INTRODUCTION

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POSTSPACEFLIGHT ORTHOSTATIC instability is a common problem in returning astronauts. In most astronauts, this is evidenced by increased heart rate responses to upright posture (3, 11, 12, 38) but not by actual hypotension. However, ~20% of all astronauts returning from 5-16 days of spaceflight experience inadequate cardiovascular responses during orthostatic challenge severe enough to cause presyncope (lightheadedness, loss of peripheral vision, or a sudden drop in systolic blood pressure below 70 mmHg) (3, 11, 12, 29, 31, 38). In a previous paper (12), it was noted that women seemed to have a greater propensity toward postflight orthostatic hypotension and presyncope than men. Specific mechanisms contributing to individual susceptibility still are not completely understood, but they appear to be multifactorial. Postflight orthostatic hypotension certainly is aggravated by loss of plasma volume. However, although all astronauts suffer losses of plasma volume, not all astronauts become presyncopal on landing day, and our laboratory previously showed no differences in plasma volume losses between those who did and those who did not become presyncopal (12). Rather than by plasma volume, presyncopal astronauts are defined primarily by their smaller standing plasma norepinephrine levels (12) and total peripheral resistance (3, 12) compared with nonpresyncopal astronauts. There also is evidence of indicators of postflight orthostatic hypotension that may be discernable preflight. As a group, those who will become presyncopal after flight have lower supine and standing peripheral vascular resistance and mean arterial pressure than those who will not (12). To date, no study has performed a systematic analysis of hemodynamic, volume, and neuroendocrine variables in a large enough sample of astronauts to definitively assess the relative contributions of gender, plasma volume, autonomic function, and preflight predisposition to susceptibility to postflight orthostatic hypotension.

The purpose of the present study was fourfold. First, we sought to extend the previous observations mentioned above in a larger sample of astronauts and test the hypothesis that women are more susceptible to postspaceflight orthostatic hypotension than men. Having shown that to be true, our second goal was to compare and contrast supine and standing hemodynamic and neuroendocrine variables in the three classifications of astronauts: presyncopal women, presyncopal men, and nonpresyncopal men. These comparisons were made both before and after flight. The third purpose was to examine the relationships between plasma volume and hemodynamic responses to tilt in the three groups. The fourth purpose was to test the hypothesis that the basic relationships among vascular resistance, cardiac output, and mean arterial pressure differ between presyncopal and nonpresyncopal groups.

	METHODS

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The data presented include both retrospective analyses of previously published data (12) and new findings. Subjects were recruited from the Astronaut Corps at Johnson Space Center (5 women, 30 men). Protocols were approved by the Johnson Space Center Institutional Review Board, and all subjects gave their written informed consent. Studies were conducted between 10 and 90 days before Shuttle spaceflight, on landing day (1-3 h after landing), and 3 days after landing. The duration of spaceflight ranged from 5 to 16 days. On each test day, subjects had abstained from caffeine, alcohol, and any vasoactive medications for the preceding 12 h; were at least 2 h postprandial; and had not exercised maximally in 24 h. The subjects were instrumented for electrocardiogram and manual (sphygmomanometer) or automated blood pressure (Dinamap, General Electric Medical Systems Information Technologies, Milwaukee, WI). Two-dimensional echocardiography and Doppler ultrasound (Biosound Genesis II, Esoate, Indianapolis, IN) were used to determine aortic cross-sectional diameter and flow, respectively. An intravenous catheter was inserted into an antecubital vein. After a 20-min supine rest period, a blood sample was drawn for baseline plasma norepinephrine and epinephrine levels. Next, plasma volume was determined by using carbon monoxide rebreathing (6, 27, 34). Baseline hemodynamic measurements continued while the subjects remained supine for an additional 5 min. Subjects were then placed in the upright position by one of two methods: 1) three investigators lifted the subject to a standing position by supporting both shoulders while the subject's feet were swept off the bed (stand protocol) or 2) an automated tilt table was used that raised the subject to an 80° upright position (tilt protocol). The hand with the continuous arterial pressure device was held at heart level either by a system of Velcro straps (stand protocol) or an arm board attached to the bed (tilt protocol). Four of the five women and twenty-four of the thirty men underwent stand tests. The remaining subjects underwent tilt tests. Subjects were instructed to remain relaxed and not to contract skeletal muscles during standing. Subjects remained standing for 10 min or until presyncopal symptoms (lightheadedness, loss of peripheral vision, or a sudden drop in systolic blood pressure below 70 mmHg) intervened. A final blood sample for plasma norepinephrine and epinephrine levels was drawn at the end of the test. If subjects became presyncopal, the blood sample was drawn immediately. Arterial pressure and heart rate were recorded on analog instrumentation tape and digital audiotape and paper for later analyses. Echocardiographic images were recorded on videotape. Before landing, all subjects followed the standard oral fluid loading procedure (equivalent to isotonic saline at a rate of 15 ml/kg within 2 h). This ranged from 728 ml for the lightest crew member to 1,483 ml for the heaviest crew member. After landing, the physicians allowed the crew members to drink water ad libitum before entering the test room. In these subjects, the amount consumed was 272 ± 51 (SE) ml fluid with a range from 0 to 1,000 ml. No additional fluids were allowed after testing was in progress.

