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A directional sensitivity of the cerebral pressure-flow relationship has been described using repeated squat-stands. Oscillatory lower body negative pressure (OLBNP) is a reproducible method to characterize dynamic cerebral autoregulation (dCA). It could represent a safer method to examine the directional sensitivity of the cerebral pressure-flow relationship within clinical populations and/or during pharmaceutical administration. Therefore, examining the cerebral pressure-flow directional sensitivity during an OLBNP-induced cyclic physiological stress is crucial. We calculated changes in middle cerebral artery mean blood velocity (MCAv) per alterations to mean arterial pressure (MAP) to compute ratios adjusted for time intervals (ΔMCAv T /ΔMAP T ) with respect to the minimum-to-maximum MCAv and MAP, for each OLBNP transition (0 to -90 Torr), during 0.05 Hz and 0.10 Hz OLBNP. We then compared averaged ΔMCAv T /ΔMAP T during OLBNP-induced MAP increases (INC) (ΔMCAv T / Δ MAP T INC ) and decreases (DEC) (ΔMCAv T / Δ MAP T DEC ). Nineteen healthy participants [9 females; 30 ± 6 years] were included. There were no differences in ΔMCAv T /ΔMAP T between INC and DEC at 0.05 Hz. ΔMCAv T / Δ MAP T INC (1.06 ± 0.35 vs. 1.33 ± 0.60 cm⋅s -1 /mmHg; p = 0.0076) was lower than ΔMCAv T / Δ MAP T DEC at 0.10 Hz. These results support OLBNP as a model to evaluate the directional sensitivity of the cerebral pressure-flow relationship., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Lower Body Negative Pressure (LBNP) redistributes blood from the upper body to the lower body. LBNP may prove to be a countermeasure for the multifaceted physiological changes endured by astronauts during spaceflight related to cephalad fluid shift. Over more than five decades, beginning with the era of Skylab, advancements in LBNP technology have expanded our understanding of neurological, ophthalmological, cardiovascular, and musculoskeletal adaptations in space, with particular emphasis on mitigating issues such as bone loss. To date however, no comprehensive review has been conducted that chronicles the evolution of this technology or elucidates the broad-spectrum potential of LBNP in managing the diverse physiological challenges encountered in the microgravity environment. Our study takes a chronological perspective, systematically reviewing the historical development and application of LBNP technology in relation to the various pathophysiological impacts of spaceflight. The primary objective is to illustrate how this technology, as it has evolved, offers an increasingly sophisticated lens through which to interpret the systemic effects of space travel on human physiology. We contend that the insights gained from LBNP studies can significantly aid in formulating targeted and effective countermeasures to ensure the health and safety of astronauts. Ultimately, this paper aspires to promote a more cohesive understanding of the broad applicability of LBNP as a countermeasure against multiple bodily effects of space travel, thereby contributing to a safer and more scientifically informed approach to human space exploration., Competing Interests: Declaration of competing interest The authors declare that they have no financial or non-financial competing interests., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hemorrhage is a leading cause of death in the prehospital setting. Since trauma-induced pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic regulation of arterial blood pressure and vital organ perfusion. The purpose of this study was to test two unrelated hypotheses: 1 ) sublingual sufentanil (Dsuvia) impairs tolerance to progressive central hypovolemia and 2 ) sublingual sufentanil attenuates pain sensation and the accompanying cardiovascular responses to a noxious stimulus. Twenty-nine adults participated in this double-blinded, randomized, crossover, placebo-controlled trial. After sublingual administration of sufentanil (30 μg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) challenge to tolerance ( aim 1 ). After a recovery period, participants completed a cold pressor test (CPT; aim 2 ). Addressing the first aim, tolerance to LBNP was not different between trials ( P = 0.495). Decreases in systolic blood pressure from baseline to the end of LBNP also did not differ between trials (time P < 0.001, trial P = 0.477, interaction P = 0.587). Finally, increases in heart rate from baseline to the end of LBNP did not differ between trials (time P < 0.001, trial P = 0.626, interaction P = 0.424). Addressing the second aim, sufentanil attenuated perceived pain ( P < 0.001) in response to the CPT, though the magnitude of the change in mean blood pressure during the CPT ( P = 0.078) was not different between trials. These data demonstrate that sublingual sufentanil does not impair tolerance to progressive central hypovolemia. Additionally, sublingual sufentanil attenuates perceived pain, but not the accompanying mean blood pressure responses to the CPT. NEW & NOTEWORTHY Addressing two unique aims, we observed that sublingual sufentanil administration does not impair tolerance or cardiovascular responses to lower-body negative pressure (LBNP)-induced progressive central hypovolemia. Second, despite pain perception being reduced, sublingual sufentanil did not attenuate mean blood pressure responses to a cold pressor test (CPT).

