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Inflight leg cuff test does not identify the risk for orthostatic hypotension after long-duration spaceflight

Inflight leg cuff test does not identify the risk for orthostatic hypotension after long-duration... www.nature.com/npjmgrav ARTICLE OPEN Inflight leg cuff test does not identify the risk for orthostatic hypotension after long-duration spaceflight 1 1 1 1 Katelyn N. Wood , Kevin R. Murray , Danielle K. Greaves and Richard L. Hughson Landing day symptoms from orthostatic hypotension after prolonged spaceflight can be debilitating, but severity of these symptoms can be unpredictable and highly individual. We tested the hypothesis that an impaired baroreflex response to an inflight leg cuff test could predict orthostatic intolerance on return to Earth. Eight male astronauts (44 ± 7 years of age (mean ± SD); mean mission length: 167 ± 12 days) participated in a standardized supine-to-sit-to-stand test (5 min–30s–3 min) pre- and postflight, and a 3 min thigh cuff occlusion test pre- and inflight with continuous monitoring of heart rate and arterial blood pressure. The arterial baroreflex was not changed inflight as shown by similar reductions in mean arterial pressure (MAP) response to leg cuff deflation (preflight −19 ± 2 mmHg vs. inflight −18 ± 5 mmHg). With the sit/stand test, the nadir of MAP was lower postflight (−17 ± 9 mmHg) than preflight (−11 ± 6 mmHg, p < 0.05). A greater increase in heart rate (25 ± 7; 16 ± 3 bpm) and decrease in stroke volume (−24 ± 11; −6 ± 4 mL) occurred with sit/stand postflight than leg cuffs inflight (p < 0.001). Inflight testing was influenced by elevated cardiac output resulting in a smaller drop in total peripheral resistance. Two of eight subjects exhibited orthostatic hypotension during the postflight stand test; their responses were not predicted by the inflight leg cuff deflation test. These results suggest that the baroreflex response examined by inflight leg cuff deflation was not a reliable indicator of postflight stand responses. npj Microgravity (2019) 5:22 ; https://doi.org/10.1038/s41526-019-0082-3 INTRODUCTION cuff inflation to occlude arterial inflow followed by rapid release of the cuffs causes a drop in arterial BP that is similar to that of Orthostatic intolerance, a major problem for the return of 17,18 1,2 transition from supine to upright posture. This leg cuff test astronauts to the gravitational forces of Earth, is aggravated detected differences in arterial baroreflex response between by long-duration spaceflight. NASA included this important endurance athletes and healthy controls, with the athletes health risk in the Human Research Roadmap of problems that experiencing a greater drop in BP and a longer time for recovery. need to be resolved prior to future exploration missions (NASA It was hypothesized that astronauts who experienced postflight Human Research Roadmap). Multiple mechanisms contribute to orthostatic intolerance during a stand test would have impairment orthostatic intolerance on return to Earth including impaired 5,6 of arterial baroreflex manifested by a greater drop and delayed venous properties that reduce return of blood to the heart, 7 8,9 recovery of arterial BP in the leg cuff test when measured late in lower blood volume, diminished cardiac mass, reduced spaceflight. cardiac output, inadequate sympathetic nervous system- 1,11–13 mediated vasoconstriction, and impairment of the arterial 14,15 baroreflex. RESULTS Based on the current knowledge and understanding of cardiovascular mechanisms that are altered during exposure to Preflight posture microgravity, a test, administered during spaceflight, to identify The cardiovascular responses to the supine-to-seated-to-standing individual astronauts at greatest risk for postflight orthostatic posture transitions displayed an anticipated biphasic response hypotension could provide input guiding the extent of near end- (solid black line, Fig. 1). Heart rate (HR) increased from supine to of-flight and immediate postflight countermeasures designed to seated (p < 0.001) and remained elevated above supine values at reduce the risk of impairment of performance and loss of the end of the 3 min stand (p < 0.01, Table 1). Systolic (SBP), consciousness. These end-of-flight countermeasures could include diastolic (DBP), and mean arterial pressure (MAP) decreased from lower body negative pressure, as used by Russian cosmonauts, supine to seated (p < 0.05) with a gradual return to above supine high intensity exercise, and fluid loading during re-entry; whole values at end stand (Fig. 1, Table 1). Cardiac output (Q) increased body cooling, and lower body compression garments alone or in from supine to seated (p < 0.001) and was slightly elevated at end combination, can provide protection against postflight orthostatic stand (p = 0.06). Stroke volume (SV) decreased in the seated intolerance. Methods to challenge the arterial blood pressure posture (p < 0.001) and remained lower at end stand (p < 0.05). (BP) regulatory mechanisms can be applied while in microgravity. Total peripheral resistance (TPR) decreased from supine to seated A human centrifuge could generate a head-to-foot gravitational (p < 0.001) and was above supine values at end stand (p < 0.05). vector, but this facility is not currently available in space. Lower body negative pressure could stimulate the effects of gravity and Postflight posture and comparison retain blood volume in the lower part of the body. In the Russian segment of the International Space Station (ISS) the Chibis device Dotted black lines in Fig. 1 show the postflight posture transition generates lower body negative pressure, but this device was responses. Compared to preflight, postflight supine HR was higher unavailable to the researchers at the time of this experiment. Leg than preflight leading to a higher HR during the posture test Schlegel-University of Waterloo Research Institute for Aging, Waterloo, ON, Canada. *email: k24wood@uwaterloo.ca Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; K.N. Wood et al. to preflight (p = 0.15). There were no differences in the TPR Preflight Stand response pre- to postflight, despite a trend for higher postflight Preflight Cuffs resistance. Inflight Cuffs Preflight leg cuffs Postflight Stand 20 40 The cardiovascular responses to the sudden release of occluding leg cuffs revealed the anticipated drop in arterial pressure and compensatory recovery responses (solid red line, Fig. 1). HR increased with cuff release (p < 0.001), while SBP, DBP, and MAP were reduced (p < 0.001, Table 2). On average, there was no significant change in SV with cuff release. Q increased with cuff release (p < 0.001), while TPR decreased (p < 0.001, Fig. 1, Table 2). Inflight leg cuffs and comparison The inflight leg cuff responses are shown by dotted red lines in -10 Fig. 1. Spaceflight did not change HR, SBP, or MAP compared to -20 preflight. DBP, SV, and Q were greater inflight (p < 0.05, Table 2). TPR was lower inflight (p < 0.05, Table 2). In addition, the 0 -30 magnitude of the response (Table 3) to cuff release was not different from preflight for HR, SBP, DBP, MAP, and Q. SV was higher inflight than preflight across all time points (Table 2), yet the magnitude of the reduction was the same compared to 120 preflight (Table 3). TPR was lower inflight, and after the release of leg ischemia, the drop in TPR was smaller inflight (p < 0.01, Table 80 3) than preflight. There were no differences for any measured variable in the response rate to leg cuff deflation or the recovery rate (Table 3). Arterial baroreflex and Blood pressure The arterial baroreflex response slope was assessed inflight as well -40 as pre- and postflight. The inflight baroreflex slope was significantly greater than preflight stand, and postflight supine -80 and stand (p < 0.05, Fig. 2). Overall, there was a linear relationship 40 between each individual’s baroreflex slope and his RR-interval, r ≥ 0.71 for all but one individual, and significant correlation coefficients for three individuals (r = > 0.96). While 6 of 8 subjects had remarkably stable BP during the postflight stand test, two subjects had patterns of BP consistent with orthostatic hypotension and suggestive of potential for syncope if the stand test had been sustained. Figure 3 demonstrates the pre- and postflight BP and HR response in one of the most vulnerable crewmembers. This figure also shows the leg cuff deflation tests revealing that the inflight leg cuff deflation test for this individual was not able to predict his postflight response to standing. DISCUSSION Two of eight male astronauts presented with orthostatic hypotension during a 3-min stand test conducted between 18 and 36 h of returning from 6 months on the ISS. Previous reports -20 0 20 40 60 of orthostatic tolerance during a 10-min tilt test after short- duration shuttle flights found 20% of men and 100% of women to Time (s) 19,20 3 be intolerant. Meck et al. found that orthostatic testing by 10- Fig. 1 Cardiovascular response to posture (black) vs. leg cuffs (red) min head-up tilt following long-duration spaceflight suggests a in all subjects, preflight (solid lines) and postflight/inflight (dotted higher incidence rate (5 of 6 male astronauts) even though these lines). Solid vertical line denotes initiation of cuff deflation or astronauts had participated in inflight countermeasures while on moving from supine to seated. Values are means ± SD the Mir space station. A compilation study of orthostatic tolerance after short-duration shuttle and long-duration stays on the ISS (Table 1), yet the magnitude of change was not different (p = 0.45, observed intolerance in 13 of 65 short-duration and 4 of 6 long- Δ in Table 3). Supine arterial BP tended to be higher postflight duration astronauts (sex of the intolerant astronauts was not than preflight, with a larger decrease (Δ) postflight on moving to specified). The primary hypothesis of this study, an inflight BP the seated position for SBP. There was a longer time to nadir for challenge caused by rapid deflation of leg cuffs, after a 3-min total DBP and MAP (p < 0.05, Table 3). There were no differences in the arterial occlusion, would be predictive of those individuals most Q response pre- to postflight. Supine SV was lower postflight (p < susceptible to postflight orthostatic hypotension, was not 0.05), but the magnitude of change was the same when compared supported, but pointed to unique physiological adaptations to npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Cardiac Output (L/min) Stroke Volume (mL) TPR (mmHg/L/Min) K.N. Wood et al. Table 1. Cardiovascular variables for supine (SUP) to seated (SIT), to standing (STAND) posture pre- and postflight Pre-SUP Pre-SIT Pre-STAND Pre-END STAND Post-SUP Post-SIT Post-STAND Post-END STAND BRS, ms/mmHg 20.0 ± 5.6 NA 6.3 ± 3.0* NA 19.1 ± 7.1 NA 7.4 ± 4.1* NA + + HR, bpm 57 ± 6 81 ± 11* 81 ± 11* 74 ± 11* 65 ± 8 90 ± 10* 88 ± 14* 86 ± 18* SBP, mmHg 127 ± 14 101 ± 15* 106 ± 26 129 ± 12 134 ± 8 97 ± 25* 111 ± 27 125 ± 11 ~ + ~ DBP, mmHg 69 ± 8 54 ± 11* 61 ± 16 78 ± 4* 78 ± 6 54 ± 13* 63 ± 18* 76 ± 9 MAP, mmHg 92 ± 7 73 ± 13* 80 ± 19 97 ± 6 98 ± 5 67 ± 18* 82 ± 20* 93 ± 11 ~ ~ Q, L/min 5.2 ± 0.9 7.9 ± 2.3* 6.9 ± 2.2 4.8 ± 0.8 5.0 ± 1.5 7.4 ± 3.3* 6.6 ± 2.7 4.7 ± 1.2 ~ + SV, mL/min 93 ± 24 63 ± 26* 51 ± 20 65 ± 16* 78 ± 25 53 ± 27* 46 ± 21* 55 ± 13* TPR 18.0 ± 5.0 10.5 ± 3.0* 13.4 ± 3.8* 20.4 ± 4.4* 21.6 ± 7.4 14.0 ± 8.3* 15.7 ± 7.8* 21.1 ± 6.8 Values are ±SD. SUP is the mean of the 30 s supine period before moving to a seated position, SIT is the peak/nadir during the 30 s seated posture, STAND is the peak/nadir of the first 60 s of the stand, and END STAND is the mean value for the final 15 s of the stand test. BRS baroreflex slope (mean values shown); HR, heart rate (peak values shown), SBP systolic blood pressure (nadir values shown), DBP, diastolic blood pressure (nadir), MAP mean arterial pressure (nadir), Q cardiac output (peak), SV stroke volume (nadir), TPR total peripheral resistance (nadir) *Different from sessional SUP Different from sessional SIT Different from corresponding preflight value, p < 0.05 smaller, but the reduced TPR and greater flow through the Table 2. Cardiovascular variables for leg cuff inflation-deflation pre- 9 splanchnic region might account for this. Consistent with the and inflight current study, the 45% increase in supine Q, corrected by the rebreathing value, was similar to values reported by Norsk Pre-CUFF Pre-Max or Min Inflight CUFF Inflight et al. Max or Min Leg cuff deflation provides a rapid drop in arterial BP enabling 18 17 HR, bpm 56 ± 6 74 ± 7* 57 ± 6 74 ± 5* testing of arterial baroreflex and cerebrovascular function. This study is the first use of the leg cuff system during spaceflight to SBP, mmHg 123 ± 11 107 ± 13* 123 ± 14 107 ± 16* + + test BP regulation. With the elevated inflight Q, but unchanged BP, DBP, mmHg 62 ± 7 47 ± 7* 69 ± 8 55 ± 9* release of the leg occlusion cuffs caused reductions in SBP, DBP, + + MAP, mmHg 82 ± 8 63 ± 9* 89 ± 10 71 ± 11* and MAP that were not different between preflight and inflight + + Q, L/min 4.6 ± 0.7 7.0 ± 1.4* 6.7 ± 1.2 9.5 ± 2.3* testing. In addition to the similar drops in BP, the response and + + SV, mL/min 84 ± 16 81 ± 15 119 ± 32 115 ± 32* recovery rates from nadir of the BP were not different comparing preflight to inflight. Likewise, the HR response to the drop in TPR, mmHg/ 18.4 ± 2.3 9.6 ± 1.6* 13.7 ± 3.5 8.3 ± 2.6* L/min arterial BP on cuff release was not different inflight as was the arterial baroreflex response slope not different inflight compared Values are mean ± SD. “Cuff” is near end of occlusion before the release of to preflight supine posture. Taken together, these data support the thigh cuffs, ‘Max or Min’ is the maximal or minimal value after deflation. the notion of maintenance of cardiovascular reflex control of heart HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, rate and peripheral vascular resistance during long-duration MAP mean arterial pressure, Q cardiac output, SV stroke volume, TPR total peripheral resistance. Note that Q and SV have been corrected for spaceflight. These observations are consistent with measurements 23,24 rebreathing estimate of arterial baroreflex during long-duration spaceflight, but *Different from sessional baseline during cuff inflation contrast with reduced baroreflex responses during short-duration Different from corresponding pre-flight value, p < 0.05 spaceflights. The similar drop in arterial BP on leg cuff release inflight compared to preflight indicated that the reduction in leg vascular long-duration spaceflight that can influence predictive tests resistance on cuff release was probably the same between the two attempted in the future. Predictive tests, if they can be developed, tests. However, the change in TPR was less inflight compared to could permit more aggressive near end of flight countermeasures preflight because of the elevated inflight Q. Underlying the for the 25% of male astronauts, and probably a greater proportion different TPR responses was a preferential distribution of blood of female astronauts, at risk of impaired function due to cerebral flow to the splanchnic circulation reflected by the 45% increase in hypoperfusion in the critical immediate postflight period. portal vein blood flow velocity, while blood flow velocity and Regulation of arterial BP in space might differ from on Earth. BP vascular resistance in the muscular and cerebral circulations are 1,21 monitoring over 24-h revealed lower inflight values in short- not affected by spaceflight. We propose that the smaller drop in and long-duration spaceflight. When measured under condi- TPR resulted from the elevated Q where a similar reduction in leg tions similar to the current study, BP was not different from vascular resistance on cuff release represented a smaller 23,24 preflight. The mechanisms underlying the reported drop in component of the whole-body TPR inflight. Further, with the arterial BP in 24-h recordings is unknown as the plasma elevated Q inflight, there was potential for a transient shift in catecholamine concentration was unchanged and direct record- blood flow from the splanchnic to the leg circulation without ing of muscle sympathetic nerve activity was increased during the affecting the overall BP response. short-duration Neurolab mission. Lower BP in space might also Clinically relevant information on BP regulation is obtained from 26 29 30 reflect the overall reduction in physical activity. The resting the supine-to-stand test and the sit-to-stand protocol. We supine DBP and MAP were slightly elevated inflight compared to included the 30-s sit phase of the study because we felt that the preflight while the SBP was not different. With an increase in drop in arterial pressure on moving directly from supine-to-stand inflight SV, it was not expected that arterial pulse would be on return from spaceflight might expose astronauts to risk of Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 22 K.N. Wood et al. Table 3. Peak changes and response dynamics comparing preflight to postflight posture (SUPINE-SIT) and preflight to inflight leg cuff deflation (CUFF), respectively Pre-SUPINE-SIT Post-SUPINE-SIT Pre-CUFF Inflight CUFF Heart rate Change to peak (Δ bpm) 23.7 ± 7.6 25.2 ± 7.0 18.6 ± 7.2 16.4 ± 3.3 Time to peak (s) 9.1 ± 4.8 12.5 ± 1.1 10.3 ± 1.8 9.3 ± 3.4 Response rate (bpm/s) 4.4 ± 5.6 2.0 ± 0.5 1.9 ± 1.0 2.0 ± 0.9 Recovery rate (bpm/s) −1.7 ± 1.3 −2.2 ± 1.0 −2.6 ± 1.2 −2.5 ± 2.8 Systolic blood pressure Change to peak (Δ mmHg) −25.8 ± 19.0 −37.1 ± 25.9 −16.4 ± 3.7 −16.4 ± 5.6 Time to Nadir (s) 11.0 ± 7.2 15.8 ± 7.5* 7.8 ± 1.3 5.4 ± 3.5 Response rate (mmHg/s) −3.5 ± 2.9 −2.9 ± 2.1 −2.2 ± 0.7 −4.7 ± 4.1 Recovery rate (mmHg/s) −1.0 ± 0.4 −2.7 ± 2.5 −3.7 ± 1.3 −3.2 ± 1.4 Diastolic blood pressure Change to peak (Δ mmHg) −15.2 ± 11.4 −23.8 ± 11.9* −15.8 ± 3.4 −14.4 ± 3.2 Time to Nadir (s) 11.6 ± 7.3 13.9 ± 8.3 8.6 ± 1.4 5.9 ± 2.7 Response rate (mmHg/s) −2.0 ± 2.1 −2.8 ± 3.0 −1.9 ± 0.5 −2.9 ± 1.3 Recovery rate (mmHg/s) −2.6 ± 4.8 −1.8 ± 0.9 −1.8 ± 2.3 −3.2 ± 1.2 Mean blood pressure Change to peak (Δ mmHg) −19.4 ± 16.5 −31.1 ± 17.9* −18.9 ± 2.3 −17.9 ± 4.5 Time to Nadir (s) 9.9 ± 5.1 13.8 ± 8.8 7.5 ± 1.2 5.5 ± 3.5 Response rate (mmHg/s) −2.4 ± 2.4 −3.6 ± 3.4 −2.6 ± 0.5 −5.5 ± 5.9 Recovery rate (mmHg/s) −1.7 ± 2.0 −2.4 ± 1.4* −3.1 ± 0.8 −3.9 ± 1.7 Cardiac output Change to peak (Δ L/min) 2.7 ± 1.8 2.4 ± 1.9 2.4 ± 1.1 2.8 ± 1.2 Time to peak (s) 8.9 ± 4.1 8.6 ± 4.9 10.1 ± 1.5 9.1 ± 4.0 Response rate (L/min/s) 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.1 0.4 ± 0.2 Recovery rate (L/min/s) −0.2 ± 0.2 −0.1 ± 0.1 −0.4 ± 0.2 −0.5 ± 0.2 Stroke volume Change to peak (Δ mL) −30.2 ± 6.2 −24.3 ± 11.0 −9.4 ± 17.7 −5.6 ± 4.2 Time to Nadir (s) 21.3 ± 9.8 11.6 ± 10.4 9.0 ± 4.7 9.4 ± 8.7 Response rate (mL/min/s) −2.3 ± 2.7 −4.5 ± 3.7 −1.3 ± 1.6 −1.7 ± 2.0 Recovery rate (mL/min/s) −4.2 ± 3.9 −2.1 ± 1.9 −1.5 ± 2.2 −0.4 ± 1.2 Total peripheral resistance Change to peak (Δ mmHg/L/min) −7.5 ± 6.6 −7.6 ± 2.6 −8.7 ± 2.0 −5.4 ± 1.1* Time to Nadir (s) 12.6 ± 6.7 16.8 ± 10.6 8.6 ± 0.9 6.5 ± 3.9 Response rate (mmHg/L/min/s) −0.8 ± 1.0 −0.8 ± 0.8 −1.0 ± 0.3 −1.2 ± 1.1 Recovery rate (mmHg/L/min/s) −0.9 ± 1.1 −0.8 ± 0.2 −1.1 ± 0.3 −0.8 ± 0.2 Values are means ± SD. SUPINE-SIT is the peak/nadir during the 30 s sit period of the posture trial, CUFF is the maximal or minimal value after leg cuff deflation. Change to peak = Δ from baseline; negative values indicate a decrease. Response rate = Δ from baseline/time to nadir; recovery rate = 50% Δ/time for recovery *Different from preflight, p < 0.05 fainting early after postural transition. The large drop in postflight arteriolar dilation resulting in reduced TPR, a fall in BP, and an BP in the seated posture for one astronaut (see Fig. 3), consistent increase in HR. Although not significant, there was a greater drop with initial orthostatic hypotension, does support the response in SBP postflight than preflight during the supine to sitting expected from typical clinical testing. For the group of astronauts, transition. In addition, the time to nadir was longer postflight supine cardiovascular responses were different between pre- and reflecting a delay in reaching this lower SBP. For DBP and MAP, the postflight testing. HR was elevated, DBP was higher and SV was drop to nadir was also longer postflight. The response rate and the smaller in post- compared to preflight. The smaller SV might recovery rate determined as the time from supine to nadir and reflect a state of hypovolemia postflight, but the elevated HR from nadir to 50% recovery of the drop in BP was not different maintained Q that combined with a slight elevation in TPR to keep except for the recovery rate of MAP. Individual variations in BP MAP at, or slightly above, preflight supine. The elevation in DBP, patterns limited the ability of these time course markers to reflect with a consequent reduction in pulse pressure, reflected the the integrated baroreflex response during the posture transition smaller SV. with this methodology. Active sitting from a supine position required muscular activity Moving from seated to standing position activated the muscle that compresses leg and splanchnic veins promoting increased pump assisting venous return and further dilating peripheral venous return and Q. However, the muscular activity also caused resistance vessels. With our protocol involving a 30-s period of npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.N. Wood et al. seated posture between supine and standing, the magnitude of greatest drop in BP. HR increased as anticipated suggesting that changes in cardiovascular variables appeared to be less than the cardiac component of the arterial baroreflex was intact, but at a HR of ~120 