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NASA NTRS1992

Oxygen transport and cardiovascular function at extreme altitude: lessons from Operation Everest II

Operation Everest II was designed to examine the physiological responses to gradual decompression simulating an ascent of Mt Everest (8,848 m) to an inspired PO2 of 43 mmHg. The principal studies conducted were cardiovascular, respiratory, muscular-skeletal and metabolic responses to exercise. Eight healthy males aged 21-31 years began the "ascent" and six successfully reached the "summit", where their resting arterial blood gases were PO2 = 30 mmHg and PCO2 = 11 mmHg, pH = 7.56. Their maximal oxygen uptake decreased from 3.98 +/- 0.2 L/min at sea level to 1.17 +/- 0.08 L/min at PIO2 43 mmHg. The principal factors responsible for oxygen transport from the atmosphere to tissues were (1) Alveolar ventilation--a four fold increase. (2) Diffusion from the alveolus to end capillary blood--unchanged. (3) Cardiac function (assessed by hemodynamics, echocardiography and electrocardiography)--normal--although maximum cardiac output and heart rate were reduced. (4) Oxygen extraction--maximal with PvO2 14.8 +/- 1 mmHg. With increasing altitude maximal blood and muscle lactate progressively declined although at any submaximal intensity blood and muscle lactate was higher at higher altitudes.

Non-NASA Center↗
NASA NTRS1992

The effects of 7.5% NaCl/6% dextran 70 on coagulation and platelet aggregation in humans

The combination solution of 7.5% NaCl/6% dextran 70 (HSD) administered IV gives hemodynamic improvement in the treatment of hemorrhagic hypotension. Since earlier dextran solutions were reported to interfere with blood coagulation, the effects of HSD on the prothrombin time (PT), the activated partial thromboplastin time (APTT), platelet aggregation, and platelet concentration were studied. The HSD mixed with human plasma (1:5 and 1:10) slightly prolonged PT, but had no effect on the APTT, compared with saline controls. The HSD also decreased human platelet aggregation at the 1:5 dilution. In separate mixing studies, the hypertonic saline component of HSD was associated with the prolongation of PT and decreased platelet aggregation. The data from these studies indicate that at its proposed therapeutic dose, HSD is expected to have minimal effect on blood coagulation.

NASA Center ARC↗
NASA NTRS2004

Strategies for Small Volume Resuscitation: Hyperosmotic-Hyperoncotic Solutions, Hemoglobin Based Oxygen Carriers and Closed-Loop Resuscitation

Introduction: Logistic constraints on combat casualty care preclude traditional resuscitation strategies which can require volumes and weights 3 fold or greater than hemorrhaged volume. We present a review of quantitative analyses of clinical and animal data on small volume strategies using 1) hypertonic-hyperosmotic solutions (HHS); 2) hemoglobin based oxygen carriers (HBOCs) and 3) closed-loop infusion regimens.Methods and Results: Literature searches and recent queries to industry and academic researchers have allowed us to evaluate the record of 81 human HHS studies (12 trauma trials), 19 human HBOCs studies (3trauma trials) and two clinical studies of closed-loop resuscitation.There are several hundreds animal studies and at least 82 clinical trials and reports evaluating small volume7.2%-7.5% hypertonic saline (HS) most often combined with colloids, e.g., dextran (HSD) or hetastarch(HSS). HSD and HSS data has been published for 1,108 and 392 patients, respectively. Human studies have documented volume sparing and hemodynamic improvements. Meta-analyses suggest improved survival for hypotensive trauma patients treated with HSD with significant reductions in mortality found for patients with blood pressure < 70 mmHg, head trauma, and penetrating injury requiring surgery. HSD and HSS have received regulatory approval in 14 and 3 countries, respectively, with 81,000+ units sold. The primary reported use was head injury and trauma resuscitation. Complications and reported adverse events are surprisingly rare and not significantly different from other solutions.HBOCs are potent volume expanders in addition to oxygen carriers with volume expansion greater than standard colloids. Several investigators have evaluated small volume hyperoncotic HBOCs or HS-HBOC formulations for hypotensive and normotensive resuscitation in animals. A consistent finding in resuscitation with HBOCs is depressed cardiac output. There is some evidence that HBOCs more efficiently unload oxygen from plasma hemoglobin as well as facilitate RBC unloading. We analyzed one volunteer study, 15 intraoperative trials, and 3 trauma studies using HBOCs. Perioperative studies generally suggest ability to deliver oxygen, but one trauma trial using HBOCs (HemAssist) for treatment of trauma resulted in a dramatic increase in mortality, while an intraoperative trauma study using Polyheme demonstrated reductions in blood use and lower mortality compared to historic controls of patients refusing blood. Transfusion reductions with HBOC use have been modest. Two HBOCs (Hemopure and Polyheme) are now in new or planned large-scale multicenter prehospital trials of trauma treatment. A new implementation of small volume resuscitation is closed-loop resuscitation (CLR), which employs microprocessors to titrate just enough fluid to reach a physiologic target . Animal studies suggest less risk of rebleeding in uncontrolled hemorrhage and a reduction in fluid needs with CLR. The first clinical application of CLR was treatment of burn shock and the US Army. Conclusions: Independently sponsored civilian trauma trials and clinical evaluations in operational combat conditions of different small volume strategies are warranted.

