Payload Specialist Jay C.Buckley, Jr., Payload Commander Richard M.Linnehan, and Astronaut Dafydd R. (Dave) Williams (left to right) during pulmonary function tests in support of the Neurolab mission aboard the Earth-orbiting space shuttle Columbia, April 24, 1998, during the STS-90 mission. NASA image.



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Safe Passage: Astronaut Care for Exploration Missions Payload Specialist Jay C.Buckley, Jr., Payload Commander Richard M.Linnehan, and Astronaut Dafydd R. (Dave) Williams (left to right) during pulmonary function tests in support of the Neurolab mission aboard the Earth-orbiting space shuttle Columbia, April 24, 1998, during the STS-90 mission. NASA image.

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Safe Passage: Astronaut Care for Exploration Missions 2 Risks to Astronaut Health During Space Travel …we must assume that for a long time to come (although not forever), weightlessness will be an obligatory condition of space flight. For this reason, all aspects of this issue must be considered from the point of view of the possibility of functioning in microgravity. G.I.Meleshko, Y.Y.Shepelev, M.M.Averner, and T.Volk, 1994 OVERVIEW Over the life of the U.S. space program, generations of astronauts have learned how to live and work in weightlessness. Humans evolved in gravity; how the body would function in its absence or near absence was an unanswered question. Would it be possible to eat and drink in microgravity? Would it be possible to perform complex tasks? The early answers were affirmative. Thus, selected fit and healthy humans have been sent into space for three decades and have functioned well (Lane and Schoeller, 2000). Although humans have adapted to weightlessness, readapting to Earth’s gravity is problematic. Exposure to microgravity affects the body in many ways. Some effects are severe and long lasting, such as loss of bone mineral density. Others are minor and temporary, such as facial puffiness due to fluid shifts (Nicogossian et al., in press). It is unlikely that all effects of

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Safe Passage: Astronaut Care for Exploration Missions microgravity are known, and surprises may yet be in store as humans venture longer and farther into space. This chapter is about human physiological adaptation to space travel. In it, the Institute of Medicine (IOM) Committee on Creating a Vision for Space Medicine During Travel Beyond Earth Orbit examines what is known about the effects of microgravity and space travel on the human body. This is the starting point for generating priorities in clinical research and health care for space travel beyond Earth orbit. In developing this chapter, the committee has relied heavily on briefings and published information from the study’s sponsor, published scientific articles, and two recent National Research Council (NRC) reports. The first report, A Strategy for Research in Space Biology and Medicine in the New Century (SSB and NRC, 1998a), provided a science-based assessment of the most important biomedical research topics in 1998 to be pursued over the next decade. The second report, Review of NASA’s Biomedical Research Program (SSB and NRC, 2000), examined the National Aeronautics and Space Administration’s (NASA’s) biomedical research enterprise 2 years later and measured it against the plan set forth in the earlier report. The IOM committee endorses the findings and recommendations of both NRC reports. The current report extends the vision of the two previous NRC reports to clinical research and clinical care in space. This chapter responds to the portion of NASA’s charge to the IOM committee to “conduct an independent assessment of the current status of scientific knowledge” relevant to providing optimal health care for astronauts traveling beyond Earth orbit. In so doing, the chapter describes the effects of weightlessness and space travel on the physiology and functioning of the human body. It discusses the evidence on which the findings are based, the steps that need to be taken, and the research challenges and opportunities that lie ahead. Most of what is known about the effects of microgravity on the human body has been learned on short missions into space. NASA is now looking ahead to longer-duration space missions, initially in Earth orbit and later into deep space. Over the next decade, a number of astronauts will have 3-to 6-month tours of duty aboard the International Space Station (ISS). These may be followed by extended stays on the Moon or exploration-class missions to Mars, or both. Before the United States and its international space partners commit to any such plans, however, there needs to be a better and fuller understanding of the risks to astronaut well-being and the safety of long-duration space travel in and beyond Earth orbit. The chapter presents numerous examples of the effects of exposure to microgravity and space travel on human physiology (Box 2–1). The examples

