Indirect measurement of absolute cardiac output during exercise in simulated altered gravity is highly dependent on the method.

PURPOSE: Altered gravity environments introduce cardiovascular changes that may require continuous hemodynamic monitoring in both spaceflight and terrestrial analogs. Conditions in such environments are often prohibitive to direct/invasive methods and therefore, indirect measurement techniques must be used. This study compares two common cardiac measurement techniques used in the human spaceflight domain, pulse contour analysis (PCA-Nexfin) and inert gas rebreathing (IGR-Innocor), in subjects completing ergometer exercise under altered gravity conditions simulated using a tilt paradigm. METHODS: Seven subjects were tilted to three different angles representing Martian, Lunar, and microgravity conditions in the rostrocaudal direction. They completed a 36-min submaximal cardiovascular exercise protocol in each condition. Hemodynamics were continuously monitored using Nexfin and Innocor. RESULTS: Linear mixed-effects models revealed a significant bias of [Formula: see text] ml ([Formula: see text]) in stroke volume and [Formula: see text] l/min ([Formula: see text]) in cardiac output, with Nexfin measuring greater than Innocor in both variables. These values are in agreement with a Bland-Altman analysis. The correlation of stroke volume and cardiac output measurements between Nexfin and Innocor were [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) respectively. CONCLUSION: There is a poor agreement in absolute stroke volume and cardiac output values between measurement via PCA (Nexfin) and IGR (Innocor) in subjects who are exercising in simulated altered gravity environments. These results suggest that the chosen measurement method and device greatly impacts absolute measurements of cardiac output. However, there is a good level of agreement between the two devices when measuring relative changes. Either of these devices seem adequate to capture cardiac changes, but should not be solely relied upon for accurate measurement of absolute cardiac output.

Lumbar puncture position influences intracranial pressure.

BACKGROUND: The standard lumbar puncture position involves maximum flexion of both lumbar and cervical spine. The cerebrospinal fluid opening pressure (CSFop) is measured in a horizontal position. This study investigated if flexion of hip and neck both separately and simultaneously influence intracranial pressure (ICP) to a clinically relevant extent. METHODS: Thirty-nine patients, undergoing invasive ICP monitoring as part of diagnostic work-up, were included. The patients underwent either a vertical postural examination (n = 24) or a horizontal postural examination (n = 15) to examine a varying degree of spine flexion. RESULTS: The vertical examination showed that ICP decreased by 15.2 mmHg when straightening the neck in a sitting lumbar puncture position (n = 24, IQR - 20.1 to - 9.7). In the horizontal examination, ICP increased in all but one patient when changing from supine position to lateral recumbent position (n = 15, median increase of 6.9 mmHg, IQR 3.1 to 9.9). Straightening the hips alone decreased ICP with 0.2 mmHg (n = 15, IQR - 0.5 to 2.0), while straightening the neck alone decreased ICP by 4.0 mmHg (n = 15, IQR - 5.9 to - 1.7). However, when straightening the hip and neck simultaneously ICP decreased by 6.4 mmHg (n = 6, IQR - 9.5 to - 4.4). CONCLUSIONS: Neck flexion alone, and neck flexion and hip flexion in combination, has significant confounding influence on ICP. This may cause patients to shift from a normal ICP range to a pathological ICP range, which will potentially affect treatment decisions. Consensus on guidelines for body position including neck and hip flexion measuring CSFop may be needed.

Lower body negative pressure to safely reduce intracranial pressure.

KEY POINTS: During long-term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure 'unloading' associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non-linear dose-response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non-invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension. ABSTRACT: Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space-flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP-sensors and four former cancer patients with Ommaya-reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head-down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non-linear dose-dependent fashion; when supine (n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively (P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head-down tilt (n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP (P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight-associated neuro-ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non-invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth.

Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men.

