Long-duration spaceflight alters estimated intracranial pressure and cerebral blood velocity.

KEY POINTS: During long-duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension. In the present study, intracranial pressure was estimated non-invasively (nICP) using a model-based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long-duration spaceflights. Our results show that group-averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long-duration spaceflight rarely increased postflight intracranial pressure. The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post-flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes. Cerebral blood velocity increased independently of nICP and spaceflight-associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long-duration spaceflight. ABSTRACT: Persistently elevated intracranial pressure (ICP) above upright values is a suspected cause of optic disc oedema in astronauts. However, no systematic studies have evaluated changes in ICP from preflight. Therefore, ICP was estimated non-invasively before and after spaceflight to test whether ICP would increase after long-duration spaceflight. Cerebral blood velocity in the middle cerebral artery (MCAv) was obtained by transcranial Doppler sonography and arterial pressure in the radial artery was obtained by tonometry, in the supine and sitting positions before and after 4-12 months of spaceflight in 11 astronauts (10 males and 1 female, 46 ± 7 years old at launch). Non-invasive ICP (nICP) was computed using a validated model-based estimation method. Mean MCAv increased significantly after spaceflight (ANOVA, P = 0.007). Haemoglobin decreased significantly after spaceflight (14.6 ± 0.8 to 13.3 ± 0.7 g/dL, P < 0.001). A repeated measures correlation analysis indicated a negative correlation between haemoglobin and mean MCAv (r = -0.589, regression coefficient = -4.68). The nICP did not change significantly after spaceflight in the 11 astronauts. However, nICP decreased significantly by 15% in nine astronauts without optic disc oedema (P < 0.005). Only one astronaut increased nICP to relatively high levels after spaceflight. Contrary to our hypothesis, nICP did not increase after long-duration spaceflight in the vast majority (>90%) of astronauts, suggesting that the cephalad fluid shift during spaceflight does not systematically or consistently elevate postflight ICP in astronauts. Independently of nICP and ocular alterations, the present results of mean MCAv suggest that long-duration spaceflight may increase cerebral blood flow, possibly due to reduced haemoglobin concentration.

Dynamic cerebral autoregulation after confinement in an isolated environment for 14 days.

BACKGROUND: To develop human space exploration, it is necessary to study the effects of an isolated and confined environment, as well as a microgravity environment, on cerebral circulation. However, no studies on cerebral circulation in an isolated and confined environment have been reported. Therefore, we investigated the effects of a 14-day period of confinement in an isolated environment on dynamic cerebral autoregulation. METHODS: We participated in an isolation and confinement experiment conducted by the Japan Aerospace Exploration Agency in 2016. Eight healthy males were isolated and confined in a facility for 14 days. Data were collected on the days immediately before and after confinement. Arterial blood pressure waveforms were obtained using a finger blood pressure monitor, and cerebral blood flow velocity waveforms in the middle cerebral artery were obtained using transcranial Doppler ultrasonography for 6 min during quiet rest in a supine position. Dynamic cerebral autoregulation was evaluated by transfer function analysis between spontaneous variability of beat-to-beat mean arterial blood pressure and mean cerebral blood flow velocity. RESULTS: Transfer function gain in the low- and high-frequency ranges increased significantly (0.54 ± 0.07 to 0.69 ± 0.09 cm/s/mmHg and 0.80 ± 0.05 to 0.92 ± 0.09 cm/s/mmHg, respectively) after the confinement. CONCLUSION: The increases observed in transfer function gain may be interpreted as indicating less suppressive capability against transmission from arterial blood pressure oscillation to cerebral blood flow velocity fluctuation. These results suggest that confinement in an isolated environment for 14 days may impair dynamic cerebral autoregulation. TRIAL REGISTRATION: UMIN000020703 , Registered 2016/01/22.

Non-Invasive Intracranial Pressure Estimation During Combined Exposure to CO2 and Head-Down Tilt.