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Safe Passage: Astronaut Care for Exploration Missions BOX 2–1 Some Major Human Physiological Changes Resulting from Extended Travel in Earth Orbit Musculoskeletal System Loss of bone mineral density Loss of skeletal muscle Cardiovascular System Orthostatic hypotension Loss of hydrostatic pressure Pulmonary System Changes in pulmonary circulation and gas exchange Alimentary System Ileus Decrease in absorption or malabsorption Nervous System Ataxia Motion sickness Disturbed fine motor and gross motor functions Altered sleep-circadian rhythm and sleep deprivation Reproductive System Effects of radiation on gametes Urinary System Renal calculi Hematological and Immunological Systems Anemia Potential immunologic depression Source: Billica, 2000. are by no means exhaustive, however. The material in this chapter is arranged by organ system, with those for which the physiological effects are best documented presented first. The chapter also includes a discussion of future methods for the monitoring of astronauts’ health status—an important aspect of detecting, understanding, and countering the untoward physiological changes that may affect astronaut well-being and mission performance.

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Safe Passage: Astronaut Care for Exploration Missions Finally, the chapter includes a discussion of the comprehensive, long-range approach to clinical research that NASA needs to consider implementing to best protect human health and safety during long-duration space travel. Historically, NASA has faced difficulty in conducting clinical research in space medicine. One problem is the small numbers of research subjects (astronauts) available for study. The overriding reason, however, is that microgravity cannot be duplicated on Earth; it can only be approximated. The terrestrial means of research on bone mineral density loss in microgravity are bed rest, immersion in water, or immobilization. All have their own disadvantages. The opening era of the permanent presence of humans in Earth orbit on the ISS in October 2000, however, provides an enduring test bed that will eventually help provide an understanding of human physiology in microgravity. Countermeasures to Solve Physiological Adaptations to Space Faced with the necessity to maintain astronauts’ health during periods of exposure to microgravity and other extreme conditions of spaceflight, NASA has pursued the development of preventive and counteracting measures (i.e., countermeasures) to guard against or reverse the potential pathophysiological effects of space travel. A variety of countermeasures have been used in longer-duration spaceflights (Mikhailov et al., 1984; Bungo et al., 1985; Greenleaf et al., 1989; Fortney, 1991; Arbeille et al., 1992; Cavanagh et al., 1992; Charles and Lathers, 1994; Hargens, 1994; Convertino, 1996b). The American and Russian space programs use different strategies. Some examples of countermeasures that had been developed as of 2000 include subcutaneous injections of erythropoietin to prevent decreases in erythrocyte mass and vigorous in-flight exercise regimens to reduce loss of bone mineral density. So far, countermeasures appear to be largely ineffective, but the data are sparse (Bungo et al., 1985; Buckey et al., 1996b; Convertino et al., 1997; Lane and Schoeller, 2000). NASA’s general approach to the development of countermeasures was presented to the IOM committee at the Johnson Space Center (Paloski, 2000; Sawin, 2000). The rationale (Figure 2–1) outlined a number of steps that have been incorporated into NASA’s Countermeasure Evaluation and Validation Project, which can be summarized as follows: conduct research to understand the basic nature of the physiological problem,

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Safe Passage: Astronaut Care for Exploration Missions FIGURE 2–1 Countermeasure (CM) evolution. Source: Paloski, 2000. formulate a countermeasure strategy based upon that physiological understanding, test the countermeasure and demonstrate its efficacy on the ground, and validate the countermeasure in space. It has been difficult for NASA to design and test effective countermeasures, and no single countermeasure has yet to be validated as clinically efficacious. The potential for better design and evaluation of countermeasures improved dramatically on October 30, 2000, with the arrival of the first multinational astronaut crew to inhabit space as residents on the ISS. The ISS offers NASA and its international partners a longer-term orbiting clinical research laboratory in microgravity to investigate—and ultimately prevent—the adverse changes in human physiology described in the pages that follow. To assume that a terrestrial model duplicates the physiological effects of microgravity is a logical flaw that could lead to reliance on ineffective countermeasures. The plan outlined by NASA therefore demands that a significant amount of physiological research be conducted on the ISS and