High-intensity interval exercise (HIIE) improves cerebral executive function (EF), but the improvement in EF is attenuated after repeated HIIE, perhaps because of lower lactate availability for the brain. This investigation examined whether improved EF after exercise relates to brain lactate uptake. Fourteen healthy, male subjects performed 2 HIIE protocols separated by 60 min of rest. Blood samples were obtained from the right internal jugular venous bulb and from the brachial artery to determine arterial-venous differences across the brain for lactate (a-v difflactate), glucose (a-v diffglucose), oxygen (a-v diffoxygen), and brain-derived neurotrophic factor (BDNF; a-v diffBDNF). EF was evaluated by the color-word Stroop task. The first HIIE improved EF for 40 min, whereas the second HIIE improved EF only immediately after exercise. The a-v diffglucose was unchanged, whereas the a-v diffBDNF increased similarly after both HIIEs, and the a-v difflactate increased, but the increase was attenuated after the second HIIE, compared with the first HIIE ( P < 0.05). The EF after HIIE correlated with the a-v difflactate ( r2 = 0.62; P < 0.01). We propose that attenuated improvement in EF after repeated HIIE relates to reduced cerebral lactate metabolism and is, thereby, linked to systemic metabolism as an example of the lactate shuttle mechanism.-Hashimoto, T., Tsukamoto, H., Takenaka, S., Olesen, N. D., Petersen, L. G., Sørensen, H., Nielsen, H. B., Secher, N. H., Ogoh, S. Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men.

Effect of gravity and microgravity on intracranial pressure.

KEY POINTS: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts. ABSTRACT: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure (ICP). This syndrome is considered the most mission-critical medical problem identified in the past decade of manned spaceflight. We recruited five men and three women who had an Ommaya reservoir inserted for the delivery of prophylactic CNS chemotherapy, but were free of their malignant disease for at least 1 year. ICP was assessed by placing a fluid-filled 25 gauge butterfly needle into the Ommaya reservoir. Subjects were studied in the upright and supine position, during acute zero gravity (parabolic flight) and prolonged simulated microgravity (6 deg head-down tilt bedrest). ICP was lower when seated in the 90 deg upright posture compared to lying supine (seated, 4 ± 1 vs. supine, 15 ± 2 mmHg). Whilst lying in the supine posture, central venous pressure (supine, 7 ± 3 vs. microgravity, 4 ± 2 mmHg) and ICP (supine, 17 ± 2 vs. microgravity, 13 ± 2 mmHg) were reduced in acute zero gravity, although not to the levels observed in the 90 deg seated upright posture on Earth. Prolonged periods of simulated microgravity did not cause progressive elevations in ICP (supine, 15 ± 2 vs. 24 h head-down tilt, 15 ± 4 mmHg). Complete removal of gravity does not pathologically elevate ICP but does prevent the normal lowering of ICP when upright. These findings suggest the human brain is protected by the daily circadian cycles in regional ICPs, without which pathology may occur.

Coupling between arterial and venous cerebral blood flow during postural change.

In supine humans the main drainage from the brain is through the internal jugular vein (IJV), but the vertebral veins (VV) become important during orthostatic stress because the IJV is partially collapsed. To identify the effect of this shift in venous drainage from the brain on the cerebral circulation, this study addressed both arterial and venous flow responses in the "anterior" and "posterior" parts of the brain when nine healthy subjects (5 men) were seated and flow was manipulated by hyperventilation and inhalation of 6% carbon dioxide (CO2). From a supine to a seated position, both internal carotid artery (ICA) and IJV blood flow decreased (P = 0.004 and P = 0.002), while vertebral artery (VA) flow did not change (P = 0.348) and VV flow increased (P = 0.024). In both supine and seated positions the ICA response to manipulation of end-tidal CO2 tension was reflected in IJV (r = 0.645 and r = 0.790, P < 0.001) and VV blood flow (r = 0.771 and r = 0.828, P < 0.001). When seated, the decrease in ICA blood flow did not affect venous outflow, but the decrease in IJV blood flow was associated with the increase in VV blood flow (r = 0.479, P = 0.044). In addition, the increase in VV blood flow when seated was reflected in VA blood flow (r = 0.649, P = 0.004), and the two flows were coupled during manipulation of the end-tidal CO2 tension (supine, r = 0.551, P = 0.004; seated, r = 0.612, P < 0001). These results support that VV compensates for the reduction in IJV blood flow when seated and that VV may influence VA blood flow.

Carotid baroreflex function at the onset of cycling in men.