Kramer, George C.↗
NASA NTRS2003

Growth and Remodeling in Blood Vessels Studied In Vivo With Fractal Analysis

Every cell in the human body must reside in close proximity to a blood vessel (within approximately 200 mm) because blood vessels provide the oxygen, metabolite, and fluid exchanges required for cellular existence. The growth and remodeling of blood vessels are required to support the normal physiology of embryonic development, reproductive biology, wound healing and adaptive remodeling to exercise, as well as abnormal tissue change in diseases such as cancer, diabetes, and coronary heart disease. Cardiovascular and hemodynamic (blood flow dynamics) alterations experienced by astronauts during long-term spaceflight, including orthostatic intolerance, fluid shifts in the body, and reduced numbers of red (erythrocyte) and white (immune) blood cells, are identified as risk factors of very high priority in the NASA task force report on risk reduction for human spaceflight, the "Critical Path Roadmap."

Parsons-Wingerter, Patricia A.↗
NASA NTRS2004

PIV Investigations of the Flow Field in the Volute of a Rotary Blood Pump

A full-size acrylic model of a rotary blood pump was developed in order to utilize Particle Image Velocimetry (PIV) to make measurements of the fluid velocities and turbulent stresses throughout the device. The development of an understanding of the hemodynamics within the blood pump is critical to the development and validation of computational models. A blood analog solution, consisting of sodium iodide solution and glycerin, was developed to match physiological kinematic viscosity. The refractive indices of the fluid, the pump casing, and the impeller were matched to facilitate the use of PIV to make velocity measurements. Velocity measurements made in the volute exit/diffuser region are presented for pumps speeds of 3000-3850 rpm. At each speed data were obtained at a physiological pressure of 12 kPa and at a maximum flow condition. Four hundred data pairs were used for each resultant mean velocity vector value, representing greater than an order of magnitude more data pairs than reported previously in the literature on similar devices and resulting in velocity uncertainty levels of approximately 22.9%.

Sankovic, John M.↗
NASA NTRS2007

Midodrine as a Countermeasure for Post-spaceflight Orthostatic Hypotension

Up to 30 % of astronauts exhibit post-spaceflight orthostatic hypotension due to inadequate norepinephrine release during upright posture following short duration spaceflight. We hypothesize that the (alpha)1-adrenergic agonist midodrine will be an effective countermeasure. This study is being conducted in 2 phases. The first phase is complete and consisted testing six short duration crew members. All of these subjects participated in preflight and postflight tilt testing on a control flight as well as on the test flights, where midodrine was administered after landing, 1 hour before testing. Hemodynamic variables were compared between the 2 flights. Midodrine improved stroke volume, cardiac output, systolic pressure and heart rate, without increasing vascular resistance. None of these subjects experienced orthostatic hypotension on landing day. Phase II is similar to phase I, except that midodrine is ingested in flight (near TIG) and the tilt test is performed immediately after landing on the CTV. One crewmember has completed phase II testing. This crewmember had no evidence of orthostatic hypotension or presyncope, four additional crewmembers have volunteered for this study. To date, midodrine has been shown to be a safe and effective countermeasure to post-spaceflight orthostatic hypotension.