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Safe Passage: Astronaut Care for Exploration Missions immediately following long-duration space missions on the ISS. The amount of research required, the duration of the research, and the extensive nature of the research will have to be considered in the planning phases of ISS missions. This chapter also discusses new and future methods for the diagnosis and monitoring of astronaut health status in space and NASA’s health risk assessment and management process that includes countermeasure development. The chapter concludes with a discussion of the comprehensive long-range approach to clinical research that NASA needs to consider to prepare for successful long-duration missions with humans beyond Earth orbit. MUSCULOSKELETAL SYSTEM Loss of Bone Mineral Density in Microgravity Changes in bone mineral density, muscle mass, and muscle function are the best-documented physiological effects of human space travel. The loss of bone mineral density in microgravity is well documented (Vico et al., 2000). Serious acute consequences of bone mineral density loss (i.e., fracture and the formation of renal stones) as well as long-term morbidity may complicate long-duration space travel beyond Earth orbit. Working in microgravity within a spacecraft, during extravehicular activity, and upon a low-gravity moon or planet presents many increased risks for bone fracture and the necessity for wound healing. From a practical viewpoint, virtually nothing is known about how microgravity will affect fracture management and healing during long-duration space missions. For example, is it better to cast, internally fixate, externally fixate, or electrically stimulate a fracture sustained on Mars? The committee was unable to locate data from studies with animals or humans or from basic, translational, or clinical studies on these clinical treatments issues; but knowledge about such clinical treatments issues will be important to sustain human health and performance should a bone fracture occur during space travel beyond Earth orbit. At the basic science level, little is known about the fundamental mechanisms underlying the loss of bone mineral density in microgravity; hence, scant progress has been made on the development of effective countermeasures. This must be an extremely high priority before long-duration space travel can be deemed reasonably safe with regard to the risk of fractures, the associated increased risk of renal stones, and basic skeletal support. Small numbers of subjects and, in many cases, incomplete data have hindered clinical studies, resulting in a lack of reliable databases (SSB and

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Safe Passage: Astronaut Care for Exploration Missions NRC 1998b; Lane et al., 1999; Lane and Schoeller, 2000). Thus, it is difficult, if not impossible, to generate reliable conclusions that can be applied to individual astronauts. A recent review (Smith et al., 1999) focusing on calcium metabolism after a 3-month space mission showed an approximately 50 percent increase in the level of calcium absorption accompanied by a 50 percent increase in the levels of both calcium excretion and bone resorption, as determined by calcium kinetics and bone marker analyses, respectively. Subjects lost approximately 250 milligrams of bone calcium per day during space travel in Earth orbit and appeared to regain it at a slower rate after their return to Earth. There is a suggestion from limited studies of bone density markers in serum and urine, which are used to approximate the relative rates of bone formation in relation to rates of bone resorption, that an uncoupling of the two processes led to an imbalance, with bone resorption predominating (Caillot-Augusseau et al., 1998). Again, because of the small numbers of subjects, this conclusion cannot be generalized and may not be applicable to all astronauts. As shown in Table 2–1, mainly weight-bearing bones (spine, neck, femur, trochanter, and pelvis) lost bone mineral density during space missions in Earth orbit: on average, greater than 1 percent per month for cosmonauts on the Russian Mir space station. In contrast, there was no significant loss from bones in the upper extremity (arm). Additional measurements (n=40) that include shorter-term (<3 weeks) U.S. space shuttle flights show that loss of bone mineral density begins within a few days and continues for the longest period measured (1 year) without showing signs of leveling off. It is noteworthy that the standard deviations in all studies are high, which may indicate wide variations in the responses of individuals. This suggests that there may be substantial phenotypic (and presumably genotypic) variations in susceptibility to microgravity-induced bone mineral density loss. If shown to be true, this concept would have important implications for the selection of crewmembers for long-duration missions (e.g., are menopausal female astronauts or specific male or female astronauts phenotypically at greatly enhanced risk?). The collection and analysis of clinical data for a comprehensive database to determine whether individuals with phenotypes that make them “resistant” to and “at risk” for space travel-induced bone mineral density loss exist represent but one set of important challenges for NASA that has been identified. Understanding these patterns in relation to basic patterns of up-and downregulation of gene arrays as a result of exposure to microgravity could lead to the development of specific interventions to prevent microgravity-induced bone mineral density loss.