BACKGROUND: Exposure to carbon dioxide (CO2) and cephalad fluid shift are considered factors that affect intracranial pressure (ICP) during spaceflight. Increases in ICP were reported during cephalad fluid shift induced by head-down tilt (HDT), while little is known regarding the effect of additional CO2 during HDT on ICP. Therefore, we tested the hypothesis that this combination increases ICP more than HDT alone. METHODS: There were 15 healthy male volunteers who underwent 4 types of 10-min interventions consisting of Placebo/Supine (air and supine), CO2/Supine (3% CO2 and supine, CO2 alone), Placebo/HDT (air and -10° HDT, HDT alone), and CO2/HDT (3% CO2 and -10° HDT, combination). Using arterial blood pressure (ABP) and cerebral blood flow velocity waveforms, ICP was estimated noninvasively before and during the four interventions. Two calculation methods were employed. One is based on the signal transformation from ABP to ICP with the intracranial component as a "black box" system (nICP_BB), and the other is based on the equation ICP = ABP - cerebral perfusion pressure, reflecting critical closing pressure (nICP_CrCP). RESULTS: Both nICP_BB and nICP_CrCP significantly increased during Placebo/HDT and CO2/HDT, although there was no statistically significant difference between the nICP indexes of these two interventions. DISCUSSION: Increases in ICP were observed during both Placebo/HDT and CO2/HDT. Contrary to our hypothesis, the combination of 3% CO2 and -10° HDT did not increase ICP remarkably compared to -10° HDT alone. Therefore, the addition of 3% CO2 is considered to have little effect on increasing ICP during cephalad fluid shift.Kurazumi T, Ogawa Y, Yanagida R, Morisaki H, Iwasaki K. Non-invasive intracranial pressure estimation during combined exposure to CO2 and head-down tilt. Aerosp Med Hum Perform. 2018; 89(4):365-370.

Dynamic Cerebral Autoregulation During the Combination of Mild Hypercapnia and Cephalad Fluid Shift.

BACKGROUND: Mild hypercapnia combined with a cephalad fluid shift [e.g., that occurring during spaceflight or laparoscopic surgery with head-down tilt (HDT)] might affect cerebral autoregulation. However, no reports have described the effects of the combination on dynamic cerebral autoregulation. Therefore, we tested the hypothesis that the combination of mild hypercapnia and a cephalad fluid shift would attenuate dynamic cerebral autoregulation. METHODS: There were 15 healthy male volunteers who were exposed to 4 10-min protocols in which they received air in the supine position (Placebo/Supine), 3% carbon dioxide (CO2) in the supine position (CO2/Supine), air with -10° HDT (Placebo/HDT) and 3% CO2 with -10° HDT (CO2/HDT). Dynamic cerebral autoregulation was evaluated using a transfer function analysis of the beat-to-beat variability in mean arterial blood pressure (ABP) and mean cerebral blood flow (CBF) velocity. RESULTS: The phase in the low-frequency range was significantly lower during CO2/HDT than all other protocols, where CO2/HDT was -25% lower than Placebo/Supine (CO2/HDT, 0.49 ± 0.21; Placebo/Supine, 0.65 ± 0.16 radians). The transfer function gain in the low-frequency range was significantly higher during CO2/HDT than all other protocols, where CO2/HDT was 26% higher than Placebo/Supine (CO2/HDT, 1.08 ± 0.34; Placebo/Supine, 0.86 ± 0.28 cm · s-1 · mmHg-1). However, neither the CO2/Supine nor Placebo/HDT showed significant differences compared with the Placebo/Supine. DISCUSSION: Even short-term exposure to 3% CO2 plus HDT increased synchrony and the magnitude of transmission between ABP and CBF in the low-frequency range. Thus, the combination of mild hypercapnia and a cephalad fluid shift attenuated dynamic cerebral autoregulation.Kurazumi T, Ogawa Y, Yanagida R, Morisaki H, Iwasaki K. Dynamic cerebral autoregulation during the combination of mild hypercapnia and cephalad fluid shift. Aerosp Med Hum Perform. 2017; 88(9):819-826.

Speed ratio but cabin temperature positively correlated with increased heart rates among professional drivers during car races.

OBJECTIVES: The present study measures heart rate (HR) on a number of professional race-car drivers during actual car races through annual seasons to test hypotheses that faster relative speed and higher cabin temperature would induce higher HR. METHODS: Heart rates in fifteen male drivers (31.2 ± 5.5 years old) were obtained by chest-strap sensors during official-professional 13 races. Average HR was calculated while the driver was racing from the start to the end of each race. RESULTS: The average HR during races was 164.5 ± 15.1 beats min-1 and the average amount of time each driver spent driving per race was 54.2 ± 13.7 min. Average HR significantly and positively correlated with mean speed ratio (P < 0.001), but not with the average cabin temperatures (P = 0.533, range 25.6-41.8 °C) by the multiple linear regression analysis. Both average HR and mean speed ratio were significantly lower under wet, than dry conditions (151.9 ± 16.5 vs. 168.3 ± 12.5 beats min-1, 86.9 ± 4.4 vs. 93.4 ± 1.5 %). CONCLUSIONS: The cardiovascular system of drivers is considerably stressed at extremely high HR. This high average HR positively correlated with mean speed ratio, suggesting that faster driving speed would induce greater cardiovascular stress to professional drivers during actual races. However, contrary to our hypothesis, cabin temperature was not significantly correlated with average HR. It is speculated that direct body cooling systems used in this professional race category work well against increases in HR by thermal stress under the temperature range found herein.

