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Reduced-caloric intake lowers blood pressure through sympathetic inhibition, and worsens orthostatic tolerance within days. Conversely, hypercaloric nutrition augments sympathetic activity and blood pressure. Because dietary interventions could be applied in patients with syncope, we tested the hypothesis that short-term hypercaloric dieting improves orthostatic tolerance. In a randomized crossover trial, 20 healthy individuals (7 women, 26.7 ± 8 years, 22.6 ± 2 kg/m2) followed a 4-day hypercaloric (25% increase of energy intake by fat) or normocaloric nutritional plan, with a washout period of at least 23 days between interventions. We then performed head-up tilt table testing with incremental lower body negative pressure while recording beat-by-beat blood pressure and heart rate. The primary endpoint was orthostatic tolerance defined as time to presyncope. Time to presyncope during combined head-up tilt and lower body negative pressure did not differ between hypercaloric and normocaloric dieting (median 23.19 versus 23.04 min, ratio of median 1.01, 95% CI of ratio 0.5–1.9). Heart rate, blood pressure, heart rate variability, and blood pressure variability in the supine position and during orthostatic testing did not differ between interventions. We conclude that 4 days of moderate hypercaloric nutrition does not significantly improve orthostatic tolerance in healthy individuals. Nevertheless, given the important interaction between energy balance and cardiovascular autonomic control in the brain, caloric intake deserves more attention as a potential contributor and treatment target for orthostatic intolerance.

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m(−2), means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473–997] vs. morphine: 385 [251–728] mmHg·min, P < 0.001, CI: −394 to −128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting. NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.

Sympathetic transduction of blood pressure (BP) is correlated negatively with resting muscle sympathetic nerve activity (MSNA) in cross-sectional data, but the acute effects of increasing MSNA are unclear. Sixteen (4 female) healthy adults (26 ± 3 years) underwent continuous measurement of heart rate, BP, and MSNA at rest and during graded lower body negative pressure (LBNP) at −10, −20, and −30 mmHg. Sympathetic transduction of BP was quantified in the time (signal averaging) and frequency (MSNA-BP gain) domains. The proportions of MSNA bursts firing within each tertile of BP were calculated. As expected, LBNP increased MSNA burst frequency ( P < 0.01) and burst amplitude ( P < 0.02), although the proportions of MSNA bursts firing across each BP tertile remained stable (all P > 0.44). The MSNA-diastolic BP low-frequency transfer function gain ( P = 0.25) was unchanged during LBNP; the spectral coherence was increased ( P = 0.03). Signal-averaged sympathetic transduction of diastolic BP was unchanged (from 2.1 ± 1.0 at rest to 2.4 ± 1.5, 2.2 ± 1.3, and 2.3 ± 1.4 mmHg; P = 0.43) during LBNP, but diastolic BP responses following nonburst cardiac cycles progressively decreased (from −0.8 ± 0.4 at rest to −1.0 ± 0.6, −1.2 ± 0.6, and −1.6 ± 0.9 mmHg; P < 0.01). As a result, the difference between MSNA burst and nonburst diastolic BP responses was increased (from 2.9 ± 1.4 at rest to 3.4 ± 1.9, 3.4 ± 1.9, and 3.9 ± 2.1 mmHg; P < 0.01). In conclusion, acute increases in MSNA using LBNP did not alter traditional signal-averaged or frequency-domain measures of sympathetic transduction of BP or the proportion of MSNA bursts firing at different BP levels. The factors that determine changes in the firing of MSNA bursts relative to oscillations in BP require further investigation.

We have developed a wireless, wearable Doppler ultrasound system that continuously measures the common carotid artery Doppler pulse. A novel measure from this device, the Doppler shock index, accurately detected moderate-to-severe central blood volume loss in a human hemorrhage model generated by lower body negative pressure. In this analysis, we tested whether the wearable Doppler could identify only mild-to-moderate central blood volume loss.Eleven healthy volunteers were recruited and studied in a physiology laboratory at the Mayo Clinic. Each participant underwent a lower body negative protocol in duplicate. Carotid Doppler measures including Doppler shock indices were compared with blood pressure and the shock index for their ability to detect both 10% and 20% reductions in stroke volume.All carotid Doppler measures were better able to detect diminishing stroke volume than either systolic or mean arterial pressure. Falling carotid artery corrected flow time and rising heart rate/corrected flow time (DSI FTc ) were the most sensitive measures for detecting 10% and 20% stroke volume reductions, respectively. The area under the receiver operator curves (AUROCs) for all shock indices was at least 0.86; however, the denominators of the two Doppler shock indices (i.e., the corrected flow time and velocity time integral) had AUROCs ranging between 0.81 and 0.9, while the denominator of the traditional shock index (i.e., systolic blood pressure) had AUROCs between 0.54 and 0.7.The wearable Doppler ultrasound was able to continuously measure the common carotid artery Doppler pulse. Carotid Doppler measures were highly sensitive at detecting both 10% and 20% stroke volume reduction. All shock indices performed well in their diagnostic ability to measure mild-to-moderate central volume loss, although the denominators of both Doppler shock indices individually outperformed the denominator of the traditional shock index.Diagnostic test or criteria; Level III.

Purpose Bolus water drinking, at room temperature, has been shown to improve orthostatic tolerance (OT), probably via sympathetic activation; however, it is not clear whether the temperature of the water bolus modifies the effect on OT or the cardiovascular responses to orthostatic stress. The aim of this study was to assess whether differing water temperature of the water bolus would alter time to presyncope and/or cardiovascular parameters during incremental orthostatic stress. Methods Fourteen participants underwent three head-up tilt (HUT) tests with graded lower body negative pressure (LBNP) continued until presyncope. Fifteen minutes prior to each HUT, participants drank a 500 mL bolus of water which was randomised, in single-blind crossover fashion, to either room temperature water (20 °C) (ROOM), ice-cold water (0–3 °C) (COLD) or warm water (45 °C) (WARM). Cardiovascular parameters were monitored continuously. Results There was no significant difference in OT in the COLD (33 ± 3 min; p = 0.3321) and WARM (32 ± 3 min; p = 0.6764) conditions in comparison to the ROOM condition (31 ± 3 min). During the HUT tests, heart rate and cardiac output were significantly reduced (p p Conclusions In healthy controls, bolus cold water drinking results in favourable orthostatic cardiovascular responses during HUT/LBNP without significantly altering OT. Using a cold water bolus may result in additional benefits in patients with orthostatic intolerance above those conferred by bolus water at room temperature (by ameliorating orthostatic tachycardia and enhancing vascular resistance responses). Further research in patients with orthostatic intolerance is warranted.

Existing technologies to measure central blood pressure (CBP) intrinsically depend on peripheral pressure or calibration models derived from it. Pharmacological or physiological interventions yielding different central and peripheral responses compromise the accuracy of such methods. We present a high-frame-rate ultrasound technology for cuffless and calibration-free evaluation of BP from the carotid artery. The system uses a pair of single-element ultrasound transducers to capture the arterial diameter and local pulse wave velocity (PWV) for the evaluation of beat-by-beat BP employing a novel biomechanical model.System's functionality assessment was conducted on eight male subjects (26 ± 4 years, normotensive and no history of cardiovascular risks) by perturbing pressureWhile the carotid pressure manifested trends similar to finger measurements during LBNP, the system also captured the differential carotid-to-peripheral pressure response, which corroborates the literature. The carotid diastolic and mean pressures agreed with the finger pressures (limits-of-agreement within ±7 mmHg) and exhibited acceptable uncertainty (mean absolute errors were 2.4 ± 3.5 and 2.6 ± 4.0 mmHg, respectively). Concurrent to the literature, the carotid systolic and pulse pressures (PPs) were significantly lower than those of the finger pressures by 11.1 ± 9.4 and 11.3 ± 8.2 mmHg, respectively (The study demonstrated the method's potential for providing cuffless and calibration-free pressure measurements while reliably capturing the physiological aspects, such as PP amplification and dynamic pressure responses to intervention.