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Safe Passage: Astronaut Care for Exploration Missions TABLE 2–1 Average Bone Mineral Density Loss on Mir Variable Number of Crewmembers Mean Loss (Percent/Month) Standard Deviation Spine 18 1.07a 0.63 Neck of femur 18 1.16a 0.85 Trochanter 18 1.58a 0.98 Total body 17 0.35a 0.25 Pelvis 17 1.35a 0.54 Arm 17 0.04a 0.88 Leg 16 0.34 0.33 ap<0.01. SOURCE: LeBlanc et al., 1996. Associated with the bone mineral density loss is a rather consistent hypercalciuria, which increases the risk of formation of renal stones (Schneider et al., 1994). Importantly, this limits pharmacological options such as treatment with normal dietary supplements (e.g., calcium and vitamin D). Reversibility, Genetic Variability, and Mechanism of Bone Mineral Density Loss Although data are limited, it appears that changes in calcium metabolism and bone mineral density are reversible. There are suggestions, however, that reversal of the changes is slower than their evolution and that the rate and extent of reversal are highly variable (Vico et al., 2000). A mission to Mars, for example, would involve a period of low or nearly zero gravity during space travel, a second period of time in gravity well lower than that on Earth while the expedition was on the surface of Mars, a third period of time again spent in low gravity during the return flight, and the ultimate return to Earth’s gravity. How these sequential changes in gravity loading will influence bone mineral density loss is unknown. It is possible that they may exacerbate and accelerate the incidence of Earth-based diseases such as

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Safe Passage: Astronaut Care for Exploration Missions osteoporosis. As such, it may be appropriate to consider terrestrial referenced 6- and 9-year windows of disease incidence instead of the disease incidence for a 3-year period. Limitations in data collection and analysis, the small sizes of databases, the lack of precise bone mineral density measurements (which have a 1 to 2 percent coefficient of variation), and the very high natural variations of markers of bone mineral density turnover all contribute to the difficulty of obtaining reliable data that would be useful for clinical decision making for space travel. Therefore, the most reliable and efficient clinical studies must probably use individual astronauts as their own controls. The etiology of bone mineral density loss is multifactorial and likely polygenic, like most common diseases. The basis for or the implications of individual variability is not known, further complicating interpretation of the limited clinical data. Long-duration space missions in Earth orbit offer the opportunity to obtain crucial data by careful clinical research. These data could then be used to generate hypotheses and to guide measures to protect subsequent astronauts from unnecessary morbidity and even death. Additional factors that may affect the relative risk of bone mineral density loss during space missions are bone mass as measured by bone densitometry and bone turnover rates as measured by markers of bone density in serum and urine determined before the initiation of a space mission. Although the selection of astronauts with higher bone masses may not prevent bone mineral density loss, it may prevent the consequences of decreased bone mineral density; that is, bones with higher mineral densities may be at decreased risk of fracture. Thus, because of unknown genetic components and the variability among astronauts with regard to the rate of bone mineral density loss, it might be increasingly important to identify individuals whose bodies are able to resist bone mineral density loss on prolonged space missions (Vico et al., 2000). This can be accomplished only by extensive premission, intramission, and postmission analyses of bone mineral density and markers of bone mineral density turnover in serum. It may be possible to identify individuals who are less prone to the effects of microgravity on bone mineral metabolism and bone mineral density loss. This knowledge not only might have implications for space travel, but it also may well provide important information about diseases such as osteoporosis. A number of animal models, including models of unloading, have been used to simulate weightlessness (SSB and NRC, 1998a; Lane and Schoeller, 2000). It is unknown whether such models reflect the physiology of humans during space travel. Rats have been used in microgravity experiments, but the results of those experiments may be of limited value given the poor cor-