Analyses. The following variables were compared during the minute before standing and the last minute of standing: heart rate, arterial pressure, stroke volume, cardiac output (stroke volume × heart rate), and total peripheral resistance (mean arterial pressure/cardiac output). Analyses of all physiological signals were made off-line by using standard data acquisition and analyses packages. The echo analysis was double blinded. If a >10% difference existed between the first two analyses, a third analysis was performed. Plasma norepinephrine and epinephrine levels were determined by radioimmunoassay (21). Plasma volume, stroke volume, cardiac output, and total peripheral resistance were each divided by the subject's body surface area [0.007184 · (weight in kg)^0.425 · (height in cm)^0.725] to create an indexed parameter used for all statistical analyses. For discussion purposes, all nonindexed terms were used.

Statistics. All results are presented as means ± SE. All data were tested for normalcy and equal variance by using the Kolmogorov-Smirnov test and the Levene median test, respectively. For analyses, astronauts were separated both by gender and occurrence of presyncope (those who could not maintain 10 min of upright posture on landing day). Because there were no nonpresyncopal women in this study, the effects of interest were group (presyncopal women, presyncopal men, and nonpresyncopal men) and day (preflight, landing day, and 3 days after landing). Women were not separated by menstrual status, which was not evaluated. A two-way analysis of variance or two-way analysis of variance on ranks (for nonparametric data) was used. Student's paired or unpaired t-tests and signed-rank or rank-sum tests (for nonparametric data) were performed to document differences among groups in variables when there were significant day or group effects. Least squares regression analyses were performed on standing stroke index vs. plasma volume. A Fisher exact test was used to compare the incidence of presyncope on landing day between men and women. Comparisons were considered significant if P  0.05.

	RESULTS

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Incidences of presyncope. No astronaut in this study became presyncopal during preflight testing. As a group, the female astronauts suffered postflight presyncope at a significantly higher rate (P = 0.001) compared with the male astronauts (Fig. 1). All five women studied (100%), but only 6 of 30 men studied (20%), were presyncopal (Fig. 1, top). Presyncopal symptoms occurred between 2 and 9 min after standing. There were no vasovagal incidents, and no subject lost consciousness. Many astronauts, 18 of the 30 men, and 1 of the 5 women, were pilots of military high-performance jet aircraft. All other astronauts were mission specialists, mostly scientists who were not military pilots. To avoid possible differences in G tolerance due to previous experience, all pilots were removed from the data set and comparisons were repeated using only the mission specialists. Still, four times more women (100%) than men (25%) became presyncopal on landing day (Fig. 1, bottom; P = 0.02, between groups).

