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Background: Orthostatic intolerance occurs following immobilization in patients on Earth and in astronauts after spaceflight. Head-down tilt bedrest is a terrestrial model for weightlessness and induces orthostatic intolerance. We hypothesized that lower-body negative pressure (LBNP) or cycling followed by wearing venous constrictive thigh cuffs mitigates orthostatic intolerance after head-down tilt bedrest., Methods and Results: We enrolled 47 healthy individuals (20 women, 35±9 years) to a 30-day strict head-down tilt bedrest study. During bedrest, they were assigned to 6 hours of 25 mm Hg LBNP (n=12) per day and 1 hour of supine cycling followed by 6 hours of venous constriction through thigh cuffs 6 days per week (n=12), 6 hours of daily upright sitting (positive control, n=11), or no countermeasure (negative control, n=12). We measured orthostatic tolerance as the time to presyncope during 80° head-up tilt testing with incremental LBNP before and immediately after bedrest. We determined plasma volume with carbon monoxide rebreathing before and at the end of bedrest. After bedrest, orthostatic tolerance decreased 540±457 seconds in the control group, 539±68 seconds in the cycling group, 217±379 seconds in the LBNP group, and 289±89 seconds in the seated group ( P <0.0001 time point, P =0.009 for group differences). Supine and upright heart rate increased in all groups following bedrest. Plasma volume was only maintained in the cycling group but decreased in all others (interaction countermeasure×time point P <0.0001)., Conclusions: Six hours of moderate LBNP training was as effective as sitting in attenuating orthostatic intolerance after 30 days of head-down tilt bedrest. Daily cycling exercise followed by 6 hours of wearing venous constrictive thigh cuffs, while maintaining plasma volume, did not improve orthostatic tolerance., Registration: URL: https://www.bfarm.de/EN; Identifiers: DRKS00027643 and DRKS00030848.

Long-duration spaceflight is associated with pathophysiological changes in the intracranial compartment hypothetically linked to microgravity-induced headward fluid shift. This study aimed to determine whether daily artificial gravity (AG) sessions can mitigate these effects, supporting its application as a countermeasure to spaceflight. Twenty-four healthy adult volunteers (16 men) were exposed to 60 days of 6° head-down tilt bed rest (HDTBR) as a ground-based analog of chronic headward fluid shift. Subjects were divided equally into three groups: no AG (control), daily 30-min intermittent AG (iAG), and daily 30-min continuous (cAG). Internal carotid artery (ICA) stroke volume (ICA SV ), ICA resistive index (ICA RI ), ICA flow rate (ICA FR ), aqueductal cerebral spinal fluid flow velocity (CSF V ), and intracranial volumetrics were quantified at 3 T. MRI was performed at baseline, 14 and 52 days into HDTBR, and 3 days after HDTBR (recovery). A mixed model approach was used with intervention and time as the fixed effect factors and the subject as the random effect factor. Compared with baseline, HDTBR was characterized by expansion of lateral ventricular, white matter, gray matter, and brain + total intracranial cerebral spinal fluid volumes, increased CSFv, decreased ICA SV , and decreased ICA FR by 52 days into HBTBR (All P s < 0.05). ICA RI was only increased 14 days into HDTBR ( P < 0.05). Neither iAG nor cAG significantly affected measurements compared with HDTBR alone, indicating that 30 min of daily exposure was insufficient to mitigate the intracranial effects of headward fluid shift. Greater AG session exposure time, gravitational force, or both are suggested for future countermeasure research. NEW & NOTEWORTHY Brief exposure to continuous or intermittent artificial gravity via short-arm centrifugation was insufficient in mitigating the intracranial pathophysiological effects of the headward fluid shift simulated during head-down tilt bed rest (HDTBR). Our results suggest that greater centrifugation session duration, gravitational force, or both may be required to prevent the development of spaceflight-associated neuro-ocular syndrome and should be considered in future ground-based countermeasure studies.

Orthostatic hypertension, defined by an increase of systolic blood pressure (SBP) of ≥20 mmHg upon standing, harbors an increased cardiovascular risk. We pooled data from two rigorously conducted head-down tilt bedrest studies to test the hypothesis that cardiopulmonary deconditioning and hypovolemia predispose to orthostatic hypertension. With bedrest, peak VO 2 decreased by 6 ± 4 mlO 2 /min/kg (p < 0.0001) and plasma volume by 367 ± 348 ml (p < 0.0001). Supine SBP increased from 127 ± 9 mmHg before to 133 ± 10 mmHg after bedrest (p < 0.0001). In participants with stable hemodynamics following head-up tilt, the incidence of orthostatic hypertension was 2 out of 67 participants before bedrest and 2 out of 57 after bedrest. We conclude that in most healthy persons, cardiovascular deconditioning and volume loss associated with long-term bedrest are not sufficient to cause orthostatic hypertension., (© 2024. The Author(s).)