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Safe Passage: Astronaut Care for Exploration Missions relation between rat bone metabolism and the bone architecture in humans (SSB and NRC, 1998a, 2000). The development of land-based animal models for investigation of the pathophysiology and pharmacotherapeutics of bone mineral density loss during space missions beyond Earth orbit will require more knowledge of bone mineral density loss in humans. Although the advantage of using experimental and natural animal models, for example, hibernating bears (Harlow et al., 2001), is evident—in that it allows more focused investigation into basic molecular and cellular mechanisms—successes from the study or development of such models will likely lag behind the need to test the effectiveness of therapeutic interventions in humans during space missions beyond Earth orbit. The use of immobilized human subjects on Earth as models may have its place. However, the high priority for the evaluation of the effectiveness of countermeasures in the microgravity environment renders such models less valuable in the short term. The technology for the accurate testing of bone mineral density is improving and is becoming increasingly miniaturized. It will probably become necessary to assess bone mineral density changes during space missions both in and beyond Earth orbit with reasonable precision for clinical research purposes. It is anticipated that this technology will be useful in assessments of the need for and testing of the effectiveness of specific interventions during space travel. In addition, it is anticipated that better documentation of the validity of bone mineral density markers in evaluations of the mechanisms of bone mineral density loss would also provide a means for optimization of highly targeted interventions. Therefore, the development of a means to measure such markers in the long-duration space mission environment should be a high priority in conjunction with an aggressive NASA countermeasure research program. Better measures of bone integrity, for example, three-dimensional assessments, not just bone mineral density, are also needed. Ultimately, intramission tests should be the indicators that guide specific therapies. Clinical Research Opportunities in Astronaut Physiology and Health Clinical Research Opportunity 1. Establishing the course of changes in bone mineral density and markers of bone mineral density turnover in serum and urine before, during, and after space travel. Clinical Research Opportunity 2. Developing a capacity for real-time measurement of bone mineral density and enhanced three-dimensional technology to assess the risk of fracture during space travel.

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Safe Passage: Astronaut Care for Exploration Missions BOX 2–3 Elements of the Critical Path Roadmap Project ✓ Risks: Likelihood of an undesirable event occurring as a result of exposure to the space environment. Risk assessment includes the probability of the risk’s occurrence, the severity of the consequences of the occurrence, and the current status of mitigation of the risk. Examples: Occurrence of serious cardiac dysrhythmias Fracture and impaired fracture healing ✓ Risk Factors: A condition or precipitating factor that must be present for the risk to occur. Such conditions can operate singly or in combination to contribute to the occurrence of risk. Examples: Poor nutrition In-flight work schedule overload ✓ Important Questions: What research and technology need to be developed to further assess the risk and address its mitigation? Example: Will bone mass loss continue unabated for missions longer than 6 months, or will it plateau at some time consistent with absolute bone mineral density? ✓ Risk Mitigation: Strategies, devices, interventions, and requirements that need to be in place to modify the occurrence or impact of the risk. Examples: Resistive exercise regimens Medications Preflight fitness requirements ✓ Critical Path Roadmap Project: Graphic representation(s) of the essential set of research and technology development tasks required to address the risks associated with exploration-class space missions with humans, specifically denoting ➝relationships (causal pathway among risks, risk factors, and consequences) ➝priorities ➝temporal sequencing (predecessor questions or tasks) ✓ Requirements Examples: Crew screening and selection requirements for minimization of bone loss Habitability requirements Nutritional requirements Medical care systems for diagnosis, monitoring, and treatment of illness and injury ✓ Deliverables: Specific end items that can be identified, completed, and available at known dates. Examples: Validated, preflight training countermeasures (see Table 2–2) for psychosocial adaptation Validated, in-flight virtual reality-based training for emergency egress Exercise countermeasures for bone loss, muscle atrophy, and cardiovascular and neurovestibular adaptation Source: Charles, 2000.