Blood oxygen (O2)-carrying capacity is reduced with aging and has been previously linked with the capacity to withstand the upright posture, that is, orthostatic tolerance (OT). This study experimentally tested the hypothesis that a definite reduction in blood O2-carrying capacity via hemoglobin manipulation differently affects the OT of older women and men as assessed by lower body negative pressure (LBNP). Secondary hemodynamic parameters were determined with transthoracic echocardiography throughout incremental LBNP levels for 1 hour or until presyncope in healthy older women and men (total n = 26) matched by age (64 ± 7 vs 65 ± 8 years, p < .618) and physical activity levels. Measurements were repeated within a week period after a 10% reduction of blood O2-carrying capacity via carbon monoxide rebreathing and analyzed via 2-way analysis of covariance. In the assessment session, OT time was similar between women and men (53.5 ± 6.1 vs 56.4 ± 6.0 minutes, p = .238). Following a 10% reduction of blood O2-carrying capacity, OT time was reduced in women compared with men (51.3 ± 7.0 vs 58.2 ± 2.8 minutes, p = .003). The effect of reduced O2-carrying capacity on OT time differed between sexes (mean difference [MD] = −5.30 minutes, p = .010). Prior to presyncope, reduced O2-carrying capacity resulted in lower left ventricular end-diastolic volume (MD = −8.11 mL∙m−2, p = .043) and stroke volume (MD = −8.04 mL∙m−2, 95% confidence interval = −14.36, −1.71, p = .018) in women relative to men, even after adjusting for baseline variables. In conclusion, present results suggest that reduced blood O2-carrying capacity specifically impairs OT and its circulatory determinants in older women.

Journal of the American Heart Association : JAHA 11(21), e026437 (2022). doi:10.1161/JAHA.122.026437, Published by Association, New York, NY

In this paper we assessed how lower body negative pressure (LBNP) can be used to teach students the physiological effects of central hypovolemia in the absence of the LBNP and/or a medical monitor using a “dry lab” activity using LBNP data that have been previously collected. This activity was performed using published LBNP papers, with which students could explore LBNP as an important tool to study physiological responses to central hypovolemia as well as consider issues in performing an LBNP experiment and interpreting experimental results. The activity was performed at the All India Institute of Medical Sciences, New Delhi, with 31 graduate students and 4 teachers of physiology. Both students and teachers were provided with a set of questionnaires that inquired about aspects related to the structure of the activity and how this activity integrated research and knowledge, as well as aspects related to motivation of the students and teachers to perform the activity. Our results from student and teacher surveys suggest that a “dry lab” activity using LBNP to teach physiology can be an important tool to expose students to the basics of systems physiology as well as to provide useful insights into how research is performed. Providing insight into research includes formulating a research question and then designing (including taking into account confounding variables), implementing, conducting, and interpreting research studies. Finally, developing such an activity using LBNP can also serve as a basis for developing research capacities and interests of students even early in their medical studies.

Cephalad fluid shifts in space have been hypothesized to cause the spaceflight-associated neuro-ocular syndrome (SANS) by increasing the intracranial-ocular translaminal pressure gradient. Lower body negative pressure (LBNP) can be used to shift upper-body blood and other fluids toward the legs during spaceflight. We hypothesized that microgravity would increase jugular vein volume (JVvol), portal vein cross-sectional area (PV), and intracranial venous blood velocity (MCV) and that LBNP application would return these variables toward preflight levels. Data were collected from 14 subjects (11 males) before and during long-duration International Space Station (ISS) spaceflights. Ultrasound measures of JVvol, PV, and MCV were acquired while seated and supine before flight and early during spaceflight at day 45 (FD45) and late at day 150 (FD150) with and without LBNP. JVvol increased from preflight supine and seated postures (46 ± 48% and 646 ± 595% on FD45 and 43 ± 43% and 702 ± 631% on FD150, P < 0.05), MCV increased from preflight supine (44 ± 31% on FD45 and 115 ± 116% on FD150, P < 0.05), and PV increased from preflight supine and seated (51 ± 56% on FD45 and 100 ± 74% on FD150, P < 0.05). Inflight LBNP of −25 mmHg restored JVvol and MCV to preflight supine level and PV to preflight seated level. Elevated JVvol confirms the sustained neck-head blood engorgement inflight, whereas increased PV area supports the fluid shift at the splanchnic level. Also, MCV increased potentially due to reduced lumen diameter. LBNP, returning variables to preflight levels, may be an effective countermeasure. NEW & NOTEWORTHY Microgravity-induced fluid shifts markedly enlarge jugular and portal veins and increase cerebral vein velocity. These findings demonstrate a marked flow engorgement at neck and splanchnic levels and may suggest compression of the cerebral veins by the brain tissue in space. LBNP (−25 mmHg for 30 min) returns these changes to preflight levels and, thus, reduces the associated flow and tissue disturbances.

Orthostatic intolerance (OI), a disorder of the autonomic nervous system, it is the development of symptoms when standing upright which are relieved when reclining. Head-up tilt (HUT) table test is a common test for assessing orthostatic tolerance. However, HUT is limited with low sensitivity and specificity. Another approach to stimulate the changing direction and value of the gravity field vector is the lower body negative pressure (LBNP) chamber. The aims of the study is to evaluate the physiological responses of healthy subjects on HUT and LBNP, and examine the relations of two tests. A total of 19 subjects were recruited. A validated wearable device, Sotera Visi Mobile was use to collect physiological signals simultaneously throughout the experiment procedures. Each subject went through a baseline supine rest, 70o of HUT test, another round of baseline supine rest, followed by activation of LBNP test. Three level of suction were applied, i.e. -30 mmHg, -40 mmHg, and -50 mmHg. In this pilot study, healthy subjects showed significantly increased of heart rate, and decreased of systolic blood pressure and diastolic blood pressure, in both HUT and LBNP tests. Although both tests are capable of stimulating a decreased blood volume in the central circulation, but the physiological responses behaved differently and shown only very week correlation. This suggesting that a combination of LBNP test with HUT test might work the best in orthostatic intolerance assessment.

Hemorrhage is the leading cause of preventable death from trauma. Traditionally, vital signs have been used to detect blood loss and possible hemorrhagic shock. However, vital signs are not sensitive for early detection because of physiological mechanisms that compensate for blood loss. As an alternative, machine learning algorithms that operate on an arterial blood pressure (ABP) waveform acquired via photoplethysmography have been shown to provide an effective early indicator. However, these machine learning approaches lack physiological interpretability. In this paper, we evaluate the importance of nine ABP-derived features that provide physiological insight, using a database of 40 human subjects from a lower-body negative pressure model of progressive central hypovolemia. One feature was found to be considerably more important than any other. That feature, the half-rise to dicrotic notch (HRDN), measures an approximate time delay between the ABP ejected and reflected wave components. This delay is an indication of compensatory mechanisms such as reduced arterial compliance and vasoconstriction. For a scale of 0% to 100%, with 100% representing normovolemia and 0% representing decompensation, linear regression of the HRDN feature results in root-mean-squared error of 16.9%, R2 of 0.72, and an area under the receiver operating curve for detecting decompensation of 0.88. These results are comparable to previously reported results from the more complex black box machine learning models. Clinical Relevance- A single physiologically interpretable feature measured from an arterial blood pressure waveform is shown to be effective in monitoring for blood loss and impending hemorrhagic shock based on data from a human lower-body negative pressure model of progressive central hypolemia.