Arterial baroreflex function is important for blood pressure control during exercise, but its contribution to cardiovascular adjustments at the onset of cycling exercise remains unclear. Fifteen healthy male subjects (24 ± 1 yr) performed 45-s trials of low- and moderate-intensity cycling, with carotid baroreceptor stimulation by neck suction at -60 Torr applied 0-5, 10-15, and 30-35 s after the onset of exercise. Cardiovascular responses to neck suction during cycling were compared with those obtained at rest. An attenuated reflex decrease in heart rate following neck suction was detected during moderate-intensity exercise, compared with the response at rest (P < 0.05). Furthermore, compared with the reflex decrease in blood pressure elicited at rest, neck suction elicited an augmented decrease in blood pressure at 0-5 and 10-15 s during low-intensity exercise and in all periods during moderate-intensity exercise (P < 0.05). The reflex depressor response at the onset of cycling was primarily mediated by an increase in the total vascular conductance. These findings evidence altered carotid baroreflex function during the first 35 s of cycling compared with rest, with attenuated bradycardic response, and augmented depressor response to carotid baroreceptor stimulation.

Thoracic epidural analgesia reduces gastric microcirculation in the pig.

BACKGROUND: Thoracic epidural analgesia (TEA) is used for pain relief during and after abdominal surgery, but the effect of TEA on the splanchnic microcirculation remains debated. We evaluated whether TEA affects splanchnic microcirculation in the pig. METHODS: Splanchnic microcirculation was assessed in nine pigs prior to and 15 and 30 min after induction of TEA. Regional blood flow was assessed by neutron activated microspheres and changes in microcirculation by laser speckle contrast imaging (LSCI). RESULTS: As assessed by LSCI 15 min following TEA, gastric arteriolar flow decreased by 22 % at the antrum (p = 0.020) and by 19 % at the corpus (p = 0.029) of the stomach. In parallel, the microcirculation decreased by 19 % at the antrum (p = 0.015) and by 20 % at the corpus (p = 0.028). Reduced arteriolar flow and microcirculation at the antrum was confirmed by a reduction in microsphere assessed regional blood flow 30 min following induction of TEA (p = 0.048). These manifestations took place along with a drop in systolic blood pressure (p = 0.030), but with no significant change in mean arterial pressure, cardiac output, or heart rate. CONCLUSION: The results indicate that TEA may have an adverse effect on gastric arteriolar blood flow and microcirculation. LSCI is a non-touch technique and displays changes in blood flow in real-time and may be important for further evaluation of the concern regarding the effect of thoracic epidural anesthesia on gastric microcirculation in humans. TRIAL REGISTRATIONS: Not applicable, non-human study.

Body height and arterial pressure in seated and supine young males during +2 G centrifugation.

It is known that arterial pressure correlates positively with body height in males, and it has been suggested that this is due to the increasing vertical hydrostatic gradient from the heart to the carotid baroreceptors. Therefore, we tested the hypothesis that a higher gravito-inertial stress induced by the use of a human centrifuge would increase mean arterial pressure (MAP) more in tall than in short males in the seated position. In short (162-171 cm; n = 8) and tall (194-203 cm; n = 10) healthy males (18-41 yr), brachial arterial pressure, heart rate (HR), and cardiac output were measured during +2G centrifugation, while they were seated upright with the legs kept horizontal (+2Gz). In a separate experiment, the same measurements were done with the subjects supine (+2Gx). During +2Gz MAP increased in the short (22 ± 2 mmHg, P < 0.0001) and tall (23 ± 2 mmHg, P < 0.0001) males, with no significant difference between the groups. HR increased more (P < 0.05) in the tall than in the short group (14 ± 2 vs. 7 ± 2 bpm). Stroke volume (SV) decreased in the short group (26 ± 4 ml, P = 0.001) and more so in the tall group (39 ± 5 ml, P < 0.0001; short vs. tall, P = 0.047). During +2Gx, systolic arterial pressure increased (P < 0.001) and SV (P = 0.012) decreased in the tall group only. In conclusion, during +2Gz, MAP increased in both short and tall males, with no difference between the groups. However, in the tall group, HR increased more during +2Gz, which could be caused by a larger hydrostatic pressure gradient from heart to head, leading to greater inhibition of the carotid baroreceptors.

