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13 July 2012 No. 23 Anaesthesia and Spaceflight SM Roberts Commentator: D Naidoo Department of Anaesthetics Moderator: S Tarr CONTENTS INTRODUCTION ................................................................................................... 3 CONTEXT ............................................................................................................. 3 PHYSIOLOGY ...................................................................................................... 5 SURGICAL AND ANAESTHETIC CONCERNS ................................................. 11 CONCLUSION .................................................................................................... 16 APPENDIX .......................................................................................................... 17 REFERENCES.................................................................................................... 19 Page 2 of 19 INTRODUCTION The primary goal of this text is to outline interesting information and published literature on the topic of Anaesthesia and Spaceflight. From a South African perspective, on 25 April 2002, Mark Shuttleworth became the second self-funded space tourist and the first African in space [1], and this year on the 2nd May 2012, Virgin Galactic announced that Virgin Atlantic (Johannesburg) became one of the 140 international space agents to sell commercial space flights in South Africa [2]. It is understandable that a reader could question the relevance of the topic of Anaesthesia and Spaceflight. These reasons include: the absence of a national space program; the likely perception that the practice of anaesthesia in space is futuristic and non-clinical to the majority of anaesthetists in Africa; and that in light of the global financial situation, funding for space programs would likely be reduced. Hopefully, as secondary goals, this text will also reveal that the topic is not so “far-fetched”, that the ongoing contribution to medical knowledge from experiments during spaceflight is significant, that research and development of anaesthesia in this context is important and, lastly, to acknowledge our international colleagues who are demonstrating passion, bravery and intellect for human exploration. CONTEXT The context of the topic of Anaesthesia and Spaceflight first needs to be established. Without an interest in spaceflight, there is little common knowledge of participating countries, the complexities of spaceflight and establishing a space station, current expeditions and experiments, and spaceflight crew structure and training. Probably the most globally known organisation is the National Aeronautics and Space Administration (NASA) in the United States of America. However, currently there are 17 other countries represented by 37 agencies, administrations and organizations (Appendix 1). Facts, figures and quotes below are from the official NASA website [3]. NASA conducts its work through three mission directorates: Aeronautics: which pioneers flight technologies to improve the ability to explore space and have practical applications on earth Human Exploration and Operations: which focuses on the International Space Station (ISS) and human exploration beyond low Earth orbit Science: which explores the Earth, solar system and universe beyond. Page 3 of 19 Even though the NASA space shuttle program has ended, some of the future plans of NASA listed below will require the field of Anaesthesia to continue to provide input into the establishment of medical care in space: NASA is designing and building capabilities to send humans to explore the solar system, working toward a goal of landing humans on Mars. The ISS remains fully staffed with a crew of six, with humans living and working in space 365 days a year. Commercial companies are on their way forward to providing cargo and crew flights to the ISS. NASA is part of the team working on the Next Generation Air Transportation System, to be in place by 2025. As space travel develops into flights of longer duration reaching further locations and possibly even one day habitation on another planet, the need for surgical intervention, anaesthesia and critical care in space is inevitable [4]. NASA expeditions and the ISS will serve as the prototype for spaceflight in this text. Some facts about the ISS are given below, with more in Appendix 2, to get a better idea of what was required to establish it. The ISS marked 10 years of human occupation in 2010. The space station has been visited by 202 individuals. At the time