronauts and 77% of mission specialist astronauts require some form of visual correction (Figure 25.2). Among those who wear visual corrective devices, 15% of the pilots and 33% of the mission specialists elect to wear contact lenses. Among those with ametropia (nearsightedness, farsightedness, or astigmatism), a multifocal correction is required for 50% of the pilots and 53% of the mission specialists (Figure 25.3). Interestingly, in the multifocal-correction group, progressive addition lenses are preferred over bifocals by 42% of the pilots and 49% of the mission specialist astronauts.

25. Ophthalmologic Concerns

Figure 25.3. Spectacle types used by 96 pilots and mission specialists in the U.S. Astronaut Corps

Spectacles Many modifications have been made to standard spectacles to meet the unique demands of training for space flight and the activities in that environment. One such modification is the insertion of vertical bifocal lenses in the temporal aspect of the spectacle lens; these lenses allow the wearer to see small nearby objects located in the extreme lateral viewing area while wearing the extravehicular-activity helmet. Many presbyopic astronauts have found such lenses extremely useful in this confined environment. Another vision system that has proven useful in space is the FD trifocal (Vision Ease, Azusa, CA), an executive-style trifocal lens with a line traversing the width of the lens and a flattop 28-mm bifocal inset. The vertical separation of bifocal and trifocal lines in these lenses is 11 mm rather than the standard 7-mm separation. The exceptional amount of lateral viewing area provided by the wide intermediate lens area has proven practical in the operational space flight environment. Another type of multifocal corrective lens, the Access progressive addition lens (Sola Optical USA, Petaluma, CA), was designed for near and intermediate-distance work. The designated reading area of the lens has a centrally located 10-mm transition zone of +0.75 or +1.25 D (depending on the prescription required) and an upper segment of uniform intermediate power. This lens has been used successfully during underwater training sessions for extravehicular activities, in which the interface between the water and the helmet mask produces a −2.57-D myopic effect. Because many space crewmembers are presbyopic and a vital control panel on the chest of the suit is located ~10 in. (25 cm) from the crewmember’s eyes, a compensatory spectacle prescription is often needed to meet this increased demand for accommodation. The Access lens design, with +2.50 D added to the normal calculated prescription, has been successful for this purpose.

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Slight modifications to traditional bifocal or trifocal line settings are also useful during T-38 missions. This aircraft, which NASA pilots and mission specialists are required to fly to maintain flight proficiency, includes a tilted seat that mandates the lines on bifocals or trifocals be set lower than standard levels. Experience has shown that in standard aviator frames, segment lines 10 mm above the lower eye-wire are successful. A slightly longer bifocal focal length calculation of 20 in. (51 cm) works well for individuals with early presbyopia and can help avoid the need for trifocals for older presbyopic individuals. Other ocular challenges associated with orbital flight include glare from extreme sun intensity and the potential for exposure to UVA, UVB, and UVC electromagnetic radiation. The Adidas model A125 wrap-around sunglass frame (Silhouette Ltd, Northvale, NJ) design has been found to be effective for this purpose. This product fits comfortably, blocks 100% of electromagnetic radiation at less than 400-nm wavelengths, limits visible blue light to 5%, limits all visible light to 7%, and restricts infrared light to less than 31%. A mirror-coated front surface lens wraps around, giving excellent peripheral vision protection. A prescription spectacle insert is easily added behind the tinted carrier lens if necessary. Suspension frames, a specialty frame from Suspension Eyewear Enterprises (Fountain Valley, CA), have proven useful in situations requiring long-term use of helmets during T-38 flights and communication gear during space flights. Wearing such headgear for long periods frequently causes “hot spots” where the temple of standard spectacle frames is pressed against the temporal aspects of the crewmember’s head. In the unique suspension frame design, each temple portion of the glasses frame is replaced with 2 monofilament nylon lines that originate from 2 drilled holes in the temporal aspects of the spectacle lens. The strings are then tied into a small earpiece when the glasses are fit, thus allowing a customized fit. The monofilament lines preclude any compression “hot spots.” After manufacture of the suspension frame was discontinued, a titanium-frame product has been used in its stead. Manufactured by Silhouette Optical, these frames are thin, lightweight, and highly durable. The temple wires are thin enough to avoid causing hot spots around the temples, and their low mass helps stabilize the frames during head movements made in microgravity. The absence of screws in this eyewear design further reduces risk to the crewmembers from product failure. If a screw in a typical spectacle design were to back out, the corresponding release of the spectacle lens poses potential hazards, particularly during extravehicular activities. A free-floating lens could become lodged between the astronaut and a firm area of the suit, possibly cutting the inside suit bladders and causing suit depressurization. Freefloating screws could be drawn into the suit-cooling impeller, resulting in mechanical malfunction, or could be accidentally ingested or aspirated as well as becoming lodged in the eye of a crewmember. For these reasons, the titanium-frame design is recommended for crewmembers who elect to wear spectacles during space flight.

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Contact Lenses Approximately one-third of U.S. astronauts who wear spectacles prefer to wear contact lenses during space missions. NASA has evaluated a variety of soft and hard contact lenses aboard the parabolic-flight aircraft. In these studies, alternating exposure to simulated hypergravity conditions and simulated microgravity (free fall of 30 s’ duration) did not affect the performance of spherical or toric soft contact lens. Rigid gaspermeable lenses, however, tended to be displaced superiorly. As a result of these assessments, nearly all types of contact lenses are approved for all phases of orbital flight. However, segmented or progressive power rigid gas-permeable multifocal lenses are not recommended because of their tendency for superior displacement on the cornea. Our clinical experience since 1990 has supported these findings, with no reports to date of poor visual performance or permanent corneal insults as a result of wearing contact lenses during space flight. Nevertheless, caution is required when contact lenses are used during space flight because of limited on-board diagnostic and treatment capabilities in the event of ocular complications. Altered fluid dynamics in microgravity and the limited hand-washing capability aboard spacecraft require some changes in the procedures for cleaning and handling contact lenses in microgravity. Hand cleaning is best accomplished with evaporating finger wipes; however, alcohol-based products should be avoided because of the potential for ocular irritation if residual alcohol is transferred from the fingers to the contact lenses. An alternative hand-cleaning agent approved for use in space flight is a benzalkonium chloride-based product. The risks of ocular contamination make the use of single-day, disposable contact lenses prudent. When reusable lenses are necessary, AMCON’s SoftMate hydromat cleaner has proven useful for both cleaning and rinsing in microgravity, with the added benefit of fluid containment. No hydrogenbased disinfection systems that require venting of gases are used, as their function depends on fluids remaining in the bottom of a container and off-gassing through a vent in the container lid. Because fluids do not settle in microgravity, such gravitydependent systems have proven suboptimal for use in space.

Ophthalmic Medications: Microgravity Considerations Ophthalmic medications are available in several forms, including ointments and solutions. The effects of microgravity on fluid dynamics make some of these formulations more advantageous than others. Ointments can be applied effectively in microgravity; however, the reduction in minimum force required to move objects in microgravity dictates that caution be used to avoid a conjunctival or corneal abrasion from the applicator tip. Solutions continue to be the most common formulation used in U.S. space programs; however, several challenges remain. Because drops do not “drop” in microgravity, the normal

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delivery mode must be modified. If a medicine vial is squeezed slowly, a globule of medication forms on the dropper tip. This globule can then be gently touched to the inferior conjunctival cul de sac or to the lateral canthus while the eye is directed away; surface tension quickly wicks the solution to the ocular surface. However, use of the globule technique is problematic with regard to dose control. Experience from past flights suggests that each globule contains 3 to 6 drops; thus, dispensing medications as globules can result in overdoses in addition to wasting limited medication resources. Medication should not be applied to the central palpebral fissure area because of the risk of corneal or conjunctival abrasions. Ocular medications must not be shared among crew members because of the potential for cross contamination. Finally, given the limited refrigerated storage capacity aboard spacecraft, ophthalmic drugs that require refrigeration should be avoided and alternate selections made if possible.

Preflight Surgical Treatment of Refractive Error: Microgravity Considerations Over the past few decades, numerous surgical procedures have become available for correcting myopia. Many of these procedures have been accompanied by huge and occasionally misleading marketing campaigns. The rapid technologic changes in this field have made objective analysis of the sequelae of these procedures difficult. This section briefly reviews the surgical options currently available for correcting myopia and the possible effects of these procedures in the environmental conditions encountered during preflight training and orbital space flight.

Radial Keratotomy Radial keratotomy has been performed on millions of active young myopic individuals. The procedure usually involves making 4 to 8 radial incisions at a depth of 90% in the periphery of the cornea. These incisions are normally made with a diamond blade, and the visual axis of the cornea remains untouched. These wounds may never heal completely and can remain weak even years after the surgery. Diurnal changes in vision at sea level after radial keratotomy have been well documented [4]. Several reports have also documented visual changes after this procedure at altitudes in excess of 9,000 ft (2,743 m) [5–9]. Any cornea exposed to hypoxia will thicken [10]. However, research suggests that when the normal corneal architecture is weakened by radial incisions, the hypoxic cornea may preferentially expand circumferentially in the periphery, leading to flattening of the central cornea and a resultant hyperopic (farsighted) shift [8,10]. Such changes normally require overnight exposure to hypoxia to become manifest [11,12]. Conversely, exposures to increased oxygen concentrations result in a myopic (nearsighted) shift [8,12]. The environments of flight training, underwater training, extravehicular

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activities, and space flight all subject the cornea to varying oxygen concentrations. Because such variations may affect corneal curvature and result in visual alterations, radial keratotomy is not suitable for astronauts.

Photorefractive Keratectomy Photorefractive keratectomy (PRK), another surgical procedure designed to correct myopia, involves a laser ablation of the anterior cornea resulting in a resculpturing of the corneal surface. This procedure ablates the central 6 mm or so of the cornea to a maximum depth of about 100 µm. Although PRK has been used to correct very high degrees of myopia, it has been most successful for low to moderate myopia (up to 6.0 D). Mild optical aberrations may be present after PRK if the entire corneal surface is not uniformly ablated [13]. When a corneal surface irregularity persists after PRK, the image produced may lack edge definition and contrast [14–17]. Numerous studies have documented glare and ghost images after PRK that may become more prominent with increased pupil size [18–22]. This effect was particularly true of early PRK procedures, which ablated only 4 to 5.5 mm of the central cornea. Optical zone diameters must be at least as large as the entrance pupil to preclude glare at the fovea and larger than the entrance pupil to preclude perifoveal glare [23]. More modern lasers that ablate the optical zone to 6 mm or more have greatly decreased the incidence of these complaints. Temporary corneal haze within the optical zone can also occur after PRK; this effect is more prominent when deeper ablations are used for more severe myopia [24–29]. On the positive side, the visual results from PRK have been well accepted by most patients, and PRK produces no diurnal variations in refraction. In one study, subjects who had undergone PRK were exposed to simulated altitudes of 14,000 ft (4,267 m) for 72 h and demonstrated no significant change in refractive error [8]. Thus, those individuals who have undergone PRK for myopia do not seem to be susceptible to altitude-related refractive shifts. PRK is currently disqualifying. In the future, because of possible visual aberrations, PRK may not be suitable for pilots but may be considered for mission or payload specialists.

Laser in Situ Keratomileusis A newer procedure for the correction of myopia is laser in situ keratomileusis (LASIK). This procedure involves creating a planolamellar corneal flap by incising the anterior stroma with a microkeratome. Refractive ablation with an excimer laser is then performed in the anterior corneal stromal bed, and the flap is replaced without sutures or adhesives. The LASIK procedure preserves the central epithelium, basement membrane, and Bowman’s membrane and is frequently used to correct myopia of up to about 12 D. Although long-term studies have yet to be conducted, early reports suggest that LASIK can result in predictable and stable visual acuity [30,31]. Findings

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from high-altitude studies of patients who had undergone LASIK, however, have been controversial. In one case report, refraction and near point of accommodation were found to be stable at 16,000 ft (4,877 m) in a 29-year-old climber who had previously undergone LASIK [32]. However, no cycloplegic refraction was performed at high altitude [33]. Three other reports have documented various degrees of myopic shifts in refraction upon exposure to high altitude [34–36]. Sea-level laboratory studies in which the corneas of 10 healthy subjects were subjected to total surface hypoxia for 2 h documented a statistically significant myopic shift in refraction in subjects who had undergone LASIK [37]. The clinical significance of this myopic shift for aviators is unknown. To date, no longterm studies after LASIK have been done, and the potential of LASIK for use in astronauts is promising but largely speculative.

Intrastromal Corneal Ring Another new device for the surgical correction of myopia is the intrastromal corneal ring. This ring device, made of a clear polymer, is surgically inserted through a single small radial incision in the peripheral stroma of the cornea, outside the central optical zone [38]. The intracorneal inlay mechanically flattens the central cornea and can correct myopia in the range of −1.0 to −3.5 D. Unlike other procedures for correcting myopia, the intracorneal ring technique does not involve disruption of the optical zone, multiple incisions, or the removal of large amounts of corneal tissue. Exchanging the implanted rings for others of different sizes allows surgical outcome to be adjusted as necessary; moreover, the refractive effect theoretically can be reversed by removing the ring. Neither longterm nor altitude studies of patients who have undergone this procedure have been conducted.

Intraocular Lenses Perhaps the most common ocular surgical procedure performed worldwide is removal of a cataractous lens and replacement with an intraocular lens. This is also a refractive procedure. Before performing the procedure, the surgeon calculates the power of the intraocular lens from measurements of the curvature of the cornea and the axial length of the eye. With this information, the surgeon can choose a lens power that corrects existing refractive error. For example, a patient with a history of severe myopia or hyperopia can be made emmetropic (i.e., no longer needing glasses for distant vision) by inserting an intraocular lens of the appropriate power. Modern intraocular lens surgery has successfully withstood the test of time. A variety of intraocular lenses, most with ultraviolet protection, can be inserted through incisions as small as 2.5 mm. The success of this procedure for aviators is well documented [39–42], and this procedure is now considered acceptable in all three U.S. military services and the Federal Aviation Administration. A 64-year-old NASA astronaut who had undergone bilateral intraocular lens implantation was found to

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have stable vision during a 2-week space flight [43]. As is true for any surgical procedure, intraocular lens implantation can be associated with intraoperative and postoperative complications such as infection, lens dislocation, or macular edema. Moreover, because accommodation is no longer possible after this procedure, the focal length becomes fixed. Nevertheless, this procedure has been extremely successful and will no doubt continue to play a major role in the visual rehabilitation of astronauts. The aging of the astronaut population as well as the possible effects of space radiation on the human lens may increase the need for this procedure in the future [44].

Clinical Conditions That May Affect Astronaut Duty Elevated Intraocular Pressure Intraocular pressure (IOP) has been observed to increase during parabolic flight and during microgravity exposure [45–48]. Specific evidence for IOP elevation in microgravity, the possible mechanism by which this occurs, and the potential significance of such an increase for astronauts are discussed briefly in this section. Also discussed are the clinical presentation of a rise in IOP and methods for treating this condition during space flight. Several sources of information indicate that IOP rises in microgravity. Draeger and colleagues documented a mean 5-mm increase in IOP during the free-fall phase of parabolic flight by using a hand-held applanation tonometer [45,46]. A later study, also performed during parabolic flight, documented a 58% increase in IOP measured with TonoPen tonometry [47]. Draeger reported measurements of IOP made with a hand-held applanation tonometer during a Space Shuttle flight [45,46]. An initial 20% to 25% increase in IOP was noted 44 min into the mission. Several years later, the same group documented a 92% increase in IOP in cosmonauts bound for Mir ~16 min after reaching microgravity [48]. These studies suggest that in healthy subjects, the initial rise in IOP after reaching microgravity declines to roughly normal values after several hours. IOP has not been measured during extended space flight. The specific mechanism by which IOP rises in microgravity is open to speculation. The microgravity environment is thought to affect ocular physiology through the cephalad shift in intravascular and extravascular body fluids resulting from the absence of the 1-G hydrostatic gradient [49]. The effects of this fluid shift have been documented by changes in leg girth, photographic evidence of facial edema, and verbal reports of head fullness and nasal stuffiness [49–51]. These shifts occur within 20 s of microgravity exposure. Whole-body head-down tilt studies suggest that a sudden elevation in IOP may be due to vascular engorgement of the choroid brought about by the cephalad fluid shift [52]. Since the rigid sclera does not expand as ocular volume increases, the IOP may rise. Previous experiments noted that a 20-µl increase in choroi-

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dal volume produced a 20-mm increase in IOP [53]. Thus, a very small increase in choroidal volume may produce an immediate and prominent increase in IOP. Other investigators have hypothesized that the change in IOP is caused mainly by increased intracranial blood pressure [45,46,48], which may lead to increased perfusion of the ciliary body and increased production of aqueous humor. Congestion in the venous system and a concomitant rise in pressure in the episcleral vessels may increase the resistance to aqueous-humor outflow, leading to a rise in IOP. The clinical significance of a rise in IOP in microgravity is unknown but merits discussion [54]. A prolonged increase in IOP during space flight could put astronauts at risk for optic nerve damage. Those at risk for glaucomatous optic nerve damage would most likely be those who are exposed to microgravity for months to years. Glaucomatous damage would present clinically as a slow, painless loss of vision. Astronauts with moderate increases in IOP for brief periods, as may occur with relatively short space shuttle operations, would not be expected to develop measurable optic nerve damage. Astronauts with elevated IOP or frank glaucoma at baseline may be at risk during extended space operations because their ability to adapt to elevated IOPs may be impaired. In the past, strict screening programs have excluded individuals with ocular anomalies from space flight. Most of the subjects whose IOP was monitored in the bed-rest, parabolic flight, Space Shuttle, and Mir studies described in the previous paragraphs had low to normal baseline IOP at 1-G. Individuals with higher baseline IOP may be particularly vulnerable to a rise in IOP associated with microgravity exposure. For this high-risk subgroup, it may be prudent to measure visual fields and obtain stereo-optic nerve photos before and after the space missions and to measure IOP during the missions. Pressure-lowering medications should be continued on patients already taking such medications and should be made available for others in the event of a pressure rise. Theoretically, acute angle closure glaucoma would also be possible in some predisposed individuals. Two mechanisms could produce angle closure in microgravity. First, if the choroid were to expand in microgravity, this could lead to a slight anterior displacement of the vitreous, lens, and ciliary body. The lens-iris diaphragm thus could be pushed forward sufficiently to narrow or close the anterior chamber angle, which in turn could obstruct the aqueous drainage from the eye and lead to a rise in IOP over a period of several hours. Alternatively, swelling of the ciliary body associated with cephalad fluid shifts may rotate the ciliary body and iris root further into the angle, worsening angle closure. Subjects with normal anterior chamber angles would not be expected to be affected by such shifts. However, subjects with preexisting narrow angles may be predisposed to angle closure. The actual effect of such fluid shifts on anterior chamber depth, if any, is unknown since anterior chamber depth has never been measured in microgravity. The treatment for an acute rise in IOP would include oral acetazolimide as well as topical medications such as pilocarpine to promote reopening of the chamber angle.

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Assuming that IOP does rise significantly in the microgravity environment, how could it be controlled? If increased choroidal volume is responsible for the rise in IOP, no direct means of pharmacologic control would exist since choroidal blood flow is not autoregulated [55]. A more practical approach may be to control aqueous production. Moreover, if a rise in episcleral venous pressure or increased ciliary perfusion were the cause of elevated IOP, then decreasing aqueous production pharmacologically would also be advantageous. Several systemic and many topical antiglaucoma medications decrease aqueous production and thus reduce IOP. Topical beta blockers would be a logical first choice because they effectively decrease aqueous production, are easy to administer, and have few side effects. Preliminary studies performed with patients transiently exposed to simulated microgravity have demonstrated the effectiveness of these agents [56]. Unfortunately, the long-term effectiveness of pressure-lowering medications in microgravity is thus far unknown. Also, since most antiglaucoma medications are given topically, they may be difficult to administer in microgravity. As noted earlier in this chapter, giving an eye drop in microgravity requires touching the tip of the dropper bottle to the conjunctival cul de sac so that capillary action draws the medication to the eye. Such direct contact with the eye could contaminate the medication container. Therefore, a unit-dose container of the antiglaucoma medications, one that could be used for a maximum of 24 h and then discarded, may be a practical alternative. In summary, data from parabolic flight, bed-rest, and orbital flight studies suggest that IOP may be significantly elevated immediately after exposure to microgravity. This rise in IOP may result from increased choroidal volume or increased ciliary-body perfusion caused by cephalad fluid shifts. Astronauts with low to normal IOP seem to undergo a pressure-lowering adaptation phase lasting several hours. We hypothesize that individuals with ocular hypertension or clinical glaucoma may be at risk for a prolonged increase in IOP. Chronic exposure to an elevated IOP could cause glaucomatous optic nerve damage. Should a long-term increase in IOP occur, topical pressure-lowering medications would probably be the best means of controlling it. Although unlikely, the potential does exist for acute glaucoma in a small number of individuals upon exposure to microgravity. Means of measuring intraocular pressure during prolonged space flight should be available, both for monitoring individuals at high risk and for diagnostic purposes should suggestive symptoms arise. Although several intraocular pressure-measuring devices have been used in microgravity, the optimal device for use in prolonged space flight remains unclear [45–48,57].

Ophthalmic Emergencies Although a wide variety of ocular emergencies are possible in the microgravity environment, the following discussion is limited to those most commonly anticipated. Our goal is to

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concentrate on realistic diagnostic and treatment measures that are practical in the current microgravity environment.

Bacterial Corneal Ulcers The unique environment in which space operations take place poses challenges for the diagnosis and treatment of corneal ulcers. The term corneal ulcer (bacterial ulcerative keratitis) refers to the breakdown of the corneal epithelium from an underlying bacterial infection of the corneal stroma. These ulcers can be extremely painful and can profoundly and sometimes permanently impair vision. Their occurrence during a space mission could be catastrophic. It is imperative that clinicians be familiar with the diagnosis and treatment of this condition. The first line of defense against ulcerative keratitis is an intact corneal epithelial barrier. A corneal abrasion, foreign body, or any condition leading to an epithelial defect could precipitate the development of bacterial keratitis. The risk of injury from a foreign body in particular is heightened in microgravity because particulates that would normally settle out in 1-G float freely in the cabin and follow prevailing air currents. Even seemingly trivial trauma that causes microabrasions to the corneal epithelium may set the stage for bacterial adherence and subsequent invasion of the cornea by microorganisms. Thus, any ocular injury that causes a corneal epithelial defect should be treated promptly with topical antibiotics and followed up appropriately. The use of contact lenses during space flight is a risk factor for the development of corneal ulcers. As noted previously, contact lenses are commonly used by astronauts, particularly mission specialists and payload specialists. Contact lenses provide excellent vision for myopic individuals and are an appealing alternative to glasses. However, the use of any type of contact lens, including rigid gas-permeable lenses as well as disposable or conventional soft lenses, predisposes the wearer to corneal ulcers [58–60]. Furthermore, the overnight use of conventional or disposable soft extended-wear contact lenses confers at least a 10-fold higher risk of ulcerative keratitis than does strict daily-wear use [58–60]. Eye pain in a contact lens user on a space mission should be assumed to be a bacterial corneal ulcer until proven otherwise. The most common symptoms of a corneal ulcer are pain, photophobia, tearing, and blepharospasm. Signs may include conjunctival hyperemia, lid edema, and discharge. The degree of visual incapacitation varies depending on the extent and location of the ulcer. Because prompt clinical recognition is essential to successful treatment, the index of suspicion must be kept high for any patient presenting with eye pain. Microscopic examination of the cornea usually reveals definitive clinical signs of infection. The distinguishing characteristics of bacterial ulcerative keratitis are epithelial ulceration and underlying suppurative stromal inflammation. The inflammatory reaction in the anterior chamber can vary from mild cells to obvious hypopyon. Objective quantification of both the extent of corneal involvement

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and visual acuity is very important. If possible, corneal photos or clinical drawings (as detailed as possible) should be recorded by the crew medical officer as a means of following corneal changes after the initiation of therapy. Live downlinked images should be reviewed daily in a private medical conference with the mission crew surgeon. Although a large number of pathogenic bacteria have been implicated in bacterial ulcerative keratitis, no definite clinical sign exists to identify a specific bacterial pathogen. Thus, corneal scrapings should be obtained for staining and microscopic examination if such facilities are available. Additional corneal scrapings can be plated on culture media for definitive identification of pathogenic bacteria. Normally, in a medical center setting, initial selection of antimicrobial agents is based on the results of gram staining. If gram-positive cocci are seen, then topical concentrated cephalosporin is the standard treatment; for gram-negative bacilli, topical concentrated gentamycin or tobramycin is indicated. Subsequent culture results may modify the initial antibiotic treatment. However, because such facilities and medications would not normally be available during current space operations, an alternative approach may be prudent. Recent evidence suggests that topical fluoroquinolone preparations are extremely effective against a wide variety of bacterial pathogens and are gaining acceptance as single-agent therapy for bacterial keratitis [61]. Fluoroquinolones are effective against most strains of staphylococci as well as P. aeruginosa, the most common etiologic agent in corneal ulcers caused by contact lenses. Fluoroquinolones require neither refrigeration nor special mixing and are usually well tolerated. Thus although fluoroquinolones are not universally effective against all bacterial pathogens, they may be the most practical empiric treatment for corneal ulcers encountered during space operations. Therefore, if the diagnosis of corneal ulcer is made, 0.3% ciprofloxacin, a commonly available fluoroquinolone, could be used for treatment. Specifically, a loading dose of one or two drops every 15 min for 2 h can be initiated, followed by a drop every 2 h for a day or more. Subsequent dosage can be titrated over time depending on the clinical response.

Corneal Abrasions Corneal abrasion refers to the loss of corneal epithelial tissue, most commonly through direct trauma. Fortunately, since the cornea is well endowed with nerves, even the slightest corneal epithelial injury will not go unnoticed. As nearly all corneal abrasions are accompanied by photosensitivity, examining the eye in a dimly lit area is usually advantageous. The use of 0.5% proparacaine (a topical ophthalmic anesthetic) may allow a more complete examination. In the event of blepharospasm, a drop of proparacaine can be instilled by having the patient look up while the examiner gently pulls down on the lower lid to expose the lower conjunctival cul de sac into which a drop is placed. This single drop will quickly anesthetize the entire cornea and conjunctiva and allow a more comfortable

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examination. Biomicroscopic examination of the cornea with the aid of a fluorescein strip usually vividly demonstrates an epithelial defect. The best technique is to wet the tip of the fluorescein strip with a drop of proparacaine and then to touch the wet tip to the inferior conjunctival cul de sac while the eye is looking up. Fluorescein should not be applied directly to the cornea, as it may abrade the corneal epithelium and cause diagnostic confusion. Treatment and follow-up of a corneal abrasion vary according to the extent of the injury. Most superficial abrasions can be treated with a drop of antibiotic applied 4 times a day. A cycloplegic topical medication such as cyclopentolate, used twice daily, may also be given to reduce ciliary spasm and thus alleviate discomfort. Use of an eye patch is normally not necessary and should be avoided. Patching the eye produces a natural culture medium that may predispose the cornea to bacterial infection. Occasionally, an extensive corneal abrasion may require antibiotic application with patching for comfort. Regardless of the extent of injury, the patient should always be examined daily and reports made to ground specialists until the epithelium heals.