Platts, Steven H.↗
NASA NTRS2007

Hypovolemia Induced Orthostatic Hypotension in Presyncopal Astronauts and Normal Subjects Relates to Hypo-Sympathetic Responsiveness

Circulating blood volume is reduced during spaceflight, leaving astronauts hemodynamically compromised after landing. Because of this hypovolemia, crew members are able to withstand a postflight 10 minute upright tilt test only if they are able to mount a hyper-sympathetic response. Previous work from this laboratory has shown that about 30% of astronauts, primarily female, have postflight sympathetic responses to tilt that are equal to or less than their preflight responses and thus, they become presyncopal. Part of the mission of the cardiovascular lab at the Johnson Space Center is to identify susceptible crewmembers before flight so that individualized countermeasures can be prescribed. The goal of this study was to develop a ground based model of hypovolemia that could be used for this purpose We tested the hypothesis that hypovolemia alone, in the absence of spaceflight, would reproduce the landing day rate of presyncope during upright tilt in normal volunteers. Further, we hypothesized that, during hypovolemia, subjects who had sympathetic responses that were equal to or less than their normovolemic responses would become presyncopal during upright tilt tests. We studied 20 subjects, 13 male and 7 female, on two separate occasions: during normovolemia and hypovolemia. We induced hypovolemia with intravenous furosemide 40 hours prior to the experiment day, followed by a 10MEq Na diet. On the normovolemia and hypovolemia test days, plasma volume, tilt tolerance and supine and standing arterial pressure, heart rate and plasma norepinephrine levels were measured. A two factor, repeated measures analysis of variance was performed to examine the differences between group (presyncopal vs. non-presyncopal) and day (normovolemia vs. hypovolemia) effects. There were no differences in baseline arterial pressure between normovolemia and hypovolemia or between presyncopal and non-presyncopal groups, but heart rates were higher with hypovolemia in both groups (presyncopal: 70 5 bpm vs. 63 3 bpm, P = 0.003, non-presyncopal: 59 2 bpm vs. 52 2 bpm, P = 0.003). Similar to patterns reported after flight, non-presyncopal subjects had greater norepinephrine responses to tilt during hypovolemia compared to normovolemia (580 79 vs. 298 37 pg/ml, P < 0.05), but presyncopal subjects did not (180 44 vs. 145 32 pg/ml, P = NS). This new model has the potential to accelerate the development of countermeasures and save flight resources. It can be used to identify astronauts who will become presyncopal on landing day, so that prospective, individualized countermeasures can be developed. In addition, it can also be used to screen candidate countermeasures prior to requests for bed rest or inflight resources.

Meck, Janice V.↗
NASA NTRS2006

Hypovolemia Induced Orthostatic Hypotension in Presyncopal Astronauts and Normal Subjects Related to Hypoadrenergic Responsiveness

Circulating blood volume is reduced during spaceflight, making astronauts hemodynamically compromised. After landing, astronauts separate into two groups. One group compensates for the hypovolemia with a hyper-sympathetic response during upright tilt testing and can complete a tilt test with few symptoms. The other group is unable to mount a hyper-sympathetic response and experiences orthostatic hypotension and presyncope during upright tilt tests. We tested the hypothesis that hypovolemia alone, in the absence of spaceflight, also would cause subjects to separate into presyncopal and non-presyncopal groups according to their sympathetic responses during tilt. We studied 20 subjects, including 10 veteran astronauts, on three occasions. On Days 1 (normovolemia) and 3 (hypovolemia), plasma volume, tilt tolerance and supine and standing plasma norepinephrine levels were measured. Forty hours prior to Day 3, subjects were given intravenous furosemide, followed by 36 hours of a 10MEq Na diet. Statistical comparisons were made between normovolemia and hypovolemia responses. This protocol reproduced landing day tilt test outcomes with 100% fidelity in the astronauts. Similarly to patterns reported after flight, non-presyncopal subjects had greater norepinephrine responses to tilt during hypovolemia compared to normovolemia (580 plus or minus 79 vs. 298 plus or minus 37 pg/ml, P less than 0.05), but presyncopal subjects had no increase (180 plus or minus 44 vs. 145 plus or minus 32 pg/ml, P=NS). This model can be used to predict astronauts who will become presyncopal on landing day, so that prospective, individualized countermeasures can be developed. Within patient populations, it can be used to study the interaction of volemic state and the sympathetic nervous system.

