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How are Fluids Redistributed in Spaceflight?

STEM TODAY July 2016, No.10

Special Edition on Gap's in NASA Human Research Roadmap (HRR)

STEM TODAY July 2016 , No.10

CONTENTS CV7: How are fluids redistributed in flight?

Spaceflight Evidence Apollo Skylab MIR Space Station Shuttle International Space Station

Editorial Editor: Mr. Abhishek Kumar Sinha Advisor: Mr. Martin Cabaniss

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Cover Page International Space Station Final Configuration NASA and its international partners completed assembly of the International Space Station in the fall of 2011.

Now, science has taken center stage. Engineers at NASA’s Marshall Space Flight Center in Huntsville, Ala., manage science operations and help keep science facilities operational.

Image Credit: NASA

Back Cover The Nile at Night NASA astronaut Scott Kelly, recently past the halfway mark of his one-year mission to the International Space Station, photographed the Nile River during a nighttime flyover on Sept. 22, 2015. Kelly (@StationCDRKelly) wrote, "Day 179. The #Nile at night is a beautiful sight for these sore eyes. Good night from @space_station! #YearInSpace."

Image Credit: NASA

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CV7: How are fluids redistributed in flight?

Gap’s in NASA’s Human Research Roadmap (HRR)

Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

Fluid shifts in Microgravity

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N Earth, the hydrostatic pressure increases by roughly 10 kPa/m between the top of the head and the soles of the feet. Upon entry into microgravity, the hydrostatic pressure is abruptly removed from the tissues of the body, causing a net migration of fluid from the legs toward the upper body and head in a cephalic fluid shift.

Almost immediately, nasal congestion and a feeling of fullness in the head are reported . The forehead and facial tissues swell and the external neck veins become engorged.

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Spaceflight Evidence Apollo Before the Apollo 7 mission, considerable knowledge had been accumulated concerning the fluid and endocrine changes associated with Mercury and Gemini Earth-orbital missions . It was known that astronauts always weighed less after a mission than they did before the mission. This decrease in weight was associated with modest decreases in plasma volume. These results showed that, although cardiovascular deconditioning resulting from space flight was similar in extent to that found after bed rest, the weight changes after space flight were greater but the plasma volume changes were smaller. There is evidence from Gemini studies that the reentry sequence is associated with a sudden increase in epinephrine release as shown by a short-lived granulocytosis. This finding indicated that reentry for Gemini crewmen was a stressful experience. Before Project Mercury, certain segments of the scientific community were apprehensive that certain aspects of weightlessness might produce life-threatening conditions including hypercalcemia and hypercalciuria. This apprehension subsided when no evidence of a calcium abnormality was found. Even after the 14-day Gemini 7 mission, X-ray bone densitometry showed absent to slight loss of bone mineral.

Using this background, more extensive endocrine and metabolic studies were planned for the Apollo Program.

As with other portions of the medical program, these studies were designed to provide data relative to the maintenance of flight crew health and well-being during a mission. The purpose of this chapter is to summarize and discuss the endocrine and metabolic results obtained before and after the Apollo missions and the results of the limited inflight sampling. From these studies, it is possible to obtain an idea of the nature and the extent of endocrine responses by the crewmen who flew the Apollo missions.

As part of the overall operational medical program, the endocrinological and metabolic studies were designed to evaluate the biochemical changes in the returning Apollo crewmembers. The areas studied were balance of fluids and electrolytes, regulation of calcium metabolism, adaptation to the environment, and regulation of metabolic processes.

The same general protocol was followed for most of the Apollo missions. Deviations from the procedures occurred when the quarantine program was imposed upon the Apollo 11,12, and 14 missions. With the crewmembers reclining for 30 minutes, approximately 45 ml of peripheral venous blood were drawn three times (thirty, fifteen, and five days) before space flight. Blood was drawn approximately two hours after recovery (as soon as possible) and one, seven, and fourteen days later. All blood samples were drawn with the subject fasting from midnight until 7:00 a.m. except for the postrecovery sample, which was drawn regardless of the time of day or prior food intake by the crewmen. Generally, the crewmen had not eaten for six hours before recovery and had been awake for at least eight hours. For the preflight control samples, the crewmen had been awake less than one hour.

The 24-hour urine samples were collected preflight and postflight from each crewman on the same days as were the blood samples. The pooled urine was collected without additive, aliquoted, stabilized with acid, and frozen for analysis. Urine samples were collected inflight by means of a biomedical urine sampling system (BUSS). Each BUSS consisted of a large (four liters) pooling bag in which urine was collected. Each contained 10 gm of boric acid for stabilization of certain organic constituents. One entire 24-hour urine sample from each Apollo 16 crewman was returned. For Apollo 17 collections, a sampling bag was used. In this bag a sample of urine (as much as 120 cm3 ) was stored for later analysis. The collection bags contained 30 mg of lithium chloride. The final lithium concentration was used to estimate total urine volume.

Results Post-mission body fluid losses have been found in both American and Russian space flight crewmen. Apollo crewmen showed an average of five percent decrease in body weight after flight when the mean of the preflight results (thirty, fifteen, and five days) was compared to the individual postflight values. The average loss was 3.51 kg, approximately one-third of which was regained within the first 24 hours after recovery. These data are

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) given in Table 3.

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Body weight changes indicate significant fluid changes among all crewmembers exposed to weightlessness.

Loss of fluid does not seem to be related to the duration of the mission. Because of this fact, studies were undertaken to investigate cations and anions, both of which have critical roles in the regulation of fluid volume.

Serum electrolyte data from the Apollo crewmen are summarized in Table 4. Significant differences were observed in a 7.3 percent decrease in potassium and a 4.5 percent decrease in magnesium immediately after flight.

These changes were accompanied by no significant change in serum sodium or chloride.

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The 24-hour urine electrolyte results are given in Table 5. These samples exhibited significant decreases in sodium, potassium, chloride, and magnesium values. The results from Apollo 17 inflight collections are shown in figures 1 to 4.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

To aid in the understanding of water and electrolyte balance and of renal function, renin activity was measured as angiotensin 1 in blood samples, and aldosterone was measured in urine. Table 6 contains these results.

The plasma angiotensin I values show a 488 percent increase in the crewmen tested on the day of recovery. This elevation was followed by a significant increase (57 percent) in urinary aldosterone during the first day following recovery. In figures 5 and 6, the inflight aldosterone results for the Apollo 16 and 17 missions, respectively, are shown.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

Table 7 contains summary data on urinary volume, ADH, and osmolality. These results indicate a 32 percent decrease in urine volume after flight with significant increases in osmolality (20 percent) and ADH (152 percent).

The inflight volume and osmolality values for the Apollo 17 mission are shown in figures 7 and 8, respec-

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) tively. A summary of the measured body fluid volumes is given in Table 8. These same data are also expressed as milliliters per kilogram of body weight. Table 9 contains the total body exchangeable potassium data as measured by potassium-42. Table 10 contains blood urea nitrogen (BUN) and creatinine clearance data. The creatinine clearance results show no significant change in renal function after flight as indicated by this test. A slight but significant increase in BUN was found. Apollo 17 inflight creatinine values are shown in figure 9.

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The calcium, phosphorus, and parathormone (PTH) changes are summarized m Table 11. It is believed that the calcium, phosphorus’ and PTH results not only reflect normal bone metabolism but would seem to reflect normal renal function. These results are in agreement with the results of photon absorptiometry studies performed on several Apollo flights which s showed small to insignificant losses of bone calcium after flight.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

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Plasma cortisol and ACTH results are given in Table 12. Although no significant change was found, a mean decrease was demonstrated in both hormones.

The urinary hormonal data indicating adrenal activity are also given in Table 12. Cortisol demonstrated a 24 percent increase, whereas the total 17hydroxycorticosteroid excretion was decreased 30 percent. The inflight values for these measurements for Apollo 17 crewmen are shown in figures 10 and 11. Both catecholamine compounds show decreases after flight when the data from all crewmen are grouped for analysis. Some individual preflight values are often elevated. This is believed to be due to premission stress. The total and fractionated ketosteroid data are given in Table 13. These results demonstrate a 30 percent decrease in the total component, which is spread over four fractions: androsterone, etiocholanolone, dehydroepiandrosterone (DHEA), and 11 = 0H etiocholanolone, A slight increase was observed in pregnanediol and 11 = 0 etiocholanolone. Figures 12 and 13 demonstrate the typical inflight component of these results for Apollo 17 crewmen.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

The serum and plasma values for various hormones and related parameters are summarized in Table 14. Glucose showed a 10 percent increase after flight, and insulin increased 32 percent after flight. Human growth hormone demonstrated a 304 percent increase after flight. The postflight increase in thyroxine was statistically significant, whereas slight change was noted in percentage of triiodothyronine binding.

Table 15 is a summary of the urinary amino acid results for six representative amino acids from a total of 39 analyzed. The comparison of postflight to preflight control levels has been variable. However, taurine has been consistently elevated after flight (140 percent). The inflight data for Apollo 17 crewmen are presented in figures 14 to 16.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

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After considering all previously mentioned data together with the clinical condition of the returning Apollo crewmen, the following hypothesis was proposed to explain the changes. As a crewman enters the weightless environment, his circulating blood volume and extracellular fluid shift from the extremities and the lower abdomen and are redistributed equally throughout the vascular space. This alteration of the blood volume is interpreted as a relative volume expansion. The fluid redistribution necessitates a compensatory change in water balance with a net 1088 of fluid and electrolytes. The extent of the fluid and electrolyte loss is related also to food consumption, which has been variable and generally below basal requirements during the first 24 hours of a mission. The changes in water balance are believed to occur principally in the first or second day of flight just as they do in bed rest.

This theory explains why crewmembers showed weight decreases even after short duration Mercury and Gemini missions. On return to Earth and the one-g environment, a portion of the weight loss is regained within the first 24 hours. A rapid weight gain of this magnitude indicates a renal and endocrine response to the new environment. The remainder of the weight loss could be attributed to tissue loss. Consistently measured decreases in red cell mass and decreases in individual cell electrolyte content, determined by the electron microprobe, add support to this hypothesis. Furthermore, significant decreases in serum magnesium during the postflight period suggest previous losses of intracellular electrolyte, since magnesium is concentrated in the intracellular space along with potassium.

Postflight decreases in total body potassium of the Apollo 12 to 14 crewmen were determined by gamma spectrometric measurement of the total body potassium-40. Seven of the nine men showed a significant decrease (three to ten percent) for this measurement. Beginning with the Apollo 15 mission, total body exchangeable potassium was measured. The results are expected to differ from total body potassium because slow-to-equilibrate pools

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) may not be completely exchanged in the 24 and 48-hour periods analyzed.

However, because comparisons of measurements before and after space flight of the same individuals are being made, the relative changes are meaningful. Crewmembers of the Gemini 7 mission demonstrated positive potassium balance before and after the flight and negative balance during the flight. Results from Gemini missions and data available from Apollo crewmen confirm that aldosterone is elevated during space flight. This elevation could have been produced by decreases in renal blood flow or in carotid artery or right-heart pressures: the specific etiology must await further experimentation.

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All Apollo missions were followed by a change in the plasma volume of returning crewmen. The overall mean of the crewmen’s plasma volume decrease for the Apollo missions was considerably less than the 10 percent mean decrease associated with an equivalent period of bed rest. Only three of the twenty-one crewmembers tested showed losses greater than the average bed rest results. A smaller decrease in plasma volume could be one manifestation of an inflight increase in adrenal activity, particularly aldosterone secretion. Because no plasma volume measurements for Apollo missions were taken during flight, it was not known whether plasma volume was actually lower during flight and increased slightly before being recorded immediately after flight or whether plasma volume remained essentially stable after the 4.4 percent decrease (Table 8) had occurred.

Even with adequate calories available, most crewmen showed a weight loss after flight. Part of this weight loss was made up during the first 24 hours after recovery, but it took from several days to weeks for crewmen to return fully to their premission weight. This fact suggests that part of the weight loss during a mission is tissue and another part fluid. Only fluid loss could be made up in the first 24 hours; recovery of tissue losses takes considerably longer. Weight loss from short term dieting is generally followed by am increase in extracellular fluid, which compensates for the tissues lost. This extra fluid is ordinarily lost by diuresis at irregular intervals of several days to several weeks. The increased extracellular fluid volume seen after these missions could be explained as a compensation for tissue losses. The water retention associated with weight loss is probably accomplished by increased aldosterone secretion.