of the anniversary, the station’s odometer read more than 1.5 billion statute miles (the equivalent of eight round trips to the Sun), over the course of 57,361 orbits around the Earth. As of August 2011, there have been 135 launches to the space station since the launch of the first module, Zarya, Nov. 20, 1998: 74 Russian vehicles, 37 space shuttles, two European and two Japanese vehicles. The final space shuttle mission delivered 4 & 1/2 tons of supplies. A total of 161 spacewalks have been conducted in support of space station assembly totaling more than 1,015 hours. The space station, including its large solar arrays, spans the area of a U.S. football field, and weighs 861,804 pounds (390,907 kg), not including visiting vehicles. The complex now has more livable room than a conventional five-bedroom house, and has two bathrooms, a gymnasium and a 360-degree bay window. Research is continually underway aboard the ISS. These can be categorized as: Biology and Biotechnology: study of biological processes in microgravity Earth and Space science: at an average altitude of 400km, details of the Earth’s surface and space can be studied Human research: “The space station is being used to study the risks to human health that are inherent in space exploration. Focal research questions address the mechanisms of the risks and develop test countermeasures to reduce these risks. Page 4 of 19 Research on space station addresses the major risks to human health from residence in a long-duration microgravity environment. Results from this research are key enablers for future long-duration missions beyond low Earth orbit.” [3] Physical sciences: the study of the long term physical effects in the absence of gravity Technology: the study and testing of technologies, materials and systems needed for longer-duration exploration. Some of the current human experiments underway can be seen in at the specific referenced NASA link [5]. Who makes up the six man crew? On the latest expedition, Expedition 31, there is a commander and five flight engineers. The selection criteria to enter astronaut training include: Any adult man or woman Excellent physical health Bachelor’s degree in engineering, science or mathematics from an accredited institution, with three years experience, and an advanced degree is desirable Pilot astronauts need 1000 hours jet aircraft experience and certain vision requirements. There is an average of 4000 applicants for 20 openings every two years. Each crew will include a crew medical officer (CMO) who currently, however, may have no medical background before entering astronaut training [4]. The CMO training thereafter approximates 80 hours only. We can now explore the physiology, surgical and anaesthetic concerns of spaceflight. Most of the text will come from five good review articles [4, 6-9] and Miller’s Anesthesia [10] , which reference much of the current literature. PHYSIOLOGY The phases of spaceflight can be described as Launch, Flight (short or long duration), Landing and the Post flight period. Each phase requires acclimation, which is the acute change in normal physiology by a complex multisystem response to an abnormal environment. Recovery in the post flight period may be longer than the actual mission and some physiological effects like bone demineralization after long-duration flights may be permanent. Countermeasures pre-, intra-, and post-flight can be taken which reduce the health risks to the crew. The fact that spaceflight requires physiologic acclimation centers round the changes in gravity. During launch and landing, gravitational effects on the body increase compared to the gravitational effect on Earth (the crew experience “G forces”), whereas during flight, the body is exposed to microgravity (the literature seems to use the terms “microgravity”,” zero gravity” and “weightlessness” Page 5 of 19 interchangeably). Other factors of the abnormal environment include isolation and confinement which may have psychological and psychosomatic implications. All organ systems can be affected to varying degrees. Table 1 [6] outlines acclimation related to phases of spaceflight and flight duration, and table 2 [6] outlines countermeasures to reduce risk. Table 1: Timeline of physiologic acclimation experienced by astronauts from launch to the post flight period. Page 6 of 19 Table 2: Countermeasures to minimize risk to astronauts Page 7 of 19 Cardiovascular response and shift in body fluids The cardiovascular response to microgravity is complex and there are many published articles studying aspects of the physiology. Models