Trauma patients may suffer significant blood loss, and noninvasive methods to diagnose hypovolemia in these patients are needed. Physiologic effects of hypovolemia, aiming to maintain blood pressure, are largely mediated by increased sympathetic nervous activity. Trauma patients may however experience pain, which also increases sympathetic nervous activity, potentially confounding measures of hypovolemia. Elucidating the common and separate effects of the two stimuli on diagnostic methods is therefore important. Lower body negative pressure (LBNP) and cold pressor test (CPT) are experimental models of central hypovolemia and pain, respectively. In the present analysis, we explored the effects of LBNP and CPT on pre-ejection period and pulse transit time, aiming to further elucidate the potential use of these variables in diagnosing hypovolemia in trauma patients. We exposed healthy volunteers to four experimental sequences with hypovolemia (LBNP 60 mmHg) or normovolemia (LBNP 0 mmHg) and pain (CPT) or no pain (sham) in a 2 × 2 fashion. We calculated pre-ejection period and pulse transit time from ECG and ascending aortic blood velocity (suprasternal Doppler) and continuous noninvasive arterial pressure waveform (volume-clamp method). Fourteen subjects were available for the current analyses. This experimental study found that pre-ejection period increased with hypovolemia and remained unaltered with pain. Pulse transit time was reduced by pain and increased with hypovolemia. Thus, the direction of change in pulse transit time has the potential to distinguish hypovolemia and pain.

Compensated shock and hypovolaemia are frequent conditions that remain clinically undetected and can quickly cause deterioration of perioperative and critically ill patients. Automated, accurate and non-invasive detection methods are needed to avoid such critical situations. In this experimental study, we aimed to create a prediction model for stroke volume index (SVI) decrease based on electrical cardiometry (EC) measurements. Transthoracic echo served as reference for SVI assessment (SVI-TTE). In 30 healthy male volunteers, central hypovolaemia was simulated using a lower body negative pressure (LBNP) chamber. A machine-learning algorithm based on variables of EC was designed. During LBNP, SVI-TTE declined consecutively, whereas the vital signs (arterial pressures and heart rate) remained within normal ranges. Compared to heart rate (AUC: 0.83 (95% CI: 0.73–0.87)) and systolic arterial pressure (AUC: 0.82 (95% CI: 0.74–0.85)), a model integrating EC variables (AUC: 0.91 (0.83–0.94)) showed a superior ability to predict a decrease in SVI-TTE ≥ 20% (p = 0.013 compared to heart rate, and p = 0.002 compared to systolic blood pressure). Simulated central hypovolaemia was related to a substantial decline in SVI-TTE but only minor changes in vital signs. A model of EC variables based on machine-learning algorithms showed high predictive power to detect a relevant decrease in SVI and may provide an automated, non-invasive method to indicate hypovolaemia and compensated shock.

Lower body negative pressure (LBNP) elicits central hypovolemia, and it has been used to simulate the cardiovascular and cerebrovascular responses to hemorrhage in humans. LBNP protocols commonly use progressive stepwise reductions in chamber pressure for specific time periods. However, continuous ramp LBNP protocols have also been utilized to simulate the continuous nature of most bleeding injuries. The aim of this study was to compare tolerance and hemodynamic responses between these two LBNP profiles. Healthy human subjects (N = 19; age, 27 ± 4 y; 7 female/12 male) completed a 1) step LBNP protocol (5-min steps) and 2) continuous ramp LBNP protocol (3 mmHg/min), both to presyncope. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), middle and posterior cerebral artery velocity (MCAv and PCAv), cerebral oxygen saturation (ScO(2)), and end-tidal CO(2) (etCO(2)) were measured. LBNP tolerance, via the cumulative stress index (CSI, summation of chamber pressure × time at each pressure), and hemodynamic responses were compared between the two protocols. The CSI (step: 911 ± 97 mmHg/min vs. ramp: 823 ± 83 mmHg/min; P = 0.12) and the magnitude of central hypovolemia (%Δ SV, step: −54.6% ± 2.6% vs. ramp: −52.1% ± 2.8%; P = 0.32) were similar between protocols. Although there were no differences between protocols for the maximal %Δ HR (P = 0.88), the %Δ MAP during the step protocol was attenuated (P = 0.05), and the reductions in MCAv, PCAv, ScO(2), and etCO(2) were greater (P ≤ 0.08) when compared with the ramp protocol at presyncope. These results indicate that when comparing cardiovascular responses to LBNP across different laboratories, the specific pressure profile must be considered as a potential confounding factor. NEW & NOTEWORTHY Ramp lower body negative pressure (LBNP) protocols have been utilized to simulate the continuous nature of bleeding injuries. However, it unknown if tolerance or the physiological responses to ramp LBNP are similar to the more common stepwise LBNP protocol. We report similar tolerance between the two protocols, but the step protocol elicited a greater increase in cerebral oxygen extraction in the presence of reduced blood flow, presumably facilitating the matching of metabolic supply and demand.

Astronauts have presented with a constellation of visual changes referred to as spaceflight-associated neuro-ocular syndrome (SANS). However, neither have early markers of microgravity-induced optic remodeling been fully identified nor have countermeasures been developed. To identify early markers of SANS, we studied 10 subjects with optical coherence tomography and ultrasonography when upright and supine and again after 24 h of 6° head-down tilt (HDT) bed rest. Upon acute transition from the upright to the supine position, choroid area (2.24 ± 0.53 to 2.28 ± 0.52 mm

Based on previous experiments in nonhuman primates, we hypothesized that DOWe measured the compensatory reserve (CRM) and calculated oxygen delivery (DOHT and LT groups were matched for age, weight, BMI, and vital signs, DOAverage DO

Non-contact coded hemodynamic imaging (CHI) is a novel wide-field near-infrared spectroscopy system which monitors blood volume by quantifying attenuation of light passing through the underlying vessels. This study tested the hypothesis that CHI-based jugular venous attenuation (JVA) would be larger in men, and change in JVA would be greater in men compared to women during two fluid shift challenges. The association of JVA with ultrasound-based cross-sectional area (CSA) was also tested. Ten men and 10 women completed three levels of head-down tilt (HDT) and four levels of lower body negative pressure (LBNP). Both JVA and CSA were increased by HDT and reduced by LBNP (all p 0.001). Main effects of sex indicated that JVA was higher in men than women during both HDT (p = 0.003) and LBNP (p = 0.011). Interaction effects of sex and condition were observed for JVA during HDT (p = 0.005) and LBNP (p 0.001). We observed moderate repeated-measures correlations (r

Cerebral blood flow is tightly coupled with local neuronal activation and metabolism, i.e., neurovascular coupling (NVC). Studies suggest a role of sympathetic nervous system in the regulation of cerebral blood flow. However, this is controversial, and the sympathetic regulation of NVC in humans remains unclear. Since impaired NVC has been identified in several chronic diseases associated with a heightened sympathetic activity, we aimed to determine whether reflex-mediated sympathetic activation via lower body negative pressure (LBNP) attenuates NVC in humans. NVC was assessed using a visual stimulation protocol (5 cycles of 30 s eyes closed and 30 s of reading) in 11 healthy participants (aged 24 ± 3 yr). NVC assessments were made under control conditions and during LBNP at -20 and -40 mmHg. Posterior (PCA) and middle (MCA) cerebral artery mean blood velocity (