Spaceflight associated neuro-ocular syndrome (SANS) is hypothesized to develop as a consequence of the chronic headward fluid shift that occurs in sustained weightlessness. We exposed healthy subjects (n = 24) to strict 6° head-down tilt bed rest (HDTBR), an analog of weightlessness that generates a sustained headward fluid shift, and we monitored for ocular changes similar to findings that develop in SANS. Two-thirds of the subjects received a daily 30-min exposure to artificial gravity (AG, 1 g at center of mass, ~0.3 g at eye level) during HDTBR by either continuous (cAG, n = 8) or intermittent (iAG, n = 8) short-arm centrifugation to investigate whether this intervention would attenuate headward fluid shift-induced ocular changes. Optical coherence tomography images were acquired to quantify changes in peripapillary total retinal thickness (TRT), retinal nerve fiber layer thickness, and choroidal thickness, and to detect chorioretinal folds. Intraocular pressure (IOP), optical biometry, and standard automated perimetry data were collected. TRT increased by 35.9 µm (95% CI, 19.9-51.9 µm, p < 0.0001), 36.5 µm (95% CI, 4.7-68.2 µm, p = 0.01), and 27.6 µm (95% CI, 8.8-46.3 µm, p = 0.0005) at HDTBR day 58 in the control, cAG, and iAG groups, respectively. Chorioretinal folds developed in six subjects across the groups, despite small increases in IOP. Visual function outcomes did not change. These findings validate strict HDTBR without elevated ambient CO 2 as a model for investigating SANS and suggest that a fluid shift reversal of longer duration and/or greater magnitude at the eye may be required to prevent or mitigate SANS., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Key Points: Carbon dioxide levels are mildly elevated on the International Space Station and it is unknown whether this chronic exposure causes physiological changes to astronauts. We combined ∼4 mmHg ambient P C O 2 with the strict head-down tilt bed rest model of spaceflight and this led to the development of optic disc oedema in one-half of the subjects. We demonstrate no change in arterialized P C O 2 , cerebrovascular reactivity to CO 2 or the hypercapnic ventilatory response. Our data suggest that the mild hypercapnic environment does not contribute to the development of spaceflight associated neuro-ocular syndrome., Abstract: Chronically elevated carbon dioxide (CO 2 ) levels can occur in confined spaces such as the International Space Station. Using the spaceflight analogue 30 days of strict 6° head-down tilt bed rest (HDTBR) in a mild hypercapnic environment ( P C O 2 = ∼4 mmHg), we investigated arterialized P C O 2 , cerebrovascular reactivity and the hypercapnic ventilatory response in 11 healthy subjects (five females) before, on days 1, 9, 15 and 30 of bed rest (BR), and 6 and 13 days after HDTBR. During all HDTBR time points, arterialized P C O 2 was not significantly different from the pre-HDTBR measured in the 6° HDT posture, with a mean (95% confidence interval) increase of 1.2 mmHg (-0.2 to 2.5 mmHg, P = 0.122) on day 30 of HDTBR. Respiratory acidosis was never detected, although a mild metabolic alkalosis developed on day 30 of HDTBR by a mean (95% confidence interval) pH change of 0.032 (0.022-0.043; P < 0.001), which remained elevated by 0.021 (0.011-0.031; P < 0.001) 6 days after HDTBR. Arterialized pH returned to pre-HDTBR levels 13 days after BR with a change of -0.001 (-0.009 to 0.007; P = 0.991). Compared to pre-HDTBR, cerebrovascular reactivity during and after HDTBR did not change. Baseline ventilation, ventilatory recruitment threshold and the slope of the ventilatory response were similar between pre-HDTBR and all other time points. Taken together, these data suggest that the mildly increased ambient P C O 2 combined with 30 days of strict 6° HDTBR did not change arterialized P C O 2 levels. Therefore, the experimental conditions were not sufficient to elicit a detectable physiological response., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Background: We compared microvascular and macrovascular blood flows of the tibia and anterior tibial artery during graded whole-body tilt. We hypothesized equal responses for bone microvascular and macrovascular blood flows during varying angles of tilt., Methods: There were 18 volunteers who were randomly positioned in the following postures: supine, 15° head-up tilt, 6° head-up tilt, 6° head-down tilt, and 15° head-down tilt using an inversion table with reference to seated posture (baseline control). Ultrasonography quantified anterior tibial arterial diameter and peak systolic velocity, enabling calculation of macrovascular blood flow to the tibia. Tibial bone microvascular blood flow was measured noninvasively using photoplethysmography in the same leg., Results: Transitioning from a seated position to a supine position, macrovascular blood flow did not change significantly (1.81 ± 1.18 to 2.80 ± 1.74cm 3 · s-1). However, bone microvascular flow increased significantly (0.36 ± 0.23 to 1.11 ± 0.79 V) from the seated to the supine position. Transitioning from a seated posture to 15° head-down tilt, both arterial macrovascular and bone microvascular flows increased significantly (1.81 ± 1.18 to 3.32 ± 2.08 cm3 · s-1 and 0.36 ± 0.23 V to 2.99 ± 2.71 V, respectively). The normalized flow for microvascular blood flow as a function of body tilt was significantly greater than that for macrovascular blood flow at 6° and 15° head-down tilt., Discussion: These data do not support our hypothesis that bone microvascular flow and arterial macrovascular flow share equal responses to altered body tilt. Therefore, for a given decrease in local blood pressure in the leg with head-down body tilt, the magnitude of increase in blood flow is greater in the microcirculation as compared to the feeding artery.Becker RL, Siamwala JH, Macias BR, Hargens AR. Tibia bone microvascular flow dynamics as compared to anterior tibial artery flow during body tilt. Aerosp Med Hum Perform. 2018; 89(4):357-364.