have been developed based on studies in real and simulated microgravity which show the immediate and delayed changes in intravascular volume, neurohumeral responses and cardiovascular reflexes, vascular tone, water and electrolyte composition, circadian rhythm and muscle mass. One such model is shown in figure 1 [7] and outlines many of the major components of the cardiovascular acclimation to microgravity. Figure 1: Suggested cardiovascular response to weightlessness The primary cause of the acclimation is the redistribution of body fluids, with an increase in the central blood volume as the blood and tissue fluid accumulates in the torso and head from the lower legs (“Puffy face-bird leg” syndrome), with resultant neurohumeral responses. Prior to launch, the astronauts are in a supine position with the legs elevated, initiating the redistribution of body fluid. During Launch, the body is exposed to an increase in G force due to the Earth’s gravity and the speed of ascent (typically 34G), which likely would contribute to this redistribution. Page 8 of 19 Once in space, the microgravity environment and loss of a hydrostatic gradient in the cardiovascular system maintain this increase in central blood volume. The increase in central blood volume leads to a baroreceptor response inhibiting the renin-angiotensin-aldosterone system and the release of atrial natriuretic peptide. Thus there is increased renal excretion of salt and water, and a reduction in plasma volume of approx 17% by 24 hours. With this reduction in plasma volume is a transient increase in the haematocrit, leading to a decrease in erythropoeitin secretion, a reduction in red cell mass and a net overall reduction of approximately 10% in total blood volume. Aerobic capacity with the reduced total blood volume can be maintained in the microgravity environment in space. However, in the presence of this reduced total blood volume (with a central distribution), combined with altered cardiovascular receptor responses (e.g. enhanced eNOS expression, down regulation of alphaadrenergic receptors) and reduced myocardial and somatic muscle mass after long-duration flights, astronauts face an orthostatic stress on landing and in the post flight period. On landing, the G forces experienced are increased (typically 1.5-4G). In the post flight period, astronauts typically experience some degree of orthostatic hypotension (with its associated symptoms of light-headedness, syncope, palpitations, sweating and nausea vomiting) and 1 out of 4 astronauts cannot stand quietly for 10 continuous minutes on the first day of landing without symptoms. Countermeasures to cope with the cardiovascular acclimation are being developed and include exercise, pressure suits (negative and positive pressure for different phases of spaceflight), fluid therapy, positioning during phases of travel and drug therapy (alpha-1 agonist midodrine [11], as shown in Table 2). Respiratory Cabin pressure in the ISS is 760mmHg. However, when the astronauts venture out of the pressurized cabin (extravehicular activity (EVA) or “spacewalks”), not only is acclimation required for the microgravity, but the space suit pressure is only 222mmHg, which is similar to the ambient pressure at the top of Mount Everest at 8 848m (Figure 2 [10]). This results in a decreased alveolar partial pressure of oxygen and hypoxia is prevented by the astronauts breathing 100% oxygen. The astronauts are at risk of decompression sickness (the formation of gas bubbles in tissue and blood), and possibly features of acute mountain sickness, high-altitude cerebral oedema, and high-altitude pulmonary oedema. Page 9 of 19 Figure 2: Ambient pressure as a function of altitude and depth. Note the NASA space suit pressure in the left graph. AMS-acute mountain sickness, HAPE- high altitude pulmonary edema, HACE- high altitude cerebral edema. Space motion sickness Space motion sickness is a syndrome of facial pallor, cold sweating, stomach awareness, nausea and in some cases vomiting. It represents neurovestibular acclimation to the first 48hours in space and again on landing and the first 48hours in the Post flight period. The physiological components include visual and vestibular perception discordance in the three dimension space environment as well as body fluid redistribution affecting gastrointestinal afferents and intracranial hypertension. This important syndrome may impact on crew performance, particularly during landing. Countermeasures include neurovestibular preconditioning and medications as in table 2. Muscle atrophy The loss of gravitational