Corneal Foreign Body Persistent sensations of a foreign body in the eye and ocular discomfort strongly suggest the presence of a corneal foreign body. Although a slit lamp or other magnification device is optimal for visualization, corneal foreign bodies can also be visualized by shining a penlight on the eye from the temporal periphery. This technique retroilluminates the cornea, and a foreign body presents as a dark spot on the bright background of the iris. The conjunctiva of the upper and lower lids should also be examined any time a foreign body is suspected. Diagnostic examination and treatment of corneal foreign bodies is heavily emphasized in preflight training for crew medical officers. Most superficial corneal foreign bodies can be removed with the tip of a 25- to 27-gauge sterile needle; removal is usually accomplished with the aid of a slit lamp but may be done with a magnifying lens or even the naked eye if necessary. The very tip of the needle is placed under the foreign body, which is then gently lifted from the cornea. Although a sharp needle near the eye may seem a bit intimidating, this technique is actually quite precise and only rarely causes iatrogenic injury to the tough cornea. The use of cotton swabs is best avoided, because the swab only rarely dislodges the foreign body and may damage the surrounding epithelial tissue. Multiple superficial corneal foreign bodies can be removed by irrigation. Means of accomplishing bilateral and unilateral irrigation in a closed system in which effluent is not lost into the cabin atmosphere are provided aboard the U.S. Space Shuttle and the International Space Station. As is true for any epithelial defect, mandatory treatment includes the use of antibiotic drops such as ciprofloxacin 4 times per day and daily ocular examinations until the epithelium is healed.

25. Ophthalmologic Concerns

References 1. NASA. Astronaut Medical Selection Manual. Houston, TX: NASA Johnson Space Center; June 1999. JSC 23086. 2. NASA. Astronaut Medical Evaluation Requirements Document, Revision A. Houston, TX: NASA Johnson Space Center; June 1998. JSC 24834. 3. NASA. Astronaut Medical Standards, Selection and Annual Medical Certification, Payload Specialist—Class III. Houston, TX: NASA Johnson Space Center; June 1997. JSC 25396. 4. Schanzlin DJ, Santos VR, Waring GO III, et al. Diurnal change in refraction, corneal curvature, visual acuity, and intraocular pressure after radial keratotomy in the PERK study. Ophthalmology 1986; 93:167–175. 5. Snyder RP, Klein P, Solomon J. The possible effect of barometric pressure on the corneas of an RK patient: A case report. Intern Cont Lens Clinics 1988; 15:130–132. 6. White LJ, Mader TH. Refractive changes with increasing altitude after radial keratotomy. Am J Ophthalmol 1993; 115:821–823. 7. Mader TH, White LJ. Refractive changes at extreme altitude after radial keratotomy. Am J Ophthalmol 1995; 119:733–737. 8. Mader TH, Blanton CL, Gilbert BN, et al. Refractive changes during 72-hour exposure to high altitude after refractive surgery. Ophthalmology 1996; 103:1188–1195. 9. Simsek S, Demirok A, Cinal A, Yasar T, Yilmaz O. The effect of altitude on radial keratotomy. Japan J Ophthalmol 1998; 42:119–123. 10. Winkle RK, Mader TH, Parmley VC, et al. The etiology of refractive changes at high altitude following radial keratotomy: Hypoxia versus hypobaria. Ophthalmology 1998; 105:282–286. 11. Ng J, White LJ, Parmley VC, et al. Effects of simulated high altitude on patients who have had radial keratotomy. Ophthalmology 1996; 103:452–457. 12. White LJ, Mader TH. Effects of hypoxia and high altitude following refractive surgery. Ophthalmic Practice 1997; 15174– 15178. 13. Maguire L. Keratorefractive surgery, success, and the public health. Am J Ophthalmol 1994; 117:394–398. 14. Baron WS, Munnerlyn C. Predicting visual performance following excimer photorefractive keratectomy. J Refract Corneal Surg 1992; 8:355–362. 15. Maguire LJ, Zabel RW, Parker P, et al. Topography and raytracing analysis of patients with excellent visual acuity 3 months after excimer laser photorefractive keratectomy for myopia. J Refract Corneal Surg 1991; 7:122–128. 16. Camp JJ, Maguire LJ, Cameron BM, et al. A computer model for the evaluation of the effect of corneal topography on optical performance. Am J Ophthalmol 1990; 109:379–386. 17. Gartry DS, Kerr-Muir MG, Marshall J. Excimer laser photorefractive keratectomy. 18 month follow-up. Ophthalmology 1990; 99:1209. 18. Kim JH, Sah WJ, Kim MS, et al. Three year results of photorefractive keratectomy for myopia. J Refract Surg 1995; 11:S248– S252. 19. O’Brart DP, Lohmann CP, Fitzke FW, et al. Discrimination between the origins and functional implications of haze and halo at night after photorefractive keratectomy. J Refract Corneal Surg 1994; 10:S281. 20. Schallhorn SC, Blanton CL, Kaupp SE, et al. Preliminary results of photorefractive keratectomy in active-duty United States Navy personnel. Ophthalmology 1996; 103:5–22.

543 21. Heitzmann J, Binder PS, Kassar BS, Nordan LT. The correction of high myopia using the excimer laser. Ophthalmology 1993; 111:1627–1634. 22. Roberts CW, Koester CJ. Optical zone diameters for photorefractive corneal surgery. Invest Ophthalmol Vis Sci 1993; 34:2275– 2281. 23. Snibson GR, Carson CA, Aldred GF, et al. One-year evaluation of excimer laser photorefractive keratectomy for myopia and myopic astigmatism. Arch Ophthalmol 1995; 113:994–1000. 24. Caubet E. Cause of subepithelial corneal haze over 18 months after keratectomy for myopia. J Refract Corneal Surg 1993; 9: S65–S70. 25. Orssaud C, Ganem S, Binaghi M, et al. Photorefractive keratectomy in 176 eyes: 1-year follow-up. J Refract Corneal Surg 1994; 10:S199–S205. 26. Wilson SE, Klyce SD, McDonald MB, et al. Changes in corneal topography after excimer laser photorefractive keratectomy for myopia. Ophthalmology 1991; 98:1338–1347. 27. Tengroth B, Epstein D, Fagerholm P, et al. Excimer laser photorefractive keratectomy for myopia. Ophthalmology 1993; 100:739–745. 28. Maguen E, Salz JJ, Nesburn AB, et al. Results of excimer laser photorefractive keratectomy for the correction of myopia. Ophthalmology 1994; 101:1548–1557. 29. Mader TH. Bilateral photorefractive keratectomy with intentional unilateral undercorrection performed on an aircraft pilot (guest editorial). J Cataract Refract Surg 1997; 23:145–147. 30. Maldonado-Bas A, Onnis R. Results of laser in situ keratomileusis in different degrees of myopia. Ophthalmology 1998; 105:606–611. 31. El-Maghraby A, Salah T, Waring GO, et al. Randomized bilateral comparison of excimer laser in situ keratomileusis and photorefractive keratectomy for 2.5–8 diopters of myopia. Ophthalmology 1999; 106:447–457. 32. Davidorf JM. LASIK at 16,000 feet (letter to the editor). Ophthalmology 1997; 104:565–566. 33. Mader TH, Parmley VC, White LJ. Authors’ reply to LASIK at 16,000 feet (letter). Ophthalmology 1997; 104:566. 34. White LJ, Mader TH. Refractive changes at high altitude after LASIK (letter). Ophthalmology 2000; 107:2118. 35. Boes DA, Omura A, Hennessy MJ. The effective of high altitude exposure on myopic laser in situ keratomileusis. J Caratact Refract Surg 2001; 27:1937–1941. 36. Dimmig JW, Tabin G. The ascent of Mount Everest following laser in situ keratomileusis. J Refract Surg 2003:19:48–51. 37. Nelson ML, Brady S, Mader TH, et al. Refractive changes caused by hypoxia after laser in situ keratomileusis surgery. Ophthalmology 2001; 108:542–544. 38. Krueger RR, Burris TE. Intrastromal corneal ring technology. Int Ophthalmol Clin 1996; 36:89–106. 39. Mader TH, Carey WG, Friedl KE, et al. Intraocular lenses in aviators: A review of the US Army experience. Aviat Space Environ Med 1987; 58:690–694. 40. Liddy BS, Boyd K, Takahashi GY. Cataracts, intraocular lens implants, and a flying career. Aviat Space Environ Med 1990; 61:660–661. 41. Moorman DL, Green RP Jr. Cataract surgery and intraocular lenses in military aviators. Aviat Space Environ Med 1992; 63:302–307. 42. Loewenstein A, Geyer O, Biger Y, et al. Intraocular lens in a fighter aircraft pilot. Brit J Ophthalmol 1991; 75:752.

544 43. Mader TH, Koch D, Manuel K, et al. Stability of vision in an astronaut with bilateral intraocular lenses during space flight. Am J Ophthalmol 1999; 127:342–343. 44. Cucinotta FA, Manuel FK, Jones J, et al. Space radiation and cataracts in astronauts. Radiat Res 2001; 156:460–466. 45. Draeger J, Wirt H, Schwartz R. Tonometry under microgravity conditions. In: Sahm PR, Jansen R, Keller MH (eds.), Proceedings of the Norderney Symposium on Scientific Results of the German Spacelab Mission D-1. 27–29 August 1986; Norderney, Germany. Koln: Wissenschaftliche Projektfuhrung D1; 1987:503–509. 46. Draeger J, Wirt H, Schwartz R. TOMEX. Messung des Augeninnendrucks unter micro-G Bedingungen [“TOMEX” monitoring of intraocular pressure under microG conditions]. Naturwissenschaften 1986; 73:450–452. 47. Mader TH, Gibson CR, Caputo M, et al. Intraocular pressure and retinal vascular changes during transient exposure to microgravity. Am J Ophthal 1993; 115:347–350. 48. Draeger J, Schwartz R, Groenhoff S, et al. Self-tonometry under microgravity conditions. Clin Investig 1993; 71:700–703. 49. Nicogossian AE, Parker JF, Jr. Space Physiology and Medicine. Washington, DC: US Government Printing Office; 1982:165– 166. NASA SP-447. 50. Hoffler GW, Bergman SA, Nicogossian AE. In flight lower limb volume measurements. In: Nicogossian AE (ed.), The ApolloSoyuz Test Project Medical Report. Washington, DC: US Government Printing Office; 1977:63–68. NASA SP-411. 51. Thornton WE, Hoffler GW, Rummel JA. Anthropometric changes and fluid shifts. In: Johnston RS, Dietlein LF (eds.), Biomedical Results from Skylab. Washington, DC: US Government Printing Office; l977:886–890. NASA SP-377.

F.K. Manuel and T.H. Mader 52. Mader TH, Taylor G, Hunter N, et al. Intraocular pressure, retinal vascular, and visual acuity changes during 48 hours of ten-degree head-down tilt. Aviat Space Environ Med 1990; 61:810–813. 53. Smith TJ, Lewis J. Effective inverted body position on intraocular pressure. Am J Ophthalmol 1985; 99:618–619. 54. Mader TH. Intraocular pressure in microgravity. J Clin Pharmacol 1991; 31:947–950. 55. Moses RA, Hart WM (eds.), Adler’s Physiology of the Eye. St. Louis: C.V. Mosby; 1987:229–238. 56. Pattinson TJ, Gibson CR, Manuel FK, et al. The effects of betaxolol hydrochloride ophthalmic solution on intraocular pressures during transient microgravity. Aviat Space Environ Med 1999; 70:1012–1017. 57. Draeger J, Michelson G, Rumberger E. Continuous assessment of intraocular pressure-telematic transmission, even under flight or space mission conditions. Eur J Med Res 2000; 5:2–4. 58. Schein OD, Glynn RJ, Poggio EC, et al. The relative risk of ulcerative keratitis among users of daily wear and extended wear soft contact lenses. N Engl J Med 1989; 321:773–778. 59. Matthews TD, Frazer DG, Minassian DC, et al. The risks of keratitis and patterns of use with disposable contact lenses. Arch Ophthal 1992; 110:1559–1562. 60. Buehler PO, Schein OD, Stamler JF, Verdier DD, Katz J. The increased risk of ulcerative keratitis among disposable soft contact lens users. Arch Ophthalmol 1992; 110:1555–1558. 61. Hyndiuk RK, Eiferman RA, Caldwell DR, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycincefazolin in treating bacterial corneal ulcers. Ophthalmology 1996; 103:1854–1862.

26 Dental Concerns Michael H. Hodapp

Dental emergencies have occurred only rarely in space flight; they are prevented through the use of comprehensive preflight examinations and preventive measures while the crew is in training. As the duration of space flights increases and as exploration-class missions are planned for travel to the Moon, Mars, and beyond, the likelihood of a dental emergency occurring in space flight also increases. Although space crews live and work in a weightless environment, the forces produced from the mass and velocity of moving objects nevertheless produce impact forces that can cause tooth fracture and other significant injuries to the face and jaws. Also possible during a long-duration flight are the development of cracked teeth, inflammation or infections of the tooth pulp, temporomandibular disorders, periodontal abscesses, and dental caries. This chapter was prepared to provide a brief for flight surgeons and chief medical officers who will be diagnosing and treating the dental emergencies of long-duration spaceflight crews. Basic information has been included to help manage a potential emergency situation. A summary of the basic approach to differential diagnosis of dental problems is given in Table 26.1. Although some of the procedures may seem to be below the standard of care advocated by dental healthcare professionals, these procedures will bring the afflicted crewmembers to a stable condition with the least risk of iatrogenic injury, so that they can perform their duties comfortably. Visiting a dentist during an extended-duration space flight is not an option. X rays, root canals, and definitive dental care are luxuries that are not available in space. Moreover, since in-flight equipment and supplies carried into space are limited by constraints on weight and storage space in addition to the requirement that they operate well in microgravity, the dental care-related equipment that can be provided is currently restricted. This restriction, however, should be all but eliminated by the advent of new technologies and the expansion of current technologies. Thus with the construction of long-term space habitats such as the International Space Station already being realized and plans for exploration-class missions maturing, the provision of comprehensive dental treatment to crews during space flights will become not only possible but practicable in the near future.

Preventive Strategies, Standards, and Screening Although the primary goal of clinical space dentistry is to return an astronaut or a cosmonaut who has a dental emergency to optimal functioning capacity as soon as possible, our focus in this chapter is prevention. NASA has established strict standards for astronaut selection, retention, and preflight dental examinations. Currently all U.S. astronauts undergo annual dental cleanings and examinations to identify any underlying problems. For astronauts who have been chosen for a specific space flight, a strict clinical schedule is followed. At 6 months before launch, crewmembers undergo an examination. If dental treatment is deemed necessary, all such treatment is completed by 3 months before launch so as to minimize potential problems in flight. The crew medical officers attend a preflight briefing that prepares them to handle the dental emergencies that might occur during a flight. Finally and most important from our perspective, all astronauts—whether assigned to a crew or not—are expected to maintain optimal physical and oral health and to follow good oral hygiene practices.

Dental Caries Presentation and Diagnosis Although astronauts are unlikely to develop dental caries because of the strict dental standards they must follow, dental caries remain the most common cause of odontalgia. Indeed, despite regularly scheduled examinations and radiography, dental caries can often remain undetected under preexisting restorations or within the pits and fissures of teeth. Caries should therefore be viewed as the likely cause whenever odontogenous pain presents itself. In most cases, the patient can localize the pain to the specific tooth involved, but in other cases the pain can be so generalized that the patient is unable to determine its true source. 545

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Table 26.1. Differential diagnosis of dental problems. Hot/cold stimulus

Diagnosis

Pain: but Spontane- does not Painful ous pain linger and lingers

Cracked tooth — Bite prematurity — Gap between tooth — and restoration Dental caries * Hyperalgesia — (exposed dentin) Reversible pulpitis * Irreversible pulpitis + Pulpal necrosis + Partial necrosis + (multirooted teeth) Apical periodontitis + Periodontal abscess + Temporomandibular + (usually joint disorder a dull headache)

Bite pressure (load)

Tooth feels high

Percussion test (tapping)

Palpation of roots

Relieves pain

Dull ache

Sharp pain

Recent restoration

No recent treatment

Uncomfortable

Comfortable

Uncomfortable

Comfortable

Hyperosmotic challenge (salt, sugar)

Immediate pain

Visible signs

Delayed pain

Pimple or boil on gum tissue

Gum inflamed around tooth

Fractured tooth or missing restoration

— + +

— — —

— — —

— + +

+ * *

— + +

— * *

— + —

+ — +

— — —

+ + +

— — +

— — +

— — —

— — —

— — *

+ +

* —

* —

— —

— —

— —

— —

— —

+ +

— —

+ +

* *

* *

— —

* —

* +

+ — — *

— + — *

— * — *

— * * *

— — * —

+ * * *

— — * *

* * * *

* * * *

— — * *

+ + * *

— — — —

— — — —

— — * *

— — — —

* * * *

— — —

— — —

— — —

+ + *

* — *

* — —

* — —

+ — —

— + +

* — —

* + +

— — —

— — —

* — —

— + —

— * —

+ = likely to be present; * = may be present; — = usually not present.

M.H. Hodapp

26. Dental Concerns

Dental caries are most commonly found, in descending order of frequency, in the pits and fissures, the proximal surfaces, and the smooth surfaces of the teeth. Caries can be detected by direct examination with a mirror and an explorer, by bite-wing radiography, or by transillumination with a fiber-optic light. Understanding the mode by which a carious lesion spreads helps when detecting caries. Pit-and-fissure caries spread in the shape of a cone with the tip facing the outer surface of the enamel and the base at the dentoenamel junction. As the caries progresses into the dentin, it re-assumes the shape of a cone—this time with the base at the dentoenamel junction and the tip progressing toward the pulp. Smooth-surface caries, which includes the proximal surfaces, also presents in the shape of a cone, but here the base is at the outer surface of the tooth and the tip progresses toward the dentoenamel junction. As the caries progresses into the dentin, the base of the cone again forms at the dentoenamel junction and the tip progresses toward the pulp. Diagnosis begins with a visual examination performed with a mirror and an explorer and a recent set of bite-wing radiographs. The mirror allows the examiner to view all exposed surfaces of the teeth, the explorer is used to feel for caries and to aid in the diagnostic process, and the bite-wing radiographs allow detection of caries between the teeth. Since radiography is unavailable on space flights, some difficulties are thus imposed in the diagnostic process. Caries are not always readily visible. In fact, caries that have a dark color are usually a slow-growing form of the disease and have become stained over time. (Some dark areas in the pits and fissures of teeth are only stains and not caries at all.) Caries that are the color of dentin typically are produced by a more vigorous type of bacteria and are usually detected with an explorer. That is why the use of an explorer is critical in the detection process. To the explorer, the carious surface is soft, allowing the explorer to sink and stick in the dentin or the enamel. In a normal state, the dentin and the enamel are both hard; the explorer will neither sink in nor have a sticky feel.

Treatment and Management Treatment of dental caries during space flight depends on the extent of the carious lesion and the type of symptoms the patient is experiencing. Whatever the case, the key to appropriate treatment is making a good diagnosis, a process that can be either simple or quite difficult depending on the presenting signs and symptoms. In the case of a carious tooth that is symptomatic, the first objective would be to make a diagnosis based on the signs and symptoms a patient is experiencing. Once a diagnosis is made, treatment can proceed accordingly. (Additional information on diagnosis can be found in the section of this chapter devoted to diagnostic testing.) Caries can present in many ways and can produce a variety of symptoms. The remainder of this section describes three classifications of the carious process: simple caries; moderate caries; and advanced caries. Each classification will be described briefly, followed by our recommendations with regard to treatment and medical disposition.

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Simple Caries Simple caries is asymptomatic. The carious lesion has destroyed a small portion of the patient’s enamel or some of the underlying dentin, sometimes causing the brittle enamel to fracture. Treatment consists of administering local anesthesia, removing the decayed structure, and placing a sedative filling. The diagnosis and treatment are straightforward. In simple caries, the carious material will feel soft or leathery and should be removed with a spoon excavator or similar dental instrument down to the hard dentinal structure. The cavity is then filled with Cavit, a temporary filling material composed of a mixture of zinc oxide and eugenol, or with another similar temporary filling material. After the filling is in place, the patient should be told to bite down before the material sets to optimize surface occlusion. If the filling is too high, it should be adjusted before the filling material hardens. The medical disposition of a patient who requires a filling in an asymptomatic tooth is good. After treatment, the patient should be able to resume assigned duties.

Moderate Caries Moderate caries destroys a moderate portion of the underlying dentin without communication with the pulp chamber. The affected tooth is either asymptomatic or exhibits symptoms of a reversible pulpitis. Symptoms in this case usually manifest while the patient eats or drinks. The treatment in most cases consists of administering local anesthesia, removing the decayed structure with a spoon excavator or similar dental instrument, and placing a sedative filling. In moderate caries, the carious material will feel soft or leathery and should be removed to the hard dentinal structure. (Care must be taken to determine that the pulp chamber of the tooth has not been exposed during removal of the carious material.) A mirror and an explorer are used to check the floor of the tooth to verify that the floor is hard dentin and that no holes leading into the pulp chamber are present. After verification that the pulp chamber has not been exposed, the cavity can be filled with Cavit or another similar temporary filling material. Once the filling is in place, the patient should be told to bite down before the material sets to optimize surface occlusion. If the filling is too high, it should be adjusted before the filling hardens. The medical disposition of a patient who needs a filling in an asymptomatic tooth or who initially had a reversible pulpitis is good. After treatment, the patient should be able to perform assigned duties.

Advanced Caries Advanced caries destroys so much dentinal structure that it affects the pulp chamber and causes spontaneous symptoms from the tooth. These symptoms are classified as an irreversible pulpitis or a pulpal necrosis depending on the type of presenting symptoms. A tooth with multiple roots can have both an irreversible pulpitis and a partial necrosis at the same time.

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M.H. Hodapp

When a tooth presents with symptoms of irreversible pulpitis or pulpal necrosis, the decision regarding the type of treatment to be provided should be based on the severity of the presenting symptoms. The first course of treatment for advanced caries is to apply anesthesia and remove all of the carious material. Then a mirror and an explorer are used to check the floor of the tooth to determine whether the cavity has exposed the pulp chamber. If the pulp chamber has been exposed (regardless of whether the pulp is bleeding or not), the best strategy is to cover the area with a cotton pellet moistened with Red Cross Medication, a mixture of eugenol and oil of cloves. Care must be taken to keep the cotton pellet in place so that it acts as a vent and also keeps the area free of food debris. Sealing an exposed vital or necrotic pulp chamber with a temporary filling could lead to infection, which could cause severe facial swelling and pain. If the treated area becomes sensitive again, additional medicament can be applied by repeating the procedure described. Subsequent applications usually can be placed without recourse to a local anesthetic. Medical disposition of a case of advanced caries is guarded. The patient should be monitored daily for any evidence of swelling. In the event of infection (which will manifest as swelling), the patient must be treated immediately with antibiotics. Depending on the time remaining in the mission, the next step may be to extract the offending tooth. It is important to note that prescribing a course of antibiotics will not eliminate the bacteria present in an infected tooth. Antibiotics serve only to control the bacteria around the bony area underneath the tooth until definitive care can be given.

Traumatic Dental Emergencies

Figure 26.1. Tooth anatomy and Ellis fracture classification.

Traumatic dental injuries can and do occur in space flight. Although space crews live in a weightless environment, the combined forces of mass and velocity can significantly injure the face and jaws. For example, a force directed to the face can fracture, subluxate, or avulse the anterior teeth, fracture either or both of the condyles, or cause other significant injuries. A force directed vertically to the lower jaw could fracture the premolar or molar teeth as a result of the wedging effect of the cusp of one tooth being forced into the fossa of an opposing tooth. However the fracture occurs, whenever teeth are fractured and tooth fragments are missing, it is always wise to palpate the patient’s lips and tongue to determine whether any fragments have lodged there. All fragments that have lodged in tissue must be removed promptly to prevent infection [1].

The simplest and most common type of fracture is the Ellis class I fracture, which involves only the enamel portion of the tooth. Managing this type of fracture usually involves no more than smoothing the rough edge with an emery board. The medical disposition of an Ellis class I fracture is good; after treatment, the patient should be able to perform assigned duties. An Ellis class II fracture involves both the enamel and the dentin but does not expose the pulpal tissue. When dentinal tissue is exposed, the tooth enamel portion will appear chalky-white, and the dentin will usually appear ivory-yellow. Management of an Ellis class II fracture typically requires applying anesthesia and placing a temporary filling that covers the exposed dentin. The medical disposition of an Ellis class II fracture is good; after treatment, the patient should be able to perform assigned duties. An Ellis class III fracture involves the enamel, dentin, and pulp tissue. The injury is frequently accompanied by serious fractures of not only the crown but the root of the tooth as well [2,3]. This fracture is the most serious type, not only because of the immediate emergency but also because of the ensu-

Fractures of Anterior Teeth Fractures of the anterior teeth are managed on the basis of fracture type. The Ellis classification, traditionally used to describe fractures of anterior teeth, includes class I, class II, and class III fractures (Figure 26.1).

26. Dental Concerns

ing problem of the tooth eventually becoming necrotic and infected. Managing an Ellis class III fracture involves administering anesthesia before removing as much of the pulp tissue as can be accessed. Once the pulp tissue has been removed, a cotton pellet moistened with Red Cross Medication is placed over the exposed area and left in place. No temporary filling should be applied over the area, since doing so could seal off the area and result in unnecessary facial swelling and pain. A thin layer of foil may be used to cover the cotton pellet to keep the area free of food debris. The medical disposition of an Ellis class III fracture is guarded, and the patient should be monitored carefully. If facial swelling occurs from infection, antibiotics are the first line of defense. Depending on the time remaining in the mission, the second line of defense is tooth extraction to prevent chronic infection, which can progress to life-threatening sepsis.

Cracked Tooth A cracked tooth can present in several ways. The tooth may be totally asymptomatic or can be quite painful during chewing. The classic symptom of a cracked posterior tooth is a sharp, stabbing pain either upon biting into something or immediately upon release. Usually these symptoms occur when a food that distributes force vertically as well as laterally (such as chicken) is being eaten, causing the cusps to separate on closure. Cracks occur most often in the maxillary premolars because of the V-shaped nature of the biting surface and the wedging effect of the mandibular cusp. Management of a cracked tooth is based on the presenting signs and symptoms and the time remaining in the mission. In most cases, all that is necessary is that the patient avoid using the affected tooth until return to Earth. If the tooth is cracked to the point of a true split, depending on the nature of the split, the only method of treatment may be extraction. This would be the case when a tooth has split down the center and essentially separates into two halves. When the tooth splits at an angle and only the cusp breaks off, the recommended treatment is to apply anesthetic and, if the pulp is not exposed, to place a temporary filling. If the pulp is exposed, we recommend that a cotton pellet moistened with Red Cross Medication be placed over the exposed area and the tooth covered with a thin sheet of foil to keep food debris out of the exposed area.