Long-term spaceflight induces a near visual acuity change in ~50% of astronauts. In some crew members, postflight cerebrospinal fluid (CSF) opening pressures by lumbar puncture are as high as 20.9 mmHg; these members demonstrated optic disc edema. CSF communicates through the cochlear aqueduct to affect perilymphatic pressure and tympanic membrane motion. We hypothesized that 50 mmHg of lower-body negative pressure (LBNP) during 15° head-down tilt (HDT) would mitigate elevations in internal jugular vein cross-sectional area (IJV CSA) and intracranial pressure (ICP). Fifteen healthy adult volunteers were positioned in sitting (5 min), supine (5 min), 15° HDT (5 min), and 15° HDT with LBNP (10 min) postures for data collection. Evoked tympanic membrane displacements (TMD) quantified ICP noninvasively. IJV CSA was measured using standard ultrasound techniques. ICP and IJV CSA increased significantly from the seated upright to the 15° HDT posture ( P < 0.05), and LBNP mitigated these increases. LBNP at 25 mmHg reduced ICP during HDT (TMD of 322.13 ± 419.17 nl) to 232.38 ± 445.85 nl, and at 50 mmHg ICP was reduced further to TMD of 199.76 ± 429.69 nl. In addition, 50 mmHg LBNP significantly reduced IJV CSA (1.50 ± 0.33 cm 2 ) during 15° HDT to 0.83 ± 0.42 cm 2 LBNP counteracts the headward fluid shift elevation of ICP and IJV CSA experienced during microgravity as simulated by15° HDT. These data provide quantitative evidence that LBNP shifts cephalic fluid to the lower body, reducing IJV CSA and ICP. NEW & NOTEWORTHY The current study provides new evidence that 25 or 50 mmHg of lower body negative pressure reduces jugular venous pooling and intracranial pressure during simulated microgravity. Therefore, spaceflight countermeasures that sequester fluid to the lower body may mitigate cephalic venous congestion and vision impairment., (Copyright © 2017 the American Physiological Society.)