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Safe Passage: Astronaut Care for Exploration Missions TABLE 2–2 Critical Path Roadmap Project: Critical Risks. SOURCE: Charles, 2000 Bone Loss Cardiovascular Alterations Human Behavior and Performance Immunology, Infection and Hematology Muscle Alterations and Atrophy Acceleration of age-related osteoporosis   Human performance failure because of poor psychosocial adaptation     Fractures (traumatic, stress, avulsion), and impaired healing of fractures Occurrence of serious cardiac dysrhythmias Human performance failure because of sleep and circadian rhythm problems   Loss of skeletal muscle mass, strength, or endurance   Impaired cardiovascular response to orthostatic stress   Inability to adequately perform tasks due to motor performance problems, poor muscle endurance, and disruptions in structural and functional properties of soft and hard connective tissues of the axial skeleton   Inability to sustain muscle performance levels to meet demands of performing activities of various intensities

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Safe Passage: Astronaut Care for Exploration Missions Neurovestibular Adaptation Radiation Effects Clinical Capability Other   Carcinogenesis caused by radiation Trauma and acute medical problems   Severe Risks Disorientation and inability to perform landing, egress, or other physical tasks, especially during/ after g-level changes Damage to central nervous system from radiation exposure Toxic exposure Inadequate nutrition (malnutrition) (three risks) Very Serious Risks Impaired neuromuscular coordination and/or strength Synergistic effects from exposure to radiation, microgravity and other environmental factors Altered pharmacodynamics and adverse drug reactions Postlanding alterations in various systems resulting in severe performance decrements and injuries     Early or acute effects from radiation exposure   Habitation and life support (eight risks)  

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Safe Passage: Astronaut Care for Exploration Missions Bone Loss Cardiovascular Alterations Human Behavior and Performance Immunology, Infection and Hematology Muscle Alterations and Atrophy Injury to connective tissue or joint cartilage, or intervertebral disc rupture with or without neurological complications Diminished cardiac function Human performance failure because of human system interface problems and ineffective habitat and equipment design, etc. Immuno-deficiency/ infections Propensity to develop muscle injury, connective tissue dysfunction, and bone fractures due to deficiencies in motor skill, muscle strength, and muscular fatigue Renal stone formation Manifestation of previously asymptomatic cardiovascular disease Human performance failure because of neurobehavioral dysfunction Carcinogenesis caused by immune system changes     Impaired cardiovascular response to   Altered hemo-and cardio-dynamics from altered blood components Impact of deficits in skeletal muscle exercise stress structure and function on other systems   Altered wound healing Altered host-microbial interactions Allergies and hypersensitivity reactions  

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Safe Passage: Astronaut Care for Exploration Missions Neurovestibular Adaptation Radiation Effects Clinical Capability Other Impaired cognitive and/or physical performance due to motion sickness symptoms or treatments, especially during/ after g-level changes Radiation effects on fertility, sterility and heredity Illness and ambulatory health problems   Serious Risks Vestibular contribution to cardioregulatory dysfunction   Development and treatment of decompression illness complicated by microgravity-induced deconditioning     Possible chronic impairment of orientation or balance function due to microgravity or radiation   Difficulty of rehabilitation following landing (two risks)  

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Safe Passage: Astronaut Care for Exploration Missions FIGURE 2–2 Countermeasure (CM) development and evolution. Sources: Feiveson, 2000; IOM, 2001e. These risk areas have been grouped into four categories: environmental and technological, human behavior and performance, human health and physiology, and medical care capabilities. It is expected that clinical research will be an integral component in the successful prevention or mitigation of the risks to astronaut health in each of the discipline risk areas. The Critical Path Roadmap project, with its clinical research program on countermeasures, is NASA’s mechanism for the development of priorities and validation of the means of mitigating the risks that humans may be expected to encounter during exploration-class missions into deep space. As a mechanism for gathering information, the Critical Path Roadmap project is an appropriate model for clinical research in space medicine, with use of the ISS as the critical platform for clinical research in space medicine and for NASA to validate countermeasures in the space travel environment as it prepares to go beyond Earth orbit (Figure 2–2). NASA has, however, not integrated a prospective and continually reevaluated understanding of clinical research on astronaut health into the Critical Path Roadmap project in any of the information that it provided to the committee or that the committee was able to find. It should be noted that the environment on Mars, at 0.4G and with some atmosphere, is different from that of the spacecraft. Whether the presence of significant gravitational pull