During recovery operations, crewmen were exposed to increased ambient temperatures in the spacecraft, in the helicopter, and on the carrier deck because of the tropical location of recovery operations. The crewmen did not eat or drink between the time they left the spacecraft and the time of blood sampling; thereafter, they could eat or drink anything they desired. The postrecovery diet was generally high in salt, protein, and calories. The postrecovery urine generally showed increased osmolality with a decrease in electrolyte content, a combination that indicated increased excretion of nonelectrolyte osmotic substances. Part of this increase in osmolality might have been a result of the increased blood urea nitrogen (BUN) found after recovery.

The clinical laboratories found postflight elevations in uric acid. Because of the increased environmental temperatures during the first four hours after recovery, a slight increase in serum sodium was to be expected then, and in osmolality later. However, serum sodium was actually less after flight than before flight, and osmolality was unchanged; therefore, serum sodium may have been even lower before reentry. This discovery, coupled with the BUN change, suggests that renal blood flow is decreased during weightlessness, and this decrease could be partly responsible for the increased aldosterone excretion by way of the renin-angiotensin system.

Balakhovskiy and others (1971) have suggested that the postflight weight loss in American astronauts was due to dehydration caused not by space flight but by environmental temperatures in the tropical recovery zones.

Apollo data do not substantiate dehydration as the causative factor for the fluid/electrolyte results because serum sodium and osmolality were not increased at recovery.

Prolonged bed rest is associated with a negative calcium balance beginning in the second week. it was postulated that exposure to weightlessness would produce similar losses of calcium from the skeleton. The results of the Apollo missions did not appear to indicate significant changes in calcium metabolism. First, no change in parathormone was found in recovery specimens; second, urine and serum calcium were elevated; and third, bone densitometry failed to show consistent decreases in bone mass.

Therefore, for missions of 14 days or less, it was apparent that significant calcium losses did not occur. Hypercalcemia does not account for the loss of sodium, as has been suggested. However, if changes in calcium dynamics had occurred, they would have probably just begun during the last few days of the missions.

Current data show no evidence of plasma cortisol and adrenocorticotrophic hormone (ACTH) increase after flight. The stress of reentry is assumed to be not great enough to produce a change in these hormones. The time of recovery, however, generally is at a different point in the diurnal cycle of the pituitary-adrenal axis than in the

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) preflight control. Without stress, higher values were to be expected at the time of the control specimens (8:00 A.M.) than at the time of recovery (between morning and early afternoon). Reentry stress may have elevated these hormones higher than they were 24 hours before recovery.

The Apollo 16 mission was the first after Gemini 7 in which inflight urine samples were returned for analysis.

The 17-hydroxycorticosteroids were found to be significantly decreased during the 14-day Gemini 7 mission.

Likewise, total 17-hydroxycorticosteroid values were decreased in second-day inflight specimens from Apollo 16 crewmen and were normal to decreased in the more comprehensive sample collection of the Apollo 17 mission.

Ordinarily, if total 17-hydroxycorticosteroid excretion decreases, a decrease in cortisol is to be expected; however, cortisol excretion during the inflight phase of both missions was normal to elevated or, stated differently, no value was lower than preflight or postflight values.

This divergence of results could be related either to a sample storage program that affected the 17hydroxycorticosteroid analyses or, possibly, to changes in blood flow to the liver that altered the conjugation rate of the free hormone resulting in decreased excretion of 17-hydroxycorticosteroids

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In several endocrine-related diseases, the determination of urinary 17-ketosteroids, either fractions or total, has been helpful in both diagnosis and understanding the pathophysiology of these diseases. The decrease in the total 17-ketosteroid fraction agrees with the decrease in the total 17-hydroxycorticosteroid data. The mechanism is believed to be related to the liver conjugation of these steroids. The inflight increase in specific fractions reflects the heightened adrenal activity during the flight phase.

The dehydroepiandrosterone (DHEA) increases shown on the Apollo 16 and 17 missions inflight are considered significant since they had been shown to occur in potassium-depleted subjects. The exact function of this steroid is not known, but it appears to be related to stress responses as well as to nitrogen and mineral metabolism.

Bed rest, the most frequently used analog of weightlessness, alters glucose metabolism. Studies have shown that glucose and insulin are elevated after two weeks of absolute bed rest. Apollo results suggest that space flight may have a similar effect with an apparent decrease in the efficiency of insulin to lower plasma glucose concentrations. However, increased growth hormone may be a factor in these observed increases. A significant change in plasma thyroxine (T4) may represent the thyroid gland’s response to increases in plasma proteins.

To assess metabolic responses in the area of nutrient use as well as stress, human growth hormone (HGH) was measured. This hormone was significantly increased (Table 14) postflight. Because HGH acts to increase blood sugar and plasma-free fatty acids, and to lower plasma amino acids by incorporating them into proteins, these results after space flight are compatible with the evidence of muscle breakdown discussed previously.

The changes in amino acid excretion patterns are thought to be related to diet a. well as to muscle metabolism.

However, as in every study of amino acid excretion, renal threshold, glomerular filtration rate, and cellular use enter into the full explanation, Furthermore, the relationship between adrenal steroid activity and amino acid excretion must be considered because adrenal steroids alter urinary excretion patterns of amino acids. Glycine, significantly elevated in the inflight samples, is required by the body for formation of nucleic acid, porphyrins, creatinine, hippuric acid, and bile acid conjugates.

Therefore, the increased excretion of this amino acid could be related to cellular mass loss or to the suspected decrease in liver blood flow. The significant increases in taurine after flight could be an indication of a decrease in bile acid formation and hence in liver function. Sarcosine, another amino acid that was increased during flight, is related to muscle protein and is believed to be a further indication of muscle breakdown during flight.

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Skylab On Skylab only leg volume measurements, and stereophotogrammetry preflight and postflight, and maximum calf girths in-flight were originally scheduled. On Skylab 2, the initial anthropometric studies were scheduled in conjunction with the muscle study. A single set of facial photographs was made in-flight. Additional measurements were made on Skylab 3, with photographs and truncal and limb girth measurements in-flight. Prior to Skylab 4, a few of researcher felt there was considerable evidence for large and rapid fluid shifts, so a series of inflight volume and center of mass measurements and infrared photographs were scheduled to be conducted as early as possible in the Skylab 4 mission.

The series of direct anthropometric measurements shown in figure 32-1 were made preflight and postflight on all missions, and in-flight on the Skylab 4 mission. Leg and arm girth measurements were made every 3 centimeters by means of a calibrated tape jig attached to the limb to insure accurate location. For general documentation, a series of pre-flight, in-flight, and postflight front, side, and back photographs were made with the crewmen in standard anatomical position. To note postural changes, an in-flight series of photographs were made with the crewman completely relaxed and free floating. An infrared sensitive color film was used in an attempt to document the superficial venous blood distribution. The infrared film had poor resolution and at the last minute, 35 mm was substituted for 70 mm film further reducing resolution. Quality of the in-flight anatomical and postural photographs suffered. However, a good deal of vascular detail could be determined that would not have been available on ordinary film. As a simple way to indicate fluid shifts, center of mass and center of

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gravity (CG) measurements were made (fig. 32-2). A teeter board was used for these measurements on Earth.

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Results

Figure 32-3 shows typical changes of the preflight and in-flight front view and the preflight, in-flight, and postflight side view; these tracings of the Skylab 4 Scientist Pilot are typical of the changes seen. Relaxed postural changes varied somewhat throughout the flight and from individual to individual. The posture in figure 32-3 is the characteristic posture of weightlessness. The spinal column was flexed with loss of the thoracolumbar curve but with retention of the cervical curvature, such that the head is thrust forward. Both upper and lower limbs have moved toward a quadruped position. Postflight, there was surprisingly little change from preflight posture.

Figure 32-4 are plots showing the effects of gravitational unloading on truncal size. The Pilot of Skylab 4 had the largest changes with gain of some 2 inches in height and loss of 4 inches in abdominal girth. Chest girth was also initially reduced in both inspiration and expiration, but trended toward "normal" in-flight. Postflight, which is poorly shown in these figures, there was a more or less rapid trend toward preflight values. It seems that most of the increase in height was caused by expansion of the intervertebral discs which were unloaded. This stretched the torso and probably aided in reduction of abdominal girth. Abdominal viscera may be considered semiliquid, and when their weight was removed the normal tone of abdominal muscles moved them in and upward. Changes in chest girth are not so easily explained, but if the spinal column moved upward without a similar anterior elevation of the sternum, then the rib (costovertebral) angles is increased, effectively reducing thoracic girth. Changes noted in the Commander were virtually the same as those noted in the Scientist Pilot.

There was considerable evidence of large and rapid shifts in fluid from the lower to upper body prior to Skylab 4. Indeed, no subject has been discussed more in space physiology; nevertheless, virtually no one was willing to accept it. Such large and rapid shifts seemed to be contradicted by the relatively small gains in postflight leg volume which obviously contained tissue increases. Single in-flight midcalf girth measurements on Skylab 2 and 3 were also misleading for they indicated much smaller and slower changes consistent with a predominant component of muscle atrophy.

Leg and arm volumes were calculated by measuring the girth of each 3cm segment and treating all the segments as a tapered cylinder, then summing these volumes. Mission day 3 was the earliest possible that these measurements could be scheduled, although it is a measurement which should have started within hours of orbital insertion; even then, only two crewmen performed these measurements on mission day 3. Figure 32-5 shows that there is a rapid loss in leg volume; the curves on these plots are only estimates, and author suspect the shift was essentially over by the first day. Remember these are changes in one leg only and on mission day

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8 total change was approximately 2 liters and 13 percent of total leg volume for each crewman. Note that on recovery the majority of the increase in leg volume was complete by the time of first measurement on the day of recovery; or within a matter of hours after reexposure to one-g.

Center of mass measurements were scheduled on this flight primarily to follow the time course of fluid shifts, since only minutes were required for the measurement. Unfortunately, schedules were changed such that the points of real interest were over before the first measurement could be made. Figure 32-6 is a plot of the center of mass, the upper curve shows the center of mass changes and the complication by the increase in height, shown in the lower curve. Center of mass shifted cephalad more than could be accounted for by the height increase which is another small confirmation of fluid shift. The astronauts have long reported objective and subjective descriptions of puffy facies, head fullness, and other symptoms of increased fluid in the head. Finally, there are the photographs. While these do not allow quantitation, they provided powerful evidence for increased fluid in the head and neck region. Figure 32-7, a photograph of the Pilot on Skylab 2, was the first taken for this purpose. Although it is slightly distorted it still demonstrates the puffy facies-note the thickened eyelids.

This in-flight photograph was made near the end of the mission and demonstrates that this type of edema and venous congestion still remained.

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Next, figure 32-8 is a picture of the Commander of Skylab 3 with the preflight view on the right-hand side; again the in-flight photograph was made near the end of the mission. Although angle and lighting differ, I believe the difference in facies is apparent.

From the first through the last mission the following was observed in all in-flight photographs of the crewmen: • Only superficial veins were visualized.

• Foot and lower leg veins were not distended as they are in standing position under one-g.

• The veins were not completely empty for the dorsal arcade of the foot and digital branches were easily seen with the infrared film.

• Calf veins were not distended but were still visible.

• Several superior branches in the anterior thigh were moderately full.

• Little difference could be seen between preflight and in-flight patterns of the trunk and upper arms. Hand and forearm veins were well filled and distended in-flight. This was surprising since superficial arm veins, like those of the leg have increasing amounts of wall muscle as they become more distal.

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• Jugular veins were always completely full and distended as were veins of temple and forehead.

• Postflight, there was a prompt reversion to preflight pattern, however, foot and lower leg filling appeared to be less in the early recovery period.

It was not possible to document body composition changes with specific gravity and other measurements. Observation of all crews, and especially those on Skylab 2 and 3, left the impression that loss of fat had occurred, except for the Commander of Skylab 4. Radioisotopic studies by Drs. P.C. Johnson and C.S. Leach confirmed an increased loss of fat by all crewmen except the Commander of Skylab 4.