bpm, the sympathetic contribution would dominate observed in sit-to-stand protocols. This was probably a the vagal component of the baroreflex as revealed by this consequence of incomplete recovery of the vasodilatory response individual’s response to postflight standing in Fig. 2. The to muscle contractions during the supine-to-seated transition. The progressive reduction in arterial pulse pressure (Fig. 3)is absolute values of cardiovascular variables at the peak or nadir in consistent with reduced venous return and smaller stroke volume; the sitting-to-standing transition were not different between pre- this type of response has been observed previously in some and postflight testing. Likewise, there were no differences in the astronauts and is highly predictive of impending syncope if the values measured in the last 15 s of the 3-min stand test from pre- test had been prolonged. to postflight, nor was there a difference in the baroreflex response The BP responses of the astronaut in Fig. 3 can be used to slope during standing. These data suggest preservation of arterial assess the objective of the current study to utilize the leg-cuff BP regulation when measured within 18–36 h of return from deflation test to assess baroreflex response inflight as a predictor 6 months in space. However, this conclusion from group data of postflight orthostatic hypotension. Inflight, the leg cuff misses the two individuals with clear orthostatic hypotension deflation caused a similar, albeit slightly smaller, drop in BP and during the 3-min stand. Figure 3 shows the astronaut with the HR response. The rationale at the onset of the study was based on the observation that the preflight leg cuff test and the supine-to- seated transition caused similar drops in BP and increases in HR. * However, the large drop in BP during the post-flight supine-to- 40 seated transition was not reflected in the inflight leg cuff. The current data suggest that the elevated inflight Q changed the way in which TPR responded to the leg cuff deflation and therefore affected the integrated HR and vascular responses of the baroreflex. Inflight identification of up to 20–25% of all male 19,20 19 astronauts and a greater percentage of female astronauts susceptible to postflight orthostatic hypotension is important for astronaut safety, but the approach needs to consider the elevated Q. Sustained movement of blood away from the heart, as in post- flight upright posture, is probably the best approach to assessing risk for orthostatic hypotension. Lower body negative pressure can progressively shift blood volume to the legs and lower abdomen evoking reflex cardiovascular responses. Currently, the Russian PreSupine PreStand Inflight PostSupine PostStand chibis would allow this; only limited data from Russian cosmonaut Fig. 2 Individual subject values of the spontaneous arterial 33 experiences with such tests have been published. A short-arm baroreflex slope from supine (pre- and postflight), standing (pre- centrifuge could also accomplish a sustained gravity-like shift of and postflight), and inflight. Two subjects who exhibited signs of fluid into the lower body, but this device is not available. postflight orthostatic intolerance have been highlighted (red). Dark Astronaut research is unique because of the exposure to black line represents the group average (n = 8). *Different from inflight, p < 0.001; different from sessional supine, p < 0.001 prolonged unloading conditions. Many factors complicate studies of physiological responses of astronauts to spaceflight and return 180 180 140 140 Pre-flight Sit-Stand Test Pre-flight Leg Cuff 160 160 140 120 140 120 120 120 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 SIT STAND CUFFS UP CUFFS DOWN 0 20 0 20 -30 0 30 60 90 120 150 180 210 -30 0 30 60 180 180 140 140 Post-flight Sit-Stand Test In-flight Leg Cuff 160 160 140 120 120 100 100 80 80 60 60 60 60 40 40 20 20 SIT STAND CUFFS UP CUFFS DOWN 0 20 0 20 -30 0 30 60 90 120 150 180 210 -30 0 30 60 Time (s) Time (s) Fig. 3 Continuous blood pressure (red) and heart rate (black) shown in one crew member who presented with orthostatic intolerance on return to Earth Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 22 Baroreflex Slope (ms/mmHg) Brachial Arterial Pressure (mmHg) Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Heart Rate (bpm) Brachial Arterial Pressure (mmHg) Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Heart Rate (bpm) K.N. Wood et al. to gravity. The most commonly referred to is the small sample unable to assess incidence of delayed orthostatic hypotension in size that also affected the current study. Different responses of astronauts after spaceflight. 19,35 male and female astronauts did not affect the current study, In conclusion, postflight orthostatic hypotension remains a real as all of our participants were men. Individual variability in risk for some astronauts returning to Earth after long-duration preflight experiences and daily routine while on the ISS spaceflight. To date, it has not been possible to predict which complicate interpretation of the varied physiological responses, astronauts will be most susceptible to the effects of orthostatic especially in view of the small sample. Six of the eight astronauts hypotension. The current study showed that the inflight response in the current study were jet fighter pilots who would have to rapid leg cuff deflation did not differ from the preflight experienced years of exposure to high gravitational stressors, and response in terms of the magnitude or timing of the drop in were selected for their occupation because they could tolerate arterial BP or the increase in HR. However, the inflight response high g-forces. It is possible that being a jet fighter pilot might have did differ in the relative contribution of Q and TPR. That is, an altered intrinsic physiological responses, or that unconscious elevated Q in the period immediately before cuff release allowed responses contributed to their ability to maintain arterial BP. the drop in TPR as a consequence of the leg cuff release to result Unlike earlier short-duration missions on shuttle that frequently in a smaller change in TPR. Even in an astronaut with marked prioritized mission tasks over countermeasures, astronauts on ISS initial orthostatic hypotension with the post-flight transition to follow a monitored inflight countermeasures routine to attenuate seated, the inflight immediate drop on cuff release did not predict cardiovascular deconditioning consisting of ~30 min/day aerobic this response. Future testing of astronauts to detect their potential 26,35,36 exercise plus resistive exercises. The astronauts in the for post-flight orthostatic intolerance needs to employ a sustained current study did not utilize the Russian chibis device to apply gravity-like challenge such as with lower body negative pressure. lower body negative pressure to achieve a gravity-like shift in blood volume. Most astronauts consume additional fluids and salt as part of the prereturn routine. Fluid loading might benefit METHODS orthostatic BP responses; but it is uncertain if this effect would Eight male astronauts (44 ± 7 years of age) scheduled for a 6-month have influenced our results obtained 18–36 h postflight when sojourn (mean mission length: 167 ± 12 days) to the ISS were recruited into the study following NASA and ESA informed consent procedures. The additional fluid consumption and hormonal responses would have protocol was approved by the University of Waterloo Office of Research contributed to plasma volume regulation. Further, physicians Ethics, the IRB, NASA Human Research Medical Review Board, the assess crewmembers immediately on return to Earth to determine European Space Agency Medical Review Board and Japanese Space if intravenous or oral fluid loading is required as astronaut health Agency Research Ethics board (NASA MPA 7116301606HR; FWA 00019876) comes before science. Personal preferences and medical assess- in accordance with the Declaration of Helsinki. No alcohol, BP medications, ments influence whether the astronauts wear compression over-the-counter cold medications, or allergy medications were consumed garments after reentry (Russian Kentavr). Only one astronaut in within 24 h of the test. Food and caffeine were not consumed in the 2 h this study continued to wear Kentavr after landing, and removed before testing, and no exercise training was conducted on the test day them prior to testing. before testing. Lower body compression garments, if worn, were removed for postflight testing. In addition to the general limitations of spaceflight research Data collection consisted of four distinct phases of cardiovascular considered above, the current study must acknowledge that measurements: (1) preflight stand test, collected 44–90 days before launch estimates of stroke volume and Q from pulse contour analysis for comparison to (2) postflight stand test, within 18–36 h of return to Earth required careful positioning of the finger cuff and calibration. The when the astronauts were returned to Johnson Space Center, Houston TX, pulse wave of the finger BP waveform was monitored in real-time or the European Astronaut Centre, Cologne, Germany; (3) preflight supine by the principal investigator and assessed for quality against the leg cuff test, collected 44–90 days before launch for comparison to (4) preflight supine. Calibration of pulse contour Q was conducted inflight leg cuff, collected during the final 21 days of flight. preflight and inflight by comparison to rebreathing estimates; a major deviation in the calibration factor was detected inflight but Stand test the current data, obtained in a continuous data collection session During preflight and postflight testing, crewmembers were instrumented with the rebreathing measurements, were adjusted by the 27 in the supine posture to measure HR (Heart Rate Module; FMS, Amsterdam, appropriate factor. We did not do rebreathing postflight and The Netherlands) and finger arterial BP (Finometer Pro; FMS) with data used the preflight correction factors for each individual astronaut. recorded at 1000 Hz (PowerLab, ADInstruments). Finger pressure was This might have affected the absolute Q in the post-flight session. referenced by a height correction system to the level of the right atrium on The pulse contour method has been used to monitor changes in the midaxillary line. Following instrumentation requiring approximately 38,39 Q. In the current study where all comparisons between 5 min, crewmembers rested in a supine position for collection of baseline conditions were with the same method, there might be an data for 5 min before moving to a seated position with the legs bent at underestimation of the magnitude of change, but this should ~90° at the hip and knee. After being seated for 30 s, subjects were instructed to move as quickly as possible to a standing