Postmenopausal women have lower resting cardiac function than premenopausal women, but whether the menopause influences maximal cardiac output and hence exercise capacity is unclear. It is possible that premenopausal and postmenopausal women achieve similar improvements in maximal aerobic capacity (V˙O2max) and cardiac output with exercise training via different regional left ventricular muscle function ("LV mechanics"), as suggested by in vitro and animal studies. The aim of this study was to investigate the effects of the menopause on LV mechanics and adaptations to exercise training.Twenty-five healthy untrained middle-age women (age, 45-58 yr; 11 premenopausal, 14 postmenopausal) completed 12 wk of exercise training. Before and after exercise training, (i) V˙O2max and blood volume were determined, and (ii) LV mechanics were assessed using echocardiography at rest and during two submaximal physiological tests - lower-body negative pressure and supine cycling.The increase in V˙O2max after exercise training was 9% smaller in postmenopausal than premenopausal women, concomitant with a smaller increase in blood volume (P0.05). However, cardiac output and LV volumes were not different between premenopausal and postmenopausal women (P0.05) despite altered regional LV muscle function, as indicated by higher basal mechanics in premenopausal women during the physiological tests after exercise training (P0.05).These findings are the first to confirm altered LV mechanics in postmenopausal women. In addition, the reduced aerobic adaptability to exercise training in postmenopausal women does not appear to be a central cardiac limitation and may be due to altered blood volume distribution and lower peripheral adaptations.

© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society Key points: Emission patterns in muscle sympathetic nerve activity stem from differently sized action potential (AP) subpopulations that express varying discharge probabilities. The mechanisms governing these firing behaviours are unclear. This study investigated the hypothesis that the arterial baroreflex exerts varying control over the different AP subpopulations. During baseline, medium APs expressed the greatest baroreflex slopes, while small and large APs exhibited weaker slopes. On going from baseline to lower body negative pressure (LBNP; simulated orthostatic stress), baroreflex slopes for some clusters of medium APs expressed the greatest increase, while slopes for large APs also increased but to a lesser degree. A subpopulation of previously silent larger APs was recruited with LBNP but these APs expressed weak baroreflex slopes. The arterial baroreflex heterogeneously regulates sympathetic AP subpopulations, exerting its strongest effect over medium APs. Weak baroreflex mechanisms govern the recruitment of latent larger AP subpopulations during orthostatic stress. Abstract: Muscle sympathetic nerve activity (MSNA) occurs primarily in bursts of action potentials (AP) with subpopulations that differ in size and discharge probabilities. The mechanisms determining these discharge patterns remain unclear. This study investigated the hypothesis that variations in AP discharge are due to subpopulation-specific baroreflex control. We employed multi-unit microneurography and a continuous wavelet analysis approach to extract sympathetic APs in 12 healthy individuals during baseline (BSL) and lower body negative pressure (LBNP; -40, -60, -80 mmHg). For each AP cluster, the baroreflex threshold slope was measured from the linear regression between AP probability (%) and diastolic blood pressure (mmHg). During BSL, the baroreflex exerted non-uniform regulation over AP subpopulations: medium-sized AP clusters expressed the greatest slopes while clusters of small and large APs expressed weaker slopes. On going from BSL to LBNP, the baroreflex slopes for each AP subpopulation were modified differently. Baroreflex slopes (%/mmHg) for some medium APs (cluster 5: −4.4 ± 4 to −9.1 ± 5) expressed the greatest increase with LBNP, while slopes for large APs (cluster 9: −1.3 ± 1 to −2.6 ± 2) also increased, but to a lesser degree. Slopes for small APs present at BSL exhibited reductions with LBNP (cluster 2: −3.9 ± 3 to −2.2 ± 3). Larger previously silent AP clusters recruited with LBNP expressed weak baroreflex regulation (cluster 14: −0.9 ± 1%/mmHg). The baroreflex exerts the strongest control over medium-sized APs. Augmenting baroreflex gain and upward resetting of discrete AP subpopulations active at BSL, as well as recruiting larger previously silent APs with weak baroreflex control, facilitates elevated MSNA during orthostatic stress.

Background Hemorrhage remains the leading cause of death following traumatic injury in both civilian and military settings. Heart rate variability (HRV) and heart rate complexity (HRC) have been proposed as potential "new vital signs" for monitoring trauma patients; however, the added benefit of HRV or HRC for decision support remains unclear. Another new paradigm, the compensatory reserve measurement (CRM), represents the integration of all cardiopulmonary mechanisms responsible for compensation during relative blood loss and was developed to identify current physiologic status by estimating the progression toward hemodynamic decompensation. In the present study, we hypothesized that CRM would provide greater sensitivity and specificity to detect progressive reductions in central circulating blood volume and onset of decompensation as compared with measurements of HRV and HRC. Methods Continuous, noninvasive measurements of compensatory reserve and electrocardiogram signals were made on 101 healthy volunteers during lower-body negative pressure (LBNP) to the point of decompensation. Measures of HRV and HRC were taken from electrocardiogram signal data. Results Compensatory reserve measurement demonstrated a superior sensitivity and specificity (receiver operator characteristic area under the curve [ROC AUC] = 0.93) compared with all HRV measures (ROC AUC ≤ 0.84) and all HRC measures (ROC AUC ≤ 0.86). Sensitivity and specificity values at the ROC optimal thresholds were greater for CRM (sensitivity = 0.84; specificity = 0.84) than HRV (sensitivity, ≤0.78; specificity, ≤0.77), and HRC (sensitivity, ≤0.79; specificity, ≤0.77). With standardized values across all levels of LBNP, CRM had a steeper decline, less variability, and explained a greater proportion of the variation in the data than both HRV and HRC during progressive hypovolemia. Conclusion These findings add to the growing body of literature describing the advantages of CRM for detecting reductions in central blood volume. Most importantly, these results provide further support for the potential use of CRM in the triage and monitoring of patients at highest risk for the onset of shock following blood loss.

Optic disc edema develops in most astronauts during long-duration spaceflight. It is hypothesized to result from weightlessness-induced venous congestion of the head and neck and is an unresolved health risk of space travel.Determine if short-term application of lower body negative pressure (LBNP) could reduce internal jugular vein (IJV) expansion associated with the supine posture without negatively impacting cerebral perfusion or causing IJV flow stasis.Prospective.Nine healthy volunteers (six women).3T/cine two-dimensional phase-contrast gradient echo; pseudo-continuous arterial spin labeling single-shot gradient echo echo-planar.The study was performed with two sequential conditions in randomized order: supine posture and supine posture with 25 mmHg LBNP (LBNPPaired t-tests were used to compare measurement means across conditions. Significance was defined as P 0.05.LBNPShort-term application of LBNP1 TECHNICAL EFFICACY STAGE: 1.