The major changes are shown in table 32-I. Change in height is observed. One crewman, for example, is shorter than his wife and was elated to find in-flight that he was finally taller. Postflight there was an undershoot, and he came home to her on the third day postflight shorter than ever. Reduction in waist girth with cephalad shift of abdominal viscera probably alters maximum lung volumes but to no great extent. Vital capacity is reduced by lying down in one-g and the effects are somewhat analagous. Apparently it did alter some internal relationships

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for at least one crewman felt that running and jumping on the treadmill produced unpleasant jouncing of gastric contents. One could speculate on the effects that such shifts would have on pathological processes of the bowel e.g., hiatus hernia or a perforation. It is hardly necessary to comment on the changes in chest girth which were small. In-flight postural changes are listed in table 32-II.

Standing upright under one-g, veins and arteries below the heart have increasing hydrostatic pressure as the veins descend toward the feet where the force may be 80 to 100 mm Hg. Shortly above the heart, the venous pressure becomes zero and the vessels are virtually empty and at least partially collapsed. Under weightlessness, without this superimposed hydrostatic pressure, venous pressure, except for negligible flow pressures, are the same throughout the body. Volumes are now shifted only in response to the compliances, the tension if you will, of the various areas of the venous systems. The result is that we have essentially central venous or right atrial pressure throughout the entire venous system. Veins such as head and neck which are normally empty, fill until their back pressure is equal to that of the pressure in, for example, a foot vein, which develops the same pressure at a much smaller volume. When a subject changes from a standing to a lying position under one-g, a nominal 700 milliliters of blood leaves the legs and probably a comparable volume is shifted centrally. Most of this blood volume moves to that undefined "central volume" and produces a small increase in pressure with a probable effect of increasing cardiac output.

A second result of the fluid shift produced results that were easier to document. Certain body sensors detect this

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) as an abnormally large volume and cause plasma to be reduced thus leaving high hemoglobin and hematocrits in the circulating blood . An as yet unknown sensor is activated to detect and reduce over a matter of weeks red blood cell production such that red cell mass becomes appropriate to the new volume. Such readjustment to altered volumes are also seen under one-g; for example, individuals with leg varicosities have increased blood volumes. Author think that the reduced loss of red cell mass in the Skylab 4 Commander is further evidence of reduced leg venous volume. Table 32.-III illustrates this.

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On return to one-g, a reverse process ensues. After the first day repeated blood tests show an anemia which is slowly replaced by an increasing red cell mass. These changes are delineated in table 32-IV. Tissue fluid shifts are larger in volume than blood shifts but somewhat slower acting. When standing under one-g there is a hydrostatic column of up to 80 to 100 mm Hg pressure on arteries, veins, and capillaries in the foot. This pressure is opposed by tissue pressures and after a period of extravasation they equalize. Under weightlessness, the reverse occurs with resorbtion of fluid by the tissues until transmural pressures are again balanced. In the upper body areas and particularly the head, we have the opposite effect from increased transmural pressure which produces edema. These processes are simultaneous. Tissue fluid shifts are delineated in table 32-V.

Whether this shift of fluid produces an increase in intravascular volume or not depends upon how rapidly fluid is regained from some areas and lost to others. It is at least theoretically possible that fluid is lost more rapidly than it is gained, with a reduction of intravascular volume. I do not think this happens and expect there may be a very slight expansion of intravascular volume which, coupled with the blood from leg veins, may result in a small fluid loss via the Gauer-Henry scheme (increased atrial pressure and diuresis), or some other mechanism. However, remember that tissue fluid shifts occur under one-g without undue diuresis. Legs are smaller in the morning and eyes are puffy, and a shave lasts longer if made an hour or so after arising.

Blood Volume Changes Decreased red blood cell mass has been found regularly among astronauts returning from space flight. This observation was first documented in the crew of the 8-day Gemini 5 mission and confirmed in the crewmembers of the 14-day Gemini 7 mission. In addition, it was observed that the red blood cell half- life (the time for half of the total amount of tagged red blood cells to be removed from circulation) was shortened, suggesting that hemolysis combined with bone marrow unresponsive to stimulation of red blood cell production caused the decrease in circulating red blood cells and subsequent decreased red blood cell mass.

Red blood cell half-life was not shortened on the Apollo missions, although the crews of both Apollo and Gemini missions were exposed to at least four hours of 100% oxygen prior to launch and during flight. It was not clear whether inhibition of erythropoiesis (decreased production of red blood cells) caused by hyperoxia, or hemolysis of red blood cells (increased destruction) was the causative agent for the decrease in red blood cell mass. The Skylab missions offered the opportunity to rule out the hyperoxia hypothesis while testing whether changes in red blood cell mass are progressive with longer periods of weightlessness.

Skylab experiment M113 was designed to :

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) (1) Determine the effect of Earth-orbital missions on plasma volume and red blood cell populations (particularly red cell mass, life span, and production and destruction rates) (2) Provide baseline data for correlation with data from other hematologic and immunologic experiments.

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Red cell mass measurements were made according to the following schedule. On the 28-day Skylab 2 mission, measurements were made 29 days prior to launch, on recovery (landing) day and 13, 42 and 67 days after recovery. On the 59-day Skylab 3 mission, measurements were made 20 days before launch, on recovery day, and 14 and 45 days after recovery. On the 84-day Skylab 4 mission, measurements were made 21 days and 1 day before launch, on recovery day and 14 and 31 days after recovery. All specimens were drawn in the morning after an overnight rest with the crewman fasting, except for the recovery day samples, which were drawn within 2 hours after the spacecraft landed.

Most measurements in this experiment were obtained by the tracer kinetics method. The red blood cell mass and half-life were determined using 51chromium (51Cr) as the tracer. A sample of 12.5 milliliters of blood was drawn and mixed with 2.5 milliliters of anticoagulant acid citrate dextrose (ACD) solution and 25 microcuries of 51Cr. Ten milliliters of 51Cr-tagged cells from the sample were reinfused into the bloodstream after incubating the cells for 4 minutes at room temperature and adding 50 milligrams of ascorbic acid. The red blood cell mass was determined by averaging the radioactivity of 30- and 31-minute red blood cell samples. Red blood cell chromium half-life was estimated from the measured activity profile of 51Cr. Plasma volume was measured by injecting 2 microcuries of 125iodine human serum albumin each time the red blood cell mass was determined.

To track the red blood cell lifespan, 50 microcuries of 14carbon-glycine was injected intravenously 30 days prior to launch. The 14C radioactivity was followed for 125 days on Skylab 2, 131 days on Skylab 3, and 141 days on Skylab 4. In general, blood was drawn weekly throughout this period, including the time in space. Radioactivity was determined by extracting heme, igniting the dried extract, and determining microcuries of 14C per milligram heme. Iron turnover was determined by injecting 2 microcuries of 59iron-citrate at recovery and using blood samples drawn at 30 and 31 minutes, and 2-3 hours later. Iron reappearance was obtained from blood samples drawn 1,3,7 and 14 days after recovery. Reticulocyte counts were made from weekly preflight and postflight blood samples.

Results The recovery mean value for the red blood cell mass of all Skylab astronauts was lower (1843 milliliters) than their preflight mean (2075 milliliters) and different from the control postflight mean (2046 milliliters).

While the postflight decrease in mean red blood cell mass was 232 milliliters for the Skylab crewmembers, the corresponding value for the controls was only 7 milliliters. There was no significant difference between preand postflight crew mean values and control mean value either for the 51Cr red blood cell half-life or for the 14C-glycine red blood cell mean life span; neither was there any statistically significant difference between the control subjects and the Skylab crews in appearance or turnover of iron, indicating that the rate of erythropoiesis was the same for both groups.

However, postflight reticulocyte counts measured at recovery following each mission were low. The postflight counts were greater than preflight values in only one crewmember of the 28-day mission 2 weeks after recovery, in all three crewmembers of the 59-day mission 1 week after recovery, and in all three crewmembers of the 84-day mission 1 week or less after recovery. The control subjects, on the other hand, did not develop a change in reticulocyte count, indicating that the changes observed in the Skylab crews were not due to blood draw amounts. Inhibited bone marrow was thought to be a possible explanation for the low red blood cell masses and low postflight reticulocyte counts, and normal iron turnover was thought to be caused by a postflight rebound in the bone marrow. As for the plasma volume, the mean percent decrease was less in the Skylab 2 crew than in the crews of the longer Skylab 3 and 4 missions, but still greater than the decrease observed during Apollo missions, which suggested that the plasma volume did not return to normal even after prolonged flights.

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Bio-Assay of Body Fluids The space flight environment with its combination of stresses offers a unique challenge to the body’s biochemical control mechanisms. Astronauts returning from Gemini and Apollo flights demonstrated biochemical changes of sufficient magnitude and complexity to warrant detailed studies of the endocrine and metabolic systems.

The Bio-Assay of Body Fluids (M073) experiment was designed to study homeostasis in the areas of : (1) fluid and electrolyte balance, (2) regulation of calcium metabolism, (3) adrenal function, and (4) carbohydrate, fat, and protein utilization.

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The study was divided into two broad categories. One category included routine blood and urine studies similar to those used in clinical medical practice. The second category included a more thorough analyses to investigate the metabolic/endocrine responses to the space flight environment, including fluid and electrolyte control mechanisms.

The nine astronauts who flew on Skylab 2, Skylab 3, and Skylab 4 all participated as test subjects. Metabolic monitoring of the astronauts began at least 21 days prior to each flight, continued throughout each flight, and proceeded for at least 17 days after flight. Following an overnight fast, blood samples were drawn. The blood volume required for preflight and postflight analyses was 25 ml and the inflight plasma averaged 3 ml. Sodium ethylenediaminetetraacetic acid (EDTA) was used as an anticoagulant for blood samples. Radioassay, fluorometric and gas chromatographic techniques were used for most hormonal analyses. Radioactive body compartment studies were conducted preflight and postflight. These included dilution studies of body water (tritium), extracellular fluid (35 sulfate), plasma volume (125 I-protein) and exchangeable potassium (42 K and 43 K) both preflight and postflight.

Urine was collected on a void-by-void basis before and after each mission. Twenty-four hour urine collections on each subject were made throughout the flights as part of the Mineral Balance (M071) experiment. Because of limitations in return storage weight and volume, a 120 ml aliquot of each day’s urine collection was collected, frozen, and returned to Earth. A measured quantity of lithium chloride, added to each 24-hour collection bag prior to flight, permitted urine volumes to be calculated based on lithium dilution. In addition, crewmembers measured the filled collection bag with a gage to provide an estimate of daily urine output. Data samples and results were shared among the three related investigations. Data on food and water consumption, body mass, and urine volume were telemetered nightly to the investigators.

Results Analysis of postflight blood samples showed elevations in calcium and phosphorous were present throughout the three missions and remained higher than preflight control values for several days following flight. Cortisol and Angiotensin I were generally elevated, though not always significantly. Potassium and creatinine increased inflight and remained high immediately postflight. Plasma aldosterone, total protein, carbon dioxide, thyroid stimulating hormone, and thyroxine increased postflight. Inflight and postflight plasma measurements showed a decrease in sodium, chloride, osmolality, and adrenocorticotropic hormone (ACTH). Glucose, insulin, and aldosterone decreased inflight, but increased postflight.

Postflight decreases were also seen in cholesterol, uric acid, magnesium, lactic dehydrogenase, and total bilirubin. Blood urea nitrogen (BUN) and albumin were not changed at recovery, but were decreased on the third and fourteenth postflight days. All electrolytes in the 24-hour urine samples inflight and postflight were increased along with aldosterone, cortisol, and total 17-ketosteroids. Postflight increases were seen in epinephrine, norepinephrine, aldosterone, and cortisol. The data also showed a trend towards inflight decreases in antidiuretic hormone (ADH), epinephrine, norepinephrine and uric acid. The inflight norepinephrine levels were probably the reflection of the high levels of physical exercise undertaken by each crew member during the flight.