loading, suboptimal nutrition and stressful working conditions contribute to the known loss of muscle mass, in particular of the postural muscles. The amount of loss is related to the duration of flight, with up to 30% muscle loss on missions of 3-6 months duration. Studies have looked at muscle fibre number, fibre size and fibre types that are affected. With the loss of muscle mass, there is loss of muscle strength, fatigueability, loss of explosive contractile force and various other changes in motor unit recruitment and the contractile apparatus. In the post flight period, astronauts can report muscle pain, plantar fasciitis and tight hamstrings and calves. Page 10 of 19 Countermeasures hinge around exercise programs and most astronauts fully recover within 2 months after landing. Bone demineralization During spaceflight, the absence of gravitational loading on bones is absent which leads to bone reabsorption and loss of bone density (osteoporosis). The lower levels of light (leading to vitamin D deficiency) and higher ambient carbon dioxide levels (with a respiratory acidosis) may contribute. The rate of decline in bone density is approximately 1-2% per month in microgravity in weight bearing bones. There is marked inter individual variation. There is marked (60-70%) increases in urinary and faecal calcium. Countermeasures include peri-flight bone density assessments, exercise programs, nutrition and the restriction of high fracture-risk activities in the recovery period, but the focus is on prevention of bone loss during flight. Recovery can take up to three years, but in some may not be complete and the remodelled bone may not have the same structure or mineralization. Psychosocial and Immune function There is much literature on the psychosocial effects and changes in immune function with spaceflight. Suffice to say, there are highly detailed processes for selection and training of the crew members with numerous support measures in place and being developed to optimize crew psychosocial stability and performance. Immune suppression occurs during spaceflight and in the recovery period with impaired cellular immunity, and reactivation of latent herpes virus. Numerous components of the immune system have been studied showing global dysregulation. The pathophysiology is complex including the effects of psychological and physical stress, nutrition changes, changes in circadian rhythm, neurohumeral (especially glucocorticoid and catecholamine) changes for microgravity acclimation, and confinement. SURGICAL AND ANAESTHETIC CONCERNS As yet, a surgical procedure has not been performed on a human in space and clinical experience is very limited. Currently on the ISS, there is an Advanced Cardiac Life Support (ACLS) pack and an Advanced Trauma Life Support (ATLS) pack, allowing ventilation and defibrillation. There is also a Shuttle Orbital Medical System Pack, with components of a minor surgical kit for lacerations. These include local anaesthetics as well as minimal-skill laceration closure techniques (e.g. steri-strips, dermabond adhesive). The capability to perform major surgery on the ISS is currently not available. The current approach would be to stabilize as far as possible and return to earth for definitive care. Page 11 of 19 The time to definitive care on the ISS is 6 to 24 hours making use of a medical evacuation spacecraft (the Crew Return Vehicle). On earth, even though a certain surgical procedure may be considered simple, we know that the provision of safe general or regional anaesthesia and critical care can be complex. This is even more so when one wonders how to provide anaesthetic care in space due to the physiological and technical challenges related to spaceflight. Studies are being done in simulated environments (like water immersion and parabolic flight), however these simulations have short comings and the best information will come from studies in actual spaceflight. Even though, through the rigorous crew selection process, the persons involved in spaceflight are in excellent physical condition, a pattern of disease can be predicted during spaceflight which may require medical care involving anaesthesia. Principally mentioned in the literature are urological procedures (to manage nephrolithiasis due to altered calcium metabolism) and trauma. However, using analog environments (such as submarine cruises) to extrapolate to spaceflight, a wide spectrum of disease could occur. As mentioned previously, with the goal of longer duration and further location spaceflights, it is safe to assume that the medical care in