PURPOSE Complex blood flow is commonly observed in the carotid bifurcation, although the factors that regulate these patterns beyond arterial geometry are unknown. The emergence of high-frame-rate ultrasound vector flow imaging allows for noninvasive, time-resolved analysis of complex hemodynamic behavior in humans, and it can potentially help researchers understand which physiological stressors can alter carotid bifurcation hemodynamics in vivo. Here, we seek to pursue the first use of vector projectile imaging (VPI), a dynamic form of vector flow imaging, to analyze the regulation of carotid bifurcation hemodynamics during experimental reductions in cardiac output induced via a physiological stressor called lower body negative pressure (LBNP). METHODS Seven healthy adults (age: 27 ± 4 yr, 4 men) underwent LBNP at -45 mmHg to simulate a postural hemodynamic response in a controlled environment. Using a research-grade, high-frame-rate ultrasound platform, vector flow estimation in each subject's right carotid bifurcation was performed through a multi-angle plane wave imaging (two transmission angles of 10° and -10°) formulation, and VPI cineloops were generated at a frame rate of 750 fps. Vector concentration was quantified by the resultant blood velocity vector angles within a region of interest; lower concentration indicated greater flow dispersion. Discrete concentration values during peak and late systole were compared across different segments of the carotid artery bifurcation before, and during, LBNP. RESULTS Vector projectile imaging revealed that external and internal carotid arteries exhibited regional hemodynamic changes during LBNP, which acted to reduce both the subject's cardiac output (Δ - 1.2 ± 0.5 L/min, -19%; P

Background & aim Active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR), which applies to cardiac arrests with contraindication of standard chest compressions (SCC) CPR, has been utilized in cardiac arrest. However, the efficacy and safety of AACD-CPR still remained controversy. This analysis was designed to comprehensively compare AACD versus SCC-CPR in patients with cardiac arrest. Methods We searched the Cochrane Library, PubMed, EMBASE, Web of Science and CNKI up to April 22, 2019. Mean difference (MD) and risk ratio (RR) with its 95% confidence intervals (CIs) were estimated to compare outcomes of the groups. Our primary outcomes were restoration of spontaneous circulation (ROSC) and short-term survival. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2 and Stata 12.0. Results A total of seventeen studies (N = 1647 patients) were identified for the present analysis. Compared with standard CPR, AACD-CPR was superior in restoration of spontaneous circulation (ROSC) and short-term survival, with pooled RRs of 1.38 (95% CI 1.23–1.55; P Conclusions Generally, in this combined analysis we found a statistically significant improvement in survival and ROSC with the use of AACD-CPR as compared with the use of standard CPR. There was also significant improvement in incidence of fracture, long-term survival, PETCO2 and CPP with AACD-CPR in comparison with standard CPR; results were not statistically different between the groups regarding to vomiting rate and adverse events. The standardized, diversified and individualized methods of clinical operation of AACD-CPR need exploration and expectingly serve as a guideline for clinical application of AACD-CPR in the future.

IMPORTANCE: Astronauts returning from long-duration spaceflight experience ocular remodeling related to cephalad fluid shifts induced by microgravity. It is hypothesized that the absence of diurnal reductions in intracranial pressure in microgravity creates a low but persistent pressure gradient at the posterior aspect of the eye, which results in ocular remodeling and space-associated neuro-ocular syndrome (SANS) over many months. OBJECTIVE: To determine whether partial reintroduction of footward fluid shifts during simulated microgravity via lower body negative pressure (LBNP) during sleep attenuates choroid engorgement, an early marker of ocular remodeling related to SANS. DESIGN, SETTING, AND PARTICIPANTS: Between May 2019 and February 2020, participants with no major cardiovascular, kidney, or ophthalmic disease completed 3 days of supine (0°) bed rest with and 3 days without 8 hours of nightly LBNP in a randomized, crossover design. This single-center investigation took place at the UT Southwestern Medical Center. All analyses were conducted blinded to condition and time point. INTERVENTIONS: Eight hours of nightly LBNP (−20 mm Hg) vs no LBNP. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in choroid area and volume after 3 days of bed rest measured by optical coherence tomography. RESULTS: Of 10 participants, 5 were female, the mean (SD) age was 29 (9) years, and the age range was 18 to 55 years. Central venous pressure increased from the seated to supine position (mean [SD], seated: −2.3 [2.0] vs supine: 6.9 [2.0] mm Hg; P

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a pre-syncopal limited progressive lower-body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg•min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model (time [LBNP stage] x trial). LBNP tolerance was not different between trials (Fentanyl: 647 ± 386 vs. Placebo: 676 ± 295 mmHg•min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

A reciprocal relationship between the baroreflex and cerebral autoregulation (CA) has been demonstrated at rest and in response to acute hypotension. We hypothesized that the reciprocal relationship between cardiac baroreflex sensitivity (BRS) and CA would be maintained during sustained central hypovolemia induced by lower body negative pressure (LBNP), and that the strength of this relationship would be greater in subjects with higher tolerance to this stress. Healthy young adults (n = 51; 23F/28M) completed a LBNP protocol to presyncope. Subjects were classified as high tolerant (HT; completion of -60 mmHg LBNP stage, ≥20-min) or low tolerant (LT; did not complete -60 mmHg LBNP stage,20-min). R-R intervals (RRI), systolic arterial pressure (SAP), mean arterial pressure (MAP), and middle cerebral artery velocity (MCAv) were measured continuously. Cardiac BRS was calculated in the time domain (ΔHR/ΔSAP) and frequency domain (RRI-SAP low frequency (LF) transfer function gain), and CA was calculated in the time domain (ΔMCAv/ΔMAP) and frequency domain (MAP-mean MCAv LF transfer function gain). There was a moderate relationship between cardiac BRS and CA for the group of 51 subjects in both the time (R = -0.54, P 0.0001) and frequency (R = 0.61, P 0.001) domains; there was a stronger relationship in the HT group (R = 0.73) compared to the LT group (R = 0.31) in the frequency domain (P = 0.08), but no difference between groups in the time domain (HT: R = -0.73 vs. LT: R = -0.63; P = 0.27). These findings suggest that an interaction between BRS and CA may be an important compensatory mechanism that contributes to tolerance to simulated hemorrhage in young healthy adults.

This study sought to evaluate the role of cardiac afferent reflexes in atrial fibrillation (AF).Efferent autonomic tone is not associated with atrial remodeling and AF persistence. However, the role of cardiac afferents is unknown.Individuals with nonpermanent AF (n = 48) were prospectively studied (23 in the in-AF group and 25 in sinus rhythm [SR]) with 12 matched control subjects. We performed: 1) low-level lower body negative pressure (LBNP), which decreases cardiac volume, offloading predominantly cardiac afferent (volume-sensitive) low-pressure baroreceptors; 2) Valsalva reflex (predominantly arterial high-pressure baroreceptors); and 3) isometric handgrip reflex (both baroreceptors). We measured beat-to-beat mean arterial pressure (MAP) and heart rate (HR). LBNP elicits reflex vasoconstriction, estimated using venous occlusion plethysmography-derived forearm blood flow (∝1/vascular resistance), maintaining MAP. To assess reversibility, we repeated LBNP (same day) after 1-hour low-level tragus stimulation (in n = 5 in the in-AF group and n = 10 in the in-SR group) and6 weeks post-cardioversion (n = 7).The 3 groups were well matched for age (59 ± 12 years, 83% male), body mass index, and risk factors (P = NS). The in-AF group had higher left atrial volume (P 0.001) and resting HR (P = 0.01) but similar MAP (P = 0.7). The normal LBNP vasoconstriction (-49 ± 5%) maintaining MAP (control subjects) was attenuated in the in-SR group (-12 ± 9%; P = 0.005) and dysfunctional in the in-AF group (+11 ± 6%; P 0.001), in which MAP decreased and HR was unchanged. Valsalva was normal throughout. Handgrip MAP response was lowest in the in-AF group (P = 0.01). Interestingly, low-level tragus stimulation and cardioversion improved LBNP vasoconstriction (-48 ± 15%; P = 0.04; and -32 ± 9%; P = 0.02, respectively).Cardiac afferent (volume-sensitive) reflexes are abnormal in AF patients during SR and dysfunctional during AF. This could contribute to AF progression, thus explaining "AF begets AF." (Characterisation of Autonomic function in Atrial Fibrillation [AF-AF Study]; ACTRN12619000186156).