Significant decreases in sodium, potassium, chloride, osmolality, phosphate, magnesium, uric acid, ADH, and total 17-hydroxycorticosteroids were observed postflight. This experiment examined the biochemical reactions of the body to the stress of space flight. The experiment was the first comprehensive and integrated study of endocrinology and metabolism during prolonged space flight. Significant biochemical changes were observed, but all disappeared shortly after returning to Earth. These changes for the most part indicated a successful adaptation of the body to the combined stresses of weightlessness. The transient nature of some changes, particularly in fluid and electrolyte metabolism, supported the conclusion that a new and stable condition of homeostasis had been achieved. In other areas, particularly those concerned with the metabolism of bone mineral, protein, and carbohydrates, unstable states appeared to persist.

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MIR Space Station During 1986-1990, seven prime crews (PC) carried out missions on the Mir space station and an 8th prime crew has started its space work which will be finished in 1991. A total of 18 cosmonauts (including the 8th prime crew) have participated in extended missions on the Mir space station, one cosmonaut being launched twice.

The primary medical goals for these extended space missions have been maintenance of good health status and performance of space crews and making medical investigations.

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The most regular inflight changes have occurred in the latter part of electrocardiographic tracings (12 standard leads). These demonstrate a decrease of T-wave amplitude in most leads in all cosmonauts. Analysis of hemodynamic parameters has shown a tendency for an increase in mean heart rates (HR) and a lack of change in stroke volume (SV), cardiac output (CO) and actual specific peripheral resistance (SPRa). Ultrasonic examinations of the physician cosmonaut made during months 7-8 inflight did not reveal changes in left ventricular volumes, SV or ejection fraction (EF). Arterial pressure (AP) measurements showed that diastolic pressure (DBP) had a tendency to decrease (P < 0.18) and pulse pressure (PP) to increase (P < 0.07).

Abdominal ultrasonic examinations carried out both inflight (7 cosmonauts examined–4 at the end of 5-6 months, 3 at the end of 8-9 months) and postflight (16 cosmonauts) demonstrated: a moderate increase in the size of the liver, spleen, kidneys, pancreas, blood filling of the lungs, cross-sectional area of the large ventral vessels, and a clearer vascular pattern of liver; decreased acoustic density of the pancreas; signs of lateral renal pelvic enlargement with a decrease in renal parenchyma (decreased parenchymal-pelvic system area ratios).

These changes are considered to be echographic signs of venous engorgement. An increased gall bladder area and dilatation of the common bile duct also point to the development of bile congestion in the biliary tree. In contrast to the preflight period graded physical exercise tests on a bicycle ergometer during flight (at a work load of 125 W and 175 W for 5 and 3min, respectively with a l min interval) resulted in insignificant rises of HR, a decrease of SV and CO (by 14.5 and 15.1%) decline in D BP by 6.8% and a PP increase of 13.5% (P < 0.01). These reactions point to the nature of adaptive inflight processes uncovered by exposure to graded exercise when findings are compared to the preflight period.

Postflight hemodynamic studies during graded step-wise exercise demonstrated a more distinct increase in absolute values of HR, systolic AP and diastolic AP (in most cases); and smaller increment of SV and shortening of the left ventricular ejection period vs its corrected value for changes in HR. No HR and ECG changes of an ischemic type were found. Severity of hemodynamic changes did not depend on flight duration. When compared to pretest hemodynamic parameters, lower body negative pressure (LBNP) tests(at -25, -35, and -45mmHg for 1, 3, and 5 min respectively) applied in flight led to decreases of SV (5.2%) and CO (8%) as well as an increase in SPRa (15.7%). Blood pressure did not change significantly. Inflight relative and absolute increases in SPRa were considered to be reactions to prevent pronounced changes in SV, CO and BP. It should be noted that cardiovascular responses to postflight postural tests had no correlation with flight duration.

Blood alterations during a long stay in microgravity typically include development of transient erythrocytopenia. In the flights of PC-3 and PC-4 there was a decrease in erythrocyte counts (in the physician-cosmonaut from 3.6 X 1012 /l to 3.8 X 1012 /l), anisocytosis and hypochromy. The hematocrit decreased by 4-14%.

Postflight studies several hours following landing revealed a decrease in reticulocytes (from 32.8 X 109 /l to 21.4 X 109 /l), erythrocytes (average count decreased from 4.91 X 1012 /l to 4.68 X 1012 /l), hemoglobin concentration (decrease from 152 to 145 g/l) and hematocrit (decrease from 45 to 42%). Further declines occurred during the first 7 days following flight as body fluids were restored and symptoms of body hypohydration abated: erythrocyte counts fell to 4.1 X 1012 /l, hemoglobin concentration to 131 g/1 and hematocrit to 38.5%. In this case there was the rapid onset of reticulocytosis and counts increased to 60.8 X 109 /l, i.e. an 85% increase.

Hemoglobin mass at R + 7 decreased from 738 to 589 g, i.e. fell 20% compared to preflight baseline values.

The reticulocytosis associated with readaptation gradually normalized over the following 1.5-3 month postflight period. By this time there was practically complete restoration of all remaining "red blood" parameters.

The physician-cosmonaut displayed changes in erythrocyte shape during flight: target cells, ovalocytes, and spherocytes. Target cells were also found in other crewmembers of PC-3 (year-long flight) and PC-4 . The target cells disappeared after a period following landing.

Postflight endocrine stress reactions demonstrated increased plasma concentrations of cortisol (excluding the year-long mission), insulin, thyroxin and catecholamines . In some cases an increase in blood cortisol occurred with an unchanged or decreased level of ACTH. After the 12 month flight there was a 10-fold increase in plasma ACTH concentration which was associated with an insignificant change in blood cortisol level. Studies

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) of hormones regulating fluid-electrolyte metabolism in most cosmonauts revealed a 2-3-fold rise in plasma antidiuretic hormone (ADH) as well as renin and aldosterone at R + 1. Following the year long mission renin and aldosterone concentrations increased only at R + 7 which pointed to the nature of the adaptation process to microgravity. In most cases the postflight blood levels of calcitropic hormones were characterized by increased and decreased levels of parathyroid hormone and calcitonin, respectively.

Metabolic studies revealed regular postflight changes. Fluid-electrolyte studies revealed increased blood calcium levels and in most cases decreased blood potassium levels (in the 4th prime crew it decreased). Over several postflight days urine volume decreased as did renal excretion of sodium, chloride and osmotically active substances. Divalention excretion changed insignificantly.

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Measurements of osmo and ion-regulating renal function using water and salt loading tests revealed a mismatch in the ion regulating system manifest as multidirectional changes for excretion of fluid and some ions.

Nitrogen metabolism was usually characterized by multidirectional and insignificant changes in blood levels of total protein. In the case following a year long flight there was a decrease in plasma levels of α and γ-globulin fractions which assume a decline in biosynthetic-liver activity and/or simultaneous increase of atherosclerotic β-globulins.

In most cases postflight carbohydrate metabolism manifested a moderate hyperglycemia and was associated with an increased secretion of insulin and significant accumulation of underoxidized products of carbohydrate metabolism–lactate and pyruvate. These data combined with changes in plasma lipid parameters point to a significant rise in anaerobic metabolic processes which at R + 7 still exceeded baseline values. Examinations indicated that on the 69th day of flight of the physician-cosmonaut, as well as on days 321-322 in both cosmonauts, glucose utilization slowed down, as determined by a glucose tolerance test. Glucose tolerance curve findings returned to baseline levels over the 2-week period following flight in most cases, but this depended to some extent on flight duration.

Changes in lipid metabolism were characterized by both an increase and decrease in levels of basic lipid substrates–triglycerides and free fatty acids. The content of POL products in blood and erythrocyte membranes was increased at R + 7 following 5 and 7 month flights and frequently at R + 1 and R + 2 when flights were longer than 8 months. Lipoperoxidation, as a rule, was not increased at R + 1 and R + 2 with flights longer than 200 days duration when cosmonauts did not show signs of vestibular disorders. In some cases an activation of POL occurred by R + 7. Thus, data obtained to date in man points to rather extensive and widespread metabolic changes after long-term exposures to microgravity.

Serum enzyme measurements did not demonstrate significant changes in levels of lactate dehydrogenase activity following flights lasting up to 8 months. Its levels did decrease after 11-12 month flights as did levels of malate dehydrogenase activity (MDG) and isocitratedehydrogenase. The fraction of cytoplasmic form of MDG increased due to a decrease in fraction of mitochondrial isoenzyme MDG-3–a sign of a diminished intensity of the basic energy generating process at the cellular level and of changed permeability of membrane structures at the cellular and subcellular levels. The observed postflight increase in serum creatinephosphokinase activity at the cost of its muscular fraction is probably the result of an increased gravitational load on the musculoskeletal system during the readaptation period following microgravity exposure. Specific postflight decrement of the hepatic isoenzyme component of alkaline phosphatase and an increase in its osseous isovnzyme component in a number of flights appears to indicate increased activity of bone cells in response to return to Earth gravity.

Over 200 complex studies of hemodynamics of 26 cosmonauts were performed during space flights of different duration (from 8 to 438 days) in the period from 1982 to 1999 using modern methods (ultrasound echocardiography, 2D echography of visceral vessels, Doppler flowmetry, and occlusion aeroplethysmography).

According to EchoCG data, exposure to microgravity in the first three months caused individual oppositely directed changes in the stroke volume (SV) and cardiac output (CO). Further exposure in microgravity (months 4-6) was accompanied by a statistically significant decrease in SV and CO (p < 0.05) in all cosmonauts. According to EchoCG data, the left ventricular end-diastolic volume (EDV) decreased compared to the pre-flight value.

During the first month of flight, this decrease was small (3-6%) but tended to increase to 8-10% by months 5-6 of flight. The high degree of correlation (r = 0.95) between the dynamics of this parameter and the total body fluid volume led us to assume that the decreased blood filling of heart chambers was due to hypovolemia, which was detected throughout the exposure in microgravity (Table 1).

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In turn, the decrease in EDV was the most probable cause of a certain decrease in the SV. The left ventricular ejection fraction (LVEF; LVEF = SV/EDV) in all cases remained within the range of standard values: changes from 69 ± 2% before flight to 64 ± 2% during exposure to microgravity for six month and longer, from our standpoint, cannot be regarded as significant. As early as on day 1-3 after the return to Earth, the LVEF value practically coincided with the preflight values. Ultrasonographic studies of the cardiovascular system in flights of different duration, which have been carried out for almost 20 years, have not revealed any case of reduced pumping function of the heart.

The results of ultrasonographic studies of the large arterial and venous vessels showed that microgravity significantly affects peripheral hemodynamics (both arterial and venous). Microgravity-induced changes were especially pronounced in regions located below and above the heart level. Under the Earth’s gravity, the high tone of the arterial vessels of the lower body and the low resistance in cerebral, pulmonary, and renal vessels ensure normal blood supply of vitally important organs. In microgravity, blood is redistributed from the region with high vascular resistance to low-resistance zones, which initiates all subsequent changes in the cardiovascular system, including the changes in the vascular tone. Among the regions of the cardiovascular system located above the heart, the cervicocephalic hemodynamics (blood circulation in the head and neck region) is of the most interest. The resistance and the blood flow of common carotid arteries, and the blood filling and blood flow parameters of the jugular veins were researched. The intracephalic blood flow was estimated by the results of study of the medial cephalic artery (a component of the arterial circle of Willis). A characteristic phenomenon important for cerebral blood flow, observed in microgravity, was a significant (by 25-35% compared to the preflight data) dilatation of jugular veins, which was accompanied by a slowed blood flow through them (Fig. 1). This phenomenon was observed in all cosmonauts starting from the first days of flight. As the duration of exposure in microgravity increased, the cross-section of jugular veins tended to further increase (on average, by 38.9 ± 9.0% compared to the preflight data).

This was accompanied by indirect signs of a labored blood return through the jugular veins: the cosmonauts mentioned that it was difficult for them to pronounce long sentences, because the sensation of blood flow to the head was drastically enhanced in this case and significantly decreased after a deep expiration. A significant increase in the cross-section of jugular veins during conversation, comparable to that observed in the Valsalva test, was detected. These data demonstrate the effect of intrathoracic pressure on the blood flow to the right heart: during conversation (i.e., during exhalation with resistance), the pressure in the thorax increases, which hampers venous return. During deep inhalation, conversely, the pressure in the thorax and in the right atrium decreases; as a result, the blood flow to the right heart (the so-called suction effect) is enhanced.

