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1Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Boston 02115; and 2NASA Center for Quantitative Cardiovascular Physiology, Modeling and Data Analysis, Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and 3Department of Cardio-Thoracic Surgery, McGill University, Montreal, Quebec, Canada H3G 1A4
Submitted 25 March 2004 ; accepted in final form 23 June 2004
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ABSTRACT |
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renin-angiotensin-aldosterone system; autonomic function
Orthostatic intolerance (OI) is known to occur after spaceflight. Several systems have been implicated in the pathophysiology of post-spaceflight OI, including the autonomic system through altered baroreflex reactivity (5, 8, 9) and adrenergic responsiveness (10, 11), leg venous compliance (31), cardiac pump function (20, 27, 28), volume-regulating systems (18), and vascular function and reactivity through nitric oxide synthase-dependent mechanisms (32). Furthermore, the strong role of individual predisposition has recently been emphasized (13). The role and contribution of sleep restriction to post-spaceflight OI are still unknown. To our knowledge, only one study addresses the effects of sleep restriction on OI in healthy volunteers; it demonstrates no increase in OI following a sleep deprivation protocol of 4 h/night for 4 nights (23). However, this study was not conducted in the simulated microgravity environment, where several physiological changes involving the renal, cardioendocrine, and cardiovascular systems are known to take place. Hence, there is the possibility of an interaction between physiological changes taking place during simulated microgravity (or spaceflight) and sleep deprivation or restriction. Knowing that astronauts sleep on average 6–6.5 h/day during spaceflight (6, 29), and that <6 h of sleep have been associated with an increased cardiovascular risk (2), could the increased risk of OI after spaceflight be related to the sleep decrement?
Our goals in the present study were twofold: 1) to study the effect of sleep restriction on OI after simulated microgravity, and 2) to study the effect of sleep restriction on the renal, cardioendocrine, and cardiovascular systems, to assess the possible contribution of this interaction to post-spaceflight OI. To address these questions, we studied two groups of volunteers in either simple head-down tilt bed rest (HDTB) [nonsleep restricted (NSR)] or a combination of HDTB and sleep restriction (SR) protocol. We hypothesized that SR would lead to a greater increase in OI in the SR group than in the NSR group and that the renal, cardioendocrine, and cardiovascular responses to simulated microgravity would be altered by sleep restriction and contribute to the increase in OI.
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METHODS |
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Nineteen healthy men (age = 36 ± 2 yr; weight = 80 ± 3 kg; height = 178 ± 1 cm) were recruited for the study. Screening procedures included a history and physical examination, 12-lead electrocardiogram, complete blood count with differential, chemistry profile, thyroid function tests, urinalysis, toxicology screen, and psychological evaluation. Subjects were nonsmokers and were taking no medication before enrollment in the study. The exclusion criteria included a history or evidence of hypertension, coronary artery disease, diabetes, renal insufficiency, thyroid disease, hepatitis, anemia, psychiatric disorder, and alcohol or drug abuse, sleep disorders, shift work, and transmeridian travel within the 6 mo before study. None of the subjects had a history of syncope.
Research Protocol and Sleep Patterns
This investigation was part of a larger trial examining the effects of bed rest on the cardiovascular system (12, 34). Subjects were admitted to the General Clinical Research Center at Brigham and Women's Hospital and maintained on an isocaloric diet containing 200 meq of sodium, 100 meq of potassium, 1,000 mg of calcium, and 2,500 ml of fluid throughout the study period. The subjects were equilibrated on the diet in the General Clinical Research Center for 3–5 days pre-bed rest (pre-HDTB) and then entered a 14- to 16-day period of 4° HDTB. Bed rest was initiated at 1500 on the last day of pre-HDTB after the tilt-stand test (pre-TST) and ended on day 14 or 16 at 1000 with the post-HDTB tilt-stand test (post-TST). Sleep-wake cycles remained constant throughout the study, with 8 h of sleep each day between 2200 and 600 in the NSR group, comprising 11 subjects, and 6 h of sleep (between 2400 and 0600) in the SR group, comprising 8 subjects. The SR group was studied prospectively once the studies in the NSR group were concluded. The amount of time of sleep restriction was chosen to reflect the sleep schedule of astronauts (6, 14, 29). To ensure compliance with sleep-wake cycles, nursing or camera-monitoring of subjects was performed at all times. Room temperature was maintained at 21–22°C. Subjects were strictly confined to bed for the entire HDTB period. They were allowed to lie on their side, back, or front. Voiding and defecation occurred in the supine position. Meals were eaten while subjects were lying on their sides, propped up on one elbow. No medications, smoking, alcohol, or caffeine were allowed during the study. The study protocol was approved in advance by the Institutional Review Board of the Brigham and Women's Hospital. Each subject provided written, informed consent before participating in the study.