View larger version (22K): [in this window] [in a new window]   Fig. 1.   Incidence of presyncope (gray areas) during standing immediately after spaceflight in all subjects (top) and mission specialists alone (bottom). Incidence was greater in the women than in the men (P = 0.001, top; P = 0.02, bottom). Presyncope is defined as the failure to complete 10 min of standing without symptoms. n, No. of subjects.

Blood volumes. Table 1 depicts plasma volumes in presyncopal women, presyncopal men, and nonpresyncopal men. On landing day, all three groups had significant reductions in plasma volume from preflight, but the losses were significantly greater in the women (20%) than either group of men (7%). Three days after landing, plasma volumes were recovered. Table 2 depicts red blood cell volumes in the three groups. There were no significant differences in the spaceflight-induced losses among the groups.

Comparisons among women, presyncopal men, and nonpresyncopal men before flight. Figure 2, left, shows preflight supine and standing data in the three groups. Before flight, both presyncopal groups showed a propensity toward higher cardiac output and lower vascular resistance. Women had significantly lower supine and standing mean arterial pressures and total peripheral resistances, higher supine heart rates, and higher supine and standing cardiac indexes than nonpresyncopal men. Women also had significantly lower supine and standing mean arterial pressures and tended to have higher heart rates and lower vascular resistances than those of the presyncopal men. Presyncopal men had significantly higher standing cardiac indexes and tended to have lower (P = 0.08) standing vascular resistance than nonpresyncopal men. There were no significant intergroup differences in stroke index. Thus, hemodynamically, presyncopal men fell between nonpresyncopal men and women in most variables. Plasma catecholamine levels are shown in Table 3 and Fig. 3. There were no preflight intergroup differences in supine, standing, or standing-supine plasma epinephrine or norepinephrine.

View larger version (27K): [in this window] [in a new window]   Fig. 2.   Hemodynamic measurements in women (n = 5, ), presyncopal men (n = 6; ), and nonpresyncopal men (n = 24; ) when tested preflight (left), on landing day (middle), and 3 days postspaceflight (right). Values are means ± SE.  P = 0.06. *P  0.05. **P  0.01. ***P  0.001.

View larger version (18K): [in this window] [in a new window]   Fig. 3.   Plasma norepinephrine (top) and epinephrine (bottom) responses in women (n = 4; black bars), presyncopal men (n = 6; light gray bars), and nonpresyncopal men (n = 22; dark gray bars) when tested preflight (A), on landing day (B), and 3 days postspaceflight (C). Values are means ± SE.  P = 0.058. *P  0.05. **P  0.01

Comparisons between women, presyncopal men, and nonpresyncopal men on landing day. Figure 2, middle, presents supine and standing data on landing day. Both women and presyncopal men had significantly lower standing mean arterial pressures than nonpresyncopal men, with presyncopal men having the lowest pressures. Women also had significantly higher standing heart rates and supine cardiac indexes than nonpresyncopal men. The three groups had virtually identical standing stroke and cardiac indexes. Women and presyncopal men both had significantly lower standing resistances than nonpresyncopal men.

Comparisons between women, presyncopal men, and nonpresyncopal men 3 days postflight. All but four subjects (1 nonpresyncopal man, 2 presyncopal men, and 1 presyncopal woman) maintained 10 min of upright posture 3 days after landing. Mean responses of all subjects 3 days after landing are shown in Fig. 2, right. Mean arterial pressures were again significantly lower in women than men. Standing heart rates were significantly higher in presyncopal men than either women or nonpresyncopal men. Standing stroke indexes were significantly higher in women, possibly due to their high plasma volumes. Cardiac index showed similar patterns to preflight, with women and presyncopal men having higher values than the nonpresyncopal men. Total peripheral resistance also was similar to preflight, with nonpresyncopal men having the highest and women having the lowest resistances. There were no intergroup differences in supine, standing, or standing-supine plasma norepinephrine or epinephrine levels (Table 3, Fig. 3C).