At the beginning of flight (during the first week), blood redistribution was accompanied by a slight (p >0.05) increase in the resistance to the blood flow in the common carotid, internal carotid, and medial cerebral arteries.

Two to three weeks later, these parameters returned to the norm. As the duration of exposure to microgravity increased, the resistance index of the medial cerebral artery tended to gradually increase in all cosmonauts; in month 5-6 of flight, it increased by 5-6% compared to the preflight value. The volume cerebral blood flow remained at the preflight level until the third month of space flight. Starting from month 5-6 of the space flight, a slight (by 4-6%) decrease in the volume blood flow through the medial cerebral artery was detected in the majority of the examined cosmonauts. Authors assumed that this tendency should be regarded as a sign of venous stasis developing in the cervicocephalic region.

The changes in the arterial cerebral blood flow during space flight were several times less pronounced than

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the changes in the venous blood return through the jugular veins. Despite the signs of venous stasis, the arterial cerebral blood flow at rest during exposure in microgravity changed insignificantly. A characteristic phenomenon observed during space flights was a significant and progressive decrease in the resistance of the renal arteries throughout the exposure in microgravity (by -5.3 ± 2.0% at the beginning of flight and 15.4 ± 3.1% at the end of half-year flights, p < 0.01).

The exposure in microgravity was accompanied by a decrease in the resistance to blood flow through the femoral arteries and a considerable dilatation of the great venous vessels of the legs. This phenomenon largely accounted for the development of orthostatic intolerance. The major role of venous vessels of the legs in the etiology of orthostatic intolerance was mentioned by many researchers. L.L. Shik, believed that the increased compliance of the leg veins is the key factor underlying the development of orthostatic disorders and that the absence of a hydrostatic gradient causes a decrease in the intravascular venous pressure and a decrease in the turgor of tissues surrounding the leg veins. The role of extramural pressure created by the muscles and perivascular tissues surrounding the veins in the increase in the venous capacity was also mentioned by other authors.

An increase in the cross-section area of the femoral veins by 20-50% was recorded during ultrasonographic scanning starting from week 3 of flight. In the majority of cosmonauts examines, it steadily increased during six-month exposure in microgravity. This finding allowed authors to assume that the decrease in the hydration of soft tissues and in the tone of the skeletal muscles of the legs, which developed during flights in space, significantly reduced the extramural pressure on the walls of veins, thereby increasing the so- called vein-free compliance zone (Table 2). It was also important to determine how the capacity of venous vasculature of the legs changes in microgravity against the background of hypovolemia and blood redistribution to the upper body.

Such studies were performed using occlusion aeroplethysmography, which allows the exact parameters of venous filling and return, including the so-called "leg venous network capacity," to be determined. This parameter makes it possible to estimate, which blood volume can be redistributed to leg veins in the orthostatic test, or the under exposure of the lower body to negative pressure (to 50 mm Hg.) (the LBNP test).

It was discovered that, during space flights, the leg venous network capacity significantly increased as early as in the first week of flight. During the first month of exposure in microgravity, these changes increased, reached a maximum in the second or third months of flight, and remained stably increased throughout the period of

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) exposure in microgravity (Table 2). In some cosmonauts, the capacity of the legs’ venous network continued to increase until the end of flight.

In microgravity, 100% of the studies using occlusion plethysmography showed that an increase in the calf volume (i.e., blood stagnation) was observed at a lower occlusion pressure than on the Earth (10 mm Hg), which has never been detected in the Earth’s gravity both before and after flight. This fact indirectly confirms the assumption that exposure in microgravity causes (1) a decrease in the intravascular pressure in the distal leg veins and (2) an increase in the vein-free compliance zone of the legs.

The fact that this effect was recorded beginning from the very early studies in flight (on day 5) and completely disappeared on the first day after the end of the flight, allowed us to postulate that it is based mostly on a rapid hemodynamic process, namely, blood redistribution. Thus, hemodynamic changes (slowed venous return, decreased resistance of the lower body vasculature, and increased leg venous network capacity) were detected in cosmonauts at rest. Each of these changes might facilitate the development of orthostatic intolerance.

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Thus, hemodynamic changes (slowed venous return, decreased resistance of the lower body vasculature, and increased leg venous network capacity) were detected in cosmonauts at rest. Each of these changes might facilitate the development of orthostatic intolerance.

Fluid And Electrolyte Homeostasis The microgravity environment has long been known to affect the body’s fluid and electrolyte homeostasis. The headward shift of fluids results in increased excretion of fluids and electrolytes. The loss can be further increased through the onset of space motion sickness. Apart from the issue of fluid loss, i.e. loss of total body water (TBW), is the redistribution among the major fluid compartments: intracellular fluid, extracellular fluid, and plasma volume.

During short-term Space Shuttle missions it was evident that fluid loss mainly occurred in the beginning of the mission, reaching its maximum after a few days. This level of fluid loss was maintained throughout the flight. The effects of prolonged exposure to microgravity on fluid and electrolyte homeostasis have not been well defined. The information is required for the development of countermeasures for future extended duration missions. This includes the determination of the nature and extent of fluid and electrolyte loss, as well as the physiological processes of adaptation to microgravity.

The fluid and electrolyte balance in the human body is regulated by several systems. The kidneys play an important role in the regulation of fluid and electrolyte excretion and retention. There are also many endocrine and circulatory factors which act to regulate fluid homeostasis. This study investigated the possible effects of endocrine, renal, and circulatory influences on fluid and electrolyte homeostasis in microgravity. The Mir 18 mission provided an excellent opportunity to study these systems before, during, and after four months of exposure to microgravity.

To assess the impact of extended duration space flight on fluid and electrolyte homeostasis, blood, urine, and saliva samples were collected. The specimen samples were assayed for different biochemical and endocrine indices to determine electrolyte balance (electrolyte concentration in blood/serum, electrolyte excretion), kidney function, and regulatory hormones (aldosterone, plasma renin activity, antidiuretic hormone (ADH), and atrial natriuretic peptide(ANP)). In addition, measurements of body mass were taken and dietary intake was monitored. Tracers were used to estimate fluid compartments and water turnover. All three crewmembers of the Mir 18 mission participated in data collection for this experiment.

Preflight urine collection was performed during three time periods, at L-150 to L-145, L-60 to L-55 and L35 to L-33. A total of 365 urine samples were collected during all three data collection sessions (including back-up crewmembers). Inflight urine collection was performed on MD 12 and MD 93 on board Mir and on FD 5 (=MD 110) aboard STS-71. Overall, 51 urine samples were collected aboard Mir and 22 samples aboard STS-71. During three postflight sessions (R+0 to R+7, R+7 to R+14, and R+75/115) 225 urine samples were collected. The samples were either frozen at -20 degrees Celsius or preserved with thimerosal or thymol. Saliva samples were collected immediately postsleep during the same time periods. The inflight saliva samples were frozen at -20 degrees Celsius until analysis.

Blood collection was performed three times preflight (L-150, L-60, L-35) and three times inflight (MD 12, MD 93, and FD 5). A total of 32 blood samples were collected aboard Mir and 25 samples on board the Shuttle.

All blood samples were aliquoted and frozen at -20 degrees Celsius. Blood sodium and potassium were deter-

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) mined in ’real-time’ using the Portable Clinical Blood Analyzer (PCBA) kit, while aldosterone, ADH and ANP were assayed postflight at JSC laboratories. Postflight blood collection took place at R+0, R+9 and R+75/115.

Body mass measurements were taken periodically before, during and after the mission. Dietary intake was logged in a fluid/food/mediation log book or by using the Bar Code Reader (BCR) hardware.

Water distribution in the body was determined by measuring total body water (TBW), plasma volume (PV), and extracellular fluid (ECF) volume. To measure the total body water (TBW), labeled water (H2 18O) was ingested by the astronauts, followed by a seven hour period of urine and saliva sampling. Extracellular fluid (ECF) volume was determined using the bromide dilution technique.

Three hours after the non-radioactive bromide solution was ingested, a blood sample was drawn. Water distribution and extracellular fluid were measured three times preflight (L-150, L-60, L-35) and three times during flight (MD 12, MD 56, and FD 5). Postflight measurements were performed on R+0, R+7, and R+75/115).

Plasma volume (PV) was estimated pre- and postflight, on L-35, L-11, R+0, R+9, and R+75/115, using the carbon monoxide (CO) rebreathing method.

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Only two of four scheduled data collection sessions were performed by all three Mir 18 crewmembers (MD 13 and FD 5). The third session (MD 93) was performed by one crewmember only and the fourth session, (planned for MD 70) was completely canceled. Also, during the Mir 18 mission, the EuroMir freezer failed, compromising the quality of urine and saliva samples collected early inflight. Following the shutdown of the EuroMir freezer, the samples were transferred to the Mir Refrigerator, which apparently protected some of the analytes. Blood samples were not affected by the freezer failure.

It was hypothesized that within hours of entering microgravity plasma volume (PV) would decrease by 1215% and extracellular fluid (ECF) would decrease by 10%. Measurements taken preflight and inflight showed that the mean of plasma volume decreased from 3.16 liters to 3.01 liters (average of three crewmembers), and extracellular fluid volume was reduced from 19.53 liters to 15.56 liters.

After 110 days of flight the plasma antidiuretic hormone (ADH) concentrations of all three crewmembers and atrial natriuretic peptide (ANP) levels of 2 of the 3 crewmembers had decreased compared to preflight values. ADH dropped from 2.6 pg/ml to 0.9 pg/ml , and ANP from 20.0 pg/ml to 12.6 pg/ml (averages of all 3 crewmembers).

The decrease in plasma and extracellular fluid volume were similar to changes found during 14 day Shuttle flights. The changes in fluid volumes that occurred during early measurements appeared to remain throughout the long-term mission. This indicated that these are not transient effects, but rather reflect an adaptation to space flight which occurs within the first days to weeks of flight.

Tolerance of +Gz loads by space physician Poliakov VV during the active phases of his 438 days space mission Tolerance of +Gz loads was assessed in space physician V.V. Polyakov during the active phases of his record, 438 day space mission. On the phases of insertion into orbit the +Gz-tolerance of the space physician was good; a fairly satisfactory gtolerance during departure of orbit was extenuated by wearing of two anti-g suits (KARKAS3 and CENTAUR) and administration of countermeasures against the unfavorable effects of space microgravity.

His general health state and selfrating were not noticeably altered. +Gz loads in the course of descent from orbit instigated a syndrome characteristic of return to Earth from prolonged microgravity, i.e. a sensation of fierce pressure on the body, difficult breathing and speech, sine tachycardia, tachypnea, singular arrhythmias, petechial hemorrhage in the back integument, and vestibular/autonomous reactions.

However, no evidence of any unusual physiological reactions that had never been seen in the other cosmonauts donned in the anti-g suits on earlier and less extended (from 65 to 366 day) missions were found. Extra systoles were registered on the phase of return to Earth after the 438 day but not previous 241 day mission of the space physician; they were probably associated with aging as he made his maiden flight at 47, and the second, at 53. The results speak in favor of the countermeasures against the adverse effects of microgravity applied during the mission, and the anti-g suits worn on the stage of return to Earth.

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D ID YOU KNOW ?

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L OWER B ODY N EGATIVE P RESSURE (LBNP) T RAINING

LBNP training is performed using a "Chibis" pneumovacuum suit (PVS), which provides the possibility for a human to move and imitate walking under low barometric pressure. The suit consists of a container for the pelvis, two corrugated trouser legs made of rubberized fabric, and shoes. It is equipped with shoulder belts, a pressel for emergency stop of the rarefaction in the container, and a valve that limits the value of the air rarefaction by 60-70 mm Hg.

The hermetization of the suit is performed at the level of the iliac crest bones. Chibis PVS allows cosmonauts to perform alternating movements from foot to foot and knee bends, the combination of which promotes training the vessels of the legs and counteracts the excessive deposit of blood in them during prolonged flights.

The basic principles LBNP training during a space flight are the following : performance of LBNP training only in the final phase of flight; a gradual increase in the value and duration of rarefaction both within one session of training, and in series of consistently repeated exercises; combination of LBNP training with drinking 300 ml of liquid before the training.