TSTs
Pre-TST was performed at 1000 before initiation of bed rest and at the end of bed rest (post-TST) by using a motorized tilt-table (American Echo, model 9607). Subjects were tilted to the upright position with 10-min stops at 30, 60, and 90°, during which hemodynamic, hormonal, and autonomic measurements were taken (see Measurements). After the measurements were done in the upright position (90°), subjects remained standing by themselves for an additional 120 min. Nontolerance to TST was defined as clinical signs of OI (diaphoresis, nausea, lightheadedness, or dizziness) accompanied by a decrease in systolic blood pressure (SBP) >20 mmHg below baseline or an increase in HR >20 beats/min above baseline. If signs of nontolerance were noted, subjects were returned to the supine position.
Measurements
TSTs. Initiation of TST marked time zero. Blood samples were drawn for plasma renin activity (PRA), aldosterone, cortisol, and catecholamines in the supine position (–10 min, –1 min, baseline), at 30° of tilt (+5 min), 60° (+15 min), 90° of tilt (+20 min), and in the standing position (+40 min, +80 min).
Cardiovascular system identification. Before TST and at 30, 60, and 90° of tilt, data were recorded for cardiovascular system identification (CSI) analysis. Subjects were instrumented for continuous noninvasive monitoring of arterial blood pressure (ABP; Portapres, TNO, or Finapres, Ohmeda), instantaneous lung volume (ILV; Respitrace system, Ambulatory Monitoring Systems), and HR (surface electrocardiogram). During data collection, the subjects were instructed to breathe in response to auditory tones spaced at random intervals ranging from 1 to 15 s, with a mean of 5 s. They controlled their own tidal volume to maintain normal ventilation. This random-breathing protocol excites a broad range of frequencies, thereby facilitating system identification (1). ABP, ILV, and HR data collected in supine and upright postures were saved for later CSI analysis (24, 25).
The CSI technique evaluates the interactions between physiological signals (HR, ABP, and ILV) on a second-to-second basis to enable dynamic assessment of important physiological mechanisms without perturbing normal system operation. From analysis of the physiological signals, CSI generates a closed-loop model of cardiovascular regulation specific for the individual subject at the time the signals are collected. CSI may be used to quantify separately the parasympathetic responsiveness and the sympathetic responsiveness (34).1
Hemodynamic, renal, and cardioendocrine measurements. ABP and HR were recorded by indirect sphygmomanometer at 0600 on all study days. Body weight was determined every morning at 0600 following a morning void (subjects remained supine during HDTB). The 24-h urine samples were collected by voluntary micturition for measurements of daily urine volume, sodium, potassium, aldosterone, cortisol, and creatinine excretion. Blood samples were collected at 0600 from a peripheral venous catheter after the subject had remained supine overnight on the last day of the pre-HDTB ambulatory baseline period and at the completion of HDTB for measurement of PRA, aldosterone, creatinine, sodium, potassium, cortisol, epinephrine, and norepinephrine.
Laboratory Analysis
Blood samples were collected on ice, and the serum or plasma was frozen until assayed. Sodium and potassium levels in serum and urine were measured with the AVL 987-S Electrolyte Analyzer (AVL Scientific, Roswell, GA), which uses flame photometry, with lithium used as an internal standard. A Beckman Creatinine Analyzer 2 (Beckman Instruments, Fullerton, CA) was used to measure creatinine concentrations in serum and urine. Cortisol in plasma and urine was measured with the Beckman Access Immunoassay (Beckman Instruments). PRA was measured with GammaCoat Plasma Renin Activity 125I RIA kit (DiaSorin, Stillwater, MN). The KatCombi RIA kit was used to measure epinephrine and norepinephrine in plasma and urine (IBL Immuno-Biological Laboratories, Hamburg, Germany). The method used for measuring aldosterone was the DPC Coat-A-Count RIA procedure (Diagnostic Products, Los Angeles, CA).