Subluxation In dentistry, the term subluxation (dislocation) is used to describe a tooth that has loosened because of a traumatic injury. Because subluxation may be related to fracture of the jaws or teeth, the patient should be checked carefully. If the injury caused only slight mobility of the affected tooth, the condition will respond well to restricting food intake to soft foods for about 1 week. If the injury displaces the tooth

549

to the point of causing a traumatic occlusion (bite) with the opposing teeth, the treatment involves physically moving the tooth into a more acceptable bite position, a procedure that might require local anesthesia. Once the tooth has been moved into a more acceptable position, food intake should be restricted to soft foods.

Avulsion Avulsion, the complete displacement of a tooth from the socket, constitutes a true dental emergency. When a tooth has been avulsed after a traumatic injury, the first priority is to locate the tooth. The possibility of aspiration or entrapment in soft tissue must always be considered whenever a patient sustains a traumatic injury to the face [1]. This is especially true in microgravity, where an avulsed tooth could float freely into the oropharynx or elsewhere. Once the avulsed tooth has been found, it should be stored for examination upon return to Earth. Reimplantation, although possible, is too risky a procedure to attempt during space flight because of the pulpal infection that inevitably ensues.

Necrosis Presentation and Diagnosis Pulpal necrosis involves death of a portion of the pulp or the entire pulpal tissue of a tooth. This condition can manifest in many different forms, and the tooth itself may present as symptomatic or asymptomatic. In teeth with multiple roots, the pulp may be partially or fully necrotic.

Partial Necrosis Necrosis of a tooth with multiple canals (e.g., a molar or premolar) fully tests the clinician’s diagnostic skill, as the results can be confusing even when vital testing is available. For example, a maxillary molar with three roots can have one root that is necrotic, another root that is vital, and a third root that has gone through various stages of inflammation depending on the activity of the necrotic root next to it. With regard to the dental pulp, no natural dichotomy exists between vital and necrotic tissue. When a tooth that has multiple roots exhibits symptoms that vary from day to day, partial necrosis should be suspected. However, if the symptoms are not extensive, it is best to leave the tooth untreated until the patient returns to Earth.

Total Necrosis Total necrosis is asymptomatic until it affects the periapical tissue of the tooth. Thermal tests will not produce a response in a totally necrotic tooth. In fact, until the infection has spread to the periapical tissues, percussion will produce responses

550

similar to those of the teeth around the affected tooth. Once the infection has spread to the periapical tissue, however, biting pressure will produce pain. Sometimes the affected tooth is said to feel “high” as the infection spreads out the apex of the tooth and into the periapical space below, forcing the tooth upward. Total necrosis can be dangerous, and the affected tooth may have to be extracted. An infected tooth, unlike other areas of the body, does not have a blood supply that can deliver antibiotics to the source of an infection. The tooth therefore acts as a protective chamber in which bacteria multiply freely, and the infection remains until either a root canal is performed or the necrotic tooth is extracted. Antibiotics only temporarily fight the bony infection at the tooth apex, the area in which the patient feels pain. Without definitive treatment, the infection can spread after the antibiotics are discontinued; such spreading frequently produces resistant strains of the infectious agent.I

Acute Apical Periodontitis Acute apical periodontitis is a local painful inflammation around the apex of a tooth that may be associated with a vital tooth, a partially necrotic tooth, or a totally necrotic tooth. It can be caused by trauma, a recent high restoration, bruxism, or infection. Given the range of possible causes, it is important for the clinician to run a series of pulp tests before initiating treatment. For a patient with necrotic pulp, antibiotic therapy is the initial course of treatment. The time remaining in the mission will determine the next course of treatment. If the patient is to return to Earth in less than a month, the tooth should be treated with root canal therapy immediately upon return. If the mission is to last more than a month longer, it might be best to extract the offending tooth. If the tooth is found to be vital, the treatment consists of removing the cause of the trauma, such as making a minor adjustment in the patient’s bite.

Acute Apical Abscess An acute apical abscess manifests with pain and a purulent exudate around the apex of a tooth. It is caused by an advanced case of acute apical periodontitis, which itself results from pulpal necrosis and extensive suppurative inflammation. An acute apical abscess is a serious condition that can quickly incapacitate a patient. It presents with a rapid onset of slight to severe swelling and pain. The tooth will be painful to percussion, bite pressure, and palpation, and it may be mobile. In severe cases, the patient may become febrile. Once an acute apical abscess is diagnosed, a course of antibiotics should be started immediately. The time remaining in the mission will determine the next course of treatment. If the patient is returning to Earth in less than a month and the infection can be controlled with antibiotics, the tooth should be treated with root canal therapy immediately upon return.

M.H. Hodapp

However, if the mission is to last more than a month longer, the best course of treatment may be to extract the offending tooth.

Diagnostic Testing Determining the source of dental pain can be simple or, in cases involving multirooted teeth or temporomandibular disorders, complex. The source of the pain is usually revealed in the course of a thorough dental history, examination, and testing. The vast majority of cases in which pain is reported encompass conditions of irreversible pulpitis, with or without partial necrosis [4]. Since pain can be described in several ways, an accurate description of pain plays a significant role in the diagnosis of dental disorders. Some common terms used for odontogenous pain are sharp, dull, intermittent, spontaneous, continuous, mild, moderate, and severe. Since the neural portion of the tooth contains only afferent pain fibers, inflammation that is limited to the pulp tissue can produce pain that is quite difficult for a patient to localize. Once the inflammation progresses beyond the apical foramen to include the periodontal ligament, which contains proprioceptive fibers, the source of pain becomes clearer and the patient can usually locate the offending tooth. Whether the source of the pain is clear or not, diagnostic procedures should be performed systematically, with the examiner making note of the patient’s presenting signs and symptoms and analyzing the results of clinical testing. Usually the diagnosis is straightforward once the examination process is complete. When a patient reports pain, the examination should begin with a brief dental history while the examiner observes the patient for any facial asymmetry or distensions that might indicate facial swelling of systemic or odontogenous origin. Examination of the inside of the mouth should then proceed with the aid of a mouth mirror and light source. Intraoral screening begins with an examination of the soft tissue, with the examiner looking for changes in tissue color or contour and for the presence of a raised bump with either a head resembling a pimple or a small opening (sinus tract) on the buccal or palatal mucosa. This type of lesion could signify a necrotic root or necrotic tooth next to the lesion. Once the soft tissue and teeth have been evaluated visually for any obvious lesions, a series of tests-palpation, percussion, bite test, periodontal probing, thermal tests, and transillumination—can aid in the diagnosis.

Palpation Test When pulpal necrosis has extended to involve periapical inflammation, the inflammatory reaction may involve burrowing through the cortical bone to affect the mucoperiosteum. Before incipient swelling is clinically evident, it can be detected through gentle palpation. The palpation test entails placing a finger along the gingiva at about the height of the root tip and gently palpating the

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tissue on both the palatal and facial aspects of the teeth. A painful response over the root apex of a tooth should raise suspicion of pulpal necrosis. Another area to palpate to determine whether an infection is arising from the oral cavity is at the submandibular nodes, located just below the border of the mandible and the cervical nodes on each side of the neck [5]. Raised, tender nodes can be the first noticeable sign of an intraoral infection.

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If the patient feels some pain when the probe is being used, either the examiner is putting too much force on the instrument or the area is inflamed. If the patient experiences a great deal of pain in an area of a tooth, this suggests the presence of a periodontal abscess due to a retained popcorn hull (this would be highly unlikely during space flight) or similar substance, a tooth with a cracked root that is causing pulpal inflammation, a tooth with a failing root canal or pulpal necrosis, or some other form of periodontal disease.

Percussion Test The percussion test consists of gentle tapping on the biting surface of the teeth and can help detect apical abnormalities. It should be performed initially with a finger in the event the questionable tooth is highly inflamed and painful. The handle of a mouth mirror can then be used to help identify the tooth in question. The diagnostic value of the percussion test is in determining whether the apical tissues of a tooth are inflamed. The test does not reveal whether a tooth is vital or necrotic; apical tissue can be irritated in either situation depending on the circumstances. In the case of a vital tooth, the irritation is usually caused by a recently placed restoration or by bruxism (grinding of the teeth). This irritation can cause the periodontal ligament to become irritated, and thus the tooth will be painful upon application of biting pressure. In the case of a necrotic tooth, the necrotic tissue within the tooth multiplies and pushes out through the apical foramen into the bone beneath the tooth, causing a painful response to biting pressure. Any time a painful response to the percussion test presents itself, further tests and questioning should follow.

Bite Test The percussion test helps to determine whether a tooth has inflammation in the apical tissues; the bite test, in contrast, is done to check for a split in the tooth. The bite test is performed by placing the head of a cottontipped applicator or an orangewood stick at different positions on the tooth or teeth under suspicion at different angles to determine whether the patient experiences a painful response. A patient with a cracked tooth will respond to this test with a sharp stabbing pain, either upon biting the applicator or immediately upon release of it.

Periodontal Probing Test The periodontal probe is a valuable diagnostic aid that is used to distinguish between dental or periodontal pain. The probe is inserted between the patient’s gum and tooth, using only very light pressure, and then is walked gently along the side of the tooth between the gum and the tooth, sounding the height and contour of the tissue. This sounding should not be painful, and the measured depth of the probe should range from about 1–3 mm, with no bleeding in the absence of disease.

Thermal Tests One of the most common symptoms associated with an inflamed pulp is pain that is triggered by a hot or cold stimulus. In this case, thermal testing is a valuable diagnostic aid because it can help determine whether a pulp is healthy, inflamed, or necrotic. Testing several teeth in a quadrant by the application of cold, heat, or both also can identify the offending tooth.

Cold Test Before the cold test is performed, the patient should be informed of the nature of the test and what to expect. The nerve fibers in the tooth can sense only pain. The proper method of performing the test is to dry the teeth in the quadrant with 2 × 2-in. gauze. The teeth are then tested individually, starting with the last tooth in the quadrant and proceeding anteriorly. The cold test is performed most commonly with ice sticks, ethyl chloride, CO2 “snow” (dry ice), 1,1,1,2-tetrafluoroethane, or Freon [6]. Of these five methods, all of which are generally accepted, ethyl chloride and 1,1,1,2 tetrafluoroethane are the methods of choice on Earth. However, given the risk of contaminating the spacecraft cabin atmosphere, a moistened and frozen cottontipped applicator is the preferred means of applying the cold stimulus in space. The moistened and frozen cotton-tipped applicator is first placed on a tooth on the other side of the arch being tested to check the response of the patient’s healthy pulp. The patient is asked to respond by raising a hand the moment the cold stimulus is felt. Once the patient responds, the cotton-tipped applicator is removed from the tooth and the number of seconds are counted until the stimulus subsides. (The patient may not always respond if the tooth has had a previous root canal or porcelain crown.) Once the patient has felt the cold stimulus on a healthy tooth and understands how to properly respond, the test is performed on the tooth in question. All teeth in the quadrant should be tested if there is any question of which tooth is affected.

Heat Test The heat test, although it can aid in the diagnostic process, is too difficult to perform in weightlessness, especially by inexperienced examiners. Since the neural fibers in the pulp of a tooth transmit only the sensation of pain, the patient’s response to

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both types of thermal testing is essentially the same, and thus the heat test is of little use in these circumstances.

Evaluating Results of a Thermal Test The pulp usually responds to a thermal test in one of four ways: with a mild transient response; with no response at all; with a painful response that subsides quickly after the stimulus is removed; or with a painful response that lingers after removal of the stimulus. A mild and transient response is typically considered normal, and any other response usually signifies some type of pulpal abnormality. If the pulp does not respond at all, the tooth may be either nonvital or the result may be a false-negative. A false negative may occur with excessive calcification of pulp, a previous root canal, an insulated restoration (e.g., a porcelain crown or large composite filling), an immature apex, recent trauma, or secondary to some medications that may have been taken before pulp testing. A painful response that subsides quickly after removal of the stimulus usually indicates a reversible pulpitis. This type of inflammation will often heal itself once the traumatic stimulus is removed. Finally, a painful response that lingers even after the stimulus is removed indicates a symptomatic, irreversible pulpitis. The disease process in this case generally requires treatment to alleviate the symptoms.

Transillumination A strong fiber-optic light is an excellent adjunct for identifying an offending tooth. Transillumination of the anterior teeth can help detect interproximal caries and determine whether the tooth is vital or necrotic. A vital anterior tooth, when transilluminated, appears clear and slightly pink. A necrotic tooth appears opaque and darker than the surrounding teeth because of the breakdown of blood in the pulp chamber. Transillumination can also help in the diagnosis of cracked teeth in the posterior region of the mouth. Normally, a light source placed against the outside surface of a tooth will transmit light through the tooth, illuminating the whole tooth. If the light source is placed against the side of a tooth and the light goes through the tooth only to the point of a crack before stopping and the patient has shown symptoms of a cracked tooth, it is safe to assume that the tooth is cracked. If light goes all the way through the tooth, even if crack lines are showing on the outer surface of the tooth, it could be that the cracks only go through the enamel surface and this tooth should not be suspect. This test is invalid if a restoration is present that prevents the transmission of light.

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methods, the first of which involves use of block anesthesia, the second infiltration, and the third intraligamentary anesthesia. Block anesthesia is used for the mandibular teeth if, for example, the pain is diffuse over the right side of the face, all pulp tests have been exhausted, and the source of pain is indeterminate. Block anesthesia is used on the mandible because infiltration alone usually does not work for mandibular teeth owing to the dense nature of the mandibular bone. If the pain subsides 3–5 min after a mandibular block is administered, it can be surmised that a mandibular tooth is causing the pain. However, if the pain continues despite achievement of profound anesthesia of the mandibular teeth, then each maxillary tooth can be infiltrated until the pain subsides. It is important to wait 3–5 min between each injection to allow the anesthetic to take effect in order to determine which tooth is the culprit. If a mandibular tooth has been demonstrated to be the culprit, intraligamentary anesthesia can then be administered after the block anesthetic has worn off to permit definitive treatment. (To administer intraligamentary anesthesia, a short, preferably 30-gauge needle is placed into the sulcus at an angle 30 degrees from the perpendicular, with the bevel facing away from the tooth and very firm pressure placed on the plunger of the syringe for several seconds. Approximately 0.2 ml of local anesthetic is used.) When the offending tooth has been anesthetized with this intraligamentary technique, the pain will immediately disappear [7]. On rare occasions, the pain does not disappear despite the correct administration of an anesthetic. If it is determined that all tests have been performed correctly and a definitive diagnosis could not be made, the differential diagnosis must include the possibility of a temporomandibular disorder or some form of organic disease of nonodontogenic origin.

Classification of Tooth Disorders Normal A tooth that is considered normal is asymptomatic. During pulp testing, percussion or palpation of the tooth and its surrounding attachment does not elicit a painful response. Thermal or electrical stimulation, on the other hand, does produce a mild to moderate transient response. On radiography, no evidence of internal calcification of the canal space or root resorption is present, the lamina dura (the bony outline around the surface of the tooth) is intact, and the periodontal ligament is viewed as a thin, equally spaced dark line between the root surface and the lamina dura without interruption or widening.

Anesthesia Tests Tests involving selective local anesthesia are used when pain is diffuse and of vague origin and the results of all other tests are inconclusive. Anesthesia testing is based on the fact that pulpal pain, even when it is referred, is almost invariably unilateral. The anesthesia test can be given by one of three

Reversible Pulpitis In the case of reversible pulpitis, the pulp is not diseased but rather is only symptomatic. The pulpal tissue is inflamed to the point where a thermal stimulus causes a sharp hypersensitive response that subsides as soon as the stimulus is removed.

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Potential causes of reversible pulpitis are essentially anything that can affect the pulp tissue. These include caries, abfractive (wedge-shaped) lesions causing gingival recession, a recent restoration that was left high, a filling without a good bond, and bruxism. The symptoms usually subside once the irritating stimulus is removed. Treatment consists of removing the irritating stimulus. If the cause of irritation is bruxism, then removing the interference is the only treatment necessary. If reversible pulpitis is due to a carious lesion, the carious material should be removed and a sedative dressing (e.g., Cavit) should be placed. Abfractive lesions sometimes can also be covered with a sedative dressing.

Irreversible Pulpitis Irreversible pulpitis can be described as acute, subacute, or chronic. It can occasionally be detected radiographically in forms such as canal calcification and internal resorption. Affected pulp can be partially or totally inflamed. The pulp can also be partially infected or sterile. Irreversible pulpitis can present as a lingering sensitivity to hot or cold, or it may be relieved by either of the same stimuli. The pulp of a tooth is always in a dynamic state, and a change in pulpitis from quiescent chronicity to acute symptomology can occur over several years or in a matter of hours. When a tooth is in the acute symptomatic stage, it requires treatment (e.g., root canal therapy or extraction), particularly when the individual has symptomatic irreversible pulpitis, as described in the following paragraph. Symptomatic irreversible pulpitis is characterized by spontaneous intermittent or continuous paroxysms of pain that can range from moderate to severe depending on the extent of the inflammation. The pain may present as sharp or dull, and it may be localized or referred. A mandibular molar, for example, commonly refers pain to the ear or temporal area. This referral occurs because of the protective nature of the neuromuscular system, which can be compounded by muscle splinting and spasms. The treatment of choice for irreversible pulpitis—root canal therapy—is unfortunately not feasible at this time in space flight. Thus, if pain cannot be controlled with analgesic medication, the only in-flight alternative is extraction. (The technique for tooth extraction in flight is described in further detail later in this chapter.) Asymptomatic irreversible pulpitis is a condition in which inflammatory exudates are present but are quickly vented. This condition sometimes develops during the conversion of acute irreversible pulpitis to a chronic state. In the chronic state, the patient usually has no symptoms and can function normally. If the tooth is left untreated, however, it will usually become necrotic. The treatment to be taken will depend on the duration of the mission, at what point the condition manifests itself within the mission, and the symptoms that the patient may be experiencing. In most cases, immediate care is not necessary, but treatment should be given immediately upon return to Earth. However, if the tooth becomes necrotic

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and the patient begins to experience symptoms of pain and swelling during flight, treatment for a necrotic tooth should then proceed.

Other Dental Emergencies Temporomandibular Joint Disorders Temporomandibular joint disorders are quite common and are expressed in many different forms. Typically, most temporomandibular disorders go undiagnosed and untreated because the disease is not in an acute phase or form. During periods of unusual stress, an asymptomatic condition can become symptomatic. Under normal conditions, the disorder usually presents itself during the third through fifth decades of life and most often occurs in women. Since temporomandibular disorders are often multifaceted in nature, their diagnosis can be quite complex. The important point to note is that when dental pain is expressed but the pain cannot readily be pinpointed to a specific tooth, the patient should be evaluated for the possibility of a temporomandibular disorder. Several types of such disorders are described below.

Myofascial Pain Dysfunction Myofascial pain dysfunction, also known as trigger-point myalgia, is the most common form of temporomandibular joint disorder. In one study [8], myofascial pain dysfunction was diagnosed in more than 50% of the patients reporting to a university pain center. Although the exact cause of the disorder is not fully understood, myofascial pain dysfunction is thought to arise from trauma, stress, and discrepancies between the temporomandibular joints and the occlusion of teeth. Myofascial pain arises from hypersensitive localized areas within the muscles known as trigger points. These trigger points, which are either within the muscles or their fibrous attachments, are often felt as tight bands or knots that are painful upon palpation of the area. However, since only a select group of motor units is firing, no overall shortening of the muscle like that in myospasm is observed. Uniquely, since trigger points can be a source of deep, constant pain, they can produce central excitatory effects. Trigger-point pain is often reported as a headache, and in many instances the patient is aware of only the referred pain— they may not even acknowledge the actual trigger point. This situation can be confusing to the clinician who is attempting a differential diagnosis of dental pain, because the trigger points have been known to refer pain to areas of the oral cavity. Several cases have been reported cases of in which pain that was originally thought to be of dental origin was later found to be myofascial pain dysfunction or some other temporomandibular disorder. This is why pulp testing and questioning the patient is so critical before any form of dental treatment is administered.

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Myofascial pain dysfunction is treated with warm and cold compresses over the trigger-point area to break up the trigger points and to increase circulation to the muscle tissue. Since the trigger point is usually in a different location than the referred source of pain, it can be identified only by palpating the muscle tissue of the face and neck [9]. Treatment is relatively straightforward in that rest, a soft food diet, and nonsteroidal anti-inflammatory drugs (e.g., aspirin or ibuprofen) have been shown to be helpful in alleviating discomfort. The medical disposition of individuals diagnosed as having myofascial pain dysfunction is directly related to their pain level. In most cases, patients should be able to perform their normal duties after treatment.

Trigeminal Neuralgia Trigeminal neuralgia or tic douloureux presents as paroxysmal pain of neuropathic origin. Fortunately, this painful disorder is not very common. When it does occur, the pain is described as being excruciating, sharp, and stabbing. Trigeminal neuralgia can be aggravated by brushing the teeth, chewing, or even talking [10]. Pain can also be induced by touching a specific area of the face. The slightest touch on such trigger zones can produce several excruciatingly painful shocks. The difference between these trigger zones and the trigger point commonly found in myofascial pain dysfunction is that a trigger zone requires only a light touch on the outer skin to elicit paroxysms of pain, whereas trigger points require pressure to elicit pain within the muscle tissue. Trigeminal neuralgia is usually caused by compression of a blood vessel where the trigeminal nerve root enters and exits the base of the skull. The features that distinguish trigeminal neuralgia from myofascial pain dysfunction are the dystonic paroxysm, grimace, or “tic.” [11] Trigeminal neuralgia is treated with anticonvulsant drugs such as carbamazepine. Medical disposition depends on the severity of symptoms. In most cases, patients can perform their duties as long as the trigger area is not touched or disturbed.

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mouth, as occurs during yawning. Anterior dislocation takes place when the condyle of the lower jaw extends beyond the articular eminence of the temporal bone, after which the elevator muscles of the mandible go into spasm. Trismus results, and the condyle cannot return to its proper location within the mandibular fossa. Mandibular dislocation can be frightening and painful. However, in most cases the mandible can be physically manipulated (reduced) into its original position without recourse to sedatives. Occasionally, a sedative such as diazepam may be needed to allow the muscles to release. Reduction is performed by grasping the patient’s mandible intraorally, with the thumbs of both hands placed on the bony ridge adjacent to the molars and the fingers wrapped around the underside of the jaw (Figure 26.2). Downward pressure is then applied to the bony ridge of the mandible while an upward force is applied to the anterior region of the mouth. The effect is to free the condyles from the anterior portion of the articular eminence of the temporal bone. Care must be taken to keep the thumbs away from the biting surfaces of the teeth, since the elevator muscles of the mandible tend to contract with intense force once reduction has occurred. Under no circumstances should the mandible be forced back or the mouth forced closed.

Arthralgia Pain in any joint structure that includes the temporomandibular joint is known as arthralgia. Arthralgia can be caused by discrepancies between occlusion of teeth and joint position, rheumatoid arthritis, inflammation, or trauma. The patient usually complains of sharp, sudden, intense pain in the joint area when moving the lower jaw. When the joint area is rested, the pain usually resolves quickly. Patients with arthralgia typically also suffer with myofascial pain dysfunction that can be controlled by nonsteroidal anti-inflammatory drugs and warm and cold compresses.

Dislocation of the Temporomandibular Joint Although trauma can cause temporomandibular dislocation, its most common cause is excessively wide opening of the

Figure 26.2. Reduction of a dislocated temporomandibular joint

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Dental Techniques for Use in Space Flight Dental Injection Anesthetizing the upper teeth for most procedures usually requires injecting a small amount of anesthetic proximate to the offending tooth. If a tooth extraction is involved, however, the palatal portion of the tissue will also require anesthetization. To anesthetize the desired tooth the needle is placed at the height of the moveable membrane (mucobuccal fold) above the fixed gum tissue and the needle inserted, with the tip directed upward towards the root apex of the tooth to be anesthetized. Once the needle is in position, the plunger should be gently drawn back to aspirate and determine whether the needle has entered a blood vessel. If the aspirant is clear, about one-third of a carpule of anesthetic is delivered and the syringe withdrawn. The patient’s pain should subside within 3–5 min; if it does not subside after 5 min, reinjection may be necessary. Since the mandible is dense, anesthetizing the lower teeth requires block anesthesia, a technique in which an entire section of the mandibular nerve and usually the lingual nerve are anesthetized. A successful block of the mandibular and lingual nerve will produce a numbing sensation on half of the tongue and on the lower lip on the side into which the anesthetic was delivered. This method requires careful attention to technique in order to achieve profound anesthesia. To anesthetize the lower teeth, the syringe is first loaded with a long needle and the yellow needle cap removed as described above. Next, the thumb of the examiner’s nondominant hand is positioned in the deepest portion of the coronoid notch of the mandibular ramus. The centerline of the thumb is used as a guide for the height at which the needle is to be inserted (Figure 26.3). While the patient holds his or her mouth open wide, the examiner, holding the syringe in the dominant hand, places the barrel of the syringe so that it is resting over the mandibular teeth between the canine and first premolar (the third and fourth teeth back from the midline). The needle is then inserted, at this angle, where the seam between the cheek and

Figure 26.3. Administration of block anesthesia to the mandibular and lingual nerve

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throat (the pterygomandibular raphe) turns upward towards the maxilla until the jawbone is contacted. At the point where the jawbone is contacted, only about 5–10 mm of needle should be left exposed from the tissue. If the angle of the patient’s jaw is such that bone was not contacted and the needle hub is pressed against the tissue, the needle should be withdrawn halfway and reinserted with the syringe barrel resting over the 2 premolars (the fourth and fifth teeth back from the midline). If, on the other hand, the needle contacts bone before reaching the proper depth (i.e., more than 5–10 mm of needle is left exposed from the tissue), the needle should be withdrawn halfway and reinserted with the syringe barrel resting over the lateral incisor and canine (the second and third teeth back from the midline). Once the proper depth is achieved and the patient’s jawbone has been contacted at the same time, the plunger of the syringe is drawn back gently to check for aspiration of blood. If no blood is aspirated, the entire contents of the syringe are slowly injected over a 1- to 2-min period. Once the contents of the carpule have been delivered, the syringe is withdrawn. Profound anesthesia should be obtained within 3–5 min; if not, then reinjection will be necessary.

Temporary Filling A temporary filling is a means of covering sensitive, exposed dentin. Dentin can be exposed as a result of caries, trauma, or wear. Covering a sensitive dentinal surface ensures that the patient can continue to function comfortably. If a temporary filling is to be placed, the tooth should be anesthetized and all carious material and any food debris removed with a spoon excavator or similar instrument. However, before a temporary filling is considered, it must be determined with absolute certainty that the pulp chamber is not exposed—even if the pulp is nonvital. An easy way of determining whether pulp has been exposed is to use a good light source, a dental mirror, and an explorer to sound the floor of the tooth. If the floor of the tooth is oozing blood, the pulp of a vital tooth has been exposed. If no blood is present, the next step is to rub the explorer along the floor of the tooth to feel for a pinholetype opening. If an opening is found, the pulp chamber can be assumed to have been exposed, and the area should be treated as exposed pulp. (When in doubt, it is always best to assume that the pulp chamber has been exposed.) If the dentinal surface is intact (it is assumed at this point that the tooth has been anesthetized, the dentinal surface is clean, and pulpal exposure has not occurred), a temporary restoration can be placed as follows. First, a small amount of Cavit or similar filling material is squeezed onto a small work surface, such as a wooden tongue blade, and the material is rolled into a ball. Next, with the aid of the spoon excavator, the filling material is placed into the exposed cavity and the material condensed into the dentinal surface. Once the material is in place, 2 × 2-in. gauze pads are used to wipe off and contain the excess filling material. To determine whether the bite is

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correct, the patient is asked to close his or her teeth together. If the filling is too high, it should be adjusted immediately. (It is better for the filling to be a little low than a little high.) The filling material should set for approximately 20 min before the patient is allowed to eat.