Figure 1: NASA Image: ISS045E015466 - NASA asThe water-salt additive (WSA), which supplies the tronaut Scott Kelly wearing a headset and a Chibis body with additional sodium chloride and water, is Lower Body Negative Pressure (LBNP) Suit, underapplied at the final phase of the flight to make up for goes ultrasound measurements for the Fluid Shifts the intravascular liquid volume reduced under the inexperiment. fluence of microgravity, to bring it in correspondence with the capacity of the vessels, and to prevent orthostatic instability. The WSA consists of three tablets of 0.9 g of sodium chloride and 300 ml of fluid. It is taken with food before putting on the spacesuit with the performance of the regular cycle of LBNP and PT. Cosmonauts who included the WSA in a complex of prophylactic measures exhibited a better ability to withstand overloads in the final phase of the flight. During the rehabilitation period, they had a more stable hemodynamic state and smaller reduction of the excretion of fluid, sodium, and osmotically active substances.

LBNP training includes two stages: the first consists in four preliminary trainings aimed to test the orthostatic stability and train cosmonauts for the intense stage of LBNP, and the second (final) is designed to activate the regulation of cardiovascular and neuroendocrine systems and water-salt homeostasis.

At four preliminary trainings 18, 14, 10, and 6 days before the end of the flight, the following approximate regimens of air rarefaction are used: Day 1: -20, -25, -30, and -35 mm Hg; Day 2: -25, -30, -35, and -40 mm Hg; Days 3 and 4: -25, -35, -40, and -45 mm Hg. The duration of each stage of rarefaction is 5 min on each training day.

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At the second stage, the following training is performed during the last two days before the end of the flight: Day 1. The first cycle: -25, -35, -40 and -45 mm Hg for 5 min at each step, followed by a smooth decrease to zero for 1 min; the second cycle: -25, -35 and -45 mm Hg for 10 min at each stage; then, 30 mm Hg for 5 min, and a decrease to zero for 1 min.

Day 2. The first cycle: -25, -35, -40, and -45 mm Hg for 5 min at each step, followed by a smooth decrease to zero for 1 min; the second cycle: -25, -35, and -45 mm Hg for 10 min at each step; then, 30 mm Hg for 5 min and a decrease to zero for about 1 min.

To ensure the safety of LBNP exercises during a flight, they are performed under strict medical monitoring, as well as self-control and mutual control. It is recommended to simulate walking at a rate of 10-12 steps/min, shifting from one foot to the other during the rarefaction. If necessary, when the values of the rarefaction are more than -35 mm Hg, cosmonauts can use the pressel. Tolerance to training is estimated by means of recording the heart rate, blood pressure, and some other physiological parameters.

Reference: R

I. B. Kozlovskaya, I. D. Pestov, A. D. Egorov , The system of preventive measures in long space flights , Human Physiology December 2010, Volume 36, Issue 7, pp 773-779.

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Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment (Fluid Shifts) , NASA. Available Online : http://www.nasa.gov/mission_pages/station/research/experiments/1257.html

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Evgeniya N. Yarmanova ,Inesa B. Kozlovskaya , Perspective means in Russian system of countermeasure , Institute of Biomedical Problems of the RAS. Available Online : https://www.nasa.gov/centers/johnson/pdf/505722main_Perspective_Means_In_Russian_System_Of_Countermeasure.pdf

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Chibis Lower Body Negative Pressure (LBNP) Device , NASA .Available Online : https://lsda.jsc.nasa.gov/scripts/hardware/hardw.aspx?hardware_id=736

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A Lab Aloft (International Space Station Research) ,NASA Blog , NASA .Available Online : https://blogs.nasa.gov/ISS_Science_Blog/2015/06/02/rubber-vacuum-pants-that-suck/

Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

Shuttle On Earth, the parts of the cardiovascular system (the heart, lungs, and blood vessels) work together in a stable state of equilibrium. In weightlessness, blood and other fluids are redistributed to the head and upper body.

In response to the fluid shift, the body’s normal homeostatic mechanisms appear to adjust the operation of the heart and other parts of the body.

For Spacelab research, an instrument was developed to record changes as the heart adjusts to microgravity.

Called an echocardiograph, the instrument generates two-dimensional images by interpreting high-frequency sound waves directed at the heart. It was tested during Shuttle mission 51-D in April 1985 when real-time images of four crewmembers’ hearts revealed major cardiovascular adjustments during the first day of spaceflight.

The left side of the heart (which propels blood through the circulatory system) reached its maximum size, as did the blood volume it pumps, on the first day; the right side of the heart (which collects blood returning from the rest of the body) was smaller than when imaged preflight. By the second day of the mission, the entire heart was smaller and subsequent changes progressed more slowly. The reduction in the left heart volume remained unchanged for at least 1 week after return to Earth.

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From these observations, investigators concluded that the cardiovascular system adjusts quickly to fluid shifts and blood volume loss during spaceflight. Results from a French echocardiograph flown on the 51-G mission confirmed the U.S. observations on the 51-D mission. More extensive tests are needed to determine if the decrease in heart volume is associated with any reductions in heart performance. A U.S. echocardiograph is scheduled to be flown again with complementary instruments on a mission dedicated to life sciences research.

Since changes in the heart appear to be linked directly to fluid shifts, it is important to track the time course of fluid shifts in microgravity. One way to measure changes in the amount of fluid in the upper body is to measure corresponding changes in the circulatory system. As fluid volume increases, scientists have predicted that more pressure than usual should be exerted on the upper body veins; as upward fluid flow decreases, the pressure should equalize. Spacelab 1 investigators tried to determine the degree and rapidity of the fluid shift by measuring central venous pressure in the arm veins of four crewmembers. Before this mission, no direct measurements of venous pressure were available to test the hypothesis.

Surprisingly when venous pressure was measured 22 hours into the mission, it was lower, not higher, than preflight measurements. One hour after landing, venous pressures were high for all four crewmembers, indicating fluid shifts associated with the body’s readaptation to Earth.

This experiment was repeated using four different subjects on the Spacelab D1 mission with measurements made as early as 20 minutes after launch. Even with early measurements, the venous pressure was still lower than the preflight measurements, confirming the Spacelab 1 results. The investigator was astonished at the low pressure level so early in the mission before any dehydration was possible.

From these results, investigators concluded that the fluid shift is a highly dynamic process that may occur even before launch when crewmembers spend about 2 hours seated in the Shuttle on the launch pad. To confirm this hypothesis, investigators want to make measurements during this waiting period along with measurements of hormones that regulate fluid balance. A novel device for noninvasively measuring venous pressure may help clarify the profile of fluid shifts by enabling more frequent and convenient measurements. Limited measurements with the device, which was tested on the 61-C mission, confirm the Spacelab 1 and Spacelab D1 results.

Central Venous Pressure in Space When a person enters zero gravity, a large amount of fluid (1 to 2 liters) shifts toward the head. The response to this shift includes the principal cardiovascular effects of spaceflight – e.g., hypovolemia, dehydration, and postflight orthostatic intolerance. On earth, a similar headward shift of fluid increases central venous pressure; in space, however, peripheral antecubital venous pressure does not increase.

It is not known whether such peripheral measurements reflect central venous pressure. Only direct, continuous measurements recorded during a change from earth’s gravity (1 g) to zero gravity can resolve these controversies. In June 1991, authors directly measured central venous pressure in an astronaut on a space shuttle during the National Aeronautics and Space Administration’s Spacelab Life Sciences 1 flight. Authors hypothesized that the pressure would increase as a result of the headward fluid shift.

To measure the expected small changes in pressure, a special device for continuous ambulatory measurement of central venous pressure was designed. Owing to research constraints, only one crew member of the shuttle

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could be studied. A 4-French catheter was inserted through an arm vein the night before the planned launch.

Before the launch, the crew member was strapped into the horizontally positioned orbiter seat; he remained supine, with his legs up, for four hours. Central venous pressure was measured continuously from suit-up until nine hours into the flight. Eight hours after launch, cardiac volume was measured with both two-dimensional and three-dimensional echocardiography; the heart rate and blood pressure (indirect measurement) were also recorded.

The central venous pressure rose from 5 to 6 cm of water while the crew member was seated to 10 to 12 cm of water while he was in the launch position in the shuttle orbiter (Figure 1). It increased further during launching, to approximately 15 to 17 cm of water, owing to anterior-posterior gravitational loading, in which the chest is subjected to three times the force of earth gravity. Once in zero gravity, however, the central venous pressure dropped to 0 to -3 cm of water within 60 seconds. It remained within 1 to 2 cm of 0 until the catheter was removed. The left ventricular internal end-diastolic dimension increased during flight from 4.6 (its preflight value in the supine position) to 5.2 cm; the left ventricular end-diastolic volume, from 141 to 167 ml; the stroke volume, from 68 to 89 ml; and the cardiac output, from 5.2 to 6.0 liters per minute.

The central venous pressure decreased in space. This finding refutes the hypothesis that central venous pressure increases as a result of the headward fluid shift induced by zero gravity. Despite the fall in central venous pressure, the heart size increased. Thus, spaceflight produced unique hemodynamic changes in the astronaut studied that were not predicted by ground-based models. In space, gravity no longer exerts any pressure within tissues. This could alter compliance throughout the cardiovascular system, so that the same blood volume is contained at a lower pressure.

Noninvasive Estimation of Central Venous Pressure During Space Flight (DSO 462)

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

Evidence suggests that cephalad fluid shifts during weightlessness stimulate arterial and cardiopulmonary baroreceptors, leading to cardiovascular readaptation syndrome. Central venous pressure (CVP) is one variable used to monitor fluid shifts. A noninvasive Doppler technique was used to document CVP during weightlessness.

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The subjects’ jugular flow was monitored via a pocket Doppler device, which provided an audio Doppler signal. The character of the jugular flow was assessed, and after a verification trial, the target pressure was accepted as the CVP estimate. A total of 9 astronauts, 4 women and 5 men, were subjects for this investigation. They flew on 4 Shuttle flights with flight durations of 5, 5, 6, and 8 days. Preflight data were collected one or more times from all 9 subjects while they were supine, and inflight data were collected as often as possible.

Figure 2: NASA Image: This graph depicts normalFor the 9 subjects, absolute data, as well as data nor- ized central venous pressure for subjects in the DSO malized using the preflight average, showed a signif- 462 study. icant decrease in CVP from early in the mission (day 1) to late in the mission (day 6). After inspection of the data, subjects were grouped according to whether or not the last in-flight data point was greater than their preflight average. The 2 groups (n=4 and n=5) were compared with respect to the relationship between CVP response and the subjects’ sex, age, severity of motion sickness, body weight, and changes in body weight. The results for these factors were equivocal because of the small number of cases. The decrease in CVP agrees with earlier studies, but this study showed a different time course for the changes.

Changes in Total Body Water During Space Flight This investigation was designed to measure by means of direct in-flight assessment, the changes in total body water (TBW) occurring in humans as a consequence of several days’ exposure to microgravity on the Space Shuttle. TBW measurements provide important data for several cardiovascular and fluid/electrolyte experiments making up the science payload for the dedicated life sciences missions (SLS-1 and SLS-2). According to several models, changes in TBW are predicted to parallel fluid shifts. Therefore, changes in TBW can be used as a convenient indicator of the time course of adaptation to weightlessness. Because of its ease of measurement, TBW was the method of choice to verify in flight the timing proposed for fluid compartment measurements planned for SLS-1.

The subjects for this experiment were five male crewmembers of Space Shuttle missions STS-61C and STS26. The design included no special control group or control experiment. Instead, all in-flight and postflight data were compared to preflight baseline data. Because of a delay in the launch of STS 61-C and the unavailability of some crewmembers during the immediate pre-and postflight periods, the first preflight measurements were at L-31 to L-30, while some measurements were missed entirely.

TBW was measured by the isotope dilution technique utilizing 18 O-labeled water as the tracer. This method required the ingestion of a known mass of 18 O water followed by sampling of representative body fluids such as urine or saliva over a period of several hours following the administration of the tracer. The measurements were initiated immediately after a sleep cycle with the crewmember in a fasted state. After the collection of background samples, the dose was consumed followed by at least 50 ml of fruit juice or galley water. The subject was allowed to consume a light breakfast 30 minutes after dose administration and was requested to abstain from caffeine containing beverages for the duration of the experiment. All food consumed during the experiment was recorded on a log sheet.