Hemodynamic relationships. Figure 4 depicts the relationships between plasma volume and standing stroke index. Women (Fig. 4A) had a highly significant positive correlation (P < 0.001), indicating a strong dependence on plasma volume to maintain standing stroke index. Presyncopal men (Fig. 4B) also had a positive correlation, although less significant (P = 0.05) than the women. The nonpresyncopal men (Fig. 4C) had no correlation between plasma volume and standing stroke index (P = 0.24).

View larger version (12K): [in this window] [in a new window]   Fig. 4.   Relationships between plasma volume and standing stroke index in women (A; n = 5; ), presyncopal men (B; n = 6; ), and nonpresyncopal men (C; n = 24; ). Values represent individual data points from testing preflight and on landing day.

View larger version (18K): [in this window] [in a new window]   Fig. 5.   Relationships between standing-supine cardiac output and standing-supine mean arterial pressure in women (n = 5, ), presyncopal men (n = 6; ), and nonpresyncopal men (n = 24; ) when tested preflight (A), on landing day (B), and 3 days postspaceflight (C). Values represent individual data points.

View larger version (15K): [in this window] [in a new window]   Fig. 6.   Relationships between cardiac output and total peripheral resistance preflight (A), on landing day (B), and 3 days postspaceflight (C). +, Individual supine values for all subjects. Standing values are represented by the respective symbols in women (n = 5; ), presyncopal men (n = 6; ), and nonpresyncopal men (n = 24; ). Values represent individual data points for total peripheral resistance and cardiac output in both supine and standing positions.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

We compared and contrasted hemodynamic and neuroendocrine variables in three groups of astronauts before and after spaceflight: women, presyncopal men, and nonpresyncopal men. We now know that the group of astronauts most susceptible to postflight orthostatic hypotension and presyncope has at least four major defining characteristics. First, the subjects are primarily, although not exclusively, female. Second, presyncopal astronauts are characterized by low peripheral vascular resistance, both before and after flight, whether they are men or women. Third, although plasma volume loss by itself does not separate presyncopal and nonpresyncopal astronauts, compensatory adjustments to losses of plasma volume do separate them. Presyncopal astronauts are highly dependent on a normal hydration status for hemodynamic stability. The fourth finding from this study is the corroboration and extension of an earlier report (12) that autonomic changes associated with spaceflight, manifested as a relative hypoadrenergic responsiveness, seem to differentially affect the subset of susceptible astronauts in a way that causes them to become presyncopal after, but not before, spaceflight. These data are currently being used to try to characterize presyncopal astronauts before flight and to develop appropriate individualized countermeasures.

Female astronauts. In the present study, all five women became presyncopal on landing day (Fig. 1), and their preflight hemodynamic profile predicted their postflight susceptibility. They relied more on cardiac, rather than resistance, responses to maintain upright pressures on all occasions (Fig. 2). These are not unexpected findings (12). Several studies have reported that orthostatic hypotension is greater in women than in men (5, 26, 37). Women have greater heart rate responses than men during mental stress (4), standing (16, 32), infusions of pressor agents (1), and cold pressor tests (15). It also has been shown that estrogen replacement therapy in postmenopausal women reduces muscle sympathetic nerve activity (20, 36). In addition, women have smaller increases in vascular resistance than men in response to lower body negative pressure (8, 37), standing (9), cold pressor and facial cooling tests (22), and mental stress (28). This does not normally represent a functional inadequacy. However, when coupled with other factors, such as hypovolemia, these low-resistance responses could result in a failure to maintain standing pressure. The presyncopal women in this study experienced plasma volume losses after flight that were almost three times greater than those of the men (Table 1). In addition, they were very dependent on plasma volume to maintain standing stroke volume (Fig. 4). This put them at an extreme disadvantage. After spaceflight, the preflight female hemodynamic strategy was no longer effective in maintaining pressure. Stroke volumes and cardiac outputs fell lower than they had preflight and were not compensated for with greater increases in sympathetic response and vascular resistance (Figs. 2 and 3). These postflight conditions precipitated a collapse of pressure, and the high epinephrine release on landing day suggests a stress response was mounted as a result.