Exposed Pulp When the pulp chamber is exposed, regardless of whether bleeding is present after the carious material has been removed or whether the tooth is necrotic with an access hole into the pulp chamber, the best practice is to leave the area open and keep it clean. Covering an exposed vital or necrotic pulp chamber could lead to an infection that could cause severe facial swelling and pain. In the case of a carious exposure of the pulp when removing decay, the initial strategy is to remove all carious material first before removing as much of the pulpal tissue as possible. Next, Red Cross Medication should be placed on a cotton pellet. Because the eugenol in this medication can be an eye irritant, we recommend that the medication be dispensed from the tubex syringe directly onto the cotton pellet. Once the cotton pellet has been moistened with medication, the pellet is squeezed onto the 2 × 2-in. gauze to remove any excess medication. Finally, the cotton pellet is placed into the exposed area of the tooth and left there. Should the area become sensitive again, additional medication can be placed as needed by repeating the above procedure. Typically, subsequent applications can be placed without the use of a local anesthetic. The area should not be covered with a temporary filling, since doing so could cause facial swelling and pain. It is important to leave the exposed area covered only by the cotton pellet and to remove any food debris that might get into the exposed area. The medical disposition in the case of an individual with exposed pulp would be guarded, and the patient should be monitored daily for swelling. If swelling appears, immediate treatment with antibiotics would be in order, and then, depending on the proposed time remaining in flight, the next protocol may be to extract the offending tooth. As noted earlier in this chapter, a course of antibiotics will not eliminate the bacteria present in an infected tooth. Rather, antibiotics are a means of controlling the bacteria escaping into the bony area underneath the tooth until definitive care can be obtained.

Recementing a Crown When a crown becomes dislodged during space flight, the recommended procedure if the tooth is asymptomatic is to stow the crown in a secure location until the individual returns to Earth. The risk of discomfort as a result of incorrect replacement of the crown or the risk of the crown becoming dislodged and aspirated is too great to consider replacing the crown of an asymptomatic tooth. However, if the tooth is sensitive and loss

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of the crown interferes with the performance of the afflicted crewmember, the correct protocol is to recement the crown with temporary cement. When temporarily recementing a crown, it is imperative that all cement be removed from the internal aspect of the crown and tooth and the bite be checked with the crown in and out of the mouth. If the bite is changed after the crown is placed, it is better to stow the crown than to cement it in place. If the bite does not change, the following steps should be taken. First, all residual cement is removed from the inside crown surface and from around the tooth with a dental carver or spoon excavator. Next, the fit of the crown should be checked carefully by placing the crown on the tooth and asking the patient to bite down while keeping a finger on the side of the crown to prevent it from dislodging. The patient is asked whether his or her teeth feel as if they are hitting correctly (the teeth should hit the same with the crown in or out of the mouth.) If the bite feels different with the crown in the mouth, the crown should be removed and the crown and tooth should be cleaned again, since this feeling of difference is usually caused by residual cement. Once the bite feels the same when the crown is in and when it is out, the crown and tooth should be dried off and the tooth isolated with gauze or cotton rolls. Next, the luting cement is mixed on a tongue depressor and placed into the inside of the crown, after which the crown is seated on the tooth by using a positive pressure rocking force. Once the crown is in place, the patient should be told to bite down and the crown should be checked to see whether it is fully seated. If the crown is not fully seated, the crown should be carefully removed by using the spoon excavator to pry it up at different locations around the margin until it is loose. The crown is then removed and the process is begun again. If the crown is fully seated, the tip end of a cotton swab is placed over the crown and the patient is asked to bite down gently for 3–5 min, after which the remaining cement is gently cleaned from around the gum tissue with a dental carver or explorer and dental floss. To floss the cement from between the teeth, a knot is placed in the center of an 18-in. (46-cm) piece of dental floss and the floss is gently glided back and forth between the crown and the adjacent tooth.

Dental Extraction In space flight, tooth extraction should be considered only as a last resort because of the possibility of complications such as loss of a root tip, sinus exposure, jaw breakage, dry socket, or infection. Extraction should be performed only after all other treatment options have been exhausted. Understanding the physiology underlying a properly performed extraction is important when a tooth extraction is deemed necessary. The most important point that must be understood before an instrument is ever placed on a tooth is that a tooth is not pulled out. The roots of a tooth have a

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natural conical shape, a shape that gives the tooth its natural tendency to erupt. The only force keeping a tooth in its socket is the fibrous periodontal ligament. In other words, the tooth has a natural tendency to come out on its own but is essentially held in place by connective tissue. Also important to remember is that both the tooth and the underlying bone are brittle. So the question is: How can two brittle objects that are held together by fibers be safely separated? The answer is patiently, and with light force. If a gentle-to-moderate force is placed on a ligament for a long time, the ligaments will stretch and the tooth will, by its physiological nature, extract itself. The key to extraction is light-to-moderate force and time. The moment an extraction is rushed, the tooth will break. Also important to note is that a properly performed extraction involves no vertical pulling force on the forceps. To get the maximum benefit from forceps, the crown of the tooth is held in the forceps as close to the gum tissue as possible, and the tooth is rotated clockwise and held in that position so as to maximize the number of fibers being stretched at the same time. As the tooth is held in this position, an ensuing inflammatory reaction also causes the ligament fibers to weaken. This position is to be held for at least 2 min, after which the tooth is slowly rotated counterclockwise and that position again held for at least 2 min. This procedure may need to be repeated several times before the tooth comes out on its own. The points to remember are to be patient and to be gentle. Persuasion is easier than force. The recommended procedure for extraction is as follows: The tooth to be extracted should be anesthetized, using proper dental injection techniques. If the tooth to be extracted is an upper tooth, the palatal tissue next to the tooth to be extracted must be anesthetized; if a lower tooth is to be extracted, the tissue on the cheek side of the tooth may have to be anesthetized before extraction. Next, the explorer is used to disengage the attached tissue from the tooth at the base of the crown. The forceps are then placed on the tooth to be extracted, and the examiner’s other hand is used to either grasp both sides of the gum tissue of the tooth to be extracted (if an upper tooth) or stabilize the lower jaw (if a lower tooth). The crown of the tooth is held in the forceps as close to the gum tissue as possible. The tooth in the forceps is rotated clockwise and held in this position for at least 2 min. The tooth is then slowly rotated counterclockwise and again held in position for at least 2 min. This procedure should be repeated several times until the tooth comes out on its own. If after several minutes the mobility of the tooth has not increased, dental elevators can be used as described below.

Use of Elevators From the cheek side, a small elevator (#301) is placed between the tooth to be extracted and the adjacent tooth, with the lower

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edge of the elevator against the tooth that is to be extracted. Moderate rotational force is applied to the elevator (as if turning a screwdriver), thereby creating a lifting force on the tooth to be extracted, and the position is held for 60 s. This force is to be applied sequentially on both the front and back side of the tooth. Once the tooth is slightly elevated, the procedure can be repeated with a large (#34S) elevator if adequate room exists. Finally, the tooth is extracted with the forceps as described above.

Conclusions In the future, space travel will entail human travel and colonization of distant planets. The crews of these explorationclass missions must be versatile, and must be well trained in all phases of medical and dental emergency situations. Dental emergencies in space can become true medical emergencies. Infections in this area can be serious, since veins in areas of the face do not have valves to prevent backflow into the cavernous sinus area of the brain. Research into space dentistry must continue to help provide the most effective and simplified care for the crews of these missions, helping guarantee our survival in space.

References 1. Houck JR, Klingensmith MR. The tooth as a foreign body in soft tissue after head and neck trauma. Head Neck 1989; 11:545–549. 2. Laskin DM, Steinberg B. Diagnosis and treatment of common dental emergencies. Alpha Omegan 1984; 77:41–52. 3. Amsterdam JT, Hendler BH, Rose LF. Emergency dental procedures. In: Roberts JR, Hedges J (eds.), Clinical Procedures in Emergency Medicine. Philadelphia, PA: WB Saunders; 1985: 2391–2392. 4. Seltzer S, Bender IB. The Dental Pulp: Biologic Considerations in Dental Procedures. 3rd edn. Philadelphia, PA: JB Lippincott Company; 1984. 5. Rose LF, Kaye D. Internal Medicine for Dentistry. St Louis, MO: CV Mosby Co.; 1983. 6. Trowbridge HO. Changing concepts in endodontic therapy. J Am Dent Assoc 1985; 110:470–480. 7. Littner MM, Tamse A, Kaffe I. A new technique of selective anesthesia for diagnosing acute pulpitis in the mandible. J Endod 1983; 9:116–119. 8. Travell JG, Rinzter SH. The myofascial genesis of pain. Postgrad Med 1952; 11:425. 9. Travell JG, Simons DG. The upper extremities. In: Myofascial Pain and Dysfunction: The Trigger Point Manual. Vol 1. Baltimore, MD: Williams & Wilkins; 1982:59–63. 10. Gilroy J, Meyer JS. Medical Neurology. London: Macmillan; 1969: 80–81, 280–288, 547–549, 612–615. 11. Travell J. Identification of myofascial trigger point syndromes: A case of atypical facial neuralgia. Arch Phys Med Rehabil 1981; 62:100–106.

27 Spaceflight Metabolism and Nutritional Support Scott M. Smith and Helen W. Lane

Adequate nutritional status is critical to maintaining crew health during extended-duration space flight and postflight rehabilitation. Nutrition issues relate to intake of required nutrients, physiological adaptation to microgravity, psychological adaptation to extreme environments, and countermeasures to ameliorate the negative effects of space flight. Our ability to define the nutrient requirements for space flight and to ensure the provision and intake of those nutrients by spaceflight crews is thus critical for crew health and mission success. Specialized nutritional requirements have only been considered for extended-duration flights—those lasting longer than 30 days. Although adequate nutrition is important on the 1- to 3-week Space Shuttle flights, intake of specific nutrients above or below space-specific requirements for such periods is not thought to be cause for concern. Thus, planning menus for Space Shuttle flights has always used recognized nutritional requirements for adult males and females [1,2]. In this chapter, we will further classify nutritional requirements for long-duration space flight into those for orbital missions, such as on the International Space Station, and those for exploration-class missions.

Nutritional and Physiologic Effects of Space Flight Nutrition is closely, if not directly, related to many of the physiologic consequences of space flight. Specific examples of these consequences include loss of weight in the form of both lean and adipose tissue, loss of bone, hematologic changes, and increased risk of renal stone formation. Issues that should be considered related to nutrition in the weightlessness of space include dietary intake, specific nutrient deficiencies or excesses, stress, environmental features, and the influence of exercise and other countermeasures [3–12]. This chapter focuses on the clinical aspects of nutrition in space.

Dietary Intake Although the overall percentage of calories derived from protein, carbohydrate, and fat ingested by spaceflight crews has been acceptable (Figure 27.1), the total intake of food and energy (Figure 27.2) is nonetheless generally less during space flight than before flight [5,13–19]—despite data indicating that in-flight and preflight energy requirements are similar [14]. World Health Organization estimates of the energy required for moderately active individuals [2], which reflect current in-flight requirements, have been used as the standards by which spaceflight menus are planned (Table 27.1). Yet from the Apollo program onwards, crewmembers have typically consumed only about 70% of predicted requirements (Figure 27.2). The obvious and immediate reason for concern about this reduction in dietary intake is the associated risk of body mass loss and dehydration. The gap between energy intake and expenditure is widened further by the exercise associated with physical countermeasures. Results from metabolic experiments conducted during the U.S. Skylab missions showed that simply ingesting the prescribed amount of calories did not maintain astronaut body mass (Figure 27.2) [20–22]. Inadequate energy intake clearly ensures loss of body mass. Preliminary data also suggest that the lesser energy intake during space flight is associated with a decrease in protein synthesis [23]. This finding is significant not only from the point of view of crew health but also for medical and research studies, in which clear interpretation of other physiological data from malnourished subjects becomes impossible. The cause of reduced dietary intake during space flight is unknown, although anecdotal information provides potential explanations [5,17,24]. Food palatability has been identified occasionally as a cause of reduced in-flight intake. Anecdotal reports suggest that food taste and aroma change during space flight, and the fluid shifts and congestion associated with microgravity, especially during the first few days, have been hypothesized to affect taste and odor perception. Nevertheless, spaceflight studies have not demonstrated changes

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Figure 27.3. Examples of Space Shuttle foods. (Photo courtesy of NASA)

Figure 27.1. Diet composition before and during flight for Skylab and Shuttle missions. Data are expressed as percentage of calories

Figure 27.2. Energy intake during flight for four different space programs. Intake is expressed as percentage of WHO requirement as calculated for each individual crewmember (see Table 27.1 for equation) Table 27.1. Recommended macronutrient intake levels for crewmembers on missions lasting from 30 days to 1 year. Nutrient Energy

Protein Carbohydrate Fiber Fat Fluid

Recommendation From the World Health Organization (1985) equation: Men: (18–30 years): 1.7 (15.3W + 679) = kcal/day required (30–60 years): 1.7 (11.6W + 879) = kcal/day required Women: (18–30 years): 1.6 (14.7W + 496) = kcal/day required (30–60 years): 1.6 (8.7W + 829) = kcal/day required W = weight in kg. These figures are for moderate levels of activity. An additional 500 kcal/day is supplied on days when extravehicular activities are to take place or when end-of-mission counter measures are being conducted. 12–15% of calories 50–55% of calories 10–25 g/day 30–35% of calories 1.5 ml/kcal (>2 L/day)

in taste or olfaction [25,26], and results from groundbased studies have been equivocal. Tongue taste perception measured before, during, and after 30 days of −6-degree head-down bed rest produced reports of decreased appetite and lack of taste early in the bed-rest phase, but by day 13 the threshold for sensitivity to all tastes (sweet, salt, acidic, and bitter) had increased [27,28]. In contrast, a more recent study found no changes in odor or taste perception after 14 days of head-down bed rest [29], suggesting that multiple factors are involved in the process. A common cause of reduced dietary intake during the first days of a mission [16] is space motion sickness [30]. However, the effects of space motion sickness typically pass after the first several days of space flight, and the decrease in dietary intake often extends far beyond this time [5]. Moreover, anecdotal reports of appetite vary significantly, as indicated in a Russian study in which 40% of the Mir crewmembers reported decreased appetite, 40% reported no change in their appetite, and 20% reported experiencing increased appetite [31]. Other spaceflight-related changes in gastrointestinal function are also possible. Fluid shifts, combined with reduced fluid intake, would tend to decrease gastrointestinal motility. Although transit time has not been systematically studied in space flight, 10 days of −6-degree head-down bed rest significantly extended the mouth-to-cecum transit time relative to the transit time during ambulatory control periods [9]. Additional information regarding gastrointestinal function can be derived from Russian studies of humans and animals conducted during actual and simulated space flight [32]. Developing foods for space flight has proven a significant challenge from the earliest days of the crewed space program [33–35], yet the design criteria have changed little [36]. The food systems used on the Space Shuttle and those that were used on the Russian Mir station are entirely shelf stable and are composed mainly of rehydratable or thermostabilized food items [37]. Although these foods are known to be less palatable than fresh or frozen foods, ground-based studies have shown that the Space Shuttle food system (Figure 27.3) can adequately support nutritional requirements [38]. Skylab was the only U.S. space program that included frozen foods [37]; Skylab crewmembers ate essentially 100% of their predicted [2] energy requirements (Figure 27.2) [5]. Although the Skylab crews were involved in metabolic studies that required

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Figure 27.4. Examples of International Space Station foods. (Photo courtesy of NASA)

complete consumption of a prescribed diet [22,39], this finding nevertheless demonstrates that crews can, when required, consume the recommended amounts of food during space flight. Hypotheses regarding a crew’s inability to consume the requisite amount of food because of a sense of stomach fullness or other factors are therefore not likely to fully explain the decrease in in-flight dietary intake. Although we are unlikely to determine whether food consumption on Skylab was related more to the requirement that the crew consume the food or to the fact that the food was more palatable, it is difficult to argue against the benefit of palatability. Clearly, it is imperative that adequate resources to support food consumption be provided to long-duration spaceflight crews. A reliable food system must include a variety of palatable foods and the means to prepare them—including rehydration, heating, and cooling. Time for meal preparation, consumption, and cleanup is another limited resource that often hinders dietary intake. Plans for the International Space Station food system (Figure 27.4) at assembly complete should include the use of freezers and refrigerators for food storage. These items would provide a more palatable food system, which would likely increase dietary intake as well as provide the crew additional psychological support. Freezers for food are not typically flown in space because they represent a significant drain on crew resources, on-orbit volume, and vehicle power. Moreover, frozen food requires the additional launch mass of frozen food resupply, which also consumes power, volume, and conditioned stowage on the resupply vehicle. It is often difficult to balance the intangible potential increase in dietary intake and psychological support against tangible dollar and power allocations, both of which are typically, if not always, constrained.

Body Mass and Composition Losses of 1–5% of preflight body mass have been a consistent finding in the history of space flight (Figure 27.5), with losses documented on short- and long-duration flights from the U.S. and the Russian space programs [17,18,35,40,41]. Indeed, all

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Figure 27.5. Body mass loss after spaceflight. Data are expressed as percent change from preflight values for each individual. Data are included from several Shuttle and Mir flights, as well as the three Skylab missions

crewmembers from the Gemini, Apollo, Skylab, and ApolloSoyuz Test Project missions lost body mass [20,21,22,42–44]. In a study of 13 male Space Shuttle crewmembers, body weight losses ranged from 0.0 to 3.9 kg [14]. Body mass loss also reached 10–15% of preflight body mass on the longer Mir missions [45]. Although a 1% body weight loss can be explained by loss of body water [13], most of the observed loss of body weight comes from loss of muscle and adipose tissue [5,17]. A change in energy expenditure is a commonly proposed explanation for the loss of body mass in space. According to early hypotheses, energy expenditure during space flight would be lower than that on the ground because of relative hypokinesia [24]. Lower energy expenditure was observed during extravehicular activities on the lunar surface compared with similar activities performed at Earth gravity [46]. However, studies of in-flight, intravehicular energy expenditure demonstrated that in-flight energy expenditure is unchanged from preflight levels [14]. More recent studies have even shown an increase in energy expenditure during space flight relative to preflight levels, most likely as a result of increased exercise [47]. These studies, which involved Space Shuttle astronauts, determined total energy expenditure before and during space flight by using the doubly labeled water (2H218O) technique [48]. This noninvasive technique takes into account the energy cost of all activities over several days. Unfortunately, it does not provide information about the individual components of total energy expenditure, including resting, sleeping, and exercising. Although we can safely assume that less energy is expended in moving one’s body mass around the cabin during space flight, energy requirements for other metabolic activities— including resting metabolic rate and stress—may increase, resulting in unchanged total energy expenditure. Bed-rest studies have shown decreased total energy expenditure with no change in resting energy expenditure [49]. Since total energy expenditure during space flight is either unchanged [14] or increased [47], a bed-rest model may not be appropriate for

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studies of energy metabolism in space flight, possibly because of a lack of stress or metabolic response during bed rest. Lovejoy, Smith, Zachwieja, and others have suggested that exogenous addition of a metabolic stressor (e.g., triiodothyronine) provides a better ground-based model for the metabolic effects of space flight on energy and fuel metabolism than does bed rest [50].

Fluid and Electrolyte Homeostasis Fluid and electrolyte homeostasis changes significantly during space flight [51–57]. The hypothesis originally proposed was that the human body, upon entering weightlessness, would experience a headward shift of fluids, with subsequent diuresis and dehydration. A series of experiments has been conducted to assess fluid and electrolyte homeostasis during space flight. The most comprehensive stemmed from the two Spacelab Life Sciences missions flown in the early 1990s [13]. Within hours of experiencing weightlessness, which is the earliest available data point, crewmembers experience reductions in plasma and extracellular fluid volume [13], and fluid redistribution, which produce the puffy faces typically observed early in space flight [58]. Initially, the decrement in plasma volume (−17%) [13] is larger than the decrement in extracellular fluid volume (−10%) [13]. This suggests that interstitial fluid volume, the other 80% of extracellular fluid, is conserved proportionally more than is plasma volume. Conservation of interstitial fluid volume is supported by rapid decreases in total circulating protein (specifically, albumin) [13]. This shift of protein and associated oncotic pressure from the intravascular to the extravascular space would also facilitate initial changes in plasma volume [53]. After initial adaptation to weightlessness, the crew’s extracellular fluid volume decreases (between the first days of flight and 8 to 12 days of flight) from the initial 10% below preflight levels to 15% below preflight levels [13]. Plasma volume is partially restored during this period, from the initial 17% below preflight levels to 11% below preflight levels [13], and it remains 10% to 15% below preflight levels even for extended-duration missions [59]. Huntoon, Cintrón, Whitson, and Smith have hypothesized that the shift in extravascular protein and fluid is caused by adapting to weightlessness and that, after several days, some of the extravascular albumin is metabolized, with a loss of oncotic force and a resulting decreased extracellular fluid volume and increased plasma volume [53]. This intravascular or extravascular loss of extracellular protein and associated decreased oncotic potential probably plays a role in postflight orthostatic intolerance, which may result partly from reduced plasma volume at landing [60]. Further, the loss of protein may explain why fluid loading—a technique in which spaceflight crews ingest large quantities of fluids before landing to counter the effects of returning to 1 G—alone does not restore circulatory volume [61,62], since no additional solute load exists to maintain fluid volume.

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The effect of space flight on total body water has also been evaluated to assess dehydration. Studies with Space Shuttle and Skylab astronauts showed an approximately 1% decrease in total body water during space flight [13,63,64]; the percent of body mass represented by water did not change. Thus, the often-proposed weightlessness-induced dehydration does not exist in spaceflight crews. Diuresis is typically not observed during space flight [17,51,52,65–68]. Although operational constraints make it difficult to document urine volumes accurately on the first day of space flight, on the Spacelab Life Sciences missions urine volume was significantly lower on the first 3 days of space flight and tended to be lower than preflight values throughout the mission [13]. Urine volumes on a week-long mission to Mir were also less than preflight volumes [67]. On the 59-day and 84-day Skylab missions [39], urine volume decreased during the first week, and remained unchanged from preflight levels for the remainder of the missions. Decreased fluid intake most likely accounts for the decrease in urine volume accompanied by little or no change in total body water. Diuresis has been documented in bed-rest studies [69], again suggesting differences between analog studies and actual space flight. As mentioned earlier in this chapter, the percent of body mass represented by total body water remains relatively unchanged during space flight [13]. On a volume basis, however, the change in extracellular fluid volume is greater than either the change or lack of change in total body water. Thus, intracellular fluid volume increases by this difference during space flight [13]. This fact, which was previously hypothesized from ground-based studies [70], was observed in postflight studies of Apollo crews [17]. The mechanism by which space flight would induce an increase in intracellular fluid volume is unknown. It is possible that a shift in fuel use results in altered glycogen storage, a condition known to increase cellular water content. In summary, available information indicates that the fluid shift in crews during weightlessness is in fact a shift from extracellular to intracellular, or from vascular to extravascular. Clearly, a cephalad shift of fluid occurs, but it does not produce diuresis and dehydration as was originally hypothesized. The implications of either an extracellular-to-intracellular or an intravascular-toextravascular shift are unknown, but this shift may explain many of the physiologic phenomena associated with space flight.

Hematology Decreases in red blood cell mass (Figure 27.6) are consistently found after short- and long-term space flights [59,71–74]. This “spaceflight anemia” was observed as early as the Gemini missions of the 1960s [75]. Although this decrease in red blood cell mass is significant (i.e., it reaches from 10% to 15% below preflight levels within 10 to 14 days of space flight), it seems to be an adaptation to space flight that has no documented functional consequences. Several theories about the origin of the phenomenon have been advanced over the years, some of which have been eliminated and others expanded upon.

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Figure 27.6. Red blood cell mass loss after space flight. Data are expressed as percent change from preflight values for each individual. Data are included from Shuttle, Mir, and Skylab missions

A confounding factor in the U.S. space flights conducted before the Skylab program was the increased cabin partial pressure of O2 [74]. The possibility of hyperoxia-induced red blood cell membrane peroxidation was considered [59]. This possibility was ruled out when changes in erythropoiesis were also observed during Skylab [59,76] and Space Shuttle missions [72,73], during which the partial pressure of O2 was similar to that of Earth’s atmosphere [5,17]. The decrease in the release of mature red blood cells into the circulation is associated with a decrease in circulating erythropoietin concentrations. An early hypothesis for the cause of decreased red blood cell mass was that red blood cell synthesis was understimulated relative to synthesis on the ground [74]. However, since iron turnover is unchanged during space flight [72,73], this would seem to indicate that synthesis of hemoglobin and red blood cells is also unchanged. During the first several days of space flight, hematocrit is either unchanged [77] or slightly elevated [71–73]. When it is elevated, the elevation is not as great as would be predicted in relation to the decrease in plasma volume [13]. The initial decrease in red blood cell mass occurs at a rate of slightly more than 1% per day, with an eventual loss of 10–15% [71–73,78]. Although removal of mature red blood cells from the circulation is unchanged during space flight [72,79,80], the release of new red blood cells stops on entry into weightlessness [72,73,78]. In addition, newly released red blood cells, which are larger than the more mature circulating red blood cells, are selectively removed from the circulation and destroyed [78]. In-flight changes in body fluid volumes and red blood cell mass seem to be adaptive and to reach a new plateau after the first weeks of space flight, as shown by findings from long-term space flights [5,20,81,82]. The triggering mechanism for these changes is unknown. The body somehow senses a decreased requirement for blood volume and adapts accordingly.

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This adaptation may be related to changes in fluid (circulatory) dynamics and to reduced gravitational strain on the circulatory system during space flight. One consequence of a decrease in red blood cell mass is that the iron released when red blood cells are destroyed is processed for storage. This interpretation is based on findings of increased serum ferritin concentrations during and after both short- and long-duration space flights. Serum iron concentrations are also normal to elevated during and after space flight [72,73]. The implications of excess iron storage during extended-duration space flights are not known. Current space food systems provide excessive amounts of dietary iron (∼20 mg per day) [5], which could lead to deleterious effects during extended-duration space missions. Absorption of dietary iron in space has not been studied, but such studies could alleviate concern about iron overload during extendedduration space flights. Until such studies are undertaken, a panel of experts has recommended that the iron intake of male and female crewmembers be reduced to less than 10 mg per day during space flight [5,83]. Future studies will allow us to estimate dietary iron absorption and provide insight into the nature and extent of the problem. Another consequence of reduced blood volume and red blood cell mass occurs after crews return to Earth gravity. It is at this time that dilutional “anemia” often occurs [77], with a disproportionate return of plasma volume before repletion of red blood cells. For example, a 3–5% decrease in hematocrit levels between R + 0 and R + 3 is common after short- or long-duration space flights [77]. Bed-rest studies have not proven to be suitable models for studying the hematologic changes of space flight. In bed rest, red blood cell mass decreases, but erythropoietin is unchanged and hematocrit increases [84]. This difference suggests that different mechanisms are operating in space flight and analog studies. If the reduction in red blood cell mass during space flight is a result of reduced gravitational load on the circulatory system, it is reasonable to assume that bed rest alone would not alleviate these forces but would only reposition them. Indices of iron metabolism and erythropoiesis return towards normal within days after landing, although red blood cell mass replenishment may take several weeks. Efficient postflight recovery suggests that in-flight anemia represents an adaptation to weightlessness, probably in response to either the easier delivery of O2 to tissues that are not influenced by gravity or to the decrease in plasma volume and increase in concentration of red blood cells during the first few days of space flight.