Effect of postural changes on ICP in healthy and ill subjects.

BACKGROUND: Reference values and physiological measurements of intracranial pressure (ICP) are primarily reported in the supine position, while reports of ICP in the vertical position are surprisingly rare considering that humans maintain the vertical position for the majority of the day. In order to distinguish normal human physiology from disease entities such as idiopathic intracranial hypertension and normal pressure hydrocephalus, we investigated ICP in different body postures in both normal and ill subjects. METHODS: Thirty-one patients were included: four normal patients following complete removal of a solitary clearly demarcated small brain tumour and fitted with a telemetric ICP monitoring device for long-term ICP monitoring; 27 patients requiring invasive ICP monitoring as a part of their diagnostic work-up or monitoring of shunt treatment effect. ICP was recorded in the following body positions: upright standing, sitting in a chair, supine and right lateral lumbar puncture position. RESULTS: Linear regression of median ICP based on patient posture, group, and purpose of monitoring presented a significant model (p < 0.001), but could not distinguish between patient groups (p = 0.88). Regression of differences in median ICP between body postures and supine ICP as the baseline, presented a highly significant model (p < 0.001) and adjusted R (2) = 0.86. Both body posture (p < 0.001) and patient group (p < 0.001) were highly significant factors. CONCLUSIONS: Differences in ICP between body postures enabled us to distinguish the normal group from patient groups. Normal patients appear able to more tightly regulate ICP when switching body postures.

Transcutaneous vagal nerve stimulation during lower body negative pressure.

BACKGROUND: Para-sympathetic vagal activation has profound influence on heart rate and other cardiovascular parameters. We tested the hypothesis that transcutaneous Vagal Nerve Stimulation (tVNS) through the auricular branch of the vagus nerve would attenuate the normal sympathetic response to central blood volume reduction by lower body negative pressure (LBNP). METHOD: 10 healthy volunteers (6 female; age 21 ± 2 years; weight 62 ± 13 kg; height 167 ± 12 cm) were included in this cross-over design trial. After 15 min rest in supine position, subjects underwent three 15-min periods of 30 mmHg LBNP intervention with and without cyclic tVNS stimulation. Continuous cardiovascular parameters (Nexfin) were recorded. RESULTS: Overall tVNS did not convincingly attenuate sympathetic response to central hypovolemia. Deactivation of the tVNS during LBNP resulted in increased MAP at 2.3 ± 0.5 mmHg (P < 0.001). Comparing the cyclic actual active stimulation periods to periods with pause during tVNS intervention showed a decrease in HR by 72.9 ± 11.2 to 70.2 ± 11.6 bpm (mean ± SD; P < 0.05), and concomitant increases in SV (86.0 ± 12.1 to 87.2 ± 12.6 mL; P < 0.05), MAP (82.9 ± 6.3 to 84.0 ± 6.2 mmHg; P < 0.05) and TPR (1116.0 ± 111.1 to 1153 ± 104.8 dyn*s/cm5; P < 0.05). CONCLUSION: tVNS in 30 s cycles during LBNP can selectively attenuate HR, prompting a compensatory augmented sympathetic response. It would appear the method used in this study at least, has an isolated cardiac inhibitory effect probably mediated by augmented vagal activity on the sinoatrial or atrio-ventricular node, possibly in combination with reduced activity in the sympathetic cardiac nerve.

Circulating Plasma Oxytocin Level Is Elevated by High-Intensity Interval Exercise in Men.