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Safe Passage: Astronaut Care for Exploration Missions will tend to ameliorate the adverse effects of microgravity is unknown but is worth consideration in the planning of research. A Clinical Research Program for NASA IOM has conducted a number of studies focused on various aspects of clinical research (IOM, 1998, 1999a, 2001c,d,e). Although there are many definitions of clinical research (IOM, 1994), IOM recently endorsed the broad definition of clinical research set forth by the Graelyn Conference and National Clinical Research Summit (Box 2–4) and formed the Clinical Research Roundtable to periodically discuss continuing developments and needs in clinical research. The varied, significant, and potentially harmful changes in physiology associated with space travel require health care interventions to protect the well-beings of the participating astronauts and the integrity of the mission. However, traditional clinical research with astronauts is difficult because of the small number of participants available for study, the inability to replicate microgravity and its effects on Earth, restrictions on the use of control groups, and limitations on the substitution of results from studies with animals. A large portion of NASA’s human clinical research to date has been in the form of countermeasure development and evaluation, and this research has been conducted through trials of single interventions directed at specific physiological changes. This largely precludes, however, the classic approach of comparing alternative treatments in clinical trials with adequate statistical power (adequate sample sizes for statistical analysis) to demonstrate safety and efficacy (IOM, 2001e). Individual variations in both physiological BOX 2–4 What Constitutes Clinical Research? Clinical research embraces a continuum of studies involving interaction with patients, diagnostic clinical materials or data, or populations in any of these categories: disease mechanisms; translational research; clinical knowledge, detection, diagnosis, and natural history of disease; therapeutic interventions, including clinical trials; prevention and health promotion; behavioral research; health services research, including outcomes; epidemiology; and community-based and managed care-based research. Source: AAMC, 1999, p. 4.

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Safe Passage: Astronaut Care for Exploration Missions changes and responses make it even more difficult to evaluate results because of the small number of participants (i.e., astronauts). Because of these difficulties, NASA has had to select the most promising clinical intervention for its studies of countermeasures to avoid further dilution of its study group and possible ethical breaches. In addition to this empirical approach, more basic research is sorely needed to define the mechanisms that produce the physiological changes that result from space travel, which, it is hoped, will improve the focus of countermeasure clinical trials. The present set of NASA priorities may account for the limited success of countermeasures to date. This does not imply deficiencies on the part of NASA researchers but recognizes the severe limitations under which they work. Potential methods for improvement in clinical research with small numbers of participants are described in a recent IOM study report, sponsored by NASA, Small Clinical Trials: Issues and Challenges, which reviews study designs and statistical methods for determination of the validities and efficacies of studies with small numbers of participants (IOM, 2001e). NASA’s request for the study is one example of the agency’s attempt to reach out in new directions to better use the limited opportunities during space missions to conduct clinical research with astronauts. Formation of the National Space Biomedical Research Institute and increased collaboration with the National Institutes of Health (e.g., the new initiative with the National Cancer Institute) are additional directions that will provide NASA with wider expertise. It is not clear, however, how well clinical research design, strategies, and so forth fit into these initiatives, as clinical research with astronauts relevant to space medicine beyond Earth orbit, particularly validation of countermeasures, can largely be conducted only during space missions. There does not appear to be a clearly visible and transparent plan of who oversees, designs, reviews, and is responsible for this clinical research. NASA’s organizational charts, lines of authority and responsibility, administration, and budgeting processes and its levels of accountability presented to the committee (in official NASA policy documents and during briefings by NASA officials throughout the committee’s information-gathering process) describe a fragmented, nonuniform process of strategic planning and oversight that is insufficient to provide an effective means of understanding and mitigating the risks to human health from traveling in space. A comprehensive strategic plan for the prevention and amelioration of the many potential risks to well-being during long-duration travel beyond