Statistical Analysis
Means and SEs were used to describe the data at baseline and at the end of HDTB. The main analytic tools were the unpaired t-test to compare the groups at baseline and in terms of changes, and the paired t-test for within-group comparisons, because normality was not rejected. Because the sample sizes were relatively small, the comparisons were repeated with rank methods without contradictions. In addition, the rate of change during orthostatic challenge was reported as the linear regression coefficient or slope using data through 80 min. The rates of change were summarized by using the median and the interquartile range, and the groups were compared by the Wilcoxon rank sum test. Fisher's exact test was used to compare the groups in terms of OI, the exact McNemar test was used for the within-subjects comparisons of OI, and the Wilcoxon signed-rank test was used for the within-subjects comparisons of time until OI. The main SR and NSR comparisons were between-subject comparisons, with one enrollment for each subject. A limited secondary within-subject analysis addressed results from three subjects who enrolled once in SR and once in NSR. To offer the opportunity to judge the strength of the relationships, we report the raw numerical two-sided P values from planned hypothesis-driven tests without a stringent criterion for rejecting the null hypothesis. Because small sample sizes resulted in relatively lower power, it is important to review the magnitudes of the effects in conjunction with the P values.
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RESULTS |
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Figure 1 depicts the proportion free of OI as a function of time pre-HDTB and post-HDTB among all subjects. Overall, there was a significant decrease in the time free of OI due to HDTB (P = 0.02).
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An additional analysis was performed that was restricted to the subjects who were tolerant to orthostatic challenge at baseline (6 SR and 5 NSR) to compare the proportion of those subjects with OI after HDTB in the two groups. Among those tolerant at baseline, the proportion of subjects with HDTB-induced OI was not significantly different between SR and NSR (50 vs. 40%, P = 1.0).
Of note, three subjects from the SR protocol were also restudied on another occasion in the NSR protocol, offering an opportunity for a limited within-subjects analysis where each subject served as his own control. Two of these subjects were tolerant to orthostatic challenge at baseline and after HDTB in both the NSR and the SR protocols, demonstrating no decrement to orthostatic tolerance attributable to SR. The third subject was tolerant before and after HDTB in the NSR protocol, and in the SR protocol he became syncopal after 12 min at baseline and after 16 min at the end of HDTB.
Responses to HDTB
Table 1 demonstrates the physiological and physical characteristics in SR and NSR groups. There was no significant difference between the two groups except for baseline urinary excretion of aldosterone. There was no significant change in parasympathetic or sympathetic responsiveness with upright posture compared with the supine position in either group.
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DISCUSSION |
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Sleep Restriction and OI
It is well known that OI is a major problem after spaceflight, with up to 83% of astronauts affected following long-duration missions (21), and that sleep restriction occurs during spaceflight, with an average of 6.5 h/night (6). Hence, the possible contribution of sleep restriction to OI following spaceflight cannot be ignored. However, we were not able to demonstrate that sleep restriction had a statistically significant impact on OI after exposure to simulated microgravity. This conclusion is supported by the findings of Muenter et al. (23), who demonstrated no change in orthostatic cardiovascular control with sleep restriction. A major difference from the latter study is that our study was performed in the simulated microgravity environment, which compounded the effects of HDTB and sleep restriction. Hence, taken together, the present study and the study by Muenter et al. suggest that sleep restriction may not play a major role in the phenomenon of OI alone (23) or in combination with simulated microgravity (present study).
Physiological Mechanisms
We demonstrated in this study that an initial loss of sodium in both SR and NSR was paralleled by an increase in urinary volume (significant only in SR). We also observed a significant increase in potassium excretion at the end of HDTB. Along with those changes, we observed an increase in PRA and dissociation of the aldosterone response. These findings are supported by a previous study in our laboratory (12) done with subjects on a constant potassium and sodium diet. Hence, sleep restriction per se does not seem to alter the responses of the renal and cardioendocrine systems to HDTB. Present results did not demonstrate a statistically significant change in parasympathetic or sympathetic responsiveness with a change in posture (supine to upright), although, in the larger trial investigating that issue (34), a statistically significant change emerged. CSI was not able to detect a significant posture-related change in the small SR and NSR subgroups pre-HDTB.