PURPOSE: We evaluated whether repeated high-intensity interval exercise (HIIE) influences plasma oxytocin (OT) concentration in healthy men, and, given that OT is mainly synthesized in the hypothalamus, we assessed the concentration difference between the arterial (OT ART ) versus the internal jugular venous OT concentration (OT IJV ). Additionally, we hypothesized that an increase in cerebral OT release and the circulating concentration would be augmented by repeated HIIE. METHODS: Fourteen healthy men (age = 24 ± 2 yr; mean ± SD) performed two identical bouts of HIIE. These HIIE bouts included a warm-up at 50%-60% maximal workload ( Wmax ) for 5 min followed by four bouts of exercise at 80%-90% Wmax for 4 min interspersed by exercise at 50%-60% Wmax for 3 min. The HIIE bouts were separated by 60 min of rest. OT was evaluated in blood through radial artery and internal jugular vein catheterization. RESULTS: Both HIIE bouts increased both OT ART (median [IQR], from 3.9 [3.4-5.4] to 5.3 [4.4-6.3] ng·mL -1 in the first HIIE, P < 0.01) and OT IJV (from 4.6 [3.4-4.8] to 5.9 [4.3-8.2] ng·mL -1 , P < 0.01), but OT ART-IJV was unaffected (from -0.24 [-1.16 to 1.08] to 0.04 [-0.88 to 0.78] ng·mL -1 , P = 1.00). The increased OT levels were similar in the first and second HIIE bouts (OT ARTP = 0.25, OT IJVP = 0.36). CONCLUSIONS: Despite no change in the cerebral OT release via the internal jugular vein, circulating OT increases during HIIE regardless of the accumulated exercise volume, indicating that OT may play role as one of the exerkines.

Characterization of internal jugular vein region-specific distension and flow patterns during progressive volume shifting.

Blood volume shifts during postural adjustment leads to irregular distension of the internal jugular vein (IJV). In microgravity, distension may contribute to flow stasis and thromboembolism, though the regional implications and associated risk remain unexplored. We characterized regional differences in IJV volume distension and flow complexity during progressive head-down tilt (HDT) (0°, -6°, -15°, -30°) using conventional ultrasound and vector flow imaging. We also evaluated low-pressure thigh cuffs (40 mmHg) as a fluid shifting countermeasure during -6° HDT. Total IJV volume expanded 139±95% from supine (4.6±2.7 mL) to -30° HDT (10.3±5.0 mL). Blood flow profiles had greater vector uniformity at the cranial IJV region (P<0.01) and became more dispersed with increasing tilt (P<0.01). Qualitatively, flow was more uniform throughout the IJV during its early flow cycle phase, and more disorganized during late flow phase. This disorganized flow was accentuated closer to the vessel wall, near the caudal region, and during greater HDT. Low-pressure thigh cuffs during -6° HDT decreased IJV volume at the cranial region (-12±15%; P<0.01) but not the caudal region (P=0.20), although flow uniformity was unchanged (both regions,P>0.25). We describe a distensible IJV accommodating large volume shifts along its length. Prominent flow dispersion was primarily found at the caudal region, suggesting multi-directional blood flow. Thigh cuffs appear effective for decreasing IJV volume but effects on flow complexity are minor. Flow complexity along the vessel length is likely related to IJV distension during chronic volume shifting and may be a precipitating factor for flow stasis and future thromboembolism risk.

Systematic review of the use of ultrasound for venous assessment and venous thrombosis screening in spaceflight.

The validity of venous ultrasound (V-US) for the diagnosis of deep vein thrombosis (DVT) during spaceflight is unknown and difficult to establish in diagnostic accuracy and diagnostic management studies in this context. We performed a systematic review of the use of V-US in the upper-body venous system in spaceflight to identify microgravity-related changes and the effect of venous interventions to reverse them, and to assess appropriateness of spaceflight V-US with terrestrial standards. An appropriateness tool was developed following expert panel discussions and review of terrestrial diagnostic studies, including criteria relevant to crew experience, in-flight equipment, assessment sites, ultrasound modalities, and DVT diagnosis. Microgravity-related findings reported as an increase in internal jugular vein (IJV) cross-sectional area and pressure were associated with reduced, stagnant, and retrograde flow. Changes were on average responsive to venous interventions using lower body negative pressure, Bracelets, Valsalva and Mueller manoeuvres, and contralateral IJV compression. In comparison with terrestrial standards, spaceflight V-US did not meet all appropriateness criteria. In DVT studies (n = 3), a single thrombosis was reported and only ultrasound modality criterion met the standards. In the other studies (n = 15), all the criteria were appropriate except crew experience criterion, which was appropriate in only four studies. Future practice and research should account for microgravity-related changes, evaluate individual effect of venous interventions, and adopt Earth-based V-US standards.

Corrigendum: Editorial: Rising stars in environmental, aviation and space physiology: 2022.

[This corrects the article DOI: 10.3389/fphys.2023.1230752.].