position while affect all conditions equally. focusing on a target directly ahead and remaining stationary for 3 min The stand test was limited to 3-min. The 3-min test is clinically before returning to a seated position. This test differed from a typical relevant in diagnosis of classical orthostatic hypotension defined a 40 clinical test by introduction of a 30 s sit due to perceived higher risk of drop in SBP > 20 mmHg or in DBP > 10 mmHg. Importantly in fainting with a supine to stand transition. The test adopted clinical criteria the context of spaceflight research, this duration test was defining an acute drop in systolic BP greater than 40 mmHg or diastolic BP appropriate due to the very limited time for multiple medical greater than 20 mmHg as initial orthostatic hypotension, and classical and research activities in the first day after spaceflight. All testing orthostatic hypotension as a drop in systolic BP greater than 20 mmHg, was conducted in what was considered “R + 0”, that is, the first and/or diastolic BP greater than 10 mmHg over the 3 min. day available for testing after landing. In some cases, astronauts arrived late at night at JSC and testing was completed as early as On-ground leg cuffs possible the next morning. The duration of the orthostatic Crewmembers were instrumented with identical leg cuffs that were used 3,20,41 challenge and time post-return are relevant. Previous on ISS (CADMOS Leg-Arm Cuff System, LACS). Following a 2-min investigations of post-spaceflight orthostatic intolerance used stabilization period, leg cuffs were placed with the air bladder over the 10-min standing or tilt to identify orthostatic intolerance and femoral artery and were manually inflated to suprasystolic pressure testing was conducted in the context of shuttle return directly to (150 mmHg) using two sphygmomanometers. The cuffs remained inflated 3,20 the test site or after a shorter time to return to Star City, Russia. for 3 min to occlude leg blood flow followed by the sudden release of the With the shorter duration of standing, the current study was cuffs causing arterial pressure to transiently drop, as previously described npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.N. Wood et al. by Lind-Holst et al. This protocol was repeated three times with a post- otherwise, the Mann–Whitney rank sum test was used. Differences were cuff period of 2 min between inflations. The responses to the three cuff considered statistically significant when P < 0.05. tests were time aligned to the release of occlusion and averaged together For the posture protocol, “supine” reflects the mean value for the 30 s period before moving to a seated position, “sit” reflects the peak/nadir of before analysis. the 30-s seated period, “stand” reflects the peak/nadir of the first 60 s of the stand, and “end stand” reflects the mean value for the final 15 s of the Rebreathing cardiac output stand test. For the leg cuff ischemia protocol, “cuff” reflects mean values Following the leg cuff tests, crewmembers moved to a seated position for 30 s before the release of the thigh cuffs, “postcuff” reflects the maximal or the rebreathing maneuvers to measure Q by a foreign gas technique using minimal value after deflation, and “end cuff” reflects the final 15 s of the the Portable Pulmonary Function System (a ground-based equivalent of post-cuff period. the Pulmonary Function System, PPFS; Danish Aerospace, Copenhagen, Denmark). Measurement of Q for these same astronauts was described 27 Reporting summary previously. Participants were instructed to breathe normally through a Further information on research design is available in the Nature Research mouthpiece, while wearing a nose clip. At the start of the rebreathing Reporting Summary linked to this article. maneuver, they expired to a normal end-expiratory point and then followed a visual display that prompted smooth breathing back and forth to completely empty the bag at a rate of 20 breaths/min for 25 s. The bag DATA AVAILABILITY contained 1.5 liter of a gas mixture [1% Freon-22 (soluble tracer gas), 1% Data sharing is subject to the conditions of approval by the relevant ethics boards, SF (non-soluble tracer gas), 25% O , and balance N ]. Three separate 6 2 2 and therefore cannot be available without appropriate consent. rebreathing maneuvers were separated by 5 min for elimination of the foreign gas markers. Received: 19 November 2018; Accepted: 18 September 2019; Inflight leg cuffs This test was performed using the CADMOS LACS, a component of the ESA Cardiolab system located in the Columbus Module of the ISS. 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Reduced spontaneous baroreflex response slope during Intolerance After ISS and Space Shuttle Missions. Aerosp. Med Hum. Perform. 86, lower body negative pressure after 28 days of head-down bed rest. J. Appl A54–A67 (2015). Physiol. (1985) 77,69–77 (1994). 21. Norsk, P. et al. Vasorelaxation in space. Hypertension 47,69–73 (2006). 43. Parlow, J., Viale, J. P., Annat, G., Hughson, R. & Quintin, L. Spontaneous cardiac 22. Norsk, P., Asmar, A., Damgaard, M. & Christensen, N. J. Fluid shifts, vasodilatation baroreflex in humans. Comparison with drug-induced responses. Hypertension and ambulatory blood pressure reduction during long duration spaceflight. J. 25, 1058–1068 (1995). Physiol. 593, 573–584 (2015). 23. Hughson, R. L. et al. Cardiovascular regulation during long-duration spaceflights to the International Space Station. J. Appl Physiol. (1985) 112, 719–727 (2012). ACKNOWLEDGEMENTS 24. Verheyden, B., Liu, J., Beckers, F. & Aubert, A. E. Operational point of neural We are grateful to the astronauts in the BP Reg study who were very committed to cardiovascular regulation in humans up to 6 months in space. J. Appl Physiol. achieving high-quality data. The authors acknowledge the following individuals in (1985) 108, 646–654 (2010). particular for their invaluable assistance during data collection and processing: Poul 25. Ertl, A. C. et al. Human muscle sympathetic nerve activity and plasma nora- Knudsen (Danish Aerospace), Marty Bost (Wylie, NASA-JSC), Steve Platts (NASA-JSC), drenaline kinetics in space. J. Physiol. 538, 321–329 (2002). Stephanie Herr (Cadmos), Edwin Mulder (DLR), Wolfram Sies (DLR), and Thomas 26. Fraser, K. S., Greaves, D. K., Shoemaker, J. K., Blaber, A. P. & Hughson, R. L. Heart Beltrame (Universidade Ibirapuera, Brazil). The Canadian Space Agency Project Team rate and daily physical activity with long-duration habitation of the International provided excellent support throughout the entire BP Reg study. This work was Space Station. Aviat. Space Environ. Med. 83, 577–584 (2012). supported by Canadian Space Agency Contract #: 9F053-111259 and Natural Sciences 27. Hughson, R. L., Peterson, S. D., Yee, N. J. & Greaves, D. K. Cardiac output by pulse and Engineering Research Council of Canada Grant RGPIN-6473 (to R.L. Hughson). contour analysis does not match the increase measured by rebreathing during human spaceflight. J. Appl Physiol. (1985) 123, 1145–1149 (2017). 28. Arbeille, P., Provost, R., Zuj, K. & Vincent, N. Measurements of jugular, portal, AUTHOR CONTRIBUTIONS femoral, and calf vein cross-sectional area for the assessment of venous blood K.N.W.: Data analysis, paper preparation, and compilation. K.R.M.: Data analysis and redistribution with long duration spaceflight (Vessel Imaging Experiment). Eur. J. paper review. D.K.G.: Data collection and analysis and paper review. R.L.H.: Data Appl Physiol. 115, 2099–2106 (2015). collection and analysis, paper preparation, and compilation. 29. Finucane, C. et al. Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA). Circulation 130, 1780–1789 (2014). COMPETING INTERESTS 30. Sorond, F. A., Serrador, J. M., Jones, R. N., Shaffer, M. L. & Lipsitz, L. A. The sit-to- stand technique for the measurement of dynamic cerebral autoregulation. The authors declare no competing interests. Ultrasound Med Biol. 35,21–29 (2009). 31. Wieling, W., Krediet, C. T., van Dijk, N., Linzer, M. & Tschakovsky, M. E. Initial orthostatic hypotension: review of a forgotten condition. Clin. Sci. (Lond.) 112, ADDITIONAL INFORMATION 157–165 (2007). Supplementary information is available for this paper at https://doi.org/10.1038/ 32. Meck, J. V. et al. Mechanisms of postspaceflight orthostatic hypotension: low s41526-019-0082-3. alpha1-adrenergic receptor responses before flight and central autonomic dys- regulation postflight. Am. J. Physiol. Heart Circ. Physiol. 286, H1486–H1495 Correspondence and requests for materials should be addressed to K.N.W. (2004). 33. Kozlovskaya, I. B. et al. Russian countermeasure systems for adverse effects of Reprints and permission information is available at http://www.nature.com/ microgravity on long-duration ISS flights. Aerosp. Med Hum. Perform. 86, A24–A31 reprints (2015). 34. Pawelczyk, J. A. Big concepts, small N. J. Physiol. 572, 607–608 (2006). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 35. Hughson, R. L. et al. Increased postflight carotid artery stiffness and inflight in published maps and institutional affiliations. insulin resistance resulting from 6-mo spaceflight in male and female astronauts. Am. J. Physiol. Heart Circ. Physiol. 310, H628–H638 (2016). 36. Trappe, S. et al. Exercise in space: human skeletal muscle after 6 months aboard the International Space Station. J. Appl Physiol. (1985) 106,1159–1168 (2009). Open Access This article is licensed under a Creative Commons 37. Bungo, M. W., Charles, J. B. & Johnson, P. C. Jr. Cardiovascular deconditioning Attribution 4.0 International License, which permits use, sharing, during space flight and the use of saline as a countermeasure to orthostatic adaptation, distribution and reproduction in any medium or format, as long as you give intolerance. Aviat. Space Environ. Med. 56, 985–990 (1985). appropriate credit to the original author(s) and the source, provide a link to the Creative 38. Harms, M. P. et al. Continuous stroke volume monitoring by modelling flow from Commons license, and indicate if changes were made. The images or other third party non-invasive measurement of arterial pressure in humans under orthostatic material in this article are included in the article’s Creative Commons license, unless stress. Clin. Sci. 97, 291–301 (1999). indicated otherwise in a credit line to the material. If material is not included in the 39. Jellema, W. T., Imholz, B. P., van Goudoever, J., Wesseling, K. H. & van Lieshout, J. J. article’s Creative Commons license and your intended use is not permitted by statutory Finger arterial versus intrabrachial pressure and continuous cardiac output dur- regulation or exceeds the permitted use, you will need to obtain permission directly ing head-up tilt testing in healthy subjects. Clin. Sci. 91, 193–200 (1996). from the copyright holder. To view a copy of this license, visit http://creativecommons. 40. Brignole, M. et al. 2018 ESC Guidelines for the diagnosis and management of org/licenses/by/4.0/. syncope. Kardiol. Pol. 76, 1119–1198 (2018). 41. Mulavara, A. P. et al. Physiological and functional alterations after spaceflight and bed rest. Med Sci. Sports Exerc. 50, 1961–1980 (2018). © The Author(s) 2019 npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Microgravity Springer Journals

