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 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.

3. Medical Evaluations and Standards

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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 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 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

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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.

7. Medical Evacuation and Vehicles for Transport

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 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

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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

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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

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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

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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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207 82. Pilmanis AA, Meissner FW, Olson RM. Left ventricular gas emboli in six cases of altitude-induced decompression sickness. Aviat Space Environ Med 1996; 67:1092–1096. 83. Webb JT, Krause KM, Pilmanis AA, et al. The effect of exposure to 35,000 ft on incidence of altitude decompression sickness. Aviat Space Environ Med 2001; 72:509–512. 84. Webb JT, Pilmanis AA, Kannan N, et al. The effect of staged decompression while breathing 100% oxygen on altitude decompression sickness. Aviat Space Environ Med 2000; 71:692–698. 85. Conkin J, Foster PP, Powell MR, et al. Relationship of the time course of venous gas bubbles to altitude decompression illness. Undersea Hyperb Med 1996; 23:141–149. 86. Kumar KV, Billica RD. Classification of decompression sickness. Aviat Space Environ Med 1995; 66:912. 87. Fuchs G, Schwarz G, Stein J, Kaltenbock F, et al. Doppler colorflow imaging: Screening of a patent foramen ovale in children scheduled for neurosurgery in the sitting position. J Neurosurg Anesthesiol 1998; 10:5–9. 88. Montessuit M, Pretre R, Bruschweiler I, et al. Screening for patent foramen ovale and prevention of paradoxical embolus. Ann Vasc Surg 1997; 11:168–172. 89. Stendel R, Gramm HJ, Schroder K, et al. Transcranial Doppler ultrasonography as a screening technique for detection of a patent foramen ovale before surgery in the sitting position. Anesthesiology 2000; 93:971–975. 90. Fledelius HC. Ultrasound in ophthalmology. Ultrasound Med Biol 1997; 23:365–375. 91. Deramo VA, Shah GK, Baumal CR, et al. Ultrasound biomicroscopy as a tool for detecting and localizing occult foreign bodies after ocular trauma. Ophthalmology 1999; 106:301– 305. 92. Pietrzyk RA, Feiveson AH, Whitson PA. Mathematical model to estimate risk of calcium-containing renal stones. Miner Electrolyte Metab 1999; 25:199–203. 93. Whitson PA, Pietrzyk RA, Morukov BV, et al. The risk of renal stone formation during and after long duration space flight. Nephron 2001; 89:264–270. 94. Whitson PA, Pietrzyk RA, Pak CY. Renal stone risk assessment during Space Shuttle flights. J Urol 1997; 158:2305–2310. 95. 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. 96. Raphael DT. Acoustic reflectometry profiles of endotracheal and esophageal intubation. Anesthesiology 2000; 92:1293–1299. 97. Drescher MJ, Conard FU, Schamban NE. Identification and description of esophageal intubation using ultrasound. Acad Emerg Med 2000; 7:722–725.

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.

H.J. Ortega Jr. and D.L. Harm

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.

H.J. Ortega Jr. and D.L. Harm

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 (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,

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

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

12. Decompression-Related Disorders: Pressurization Systems, Barotrauma, and Altitude Sickness

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.

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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

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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.

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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 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

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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., 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 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].

D.R. Hamilton

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 [ 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) 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

16. Cardiovascular Disorders

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

16. Cardiovascular Disorders

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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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.

361

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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 (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.

J.T. James

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

21. Health Effects of Atmospheric Contamination

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 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

21. Health Effects of Atmospheric Contamination

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, 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

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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

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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].

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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

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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

J.A. Jones and F. Karouia

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

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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.

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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.

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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) 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.

23. Radiation Disorders

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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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

522

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 (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

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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 (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

27. Spaceflight Metabolism and Nutritional Support

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.

27. Spaceflight Metabolism and Nutritional Support

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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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