Spaceflight-associated neuro-ocular syndrome (SANS) develops during long-duration (>1 mo) spaceflight presumably because of chronic exposure to a headward fluid shift that occurs in weightlessness. We aimed to determine whether reversing this headward fluid shift with acute application of lower body negative pressure (LBNP) can influence outcome measures at the eye. Intraocular pressure (IOP) and subfoveal choroidal thickness were therefore evaluated by tonometry and optical coherence tomography (OCT), respectively, in 14 International Space Station crewmembers before flight in the seated, supine, and 15° head-down tilt (HDT) postures and during spaceflight, without and with application of 25 mmHg LBNP. IOP in the preflight seated posture was 14.4 mmHg (95% CI, 13.5–15.2 mmHg), and spaceflight elevated this value by 1.3 mmHg (95% CI, 0.7–1.8 mmHg, P < 0.001). Acute exposure to LBNP during spaceflight reduced IOP to 14.2 mmHg (95% CI, 13.4–15.0 mmHg), which was equivalent to that of the seated posture (P > 0.99), indicating that venous fluid redistribution by LBNP can influence ocular outcome variables during spaceflight. Choroidal thickness during spaceflight (374 µm, 95% CI, 325–423 µm) increased by 35 µm (95% CI, 25–45 µm, P < 0.001), compared with the preflight seated posture (339 µm, 95% CI, 289–388 µm). Acute use of LBNP during spaceflight did not affect choroidal thickness (381 µm, 95% CI, 331–430 µm, P = 0.99). The finding that transmission of reduced venous pressure by LBNP did not decrease choroidal thickness suggests that engorgement of this tissue during spaceflight may reflect changes that are secondary to the chronic cerebral venous congestion associated with spaceflight. NEW & NOTEWORTHY Spaceflight induces a chronic headward fluid shift that is believed to underlie ocular changes observed in astronauts. The present study demonstrates, for the first time, that reversing this headward fluid shift via application of lower body negative pressure (LBNP) during spaceflight may alter the ocular venous system, as evidenced by a decrease in intraocular pressure. This finding indicates that LBNP has the potential to be an effective countermeasure against the headward fluid shift during spaceflight, which may then be beneficial in preventing or reversing associated ocular changes.

© 2019 the American Physiological Society. What strategies are employed by the sympathetic system to communicate with the circulation? Muscle sympathetic nerve activity (MSNA) occurs in bursts of synchronous action potential (AP) discharge, yet whether between-burst asynchronous AP firing exists remains unknown. Using multiunit microneurography and a continuous wavelet transform to isolate APs, we studied AP synchronicity within human MSNA. Asynchronous APs were defined as those which occurred between bursts. Experiment 1 quantified AP synchronicity in eight individuals at baseline (BSL), -10 mmHg lower body negative pressure (LBNP), -40 mmHg LBNP, and end-expiratory apnea (APN). At BSL, 33 ± 12% of total AP activity was asynchronous. Asynchronous discharge was unchanged from BSL (67 ± 37 AP/min) to -10 mmHg LBNP (69 ± 33 AP/min), -40 mmHg LBNP (83 ± 68 AP/min), or APN (62 ± 39 AP/min). Across all conditions, asynchronous AP probability and frequency decreased with increasing AP size. Experiment 2 examined the impact of the ganglia on AP synchronicity by using nicotinic blockade (trimethaphan). The largest asynchronous APs were derecruited from BSL (11 ± 4 asynchronous AP clusters) to the last minute of the trimethaphan infusion with visible bursts (7 ± 2 asynchronous AP clusters). However, the 6 ± 2 smallest asynchronous AP clusters could not be blocked by trimethaphan and persisted to fire 100 ± 0% asynchronously without forming bursts. Nonnicotinic ganglionic mechanisms affect some, but not all, asynchronous activity. The fundamental behavior of human MSNA contains between- burst asynchronous AP discharge, which accounts for a considerable amount of BSL activity. NEW & NOTEWORTHY Historically, sympathetic nerve activity destined for the blood vessels supplying skeletal muscle (MSNA) has been characterized by spontaneous bursts formed by synchronous action potential (AP) discharge. However, this study found a considerable amount (~30% during baseline) of sympathetic AP discharge to fire asynchronously between bursts of human MSNA. Trimethaphan infusion revealed that nonnicotinic ganglionic mechanisms contribute to some, but not all, asynchronous discharge. Asynchronous sympathetic AP discharge represents a fundamental behavior of MSNA.

Women generally display lower tolerance to acute central hypovolemia than men. The measurement of compensatory reserve (CRM) is a novel metric that provides information about the sum total of all mechanisms that together work to compensate for the relative blood volume deficit. Hemodynamic decompensation occurs with depletion of the CRM (i.e., 0% CRM). In the present study, we hypothesized that the lower tolerance to progressive central hypovolemia reported in women can be explained by a faster reduction rate in CRM compared with men rather than sex differences in absolute integrated compensatory responses. Continuous, noninvasive measures of CRM were collected from 208 healthy volunteers (107 men and 85 women) who underwent progressive stepwise central hypovolemia induced by lower body negative pressure to the point of presyncope. Comparisons revealed shorter ( P < 0.01) times in female participants compared with male participants to reach 30% and 0% CRM. Similarly, the lower body negative pressure level, represented by the cumulative stress index, was less at 30% and 0% CRM in women compared with men ( P < 0.01). Changes in hemodynamic responses and frequency-domain data (oscillations in cerebral blood flow velocity and mean arterial blood pressure) were similar between men and women at 0% CRM ( P > 0.05). We conclude that compensatory responses to central hypovolemia in women were similar to men but were depleted at a faster rate compared with men. The earlier depletion of the compensatory reserve in women appears to be influenced by failure to maintain adequate cerebral oxygen delivery. NEW & NOTEWORTHY We compared hemodynamic and metabolic responses in men and women to experimentally controlled reductions in central blood volume at physiologically equivalent levels of compensatory reserve. We corroborated previous findings that females have lower tolerance to central hypovolemia than males but demonstrated for the first time that compensatory responses are similar. Our findings suggest lower tolerance to central hypovolemia in women results from reaching critical cerebral delivery of oxygen faster than men.