Protein and Muscle Exposure to microgravity reduces muscle mass, volume, and performance, especially in the legs, on long- [20,21] and short-duration [85] space flights. Muscle biopsy studies demonstrated postflight decreases in cross-sectional area only in type II (fast-twitch) myofibers, the fiber type that responds to resistive exercise [86].

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In the Skylab missions, potassium and nitrogen balances became increasingly negative throughout the flights, but urinary creatinine did not change [39,87] despite losses of leg volume [20,88]. Disuse atrophy of muscles in space flight may be related to changes in whole-body protein turnover. A ground-based study [89] demonstrated that whole-body protein synthesis decreased by approximately 13% during 2 weeks of bed rest and that 50% of this decrease could be accounted for by the leg muscles. This bed-rest study did not include exercise but did involve maintenance of body weight during the bed-rest period. In the same study, excretion of 4pyridoxic acid (a vitamin B6 metabolite) increased during bed rest [90], suggesting that metabolically active muscle tissue was being lost. During short-term space flight, studies of stable-isotope turnover indicate that turnover of whole-body protein increases, with elevations in protein synthesis and even greater increases in protein breakdown [91,92]. This synthesis increase was hypothesized by Stein and others to be related to physiologic stress, as indicated by increased urinary cortisol levels during space flight [13,93]. These findings are similar to those found in a catabolic state. Decreased prostaglandin secretion has also been implicated in muscle tissue loss during space flight because of decreases in the mechanical stress on muscles in weightlessness [93]. On long-duration Mir flights, on the other hand, investigators noted decreased rates of protein synthesis [23]. Because protein synthesis correlates directly with energy intake, the reduced protein synthesis was probably related to inadequate energy intake [23]. Although evaluation of plasma and urinary amino acids does not provide a clear index of muscle metabolism, an increase in plasma amino acids has been noted in cosmonauts after landing [94]. Limited Space Shuttle flight data indicate a tendency for plasma levels of branched-chain amino acids to increase during space flight as compared with preflight levels [95] with little or no change in urinary amino acid profiles [16]. Increases in the excretion of three amino acid metabolites—creatinine, sarcosine, and 3-methylhistidine [96]— were noted in Skylab studies, a finding that suggests that the contractile proteins of skeletal muscle are degraded in weightlessness. Differences between findings from space flight and ground studies may result from other variables in addition to the potential shortcomings of the analog studies. Dietary intake is greatly different in space flight versus that in ground-based studies. On the Space Life Sciences missions, consumption of protein and energy during flight was about 20% less than levels consumed before flight, which resulted in crewmembers losing 1–1.5% of their body mass [92]. Ground-based studies typically involved prescribed and controlled dietary intakes or are designed to maintain body mass. Fluctuating stress levels might explain some of the variability in results from this type of study, both spaceflight- and ground-based. Spaceflight studies are often associated with increased stress; although groundbased studies also have the potential for increased stress, this is not an entirely consistent finding. As shown in studies of

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energy metabolism, the administration of exogenous thyroid hormone provides a metabolic stress that in turn produces a more accurate ground-based model of protein metabolism during space flight [50]. The exercise protocols used to date have not succeeded in maintaining muscle mass and strength or bone mass of crews during space flight. Indeed, on a Mir mission, despite significant differences in in-flight exercise frequency and intensity among crewmembers (owing to mission requirements and personal habits), losses of leg muscle volume, which were detected immediately after landing by magnetic resonance imaging, were almost 20% in all subjects [97]. By comparison, bed-rest subjects given exogenous testosterone have maintained muscle mass and protein balance but muscle strength remained unchanged [98]. Resistive exercise protocols have been proposed to help maintain both muscle and bone during space flight. These protocols have proven effective for maintaining muscle [99] in short-term bed-rest studies; long-term studies of bone maintenance have not yet been completed.

Calcium and Bone The ability to counteract weightlessness-induced bone loss is critical for crew health and safety during and after extendedduration space station and exploration-class missions [100– 104]. Bone mineral is lost during space flight as a result of skeletal unloading [105–112], thereby increasing the excretion of calcium in the urine [87,108,110]. The loss of bone and the increased risk of renal-stone formation during and after space flight [113,114] present significant risks to crewmember health and safety. In-flight and ground-based analog studies have shown that the loss of calcium from bones varies between sites within a subject, and that the nature and degree of loss over time also varies among subjects [105,115,116]. Long-term follow-up data on bone recovery are lacking, but as astronauts return from ISS, this data will become available Negative calcium balance has been observed during Skylab [39,87,108,110,112,117] and Mir [45] missions. Increased urinary and fecal calcium excretion accounted for most of the deficit [39,45,87,108,110,114,118]. During the Skylab-4 mission, calcium losses roughly correlated with loss of calcaneal mineral [119] and with increases in the excretion of hydroxyproline [96]. If the rate at which bone calcium is lost remains constant throughout a space flight, which is a reasonable assumption based on collagen cross-link excretion data [45,120],∼250 mg of bone calcium are lost per day [45,87,121]. The rate of postflight recovery, if it is assumed to be constant (which is a reasonable assumption, based on ground-based [115] and spaceflight [45] data), is approximately +100 mg/day [45]. By these estimates, on space flights lasting as long as approximately 6 months, it will take 2 to 3 times the length of the mission flown to recover lost bone. The validity of these assumptions is questionable for longer space flights because spaceflight data are not available. Nonetheless, this hypothesis,

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which needs data to validate it, has significant implications as mission durations increase. For exploration-class missions, the potential for discovering a terrestrial partial gravity force (e.g., Mars = 0.38 G) that would reduce bone loss, or even begin recovery, is unknown. Although no data on responses to partial gravity forces are available, some investigators think that forces less than 0.5 G are likely to be of little value in recovering lost bone. Bone loss is a function of changes in the balance between formation and resorption. Bone formation, as indicated by serum concentrations of bone-specific alkaline phosphatase and osteocalcin, was unchanged during one Mir mission but was increased at 2 to 3 months after landing [45]. Apparent decreases in bone formation markers have been noted in some Mir studies [122,123]. Studies of bone formation in three Mir crewmembers using calcium-tracer techniques produced equivocal results [45]. (Formation reportedly decreased in one crewmember and was unchanged in the other two crewmembers.) Bone resorption increases during space flight. Urinary hydroxyproline levels were elevated by 33% over preflight values after 84 days of space flight [87,96]. Urinary levels of collagen cross-links, another marker of bone resorption, are elevated by more than 100% over preflight levels during space flight [45,120]. Data on the kinetics of calcium tracers also indicate that bone resorption increases by approximately 50% during space flight [45]. Analog (bed-rest) studies of humans have shown qualitative effects on bone and calcium homeostasis that are similar to those in spaceflight studies, with generally lesser quantitative effects. These effects include loss of bone mass [115,124], decreases in calcium absorption [125], increases in calcium excretion [110,125–130], increases in renal stone risk [128,129], and decreases in serum concentrations of parathyroid hormone [126] and 1,25-dihydroxyvitamin D [125,126,131]. According to histomorphometric analysis of bone biopsy samples, bone formation during bed rest was decreased [115,120,121], but no changes were found according to biochemical markers [124,125]. This difference likely reflects the difference between site-specific biopsy samples versus systemic biochemical markers as indices of bone formation. Ambulation after bed rest tends to increase bone formation [124,125]. With regard to bone resorption, both histomorphometric [132,133] and biochemical markers of bone metabolism indicate an increase in resorption during bed rest [120,125,134]. Hydroxyproline excretion is elevated during bed rest [125]. Excretion of collagen cross-links during bed rest [120,125] is elevated approximately 50% above control levels; this increase reaches more than 100% during space flight [45,120]. These data suggest that bed rest may not produce the same magnitude of bone changes as does space flight. The loss of bone and the change in calcium metabolism in paralyzed individuals, as reviewed by Elias and Gwinup

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[135], share several similarities with the changes associated with space flight. In both conditions, serum calcium is either unchanged [136] or elevated [137] relative to levels in ambulatory controls. Concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D are reduced in patients immobilized because of spinal cord trauma [136], which likely leads to increased excretion of calcium in the feces [136] and decreased absorption of calcium from the intestines. Urinary levels of calcium and hydroxyproline are also elevated [136,138,139]. Although bone loss after spinal cord injury seems to stabilize after approximately 25 weeks [140], the same cannot be said for bone loss in space flight, because studies of bone metabolism have not been possible during 25-week missions, and the limited postflight bone assessments to date do not allow rates of loss to be calculated. Circulating levels of 25-hydroxyvitamin D reflect body stores of vitamin D. The absence of ultraviolet light during space flight, coupled with the crew’s decreased consumption of vitamin D, diminish body stores of vitamin D, as observed during the 84-day Skylab mission [39] and the 115-day Mir mission [45]. However, the slight decrease noted in the Skylab mission occurred despite dietary supplements of 500 international units of vitamin D per day [39]. Decreases in levels of 1,25-dihydroxyvitamin D, the active form of vitamin D, were also observed during the Mir mission [45], but these decreases occurred before significant changes were made in vitamin D stores. The decrease in 1,25-dihydroxyvitamin D is believed to be related to decreased production secondary to decreased parathyroid hormone concentrations rather than to increased disposal. Circulating vitamin D metabolites were investigated on the Spacelab-2 mission aboard the Space Shuttle and found to be unchanged, although considerable variability was present before flight [141]. Observed changes in the endocrine regulation of bone metabolism seem to reflect adaptation to the weightless environment. Decreases in calcium absorption and decreases in plasma levels of parathyroid hormone and 1,25-dihydroxy vitamin D would be the expected physiologic responses to the presumed increase in bone resorption that occurs as the body adapts to an environment in which bones bear less weight. This evidence, as well as the lack of improvement in earlier dietary countermeasure studies, indicates that supplemental nutrients (e.g., calcium and vitamin D) will not correct the problem. However, adequate nutrition is a required component in the success of the countermeasures currently being identified and implemented. Several nutrients are known to affect bone and calcium homeostasis, including calcium, vitamin D, vitamin K, protein, sodium, and phosphorus. The importance of calcium and vitamin D are obvious, as described in this chapter. Vitamin K is responsible for carboxylation reactions in osteocalcin. Its importance during space flight has been the subject of preliminary reports [142], but further study is clearly required. Sodium also poses a concern during space flight, because space diets tend to be relatively high in sodium and increased consumption of sodium is typically associated with hypercalciuria

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[11,143,144]. Dietary sodium also seems to exacerbate the calciuric responses to physical unloading. In one bed-rest study, subjects consuming a low-sodium diet (100 mmol/day) had no change in urinary calcium, but subjects on a high-sodium diet (190 mmol/day) exhibited hypercalciuria [145]. More detailed studies of this phenomenon are required to better understand the interaction between dietary sodium and bone loss experienced during weightlessness. The effect of these and other nutrients in preserving bone during space flight highlights the importance of understanding and maintaining adequate dietary intake. This point will be especially critical, because at this time, the most promising countermeasures for bone loss are not nutrients but rather focus on exercise and pharmacologic agents.

Table 27.3. Recommended mineral intake levels for crewmembers on missions lasting from 30 days to 1 year. Nutrient Calcium Phosphorus Magnesium Sodium Potassium Iron Copper Manganese Fluoride Zinc Selenium Iodine Chromium

Recommendation 1,000–1,200 mg/day 1,000–1,200 mg/day 350 mg/day for men 280 mg/day for women < 3,500 mg 3,500 mg 10 mg 1.5–3.0 mg 2.0–5.0 mg 4.0 mg 15 mg 70 µg 150 µg 100–200 µg

Nutrient Requirements Nutritional requirements for crewmembers during space flight have been developed and reviewed by several panels of experts [5,83]. Planners developed an initial set of nutrient requirements for use on missions aboard the Mir and International Space Station lasting from 30 to 120 days [146]. These requirements were revised when the range of mission durations was extended to include missions lasting from 30 days to 1 year [147]. The nutrient requirements for missions lasting up to 1 year are shown in Tables 27.1–27.3. It has generally been agreed that crewmembers should obtain nutrients from standard foods as opposed to supplements [4,5,77,83]. This is a critical point, as natural foods provide non-nutritive substances such as fiber and carotenoids and are palatable and psychologically satisfying, considerations that will be important for long-duration missions. The need for more detailed information about the psychophysiology of hunger and eating was noted decades ago during the early space programs [24], but it has yet to be studied in detail. It is clear from the experience of astronauts and cosmonauts

Table 27.2. Recommended vitamin intake levels for crewmembers on missions lasting from 30 days to 1 year. Nutrient Vitamin A Vitamin D Vitamin E Vitamin K Vitamin C Vitamin B12 Vitamin B6 Thiamin Riboflavin Folate Niacin Biotin Pantothenic Acid

Recommendation 1,000 µg of retinol equivalents 10 µg 20 mg of α-tocopherol equivalents 80 µg for men 65 µg for women 100 mg 2.0 µg 2.0 mg 1.5 mg 2.0 mg 400 µg 20 mg 100 µg 5.0 mg

on Mir that food becomes a supportive psychological factor for humans in an isolated environment far from home. Although the question of whether to provide dietary supplements to crews is raised often, NASA currently does not recommend the use of nutritional supplements during space flight for several reasons. Experience indicates that crewmembers do not consume the recommended number of calories, and hence the intake of many individual nutrients is inadequate as well. Unfortunately, the concept of using a vitamin or mineral supplement to remedy this problem is unwarranted, because the primary problem—inadequate food consumption—cannot be resolved by taking a supplement. This situation can be exacerbated further if crewmembers conclude that taking a supplement reduces their need to consume adequate amounts of food, which may lead to their eating even less. Moreover, many nutrients, when provided as oral supplements, are not metabolized in the same way as are nutrients from food, and changes in nutrient bioavailability and metabolism can increase the risk of malnutrition. Vitamin or mineral supplements should be used only when the nutrient content of the nominal food system does not meet the requirements for a given nutrient, or when sufficient evidence indicates that the efficacy of single- or multiple-nutrient supplementation is advantageous. Nutritional requirements for crews in space will need to be evaluated throughout the evolution of the International Space Station Program. The current requirements have been defined largely by extrapolation from ground-based data and from limited spaceflight studies. As more knowledge is gained from spaceflight experience, requirements will be periodically reviewed to assure confidence in their definition. Further, as countermeasures to the negative effects of space flight are developed and implemented, assurances will be needed that countermeasures do not have secondary effects on nutrient requirements. A simple example of such an effect is the implementation of an exercise protocol that would alter energy requirements. More complex examples include the use pharmacologic agents to alter cardiovascular system function or bone metabolism.

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The nutrient requirements for exploration-class missions, when defined, will be still harder to implement in terms of the need to find a balance among a stored food system, a regenerative food system, and requests for supplements to be used instead of food [4]. Conferences have been conducted recently [148] to begin integrating horticultural and nutritional issues with the initial understanding that neither a 100% regenerative nor a 100% supplied food system will be successful. Melding the two systems is a critical, albeit difficult task. Meeting or supplementing the nutritional requirements of long-duration spaceflight crews with the consumption of fresh foods would have several advantages, including improved palatability as well as the provision of sufficient potassium, fiber, and antioxidants.

Nutritional Assessment and Implications of Malnutrition Maintaining adequate nutrition in spaceflight crews during long-duration missions requires that healthcare professionals periodically assess nutritional status to identify areas of concern. Assessment procedures should provide information about crew health and nutritional status during three periods, namely before, during, and after flight. The purpose of the assessments is to evaluate the adequacy of each crewmember’s physiological nutrient stores before flight, their health and nutritional status during flight, and the recovery of their nutrient stores to normal levels after landing. If these procedures are to be effective, means of making real-time corrective changes to crew diet must be available. These procedures will also clarify the physiological changes that occur in microgravity and will be helpful in defining and evaluating countermeasures and in developing space food systems. The nutritional status assessment profile used during Phase I of the Shuttle-Mir Program included anthropometric, biochemical, clinical, and dietary assessment components (Table 27.4) [149]. The biochemical markers are indicators of protein, bone, mineral, vitamin, and antioxidant status. Each component contributes valuable information to the total picture of nutritional status. Assessments of dietary intake allow possible nutrient deficiencies to be identified from typical patterns of individual food intake; in this way we may be able to detect potential concerns through diet evaluation before biochemical or clinical manifestations of the deficiencies present themselves. Early detection allows appropriate modifications to the diet to be made to correct the deficiency before impairment or loss of function occurs. Typically, most research samples are collected during space flight and stored for analysis after return. This restriction not only eliminates the possibility of some analyses because of problems with sample stability and storage, but more importantly it also delays the ability to identify a problem until, in many cases, long after the mission has ended. Limited biochemical assessments can be performed during space flight

567 Table 27.4. Components of nutritional status assessment. Body mass and composition Body mass Body composition Bone mineral density Protein status Total protein (serum) Retinol binding protein, transthyretin, albumin (serum) α-1 globulin, α-2 globulin, β-globulin, γ-globulin (serum) 3-methylhistidine (urine) Calcium/bone status 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (serum) Parathyroid hormone, osteocalcin (serum, total and undercarboxylated) Calcium (serum total and ionized, urine) Alkaline phosphatase (serum, total and bone-specific) Collagen crosslinks (urine n-telopeptide, pyridinoline, deoxypyridinoline) Antioxidant status Total antioxidant capacity (serum) Superoxide dismutase (serum) Glutathione peroxidase (serum) Malondialdehyde (urine) 4-hydroxy-alkenal (urine) 8-hydroxy-deoxyguanosine (urine) Iron status Hemoglobin, hematocrit (whole blood) Mean corpuscular volume (whole blood) Transferrin, transferrin receptors (serum) Ferritin, ferritin iron (serum) Mineral status Mineral profile Serum: iron, zinc, selenium, iodine Urine: iron, zinc, selenium, iodine, phosphorus, magnesium) Ceruloplasmin (serum) Fat-soluble vitamins status Vitamin A (serum; retinol, retinyl palmitate, β-carotene, α-carotene) Vitamin K (serum; phylloquinone, urinary γ-carboxyglutamic acid) Vitamin E (serum; α-tocopherol, γ-tocopherol, tocopherol:lipid ratio) Water-soluble vitamin status Transketolase stimulation (erythrocyte) Glutathione reductase activity (erythrocyte) Nicotinamide adenine dinucleotide (erythrocyte) N-methyl nicotinamide (urine) 2-pyridone (urine) Transaminase activity (erythrocyte) 4-pyridoxic acid (urine) Folate (erythrocyte) Vitamin C (serum) General chemistry Aspartate aminotransferase (serum) Alanine aminotransferase (serum) Sodium, potassium, chloride (serum) Cholesterol, triglycerides (serum) Creatinine (serum and urine)

with modified portable bedside blood analyzers or urine dipstick technologies [150]. A portable clinical blood analyzer has been successful in measuring a panel of clinical variables during space flight [77]. Development of techniques and technology that would allow more routine on-site testing would greatly benefit clinical assessments during a mission [150]. Obviously, this type of testing would be even more critical on planetary missions.

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Weight loss is a only a gross indicator of inadequate intake and ill health. Although virtually all crewmembers lose some weight during space flight [20,21,22,42,43,44], this loss needs to be monitored carefully to ensure that it does not become excessive. Since a weight loss of more than 10% of a crewmember’s preflight weight is considered clinically significant, we should attempt to control the situation before a crewmember reaches that point. By devising a means of determining body composition, we will be able to distinguish types of tissue loss during space flight so that we can better understand human adaptation to weightlessness. Assessment of in-flight dietary intake is critical and must be done as easily and unobtrusively as possible. The reliability of such assessments depends on the technique and the measurement tool. For spaceflight research studies, detailed records are currently kept using a barcode reader or related tool [5,13,45]. This method is very accurate, but it is also very time-consuming. Clinical nutritional assessments, on the other hand, do not require such detail, but their reliability is a significant concern. As a compromise, we and others developed a food frequency questionnaire that allows easy, yet reasonably accurate monitoring of in-flight dietary intake [151]. The food frequency questionnaire provides reliable estimates of the consumption of six key nutrients (water, energy [calories], protein, iron, calcium, and sodium) that have been validated in ground-based, closed-system studies [151]. Crews can complete the food frequency questionnaire in 10 to 15 min once a week and then telemeter the information to the ground. Results are provided to ground-based medical support personnel, who then make near-real-time suggestions for altering dietary intake as necessary. Undernutrition results in the metabolic overuse of body components, primarily adipose tissue and muscle, to provide energy for essential metabolic processes. Inadequate food intake has consequences for both macronutrient and micronutrient status. Adipose tissue is initially mobilized to meet most of the body’s energy needs, but it cannot be metabolized to glucose for use by the brain. Instead, visceral and somatic proteins are metabolized to supply glucose to sustain the brain’s vital functions. Because the body has no expendable protein reserves, the depletion of skeletal and vital organ protein mass is significant [152]. The consequences of body protein depletion include impaired performance, increased risk of infections, and depression [153]. Markers of protein status include serum protein levels and urinary analytes that reflect the condition of visceral and skeletal proteins. Suboptimal nutrient consumption has been documented among individuals in confined environments, including hospitals, military field operations, and nursing homes [154–157]. As discussed earlier in this chapter, loss of body mass has occurred during space flight despite consumption of adequate protein and calories [20,40]. Deficits in aspects of immune system function have also been observed during space flight [158,159] and may be exacerbated by the effects of altered protein status. However, clinical manifestations of such deficits have not been documented.

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Bone loss, as described earlier in this chapter, contributes to the increased risk of renal-stone formation during and after space flight [113,114,160]. Measuring urinary levels of collagen cross-links provides the opportunity to monitor bone resorption easily, without invasive and costly procedures such as bone biopsies and tracer kinetics studies. Cross-link excretion also provides information on bone metabolism far in advance of the changes that can be measured by absorptiometry techniques. Moreover, measurements of collagen cross-links have several advantages over other bone markers (hydroxyproline and calcium, for example) in that pyridinium cross-links are formed only in mature collagen and their excretion reflects the breakdown of the extracellular matrix. Therefore, the use of cross-links as markers is not confounded by dietary intake of collagen products [161]. Markers such as these thus provide tools with which we can assess the efficacy of treatments intended to reduce bone loss [162,163]. Space flight exposes crewmembers to greater amounts of radiation, with equivalent doses potentially up to 0.3 Sv [5], than they would be exposed to on Earth [164]. Radiation causes cell death, mutation, and oncogenic transformation in mammalian cells, either directly by interacting with nuclear DNA or indirectly by producing free radicals [165]. Free radicals are generated both from normal metabolism and from exposure to certain drugs, ultraviolet radiation, cigarette smoke, and environmental pollutants. They are highly reactive and can damage membranes, DNA, and enzymes. Free radicals can also form in response to increased atmospheric O2 concentrations such as those encountered during N2 washout (O2 prebreathe) procedures conducted before extravehicular activities. If the free radicals are not converted by antioxidants, these compounds will react with the closest molecule (lipid, protein, carbohydrate, or nucleic acid) and alter that molecule’s structure and function [166]. Antioxidants, which include β-carotene, vitamins A, C, and E, and antioxidant enzyme systems (e.g., superoxide dismutase, glutathione peroxidases, and catalase), act together as the body’s defense against free radical damage [167]. The most effective antioxidants are specific for the molecules that cause oxidative stress. When resisting oxidants attack cell membranes, vitamin E reacts with peroxyl and hydroxyl radicals, whereas carotenoids react with singlet oxygen. Vitamin E radicals can be reduced by vitamin C or glutathione, and vitamin C is reduced by glutathione [168]. The mechanisms of cell injury by oxidative stress and the protection of cells from this injury potentially involve many dietary constituents. Diets rich in antioxidants (i.e., vitamins A, C, and E and βcarotene) have also been recommended for individuals at high risk for cardiovascular disease [169]. Evidence is increasing in support of a role for nutrition in reducing the mortality and morbidity from diseases linked to oxidative stress, such as cardiovascular disease and cancer [170]. The fat-soluble vitamins (A, D, E, and K) have many functions in the body, including serving as antioxidants and coenzymes. Vitamin D takes part in the absorption of dietary

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calcium and general bone metabolism; vitamin A and its precursor, β-carotene, and vitamin E function as antioxidants; and vitamin K is required for blood clotting and bone metabolism. The body absorbs and transports these vitamins in the same manner as other lipids and can store them in the liver and adipose tissue. Although day-to-day consumption of fatsoluble vitamins is not as critical as the consumption of other nutrients, those vitamins are a matter of concern on long-duration space flights, and excessive intake can lead to toxicity. Attempts to monitor the status of fat-soluble vitamins during space flight should take into account the metabolism of the individual vitamins. For example, microgravity dampens endogenous production of vitamin D because the spacecraft cabin is shielded from ultraviolet light. No information about in-flight production of vitamin K by the gastrointestinal flora is available, but consumption of this vitamin in space could be more important than it is in Earth’s gravity [5,146,147]. The water-soluble vitamins (thiamin, riboflavin, niacin, folate, B6, B12, pantothenic acid, and C) act as coenzymes in many metabolic pathways throughout the body. Although these vitamins have vastly different functions, they are classified together because of their solubility in water and their participation in reactions in the fluid-based compartments of the body. These vitamins are transported in the bloodstream and excreted in the urine. In general, since they are not stored in the body and insufficient intake quickly lead to deficiencies, all of these vitamins must be taken daily to maintain health. Little is known regarding the requirement for these vitamins during space flight, however [5,11], so monitoring the status of water-soluble vitamins during extended-duration space flight is essential. The food systems used to support space flight are semi closed systems with a limited number of foods, most of which are highly processed to extend shelf life. Since water-soluble vitamins and minerals are frequently degraded, destroyed, or otherwise removed during food-processing procedures, the vitamin content of many spaceflight foods may differ significantly from that of the raw foods from which they are made. In a food-processing study, however, no significant degradation was found when the folate content of freeze-dried food was evaluated to assess process-related degradation [171]. It is critical that the iron status of crewmembers be assessed before, during, and after space flight because both iron deficiency and iron excess can lead to clinical problems. Iron deficiency not only reduces work capacity but also impairs temperature regulation, behavior, intellectual performance, and immune system function [172–174]. Excessive iron stores have been associated with ascorbic acid deficiency, and reductions in ascorbic acid, vitamin A, and selenium tend to exacerbate iron-induced peroxidation processes [175]. Specific clinical conditions characterized by iron overload have been well documented, including Bantu siderosis, idiopathic hemochromatosis, congenital atransferrinemia, and variants of thalassemia [176,177]. These pathologic conditions result in severe tissue damage and, frequently, death.