Introduction: Trauma-induced hemorrhage is a leading cause of death in prehospital settings. Experimental data demonstrate that females have a lower tolerance to simulated hemorrhage (i.e., central hypovolemia). However, the mechanism(s) underpinning these responses are unknown. Therefore, this study aimed to compare autonomic cardiovascular responses during central hypovolemia between the sexes. We hypothesized that females would have a lower tolerance and smaller increase in muscle sympathetic nerve activity (MSNA) to simulated hemorrhage., Methods: Data from 17 females and 19 males, aged 19-45 yr, were retrospectively analyzed. Participants completed a progressive lower-body negative pressure (LBNP) protocol to presyncope to simulate hemorrhagic tolerance with continuous measures of MSNA and beat-to-beat hemodynamic variables. We compared responses at baseline, at two LBNP stages (-40 and -50 mmHg), and at immediately before presyncope. In addition, we compared responses at relative percentages (33%, 66%, and 100%) of hemorrhagic tolerance, calculated via the cumulative stress index (i.e., the sum of the product of time and pressure at each LBNP stage)., Results: Females had lower tolerance to central hypovolemia (female: 561 ± 309 vs male: 894 ± 304 min·mmHg [time·LBNP]; P = 0.003). At LBNP -40 and -50 mmHg, females had lower diastolic blood pressures (main effect of sex: P = 0.010). For the relative LBNP analysis, females exhibited lower MSNA burst frequency (main effect of sex: P = 0.016) accompanied by a lower total vascular conductance (sex: P = 0.028; main effect of sex)., Conclusions: Females have a lower tolerance to central hypovolemia, which was accompanied by lower diastolic blood pressure at -40 and -50 mmHg LBNP. Notably, females had attenuated MSNA responses when assessed as relative LBNP tolerance time., (Copyright © 2024 by the American College of Sports Medicine.)

Background: Lower body negative Pressure (LBNP)-induced hypovolemia is simulating acute hemorrhage by sequestrating blood into lower extremities. Bioelectrical Impedance Analysis (BIA) is based on the electrical properties of biological tissues, as electrical current flows along highly conductive body tissues (such as blood). Changes in blood volume will lead to changes in bioimpedance. This study aims to study changes in upper (UL) and lower (LL) extremities bioimpedance during LBNP-induced hypovolemia., Methods: This was a prospective observational study of healthy volunteers who underwent gradual LBNP protocol which consisted of 3-minute intervals: at baseline, -15, -30, -45, -60 mmHg, then recovery phases at -30 mmHg and baseline. The UL&LL extremities bioimpedance were measured and recorded at each phase of LBNP and the percentage changes of bioimpedance from baseline were calculated and compared using student's t-test. A P-value of < 0.05 was considered significant. Correlation between relative changes in UL&LL bioimpedance and estimated blood loss (EBL) from LBNP was calculated using Pearson correlation., Results: 26 healthy volunteers were enrolled. As LBNP-induced hypovolemia progressed, there were a significant increase in UL bioimpedance and a significant decrease in LL bioimpedance. During recovery phases (where blood was shifted from the legs to the body), there were a significant increase in LL bioimpedance and a reduction in UL bioimpedance. There were significant correlations between estimated blood loss from LBNP model with UL (R = 0.97) and LL bioimpedance (R = - 0.97)., Conclusion: During LBNP-induced hypovolemia, there were reciprocal changes in UL&LL bioimpedance. These changes reflected hemodynamic compensatory mechanisms to hypovolemia., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