Meck, Janice V.↗
NASA NTRS2008

Graded Compression Stockings Prevent Post-spaceflight Orthostatic Hypotension

Post-spaceflight orthostatic intolerance is characterized by hypotension and presyncope in 20-30% of returning astronauts. Previous data from our laboratory suggests that this is largely a result of decreased venous return. Currently, NASA astronauts wear an anti-gravity suit (AGS) which consists of inflatable air bladders over the calves, thighs and abdomen, which are typically pressurized from 0.5 to 1.5 PSI (~27 to 78 mmHg). ISS crew members sometimes wear Russian Kentavr suits which consist of laced compression shorts and gaiters, providing ~30 mmHg nominally. While these garments are effective during reentry, there are a number of drawbacks that make them impractical for postflight use. We studied the ability of commercially available, custom fit, graded compression stockings (Jobst, 55 mmHg at ankle to 6 mmHg at top of thigh, 25 mmHg mean compression) to prevent postflight orthostatic intolerance, hypothesizing that these garments would prevent orthostatic intolerance following short duration space flight. Crew members from a single Space Shuttle flight were tilted to 80 degrees for 10 min while wearing the stockings (n=5 males) upon arrival at the clinic (~2 hrs after landing). Hemodynamic data were compared to data from all crewmembers tilted (without countermeasures) since return to flight (n=9). Two-way, repeated measures ANOVA, using the entire tilt time curve (0-10 min) show that systolic blood pressure (SBP, group effect p=0.008), stroke volume (SV, group effect p=0.003), and cardiac output (CO, group effect p=0.004) were higher in crewmembers who wore the Jobst stockings. A one-way ANOVA comparing the last minute standing also showed that SV (p=0.001) and CO (p less than 0.001) were higher and SBP tended to be higher (p=0.06) in Jobst subjects compared to controls. Control subjects had a higher rate of presyncope than Jobst subjects (3/9 vs 0/5) during the tilt on landing day. Orthostatic hypotension continues to present following spaceflight, despite fluid loading and other countermeasures. This preliminary study shows that commercially available compression stockings may ameliorate this problem. These stockings are readily available, inexpensive, and can be worn for days following landing. We have observed similar protection against orthostatic intolerance in ground-based studies of hypovolemic test subjects. Further refinements to the design and compression of the stockings are in progress.

Platts, S. H.↗
NASA NTRS2009

Right Ventricular Tissue Doppler Assessment in Space During Circulating Volume Modification using the Braslet-M Device

This joint U.S. - Russian work aims to establish a methodology for assessing cardiac function in microgravity in association with manipulation of central circulating volume. Russian Braslet-M occlusion cuffs were used to temporarily increase the volume of blood in the lower extremities, which effectively reduces the volume returning to the heart in the central circulation. A novel methodology was tested on the International Space Station (ISS) to assess the volume status of crewmembers by evaluating the responses to application and release of the Braslet-on-occlusion cuffs, as well as to modified Valsalva and Mueller maneuvers. Baseline echocardiographic tissue Doppler imaging (TDI) of the right ventricular free wall with no Braslet applied shows early diastolic E' (16 cm/sec), late diastolic A' (14 cm/sec), and systolic (12 cm/sec) velocities compatible with normal subjects on Earth. TDI of the RV free wall with Braslet applied shows that early diastolic E' decreased by 50% (8 cm/sec), late diastolic A' increased by 45%, and systolic S' remains unchanged. TDI of the RV free wall approximately 8 beats after the Braslet was released shows early diastolic E' (8 cm/sec), late diastolic A' (12 cm/sec), and systolic S' (13 cm/sec) velocities. During this portion of the release, early diastolic E' did not recover to baseline values but late diastolic A' and systolic S' recovered to pre-Braslet values. The pre-systolic cross-sectional area of the internal jugular vein with Braslet off was 1.07 cm(sup 2) and 1.13 cm(sup 2) 10 min after the Braslet was applied. The presystolic cross-sectional area of the common femoral vein with Braslet off was 0.50 cm(sup 2), and was 0.54 cm(sup 2) 10 min after the Braslet was applied. The right ventricular myocardial performance Tei index also was calculated for comparison with typical values found in healthy subjects on Earth. Baseline and Braslet-on values for Tei index were 0.25 and 0.22 respectively. Braslet Tei indices are within normal ranges found in healthy subjects and temporarily become greater than 0.4 during the dynamic Braslet release portion of this study. Tissue Doppler imaging of the right ventricle revealed that the Braslet influenced cardiac preload and that fluid was sequestered in the lower-extremity interstitial and vascular space after only 10 minutes of application. This report demonstrates that Braslet application affects right ventricular physiology in long-duration space flight based on TDI and that this effect is in part due to venous hemodynamics.