Effects of whole-body vibration or resistive-vibration exercise on blood clotting and related biomarkers: a systematic review.

Whole-body vibration (WBV) and resistive vibration exercise (RVE) are utilized as countermeasures against bone loss, muscle wasting, and physical deconditioning. The safety of the interventions, in terms of the risk of inducing undesired blood clotting and venous thrombosis, is not clear. We therefore performed the present systematic review of the available scientific literature on the issue. The review was conducted following the guidelines by the Space Biomedicine Systematic Review Group, based on Cochrane review guidelines. The relevant context or environment of the studies was "ground-based environment"; space analogs or diseased conditions were not included. The search retrieved 801 studies; 77 articles were selected for further consideration after an initial screening. Thirty-three studies met the inclusion criteria. The main variables related to blood markers involved angiogenic and endothelial factors, fibrinolysis and coagulation markers, cytokine levels, inflammatory and plasma oxidative stress markers. Functional and hemodynamic markers involved blood pressure measurements, systemic vascular resistance, blood flow and microvascular and endothelial functions. The available evidence suggests neutral or potentially positive effects of short- and long-term interventions with WBV and RVE on variables related to blood coagulation, fibrinolysis, inflammatory status, oxidative stress, cardiovascular, microvascular and endothelial functions. No significant warning signs towards an increased risk of undesired clotting and venous thrombosis were identified. If confirmed by further studies, WBV and RVE could be part of the countermeasures aimed at preventing or attenuating the muscular and cardiovascular deconditioning associated with spaceflights, permanence on planetary habitats and ground-based simulations of microgravity.

Pathophysiology, risk, diagnosis, and management of venous thrombosis in space: where are we now?

The recent incidental discovery of an asymptomatic venous thrombosis (VT) in the internal jugular vein of an astronaut on the International Space Station prompted a necessary, immediate response from the space medicine community. The European Space Agency formed a topical team to review the pathophysiology, risk and clinical presentation of venous thrombosis and the evaluation of its prevention, diagnosis, mitigation, and management strategies in spaceflight. In this article, we discuss the findings of the ESA VT Topical Team over its 2-year term, report the key gaps as we see them in the above areas which are hindering understanding VT in space. We provide research recommendations in a stepwise manner that build upon existing resources, and highlight the initial steps required to enable further evaluation of this newly identified pertinent medical risk.

Impact of Increasing Lower Body Negative Pressure and Its Abrupt Release on Left Ventricular Hemodynamics in Anesthetized Pigs.

Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from -15 to -45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure-volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.

Search for Venous Endothelial Biomarkers Heralding Venous Thromboembolism in Space: A Qualitative Systematic Review of Terrestrial Studies.

Background: The recent discovery of a venous thrombosis in the internal jugular vein of an astronaut has highlighted the need to predict the risk of venous thromboembolism in otherwise healthy individuals (VTE) in space. Virchow's triad defines the three classic risk factors for VTE: blood stasis, hypercoagulability, and endothelial disruption/dysfunction. Among these risk factors, venous endothelial disruption/dysfunction remains incompletely understood, making it difficult to accurately predict risk, set up relevant prophylactic measures and initiate timely treatment of VTE, especially in an extreme environment. Methods: A qualitative systematic review focused on endothelial disruption/dysfunction was conducted following the guidelines produced by the Space Biomedicine Systematic Review Group, which are based on Cochrane review guidelines. We aimed to assess the venous endothelial biochemical and imaging markers that may predict increased risk of VTE during spaceflight by surveying the existing knowledge base surrounding these markers in analogous populations to astronauts on the ground. Results: Limited imaging markers related to endothelial dysfunction that were outside the bounds of routine clinical practice were identified. While multiple potential biomarkers were identified that may provide insight into the etiology of endothelial dysfunction and its link to future VTE, insufficient prospective evidence is available to formally recommend screening potential astronauts or healthy patients with any currently available novel biomarker. Conclusion: Our review highlights a critical knowledge gap regarding the role biomarkers of venous endothelial disruption have in predicting and identifying VTE. Future population-based prospective studies are required to link potential risk factors and biomarkers for venous endothelial dysfunction to occurrence of VTE.