No changes in catecholamines or sympathetic and parasympathetic responsiveness with HDTB were seen in this study in SR or NSR. However, our laboratory previously demonstrated changes in sympathetic and parasympathetic responsiveness with HDTB (12, 34). This could be related to the fact that a different subset of subjects was studied in the present investigation, further supporting the strong role of individual variability in baseline physiological characteristics (13). Our present findings are also inconsistent with the results of Kato et al. (16), who observed a decrease in muscle sympathetic nerve activity with sleep deprivation. Differences with that study could be related to the different methodologies used to assess autonomic function (CSI vs. muscle sympathetic nerve activity), to the difference in sleep deprivation and restriction protocol (14–16 nights of 6 h sleep/night vs. 1 night of acute sleep deprivation), and to the fact that the study by Kato et al. was not performed in the simulated microgravity environment, whereas our study was. In a study by Irwin et al. (15) investigating the effect of partial sleep deprivation on catecholamines, an increase in norepinephrine and epinephrine was noted with nocturnal awakening. Once again, the difference in these results compared with those of the present study could be related to the difference in sleep deprivation protocol and the time of sampling of the catecholamines. These inconsistencies emphasize the important effect of variability in sleep deprivation or restriction protocols on autonomic function.
Last, only subtle changes in hemodynamics were observed. This was characterized by an increase in HR in NSR and a significant difference in the HR early response of NSR and SR to HDTB. However, no significant decrease in HR or changes in blood pressure were noted with regard to SR and HDTB. Our findings related to HR are supported by another study (16). However, other studies have demonstrated both a decrease (4, 23) and an increase in HR (19) with sleep deprivation or restriction. Blood pressure has generally been shown to increase (16, 19). Once again, the differences observed with the present study could be related to the fact that our study was done in the simulated microgravity environment, which, by itself, bears physiological consequences for cardiovascular control (34). Furthermore, methodological differences could explain the inconsistency of the results with those of other studies. Chen (4) used a 30-h acute sleep deprivation protocol, Lusardi et al. (19) compared 5- vs. 8-h sleep protocols, and Kato et al. (16) studied the responses to 1 night of sleep deprivation. Interestingly, in a study by Meier-Ewert et al. (22), focusing on C-reactive protein as a mediator of some of the cardiovascular changes related, respectively, to sleep deprivation and sleep restriction, a significant increase in HR was seen only in the SR group, whereas SBP increased significantly in the sleep-deprived group. This further supports the effect of the variability of the sleep restriction or deprivation protocol on cardiovascular parameters. Hence, we can conclude that the influence of sleep restriction on HR and blood pressure is still controversial.
Limitations
A potential problem with this study is the relatively few subjects studied. This is a problem experienced in human physiological aerospace studies, where testing of a small number of subjects in itself requires tremendous time and effort. The dissemination of negative results is, therefore, even more crucial in this setting so that effects of sizes can be evaluated in conjunction with evidence from other relatively small studies. Another limitation of this study is that, although the environment was controlled and light-dark cycles were regular, with constant nursing monitoring, we did not use polysomnographic recording to actually record sleep during the experiment. Hence, we have no way of verifying the exact amount of sleep on the SR and NSR protocols during the night, although we know that the subjects did not sleep during the day. Despite these limitations, a clear pattern of physiological responses still emerged, which is supported by our laboratory's previous investigations (12, 13).
Conclusions
The present study provides a better understanding of the effect of sleep restriction on OI during simulated microgravity. We found that sleep restriction did not produce additive HDTB-induced OI, nor did it degrade the renal, cardioendocrine, and cardiovascular adaptive responses to simulated microgravity. Thus, based on these data, it is unlikely that improved sleep hygiene during spaceflight will lead to a reduction in cardiovascular instability and OI postflight.
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Present address of C. D. Ramsdell: Dept. of Anesthesiology and Perioperative Medicine, Williams Beaumont Hospital, 3601 West Thirteen Mile Rd., Royal Oak, MI 48073.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 System identification models the relationship between the variation of the input and output signals. Autonomic quantification based on system identification techniques reflects the relative gain of the response relating a change in input to a change in autonomic tone. We refer in this paper to this type of quantification as autonomic responsiveness. 
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