Inflight leg cuff test does not identify the risk for orthostatic hypotension after long-duration spaceflight

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Life Sciences; Life Sciences, general; Classical and Continuum Physics; Biotechnology; Immunology; Space Sciences (including Extraterrestrial Physics, Space Exploration and Astronautics) ; Applied Microbiology
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www.nature.com/npjmgrav ARTICLE OPEN Inflight leg cuff test does not identify the risk for orthostatic hypotension after long-duration spaceflight 1 1 1 1 Katelyn N. Wood , Kevin R. Murray , Danielle K. Greaves and Richard L. Hughson Landing day symptoms from orthostatic hypotension after prolonged spaceflight can be debilitating, but severity of these symptoms can be unpredictable and highly individual. We tested the hypothesis that an impaired baroreflex response to an inflight leg cuff test could predict orthostatic intolerance on return to Earth. Eight male astronauts (44 ± 7 years of age (mean ± SD); mean mission length: 167 ± 12 days) participated in a standardized supine-to-sit-to-stand test (5 min–30s–3 min) pre- and postflight, and a 3 min thigh cuff occlusion test pre- and inflight with continuous monitoring of heart rate and arterial blood pressure. The arterial baroreflex was not changed inflight as shown by similar reductions in mean arterial pressure (MAP) response to leg cuff deflation (preflight −19 ± 2 mmHg vs. inflight −18 ± 5 mmHg). With the sit/stand test, the nadir of MAP was lower postflight (−17 ± 9 mmHg) than preflight (−11 ± 6 mmHg, p < 0.05). A greater increase in heart rate (25 ± 7; 16 ± 3 bpm) and decrease in stroke volume (−24 ± 11; −6 ± 4 mL) occurred with sit/stand postflight than leg cuffs inflight (p < 0.001). Inflight testing was influenced by elevated cardiac output resulting in a smaller drop in total peripheral resistance. Two of eight subjects exhibited orthostatic hypotension during the postflight stand test; their responses were not predicted by the inflight leg cuff deflation test. These results suggest that the baroreflex response examined by inflight leg cuff deflation was not a reliable indicator of postflight stand responses. npj Microgravity (2019) 5:22 ; https://doi.org/10.1038/s41526-019-0082-3 INTRODUCTION cuff inflation to occlude arterial inflow followed by rapid release of the cuffs causes a drop in arterial BP that is similar to that of Orthostatic intolerance, a major problem for the return of 17,18 1,2 transition from supine to upright posture. This leg cuff test astronauts to the gravitational forces of Earth, is aggravated detected differences in arterial baroreflex response between by long-duration spaceflight. NASA included this important endurance athletes and healthy controls, with the athletes health risk in the Human Research Roadmap of problems that experiencing a greater drop in BP and a longer time for recovery. need to be resolved prior to future exploration missions (NASA It was hypothesized that astronauts who experienced postflight Human Research Roadmap). Multiple mechanisms contribute to orthostatic intolerance during a stand test would have impairment orthostatic intolerance on return to Earth including impaired 5,6 of arterial baroreflex manifested by a greater drop and delayed venous properties that reduce return of blood to the heart, 7 8,9 recovery of arterial BP in the leg cuff test when measured late in lower blood volume, diminished cardiac mass, reduced spaceflight. cardiac output, inadequate sympathetic nervous system- 1,11–13 mediated vasoconstriction, and impairment of the arterial 14,15 baroreflex. RESULTS Based on the current knowledge and understanding of cardiovascular mechanisms that are altered during exposure to Preflight posture microgravity, a test, administered during spaceflight, to identify The cardiovascular responses to the supine-to-seated-to-standing individual astronauts at greatest risk for postflight orthostatic posture transitions displayed an anticipated biphasic response hypotension could provide input guiding the extent of near end- (solid black line, Fig. 1). Heart rate (HR) increased from supine to of-flight and immediate postflight countermeasures designed to seated (p < 0.001) and remained elevated above supine values at reduce the risk of impairment of performance and loss of the end of the 3 min stand (p < 0.01, Table 1). Systolic (SBP), consciousness. These end-of-flight countermeasures could include diastolic (DBP), and mean arterial pressure (MAP) decreased from lower body negative pressure, as used by Russian cosmonauts, supine to seated (p < 0.05) with a gradual return to above supine high intensity exercise, and fluid loading during re-entry; whole values at end stand (Fig. 1, Table 1). Cardiac output (Q) increased body cooling, and lower body compression garments alone or in from supine to seated (p < 0.001) and was slightly elevated at end combination, can provide protection against postflight orthostatic stand (p = 0.06). Stroke volume (SV) decreased in the seated intolerance. Methods to challenge the arterial blood pressure posture (p < 0.001) and remained lower at end stand (p < 0.05). (BP) regulatory mechanisms can be applied while in microgravity. Total peripheral resistance (TPR) decreased from supine to seated A human centrifuge could generate a head-to-foot gravitational (p < 0.001) and was above supine values at end stand (p < 0.05). vector, but this facility is not currently available in space. Lower body negative pressure could stimulate the effects of gravity and Postflight posture and comparison retain blood volume in the lower part of the body. In the Russian segment of the International Space Station (ISS) the Chibis device Dotted black lines in Fig. 1 show the postflight posture transition generates lower body negative pressure, but this device was responses. Compared to preflight, postflight supine HR was higher unavailable to the researchers at the time of this experiment. Leg than preflight leading to a higher HR during the posture test Schlegel-University of Waterloo Research Institute for Aging, Waterloo, ON, Canada. *email: k24wood@uwaterloo.ca Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; K.N. Wood et al. to preflight (p = 0.15). There were no differences in the TPR Preflight Stand response pre- to postflight, despite a trend for higher postflight Preflight Cuffs resistance. Inflight Cuffs Preflight leg cuffs Postflight Stand 20 40 The cardiovascular responses to the sudden release of occluding leg cuffs revealed the anticipated drop in arterial pressure and compensatory recovery responses (solid red line, Fig. 1). HR increased with cuff release (p < 0.001), while SBP, DBP, and MAP were reduced (p < 0.001, Table 2). On average, there was no significant change in SV with cuff release. Q increased with cuff release (p < 0.001), while TPR decreased (p < 0.001, Fig. 1, Table 2). Inflight leg cuffs and comparison The inflight leg cuff responses are shown by dotted red lines in -10 Fig. 1. Spaceflight did not change HR, SBP, or MAP compared to -20 preflight. DBP, SV, and Q were greater inflight (p < 0.05, Table 2). TPR was lower inflight (p < 0.05, Table 2). In addition, the 0 -30 magnitude of the response (Table 3) to cuff release was not different from preflight for HR, SBP, DBP, MAP, and Q. SV was higher inflight than preflight across all time points (Table 2), yet the magnitude of the reduction was the same compared to 120 preflight (Table 3). TPR was lower inflight, and after the release of leg ischemia, the drop in TPR was smaller inflight (p < 0.01, Table 80 3) than preflight. There were no differences for any measured variable in the response rate to leg cuff deflation or the recovery rate (Table 3). Arterial baroreflex and Blood pressure The arterial baroreflex response slope was assessed inflight as well -40 as pre- and postflight. The inflight baroreflex slope was significantly greater than preflight stand, and postflight supine -80 and stand (p < 0.05, Fig. 2). Overall, there was a linear relationship 40 between each individual’s baroreflex slope and his RR-interval, r ≥ 0.71 for all but one individual, and significant correlation coefficients for three individuals (r = > 0.96). While 6 of 8 subjects had remarkably stable BP during the postflight stand test, two subjects had patterns of BP consistent with orthostatic hypotension and suggestive of potential for syncope if the stand test had been sustained. Figure 3 demonstrates the pre- and postflight BP and HR response in one of the most vulnerable crewmembers. This figure also shows the leg cuff deflation tests revealing that the inflight leg cuff deflation test for this individual was not able to predict his postflight response to standing. DISCUSSION Two of eight male astronauts presented with orthostatic hypotension during a 3-min stand test conducted between 18 and 36 h of returning from 6 months on the ISS. Previous reports -20 0 20 40 60 of orthostatic tolerance during a 10-min tilt test after short- duration shuttle flights found 20% of men and 100% of women to Time (s) 19,20 3 be intolerant. Meck et al. found that orthostatic testing by 10- Fig. 1 Cardiovascular response to posture (black) vs. leg cuffs (red) min head-up tilt following long-duration spaceflight suggests a in all subjects, preflight (solid lines) and postflight/inflight (dotted higher incidence rate (5 of 6 male astronauts) even though these lines). Solid vertical line denotes initiation of cuff deflation or astronauts had participated in inflight countermeasures while on moving from supine to seated. Values are means ± SD the Mir space station. A compilation study of orthostatic tolerance after short-duration shuttle and long-duration stays on the ISS (Table 1), yet the magnitude of change was not different (p = 0.45, observed intolerance in 13 of 65 short-duration and 4 of 6 long- Δ in Table 3). Supine arterial BP tended to be higher postflight duration astronauts (sex of the intolerant astronauts was not than preflight, with a larger decrease (Δ) postflight on moving to specified). The primary hypothesis of this study, an inflight BP the seated position for SBP. There was a longer time to nadir for challenge caused by rapid deflation of leg cuffs, after a 3-min total DBP and MAP (p < 0.05, Table 3). There were no differences in the arterial occlusion, would be predictive of those individuals most Q response pre- to postflight. Supine SV was lower postflight (p < susceptible to postflight orthostatic hypotension, was not 0.05), but