To compare the construct validity and between-day reliability of projection pursuit regression (PPR) from oscillatory lower body negative pressure (OLBNP) and squat-stand maneuvers (SSMs). Nineteen participants completed 5 min of OLBNP and SSMs at driven frequencies of 0.05 and 0.10 Hz across two visits. Autoregulatory plateaus were derived at both point-estimates and across the cardiac cycle. Between-day reliability was assessed with intraclass correlation coefficients (ICCs), Bland-Altman plots with 95% limits of agreement (LOA), coefficient of variation (CoV), and smallest real differences. Construct validity between OLBNP-SSMs were quantified with Bland-Altman plots and Cohen's d. The expected autoregulatory curve with positive rising and negative falling slopes were present in only ~23% of the data. The between-day reliability for the ICCs were poor-to-good with the CoV estimates ranging from ~50% to 70%. The 95% LOA were very wide with an average spread of ~450% for OLBNP and ~350% for SSMs. Plateaus were larger from SSMs compared to OLBNPs (moderate-to-large effect sizes). The cerebral pressure-flow relationship is a complex regulatory process, and the "black-box" nature of this system can make it challenging to quantify. The current data reveals PPR analysis does not always elicit a clear-cut central plateau with distinctive rising/falling slopes., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objective. To evaluate sex differences in the reliability of absolute and relative cerebral blood velocity (CBv) during concurrent supine cycling with lower body negative pressure (LBNP). Approach . A total of 19 participants (11 females; aged 20-33 years) completed five testing sessions, occurring on 7 d intervals. Visit 1 was a maximal-ramp-cycle test to ascertain peak CBv wattage. During visits 2-5, supine cycling protocol occurred at individualized peak CBv wattages with progressive decreases in LBNP from 0 to -20, -40, -60, -70, and -80 Torr. Menstrual cycle day was self-reported via the Rhinessa Women's Questionnaire. Transcranial Doppler ultrasound insonated bilateral middle cerebral artery velocity (MCAv). Two-way ANOVA assessed potential day- and sex-differences at each LBNP stage. Reliability was determined using intraclass correlation coefficients (ICC) and coefficient of variation (CoV). Main results . For all physiological measures, no main-effects were present for day- or interaction-terms ( p > 0.067; negligible-to-small effect sizes), while sex differences were noted for MCAv, blood pressure, and heart rate ( p < 0.046). Across visits, males and females displayed excellent and good-to-excellent levels of reliability for MCAv metrics, respectively (ICC range: 0.745-0.999; CoV range: 0.33%-9.90%). Significance . During the current investigation, both relative and absolute CBv demonstrated high reliability in both male and female participants during a supine LBNP cycling protocol. An exploratory analysis revealed increased variance was found in female participants dependent on contraceptive use. Despite this, results indicate future LBNP studies may include females at any menstrual cycle stage., (Creative Commons Attribution license.)