The relationship between widespread changes in gravity and cerebral blood flow.

OBJECTIVES: We investigated the dose-effect relationship between wide changes in gravity from 0 to 2.0 Gz (Δ0.5 Gz) and cerebral blood flow (CBF), to test our hypothesis that CBF has a linear relationship with levels of gravity. SUBJECTS AND METHODS: Ten healthy seated men were exposed to 0, 0.5, 1.0, 1.5, and 2.0 Gz for 21 min, by using a tilt chair and a short-arm human centrifuge. Steady-state CBF velocity (CBFV) in the middle cerebral artery by transcranial Doppler ultrasonography, mean arterial pressure (MAP) at the heart level (MAPHeart), heart rate, stroke volume, cardiac output and respiratory conditions were obtained for the last 6 min at each gravity level. Then, MAP in the middle cerebral artery (MAPMCA), reflecting cerebral perfusion pressure, was estimated. RESULTS: Steady-state CBFV decreased stepwise from 0.5 to 2.0 Gz. Steady-state heart rate, stroke volume, estimated MAPMCA and end-tidal carbon dioxide pressure (ETCO2) also changed stepwise from hypogravity to hypergravity. On the other hand, steady-state MAPHeart and cardiac output did not change significantly. Steady-state CBFV positively and linearly correlated with estimated MAPMCA and ETCO2 in most subjects. CONCLUSION: The present study demonstrated stepwise gravity-induced changes in steady-state CBFV from 0.5 to 2.0 Gz despite unchanged steady-state MAPHeart. The combined effects of reduced MAPMCA and ETCO2 likely led to stepwise decreases in CBFV. We caution that a mild increase in gravity from 0 to 2.0 Gz reduces CBF, even if arterial blood pressure at the heart level is maintained.

Dose-Effect Relationship Between Mild Levels of Hypergravity and Autonomic Circulatory Regulation.

INTRODUCTION: The dose-effect relationships between different levels of hypergravity (>+1.0 Gz) and steady-state hemodynamic parameters have been reported in several studies. However, little has been reported on the dose-effect relationship between hypergravity levels and estimates of autonomic circulatory regulation, such as heart rate variability, arterial pressure variability, and spontaneous cardiac baroreflex sensitivity. We investigated dose-effect relationships between hypergravity levels from +1.0 Gz to +2.0 Gz (Δ0.5 Gz) and autonomic circulatory regulation to test our hypothesis that autonomic circulatory regulation has a linear relationship with hypergravity levels. METHODS: Using a short-arm human centrifuge, 10 healthy seated men were subjected to +1.0 Gz, +1.5 Gz, and +2.0 Gz hypergravity. We evaluated steady-state hemodynamic parameters and autonomic circulatory regulation indices. Heart rate variability, arterial pressure variability, and spontaneous cardiac baroreflex sensitivity between arterial pressure and R-R interval variabilities were assessed by spectral analysis, sequence analysis, and transfer function analysis. RESULTS: Steady-state heart rate, stroke volume, and sequence slope (indicating spontaneous cardiac baroreflex sensitivity in response to rapid changes in arterial pressure) showed linear correlations with increases in gravity (from +1.0 Gz to +2.0 Gz). On the other hand, steady-state cardiac output, steady-state systolic arterial pressure, and low-frequency power of diastolic arterial pressure (indicating peripheral vasomotor sympathetic activity) remained unchanged with gravity increases. CONCLUSION: Contrary to our hypothesis, the present study suggested that autonomic circulatory regulations show complex changes with hypergravity levels. Spontaneous cardiac baroreflex sensitivity reduces in a dose-dependent manner from +1.0 Gz to +2.0 Gz, whereas peripheral vasomotor sympathetic activity seems to be maintained.

The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males.