Hamilton, D. R.↗
NASA NTRS2010

Validation of On-Orbit Methodology for the Assessment of Cardiac Function and Changes in the Circulating Volume Using Ultrasound and Braslet-M Occlusion Cuffs

The objective of this joint U.S. - Russian project was the development and validation of an in-flight methodology to assess a number of cardiac and vascular parameters associated with circulating volume and its manipulation in long-duration space flight. Responses to modified Valsalva and Mueller maneuvers were measured by cardiac and vascular ultrasound (US) before, during, and after temporary volume reduction by means of Braslet-M thigh occlusion cuffs (Russia). Materials and Methods: The study protocol was conducted in 14 sessions on 9 ISS crewmembers, with an average exposure to microgravity of 122 days. Baseline cardiovascular measurements were taken by echocardiography in multiple modes (including tissue Doppler of both ventricles) and femoral and jugular vein imaging on the International Space Station (ISS). The Braslet devices were then applied and measurements were repeated after >10 minutes. The cuffs were then released and the hemodynamic recovery process was monitored. Modified Valsalva and Mueller maneuvers were used throughout the protocol. All US data were acquired by the HDI-5000 ultrasound system aboard the ISS (ATL/Philips, USA) during remotely guided sessions. The study protocol, including the use of Braslet-M for this purpose, was approved by the ISS Human Research Multilateral Review Board (HRMRB). Results: The effects of fluid sequestration on a number of echocardiographic and vascular parameters were readily detectable by in-flight US, as were responses to respiratory maneuvers. The overall volume status assessment methodology appears to be valid and practical, with a decrease in left heart lateral E (tissue Doppler) as one of the most reliable measures. Increase in the femoral vein cross-sectional areas was consistently observed with Braslet application. Other significant differences and trends within the extensive cardiovascular data were also observed. (Decreased - RV and LV preload indices, Cardiac Output, LV E all maneuvers, LV Stroke Volume). Conclusions: This Study: 1) Addressed specific aspects of operational space medicine and space physiology, including assessment of circulating volume disturbances 2) Expanded the applications of diagnostic ultrasound imaging and Doppler techniques in microgravity. 3) Used respiratory maneuvers against the background of acute circulating volume manipulations which appear to enhance our ability to noninvasively detect volume-dependency in a number of cardiac and vascular parameters. 4) Determined that Tei index is not clinically changed therefore contractility not altered in the face of reduced preload. 5) Determined that increased Femoral Vein Area indicating blood being sequestered in lower extremities correlates with reduced preload and cardiac output. 6) That Braslet may be the only feasible means of acutely treating high pressure pulmonary edema in reduced gravity environments.

Hamilton, Douglas↗
NASA NTRS2011

Cardiac and Vascular Responses to Thigh Cuffs and Respiratory Maneuvers on Crewmembers of the International Space Station

The transition to microgravity eliminates the hydrostatic gradients in the vascular system. The resulting fluid redistribution commonly manifests as facial edema, engorgement of the external neck veins, and a decrease in leg diameter. This experiment examined the responses to modified Valsalva and Mueller maneuvers measured by cardiac and vascular ultrasound (ECHO) in a baseline steady state and during preload reduction introduced with thigh occlusion cuffs used as a counter-measure device (Braslet cuffs) measured by cardiac and vascular ultrasound examinations. Methods: Nine International Space Station crewmember subjects (Expeditions 16 - 20) were examined in 15 experiment sessions 101 +/- 46.days after launch (mean +/- SD; 33 - 185). Twenty Seven cardiac and vascular parameters were obtained with/without respiratory maneuvers before and after tightening of the Braslet cuffs. Results: Non-physicians performed diagnostic-quality cardiac and vascular ultrasound examinations using remote guidance. Three of 27 combinations of maneuvers and Braslet or Braslet alone were identified as being significant changed when compared to baseline. Eleven of 81 differences between combinations of Mueller, Valsalva or baseline were significant and related to cardiac preload reduction or increase in lower extremity venous volume. Conclusions: Acute application of Braslet occlusion cuffs causes lower extremity fluid sequestration and exerts commensurate measurable effects on cardiac performance in microgravity. Ultrasound techniques to measure the hemodynamic effects of thigh cuffs in combination with respiratory maneuvers may serve as an invaluable tool in determining the volume status of the cardiac patient at the 'microgravity bedside'.