Samples of galley water were collected on FD 2 and FD 4/FD 5. The experimental design called for galley water sampling on all days on which TBW was measured because water sampled from the galley on several

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) occasions, including ST5-51D, was found to be enriched in 18 O. Test subjects collected saliva by placing a dental cotton roll under the tongue for several minutes and then replacing the saturated cotton in the vial. It was determined in supporting studies that samples could be stored for more than a week at ambient temperature without affecting isotope content, provided they were protected from evaporation. Sample vials were replaced in the original kit and stowed in a middeck locker different from the one for used dose syringes. As mentioned above, this precaution was taken to minimize the possibility of accidental contamination of the sample vial contents. The samples were frozen at -70◦ C after being returned to the laboratory.

Analyses of the samples were carried out in ground-based facilities of the USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX. Two methods of analysis were used because of the advance in technology between the two missions on which data were gathered.

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STS-61C: Frozen samples were thawed, and approximately 0.3-0.5 g were transferred to pre-weighed 20ml Vacutainer serum tubes using disposable plastic tuberculin syringes. The tubes were re-weighed to determine the mass of the sample. The tubes were then filled with 5% carbon dioxide, 95% nitrogen and equilibrated for 48-72 hours at 25◦ C. The cryogenically purified carbon dioxide was analyzed using a Model 3-60 Gas Isotope Ratio Mass Spectrometer (Nuclide Corp., University Park, PA).

STS-26: Samples were analyzed using a microchemical technique requiring only 100 µL of sample. The method employed a modified ISOPREP18 (VG Isogas Ltd., Cheshire, England) in which 100 µL of the aqueous sample was equilibrated with carbon dioxide for 10 hours at 25◦ C,300 mbar. The carbon dioxide was cryogenically purified and introduced into a VG SIRA-12 gas-isotope-ratio mass spectrometer (VG Isogas Ltd.) for determination of 18 O to 16 O ratio.

Preflight and postflight mean TBW values are significantly different from the in-flight mean values. However, the preflight and postflight values are not significantly different, nor do the in-flight means on FD 2 and FD 4/FD 5 differ appreciably from one another.

The high variability of the measurements on FD 2 suggests that individuals may differ in the rate at which they respond to the weightless environment. The difference in response may be intrinsic or may be related to some other factor such as the nausea induced by space motion sickness (SMS). Returning flight crews rate their incidence of SMS on a scale of 0 to 3, where 0 represents no symptoms and 3 represents severe symptoms including three or more episodes of vomiting. It is reasonable to assume that astronauts who are experiencing even mild nausea would limit their consumption of water and other liquids and would therefore experience some degree of dehydration.

It was noted that, of the three crewmen who reported an SMS index of 0 for the missions in question, two had not experienced a decrease of TBW by the time of the FD 2 measurement, Le., approximately 24 hours after launch. On the other hand, the two crewmen who reported either 1or 2 for SMS had experienced a decrease of several kg by this time. This observation suggests that decreased water intake may be an important factor influencing the rate of TBW decrease.

In agreement with previous observations, the galley water was found to be enriched in 18 O; e.g., on STS-26 the enrichment was 57 parts per thousand relative to the standard, Vienna Standard Mean Ocean Water (VSMOW). The actual ratio of 18 O to 16 O in galley water was 0.00212 (both at 19 and at 65 hours MET). This value may be compared with the ratio observed in V-SMOWO.0020052. The source of this enrichment seems likely attributable to the design of the Shuttle galley water system, which makes use of the water produced in the fuel cells. Enhanced evaporation of the lighter isotope during storage of the liquid oxygen may account for its enrichment in the heavier 18 O. This study represents the first time that it has been possible to measure a body fluid compartment by direct means during space flight. Based on the results observed in the five crewmembers, it is concluded that TBW decreases by 3.4% after one to three days of exposure to microgravity in the Space Shuttle. Some individuals appear to undergo this decrease within 24 hours. This effect may be enhanced by decreased water intake due to nausea associated with SMS.

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International Space Station Measurements of jugular, portal, femoral, and calf vein cross-sectional area for the assessment of venous blood redistribution with long duration spaceflight Ten astronauts participated in the study. Jugular vein (JV), portal vein (PV), femoral vein (FV), tibial vein (TibV), and gastrocnemius vein (Gast V) were assessed by echography for the measurement of vessel crosssectional area. Inflight exams were conducted by astronauts using a volume capture method in which images collected were processed to produce a 3D reconstruction of the vessel which was later analyzed by a trained sonographer. Measurements were conducted pre-flight, at the beginning of the flight (day 15), near the end of the flight (4-5.5 months), and post-flight.

Ninety percent of the video files downlinked from the ISS were of sufficient quality to be processed allowing for measurement. Due to missing data points (equipment failure and delayed replacement), two astronauts were excluded from the inflight analysis (n = 8). With spaceflight, PV volume (Fig. 2a) and JV volume (Fig. 2b) were both significantly increased with respect to pre-flight values both early and late in the spaceflight (PV: +36 and + 45 %; JV +178 and +225 %). The magnitudes of the increase in PV volume and JV volume were not equivalent resulting in a significant increase in the JV/PV ratio (JV volume to PV volume ratio–Fig. 2c, p < 0.05) both early and late in the spaceflight (JV/PV: +102 and +120 %).

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Similar to the PV and JV results, FV area (Fig. 3a) was also found to be increased early (+124 %) and late (+169 %) during the spaceflight. In contrast, TibV (Fig. 3b) and Gast V (Fig. 3c) were found to be decreased with spaceflight (TibV: -46 and -52 %; Gast V -68 and -55 %). All values measured returned to pre-flight levels on R + 4 with the exception of TibV which was still reduced (-19 %).

With the transition from a supine to a seated posture, both the TibV area and Gast V area were seen to increase. There was no difference in this change post-spaceflight compared to the pre-flight response (Table 1).

Increase in jugular, portal, femoral vein size This study demonstrated significant changes in venous dimensions with long duration spaceflight which may be indicative of venous blood pooling. These results support the hypotheses of the study in that all astronauts showed the same directional changes in JV volume, PV volume, and FV cross-sectional area indicating that the observed venous changes are the result of exposure to the spaceflight environment and are consistent across the astronaut population. As diet and exercise were not strictly controlled during the flight, and astronauts reported both increased and decreased physical activity levels and salt intake, it would appear that the observed responses occur independently of physical activity or nutritional status.

Additionally, the differences in the magnitude of venous changes in different vascular beds may indicate significant blood pooling and fluid shifts with spaceflight which may have additional physiological consequences requiring further study.

Despite a possible reduction in circulating blood volume of approximately 10 % and carotid and femoral arterial flows remaining stable as already reported during long term flights, the jugular and femoral veins in the current study were found to be significantly increased in all astronauts during spaceflight. This increase in size of the jugular and femoral veins could indicate a passive stowage of blood at the cephalic and pelvic areas, respectively, and not an increase in flow rate or circulating blood volume.

In contrast to the femoral and jugular veins, the increase in portal vein cross-sectional area and volume may indicate that more blood was stowed in the portal venous network, and that possibly, more blood was traveling through the splanchnic area. A similar increase in portal vein area was previously observed during bed rest and corresponded both to an increase in blood volume inside the portal vein network (increased crosssectional area) and in flow volume (ml/min) crossing the vessel (increased blood velocity and cross-sectional area). The increase in portal vein cross-sectional area with bed rest was observed despite a significant reduction in plasma volume and cardiac volume, and a decrease in mesenteric arterial vascular resistance.

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These observations support the idea that the increase in portal vein cross-sectional area might be indicative of increased splanchnic blood volume and flow; however, in the present study, authors did not have access to

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR) flow velocity and thus can only comment on flow volume (ml) and not flow volume change (ml/min) in the splanchnic area. Finally, the increased venous dimensions observed in this study suggest the presence of higher amounts of blood in the cephalic, splanchnic, and pelvic regions during the flight which confirm the 3 first hypotheses. Additionally, despite the high amplitude variability of these changes among the astronaut group, each show the same directional change in vein size which confirm the 4th hypothesis.

Potential consequence of the cephalic, splanchnic, and pelvic, regional venous blood pooling These networks are not designed to store large amounts of fluid over long periods of time which may have an impact on organ structure and function. The hydrostatic pressure against cephalic organs (eye, brain, thyroid, superficial muscle skin tissue) may increase and provoke a higher filtration towards these tissues as evidenced by the presence of a facial skin edema. A similar phenomenon may also be present inflight at the eye fundus level (increase papilla and vein) and may contribute to the visual impairment reported by several astronauts inflight. Additionally, the blood stagnation inside the jugular vein may contribute to increased intracranial pressure, potentially resulting in impaired cerebrovascular reactivity.

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Several studies have reported an increase in circulating insulin in astronauts during spaceflight and an increase in glycemia and insulin resistance during bed rest. These changes may be in part due to altered abdominal organ function from splanchnic venous pooling. However, this has yet to be investigated. Similarly, the increase in femoral vein cross-sectional area confirms the presence of venous blood stagnation in the pelvic region but to date, there is no evidence to suggest a potential impact on pelvic organ structure or function.

The jugular vein volume to portal vein volume ratio (JV/PV) was calculated with the objective to quantify the proportion of venous blood volume stowed at the cephalic level compared to the splanchnic one. This index of venous blood volume (blood pooling) redistribution was significantly increased with spaceflight by approximately 102 and 120 % which indicated that the increase in venous blood volume was higher at the jugular level than at the splanchnic one. Previous reports have indicated that only a subset of astronauts experience visual problems with long duration spaceflight. This may be related to individual differences in venous blood pooling as not all astronauts in the current study showed the same magnitude increase in the JV/PV ratio with spaceflight. Future studies will look to determine if the magnitude of cephalic venous blood pooling relates to the incidence and degree of visual symptoms observed during long duration spaceflight.

Reduction of calf vein in relation with microgravity induced fluid shift In contrast to the jugular, portal, and femoral veins, the calf veins were found to be significantly reduced for the duration of the spaceflight. During spaceflight, changes in body posture do not result in distension of the leg veins that would be normally seen on Earth. However, despite the veins of the calf being significantly smaller during spaceflight, the distension response to a change in body position (supine to sit) upon return to Earth was not altered. This is in contrast to results from long duration bed rest which reported greater distensibility of the veins during lower body negative pressure (LBNP) or stand tests. It is possible that the exercise countermeasures used by astronauts on the ISS may have contributed to the maintenance of the response of leg veins to posture change. Additionally, it should be noted that supine to sit transitions may not be equivalent to stand test or LBNP. Therefore, it is unclear if the lower leg vein response would be consistent if a greater orthostatic stress was applied.

EFFECT OF THIGH CUFFS ON THE INTERNATIONAL SPACE STATION The Braslet-M thigh cuff countermeasure device is intended to ameliorate the symptoms associated with the microgravity induced cephalad volume shifts in the early hours and days of microgravity exposure by impeding the venous outflow and creating commensurate fluid sequestration in the lower extremities. The cuffs are custom built for each crewmember before the mission and consist of segments of elastic and nonelastic materials to conform to the shape of the upper thigh (Fig. 1). Each device contains an adjustment belt that can be tightened to achieve the desired degree of compression selected in preflight calibration, which consists of a special negative 30◦ tilt-table procedure based on subject feedback and cranial impedance rheography to determine the appropriate compression of the extremity.

Braslet-M sets were custom made by the manufacturer (Kentavr-Nauka, Moscow, Russia) for each subject and then individually calibrated as a nominal operational countermeasure in a standardized preflight tilt-table procedure. Cranial rheographic data were acquired in supine and -30◦ HDT. The Braslet was gradually tightened in a stepwise fashion while trained experts recorded subjective feedback, rheographic tracing, and the appearance of the subject. The device setting was determined to assure subjective improvement (reduction of fullness of the head and nasal congestion and often a perception of being untilted), as well as return of rheographic tracing to the pretilt pattern (Fig. 1). This setting is considered to provide appropriate compression of the extremity for countermeasure purposes; the same setting was used in this study.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

All crewmembers were medically certified for spaceflight by the ISS Multilateral Space Medicine Board using a physical examination and screening that includes a comprehensive cardiovascular assessment with ECG, exercise stress test, transthoracic echocardiography, Holter monitoring, electron beam CT for coronary calcium scoring, a large assortment of laboratory tests, and a clinical cardiovascular risk assessment. Subjects and operators for this study were enlisted on a voluntary basis following written informed consent. The study was approved by the human research boards of each subject’s agency and then by the ISS Human Research Multilateral Review Board.