BACKGROUND: It is unknown whether flumazenil antagonizes the decrease in cerebral blood flow or the alteration in dynamic cerebral autoregulation induced by midazolam. We, therefore, investigated the effects on cerebral circulation of flumazenil administered after midazolam, to test our hypothesis that, along with complete reversal of sedation, flumazenil antagonizes the alterations in cerebral circulation induced by midazolam. METHODS: Sixteen healthy young male subjects received midazolam followed by flumazenil. The modified Observer's Assessment of Alertness/Sedation (OAA/S) scale and bispectral index (BIS) were used to assess levels of sedation/awareness. For evaluation of cerebral circulation, steady-state mean cerebral blood flow velocity (MCBFV) was measured by transcranial Doppler ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability. RESULTS: During midazolam sedation, defined by an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly), BIS, steady-state MAP, steady-state CBFV, and transfer function gain decreased significantly compared with baseline. After flumazenil administration, an OAA/S score of 5 (responds readily to name spoken in a normal tone) was confirmed. Then, BIS and MAP returned to the same level as baseline. However, steady-state MCBFV showed a further significant decrease compared with that under midazolam sedation, and the decreased transfer function gain persisted. CONCLUSIONS: Contrary to our hypothesis, the present results suggest that despite complete antagonism of the sedative effects of midazolam, flumazenil would not reverse the alterations in cerebral circulation induced by midazolam.

Sustained mild hypergravity reduces spontaneous cardiac baroreflex sensitivity.

Head-to-foot gravitational force >1G (+Gz hypergravity) augments venous pooling in the lower body and reduces central blood volume during exposure, compared with 1Gz. Central hypovolemia has been reported to reduce spontaneous cardiac baroreflex sensitivity. However, no investigations have examined spontaneous cardiac baroreflex sensitivity during exposure to sustained mild +Gz hypergravity. We therefore hypothesized that mild +Gz hypergravity would reduce spontaneous cardiac baroreflex sensitivity, compared with 1Gz. To test this hypothesis, we examined spontaneous cardiac baroreflex sensitivity in 16 healthy men during exposure to mild +Gz hypergravity using a short-arm centrifuge. Beat-to-beat arterial blood pressure (tonometry) and R-R interval (electrocardiography) were obtained during 1Gz and 1.5Gz exposures. Spontaneous cardiac baroreflex sensitivity was assessed by sequence slope and transfer function gain. Stroke volume was calculated from the arterial pressure waveform using a three-element model. All indices of spontaneous cardiac baroreflex sensitivity decreased significantly (up slope: 18.6±2.3→12.7±1.6ms/mmHg, P<0.001; down slope: 19.0±2.5→13.2±1.3ms/mmHg, P=0.002; transfer function gain in low frequency: 14.4±2.2→10.1±1.1ms/mmHg, P=0.004; transfer function gain in high frequency: 22.2±7.5→12.4±3.5ms/mmHg, P<0.001). Stroke volume decreased significantly (88±5→80±6ml, P=0.025). Moreover, although systolic arterial pressure variability increased, R-R interval variability did not increase. These results suggest that even mild +Gz hypergravity reduces spontaneous cardiac baroreflex sensitivity, increasing the risk of cardiovascular disturbance during the exposure.

[Acute mild hypoxia impairment of dynamic cerebral autoregulation assessed by spectral analysis and thigh-cuff deflation].

OBJECTIVES: Acute hypoxia may impair dynamic cerebral autoregulation. However, previous studies have been controversial. The difference in methods of estimation of dynamic cerebral autoregulation is reported to be responsible for conflicting reports. We, therefore, conducted this study using two representative methods of estimation of dynamic cerebral autoregulation to test our hypothesis that dynamic cerebral autoregulation is impaired during acute exposure to mild hypoxia. METHODS: Eleven healthy men were exposed to 15% oxygen concentration for two hours. They were examined under normoxia (21% O(2)) and hypoxia (15% O(2)). The mean arterial pressure (MAP) in the radial artery was measured by tonometry, and cerebral blood flow velocity (CBFv) in the middle cerebral artery was measured by transcranial Doppler ultrasonography. Dynamic cerebral autoregulation was assessed by spectral and transfer function analyses of beat-by-beat changes in MAP and CBFv. Moreover, the dynamic rate of regulation and percentage restoration of CBFv were estimated when a temporal decrease in arterial pressure was induced by thigh-cuff deflation. RESULTS: Arterial oxygen saturation decreased significantly during hypoxia (97±0% to 88±1%), whereas respiratory rate was unchanged, as was steady-state CBFv. With 15% O(2), the very-low-frequency power of CBFv variability increased significantly. Transfer function coherence (0.40±0.02 to 0.53±0.05) and gain (0.51±0.07 cm/s/mmHg to 0.79±0.11 cm/s/mmHg) in the very-low-frequency range increased significantly. Moreover, the percentage restoration of CBF velocity determined by thigh-cuff deflation decreased significantly during hypoxia (125±25% to 65±8%). CONCLUSIONS: Taken together, these results obtained using two representative methods consistently indicate that mild hypoxia impairs dynamic cerebral autoregulation.