Hemorrhage is a leading cause of potentially preventable death in both civilian and military trauma settings. Lower body negative pressure (LBNP) is a validated, non-invasive, and reproducible approach to simulate hemorrhage by inducing central hypovolemia in healthy conscious humans. The oxidative stress response to simulated hemorrhage via LBNP has not been quantified. We hypothesized that systemic markers of oxidative stress would increase with application of maximal, pre-syncopal limited LBNP. Fifteen healthy human subjects (11 M/4 F; age 27 ± 1 y) were recruited for a single LBNP experiment to presyncope (chamber pressure was progressively reduced every 5-min in a stepwise manner). Heart rate was assessed via ECG, arterial pressure and stroke volume (SV) were measured continuously via finger photoplethysmography, muscle oxygen saturation (SmO2) was measured via near-infrared spectroscopy, and venous blood samples were collected at baseline and presyncope. Plasma samples were analyzed for F2-isoprostanes (F2-IsoP), a global marker of oxidative stress. The magnitude of central hypovolemia, indexed by the maximal decrease (%Δ) in SV, ranged from 27 to 74% (53.5 ± 3.9%; P 2-IsoP increased by 28.5 ± 11.6% ( P = 0.05) from baseline (24 ± 2 pg/mL) to presyncope (29 ± 3 pg/mL). The increase in F2-IsoP was not associated with %Δ SV ( r = 0.21, P = 0.46), %Δ MAP ( r = 0.05, P = 0.86), %Δ SmO2 ( r = 0.05, P = 0.90), or the maximum level of LBNP attained ( r = 0.35, P = 0.20). Simulated hemorrhage induced by LBNP to presyncope elicited an increase in oxidative stress, but this response was not associated with the magnitude of central hypovolemia, hypotension, or the decrease in peripheral muscle tissue oxygen saturation. These findings have important implications for the study of hemorrhage using LBNP, and future investigations of interventions targeting oxidative stress. Impact statement We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566–595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249–1261, 2004). Since then there has been a great deal of new research that has applied LBNP to investigate complex physiological responses to a variety of challenges including orthostasis, hemorrhage, and other important stressors seen in humans such as microgravity encountered during spaceflight. The LBNP stimulus has provided novel insights into the physiology underlying areas such as intolerance to reduced central blood volume, sex differences concerning blood pressure regulation, autonomic dysfunctions, adaptations to exercise training, and effects of space flight. Furthermore, approaching cardiovascular assessment using prediction models for orthostatic capacity in healthy populations, derived from LBNP tolerance protocols, has provided important insights into the mechanisms of orthostatic hypotension and central hypovolemia, especially in some patient populations as well as in healthy subjects. This review also presents a concise discussion of mathematical modeling regarding compensatory responses induced by LBNP. Given the diverse applications of LBNP, it is to be expected that new and innovative applications of LBNP will be developed to explore the complex physiological mechanisms that underline health and disease.

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

Purpose There is ample evidence that systemic sympathetic neural activity contributes to the progression of chronic kidney disease, possibly by limiting renal blood flow and thereby inducing renal hypoxia. Up to now there have been no direct observations of this mechanism in humans. We studied the effects of systemic sympathetic activation elicited by a lower body negative pressure (LBNP) on renal blood flow (RBF) and renal oxygenation in healthy humans. Methods Eight healthy volunteers (age 19-31 years) were subjected to progressive LBNP at - 15 and - 30 mmHg, 15 min per level. Brachial artery blood pressure was monitored intermittently. RBF was measured by phase-contrast MRI in the proximal renal artery. Renal vascular resistance was calculated as the MAP divided by the RBF. Renal oxygenation (R2*) was measured for the cortex and medulla by blood oxygen level dependent (BOLD) MRI, using a monoexponential fit. Results With a LBNP of - 30 mmHg, pulse pressure decreased from 50 +/- 10 to 43 +/- 7 mmHg; MAP did not change. RBF decreased from 1152 +/- 80 to 1038 +/- 83 mL/min to 950 +/- 67 mL/min at - 30 mmHg LBNP (p = 0.013). Heart rate and renal vascular resistance increased by 38 +/- 15% and 23 +/- 8% (p = 0.04) at - 30 mmHg LBNP, respectively. There was no change in cortical or medullary R2* (20.3 +/- 1.2 s(-1) vs 19.8 +/- 0.43 s(-1); 28.6 +/- 1.1 s(-1) vs 28.0 +/- 1.3 s(-1)). Conclusion The results suggest that an increase in sympathetic vasoconstrictor drive decreases kidney perfusion without a parallel reduction in oxygenation in healthy humans. This in turn indicates that sympathetic activation suppresses renal oxygen demand and supply equally, thus allowing adequate tissue oxygenation to be maintained.

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation. Healthy young males (n = 29, 26 ± 4 yr) and females (n = 23, 27 ± 5 yr) completed a step-wise LBNP protocol to presyncope. Mean arterial pressure (MAP), stroke volume (SV), middle cerebral artery velocity (MCAv), end-tidal CO(2) (etCO(2)), and cerebral oxygen saturation (ScO(2)) were measured continuously. Unexpectedly, tolerance to LBNP was similar between the sexes (males, 1,604 ± 68 s vs. females, 1,453 ± 78 s; P = 0.15). Accordingly, decreases (%Δ) in MAP, SV, MCAv, and ScO(2) were similar between males and females throughout LBNP and at presyncope (P ≥ 0.20). Interestingly, although decreases in etCO(2) were similar between the sexes throughout LBNP (P = 0.16), at presyncope, the %Δ etCO(2) from baseline was greater in males compared to females (−30.8 ± 2.6% vs. −21.3 ± 3.0%; P = 0.02). Contrary to our hypothesis, sex does not influence tolerance, or the central or cerebral hemodynamic responses to simulated hemorrhage. However, the etCO(2) responses at presyncope do suggest potential sex differences in cerebral vascular sensitivity to CO(2) during central hypovolemia. NEW & NOTEWORTHY Tolerance and cerebral blood velocity responses to simulated hemorrhage (elicited by lower body negative pressure) were similar between male and female subjects. Interestingly, the change in etCO(2) from baseline was greater in males compared to females at presyncope, suggesting potential sex differences in cerebral vascular sensitivity to CO(2) during simulated hemorrhage. These findings may facilitate development of individualized therapeutic interventions to improve survival from hemorrhagic injuries in both men and women.

Yoga has been shown to improve autonomic conditioning in humans, as evidenced by the enhancement of parasym-pathetic activity and baroreflex sensitivity. Therefore, we hypothesized that the experience of yoga may result in adaptation to acute hemodynamic changes. To decipher the long-term effects of yoga on cardiovascular variability, yoga practitioners were compared to yoga-naïve subjects during exposure to –40 mm Hg lower-body negative pressure (LBNP). A comparative study was conducted on 40 yoganaïve subjects and 40 yoga practitioners with an average age of 31.08 ± 7.31 years and 29.93 ± 7.57 years, respectively. Heart rate variability, blood pressure variability, baroreflex sensitivity, and correlation between systolic blood pressure and RR interval were evaluated at rest and during LBNP. In yoga practitioners, the heart rate was lower in supine rest (p = 0.011) and during LBNP (p = 0.043); the pNN50 measure of heart rate variability was higher in supine rest (p = 0.011) and during LBNP (p = 0.034). The yoga practitioners’ standard deviation of successive beat-to-beat blood pressure intervals of systolic blood pressure variability was lower in supine rest (p = 0.034) and during LBNP (p = 0.007), with higher sequence baroreflex sensitivity (p = 0.019) and ~ high-frequency baroreflex sensitivity. Mean systolic blood pressure and RR interval were inversely correlated in the yoga group (r = –0.317, p = 0.049). The yoga practitioners exhibited higher parasympathetic activity and baroreflex sensitivity with lower systolic blood pressure variability, indicating better adaptability to LBNP compared to the yoga-naïve group. Our findings indicate that the yoga module was helpful in conditions of hypovolemia in healthy subjects; it is proposed to be beneficial in clinical conditions associated with sympathetic dominance, impaired barore-flex sensitivity, and orthostatic intolerance.