the magnitude of change was the same when compared supported, but pointed to unique physiological adaptations to npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Cardiac Output (L/min) Stroke Volume (mL) TPR (mmHg/L/Min) K.N. Wood et al. Table 1. Cardiovascular variables for supine (SUP) to seated (SIT), to standing (STAND) posture pre- and postflight Pre-SUP Pre-SIT Pre-STAND Pre-END STAND Post-SUP Post-SIT Post-STAND Post-END STAND BRS, ms/mmHg 20.0 ± 5.6 NA 6.3 ± 3.0* NA 19.1 ± 7.1 NA 7.4 ± 4.1* NA + + HR, bpm 57 ± 6 81 ± 11* 81 ± 11* 74 ± 11* 65 ± 8 90 ± 10* 88 ± 14* 86 ± 18* SBP, mmHg 127 ± 14 101 ± 15* 106 ± 26 129 ± 12 134 ± 8 97 ± 25* 111 ± 27 125 ± 11 ~ + ~ DBP, mmHg 69 ± 8 54 ± 11* 61 ± 16 78 ± 4* 78 ± 6 54 ± 13* 63 ± 18* 76 ± 9 MAP, mmHg 92 ± 7 73 ± 13* 80 ± 19 97 ± 6 98 ± 5 67 ± 18* 82 ± 20* 93 ± 11 ~ ~ Q, L/min 5.2 ± 0.9 7.9 ± 2.3* 6.9 ± 2.2 4.8 ± 0.8 5.0 ± 1.5 7.4 ± 3.3* 6.6 ± 2.7 4.7 ± 1.2 ~ + SV, mL/min 93 ± 24 63 ± 26* 51 ± 20 65 ± 16* 78 ± 25 53 ± 27* 46 ± 21* 55 ± 13* TPR 18.0 ± 5.0 10.5 ± 3.0* 13.4 ± 3.8* 20.4 ± 4.4* 21.6 ± 7.4 14.0 ± 8.3* 15.7 ± 7.8* 21.1 ± 6.8 Values are ±SD. SUP is the mean of the 30 s supine period before moving to a seated position, SIT is the peak/nadir during the 30 s seated posture, STAND is the peak/nadir of the first 60 s of the stand, and END STAND is the mean value for the final 15 s of the stand test. BRS baroreflex slope (mean values shown); HR, heart rate (peak values shown), SBP systolic blood pressure (nadir values shown), DBP, diastolic blood pressure (nadir), MAP mean arterial pressure (nadir), Q cardiac output (peak), SV stroke volume (nadir), TPR total peripheral resistance (nadir) *Different from sessional SUP Different from sessional SIT Different from corresponding preflight value, p < 0.05 smaller, but the reduced TPR and greater flow through the Table 2. Cardiovascular variables for leg cuff inflation-deflation pre- 9 splanchnic region might account for this. Consistent with the and inflight current study, the 45% increase in supine Q, corrected by the rebreathing value, was similar to values reported by Norsk Pre-CUFF Pre-Max or Min Inflight CUFF Inflight et al. Max or Min Leg cuff deflation provides a rapid drop in arterial BP enabling 18 17 HR, bpm 56 ± 6 74 ± 7* 57 ± 6 74 ± 5* testing of arterial baroreflex and cerebrovascular function. This study is the first use of the leg cuff system during spaceflight to SBP, mmHg 123 ± 11 107 ± 13* 123 ± 14 107 ± 16* + + test BP regulation. With the elevated inflight Q, but unchanged BP, DBP, mmHg 62 ± 7 47 ± 7* 69 ± 8 55 ± 9* release of the leg occlusion cuffs caused reductions in SBP, DBP, + + MAP, mmHg 82 ± 8 63 ± 9* 89 ± 10 71 ± 11* and MAP that were not different between preflight and inflight + + Q, L/min 4.6 ± 0.7 7.0 ± 1.4* 6.7 ± 1.2 9.5 ± 2.3* testing. In addition to the similar drops in BP, the response and + + SV, mL/min 84 ± 16 81 ± 15 119 ± 32 115 ± 32* recovery rates from nadir of the BP were not different comparing preflight to inflight. Likewise, the HR response to the drop in TPR, mmHg/ 18.4 ± 2.3 9.6 ± 1.6* 13.7 ± 3.5 8.3 ± 2.6* L/min arterial BP on cuff release was not different inflight as was the arterial baroreflex response slope not different inflight compared Values are mean ± SD. “Cuff” is near end of occlusion before the release of to preflight supine posture. Taken together, these data support the thigh cuffs, ‘Max or Min’ is the maximal or minimal value after deflation. the notion of maintenance of cardiovascular reflex control of heart HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, rate and peripheral vascular resistance during long-duration MAP mean arterial pressure, Q cardiac output, SV stroke volume, TPR total peripheral resistance. Note that Q and SV have been corrected for spaceflight. These observations are consistent with measurements 23,24 rebreathing estimate of arterial baroreflex during long-duration spaceflight, but *Different from sessional baseline during cuff inflation contrast with reduced baroreflex responses during short-duration Different from corresponding pre-flight value, p < 0.05 spaceflights. The similar drop in arterial BP on leg cuff release inflight compared to preflight indicated that the reduction in leg vascular long-duration spaceflight that can influence predictive tests resistance on cuff release was probably the same between the two attempted in the future. Predictive tests, if they can be developed, tests. However, the change in TPR was less inflight compared to could permit more aggressive near end of flight countermeasures preflight because of the elevated inflight Q. Underlying the for the 25% of male astronauts, and probably a greater proportion different TPR responses was a preferential distribution of blood of female astronauts, at risk of impaired function due to cerebral flow to the splanchnic circulation reflected by the 45% increase in hypoperfusion in the critical immediate postflight period. portal vein blood flow velocity, while blood flow velocity and Regulation of arterial BP in space might differ from on Earth. BP vascular resistance in the muscular and cerebral circulations are 1,21 monitoring over 24-h revealed lower inflight values in short- not affected by spaceflight. We propose that the smaller drop in and long-duration spaceflight. When measured under condi- TPR resulted from the elevated Q where a similar reduction in leg tions similar to the current study, BP was not different from vascular resistance on cuff release represented a smaller 23,24 preflight. The mechanisms underlying the reported drop in component of the whole-body TPR inflight. Further, with the arterial BP in 24-h recordings is unknown as the plasma elevated Q inflight, there was potential for a transient shift in catecholamine concentration was unchanged and direct record- blood flow from the splanchnic to the leg circulation without ing of muscle sympathetic nerve activity was increased during the affecting the overall BP response. short-duration Neurolab mission. Lower BP in space might also Clinically relevant information on BP regulation is obtained from 26 29 30 reflect the overall reduction in physical activity. The resting the supine-to-stand test and the sit-to-stand protocol. We supine DBP and MAP were slightly elevated inflight compared to included the 30-s sit phase of the study because we felt that the preflight while the SBP was not different. With an increase in drop in arterial pressure on moving directly from supine-to-stand inflight SV, it was not expected that arterial pulse would be on return from spaceflight might expose astronauts to risk of Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 22 K.N. Wood et al. Table 3. Peak changes and response dynamics comparing preflight to postflight posture (SUPINE-SIT) and preflight to inflight leg cuff deflation (CUFF), respectively Pre-SUPINE-SIT Post-SUPINE-SIT Pre-CUFF Inflight CUFF Heart rate Change to peak (Δ bpm) 23.7 ± 7.6 25.2 ± 7.0 18.6 ± 7.2 16.4 ± 3.3 Time to peak (s) 9.1 ± 4.8 12.5 ± 1.1 10.3 ± 1.8 9.3 ± 3.4 Response rate (bpm/s) 4.4 ± 5.6 2.0 ± 0.5 1.9 ± 1.0 2.0 ± 0.9 Recovery rate (bpm/s) −1.7 ± 1.3 −2.2 ± 1.0 −2.6 ± 1.2 −2.5 ± 2.8 Systolic blood pressure Change to peak (Δ mmHg) −25.8 ± 19.0 −37.1 ± 25.9 −16.4 ± 3.7 −16.4 ± 5.6 Time to Nadir (s) 11.0 ± 7.2 15.8 ± 7.5* 7.8 ± 1.3 5.4 ± 3.5 Response rate (mmHg/s) −3.5 ± 2.9 −2.9 ± 2.1 −2.2 ± 0.7 −4.7 ± 4.1 Recovery rate (mmHg/s) −1.0 ± 0.4 −2.7 ± 2.5 −3.7 ± 1.3 −3.2 ± 1.4 Diastolic blood pressure Change to peak (Δ mmHg) −15.2 ± 11.4 −23.8 ± 11.9* −15.8 ± 3.4 −14.4 ± 3.2 Time to Nadir (s) 11.6 ± 7.3 13.9 ± 8.3 8.6 ± 1.4 5.9 ± 2.7 Response rate (mmHg/s) −2.0 ± 2.1 −2.8 ± 3.0 −1.9 ± 0.5 −2.9 ± 1.3 Recovery rate (mmHg/s) −2.6 ± 4.8 −1.8 ± 0.9 −1.8 ± 2.3 −3.2 ± 1.2 Mean blood pressure Change to peak (Δ mmHg) −19.4 ± 16.5 −31.1 ± 17.9* −18.9 ± 2.3 −17.9 ± 4.5 Time to Nadir (s) 9.9 ± 5.1 13.8 ± 8.8 7.5 ± 1.2 5.5 ± 3.5 Response rate (mmHg/s) −2.4 ± 2.4 −3.6 ± 3.4 −2.6 ± 0.5 −5.5 ± 5.9 Recovery rate (mmHg/s) −1.7 ± 2.0 −2.4 ± 1.4* −3.1 ± 0.8 −3.9 ± 1.7 Cardiac output Change to peak (Δ L/min) 2.7 ± 1.8 2.4 ± 1.9 2.4 ± 1.1 2.8 ± 1.2 Time to peak (s) 8.9 ± 4.1 8.6 ± 4.9 10.1 ± 1.5 9.1 ± 4.0 Response rate (L/min/s) 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.1 0.4 ± 0.2 Recovery rate (L/min/s) −0.2 ± 0.2 −0.1 ± 0.1 −0.4 ± 0.2 −0.5 ± 0.2 Stroke volume Change to peak (Δ mL) −30.2 ± 6.2 −24.3 ± 11.0 −9.4 ± 17.7 −5.6 ± 4.2 Time to Nadir (s) 21.3 ± 9.8 11.6 ± 10.4 9.0 ± 4.7 9.4 ± 8.7 Response rate (mL/min/s) −2.3 ± 2.7 −4.5 ± 3.7 −1.3 ± 1.6 −1.7 ± 2.0 Recovery rate (mL/min/s) −4.2 ± 3.9 −2.1 ± 1.9 −1.5 ± 2.2 −0.4 ± 1.2 Total peripheral resistance Change to peak (Δ mmHg/L/min) −7.5 ± 6.6 −7.6 ± 2.6 −8.7 ± 2.0 −5.4 ± 1.1* Time to Nadir (s) 12.6 ± 6.7 16.8 ± 10.6 8.6 ± 0.9 6.5 ± 3.9 Response rate (mmHg/L/min/s) −0.8 ± 1.0 −0.8 ± 0.8 −1.0 ± 0.3 −1.2 ± 1.1 Recovery rate (mmHg/L/min/s) −0.9 ± 1.1 −0.8 ± 0.2 −1.1 ± 0.3 −0.8 ± 0.2 Values are means ± SD. SUPINE-SIT is the peak/nadir during the 30 s sit period of the posture trial, CUFF is the maximal or minimal value after leg cuff deflation. Change to peak = Δ from baseline; negative values indicate a decrease. Response rate = Δ from baseline/time to nadir; recovery rate = 50% Δ/time for recovery *Different from preflight, p < 0.05 fainting early after postural transition. The large drop in postflight arteriolar dilation resulting in reduced TPR, a fall in BP, and an BP in the seated posture for one astronaut (see Fig. 3), consistent increase in HR. Although not significant, there was a greater drop with initial orthostatic hypotension, does support the response in SBP postflight than preflight during the supine to sitting expected from typical clinical testing. For the group of astronauts, transition. In addition, the time to nadir was longer postflight supine cardiovascular responses were different between pre- and reflecting a delay in reaching this lower SBP. For DBP and MAP, the postflight testing. HR was elevated, DBP was higher and SV was drop to nadir was also longer postflight. The response rate and the smaller in post- compared to preflight. The smaller SV might recovery rate determined as the time from supine to nadir and reflect a state of hypovolemia postflight, but the elevated HR from nadir to 50% recovery of the drop in BP was not different maintained Q that combined with a slight elevation in TPR to keep except for the recovery rate of MAP. Individual variations in BP MAP at, or slightly above, preflight supine. The elevation in DBP, patterns limited the ability of these time course markers to reflect with a consequent reduction in pulse pressure, reflected the the integrated baroreflex response during the posture transition smaller SV. with this methodology. Active sitting from a supine position required muscular activity Moving from seated to standing position activated the muscle that compresses leg and splanchnic veins promoting increased