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Safe Passage: Astronaut Care for Exploration Missions Earth orbit and treatment of the conditions that result from those risks is vital to the future of space medicine. This requires an understanding of the relationship between human physiology and adaptation to space travel. It also requires a broad, evidence-based, collaborative, and coordinated clinical research effort to ensure that NASA has the ability to provide health care commensurate with the expectations of the medical community and society at the time of launch beyond Earth orbit. Some of the clinical research opportunities in space medicine are listed in Box 2–5. CONCLUSION AND RECOMMENDATION Conclusion NASA has devoted insufficient resources to developing and assessing the fundamental clinical information necessary for the safety of humans on long-duration missions beyond Earth orbit. Although humans have flown in space for nearly four decades, a paucity of useful clinical data have been collected and analyzed. The reasons for this include inadequate funding; competing mission priorities; and insufficient attention to research, analysis including insufficient investigator access to data and biological samples, and the scientific method. Although NASA’s current approach to addressing health issues through the use of engineering design and countermeasures has been successful for short-duration missions, deep space is a unique environment that requires a different approach. A major problem of space medicine research is the small number of astronaut research participants, which requires special design and analysis of the data from clinical trials with small numbers of participants. This necessitates a strategy focused on maximizing opportunities for learning. Recommendation NASA should develop a strategic health care research plan designed to increase the knowledge base about the risks to humans and their physiological and psychological adaptations to long-duration space travel; the pathophysiology of changes associated with environmental forces and disease processes in space; prediction, development, and validation of preventive, diagnostic, therapeutic, and rehabilitative

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Safe Passage: Astronaut Care for Exploration Missions BOX 2–5 Clinical Research Opportunities for Astronaut Health Musculoskeletal System Establishing the course of changes in bone mineral density and markers of bone mineral density turnover in serum and urine before, during, and after space travel. Developing a capacity for real-time measurement of bone mineral density and enhanced three-dimensional technology to assess the risk of fracture during space travel. Identifying human phenotypes and genotypes resistant to space travel-induced bone mineral density loss. Tailoring therapeutic interventions (i.e., countermeasures such as diet, exercise, and medications) as a high priority and then validating the promising countermeasures in studies with astronauts during exposure to microgravity. Cardiovascular Considering artificial gravity and pharmacological interventions as solutions to orthostatic hypotension. Gastrointestinal Investigating the relationship between space motion sickness and absent bowel sounds including pharmacological and adaptive countermeasures. Nervous System Building a coordinated clinical research program that addresses the issues of neurological safety and care for astronauts during long-duration space travel. Performing pharmacological trials with dose-response and pharmacokinetic measures to assess the efficacies and toxicities of medications commonly used to treat sleep disturbances during space travel. Considering clinical trials on the use of growth hormone or other countermeasures and developing devices to control spacecraft ambient light and the core temperature at appropriate levels during space travel to reduce sleep disturbances. Reproductive Health Determining whether radiation exposure during space travel causes genetic damage or altered fertility in men and women and, for women, premature ovarian failure. Determining female and male reproductive hormone levels during space travel. Determining the effect of microgravity on menstrual efflux and retrograde menstruation. Physiological Monitoring Collecting clinical data for both men and women when anatomically possible and physiologically sensible for all individuals in the space program and, on a regular basis, subjecting the data to analysis for sex-related differences. Giving priority to high-resolution, high-precision, yet minimally invasive or noninvasive methods for the monitoring of physiological parameters and for imaging of the human body during space travel.

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Safe Passage: Astronaut Care for Exploration Missions measures for pathophysiological changes including those that are associated with aging; and the care of astronauts during space missions. The strategic research plan should be systematic, prospective, comprehensive, periodically reviewed and revised, and transparent to the astronauts, the research community, and the public. It should focus on providing an understanding of basic pathophysiological mechanisms by a systems approach; using the International Space Station as the primary test bed for fundamental and human-based biological and behavioral research; using more extensively analog environments that already exist and that have yet to be developed; using the research strengths of the federal government, universities, and industry, including pharmaceutical, bioengineering, medical device, and biotechnology firms; and developing the health care system for astronauts as a research database.