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The role of iron in several subclinical circumstances in human disease has also been described. Iron is reported to be involved in the formation of potentially toxic free radicals [177–180]. Also suspected of involving iron-related radicals and of specific relevance to space flight are ionizing radiation and inflammatory immune injury [177]. Free radical involvement subsequent to elevations in iron stores has been linked to cardiovascular disease and to cancer. Associations between cardiovascular disease and iron status have been described in several recent studies [181–185]. Although the evidence is contradictory [186,187], an association has been observed between increased iron stores (as measured by serum ferritin) and increased incidence of myocardial infarction [183,185]. In a prospective Finnish study, increased risk of all types of cancer combined—and risk of colorectal cancer in particular—was associated with high iron stores [188]. A relationship has also been indicated between lowering iron stores through phlebotomy and a subsequent increase in oxidative resistance [189]. These findings suggest that changes that occur in erythropoiesis and ferrokinetics in microgravity may have significant implications for crew health. In the U.S. and Russian space programs, exercise is used to counter bone and muscle loss and to maintain cardiovascular health. Exercise has been implicated in the pathogenesis of anemias in trained and untrained individuals [190,191]. Relationships among serum iron and ferritin levels and physical activity have been linked to adaptation to sustained stress [192–196]. Howeverr, the effects of space flight on iron metabolism and stress are not fully understood, nor are the effects of space flight-induced changes in iron metabolism or stress on other physiologic systems. Further, these effects are likely to be confounded and exacerbated by exercise. Minerals play important roles in several life processes by serving as coenzymes, components of hormones, antioxidants, and components of O2 transport systems. It is essential that we monitor the status of minerals during extended-duration missions. A particularly important concern during space flight is the release of minerals into the circulation coincident with bone demineralization. Although the release of calcium is well known, other minerals such as zinc and even lead may also be released from a relatively quiescent state, with potential implications for human health. The foregoing discussion illustrates the fundamental importance of monitoring the nutritional status of crews to prevent ill effects from a closed or semi closed food system and from physiologic adaptation to weightlessness. To this end, NASA is in the process of identifying potentially problematic issues associated with food and nutrition for extended-duration space flight [197]. This project involves identifying risks associated with the nature of space missions (e.g., isolation, closed or semi closed food system, and mission duration), the spaceflight environment (including radiation and microgravity), and the consequences of a lack of countermeasures and known points of intervention where mitigating factors can be implemented to avoid outcomes such as malnutrition

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and unsafe foods. Physiologic changes that may affect nutrient requirements are also to be identified. Inadequacies in the food system—whether they arise from technical limitations, nutritional shortcomings, or inadequate intake by crewmembers—can produce serious consequences [197]. Microbial and chemical food contamination or psychological factors such as depression can also lead to insufficient food intake. Finally, more catastrophic events also pose a concern, among them being food becoming inaccessible after a module depressurization or crop failure on planetary missions. A major goal of this project is to identify critical questions that define areas in which further research is required to eliminate or ameliorate these risks, thereby enabling exploration-class missions.

Countermeasures Nutrition is often considered a convenient means of counteracting the negative effects of space flight on human physiology. Providing additional calcium to prevent bone loss, or providing protein to prevent muscle loss, has been proposed as a means of protection; however, this approach generally has not proven successful. Clearly, adequate nutritional support is required to provide biochemical building blocks when effective countermeasures are established. Nutritional requirements will also need to be assessed in light of countermeasure effects to ensure that the solution to one problem does not create another. Many countermeasures to ameliorate space flight-induced bone loss have been tested. However, those tested to date, including exercise, increased intake of calcium or phosphate, vitamin D supplementation, exposure to ultraviolet light, and the administration of early-generation bisphosphonates, have not proven effective during space flight or bed rest [198–202]. Recent studies of resistive exercise paradigms, new antiresorptive therapies [203–205], and other treatments with bone-regulating proteins show promise for preventing bone loss. Ensuring adequate intake or, in some cases, adequate synthesis of calcium, vitamin D, and other bone-related nutrients will be necessary; however, this strategy does not seem to be sufficient to solve the problem of bone loss. Other factors that may contribute to the degree of calcium loss are age, sex, fitness, genetic background, and dietary history. Nutritional means of preventing muscle disuse atrophy have been evaluated. Oral doses of branched-chain amino acids had little effect on leg-muscle protein kinetics [206], whereas feeding a bed-rest group adequate energy with excess protein reversed loss of N2 [207]. However, feeding Skylab crewmembers energy and protein at levels equivalent to those given the bed-rest group did not prevent negative N2 balance and loss of leg muscle strength during space flight [21,87,88]. It is unclear whether nutritional means beyond consuming adequate energy and protein would be beneficial in reducing muscle atrophy. The effect of exercise countermeasures on energy requirements also needs to be considered

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so that energy balance is not compromised in a futile attempt to maintain crew health. Since maintaining adequate intake of all nutrients and non-nutritive compounds such as fiber is so important, the use of dietary supplements is discouraged unless absolutely necessary. At this time, vitamin D seems to be a candidate for supplementation, because the adequacy of the amount of vitamin D provided by the International Space Station food system remains unclear. Antioxidant supplements may play a role in ameliorating radiation effects on the human body during space flight, but no hard evidence exists to substantiate this idea. Concern has been expressed, however, that use of multivitamin supplements may counteract a deficiency of one nutrient and simultaneously create an excess of another (e.g., iron). Multivitamins are provided to cosmonauts in the Russian space program, but no information is available on the frequency of their use. U.S. astronauts can elect to bring dietary supplements aboard, but they are not required to take any supplement. Under special circumstances, recommendations have been made to take dietary supplements; for example, crewmembers and support staff who worked in Russia throughout the winter were advised to take vitamin D supplements to counteract their limited exposure to ultraviolet light.

Nutrition in Future Missions The role of nutrition in future space programs will depend on mission duration and the limitations imposed by available food systems. The main goal of food-system development from a nutritional viewpoint is to deliver all of the required nutrients in palatable foods. Space-based food systems also must meet the design criteria of the space vehicle or habitat. Using regenerative systems for food production will require careful study to ensure that crewmembers will receive a palatable, nutritious diet within an acceptable mission risk scenario. The prospect of interplanetary space flights and surface settlement missions raises significant issues with respect to space food systems. The required 3- to 5-year shelf life that is typical of food types today obviously constrains selection. Degradation of many nutrients, particularly vitamins, and oxidation of lipids occur over time and need to be taken into account. How to balance normally hydrated food and dehydrated food stores is an issue that also needs to be addressed because dehydrated foods are known to be less palatable than fresh foods. Although the desired ratio of transported to produced food is also subject to debate, feasibility, palatability, and mission risk are likely to drive the ultimate decision; resource requirements and nutritional yield must be balanced. In-situ-produced food will likely supplement, but not replace, the stored food system. Crew interactions during mealtimes are difficult to quantify; however, mealtimes can provide important periods of relaxation and camaraderie. These benefits will become critical on

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extended-duration missions, during which the sense of confinement and heavy workloads will probably increase psychological stress. Various foods that the crew will find palatable will be needed. Schedules for mealtimes must include time for food preparation and cleanup activities, as well as for food consumption. On exploration-class missions, a significant amount of time will be needed for food processing. During the International Space Station era, multicultural issues may arise. Foods from different cultures should be included in the food system to provide all individuals with a sense of ownership while also taking into account occasional food dislikes. Familiarization with the food system before flight will help mitigate some of these risks, but only within the constraints of the food system. A thorough understanding of the effect of countermeasures on nutritional requirements will be required before flight to ensure that the station food system will support the crew. Countermeasures often fall into categories of exercise, pharmacologic, or dietary manipulations. These will clearly affect energy requirements, and they may also affect individual nutrient requirements. Extended-duration space flights will require nutritional status assessments to ensure optimal missions. In-flight monitoring of dietary intake and nutritional status will also be critical to allow near-real-time mitigation of problems.

Conclusions Nutrition plays a multifaceted role during space flight. Although its most obvious function is general health maintenance through the consumption of required nutrients, the particular importance of proper nutrition lies in maintaining endocrine and immune system function, skeletal and muscle integrity, and hydration status of space flight crews. In addition, interpersonal interactions during mealtimes build team morale and enhance productivity. Providing high quality, palatable foods is imperative for ensuring adequate nutritional intake, and careful assessment is required to monitor the success or failure of the food system and to ensure crew health. We believe that acknowledging the full role of nutrition will be critical to the success of extended-duration space missions.

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S.M. Smith and H.W. Lane 197. Vodovotz Y, Bourland C, Kloeris V, et al. Critical path plan for food and nutrition research required for planetary exploration missions. Presented at: International Congress on Environmental Systems; July 1999; Denver, CO. 198. Baldwin KM, White TP, Arnaud SB, et al. Musculoskeletal adaptations to weightlessness and development of effective countermeasures. Med Sci Sports Exerc 1996; 28:1247– 1253. 199. LeBlanc AD, Schneider VS. Countermeasures against space flight related bone loss. Acta Astronautica 1992; 27:89–92. 200. LeBlanc A, Shackelford L, Schneider V. Future human bone research in space. Bone 1998; 22:113S–116S. 201. Lockwood DR, Vogel JM, Schneider VS, et al. Effect of the diphosphonate EHDP on bone mineral metabolism during prolonged bed rest. J Clin Endocrinol Metab 1975; 41:533–541. 202. Hulley SB, Vogel JM, Donaldson CL, et al. The effect of supplemental oral phosphate on the bone mineral changes during prolonged bed rest. J Clin Invest 1971; 50:2506–2518. 203. LeBlanc AD, Driscoll TB, Shackelford LC, et al. Alendronate as an effective countermeasure to disuse-induced bone loss. J Musculoskel Neuronal Interact 2002; 335–343. 204. Shackelford LC, LeBlanc AD, Feiveson A, et el. Exercise countermeasure to disuse osteoporosis [abstract. J Bone Miner Res 2001; 16(suppl 1):S485. Abstract M209. 205. Smith SM, Nillen JL, Davis-Street JE, et al. Alendronate and resistive exercise countermeasures against bed rest-induced bone loss: Biochemical markers of bone and calcium metabolism [abstract]. FASEB J 2001; 15:A1096. Abstract 841.8. 206. Ferrando AA, Williams BD, Stuart CA, et al. Oral branchedchain amino acids decrease whole-body proteolysis. JPEN J Parenter Enteral Nutr 1995; 19:47–54. 207. Stuart CA, Shangraw RE, Peters EJ, et al. Effect of dietary protein on bed-rest-related changes in whole-body-protein synthesis. Am J Clin Nutr 1990; 52:509–514.

Index

A Abdominal distress, from expansion of trapped gases within GI tract, 255 Abdominal sweep, for detecting blood collections in terrestrially atypical locations, 200 Abdominal trauma management, in spaceflight, 134 ABV. See Alternobaric vertigo Acceleration forces Earth launch and landing loads, 12 in space flight angular acceleration, 14–15 linear acceleration, 12–14 radial acceleration, 14 and spaceflight deconditioning, 15 Acclimatization to environmental hypoxia, 265 for preventing symptoms of high-altitude illness, 261 for space operations, 456 strategies to prevent AMS, 262 ACESs. See Advanced crew-escape suits Acetaminophen drug, 110 Acetazolamide, 266 ACGIH. See American Conference of Governmental Industrial Hygienists ACLS. See Advanced cardiac life support ACRV. See Assured Crew Return Vehicle program ACS. See Acute coronary syndrome ACTH. See Adrenal corticotropic hormone Actigraphs, 414 Active noise reduction, 526, 528, 530, 531 ACTS. See Advanced communications technology satellite Acute angle closure glaucoma, 540, 541 Acute appendicitis, treatment of, 126 Acute care, definition of, 101 Acute coronary syndrome, 318 Acute hypoxia hyperventilation, 454, 455 physiological effects of, 452, 453 recognition and treatment of, 454, 455 symptoms of, 453 types of, 451 Acute mountain sickness (AMS) acclimatization, 262

associated infectious disease, 265 biochemical markers, 264 cerebral blood flow, 264 Environmental Symptoms Questionnaire (ESQ), 261, 262 high altitude cerebral edema (HACE), 266 high altitude pulmonary edema (HAPE), 265, 266 hypoxia and simulated microgravity, 263 Longitudinal Study of Astronaut Health (LSAH) database, 267 medication management, 268 pathophysiology of, 261 physical conditioning, 262, 263 respiratory and diurnal effects, 264 susceptibility, 263 treatment calcium channel blockers, 267 carbonic anhydrase inhibitors, 266 glucocorticosteroids, 266, 267 hyperbaric recompression, 267 Acute myocardial infarction, 344 Acute radiation syndromes, 501 ADH. See Antidiuretic hormone Adjustment disorders, 406 Adrenal corticotropic hormone, 212 Advanced cardiac life support, 117, 118, 145, 345 Advanced Communications Technology Satellite Program, NASA, 171 Advanced crew-escape suits, 329 Advanced life support (ALS) pack, 89, 145 Advanced Trauma Life Support program, 145 Advisory Group for Aerospace Research and Development, 523 Aeromedical transport and evacuation, risks in, 149–152 AGARD. See Advisory Group for Aerospace Research and Development Airborne particles and dust Apollo program, 439 environment, decontamination, 440–441 lint particles, 440 properties of, 440 protection and treatment of, 440 smoke detectors, 440 smoke particles, 439 sources of, 439 toxicity, mechanism of, 440 577

578 Air contamination, 427 Air revitalization system, 437 ALARA principle, 512 Alert somnotype, 414 Allergic reactions, in crewmembers, 115 Alpha particles, 479 Alternobaric vertigo, 257 Altitude DCS. See Hyperbaric DCS Alveolar gas equation, 448, 449 Ambient cabin pressure, 343 Ambulatory medical pack, 89–94 American College of Radiology, 164 American Conference of Governmental Industrial Hygienists, 505 American Heart Association Advanced Cardiac Life Support program, 145 Cardiopulmonary Resuscitation program, 145 American National Standards Institute, 524 American Red Cross, ATS-3 provision by NASA, 170 American Society for Testing and Materials, 523 Amikacin drug, 108 Ammonia environment, decontamination, 439 sampling and analysis, 439 sources of, 438 susceptibility, 439 toxicity, mechanisms and properties of, 438 Analog populations, medical event analysis from, 140–142 Analog remote medical care systems, 125, 126 Anemic hypoxia. See Hypemic hypoxia Anesthesia administration, in spaceflight, 134–135 Anesthesia tests, 552 Angular acceleration, 14–15 ANR. See Active Noise Reduction ANSI. See American National Standards Institute Antarctic stations, importance of, 142 Anterior teeth, fractures, 548–549 Anthropometric changes limb volume changes, 32 trunk, changes in, 32, 33 Antidiuretic hormone, 212 Antiemetics drug, 103 Anti-motion-sickness drugs, 362–363 Antioxidants, 568 Apollo mission biomedical observations in, 28 fractional gravity, 50 gastrointestinal problems during, 112 human spaceflight activity during, 22 lunar dust during, 23 medical kit, 72–74 Apollo program (U.S.), crew members of, 167 Apollo-Soyuz mission, 182 Apollo-Soyuz Test Project (U.S.), 168 Apollo spacecraft environment control system in, 467, 468 radiation exposure in, 510 Applications technology satellite-1 (ATS-1), 170 Armenia project, 171 ARPCS. See Atmosphere revitalization pressure control system ART. See Assisted reproductive technology

Index Artemia, 500 Arterial gas embolism (AGE), 254 clinical picture and disposition, 239 pathophysiology, 238, 239 Arthralgia, 554 Artificial atmosphere control system, 446 Artificial gravity, 10, 377 and bioelectric activity, 19 provisions of, 17 Aspirin drug, 110 Assisted reproductive technology, 384 Assured Crew Return Vehicle program, 151 Asthenia, 395, 402 ASTM. See American Society for Testing and Materials Astronauts flying to low Earth orbit (LEO), 4 genitourinary tract examination, 285 hospitalizations, categories for, 144 medical event analysis from, 140–142 medical screening of Mercury, 61 population bias in, 65–66 selection and requalification examinations, requirements for, 64 Ataxia telangiectasia, 493 ATLS. See Advanced Trauma Life Support Atmosphere revitalization pressure control system, 248, 249 Atmospheric functions, 4 Atmospheric pressure, 339 Atomic Bomb Casualty Commission. See Radiation Effects Research Foundation Automated ventilation, 70 Aviation medicine, 3 Aviation safety board, 414 Avogadro’s law, 446 Avulsion, 549 B Back pain, in crewmembers, 104 Bacterial ulcerative keratitis. See Corneal ulcer Ballistic vehicles, designing, 151–152 Bandwidth influence, on telemedicine program, 165 Barodontalgia, 255 Barotitis, 255. See also Ear barotrauma Baryons, 479, 484 Beance Tubaire Voluntaire (BTV) maneuver, 260 Bed rest and space flight bone mineral loss difference in degree, 301 similarity in pattern, 273, 274, 301 muscle cell decrements, 295 redistribution of body fluids, 273 Behavioral health problems adjustment disorders, 406 anxiety disorders, 405 asthenia, 402 behavioral illness four-factor concept, diagnosis, 401 mental status examination, components, 402 monitoring, 400

Index prevention of, 400–401 circadian health problems, 398 euphoria, 402–404 human-system interface problems prevention of, 400 work effectiveness, 399 workplace environment, 399 medical disposition, 406–407 monitoring of, 396 prevention of mission training events, 397 psychological tests, Selecting-In, 397 psychosocial support, 397 psychiatric emergencies, 406–407 psychotic disorders hallucinations, 404 organic mental disorders and delirium, 404 treatment for, 405 Benzodiazepines, 405–406 Benzoin, 104 Betadine drug, 127 Beta particles, electrons and positrons, 479 Biologically equivalent dose, 475 Biologically weighted dose-equivalent, 476 Biosound genesis II scanner (AERIS) development, by NASA, 182 Biphasic sleepiness, 414 Bite test, for determining inflammation in apical tissues, 551 Body mass density (BMD), 297, 298 Body weight, space flight effects on, 32 Bohr effect, 450 Bone anatomy and structure axial division, 294 cancellous or trabecular bone, 294 compact or cortical bone, 294 Bone density measurements DEXA and QCT, comparative study for, 296 Gemini and Apollo missions, 296 Bone mineral density (BMD) calcium balance studies, countermeasures, 298 changes in, during space flight, 38 in-flight countermeasures astronaut/cosmonaut comparison, 302 challenges for Mars mission, 302 ergonomic spacecraft design, 303 in-flight treatment exercise devices evolution, 300 resistance exercise, benefits of, 301 postflight treatment, 298 renal stone formation, 298 Bone physiology remodeling regulation, 295 resorption and formation, 294 Bowel activity, space flight, 44–45 Boyle’s law, 446 Bromotrifluoromethane, 435 Bupavicaine drug, 106 Burkholdera cepacia, 105 Burns, in crewmembers, 108

579 C Cabin pressure loss rate, 249 Cabin pressurization, 247, 248 Cabin telemetry, 217 CAD. See Coronary artery disease CAF. See Coronary artery fluoroscopy Caffeine, in headache treatment, 109 Calcium channel blockers, 267 Canadian astronaut selection, medical disqualification reasons in, 63 Canadian Space Agency, 143, 188 Candida albicans, 502 Carbonic anhydrase inhibitors, 266 Carbon monoxide clinical presentation effects of hypoxia, 430 space motion sickness, symptom of, 429 environment decontamination catalytic oxidizer, 430 palladium catalyst canister, 431 protection and treatment after exposure, 430 inhalation treatment, 430 sampling and analysis, 430 sources of catalytic oxidizers, 428 most hazardous, 427 Oxygen generator, 427, 428 Symptoms of Co poisoning, 428 toxicity, effects of airborne concentration, 429 Coburn-Foster-Kane, 429 CoHb, 428 effects on hemoglobin, 428 lack of warning properties, 429 properties of, 432 Stewart equation, 429 Carbon monoxide and headache, 109 Carboxy hemoglobin, 428 Cardiac abnormalities, 318 flight surgeons, 319 Cardiac and trauma life support, in parabolic flight, 129–130 Cardiac defibrillation, 71 Cardiac disease in military aviators, 318 occurrence of, 321 prevalence of, 317 risk of, 317 mitigation strategies, spaceflight crews, 322, 323 in space flight, 317 treatment of on exploration-class missions, 346–348 in low Earth orbit, 344 Cardiac disorders, in crewmembers, 116–118 Cardiac events, prevalence of, 319 Cardiac imaging, phased-array probe for, 194 Cardiac pressure pulses, monitored by, 337 Cardiac rhythms, military aviators, 334 Cardiac sympathetic modulation, 414 Cardiomyopathy, 320 Cardiopulmonary resuscitation, 71, 145

580 Cardiovascular abnormalities, 344 Cardiovascular evaluations, periodically, 334 Cardiovascular medical care, 322 Cardiovascular physiology, 317 Cardiovascular risk mitigation, 323 Cardiovascular screening tests electrocardiography, 325 electron-beam computed tomography, 328 exercise testing, 326 nuclide and coronary artery calcium imaging, 327 Cardiovascular selection standards, 325 Cardiovascular system, 331 baroreceptor reflex, 34 disqualification standards for astronauts and cosmonauts, 63 limitations, in crewmembers, 147–148 volume status and central venous pressure, 332 in weightlessness plasma volume loss, 36 short-term and long-term response, 35 β-Carotene, 568, 569 Carotid baroreceptors, 338 Cefoxitin drug, 126 Central nervous system, 310, 365, 430 Central venous pressure (CVP), 330 microgravity measurements of, 333 Cephalosporins drug, 114 Cerebral arterial gas embolism, 254 Cerebral DCS, 229, 230 Cerenkov detector, 508 CEV. See Crew Exploration Vehicle Charles’s law, 446 CHeCS. See Crew Health Care System; Crew health care system Chemical rockets lofting force, 4 payload mass and, 9 Chemoprotective agents, 504 Chest trauma management, in spaceflight, 134 CHF. See Congestive heart failure Chromosphere, 485. See also Coronal mass ejection Chronic hypercapnia syndromes corresponding to, 461 treatment for, 463 Chronic hypoxia acclimatization, 455 complex adaptation to, 456 Ciprofloxacin drug, 111 Circadian health problems monitoring of, 397 prevention of, 398 psychotropic medications for, 398 Circadian rhythms in light environment aboard spacecraft, 419 actillume devices, 420 digital monitioring system, 420 light illumination, 419 markers of, core body temperature, 417 cortisol level, 418

Index melatonin measurement, 418 physiological and biochemical markers, 417 pineal hormone, 417 periodicity spectrum biological functions of, 417 photo-period, 417 sleep and performance in space light therapy, 420 pharmacologic counter measures, 420 strategies for, 420 in space acrophase, 418 cosinor methods, 418 Closed head injuries management, in spaceflight, 134 CME. See Coronal mass ejection CMO. See Crew medical officer CMRS. See Crew medical restraint system CNS. See Central nervous system CNS syndrome, 501 Coburn-Foster-Kane equation, 429 CO2 contamination, in spacecraft, 109 Colony forming units (CFU), 105 Colorimetric analysis, for quantifying formaldehyde, 433 Commercial-off-the-shelf (COTS), 168, 176–177 Compton scattering, 480 Congestive heart failure, 338 Conjunctivitis, 111 Constipation, in crewmembers, 112 Contingency depressurization, 249 Coriolis acceleration effects, 18 Corneal abrasion, 542 Corneal ulcer diagnosis and treatment, 542 risk factor for, 541 Coronal mass ejection, 485 Coronary angiography, 327 Coronary artery disease EBCT for, 184 mortality rate, 318 predictive value of, 327 in spaceflight crews, 321 Coronary artery fluoroscopy, 327 Coronary atherosclerosis, 318, 320 Cosmonaut, medical event analysis from, 140–142 CPR. See Cardiopulmonary Resuscitation CPTD. See Cumulative pulmonary toxicity dose C-reactive protein (CRP) biochemical markers for, 264 utility of measuring, 318 Creatinine, 564 Crew behavioral health crew’s adaptation, 396 family stability, role, 392 flight surgeon role, 392 human systems interface issues, 394 medical disposition, 406 monitoring of, 396 prevention of, 397 simple model approach, 393 Crew Exploration Vehicle, 139

Index Crew health care system, 82, 143 components of, 89 crew training on, 98 onboard diagnostic and therapeutic capabilities, 99 Crew medical officer, 69, 123, 139, 323, 345 cardiac defibrillation, 70 training, 98 Crew medical restraint system, 146, 196 Crewmembers allergic reactions in, 115 biomedical training of, 90 burns in, 108 cardiac disorders in, 116–118 cross-coupling effects and neurovestibular dysfunction, 18 dental disorders in, 115–116 eye disorders in, 111–112 facial fullness, complains of, 31 gastrointestinal disorders in, 112–113 hand injuries in, 108 headache in, 108–110 lacerations in, 104–106 medical care of, 69 medicines intake by, 103 muscular strain syndromes and, 104 musculoskeletal trauma in, 106–108 on-orbit medical resources usage by, 101–102 preflight training, 29 psychological tolerance and mission performance, 10 pulmonary disorders in, 114–115 radiation exposure and bone mineral loss, 10 respiratory irritation in, lunar dust, 23 selection standards and operational considerations, 59–60 skin disorders in, 110 sleep disorders in, 110 space motion sickness, 31–32 superficial trauma and, 103–104 upper respiratory disorders in, 113–114 urologic disorders in, 116 Crew rescue, treaties for, 157–158 Crew return vehicle, 140 crew compartment design for, 155–156 development of, 150–151 environment control and life support system in, 156–157 limitations in designing, 148–149 Crohn’s disease, 201 CRV. See Crew return vehicle CSA. See Canadian Space Agency Cumulative pulmonary toxicity dose, 233 Cytokines bi-directional interplay with CNS, 310 role in immune function, 309 D Dalton’s law, 446 DCS. See Decompression sickness Decompression orbital debris objects, 249–252 physical factors pressure of stabilization (POS), 253 rapid cabin depressurization consequences, 252

581 physiological effects evolved and trapped gas disorders, 253, 254 gastrointestinal (GI) tract barotrauma, 254, 255 hypoxia and hypothermia, 253 sinus barotrauma, 255 Decompression sickness, 117, 156, 201 bubble formation, 224 cerebral, 229, 230 clinical course of, 231, 232 differential diagnosis, 231 evolved gas disorder, 253 inert gas uptake and elimination, 225, 226 intravascular and extravascular bubbles, 224, 225 otologic manifestations of, 259 pathophysiology blood, 228 bubble formation time course, 227 hyperbaric vs. hypobaric, 226 musculoskeletal system, 228 of peripheral nerves, 230, 231 of skin bends, 230 spacewalker’s pressure profile, 226 spinal, 228, 229 treatment ground-level oxygen (GLO) breathing, 232, 233 hyperbaric oxygen (HBO) therapy, 233 neurologic oxygen toxicity, 234 pulmonary oxygen toxicity, 233, 234 treatment table 5 (TT5), 237 treatment table 6 (TT6), 235, 236 type I and type II, 223 Deep vein thrombosis (DVT), in space, 182 Definitive medical care facility, 139 Delirium, 404 Dental diagnosis, testing procedures for, 550–551 Dental disorders about traumatic emergencies, 548–549 advanced caries, 547–548 in crewmembers, 115–116 iatrogenic injury, 542, 545 moderate caries, 547 odontalgia in, 545 simple caries, 547 techniques, use in space flight dental extraction, 556–557 dental injection, 555 exposed pulp, 556 recementing a crown, 556 temporary filling, 555 use of elevators, 557 treatment and management of, 547 Dentin, 560–562, 569 Deoxyribonucleic acid, 417 Department of Defense military criteria standard (MIL-STD-1472), 523 Design Reference Missions, 140 Device for orientation and motion environments, 219 DEXA. See Dual energy X-ray absorptiometry Dexamethasone, 266, 267 Dextroamphetamine drug, 103, 420