Hamilton, Douglas↗
NASA NTRS2004

Extraterrestrial Hemorrhage Control: Terrestrial Developments in Technique, Technology, and Philosophy with Applicability to Traumatic Hemorrhage in Space

Managing injury and illness during long duration space flight limits efforts to explore beyond low earths orbit. Traumatic injury may be expected to occur in space and is a frequent cause of preventable deaths, often related to uncontrolled or ongoing hemorrhage (H). Such bleeding causes 40% of terrestrial injury mortality. Current guidelines emphasize early control of H compared to intravenous infusions. Recent advances in surgical and critical care may be applicable to trauma care in space, with appropriate considerations of the extreme logistical and personnel limitations. Methods: Recent developments in technique, resuscitation fluids, hemoglobin (Hb) substitutes, hemostatic agents, interventional angiography, damage control principles, and concepts related to suspended animation were reviewed. Results: H associated with instability frequently requires definitive intervention. Direct pressure should be applied to all compressible bleeding, but novel approaches are required for intracavitary noncompressible bleeding. Intravenous hemostatic agents such as recombinant Factor VII may facilitate hemostasis especially when combined with a controlled hypotension approach. Both open and laparoscopic techniques could be used in weightlessness, but require technical expertise not likely to be available. Specific rehearsed invasive techniques such as laparotomy with packing, or arterial catherterization with with robotic intravascular embolization might be considered . Hemodynamic support, thermal manipulation, or pharmacologic induction of a state of metabolic down regulation for whole body preservation may be appropriate. Hypertonic saline, with or without dextran, may temporize vascular support and decrease reperfusion injury, with less mass than other solutions. Hb substitutes have other theoretical advantages. Conclusions: Terrestrial developments suggest potential novel strategies to control H in space, but will required a coordinated program of evaluation and training to evaluate.

Kirkpatrick, Andrew↗
NASA NTRS2012

Best Practices for the Application of Functional Near Infrared Spectroscopy to Operator State Sensing

Functional Near Infrared Spectroscopy (fNIRS) is an emerging neuronal measurement technique with many advantages for application in operational and training contexts. Instrumentation and protocol improvements, however, are required to obtain useful signals and produce expeditiously self-applicable, comfortable and unobtrusive headgear. Approaches for improving the validity and reliability of fNIRS data for the purpose of sensing the mental state of commercial aircraft operators are identified, and an exemplary system design for attentional state monitoring is outlined. Intelligent flight decks of the future can be responsive to state changes to optimally support human performance. Thus, the identification of cognitive performance decrement, such as lapses in operator attention, may be used to predict and avoid error-prone states. We propose that attentional performance may be monitored with fNIRS through the quantification of hemodynamic activations in cortical regions which are part of functionally-connected attention and resting state networks. Activations in these regions have been shown to correlate with behavioral performance and task engagement. These regions lie beneath superficial tissue in head regions beyond the forehead. Headgear development is key to reliably and robustly accessing locations beyond the hair line to measure functionally-connected networks across the whole head. Human subject trials using both fNIRS and functional Magnetic Resonance Imaging (fMRI) will be used to test this system. Data processing employs Support Vector Machines for state classification based on the fNIRS signals. If accurate state classification is achieved based on sensed activation patterns, fNIRS will be shown to be useful for monitoring attentional performance.

Harrivel, Angela R.↗
NASA NTRS2013

Fluid Shifts Before, During, and After Prolonged Space Flight and their Association with Intracranial Pressure and Visual Impairment

With the conclusion of the Space Shuttle program, NASA is focusing on long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low Earth orbit. Visual acuity changes observed in Space Shuttle crewmembers after their short-duration missions were largely transient, but more than 30% of ISS astronauts experience more profound changes in vision, some with objective structural and functional findings such as papilledema and choroidal folds on ophthalmologic examination. Globe flattening, optic nerve sheath dilatation, optic nerve tortuosity, and other findings have been noted in imaging studies. This pattern is referred to as visual impairment and intracranial pressure (VIIP) syndrome. The VIIP signs and symptoms, as well as postflight lumbar puncture data, suggest that elevated intracranial pressure (ICP) is associated with the space flight-induced cephalad fluid shifts, but this hypothesis has not been systematically tested. The purpose of this study is to objectively characterize the fluid distribution and compartmentalization associated with long-duration space flight, and to correlate the findings with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during space flight, as well as the VIIP-related effects of those shifts, can be predicted by crewmember baseline data and responses to acute hemodynamic manipulations (such as head-down tilt tests) obtained before flight. Lastly, we will evaluate the patterns of fluid distribution in astronaut subjects on the ISS during the use of lower body negative pressure (LBNP) and respiratory maneuvers to characterize and explain general and individual responses during space flight.