Presyncopal male astronauts. Even though the women, as a group, are more susceptible than the men, postflight orthostatic hypotension is not exclusively a female problem. Twenty percent of the men in the present study were presyncopal on landing day (Fig. 1). Unlike the women, these men showed no evidence of hypotension preflight (Fig. 2). However, like the women, their preflight hemodynamic responses to standing relied more on cardiac and less on resistance responses to maintain arterial pressures. These men are severely affected by spaceflight, having the lowest standing arterial pressures and total peripheral resistances on landing day of any of the groups.

Nonpresyncopal male astronauts. The nonpresyncopal men have three factors that protect them from postspaceflight orthostatic hypotension. First, on all occasions, they have the highest total peripheral resistance (both supine and standing) of the three groups (Fig. 2). Their resistance, when related to falls in cardiac index with standing, is on the highest portion of the response relation (Fig. 6). Second, they maintain standing stroke volume irrespective of plasma volume changes, unlike either of the presyncopal groups (Fig. 4). Third, and probably most importantly, this group is able to mount hyperadrenergic responses to standing on landing day, as evidenced by the amount of norepinephrine released (Table 3, Fig. 3). This ability is most likely the primary factor that allows them to increase resistance and maintain pressures. This idea is supported by data from Whitson et al. (38) and Pawelczyk et al. (31), both of whom reported hyperadrenergic responses in nonpresyncopal astronauts on landing day.

Hemodynamic relationships in presyncopal and nonpresyncopal astronauts. Our laboratory reported previously that there were no differences in plasma volume losses between presyncopal and nonpresyncopal groups (12). This new examination of the data reveals that, whereas that is true in men, presyncopal women do in fact lose more plasma volume. Furthermore, in presyncopal astronauts, losses of plasma volume represent a greater threat to orthostatic tolerance. Dependence on volume status suggests that susceptible astronauts have less ability to maintain venous return in the upright posture. In these subjects, it is possible that low vascular responsiveness is not only a problem in the arterial circulation but also in the venous circulation. Because preflight norepinephrine release does not differ among the groups, the adrenergic receptors, vascular smooth muscle, or local factors may be responsible for the low resistance in susceptible persons.

Autonomic changes associated with spaceflight. On landing day, astronauts who become presyncopal do not have the ability to increase standing norepinephrine levels beyond their preflight levels, even in the presence of very low arterial pressures. Regardless of how it is reported (delta or absolute), the fact remains that presyncopal astronauts have a relative hypoadrenergic response in comparison to their nonpresyncopal counterparts. We cannot determine whether this condition was present before flight, because the arterial pressure challenge was insufficient at that time. However, we can conclude that this low response contributed to the hypotension and presyncope experienced by this subset of astronauts.

Recovery. Virtually every figure in the present paper shows that, only 3 days after landing, responses to upright posture have returned toward preflight levels. The occurrence of hypotension and presyncope is very rare at this time point. The differences among groups are just as evident as they were preflight. This indicates that the cardiovascular changes associated with short-duration spaceflight are not permanent but reverse spontaneously without treatment. A more clear understanding of the mechanisms of the reversible changes in astronauts may lead to a better understanding of the irreversible changes associated with many disease states.

Limitations. One limitation to this study is that both stand and tilt tests were used to assess orthostatic tolerance. Because tilt tests are thought to be more provocative than stand tests, we compared the incidence of presyncope between stand and tilt tests in a larger data set of 156 male and female astronauts (n = 131, stand; n = 25, tilt) and found no significant difference (P > 0.1). In addition, four of the women in the present study underwent stand testing and only one underwent tilt testing. Thus it does not appear that the different modes of testing contributed to the different rates of presyncope in these subjects.