[Relationship between baroreflex function and training effects on altitude training].

OBJECTIVE: Altitude training is frequently used for athletes requiring competitive endurance in an attempt to improve their sea-level performance. However, there has been no study in which the mechanisms by which spontaneous arterial-cardiac baroreflex function changes was examined in responders or nonresponders of altitude training. The purpose of this study was to clarify the different effects of altitude training on baroreflex function between responders and nonresponders. METHODS: Twelve university student cross-country skiers (6 men, 6 women; age, 19±1 years) participated in the altitude training in a camp for 3 weeks, which was carried out in accordance with the method of Living High-Training Low. Baroreflex function was estimated by transfer function analysis before and after the training. RESULTS: The responders of the training were 3 men and 2 women, and the nonresponders were 3 men and 4 women. In the responders, the transfer function gain in the high-frequency range significantly increased after the training (28.9→46.5 ms/mmHg p=0.021). On the other hand, no significant change in this index was observed in the nonresponders (25.9→21.2 ms/mmHg p=0.405). CONCLUSION: As indicated by the results of transfer function gain in the high-frequency range, the baroreflex function in the responders increased significantly after the altitude training, whereas no significant change was observed in the nonresponders.

Subfoveal choroidal thickness and foveal retinal thickness during head-down tilt.

INTRODUCTION: To reveal subtle morphological changes in the eye during simulated microgravity for spaceflights, we measured subfoveal choroidal thickness and foveal retinal thickness during 10 degrees head-down tilt (HDT). We hypothesized that elevated ophthalmic vein pressure during simulated microgravity increases subfoveal choroidal thickness via enlargement of the choroidal vasculature and greater choroidal blood volume. METHODS: The right eyes of nine healthy subjects (seven men, two women) were examined. Subfoveal choroidal thickness and foveal retinal thickness were measured using spectral domain-optical coherence tomography in the sitting position, and after 15 and 30 min of 10 degrees HDT. Intraocular pressure was also measured. RESULTS: Mean subfoveal choroidal thickness (+/- SEM) increased from 300 +/- 31 microm in the sitting position to 315 +/- 31 microm with 15-min HDT, and 333 +/- 31 microm with 30-min HDT. However, no change in foveal retinal thickness was observed (228 +/- 9 microm in the sitting position, 228 +/- 10 microm with 15-min HDT and 228 +/- 9 microm with 30-min HDT). Intraocular pressure increased from 14 +/- 1 mmHg in the sitting position to 21 +/- 2 mmHg with 30-min HDT (54 +/- 6%, N = 5). DISCUSSION: Subfoveal choroidal thickness and intraocular pressure were increased by HDT during simulated microgravity, although no change in foveal retinal thickness was observed.

Cerebral circulation during mild +Gz hypergravity by short-arm human centrifuge.

We examined changes in cerebral circulation in 15 healthy men during exposure to mild +Gz hypergravity (1.5 Gz, head-to-foot) using a short-arm centrifuge. Continuous arterial pressure waveform (tonometry), cerebral blood flow (CBF) velocity in the middle cerebral artery (transcranial Doppler ultrasonography), and partial pressure of end-tidal carbon dioxide (ETco(2)) were measured in the sitting position (1 Gz) and during 21 min of exposure to mild hypergravity (1.5 Gz). Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between beat-to-beat mean arterial pressure (MAP) and mean CBF velocity (MCBFV). Steady-state MAP did not change, but MCBFV was significantly reduced with 1.5 Gz (-7%). ETco(2) was also reduced (-12%). Variability of MAP increased significantly with 1.5 Gz in low (53%)- and high-frequency ranges (88%), but variability of MCBFV did not change in these frequency ranges, resulting in significant decreases in transfer function gain between MAP and MCBFV (gain in low-frequency range, -17%; gain in high-frequency range, -13%). In contrast, all of these indexes in the very low-frequency range were unchanged. Transfer from arterial pressure oscillations to CBF fluctuations was thus suppressed in low- and high-frequency ranges. These results suggest that steady-state global CBF was reduced, but dynamic cerebral autoregulation in low- and high-frequency ranges was improved with stabilization of CBF fluctuations despite increases in arterial pressure oscillations during mild +Gz hypergravity. We speculate that this improvement in dynamic cerebral autoregulation within these frequency ranges may have been due to compensatory effects against the reduction in steady-state global CBF.