582 Diagnostic peritoneal lavage (DPL), 200 Dichlorofluoromethane, 436 DICOM. See Digital Imaging and Communications in Medicine Digital Imaging and Communications in Medicine, 164 Digital radiography, in spaceflight, 135 Distortion-product otoacoustic emissions, 528, 529 Diving medicine, 3 DMCF. See Definitive medical care facility DNA. See Deoxyribonucleic acid DOME. See Device for orientation and motion environments Doppler sonography, 329 Dorsogluteal IM injection, 103 Dose equivalent. See Biologically equivalent dose Dose rate effectiveness factor, 476 Dosimetry. See Space radiation dosimetry monitoring DPOAE. See Distortion-product otoacoustic emissions DREF. See Dose rate effectiveness factor DRM. See Design Reference Missions Drosophila melanogaster, 500 Dual adaptation, 218 Dual energy X-ray absorptiometry, 296 Duraprep drug, 127 Dvorine pseudoisochromatic test, 535 Dynamic Soaring Vehicle (DynaSoar) X-20 program, 151 E Ear barotrauma eustachian tube (ET) dysfunction causes and symptoms, 255 evaluation techniques, 256 syndromes alternobaric facial paralysis, 257 inner ear barotrauma (IEBT), 257–259 middle ear barotrauma (MEBT), 259, 260 post-oxygen exposure ear block, 257 pressure-related ear block, 256, 257 EarQ Software™, 529 Earth atmosphere, composed of, 445 Earth gravity, 361 Earth’s atmosphere acceleration forces, 27 Van Allen radiation belts and external field lines, 21 EASI electrode system, 335 EBCT. See Electron-beam computed tomography Ebullism syndrome clinical picture, 240, 241 description, 239 disposition, 241 pathophysiology, 240 ECG. See Electrocardiography Echocardiography, LV end-diastolic dimension measured by, 333 ECLSS. See Environmental control and life support systems E. coli. See Escherichia coli Effective performance time (EPT), 453–454 EHS. See Environmental health system Electrocardiography, 414 analysis, 326 monitoring, 322, 334

Index Electromagnetic radiation effects of, 506, 507 ionizing, 477 non-ionizing, 477, 478 Electromyography, 413 Electron-beam computed tomography, 184 Electrooculography, 413 Emergency medical technician (EMT), 146, 147, 165 EMUs. See Extravehicular mobility units EMU space suit, 469 EMV. See Extravehicular mobility units Endeavour, space shuttle, 169 Endocrine systems fluid regulation in weightlessness, 43 norepinephrine levels, 44 Endometrial ablation, 386, 387 Endometriosis, 382, 384–386 Endometriosis, risk of, 382 Endothelial cell, 318 Entry motion sickness (EMS) clinical and differential diagnosis, 217 definition, 211 epidemiology influencing and precipitating factors, 214 time course, 215 U.S. and Russian space programs, 213, 214 in-flight treatment for, 219, 220 laboratory interpretation, electrolytes and harmones, 212 microgravity environment of, 212 preflight adaptation training, 218, 219 prognosis, 220 prophylaxis, 218 Russian cosmonaut Gherman Titov, 212 symptoms of, 212, 214, 215 Environmental control and life support systems, 154 Environmental health system, 89, 98 Environmental Symptoms Questionnaire (ESQ), 261, 262 Erythromycin drug, 111 Erythropoietin, 563 ESA. See European Space Agency Escherichia coli, 116, 502 ESS. See European Space Station Ethylene glycol Apollo space vehicle, 433 CNS effects, 434 environment, decontamination of, 435 heat-exchange loops, 433 oxalic acid, 434 properties of, 434 protection and treatment of, 435 sampling and analysis of, 435 sources of, 433 toxicity, mechanisms of, 434 triol, 433 Euphoria and mania, 402 symptoms of, 403 treatment for, 403 European Commission Biomedicine & Health Research Program (U.K.), 187

Index European Space Agency, 152 European Space Station, 152 Eustachian tube (ET) dysfunction causes and symptoms, 255 evaluation techniques, 256 Exercise treadmill tests (ETT), 325 Exploration-class missions cardiovascular illness treatment on, 346 surgical challenges in, 124–125 Extravehicular activity (EVA), 101, 103, 274, 308, 321, 362, 446, 530 crew members training, 383 radiation monitoring, 511 training, 383 Extravehicular mobility units, 252, 340, 383, 451 Eye disorders, in crewmembers, 111–112 F Farnsworth Lantern Test, 535 FAST. See Focused assessment by sonography in trauma Fatigue anecdotal information, 417 circadian rhythms, 416 indication of drowsiness, 417 protective mechanism of, 416 during space flight, 417 stress, responses to, 416 Federal Aviation Administration, 449 Female astronaut for long-duration space flights avoiding surgery, 387 KC-135E and DC-9, porcine models, 388 menstrual cycle, 385 osteoporosis risk, neurovestibular problems, 385 preventive concepts, 386 maternal age of, 384 medical selection criteria, 381–382 menstruation and hygiene, 384 operational gynecologic considerations, 383 contraception, 384 pregnancy, 383 preflight medical examinations, pregnancy test, 383 reproductive considerations, 383 selection and disqualification criteria for, 383 space flight considerations endometriosis risks, 384–385 menstrual cycling, 385 prevention concepts, 386–387 reproductive function and osteoporosis risk, 385–386 surgical conditions, mitigating, 387 training, reproductive considerations during, 383 Final transfer protocol (FTP) server, at JSC center, 174 Fitzsimons Army Medical Center, 171 Flight surgeon, 317, 319, 323 diagnosis and treatment of crewmember, 102 ground-based, role of, 101 sleep disorders and, 110 Fluid shift theory, in motion sickness, 216, 217 Flumazenil, 420 Fluorescein strip test, cornea, 542 Fluoroquinolones, 542

583 Focused assessment by sonography in trauma, 199 Formaldehyde environment, decontamination, 433 irritating compound, 431 payload experiments, 431 polymer delrin, 431 protection and treatment, 433 sources of, 431 toxicity, mechanism of, airborne concentration, 432 molecular mechanism, 432 properties of, 432 sampling and analysis, 433 ultraviolet spectrophotometry, 433 Fracture management, in spaceflight, 134 Framingham risk scores (FRS), 324 Frenzel maneuver, 259 Freons and halocarbons environment, decontamination of, 436 freon leak detection and quantification, 436 properties of, 436 sources of, 435 toxicity, mechanisms of, 435 G Galactic cosmic radiation, 20 Galactic cosmic rays, 484 Gamma-scintillation cameras, 184 Gastrointestinal disorders, in crewmembers, 112–113 Gastrointestinal syndrome, 501 Gastrointestinal tract barotrauma, 254, 255 GCR. See Galactic cosmic radiation; Galactic cosmic rays Gemini spacecraft environment control system in, 467 radiation exposure, 509 Gemini VII medical kit, 72, 73 Gemini VII mission, 419 Genitourinary (GU) issues glomerular disease, occurrence and prevalence, 286 in-flight management Bartholin’s gland infection, 289 epididymitis, 289 prostatitis, 289 pyelonephritis, 288–289 testicular torsion, 290 urethritis/cystitis infections 287–288 urinary obstruction/retention, 290 nephrolithiasis or stone formation classic signs and symptoms, 278 in-flight history and significance, 279 inhibitory factors, 277 physical examination, 279 prevalence and recurrence rates, 276 sites of occurrence, 278 space flight history of, 279 urinary calculi, types of, 276, 277 spaceflight factors body fluid balance, 273 bone mineral loss, 273, 274 Gentamicin drug, 111

584 Gentamycin drug, 126 Geomagnetically bound radiation, 21 Geomagnetically trapped radiation, 482 Glomerular filtration rate (GFR), 273 Glucocorticosteroids, 266, 267 Glutathione, 568 Gold salt method, for contaminant monitoring, 465 Goldstone Deep Space Network radars, 249 Gravito-inertial acceleration vector, 378 Gravity suit protocol, 342 GT-7 mission. See Project Gemini Gynecologic medical standards, for female astronaut selection, 381–382 Gynecologic selection standards endometriosis, risk of, 382 mission-specific training, 383 operational gynecologic considerations menstruation and hygiene, 384 pregnancy after space flight, 384 pregnancy and contraception, 383 H Habrobracon juglandis, 500 HACE. See High altitude cerebral edema Hadrons, 479 Haldane effect, 450 Hand injuries, in crewmembers, 108 HAPE. See High altitude pulmonary edema HBO therapy. See Hyperbaric oxygen (HBO) therapy HCN. See Hydrogen Cyanide HDL. See High-density lipoprotein Headache, in crewmembers, 108–110 Health Maintenance Facility, for Mars expedition, 125 Health Maintenance System, 143 Hearing assessment in space, 528–530 clinical assessment, 524 definition, 521 mechanics, 521–523 Heimlich valve, uses of, 129 Hematopoietic syndrome, 501 Hemorrhage controlling, methods of, 131 Henry’s law, 446 High altitude cerebral edema, 266 High altitude pulmonary edema periodic breathing (PB), 265 treatment of, 266 High-density lipoprotein, 324 High-energy particles, 480 Histotoxic hypoxia, 451 HMS. See Health Maintenance System HNE. See 4-Hydroxy 2,3-nonenal Holter analysis, 321 Hormone replacement therapy, 385 Human immune system allergic and hypersensitive reactions experience and need for research, 315 prevention strategies, 314 alteration in cytokine production, 312 CD4:CD8 ratio increase, 312

Index chronic stress and isolation closed chamber studies, 310, 311 cytokines, dysregulation effects, 309, 310 delayed-type hypersensitivity (DTH) tests, 311 risk of immune alterations, 309 defects in function and impact, 307 dysregulation during spaceflight alterations in cell-mediated immunity, 311 Epstein Barr virus, reactivation analysis, 313 Health Stabilization Program (HSP) implementation, 311, 314 hypothalamic-pituitary-adrenal (HPA) axis, 313 viral reactivation, 313 extravehicular activities (EVAs), 308 infectious disease development adverse effects, 313 minimization strategies, 314 inflight vs. postflight changes, 312 long duration spacecraft problems exposure to radiation, 309 microbial colonies establishment, 308 spacecraft-related risks air and water system limitations, 308 atmospheric restrictions, 308 life support equipment malfunction, 308 microgravity and particulates, 308 physical constraints, 307 Human research facility (HRF) ultrasound on, ISS program, 186, 190 Human space flight, general physics of, 3 absolute radiation dose, 10 acceleration forces, 11 Earth launch and landing loads, 12 linear, radial, and angular, 12–15 escape velocity, 9 landing loads, 15 lofting force, 4 microgravity and partial gravity, 15–19 onboard power generation, technologies for, 11 orbital debris, collision potential with, 8–9 planetary surface factors, 22 radiation sources, 19 galactic cosmic radiation, 20 geomagnetically bound radiation, 21–22 solar radiation and solar cosmic particles, 20–21 surface dust, 23–25 Human-system interface problems, 399, 400 Hydrogen cyanide chemical and infrared sensors for monitoring, 115 symptoms on exposure to, 429 use of various physical barriers for removing, 465 Hydrostatic pressure and weightlessness, 16–17 4-Hydroxy 2,3-nonenal, 522 Hydroxyproline, 565 1, 2-Hydroxyvitamin D, 565 Hypemic hypoxia, 451 Hyperbaric DCS, 223, 226, 227, 234 Hyperbaric hyperoxia, 458, 459 Hyperbaric oxygen (HBO) therapy, 233 Hypercalciuria, 565, 566 Hypercapnia. See Chronic hypercapnia

Index Hypercarbia causes and prevention of, 460 effects of, 461 signs and symptoms of, 461, 462 symptoms for, 375 Hyperoxia in aerospace operations, 457 oxygen toxicity, 457 toxic effects of, 458 Hyperuricemia, 268 Hypobaric DCS, 231. See also Decompression sickness Hypobaric hyperoxia, 458 Hypokinesia, 418, 561 Hypothermia, 253 Hypoxia acute, 451–455 in acute mountain sickness (AMS), 263, 264 chronic, 455, 456 in decompression, 253 normobaric vs. hypobaric, 263, 264 Hypoxic acclimatization, for space operations, 456, 457 Hypoxic cornea, 538, 539 Hypoxic hypoxia, 451 Hypoxic ventilatory response, 452 I Ibuprofen drug, 110 ICRP. See International Commission on Radiological Protection Ideal gas laws, 446 IE-DCS. See Inner ear decompression sickness Imipenem drug, 108, 113 Immune system. See Human immune system Impedance threshold device (ITD), 343 In-flight exercise, 341 In-flight imaging (1982), 181 In-flight management of GU problems Bartholin’s gland infection, 289 epididymitis, 289 prostatitis, 289 pyelonephritis, 289 urethritis/cystitis infections community acquired organisms, 288 symptoms and signs, 287 treatment, 288 urinalysis as clinical indicator, 287 urinary obstruction/retention, symptoms, causes and treatment for, 290 Inflight physical performance exercise tolerance, 41 heart rate and stroke volume, 42 oxygen uptake, 41–42 Inner ear barotrauma (IEB) composition, 257 implosive injury mechanism, 258 irreversible hearing loss, 259 Inner ear decompression sickness, 259 Inspired Partial Pressure, 448 Integrated medical system (IMedS), 344 Crew Health Care System, 345 International Civil Aviation Organization, 445 International Commission on Radiological Protection, 489

585 International Council on Radiation Protection, 386 International Space Station (ISS), 102, 123, 249, 251, 319, 362, 382, 415, 428, 523, 527, 528 air circulation in, 471 atmosphere control and supply system, 470 contingency plans for, 66 crew health care system (CHeCS) for, 82, 89, 98 crews, medical selection and evaluation standards for, 62–65 EASI lead system, for cardiac monitoring, 335 evacuation estimates for, 145 exercise countermeasures, 340 food system in, 561 health maintenance system, 89–90 launch window, 7 medical checklist, 72 medical event classification of, 142–143 medical requirements for, 154 medical restraint system, 70 minimum care standards, medical capabilities for, 146 orbital inclination of, 6 oxygen production in, 472 radiation exposure, 510 surgical capability for, 125–126 International Space Station program, 163, 566 crew medical restraint system (CMRS), 197 HRF ultrasound on, 186, 190 local area network, provision for, 173 L12-5 ultrasound probing, 193 medical data communication systems, 174 medical data management in, 172 preflight imaging study, 188 Russian segment of, 174 S-band system use, 173 video baseband signal processor (VBSP), 185 Internet, in telemedicine program, 163 Interplanetary transit times, operational factors affecting, 10 Intracorneal ring technique, 539 Intracranial pressure measurements, 264 Intramuscular (IM) injection, 103, 118 Intraocular lens implantation, 539, 540 Intraocular pressure, 540 Intraocular pressure rise, microgravity clinical significance of, 540 mechanism of, 540 treatment for, 540, 541 Intrathoracic gas, 238 Intrathoracic trauma, 238 Intravascular coronary ultrasound, 320 Intravenous catheterization, 118–119 Intravenous fluid therapy, 71 Ionizing radiation, spacecraft acceleration and vibration, 500 acute cellular and molecular effects of cell membrane damage, 493 cell sensitivity, 490 DNA damage, 491–494 epigenetic effects, 493 acute response to, 501, 502 acute tissue and organ specific effects of, 494–497 biological effects of

586 Ionizing radiation, spacecraft (Continued) animal model study, 490 medical exposures, 489, 490 nuclear weapons, 489 occupational exposures, 488 chronic effects of cancer, 497, 498 cataracts, 498, 499 nervous system, 499 skin, 498 clinical management, 502, 503 clinical manifestations, 500, 501 immune function changes, 499, 500 natural sources of, 481, 482 toxic vehicular agents, 500 IOP. See Intraocular pressure Ischemic hypoxia, 451 Isobaric-differential pressurization system, 247, 248 Isobaric pressurization system, 247 Isotonic fluid-loading, 342 Isotope-dilution technique, 332 ISS astronaut, 319 J J2000 Inertial Reference Frame, 6 Johnson Space Center Aerospace Medicine Board, 382 Johnson Space Center (JSC), 102, 103, 167, 393, 396, 418, 431 ACTS program use by, 171 space medicine development, by NASA, 174 Just-in-time concept, 164 K Klebsiella pneumonia, 502 Ku-band system, for data communication, 169, 173 Kurtotic noise, 522 Kvant-1 module, 428 L Lacerations, in crewmembers, 104–106 β−Lactamase penicillins, 114 Lagrangian points and payload, 9 Laminar airflow device, in parabolic flight, 128–129 Laparoscopic surgery, in space flight, 130–131 Laparotomy, 387–388 Laser in situ keratomileusis (LASIK), 539 Laser surgical techniques, 128 Launching to orbit from higher latitude sites, 5 lofting force, 4 Launch window, 6 LBNP. See Lower-body negative pressure LBNP device, 343 LDL. See Low-density lipoprotein Left ventricular (LV) cardiac chamber volume, 332 Leptons, 478 LET. See Linear energy transfer Lidocaine drug, 106, 117 Lifting body spacecraft, development, 151 Limb volume, space flight effects on, 32

Index Linear acceleration, 12–14 detection thresholds for, 365 Linear energy transfer, 476 Linear G field, for interplanetary flight, 18 Lithium-perchlorate, 108 Locomotor coordination test battery, 372 Locomotor oculomotor interaction, assessment of, 372 Longitudinal Study of Astronaut Health, 143, 174 Low-density lipoprotein, 324 Low Earth Orbit (LEO), 106, 139, 181, 182, 475 cardiovascular illness treatment, 344 ground track of spacecraft in, 8 medical capabilities for, 147 medical evacuation from, 157–158 orbital debris, 9 Lower-body negative pressure, 321, 343 caudal fluid shift induced by, 343 termination criteria for, 344 LSAH. See Longitudinal Study of Astronaut Health Lunar dust, chronic pulmonary diseases due to, 23 Lunar Mars life support test, 431 Lunar mission, radiation assessment, 513, 514 Lunar regolith, 23, 500, 513, 514 Lung parenchyma, visualization of, 182 M Macrolides drug, 114 Magnetic resonance imaging usage, for space medicine, 184 Magnetoplasmadynamic engines, 10 Maneuverable Entry Research Vehicle, 151 Mania, euphoria and development of, 402–403 Manned Orbital Laboratory, 151 Mars atmosphere, 514 communication, 164 expedition future perspective for surgical care in, 135 medical care system for, 124 medical transport and evacuation, 158 surgical capability for, 125–126 flight mission for, 9 gravitational effects on osteoporosis, 303 microgravity and Martian gravity, 303, 304 radiation assessment for, 513, 514 surface dust on, 24 Marshall Space Flight Center (Huntsville), 174 MASH. See Mobile Army Surgical Hospital McMurdo Station, medical evacuation in, 142 Medical assessment testing, for flight crews, 60 Medical care delivery, in space, 163 Medical equipment in space flight, lack of, 132 Medical imaging, in space altered gravity implication for, 189–190 application, 182 endoscopy techniques for, 184–185 history of echocardiographic series development (U.S.), 182 in-flight imaging, 181 Soviet-French research study, 181 limitations on, 197–198

Index magnetic resonance imaging (MRI), 184 nuclear imaging techniques, 184 optical imaging, 185 patient positioning techniques, 197 radiography for gastrointestinal pathology, 183 ultrasound imaging use, 185–186, 191–194 Medical restraint systems cardiac defibrillation and cardiopulmonary resuscitation, 71 cardiac drug kit, 78, 82 contingency respiratory capability, 71 features of ideal, 70 injection fluids, 71 microbiology and radiation hardware, 89 pressure-driven ventilator, 70 Medical screening after crew selection, 59–60 mercury astronaut candidates, 61 mission-specific, 65 NASA astronaut program and Canadian astronaut selection, 62–65 operational considerations, 60 select-in vs. select-out concepts in, 60–61 Medical standards astronaut specific, 61 for future space exploration intensive medical evaluation, 67 onboard medical facilities, 66 Russian and U.S. cardiovascular standards, 62, 63 for spaceflight candidates selection, 59 waiver process, 65 Medical support system first aid equipment, 89, 95–98 Medical systems of spacecraft, 72–78 of space shuttle, 73, 77–79–82 of space stations International Space Station, 82, 89–90 Mir space station, 78, 82, 84–89 Medical transport and evacuation, in spaceflight, 139 aeromedical transport, risk for, 149–152 anthropometric requirements in, 152–153 crew return vehicle, medical requirements for, 154–157 deconditioned crewmembers, pathophysiology, 146–148 epidemiological risk analysis for, 140–144 from LEO, 157–158 for Moon and Mars expedition, 158 patient accessibility and treatment capabilities, 153–154 psychological deconditioning of crewmembers, 148 risk analysis based on evidences, 140 standards of, 144–146 Melatonin drug, 110, 398 Mercury astronaut, medical screening tests of, 61 Mercury medical kits, 72 Mercury spacecraft cabin pressure, 466 environment control system in, 466, 467 radiation exposure in, 509 MERV. See Maneuverable Entry Research Vehicle Mesenteric ischemia, in crewmembers, 112 Metronidazole drug, 113 Microbial content, in spacecraft, 105

587 Microbiology hardware, 89 Microgravity, 15 body fluid redistribution, 273 bone mineral density loss artificial loading of the bone, 300 exercise devices evolution, 300 ISS astronauts recovery, 297 Mir cosmonauts recovery, 297 cephalic fluid shift, 374 comparative study of BMD, 297, 298 effect on carotid baroreceptor, 338 effect on venous vascular system, 331 eye-head coordination, 361 functional loading, 293 herniated nucleus pulposus (HNP), 299, 304 human response to, 16 influence on buoyancy and sedimentation, 16 convection, 17 hydrostatic pressure, 16–17 medical examination techniques under, 70 muscle loss, 299 oculomotor effects, 367, 374 postural and gait effects of, 369, 370 sensory illusions in, 361 space motion sickness, 363 spinal lengthening, 299 surgical care in atmospheric contamination, 130 capabilities of, 125 challenges in, 123 future perspectives of, 135 issues for, 124 limitations to, 132–133 surgical researches, 126–131 surgical techniques for, 387 vestibular function, 373, 374 Midazolam, 420 Middle ear barotrauma (MEBT) pressure-related hearing loss, 259 Tonybee and Edmonds maneuver, 260 treatment of, 260, 261 Valsalva and Frenzel maneuver, 259, 260 Military pilots, screening for, 64 Mir space station, 103, 168, 470 cosmonaut, medical event analysis from, 140–142 mission for, 525, 526 supplemental medical kit components of, 82 training, 98 Mobile Army Surgical Hospital, 145 MOL. See Manned Orbital Laboratory Monophasic sleep pattern, 414 Moon expedition, medical care systems for, 124, 140, 158 Motion Picture Experts Group (MPEG), 165 Motion sickness anatomy and physiology central neural connections, 215, 216 vestibular system, 215

588 Motion sickness (Continued) etiology fluid shift theory, 216, 217 sensory conflict theory, 216 MRI. See Magnetic resonance imaging MSMK. See Mir supplemental medical kit Multicast backbone (MBONE), 170 Muscle loss countermeasures pharmaceutical measures, advantages/disadvantages of, 303 physical measures artificial gravity, 302 ergonomic spacecraft design, 303 resistive exercise developments, 302 Muscle strain and overuse syndromes, in crewmembers, 104 Musculoskeletal response connective tissue changes, 299 in-flight muscle loss, 299 influence of mechanical forces, 293 Musculoskeletal system, 38 limitations, in crewmembers, 147 Musculoskeletal trauma, in crewmembers, 106–108 Myofascial pain dysfunction, 553 Myopia, surgical procedures intracorneal ring technique, 538, 539 intraocular lens implantation, 539, 540 LASIK, 539 photorefractive keratectomy, 539 radial keratotomy, 538, 539 N Nasopharyngeal congestion, in astronauts, 113 National Aeronautics and Space Administration (NASA), 418 Advanced Communications Technology Satellite (ACTS) program, 171 astronaut selection procedure, 62, 65 biosound genesis II scanner (AERIS), development of, 182 crew return vehicle development and capabilities, 150–153 medical requirements for, 154–157 database development by, 199 design reference missions of, 140 ground-based simulation program, 195 high-altitude physiologic training, 383 lifting body spacecraft, 151 longitudinal study of astronaut health, 66 medical devices communication system, 173–174 medical operations risk study, 143, 144 microgravity program, 124, 126 Mir program, 213, 220, 428 heat stress, 274 Reduced Gravity Program, 387 remote guidance of, 197 “Spacebridge to Russia” project, 171 space medicine, 174 and NEDU, 201 “strong angel” humanitarian relief exercise, 172 terrestrial telemedicine project, 170 ultrasound imaging, 186 for pneumothorax treatment, 199 video baseband signal processor (VBSP) testing by, 185

Index National Council on Radiation Protection and Measurements, 382, 386, 489 National Electrical Manufacturers Association, 164 National Institute of Health, 523 National Science Foundation, 140 National Sleep Foundation, 414 National Television Standards Committee (NTSC), 165 Navy experimental diving unit, 201 NCRP. See National Council on Radiation Protection and Measurements Necrosis acute apical abscess, 550 acute apical periodontitis, 550 partial, 549 total, 549–550 NEDU. See Navy experimental diving unit Nephrolithiasis, 44 in astronauts inflight management, 284 preflight management, 283, 284 preventive measures in flight, 284 risk profile and lifestyle, 281 space flight history of factors for increased risk, 280 risk assessment and countermeasures, 280 Russian space programs, 279 space shuttle flights, 279 treatment of renal stones extracorporeal shock wave lithotripsy (ESWL), 282 percutaneous nephrolithotripsy, 283 Neural integrator, 369 Neural plasticity, 368 Neural receptors, 331 Neurological countermeasures, 376 Neurologic dysfunction, 239 Neurologic function rating scale, 374 Neuromotor dysfunction and assessment, 366 Neurovestibular symptoms, 366 Neurovestibular system, 361 adaptation, operational concerns due extravehicular activity, 362 spacecraft reentry and landing, 362 unaided vehicle egress, 363 dysfunction, spaceflight adaptation, 363 RMS operations, 362 visual vestibular ocular reflex, 361 Neurovestibular system limitations, in crewmembers, 147 Neutral buoyancy, surgery in, 126 NIH. See National Institute of Health NIHL. See Noise induced hearing loss NIPTS. See Noise induced permanent threshold shift Nodal regression, 7 Noise induced hearing loss, 523, 524, 529, 530, 532 Noise induced permanent threshold shift, 531 Noise, spacecraft countermeasures to, 530, 531 criterion for, 521 environmental factors, effects of, 530 hearing assessment, 524 level, 521