general, and anaesthetic capabilities in particular, would have to be able to manage a wide range of disease and injuries in the future. Technical challenges There are many technical challenges to the provision of medical care and anaesthesia in spaceflight. These relate to the limited space, closed environment, cost, available equipment and stock, information technology and backup, CMO skills, and the microgravity environment. The station or shuttle is a tightly closed environment, sealed off from the outside for obvious reasons. However, this requires a tightly controlled and unpolluted cabin atmosphere. Drugs used must not contaminate the atmosphere or the water systems. Flushed oxygen may increase the fire hazard in the cabin. The safe use of volatile anaesthesia would be difficult. The choice of equipment, drugs, disposable vs. reusable stock, fluids, blood products, item shelf life, cold chain storage, etc. requires careful planning, and cost-benefit analyses will be complex. It approximately costs US$22 000 to take 1kg material (e.g. a vacolitre) into orbit. Storage restrictions are significant. As discussed previously, the single CMO is generally not from a medical background, has limited hours of medical training during the astronaut training program and would not have the necessary skills for major surgery or anaesthesia. Crew composition would need to include two CMO’s with the appropriate surgical and anaesthetic skills to perform surgery in space. Page 12 of 19 Some studies have looked at telemedicine support and remotely guided diagnostic ultrasound. Robotic surgery with the operators on earth has been considered, but with current technology, even robotic surgery performed on earth with the robot and operator at different locations has limitations with the system time delay. These advanced remote-support possibilities as well as on-board information systems would need further investigation. Microgravity has many implications for the functioning of a “theatre environment”: o The need for restraint: The patient, operating staff and equipment needs restraint in microgravity otherwise physical actions are made more difficult and awkward. Currently on the ISS, is a Crew Medical Restraint System at the level of the floor. Careful planning is needed to have all necessary equipment within arm’s length of the restrained operators. Sharp objects can be inserted into a Styrofoam block to prevent them floating around the surgical area until they can be stored safely. Securing an airway has been described using a technique to restrain the operator and mannequin, and a technique with the CMO stabilizing a free floating mannequin’s head between one’s knees (Figure 3. [10]) o Cleaning, draping and preventing contamination: Investigators propose a closed system around the surgical site to manage the dual issues of maintaining sterility and preventing contamination of the ambient environment with blood, pus and/or tissue particles. A canopy prototype is depicted in Figure 4 [8] which has a patient interface and ports through which the operators arms can protrude to operate. o Fluid and vaporizer management: There is no separation of gases and fluids due to different densities in microgravity, with the absence of airfluid levels and fluids being similar to a foam with numerous air bubbles (Figure 5 [4]). This makes administering IV fluids, drawing up IV drugs, providing total intravenous anaesthesia and managing intercostals drains extremely difficult. Conventional volatile anaesthetic vaporizers do not function in microgravity as they depend on the gravity-induced separation of gases and liquids. New devices would need to be developed to deal with these challenges. Page 13 of 19 Figure 3: Tracheal intubation in microgravity stabilizing a mannequin’s head between one’s knees. Figure 4: A surgical containment canopywith ports for the operators arms. Page 14 of 19 Figure 5: A bag of normal saline in orbital flight with numerous gas bubbles. Physiological challenges An outline of the physiological changes of acclimation to spaceflight was given in the previous sections. One can accept that these changes need to be taken into account for the provision of anaesthesia during flight or in the post flight period, in particular the cardiovascular changes. In one animal experiment (Bion 11 mission) described in Miller’s Anesthesia [10]and Norfleet’s review article [4], two primates were administered general anaesthesia (ketamine, isoflurane) within 24 hours after landing, having spent 14 days in space, by competent veterinary anaesthetists for minor