pump assisting venous return and further dilating peripheral venous return and Q. However, the muscular activity also caused resistance vessels. With our protocol involving a 30-s period of npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.N. Wood et al. seated posture between supine and standing, the magnitude of greatest drop in BP. HR increased as anticipated suggesting that changes in cardiovascular variables appeared to be less than the cardiac component of the arterial baroreflex was intact, but at a HR of ~120 bpm, the sympathetic contribution would dominate observed in sit-to-stand protocols. This was probably a the vagal component of the baroreflex as revealed by this consequence of incomplete recovery of the vasodilatory response individual’s response to postflight standing in Fig. 2. The to muscle contractions during the supine-to-seated transition. The progressive reduction in arterial pulse pressure (Fig. 3)is absolute values of cardiovascular variables at the peak or nadir in consistent with reduced venous return and smaller stroke volume; the sitting-to-standing transition were not different between pre- this type of response has been observed previously in some and postflight testing. Likewise, there were no differences in the astronauts and is highly predictive of impending syncope if the values measured in the last 15 s of the 3-min stand test from pre- test had been prolonged. to postflight, nor was there a difference in the baroreflex response The BP responses of the astronaut in Fig. 3 can be used to slope during standing. These data suggest preservation of arterial assess the objective of the current study to utilize the leg-cuff BP regulation when measured within 18–36 h of return from deflation test to assess baroreflex response inflight as a predictor 6 months in space. However, this conclusion from group data of postflight orthostatic hypotension. Inflight, the leg cuff misses the two individuals with clear orthostatic hypotension deflation caused a similar, albeit slightly smaller, drop in BP and during the 3-min stand. Figure 3 shows the astronaut with the HR response. The rationale at the onset of the study was based on the observation that the preflight leg cuff test and the supine-to- seated transition caused similar drops in BP and increases in HR. * However, the large drop in BP during the post-flight supine-to- 40 seated transition was not reflected in the inflight leg cuff. The current data suggest that the elevated inflight Q changed the way in which TPR responded to the leg cuff deflation and therefore affected the integrated HR and vascular responses of the baroreflex. Inflight identification of up to 20–25% of all male 19,20 19 astronauts and a greater percentage of female astronauts susceptible to postflight orthostatic hypotension is important for astronaut safety, but the approach needs to consider the elevated Q. Sustained movement of blood away from the heart, as in post- flight upright posture, is probably the best approach to assessing risk for orthostatic hypotension. Lower body negative pressure can progressively shift blood volume to the legs and lower abdomen evoking reflex cardiovascular responses. Currently, the Russian PreSupine PreStand Inflight PostSupine PostStand chibis would allow this; only limited data from Russian cosmonaut Fig. 2 Individual subject values of the spontaneous arterial 33 experiences with such tests have been published. A short-arm baroreflex slope from supine (pre- and postflight), standing (pre- centrifuge could also accomplish a sustained gravity-like shift of and postflight), and inflight. Two subjects who exhibited signs of fluid into the lower body, but this device is not available. postflight orthostatic intolerance have been highlighted (red). Dark Astronaut research is unique because of the exposure to black line represents the group average (n = 8). *Different from inflight, p < 0.001; different from sessional supine, p < 0.001 prolonged unloading conditions. Many factors complicate studies of physiological responses of astronauts to spaceflight and return 180 180 140 140 Pre-flight Sit-Stand Test Pre-flight Leg Cuff 160 160 140 120 140 120 120 120 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 SIT STAND CUFFS UP CUFFS DOWN 0 20 0 20 -30 0 30 60 90 120 150 180 210 -30 0 30 60 180 180 140 140 Post-flight Sit-Stand Test In-flight Leg Cuff 160 160 140 120 120 100 100 80 80 60 60 60 60 40 40 20 20 SIT STAND CUFFS UP CUFFS DOWN 0 20 0 20 -30 0 30 60 90 120 150 180 210 -30 0 30 60 Time (s) Time (s) Fig. 3 Continuous blood pressure (red) and heart rate (black) shown in one crew member who presented with orthostatic intolerance on return to Earth Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 22 Baroreflex Slope (ms/mmHg) Brachial Arterial Pressure (mmHg) Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Heart Rate (bpm) Brachial Arterial Pressure (mmHg) Brachial Arterial Pressure (mmHg) Heart Rate (bpm) Heart Rate (bpm) K.N. Wood et al. to gravity. The most commonly referred to is the small sample unable to assess incidence of delayed orthostatic hypotension in size that also affected the current study. Different responses of astronauts after spaceflight. 19,35 male and female astronauts did not affect the current study, In conclusion, postflight orthostatic hypotension remains a real as all of our participants were men. Individual variability in risk for some astronauts returning to Earth after long-duration preflight experiences and daily routine while on the ISS spaceflight. To date, it has not been possible to predict which complicate interpretation of the varied physiological responses, astronauts will be most susceptible to the effects of orthostatic especially in view of the small sample. Six of the eight astronauts hypotension. The current study showed that the inflight response in the current study were jet fighter pilots who would have to rapid leg cuff deflation did not differ from the preflight experienced years of exposure to high gravitational stressors, and response in terms of the magnitude or timing of the drop in were selected for their occupation because they could tolerate arterial BP or the increase in HR. However, the inflight response high g-forces. It is possible that being a jet fighter pilot might have did differ in the relative contribution of Q and TPR. That is, an altered intrinsic physiological responses, or that unconscious elevated Q in the period immediately before cuff release allowed responses contributed to their ability to maintain arterial BP. the drop in TPR as a consequence of the leg cuff release to result Unlike earlier short-duration missions on shuttle that frequently in a smaller change in TPR. Even in an astronaut with marked prioritized mission tasks over countermeasures, astronauts on ISS initial orthostatic hypotension with the post-flight transition to follow a monitored inflight countermeasures routine to attenuate seated, the inflight immediate drop on cuff release did not predict cardiovascular deconditioning consisting of ~30 min/day aerobic this response. Future testing of astronauts to detect their potential 26,35,36 exercise plus resistive exercises. The astronauts in the for post-flight orthostatic intolerance needs to employ a sustained current study did not utilize the Russian chibis device to apply gravity-like challenge such as with lower body negative pressure. lower body negative pressure to achieve a gravity-like shift in blood volume. Most astronauts consume additional fluids and salt as part of the prereturn routine. Fluid loading might benefit METHODS orthostatic BP responses; but it is uncertain if this effect would Eight male astronauts (44 ± 7 years of age) scheduled for a 6-month have influenced our results obtained 18–36 h postflight when sojourn (mean mission length: 167 ± 12 days) to the ISS were recruited into the study following NASA and ESA informed consent procedures. The additional fluid consumption and hormonal responses would have protocol was approved by the University of Waterloo Office of Research contributed to plasma volume regulation. Further, physicians Ethics, the IRB, NASA Human Research Medical Review Board, the assess crewmembers immediately on return to Earth to determine European Space Agency Medical Review Board and Japanese Space if intravenous or oral fluid loading is required as astronaut health Agency Research Ethics board (NASA MPA 7116301606HR; FWA 00019876) comes before science. Personal preferences and medical assess- in accordance with the Declaration of Helsinki. No alcohol, BP medications, ments influence whether the astronauts wear compression over-the-counter cold medications, or allergy medications were consumed garments after reentry (Russian Kentavr). Only one astronaut in within 24 h of the test. Food and caffeine were not consumed in the 2 h this study continued to wear Kentavr after landing, and removed before testing, and no exercise training was conducted on the test day them prior to testing. before testing. Lower body compression garments, if worn, were removed for postflight testing. In addition to the general limitations of spaceflight research Data collection consisted of four distinct phases of cardiovascular considered above, the current study must acknowledge that measurements: (1) preflight stand test, collected 44–90 days before launch estimates of stroke volume and Q from pulse contour analysis for comparison to (2) postflight stand test, within 18–36 h of return to Earth required careful positioning of the finger cuff and calibration. The when the astronauts were returned to Johnson Space Center, Houston TX, pulse wave of the finger BP waveform was monitored in real-time or the European Astronaut Centre, Cologne, Germany; (3) preflight supine by the principal investigator and assessed for quality against the leg cuff test, collected 44–90 days before launch for comparison to (4) preflight supine. Calibration of pulse contour Q was conducted inflight leg cuff, collected during the final 21 days of flight. preflight and inflight by comparison to rebreathing estimates; a major deviation in the calibration factor was detected inflight but Stand test the current data, obtained in a continuous data collection session During preflight and postflight testing, crewmembers were instrumented with the rebreathing measurements, were adjusted by the 27 in the supine posture to measure HR (Heart Rate Module; FMS, Amsterdam, appropriate factor. We did not do rebreathing postflight and The Netherlands) and finger arterial BP (Finometer Pro; FMS) with data used the preflight correction factors for each individual astronaut. recorded at 1000 Hz (PowerLab, ADInstruments). Finger pressure was This might have affected the absolute Q in the post-flight session. referenced by a height correction system to the level of the right atrium on The pulse contour method has been used to monitor