Index pathophysiology of, 522, 523 and performance, 523, 524 physiologic effects of, 521 specification of, 525 threshold shift, 522, 523 types, 522 Nonionizing radiation effects on eye risks associated, estimation of, 505, 506 symptoms and treatment, 504, 505 VIPOR study, 506 on skin, 506 Non-rapid eye movement, 413 Normobaric hyperoxia, 458 Noxious compounds environment, decontamination, 438 properties of, 438 sampling and analysis, 438 sulfurous compounds, sources of, 437 susceptibility, 438 NREM. See Non-rapid eye movement NSF. See National Science Foundation Nuclear thermal rocket engines, 10 Nutrient imbalance bone resorption and endocrine regulation, 565 erythropoiesis and ferritin levels in, 563 fluid and electrolyte homeostasis, 562 in muscle and protein, 563–564 O Obsessive–compulsive disorder, 405 Occupational Safety and Health Administration, 512 Ocular abnormalities acute angle closure glaucoma, 540, 541 bacterial corneal ulcers, 541, 542 cephalad fluid shift, effects, 540 corneal abrasions and foreign body, 542 myopia, surgical procedures, 538–540 Oculomotor dysfunction, 368 OKN. See Optokinetic nystagmus Onboard medical facilities, space expeditions, 66 On-orbit medical resources, 101–102 Optokinetic nystagmus, 368 Optokinetic stimulation, 368 Oral rehydration, 341 Orbit body in, basic elements of, 7 inclination of, 5–6 node of, 7 payload, 5 Orbital debris, 8–9 collision effects, 250 composition of, 249 from fragmentation, 249, 250 hypervelocity impact testing, 251 Orbital flight, cardiovascular issues for, 331 Orbital space flight, 344 Orbital space plane, 139 Orbiter communications adapter (OCA) system, 168 Organic mental disorders, 404–405

589 Orthopedic injuries, treatment of, 134 Orthostatic intolerance, 212, 327, 336, 338 heart rate responses and plasma volume, 48 in postflight period, 47 OSHA. See Occupational Safety and Health Administration OSP. See Orbital space plane Otoacoustic emissions advantages and clinical utility of, 529 Minimum Audibility Test, 529, 530 types of, 528 Otolith asymmetry hypothesis, 217 Otolith tilt-translation reinterpretation (OTTR) hypothesis, 216 Otoscope, 170 Ottawa ankle rules, 107–108 Oxyhemoglobin dissociation curve, 449, 450 Oxymetazolone drug, 113 P Pan American Health Organization, ATS-3 provision by NASA, 170 Panic disorder, 405 Parabolic Flight Program, surgical techniques and findings, 126 Parathyroid hormone, 565 Parenchymal blood flow, 337 Partial gravity and linear G field, 18 locomotion in, 22 sustained, importance of, 17 Patent foramen ovale (PFO), preflight screening for, 202 PCWP. See Pulmonary capillary wedge pressure PEEP. See Positive end-expiratory pressure Penicillins, 114 Periodic fitness examinations (PFE), 325 Periodontal probing test, 551 Permanent noise-induced sensorineural hearing loss. See Permanent threshold shift Permanent threshold shift, 522, 525, 530, 531 Perturbation forces, 8 Phased-array probe, for cardiac imaging, 194 PhenDex, 218 Photoconjunctivitis and photokeratitis. See Snowblindness, causes of Photoelectric effect, 480 Photons, 479 Photorefractive keratectomy, 539 Physical examination, in weightlessness, 33–34 Pions, 479 Pittsburgh knee rules, 108 Planetary surface dust, 500 Plaque calcification, 318 Plasma aldosterone, 212 Plasma osmolality, 341 Plasma proteins, 332 Platelet glycoprotein, 344 Pleural fluid, on earth, 189, 190 PMC. See Private medical conference Pneumopericardium, 254 Pneumoperitoneum diagnosis, by sonography, 200 Pneumothorax, 199 Politzerization, 260 Polysomnography, 413

590 POS. See Pressure of stabilization Posigrade launch, 5 Positive end-expiratory pressure, 114 Positive predictive value, 317 Positron emission tomography (PET), 186 Positron-emitting isotopes, 184 Post-bailout motion sickness, 362 Postflight ataxia, 370 Postflight muscle pain syndrome treatment exercise countermeasures, 301 exercise devices evolution, 300 low back pain, 299–300 plantar fasciitis, 300 Postflight neurovestibular symptoms, 363 Postural equilibrium, postflight, 370, 371 PPV. See Positive predictive value Preflight medical examinations, 383 Preflight screening, for patent foramen ovale (PFO), 202 Preflight vestibular-adaptation training, 218, 220 Premature ventricular contractions, 320 Pressure alveolar gas exchange, 447 change with altitude, 446 off-nominal event, 447 units of, 447, 448 Pressure-driven ventilator, 70 Pressure gradient, 331 Pressure of stabilization, 253 Private medical conference, 101, 102 PRK. See Photorefractive keratectomy Probability of No Penetration (PNP), 251 Project Gemini, 167 Project Mercury (U.S.), 167 Promethazine drug, 103, 118, 218–220 Propulsion concepts, relative performance characteristics of, 10 Prostaglandin, 564 Prostate specific antigen (PSA), 286 Protein synthesis, 564 Pseudomonas aeruginosa, 502, 542 Psychological deconditioning, in crewmembers, 148 Psychosis, 404 Psychosocial stressors, long duration crews, 391 PTS. See Permanent threshold shift Pulmonary artery pressures (PAP), 267 Pulmonary bullae, 254 Pulmonary capillary wedge pressure, 339 Pulmonary disorders, in crewmembers, 114–115 Pulmonary edema, 240 Pulmonary emboli, 230 Pulmonary over-inflation syndromes, 254 PVCs. See Premature ventricular contractions Q Quality factor (Q), 475 Quantitative Computed Tomography (QCT), 296 Quantum. See Photons R Radial keratotomy, 538, 539 Radiation Effects Research Foundation, 489

Index Radiation environment, in low earth orbit galactic cosmic rays consists of, 484 magnetic field effect of sun on, 485 geomagnetically trapped radiation particle consists of, 483 regions of, 482 solar flares, 485 solar particle events effects of, 485 energy spectra of, 486 Radiation environment, outside low energy orbit, 486–487 Radiation exposure, spacecraft Gemini, 509 ISS, 511 limits and medicolegal aspects, 511, 512 Mercury, 509 occupational health aspects, 512, 513 Shuttle/Mir program, 510 Skylab, 510 space shuttle, 510 Radiation hardware, 89 Radiation interaction, with target atoms neutron interaction, 481 photon interaction, 480, 481 track structure on, 481 Radiation sensitizers, 503 Radiography for gastrointestinal pathology, in space, 183 Radioprotective agents, 503, 504 Rapid eye movement sleep, 413 RBE. See Relative biological effectiveness RCS. See Reaction control system Reaction control system, 140 Red Cross Medication, 548 Reissner’s membrane, 258 Rejection criteria, cardiovascular, 326 Relative biological effectiveness, 475 REM. See Rapid eye movement sleep Remote manipulator system (RMS), 362 Remote sensing, for planets, 182 Renal stone risk index assessment (RSRI), 281 Renal system fluid regulation in weightlessness, 43 nephrolithiasis, 44 Reserve time, acute hypoxia, 454 Respiratory minute ventilation, 429 Respiratory system changes in, space flight, 37 in weightlessness, 37–38 Right lower quadrant pain (RLQ), 200–201 RMV. See Respiratory minute ventilation Rotating crew module, gravity gradient in, 18 RSA. See Russian Space Agency Russian crew return vehicle, capabilities of, 152–153 Russian medical support system, 89 Russian Orlan space suit, 462, 463 Russian Soyuz, 152 Russian Space Agency, 188, 527 Russian spaceflight program, 396 Russian space station, 394, 419, 428

Index Russia space program ISS segment in, 174 telemedicine program, 163, 168 Internet based, 171 S SAA. See South Atlantic anomaly Sabatier process, for reducing CO2, 460 Sabatier reactor, 471 Saccade for acquiring objects in peripheral visual field and scan instruments, 361 oculomotor effects of microgravity, 367 Salyut mission, 168, 525, 526 Salyut-6/7 orbital complex, 181 Salyut space station, 470 Salyut-T6 orbital complex, 181 Saturn V Apollo Lunar vehicle, 5 S-band system space-to-ground communications capabilities, 173 used in Space Shuttle and ISS communications, 488 for voice conferencing, 169 ScopeDex, 218 Scopolamine drug, 103 SCR. See Solar cosmic rays SCRAM. See Simplified Crew Rescue Alternative Module Scuba-related gas embolism, 239 Seizure disorder, operational considerations for, 60 Sensory conflict theory, in motion sickness, 216 Sensory illusions, due to loss of spatial orientation, 361 Sensory-motor systems, as mechanism used to recalibrate, 368 Sensory organization test, 371 Shift gaze, oculomotor control for, 361 Shuttle-Mir flights bone mineral loss, 274 Shuttle-Mir Program, 567 radiation exposure, 510 Shuttle mission (STS-40), 525 Shuttle Orbiter medical system components of, 73, 79–82 space motion sickness kit, 78 Silver sulfadiazine drug, 108 Simplified Crew Rescue Alternative Module, 152 Sinus barotrauma, 255 Sinusitis, in crewmembers, 113 Skeletal muscle changes in, 39 landing day vs. preflight, 41 postural muscles, 40 fiber types of, 40 Skeletal muscle atrophy, 39 Skin disorders, in crewmembers, 110 Skylab In-Flight Medical Support System, 75–77 Skylab missions, 28, 526, 560, 561 biomedical crew training, 90, 98–99 calcium balance studies in, 274 crewmembers for, 362 surgical capabilities in, 125 Skylab Operational Bioinstrumentation System, 167 Skylab program (U.S.), 167 Skylab space station

591 environment control system in, 468 radiation exposure, 510 Sleep autonomic functions, 414 disorders, in crewmembers, 110 physiological function alpha rhythm, 413 EEG characteristics, 413 sleep spindle and K-complex, 413 slow-wave sleep, 413 REM sleep characterization, 414 sleep-wake detection algorithms, 414 in space, 415 stress, 414 temporal structure of, 414 types of, 414 Sleep-shift protocols, 420 Sleepy somnotype, 414 SMAC. See Spacecraft maximum allowable concentration Snowblindness, causes of, 504 Solar cosmic rays, 20 Solar flares, 485 biphasic solar cycle, correlation with, 21 blast wave, 20 Solar magnetic activity, effects of, 7 Solar particle events exposures affect on human body, 475 galactic cosmic radiation and potential exposures from, 482 radiation exposure rate during, 386 Solar wind and GCR, 20 SOLUS-3D project (U.K.), 187 Sonographic equipments, development pf, 135 Sorenson drainage system, 129, 130 SOT. See Sensory organization test Sound pressure level on flight deck, 416 mechanics of hearing, 521 real-time measurements of, 528 South Atlantic anomaly, 22, 483, 484, 495 Soyuz and Shuttle, differences of, 152–153 Soyuz spacecraft, 112, 470 designing of, 152 Soyuz T10 orbital complex, 181 Space adaptation syndrome, 102 Spacecraft Apollo, 467, 468 artificial source of radiation in, 487, 488 carbon dioxide LiOH binding capacity, 460 production and removal of, 459 crew protection in, 465 disorders and care in allergic reactions, 115 burns, 108 cardiac problems, 116–118 dental disorders, 115–116 eye disorders, 111–112 gastrointestinal disorders, 112–113 hand injuries, 108 headache, 108–110

592 Spacecraft (Continued) lacerations, 104–106 microbial content, 105 muscle strain and overuse syndromes, 104 musculoskeletal trauma, 106–108 pulmonary disorders, 114–115 skin disorders, 110 sleep disorders, 110 SMS, 102–103 trauma, 103–104 upper respiratory disorders, 113–114 urologic disorders, 116 electromagnetic radiation ionizing, 477 non-ionizing, 477, 478 environment control systems life support system, goals of, 465, 466 major threats, 465 Gemini, 467, 509 ground track of, in low Earth orbit, 8 humidity in maintaining level of, 464 removal of, 463 ionizing radiation acceleration and vibration, 500 acute radiation syndromes, 501 clinical management, 502, 503 immune function changes, 499, 500 planetary surface dust, 500 toxic vehicular agents, 500 ionizing radiation effects acute cellular and molecular, 490–494 acute tissue and organ specific, 494–497 biological, 488–490 chronic and long term, 497–499 ionizing radiation for, natural sources of, 481, 482 ISS, 511 maneuvering acute performance effects, 363 engine circuit breakers, 364 maximum allowable concentration in, 428 Mercury, 466, 467, 509 methods of treatment, 118–119 nonionizing radiation effects, 504–506 operational limits in, 462, 463 orbit of, 7–8 oxygen dissociation curve, 449, 450 sea level pressures, 449 transport of, 449, 450 performance capability of, 5 pressurization, 248, 249 Shuttle/Mir Program, 510 Soyuz, 470 and space flight environment, 415 space shuttle, 510 temperature in, 463 trace contaminants fire suppression system and charcoal filters, 465 off-gassing hazards, 464, 465

Index transporting patients, 119 Voskhod and Vostak, 470 Space flight anemia, 562 back pain and nerve entrapment, 376 balance function, recovery of, 370 candidates for, medical screening of, 59 chronology of, 28–29 conditions urine collection devices, 275–276 waste management systems, 275 crewmember balance assessment, 371 carotid sonography for, 328 functional neurological assessment, 367 video oculography (VOG), 375 data management system, capability of, 173 deconditioning, 15 diagnostic imaging in exploration-class mission, 198 issues in, 194 role in medical risk mitigation, 187–188 on transport spacecraft, 190 female astronauts, maternal age of, 384 gynecologic malignancy, 382 habitable volumes for, 149 headache, 375 heart rate and blood pressure, 334 human response to, clinico-physiological anthropometric changes, 32 body posture changes, 33 body weight, 32 bone integrity and calcium homeostasis, 38–39 cardiovascular system, 34–36 clinical laboratory values, 49–50 digestion, 44–45 entry and landing, 45–46 functional fitness, 49 inflight clinical laboratory findings, 45 inflight physical performance, 41–42 limb volume, 32 neurological system, 42–43 neurovestibular symptoms, 48–49 orthostatic intolerance, 47 physical examination, 33–34 plasma volume loss and diuresis, 36 postflight clinical disposition, 50 postlanding period, 46–47 pulmonary changes, 37–38 renal function and hormonal regulation, 43–44 skeletal muscle, 39–41 space motion sickness, 31–32 weightlessness, 30–31 imaging procedures, factors in interventional procedures, 204–205 position and stability, operators, 195–196 training and responsibility, 194–195 locomotor coordination test battery, 372 medical care delivery medical officers training, 163 telemedicine use for, 163

Index medical evacuation and transport, risks in, 150 medical imaging for application, 182 EBCT (See Electron-beam computed tomography) history, 181–182 limitations, 197–198 magnetic resonance imaging (MRI) usage in, 184 radiography for gastrointestinal pathology, 183 tomography use, 183–184 ultrasound imaging usage in, 185–186, 191–194 medical systems Apollo program, 72 Mercury and Gemini (projects), 72 Skylab missions, 72–73 morbidity and mortality in, 141, 143 neurological disorders, clinical implications of, 373 neurovestibular symptoms, 363 nutritional and physiologic effects of body mass loss in, 561, 562 bone resorption in, 565 countermeasures for, 570 dietary intake and reduction in, 559 fluid and electrolyte homeostasis in, 562 future prospects in, 570–571 hematocrit and anemia, 562, 563 negative calcium balance in, 564 skylab missions in, 560, 561 space shuttle foods in, 560 nutritional requirements and assessment in components of, 567 free radicals and antioxidants in, 568 minerals and iron in, 569 purpose of, 567 vitamins in, 568–569 weight, bone loss in, 568 patient transport and resuscitation, 133 perceptual effects and illusions, 364–366 physical challenges associated with, 41 preflight and launch factors, 29–30 sensorimotor changes during, 42 skeletal muscle atrophy, 39 surgery conditions, mitigating, 387 toxicology, 427 vision contact lenses and spectacles, 537, 538 correction, 536 demographics, 536 selection test for, 535, 536 standards, 535 visual acuity level, 535 visual function, recovery of, 373 weight loss, 340 Space flight-induced change, 340 Spacelab life sciences (SLS), 332 Spacelab-1 mission, 365 Space medical practitioners, 69 Space medicine basic problems of, 3 historical aspects of, 27–28

593 Space missions, behavioral problems health problems, 395–396 human-to-system interface problems monitoring of, 399 prevention of, 400 psychological adaptation cultural differences, 393 depressive symptoms, 394 sleep and circadian problems, 394 Space motion sickness (SMS), 31–32, 102–103, 363, 395 clinical and differential diagnosis, 217 definition of, 211 epidemiology influencing and precipitating factors, 214 time course, 214 U.S. and Russian space programs, 213, 214 in-flight treatment for, 219, 220 laboratory interpretation for electrolytes and hormones, 212 microgravity environment of, 211, 214 preflight adaptation training, 218, 219 prognosis, 220 prophylaxis, 218 Russian cosmonaut Gherman Titov, 212 symptoms of, 211, 212, 214 vs. terrestrial motion sickness, 211 Space radiation dosimetry monitoring active dosimetry, 507, 508 active personal dosimetry, 508 biodosimetry, 509 organ dose models, 509 passive dosimetry, 507 Space shuttle. See also Spacecraft crewmembers blood pressure, heart rate, 334 body water of, 332 emergency egress, 330 entrainment strategies for, 421–422 heart rate response, 336 isotonic solution, volume of, 342 launch position, 329 microgravity adaptation, 361 neurovestibular function, 361 orthostatic hypotension, 337 phase delay and advanced, 421 role of, 101 trans-thoracic acceleration for, 335 engines specific impulse of, 5 thrust generated by, 4 environment control system in, 468 food system in, 560 life support system in, 469 medical system in, 125 orbital mechanics, 6, 7 power requirements, 11 radiation exposure, 510 STS-90 Neurolab mission, surgery in, 131–132 waste collection system in, 384

594 Space Shuttle program Russia electrocardiographic monitors during, 36 enzymes in blood samples, analysis of, 45 medical screening approaches in, 61 United States electrocardiographic monitors during, 36 inflight clinical laboratory findings, 45 medical screening approaches in, 61 short-duration space flight, 29 Space sickness and weightlessness, 364 Space Technology Applied to Rural Papago Advanced Health Care, 170 Spatial orientation, strategies for, 366 SPE. See Solar particle events SPF. See Sun protection factor Spinal cord trauma, 565 Spinal DCS. See also Decompression sickness bubble formation, 229 etiology of, 228 SPL. See Sound pressure level Stagnant hypoxia. See Ischemic hypoxia Standard threshold shift (STS), 524 Staphylococcus aureus, 105, 108, 113, 502 STARPAHC. See Space Technology Applied to Rural Papago Advanced Health Care Stereopsis, telebinocular instrument for assessing, 535 Stewart equation, for predicting COHb concentrations in blood, 429 Stone formation. See Nephrolithiasis Storm shelter for protection and safety of crewmembers, 486 for protection from most dangerous aspects of SPEs, 513 Streptococcus pyogenes, 108 Stress radionuclide imaging, 327 “Strong Angel” humanitarian relief exercise, Hawaii, 172 STS-50 mission (U.S.), 169 STS-89 mission (U.S.), 169, 185 Sun protection factor, 506 Superficial trauma, in crewmembers, 103–104 Suprachiasmatic nucleus, 417 Supraventricular tachycardia, 320 Surface dust, 23–24 Surgery in microgravity, issues of, 124 Surgical bleeding in weightlessness, control measures, 128–129 Surgical care, in space anesthesia administration in, 134–135 atmospheric contamination in, 130 bleeding and hemostasis in, 128–129 capabilities of, 125–126 cardiac and trauma life support, 129–130 challenges in performing, 123–124 experiences of, 131–132 in exploration-class missions, challenges, 124–125 factors affecting, 124 future perspectives of, 135 limitations to, 132–133 management and treatment of patients in, 134 in neutral buoyancy, 126 in Parabolic Flight Program, 126–127

Index patient monitoring, 130 restraint system in, 127–128 surgical endoscopy in, 130–131 in weightlessness, 126–128 Surgical overhead canopy, 128 Surgical resources, limitation of, 132 SVT. See Supraventricular tachycardia T TCP/IP. See Transmission control protocol/Internet protocol TDRSS. See Tracking, data, and relay system satellites Telemedicine instrumentation pack (TIP) evaluation of different TIP embodiments, 171–172 physical examinations using, 169 Telemedicine program, in space applications for, 163 bandwidth influence, 165 clinical efficacy of, 165–166 consultation in U.S.(1950), 163 definition of, 163 future, 177–179 implications of, 175 interaction modalities of, 164 Internet applications, 163 Ku-band system, 169 Mars communication, 164 medical data management, in ISS program, 172 NASA ACTS program, 171 terrestrial telemedicine project, 170 origin of, 163 real-time encounters involvement, 164 Russia, 168 United States crewmembers, ECG monitoring of, 168 Project Mercury and Gemini, 167 verbal shorthand, development, 168 videoconferencing model for, 164, 165 video fundus camera, 169 Telepresence surgery, in space flight, 131 Telepsychiatry consultation, in U.S., 163 Telerobotics surgery, in space flight, 131 Temazepam drug, for sleep medications, 110 Temporary threshold shift, 522, 523 Temporomandibular joint dislocation, 554 Temporomandibular joint disorders, 553 Tenosynovitis, on long-duration space mission, 108 Tension headaches, endogenous causes of, 109 TEOAE. See Transient evoked otoacoustic emissions TEPC. See Tissue equivalent proportional counter Terrestrial telemedicine project, NASA, 170 Testosterone impact of space flight on, 44 muscle mass and protein balance, 564 Thallium treadmills (TT), 325 Thermal loading, 329 caused by suit modifications, 335 effects of weightlessness, 30 performance under conditions of, 61 Thermal test, evaluation of, 552

Index Thermoregulation mechanisms circadian rhythms markers, 417 during flight, 44 Thorascopy, in space flight, 131 Threshold intensity, automated testing for measuring, 524 Threshold Limit Value Committee, 433 Thrust, for propelling rocket, 4 Tic douloureux. See Trigeminal neuralgia Tilt-translation device, 219 Tissue equivalent proportional counter, 507, 508 Tooth disorders, classification of, 552–553 Toxicology hardware, for International Space Station, 89 Toynbee maneuver, for unlocking ET, 260 Tracking, data, and relay system satellites, 173, 178 Transient evoked otoacoustic emissions, 528 Transillumination aid in medical diagnosis, 550 with fiber-optic light, 547, 552 Transmission control protocol/Internet protocol, 168 Transportation Safety Board, 414 Trapped gas barotrauma, conditions for, 254 Trauma, in crewmembers, 103–104 Trauma pod, in parabolic flight, 130 Treaty on Principles Governing the Activities of States in the Exploration and Uses of Outer Space, 158 Tribolium, 500 Trigeminal neuralgia, 554 TTD. See Tilt-translation device T-38 training aircraft, 383 TTS. See Temporary threshold shift T-wave amplitude, due to changes in potassium metabolism, 322 Tympanic membrane (TM), 256 U Ultrasound biomicroscopy (UBM), 202 Ultrasound imaging, for space medicine, 185–186, 191–192 CMRS deployment, 197 RLQ pain evaluation, 201 Ultrasound probing, for space medicine, 193–194 United Nations Space Treaty, 157 United States Armed Forces Institute of Pathology, 164 Unit of pulmonary toxic dose (UPTD), 233 Upper respiratory disorders, in crewmembers, 113–114 Urologic disorders, in crewmembers, 116 US Coast Guard (USCG), 523 U.S. National Science Foundation’s Polar Medicine Program, 140 U.S. Space Act, 157 U.S. Space Shuttle Program, 394, 397, 400 in admitting women, advantages of, 381 Apollo-Soyuz Test Project, 168 crew health care system (CHeCS), 172 ECG monitoring, crewmembers, 168 echocardiographic series performance, 182 intramuscular injection for in-flight medical procedure in, 118 medical selection criteria, 382 National Television Standards Committee (NTSC), 165 orbital segment of, 173 communication from, 174

595 radiation-exposure limits, 382 Skylab program, 167 space-to-ground communications, capability of, 173–174 telemedicine program, 163 Apollo program crewmembers, 167 changes in, 168 Mercury and Gemini, Project, 167 UV keratitis, in crewmembers, 111–112 V Vagal autonaomic modulation, associated with shift-work of flight crews, 414 Vagal-cardiac neural outflow, for flight crew after space mission, 337 Valsalva maneuver alternobaric facial paralysis, 257 for clearing sinus block in flight crews, 255 influence on parasympathetic control of blood pressure, 36 for maintaining aortic root pressures and cerebral perfusion during high +Gz maneuvers, 342 procedure for self-inflation of middle ear space, 259 vagal baroreflex gain in inflight measurements, 43 Van Allen belt radiation. See Geomagnetically trapped radiation Van Allen radiation belts flux, 22 inner and outer, 21 Variable specific-impulse magnetoplasma rocket (VASIMR), 11 Vascular abnormalities, in crewmembers, 112 Vectorcardiograph, 167 Ventricular tachycardia, 322 Verbal shorthand development (U.S.), by crewmembers, 168 Vestibular disorders diagnosis and disposition of flight personnel with, 367 in humans, 373 Neurocom Equitest dynamic platform posturography for assessing, 371 Vestibular ocular reflex, 368 Vestibular spinal reflex, 361 Video baseband signal processor (VBSP), 185 Videoconferencing model, telemedicine, 164, 165 Video fundus camera investigation, for NASA program, 169 Virtual private network technology, 174 Visual Investigation Program on Orbiter Operations (VIPOR), 506 Visual orientation memory, 364, 365 Visual spatial strategy, 366 Voice communications, air-to-ground, 341 Volutrauma, 238 VOR. See Vestibular ocular reflex Voskhod spacecraft (Russia), 168, 470 Vostock 1 spacecraft, medical events in, 140 Vostok spacecraft (Russia), 168, 470 VPN. See Virtual private network VT. See Ventricular tachycardia W Walter Reed Army Medical Center (U.S.), 166 Weightlessness, 15. See also Microgravity clinical changes in physiological systems associated with bone integrity and calcium homeostasis, 38–39 cardiovascular system, 34–36

596 Weightlessness (Continued) clinical laboratory values, 49–50 digestion, 44–45 entry and landing, 45–46 functional fitness, 49 inflight clinical laboratory findings, 45 inflight physical performance, 41–42 neurological system, 42–43 neurovestibular symptoms, 48–49 orthostatic intolerance, 47 plasma volume loss and diuresis, 36 postflight clinical disposition, 50

Index postlanding period, 46–47 pulmonary changes, 37–38 renal function and hormonal regulation, 43–44 skeletal muscle, 39–41 human response to, 30–31 physical examination in, 33–34 Z Zero gravity flight, human surgical procedures for, 387–388 Zolpidem drug, for assisting onset of sleep in space crews, 110