surgical procedures such as muscle biopsies. One animal aspirated during emergence and could not be resuscitated and the other developed lethargy and facial oedema in recovery 3 hours later. Anaesthetic techniques cannot be assumed to be safe in humans during flight or in the postflight period, and the physiological challenges to the provision of anaesthesia are mentioned below: Airway: The majority of crew members will experience space motion sickness in flight and the post flight period. An increased risk of gastrooesophageal reflux with reduced gastric motility has been shown in space motion sickness, possibly placing the crew member at an increased risk of aspiration on induction and awakening from general anaesthesia. Not only is a crew member at a possible increased risk of aspiration, but due to the body fluid redistribution in microgravity, they may be at risk of difficult bag mask ventilation, laryngoscopy or rescue airway placement due to facial and airway tissue oedema. Page 15 of 19 The laryngeal mask airway (LMA), intubating LMA, combitube and cuffed endotracheal tubes have been successfully placed in simulated microgravity. Hypovolaemia and autonomic dysfunction: The cardiovascular acclimation to microgravity results in hypovolaemia and adrenergic hyporesponsiveness, particularly in the post flight period resulting in orthostatic intolerance. This has many implications for the provision of anaesthesia, both regional and general, in flight or in the post flight period. Similarly, the resuscitation and transfer of a cardiovascularly unstable trauma or medical patient for definitive care is made even more difficult due to the compound effects of the baseline hypovolaemia and autonomic dysfunction, the new pathology, as well as the increased gravitational forces on landing. The cardiovascular status (a 10% reduction in total blood volume) of an uninjured crew member is similar to a Class 1 haemorrhage. After trauma and during landing, a true class 1 haemorrhage may in fact behave as a Class 2 or 3 haemorrhage. Neuromuscular physiology: Long duration flights theoretically induce similar receptor changes at the neuromuscular junction as prolonged bedrest. The will have implications for the use of suxamethonium and a hyperkalaemic response as well as the duration of action of non-depolarising neuromuscular blocking agents and further studies are needed. Electrolyte changes: Reductions in serum potassium and magnesium, as well as other electrolytes, may place patients at risk of arrhythmias. Anaesthetic agents: Little is known about the pharmacokinetics and pharmacodynamics of intravenous and volatile anaesthetic agents and other medications in microgravity as yet. Animal experiments are underway, and total intravenous anaesthesia may hold promise for performing general anaesthesia in space [12]. A more detailed discussion on the theoretical choice between regional versus general anaesthesia in space is covered in an good article by Silverman and McCartney [9]. CONCLUSION The ongoing existence of the ISS and plans by NASA and other international space agencies to pursue longer duration spaceflight and even habitation on other planets, will require the ability to provide medical and surgical care for a wider variety and greater severity of pathologies. There will be many challenges in achieving this and, even though there is already some guiding literature, further studies in microgravity and the development of new technologies and devices will be needed to make the provision of general and regional anaesthesia safe. Page 16 of 19 APPENDIX Appendix 1: International organizations [3]. space agencies, administrations ARGENTINA National Commission on Space Activities (CONAE) AUSTRALIA Commonwealth Scientific Industrial Research Organization (CSIRO) BRAZIL Instituto Nacional de Pesquisas Espaciais (National Institute for Space Research) (INPE) CANADA Canadian Space Agency FRANCE Centre National d'Etudes Spatiales (CNES) Office National d'Études et de Recherches Aérospatiales (ONERA/CERT) French Ministry of Research GERMANY German Aerospace Center (DLR) Max Planck Institutes GFZ INTERNATIONAL ORGANIZATIONS International Telecommunications Satellite Organization (INTELSAT) International Maritime Satellite Organization (INMARSAT) European Telecommunications Satellite Organisation (EUTELSAT) North Atlantic Treaty Organization (NATO) NATO / Research and Technology Organization International Standards Organization (ISO) Organization for Economic Cooperation and Development (OECD) United Nations Office for Outer Space Affairs ITALY Italian Space