Results Table 1 summarizes results from 15 experiment sessions conducted on nine subjects. Out of the 17 sessions scheduled, 15 successfully produced a useful set of data. Some anomalies included the following.

• One session not performed due to ultrasound hardware failure.

• One session in which cardiac image data were not captured properly due to a procedural error.

• One session in which no ECG tracing was obtained with vascular images.

• One session in which partial data were lost due to hardware failure.

• One session not performed due to scheduling constraints.

• One session in which respiratory maneuvers were not properly synchronized, causing difficulties with data analysis.

Effect of Braslet on cardiovascular parameters The Braslet cuff was identified as producing a statistically significant effect on the mean response during at least one type of maneuver (including baseline) in 10 of the 27 parameters measured. In particular, significant decreases with application of the cuff were observed in cardiac output, LV stroke volume, left lateral E’ mitral A and E wave velocity, and right isovolumic relaxation time (IVRT) during baseline; left lateral A’ and E’ during the modified Valsalva maneuver; and left lateral E’ right IVRT, and right Tei index (49a) during the modified Mueller maneuver. Significant increases were observed in mitral deceleration time (baseline) and in the femoral vein area (baseline) and Valsalva (Fin Table 1). Echocardiographic normal parameters were studied on the ISS and, using data, the magnitude and direction of the changes reported in Table 1 can be approximated for these subjects.

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Special Edition on Gap’s in NASA’s Human Research Roadmap (HRR)

Comparison of Valsalva, Mueller, and baseline - maneuvers with and without Braslet The effect of the Braslet cuff (on vs. off) was significantly different in seven parameters between at least two of the maneuvers (including baseline; last column of Table 1). More specifically, parameters showing evidence of this differential change were cardiac output, heart rate, IJV area, LV diastolic volume, left lateral S’, mitral deceleration time, and right lateral E’.

Braslet Release After completing all the imaging components with maneuvers in Braslet-off and Braslet-on states, the cardiac probe was positioned to get a continuous four-chamber view. The operator crewmember rapidly released the Velcro straps on both Braslet cuffs, and at least 10 cardiac cycles were recorded. Unfortunately, the four-chamber view (n = 6) was difficult to maintain during the Braslet release, resulting in deviation of the imaging plane from its original position; therefore, it was replaced with the more stable TD view (n = 9) in later sessions.

Despite extensive training of Mir cosmonauts before flight, the quality of the ultrasound data obtained inflight may be inadequate. To assure precise execution of the study protocol and quality of the data of this study, both the ultrasound video and the cabin view video were streamed in real time to the NASA Telescience Center, enabling continuous control of the experiment and verbal guidance of the crew by investigators. Each image and each cine-loop used in the analysis were acquired by the astronauts only when the ground-based expert considered the image adequate and commanded acquisition. Thus an established system of balanced expertise distribution enabled data acquisition with quality that was acceptable for real-time assessment and thorough retrospective analysis. TD was used for the first time in spaceflight during this investigation. As an excellent means to assess cardiac performance TD method is of particular importance for long-duration spaceflight (Fig. 4). TD spectra were taken from the LV lateral wall, septum, and RV free wall. Furthermore, TD spectra are easier to obtain and less vulnerable to motion artifacts than two-dimensional echocardiographic views. In subjects, LV lateral E’ decreased by >20% with the application of Braslet regardless of the maneuver, and LV Lateral A’ decreased only when Braslet was applied and a Valsalva maneuver was performed. RV isovolumic relaxation time decreased by >20% with the Braslet applied and by >30% when a Mueller was simultaneously performed.

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This indicates that preload was reduced with Braslet and that at these reduced end-diastolic volumes the reduced intrathoracic pressure from Mueller made the tricuspid valve open sooner. Mitral pulsedwave Doppler velocity of the LV inflow is a load-dependent parameter and decreases in response to reduced preload. By decreasing preload with Braslet, both Valsalva and Mueller seemed to have caused a modest reduction in LV preload as demonstrated by smaller velocities or extended relaxation slopes. Impaired LV filling is seen with Valsalva secondary to increased thoracic pressure while Mueller produces a similar result as a consequence of increased RV afterload from the subatmospheric intrathoracic pressure and the small end-diastolic cavitary and pericardial volumes created by the Braslet (Fig. 5).

Femoral vein area increased by 89% with the application of the Braslet. This change was less pronounced (51%) when a Valsalva maneuver was compared pre/post-Braslet, since without Braslet, Valsalva already increased the femoral vein area. This observation provides evidence that the Braslet, when worn and calibrated correctly, still allows for thoracic maneuvers to have a demonstrable effect on lower extremity venous filling. The pressure from occlusion cuffs compresses the superficial veins more than the deep circulation. Although Herault et al. reported the IJV area decrease in spaceflight with Braslet applied, we could affect significant changes in IJV area only when Braslet was combined with thoracic maneuvers.

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Cardiac output significantly decreased by 19% and stroke volume decreased by 12% when the Braslet was worn, and the heart rate compensation changed significantly in the increasing direction during a Valsalva maneuver. These findings are consistent with Pourcelot and Pottier and colleagues who reported a decrease in stroke volume (∼20%) and cardiac output (∼20%) using echocardiography with thigh compression during a short-duration French-Soviet Salyut flight in 1982. On flight day 4, they used pneumatic thigh cuffs at 40 and 60 mmHg, which is similar to the constraining stress of the Braslet measured by Hamilton et al. (unpublished results) using balloon pressure transducers. Herault et al. measured the effects of wearing the Braslet for 5 h on six cosmonauts during a 6-mo stay on the Mir space station and reported stroke volume and cardiac output reduction of 15 and 14%, respectively, after 1 mo of spaceflight. It is interesting to note that these changes became minuscule after 3 mo of spaceflight, and the Braslet actually increased stoke volume and cardiac output after 5 mo of spaceflight. They also report that femoral vein area increased by ∼20% with the Braslet applied at 1 and 3 mo, but 5 mo into the flight this increase was only 9%.

Authors did not observe this trend on any subject.

Muscle atrophy was more prevalent in pre-ISS missions, altering the fit and, therefore, the efficacy of the Braslet; the ISS countermeasures system is far more effective at preventing muscle atrophy and exercise deconditioning.

Hamilton et al. performed a prospective echocardiographic study in six ISS crewmembers 152, 116, 149, 34, 190, and 41 days after launch and found no clinically significant differences between cardiovascular parameters acquired on-orbit compared with pre- and postmission data. Authors therefore believe that mission length up to 6 mo does not have a significant effect on the outcome of this study. The myocardial performance index [Tei index] is calculated using diastolic and systolic time intervals derived from TD spectra as a combined measure of myocardial performance. The RV Tei index exceeded the normal terrestrial value of <0.3 in all but one subject.

Herault et al., which document that all astronauts who wore the Braslet during their study in space claim to have had a "sensation of comfort." When Braslet was employed on Soyuz-38 the cosmonauts reported a reduction in space adaptation syndrome symptoms (dizziness, congestion, and headaches). Kirsch et al. measured CVP after 22 h of microgravity during the Spacelab 1 mission and found it to be less than the preflight supine levels in two subjects. They repeated this during the Spacelab D1 missions and found that the CVP again fell to levels below preflight supine 20-40 min after liftoff. This is consistent with the findings by Buckey et al. , which found that invasive CVP fell to 2.5 cm H2 O immediately at the transition to microgravity on the Space Life Sciences 1 mission. Foldager et al.reported that CVP decreased to 6.5-2.0 mmHg after 3 h of microgravity exposure during the Spacelab D2 (n = 4) and Space Life Sciences 2 (n = 2) missions. Although Braslet did not induce a profound change in IJV area despite the obvious reduced cardiac preload, thoracic maneuvers seemed to have a profound additive effect when the Braslet was applied. This implies that the IJV is close to the pressure required to maintain its unstressed volume (i.e., to saturate its filling capacity) and that a Mueller maneuver will decrease its cross-sectional area. The Mueller - Valsalva difference is instructive since Valsalva caused a small increase in IJV area, implying the vein was close to being maximally distended despite the reduced cardiac preload caused by the Braslet.

Nonetheless, the IJV area decreases significantly when a Mueller maneuver is performed (Fig. 6). This finding is consistent with the IJV, which takes very little CVP to distend it maximally and has a low enough CVP to be manipulated with limited thoracic pressures when Braslet is applied. This can be replicated at the bedside on a healthy patient by observing the change in fullness of the jugular venous pulse when raising or lowering the patient’s neck by only 1 in. Therefore, a Mueller maneuver with Braslet applied in microgravity seems to decrease the CVP acutely to <2 mmHg. This is consistent with the maintenance of RV preload under normal terrestrial conditions where RV transmural pressures are ∼1.5 mmHg in humans. During the Braslet release the four-chamber images consistently show an immediate increase in LV stroke volume, which oscillated in magnitude over several beats and stabilized to a value that was close to the pre-Braslet application. The increased stroke volume after the Braslet release stabilized within 10 beats, which suggests that a significant amount of the volume in the leg must have been sequestered in the extravascular space (Fig. 7).

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D ID YOU KNOW ?

S PRUT-MBI

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Sprut-K Kit to determine different ing the impedance of the body ter with a range from 50 kg to kg. Hematokrit microcentrifuge to

human liquid volumes by measurand its segments. Body mass me100 kg with an accuracy of ±0.25 separate plasma from erythrocytes.

Studies performed with prolonged inactivity, or antiorthostatic hypokinesia (AOSH), on Earth and during space flights showed that gravity plays an important role in many physiological systems of the human body, including water-salt balance, and hydration. The noninvasive Sprut-MBI (Octopus-Multifrequency Bioelectrical Impedance) investigation was conducted in the course of ISS Expeditions 1-12.

Twelve Russian cosmonauts took part in monitoring their hydration state using a especially developed portable SPRUT-K impedance meter. Results showed that at different stages of 100- to 200-day flights, cosmonauts’ body liquid volume was reduced: the overall, intracellular and extracellular, volumes became on average 5.2 to 10.4% less compared to baseline level. The in-flight changes in their body’s composition were also consistent: while the lean mass loss determined by impedance measurement was insignificant (on average, from 1.9 to 4.0%), the gain of the fatty mass ranged from 4.6 to 8.2% during the first three months of the flight. Thus, hydration of a human body decreased during the long-term space flight, which was accompanied by reduction of the muscular mass and the gain in fatty mass.

A concurrent experiment studied the state of body fluids of a cosmonaut over a ten-day ISS mission with 6 ground subjects over a seven-day AOSH. Bioimpedancemetry (electrical resistance measurement of the body) was performed before the flight and on the seventh day during the flight, as well as on the first and sixth days after landing. Intracellular and extracellular fluid volumes, body composition, and total body water (TBW) content were determined and showed water compartments in the cosmonaut’s body were decreased to the same degree as in the ground group by the seventh day of AOSH. The amount of total body fluids and intracellular and extracellular volumes were decreased by 5.6 to 6.5 % from the baseline level (a decrease of ≈13% in hydration on the first day of flight was the most pronounced).

Lean body mass was insignificantly decreased, whereas the adipose (fatty) component of body weight was increased by 14.5%. When results were compared, the direction and degree of changes in the hydration status and body composition in space and on the ground, under similar body fluid shift conditions, were identical. A week after the flight, all parameters studied showed a clear tendency toward recovery to their pre-flight levels.

Bioimpedance results are in agreement with data obtained previously using invasive techniques and affirm the general concepts of adaptation of water-salt homeostasis to microgravity.

Reference: R

Determination of Intracellular and Extracellular Fluid Volume in Humans in Space Flight (Sprut-MBI (OctopusMBI)) , NASA. Available Online : http://www.nasa.gov/mission_pages/station/research/experiments/451.html

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