The purpose of the investigation was to study lower body negative pressure recovery in response to head down tilt position in men and women. The study examined the primary hypothesis that tibial bone microvascular flow responses to HDT and lower body negative pressure (LBNP) differ in women and men. Nine women and nine men between 20 to 30 years of age participated in the study. Tibial microvascular flow, head and tibial oxygenation and calf circumference were measured using photoplethysmography (PPG), near-infrared spectroscopy (NIRS) and strain gauge plethysmography (SGP), respectively, during sitting (control baseline), supine, 15° HDT, and 15° HDT with 25 mmHg LBNP Tibial microvascular flow with HDT increased by 57% from supine position (from 1.4V ± 0.7 to 2.2V ± 1.0 HDT; ANOVA P  < 0.05) in men but there is no significant difference between supine and HDT in women. Ten minutes of LBNP during 15 o HDT restored tibial bone microvascular flows to supine levels, (from 2.2V±1.0 HDT to 1.1V ± 0.7 supine; ANOVA P  < 0.05) in men but not in women. These data support the concept that there are gender specific microvascular responses to a fluid-shift countermeasure such as LBNP Thus, gender differences should be considered while developing future countermeasure strategies to headward fluid shifts in microgravity., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Skeletal unloading and cephalic fluid shifts in microgravity may alter the bone microvascular flow and may be associated with the 1-2% bone loss per month during spaceflight. The purpose of this study was to determine if lower-body negative pressure (LBNP) can prevent microgravity-induced alterations of tibial microvascular flow. Head-down tilt (HDT) simulates the cephalad fluid shift and microvascular flow responses that may occur in microgravity. We hypothesized that LBNP prevents HDT-induced increases in tibial microvascular flow. Tibial bone microvascular flow, oxygenation, and calf circumference were measured during 5 min sitting, 5 min supine, 5 min 15° HDT, and 10 min 15° HDT with 25 mmHg LBNP using photoplethysmography (PPG), near-infrared spectroscopy (NIRS), and strain-gauge plethysmography (SGP). Measurements were made simultaneously. Tibial microvascular flow increased by 36% with 5 min 15° HDT [2.2 ± 1.1 V; repeated-measures ANOVA (RMANOVA) P < 0.0001] from supine (1.4 ± 0.8 V). After 10 min of LBNP in the 15° HDT position, tibial microvascular flow returned to supine levels (1.1 ± 0.5 V; RMANOVA P < 0.001). Tibial oxygenation did not change significantly during sitting, supine, HDT, or HDT with LBNP. However, calf circumference decreased with 5 min 15° HDT (-0.7 ± 0.4 V; RMANOVA P < 0.0001) from supine (-0.5 ± 0.4 V). However, with LBNP calf circumference returned to supine levels (-0.4 ± 0.1 V; RMANOVA P = 0.002). These data establish that simulated microgravity increases tibial microvascular flow and LBNP prevents these increases. The results suggest that LBNP may provide a suitable countermeasure to normalize the bone microvascular flow during spaceflight., (Copyright © 2015 the American Physiological Society.)

Background: Seven astronauts after 6-mo missions to the International Space Station showed unexpected vision problems. Lumbar punctures performed in the four astronauts with optic disc edema showed moderate elevations of cerebral spinal fluid pressure after returning to Earth. We hypothesized that lower body negative pressure (LBNP) imposed during head-down tilt (HDT) would reduce intraocular pressure (IOP) and transcranial ultrasound pulse amplitude, a noninvasive intracranial pressure (ICP) surrogate., Methods: Participating in this study were 25 normal healthy nonsmoking volunteers (mean age: 36 yr). Subjects were positioned supine (5 min), sitting (5 min), 15° whole body HDT (5 min), and 10 min of HDT with LBNP (25 mmHg). The order of HDT and HDT+LBNP tests was balanced. Right and left IOP, transcranial ultrasound pulse amplitude, arm blood pressure, and heart rate were measured during the last minute (steady state) of each testing condition., Results: IOP significantly decreased from supine to sitting posture by 3.2 ± 1.4 mmHg (mean ± SD: N = 25), and increased by 0.9 ± 1.3 mmHg from supine to the HDT position. LBNP during HDT significantly lowered IOP to supine levels. In addition, LBNP significantly reduced transcranial ultrasound pulse amplitudes by 38% as compared to the HDT condition (N = 9). Sitting mean blood pressure (BP) was significantly higher (+5 mmHg) than BP values after 10 min of LBNP during HDT. However, heart rate was not significantly different across all conditions., Discussion: These data suggest that short duration exposures to LBNP attenuate HDT-induced increases in IOP and ICP. Macias BR, Liu JHK, Grande-Gutierrez N, Hargens AR. Intraocular and intracranial pressures during head-down tilt with lower body negative pressure.

Introduction: Intracranial pressure (ICP) may play a significant role in physiological responses to microgravity by contributing to the nausea associated with microgravity exposure. However, effects of altered gravity on ICP in astronauts have not been investigated, primarily due to the invasiveness of currently available techniques. We have developed an ultrasonic device that monitors changes in cranial diameter pulsation non-invasively so that we can evaluate ICP dynamics in astronauts during spaceflight. This study was designed to demonstrate the feasibility of our ultrasound technique under the physiological condition in which ICP dynamics are changed due to altered gravitational force., Methods: Six healthy volunteers were placed at 60 degrees head-up, 30 degrees headup, supine, and 15 degrees head-down positions for 3 min at each angle. We measured arterial blood pressure (ABP) with a finger pressure cuff, and cranial diameter pulsation with a pulsed phase lock loop device (PPLL)., Results: Analysis of covariance demonstrated that amplitudes of cranial diameter pulsations were significantly altered with the angle of tilt (p < 0.001). The 95% confidence interval for linear regression coefficients of the cranial diameter pulsation amplitudes with tilt angle was 0.862 to 0.968. However, ABP amplitudes did not show this relationship., Discussion: Our noninvasive ultrasonic technique reveals that the amplitude of cranial diameter pulsation decreases as a function of tilt angle, suggesting that ICP pulsation follows the same relationship. It is demonstrated that the PPLL device has a sufficient sensitivity to detect changes non-invasively in ICP pulsation caused by altered gravity.