Agency (ASI) JAPAN Institute of Space and Astronautical Science (ISAS) Japan Aerospace Exploration Agency (JAXA) Ministry of International Trade and Industry (MITI) Electrotechnical Laboratory (ETL) Ministry of Education, Culture, Sports, Science and Technology Japanese Patent Office THE NETHERLANDS The Netherlands Agency for Aerospace Programmes (NIVR) Space Research Organization Netherlands RUSSIAN FEDERATION Russian Space Science Internet Russian Academy of Sciences (RAS) Space Research Institute (IKI) SOUTH KOREA Ministry of Science and Technology (MOST) Korean Aerospace Research Institute (KARI) NORWAY Norwegian Space Centre SPAIN Instituto Nacional de Técnica Aeroespacial (INTA) SWEDEN Swedish Space Corporation TAIWAN National Space Program Office of Taiwan UNITED KINGDOM British National Space Centre (BNSC) Page 17 of 19 and Appendix 2: More facts about the International Space Station [3]. Size & Mass: Module Length: 167.3 feet (51 meters) Truss Length: 357.5 feet (109 meters) Solar Array Length: 239.4 feet (73 meters) Mass: 861,804 lb (390,908 kilograms) Habitable Volume: 13,696 cubic feet (388 cubic meters) Pressurized Volume: 32,333 cubic feet (916 cubic meters) Power Generation: 8 solar arrays = 84 kilowatts Lines of Computer Code: approximately 2.3 million Other facts: The ISS solar array surface area could cover the U.S. Senate Chamber three times over. ISS eventually will be larger than a five-bedroom house. ISS will have an internal pressurized volume of 33,023 cubic feet, or equal that of a Boeing 747. The solar array wingspan (240 ft) is longer than that of a Boeing 777 200/300 model, which is 212 ft. Fifty-two computers will control the systems on the ISS. More than 115 space flights will have been conducted on five different types of launch vehicles over the course of the station’s construction. More than 100 telephone-booth sized rack facilities can be in the ISS for operating the spacecraft systems and research experiments The ISS is almost four times as large as the Russian space station Mir, and about five times as large as the U.S. Skylab. The ISS will weigh almost one million pounds (925,627 lbs). That’s the equivalent of more than 320 automobiles. The ISS measures 357 feet end-to-end. That’s equivalent to the length of a football field including the end zones (well, almost – a football field is 360 feet). 3.3 million lines of software code on the ground supports 1.8 million lines of flight software code. 8 miles of wire connects the electrical power system. In the International Space Station’s U.S. segment alone, 1.5 million lines of flight software code will run on 44 computers communicating via 100 data networks transferring 400,000 signals (e.g. pressure or temperature measurements, valve positions, etc.). The ISS will manage 20 times as many signals as the Space Shuttle. Main U.S. control computers have 1.5 gigabytes of total main hard drive storage in U.S. segment compared to modern PCs, which have ~500 gigabyte hard drives. The entire 55-foot robot arm assembly is capable of lifting 220,000 pounds, which is the weight of a Space Shuttle orbiter. The 75 to 90 kilowatts of power for the ISS is supplied by an acre of solar panels. Page 18 of 19 REFERENCES 1. http://en.wikipedia.org/wiki/Mark_Shuttleworth. 2. http://www.timeslive.co.za/scitech/2012/05/02/virgin-appoints-south-africanspace-flight-agent. 3. http://www.nasa.gov/. 4. Norfleet, W.T., Anesthetic concerns of spaceflight. Anesthesiology, 2000. 92(5): p. 1219-22. 5.khttp://www.nasa.gov/mission_pages/station/research/experiments/experiment shardware.html#Human-Research. 6. Williams, D., et al., Acclimation during space flight: effects on human physiology. CMAJ, 2009. 180(13): p. 1317-23. 7. Pavy-Le Traon, A., et al., From space to Earth: advances in human physiology from 20 years of bed rest studies (1986-2006). Eur J Appl Physiol, 2007. 101(2): p. 143-94. 8. Campbell, M.R., A review of surgical care in space. J Am Coll Surg, 2002. 194(6): p. 802-12. 9. Silverman, G.L. and C.J. McCartney, Regional anesthesia for the management of limb injuries in space. Aviat Space Environ Med, 2008. 79(6): p. 620-5. 10. Miller's Anesthesia. 7 ed. Vol. 2. 2010. 11. Ramsdell, C.D., et al., Midodrine prevents orthostatic intolerance associated with simulated spaceflight. J Appl Physiol, 2001. 90(6): p. 2245-8. 12. Chad G. Ball, M.A.K., Rosaleen Chun, Michelle Groleau, MichelleTyssen, Jennifer Keyte, Timothy J. Broderick, Andrew W. Kirkpatrick, Anesthesia and critical-care delivery in weightlessness. Planetary and Space Science, 2010. 58(4): p. 732-740. Page 19 of 19