Background Treatment with lower extremity intermittent negative pressure (INP) of -40 mm Hg for one hour twice daily for 12 weeks, increases walking capacity in patients with intermittent claudication (IC). However, the effects of INP treatment beyond 12 weeks have not been elucidated. The aim of the present study was to investigate the clinical effects of INP treatment after 24 weeks in patients with IC. Methods This was a follow-up study after a randomized sham-controlled trial, where patients randomized to the active treatment group were offered to continue treatment for 12 additional weeks (24 weeks in total). Treatment with -40 mm Hg INP was applied in a pressure chamber sealed around the lower leg, and the patients were instructed to treat themselves at home one hour in the morning and one hour in the evening. Pain free walking distance (PWD), maximal walking distance (MWD), resting ankle-brachial index (ABI) and post exercise ABI were measured at baseline, after 12 and 24 weeks. Results Ten out of 32 patients (31%) from the active treatment group in the initial trial were included in this follow-up study. At baseline, PWD was (mean ±SD) 151 ± 91 m and MWD was 362 ±159 m. There was a significant increase in both PWD and MWD after 24 weeks of treatment, compared to baseline (ANOVA; P= 0.006 and P= 0.012, respectively). Post hoc tests revealed that PWD increased significantly from baseline to 12 weeks (mean 81 m; 95% CI [6, 156]; P = 0.032), and that MWD increased significantly from 12 to 24 weeks (mean 145 m; 95% CI [22, 268]; P = 0.018). There were no significant changes in resting ABI or post exercise ABI during the 24-week treatment period (ANOVA; P= 0.157 and P= 0.450, respectively). Conclusion Both PWD and MWD improved after treatment with – 40 mm Hg INP for one hour twice daily for 24 weeks, compared to baseline. The main improvement in PWD occurred during the first 12 weeks of treatment, whereas the main improvement in MWD occurred between 12 and 24 weeks of treatment.

Up to 50% of patients in intensive care units develop intraabdominal hypertension (IAH) in the course of medical treatment. If not detected on time and treated adequately, IAH may develop into an abdominal compartment syndrome (ACS) which is associated with a high mortality rate. Patients undergoing cardiac surgery are especially prone to develop ACS due to several risk factors including intraoperative hypothermia, fluid resuscitation and acidosis. We investigated patients who developed ACS after cardiac surgery and analyzed potential risk factors, treatment and outcome.From 2011 to 2016, patients with ACS after cardiac surgery requiring decompressive laparotomy were prospectively recorded. Patient characteristics, details on the cardiac surgery, mortality rate and type of treatment of the open abdomen were analyzed.Incidence of ACS in cardiac surgery patients was 1.0% (n = 42/4128), with a mortality rate of 57%. Ejection fraction, Euroscore2 as well as the perfusion time are independent risk factors for the development of ACS. The outcome of patients with ACS was independent of elective versus emergency surgery, gender, age, BMI or ASA score. In the 18 surviving patients, fascial closure was achieved in 72% after a median of 9 days.Abdominal compartment syndrome is a rare but serious complication after cardiac surgery with a high mortality rate. Independent risk factors for ACS were identified. Negative pressure wound therapy seems to promote and allow early fascia closure of the abdomen and represents therefore a likely benefit for the patient.

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; −10, −20, and −30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at −30 mmHg of LBNP (Δ−8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla. NEW & NOTEWORTHY In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.

During prolonged spaceflight, astronauts often experience ocular changes, due to constant head-ward fluid shifts in space as compared with Earth. This article reviews symptoms, likely causes, and potential solutions, such as lower body negative pressure, to counteract space-associated neuroocular syndrome (SANS).Low gravity conditions and other aspects of spaceflight affect the eye detrimentally, causing SANS which is characterized by optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. SANS is probably caused by altered hemodynamic flows in the head and neck as well as mildly elevated intracranial and intraocular pressures. Carbon dioxide and other chemicals in space-craft may influence SANS as well. SANS may be counteracted by using lower body negative pressure, thigh cuffs, spacecraft engineering, and/or artificial gravity by a centrifuge.Prolonged space missions are associated with optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. Possible causes and countermeasures are currently being researched to reduce the risk of SANS. Although many countermeasures to SANS are under investigation lower body negative pressure exhibits great promise in counteracting the headward fluid shifts in space. Understanding and prevention of SANS is critical to future space exploration, especially to long-duration missions to the moon and Mars.

Objective: An optical imaging system is proposed for quantitatively assessing jugular venous response to altered central venous pressure. Methods: The proposed system assesses sub-surface optical absorption changes from jugular venous waveforms with a spatial calibration procedure to normalize incident tissue illumination. Widefield frames of the right lateral neck were captured and calibrated using a novel flexible surface calibration method. A hemodynamic optical model was derived to quantify jugular venous optical attenuation (JVA) signals, and generate a spatial jugular venous pulsatility map. JVA was assessed in three cardiovascular protocols that altered central venous pressure: acute central hypovolemia (lower body negative pressure), venous congestion (head-down tilt), and impaired cardiac filling (Valsalva maneuver). Results: JVA waveforms exhibited biphasic wave properties consistent with jugular venous pulse dynamics when time-aligned with an electrocardiogram. JVA correlated strongly (median, interquartile range) with invasive central venous pressure during graded central hypovolemia (r = 0.85, [0.72, 0.95]), graded venous congestion (r = 0.94, [0.84, 0.99]), and impaired cardiac filling (r = 0.94, [0.85, 0.99]). Reduced JVA during graded acute hypovolemia was strongly correlated with reductions in stroke volume (SV) (r = 0.85, [0.76, 0.92]) from baseline (SV: 79 $\,\pm\,$ 15 mL, JVA: 0.56 $\,\pm\,$ 0.10 a.u.) to $-$ 40 mmHg suction (SV: 59 $\,\pm\,$ 18 mL, JVA: 0.47 $\,\pm\,$ 0.05 a.u.; p $\, 0.01). Conclusion: The proposed non-contact optical imaging system demonstrated jugular venous dynamics consistent with invasive central venous monitoring during three protocols that altered central venous pressure. Significance: This system provides non-invasive monitoring of pressure-induced jugular venous dynamics in clinically relevant conditions where catheterization is traditionally required, enabling monitoring in non-surgical environments.

Earlier reports suggest that limb venous distension evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) (i.e., venous distension reflex). Our recent report also shows that suction of arterially occluded limb evokes venous distension reflex. We postulate that the venous distension reflex contributes to autonomic responses to orthostatic stress. In this study, we hypothesized that orthostatic tolerance would be linked to the MSNA response seen with lower limb suction. Fifteen healthy subjects were tested in the supine position. Negative pressure (−100 mmHg) was applied on an arterially occluded lower limb for 2 min. MSNA from the peroneal nerve in the limb not exposed to suction, ECG, and BP (Finometer) was recorded throughout the study. Limb occlusion without suction was used as a control trial. In a separate visit, the individual’s orthostatic tolerance was assessed using a graded lower body negative pressure (LBNP) tolerance test. Mean arterial BP and MSNA (18.6 ± 1.9 to 23.6 ± 2.0 bursts/min) significantly (both P < 0.05) increased during limb suction. Orthostatic tolerance index positively correlated ( R = 0.636, P = 0.011) with the MSNA response seen with suction during occlusion. Since the venous distension reflex strength correlates with the level of orthostatic tolerance, we speculate that lower-limb venous distension reflex engagement increases the sympathetic responses during orthostatic challenge and serves to maintain BP with postural stress.