changes in the midaxillary line. Following instrumentation requiring approximately 38,39 Q. In the current study where all comparisons between 5 min, crewmembers rested in a supine position for collection of baseline conditions were with the same method, there might be an data for 5 min before moving to a seated position with the legs bent at underestimation of the magnitude of change, but this should ~90° at the hip and knee. After being seated for 30 s, subjects were instructed to move as quickly as possible to a standing position while affect all conditions equally. focusing on a target directly ahead and remaining stationary for 3 min The stand test was limited to 3-min. The 3-min test is clinically before returning to a seated position. This test differed from a typical relevant in diagnosis of classical orthostatic hypotension defined a 40 clinical test by introduction of a 30 s sit due to perceived higher risk of drop in SBP > 20 mmHg or in DBP > 10 mmHg. Importantly in fainting with a supine to stand transition. The test adopted clinical criteria the context of spaceflight research, this duration test was defining an acute drop in systolic BP greater than 40 mmHg or diastolic BP appropriate due to the very limited time for multiple medical greater than 20 mmHg as initial orthostatic hypotension, and classical and research activities in the first day after spaceflight. All testing orthostatic hypotension as a drop in systolic BP greater than 20 mmHg, was conducted in what was considered “R + 0”, that is, the first and/or diastolic BP greater than 10 mmHg over the 3 min. day available for testing after landing. In some cases, astronauts arrived late at night at JSC and testing was completed as early as On-ground leg cuffs possible the next morning. The duration of the orthostatic Crewmembers were instrumented with identical leg cuffs that were used 3,20,41 challenge and time post-return are relevant. Previous on ISS (CADMOS Leg-Arm Cuff System, LACS). Following a 2-min investigations of post-spaceflight orthostatic intolerance used stabilization period, leg cuffs were placed with the air bladder over the 10-min standing or tilt to identify orthostatic intolerance and femoral artery and were manually inflated to suprasystolic pressure testing was conducted in the context of shuttle return directly to (150 mmHg) using two sphygmomanometers. The cuffs remained inflated 3,20 the test site or after a shorter time to return to Star City, Russia. for 3 min to occlude leg blood flow followed by the sudden release of the With the shorter duration of standing, the current study was cuffs causing arterial pressure to transiently drop, as previously described npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.N. Wood et al. by Lind-Holst et al. This protocol was repeated three times with a post- otherwise, the Mann–Whitney rank sum test was used. Differences were cuff period of 2 min between inflations. The responses to the three cuff considered statistically significant when P < 0.05. tests were time aligned to the release of occlusion and averaged together For the posture protocol, “supine” reflects the mean value for the 30 s period before moving to a seated position, “sit” reflects the peak/nadir of before analysis. the 30-s seated period, “stand” reflects the peak/nadir of the first 60 s of the stand, and “end stand” reflects the mean value for the final 15 s of the Rebreathing cardiac output stand test. For the leg cuff ischemia protocol, “cuff” reflects mean values Following the leg cuff tests, crewmembers moved to a seated position for 30 s before the release of the thigh cuffs, “postcuff” reflects the maximal or the rebreathing maneuvers to measure Q by a foreign gas technique using minimal value after deflation, and “end cuff” reflects the final 15 s of the the Portable Pulmonary Function System (a ground-based equivalent of post-cuff period. the Pulmonary Function System, PPFS; Danish Aerospace, Copenhagen, Denmark). Measurement of Q for these same astronauts was described 27 Reporting summary previously. Participants were instructed to breathe normally through a Further information on research design is available in the Nature Research mouthpiece, while wearing a nose clip. At the start of the rebreathing Reporting Summary linked to this article. maneuver, they expired to a normal end-expiratory point and then followed a visual display that prompted smooth breathing back and forth to completely empty the bag at a rate of 20 breaths/min for 25 s. The bag DATA AVAILABILITY contained 1.5 liter of a gas mixture [1% Freon-22 (soluble tracer gas), 1% Data sharing is subject to the conditions of approval by the relevant ethics boards, SF (non-soluble tracer gas), 25% O , and balance N ]. Three separate 6 2 2 and therefore cannot be available without appropriate consent. rebreathing maneuvers were separated by 5 min for elimination of the foreign gas markers. Received: 19 November 2018; Accepted: 18 September 2019; Inflight leg cuffs This test was performed using the CADMOS LACS, a component of the ESA Cardiolab system located in the Columbus Module of the ISS. 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Operational point of neural We are grateful to the astronauts in the BP Reg study who were very committed to cardiovascular regulation in humans up to 6 months in space. J. Appl Physiol. achieving high-quality data. The authors acknowledge the following individuals in (1985) 108, 646–654 (2010). particular for their invaluable assistance during data collection and processing: Poul 25. Ertl, A. C. et al. Human muscle sympathetic nerve activity and plasma nora- Knudsen (Danish Aerospace), Marty Bost (Wylie, NASA-JSC), Steve Platts (NASA-JSC), drenaline kinetics in space. J. Physiol. 538, 321–329 (2002). Stephanie Herr (Cadmos), Edwin Mulder (DLR), Wolfram Sies (DLR), and Thomas 26. Fraser, K. S., Greaves, D. K., Shoemaker, J. K., Blaber, A. P. & Hughson, R. L. Heart Beltrame (Universidade Ibirapuera, Brazil). The Canadian Space Agency Project Team rate and daily physical activity with long-duration habitation of the International provided excellent support throughout the entire BP Reg study. This work was Space Station. Aviat. Space Environ. Med. 83, 577–584 (2012). supported by Canadian Space Agency Contract #: 9F053-111259 and Natural Sciences 27. Hughson, R. L., Peterson, S. D., Yee, N. J. & Greaves, D. K. Cardiac output by pulse and Engineering Research Council of Canada Grant RGPIN-6473 (to R.L. Hughson). contour analysis does not match the increase measured by rebreathing during human spaceflight. J. Appl Physiol. (1985) 123, 1145–1149 (2017). 28. Arbeille, P., Provost, R., Zuj, K. & Vincent, N. Measurements of jugular, portal, AUTHOR CONTRIBUTIONS femoral, and calf vein cross-sectional area for the assessment of venous blood K.N.W.: Data analysis, paper preparation, and compilation. K.R.M.: Data analysis and redistribution with long duration spaceflight (Vessel Imaging Experiment). Eur. J. paper review. D.K.G.: Data collection and analysis and paper review. R.L.H.: Data Appl Physiol. 115, 2099–2106 (2015). collection and analysis, paper preparation, and compilation. 29. Finucane, C. et al. Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA). Circulation 130, 1780–1789 (2014). COMPETING INTERESTS 30. Sorond, F. A., Serrador, J. M., Jones, R. N., Shaffer, M. L. & Lipsitz, L. A. The sit-to- stand technique for the measurement of dynamic cerebral autoregulation. The authors declare no competing interests. Ultrasound Med Biol. 35,21–29 (2009). 31. Wieling, W., Krediet, C. T., van Dijk, N., Linzer, M. & Tschakovsky, M. E. Initial orthostatic hypotension: review of a forgotten condition. Clin. Sci. (Lond.) 112, ADDITIONAL INFORMATION 157–165 (2007). Supplementary information is available for this paper at https://doi.org/10.1038/ 32. Meck, J. V. et al. Mechanisms of postspaceflight orthostatic hypotension: low s41526-019-0082-3. alpha1-adrenergic receptor responses before flight and central autonomic dys- regulation postflight. Am. J. Physiol. Heart Circ. Physiol. 286, H1486–H1495 Correspondence and requests for materials should be addressed to K.N.W. (2004). 33. Kozlovskaya, I. B. et al. Russian countermeasure systems for adverse effects of Reprints and permission information is available at http://www.nature.com/ microgravity on long-duration ISS flights. Aerosp. Med Hum. Perform. 86, A24–A31 reprints (2015). 34. Pawelczyk, J. A. Big concepts, small N. J. Physiol. 572, 607–608 (2006). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 35. Hughson, R. L. et al. Increased postflight carotid artery stiffness and inflight in published maps and institutional affiliations. insulin resistance resulting from 6-mo spaceflight in male and female astronauts. Am. J. Physiol. Heart Circ. Physiol. 310, H628–H638 (2016). 36. Trappe, S. et al. Exercise in space: human skeletal muscle after 6 months aboard the International Space Station. J. Appl Physiol. (1985) 106,1159–1168 (2009). Open Access This article is licensed under a Creative Commons 37. Bungo, M. W., Charles, J. B. & Johnson, P. C. Jr. Cardiovascular deconditioning Attribution 4.0 International License, which permits use, sharing, during space flight and the use of saline as a countermeasure to orthostatic adaptation, distribution and reproduction in any medium or format, as long as you give intolerance. Aviat. Space Environ. Med. 56, 985–990 (1985). appropriate credit to the original author(s) and the source, provide a link to the Creative 38. Harms, M. P. et al. Continuous stroke volume monitoring by modelling flow from Commons license, and indicate if changes were made. The images or other third party non-invasive measurement of arterial pressure in humans under orthostatic material in this article are included in the article’s Creative Commons license, unless stress. Clin. Sci. 97, 291–301 (1999). indicated otherwise in a credit line to the material. If material is not included in the 39. Jellema, W. T., Imholz, B. P., van Goudoever, J., Wesseling, K. H. & van Lieshout, J. J. article’s Creative Commons license and your intended use is not permitted by statutory Finger arterial versus intrabrachial pressure and continuous cardiac output dur- regulation or exceeds the permitted use, you will need to obtain permission directly ing head-up tilt testing in healthy subjects. Clin. Sci. 91, 193–200 (1996). from the copyright holder. To view a copy of this license, visit http://creativecommons. 40. Brignole, M. et al. 2018 ESC Guidelines for the diagnosis and management of org/licenses/by/4.0/. syncope. Kardiol. Pol. 76, 1119–1198 (2018). 41. Mulavara, A. P. et al. Physiological and functional alterations after spaceflight and bed rest. Med Sci. Sports Exerc. 50, 1961–1980 (2018). © The Author(s) 2019 npj Microgravity (2019) 22 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA

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