Stenger, M.↗
NASA NTRS2014

Defining the Relationship between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts during and after Long-duration Spaceflight

Future human space travel will consist primarily of long-duration missions onboard the International Space Station (ISS) or exploration-class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage from a variety of sources, including radiation, psychological stress, reduced physical activity, diminished nutritional status, and hyperoxic exposure during extravehicular activity. Evidence exists that increased oxidative damage and inflammation can accelerate the development of atherosclerosis. PURPOSE The purpose of this investigation is to determine whether biomarkers of oxidative and inflammatory stress are elevated during and after long-duration spaceflight and investigate if a relation exists between levels of these biomarkers and structural and functional indices of atherosclerotic risk measured in the carotid and brachial arteries. This is the first study to propose assessing atherosclerotic risk using biochemical, structural, and functional measures before, during, and immediately after spaceflight, and structural and functional measures for up to 5 years after landing. METHODS We will study 12 astronauts before, during, and up to 5 years after long-duration ISS missions. A panel of biomarkers of oxidative and inflammatory stress will be measured twice before flight, early (flight days 15 and 60) and late (2 weeks before landing) during the mission, and early in the postflight recovery phase (approx 3 days after landing). Arterial structure and vascular compliance will be measured at the same times and also at 1, 3, and 5 years after landing (surveillance). Arterial function will be measured using the same preflight, postflight, and surveillance schedule as arterial structure and vascular compliance measures, but will not be measured inflight. Biomarkers, some of which we have previously shown to be elevated with spaceflight, will be measured in venous blood samples and 24-h (in-flight) and 48-h (pre- and post-flight) urine pools. Arterial structure will be assessed from measures of carotid intima-media thickness, which have been shown to be better indicators of atherosclerotic than the Framingham Risk Score. Arterial function will be assessed using brachial flow-mediated dilation, a well-validated measure used to assess endothelium-dependent vasodilation and is a sensitive predictor of atherosclerotic risk. Arterial pulse pressure measured in the brachial artery and stroke volume measured from cardiac ultrasound will be used to assess hemodynamic status, cardiac function, and systemic vascular compliance. Three astronauts are actively participating in the preflight data collection and training activities. One astronaut has completed all preflight activities and will participate in the first in-flight data collection sessions by the end of 2013. The first post-flight data collection sessions will occur in the spring of 2014. EXPECTED RESULTS We hypothesize that biomarkers of oxidative and inflammatory stress will increased with spaceflight and will correlate with increased carotid intima-media thickness during and after flight and with decreased flow-mediated dilation after the mission. Furthermore, we hypothesize that measures of oxidative stress will return to baseline after flight, but biomarkers of inflammatory stress and vascular indices of atherosclerotic risk will remain elevated.

Lee, Stuart M. C.↗
NASA NTRS2014

Fluid Shifts

NASA is focusing on long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but more than 30% of ISS astronauts experience more profound, chronic changes with objective structural and functional findings such as papilledema and choroidal folds. Globe flattening, optic nerve sheath dilation, and optic nerve tortuosity also are apparent. This pattern is referred to as the visual impairment and intracranial pressure (VIIP) syndrome. VIIP signs and symptoms, as well as postflight lumbar puncture data, suggest that elevated intracranial pressure (ICP) may be associated with the space flight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration space flight, and to correlate these findings with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during space flight, as well as the VIIP-related effects of those shifts, is predicted by the crewmember's pre-flight condition and responses to acute hemodynamic manipulations (such as head-down tilt). Lastly, we will evaluate the patterns of fluid distribution in ISS astronauts during acute reversal of fluid shifts through application of lower body negative pressure (LBNP) interventions to characterize and explain general and individual responses. We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the Figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography, intraocular pressure, 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness, Doppler ultrasound of ophthalmic and retinal arteries, and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, distortion-product otoacoustic emissions, and ICP calculated by MRI). On the ground, acute head-down tilt will induce cephalad fluid shifts, whereas LBNP will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome. This study has been selected for flight implementation and is one of the candidate investigations being considered for the one year mission.

Stenger, Michael↗