Introduction . The effect of concurrent head-up tilt and lower body negative pressure (LBNP) have been examined on middle cerebral artery velocity (MCAv) at rest; however, it is unknown the superimposed effect these factors have on blunting the elevation in cerebral blood velocity associated with moderate-intensity exercise. Methods . 23 healthy adults (11 females / 12 males, 20-33 years) completed three visits. The first consisted of a maximal ramp supine cycling test to identify the wattage associated with individualized maximal MCAv. Subsequent visits included randomized no LBNP (control) or LBNP at -40 Torr (experimental) with successively increasing head-up tilt stages of 0, 15, 30, and 45 degrees during the pre-described individualized wattage. Transcranial Doppler ultrasound was utilized to quantify MCAv. Two-factorial repeated measures analysis of variance with effect sizes were used to determine differences between days and tilt stages. Results . Between-day baseline values for MCAv, heart rate, and blood pressure displayed low variability with <5% variation. With no LBNP, MCAv was above baseline on average for all participants; however, 15 degrees and 30 degrees tilt with concurrent -40 Torr LBNP was sufficient to return MCAv to 100% of baseline values in females and males, respectively. Body-weight did not impact the association between tilt and pressure ( R 2 range: 0.01-0.12). Conclusion . Combined LBNP and tilt were sufficient to reduce the increase in MCAv associated with moderate-intensity exercise. This exercise modality shows utility to enable individuals with a concussion to obtain the positive physiological adaptions associated with exercise while minimizing symptom exacerbation due to the notion of the Monro-Kellie doctrine., (Creative Commons Attribution license.)

Moderate-intensity aerobic exercise increases cerebral blood velocity (CBv) primarily due to hyperpnea-induced vasodilation; however, the integrative control of cerebral blood flow (CBF) allows other factors to contribute to the vasodilation. Although lower body negative pressure (LBNP) can reduce CBv, the exact LBNP intensity required to blunt the aforementioned exercise-induced CBv response is unknown. This could hold utility for concussion recovery, allowing individuals to exercise at higher intensities without symptom exacerbation. Thirty-two healthy adults (age: 20-33 yr; 19 females/13 males) completed a stepwise maximal exercise test during a first visit to determine each participant's wattage associated with their exercise-induced maximal CBv increase. During the second visit, following supine rest, participants completed moderate-intensity exercise at their determined threshold, while progressive LBNP was applied at 0, -20, -40, -60, -70, -80, and ∼88 Torr. Bilateral middle cerebral artery blood velocities (MCAvs), mean arterial pressure (MAP), heart rate, respiratory rate, and end-tidal carbon dioxide levels were measured continuously. Two-way analysis of variance with effect sizes compared between sexes and stages. Compared with resting supine baseline, averaged MCAv was elevated during 0 and -20 Torr LBNP ( q value > 7.73; P < 0.001); however, no differences were noted between baseline and -40 to -70 Torr ( q value < |4.24|; P > 0.262). Differences were present between females and males for absolute MCAv measures ( q value > 11.2; P < 0.001), but not when normalized to baseline ( q value < 0.03; P > 0.951). Supine cycling-elicited increases in MCAv are able to be blunted during the application of LBNP ranging from -40 to -70 Torr. The blunted CBv response demonstrates the potential benefit of allowing individuals to aerobically train (moderate-intensity supine cycling with LBNP) without exacerbating symptoms during the concussion recovery phase. NEW & NOTEWORTHY The current investigation demonstrated that moderate-intensity supine cycling-induced increases in cerebral blood velocities were balanced by the lower body negative pressure-induced decreases in cerebral blood velocity. Although performed in a healthy population, the results may lend themselves to a potential treatment option for individuals recovering from concussion or experience persistent concussion symptoms.

Objective . To study the photoplethysmographic (PPG) waveforms of different locations (ear and finger) during lower body negative pressure (LBNP) induced hypovolemia. Then, to determine whether the PPG waveform can be used to detect hypovolemia during the early stage of LBNP. Approach . 36 healthy volunteers were recruited for progressive LBNP induced hypovolemia, with an endpoint of -60 mmHg or development of hypoperfusion symptoms, whichever comes first. Subjects tolerating the entire protocol without symptoms were designated as high tolerance (HT), while symptomatic subjects were designated as low tolerance (LT). Subjects were monitored with an electrocardiogram, continuous noninvasive blood pressure monitor, and two pulse oximetry probes, one on the ear (Xhale) and one the finger (Nellcor). Stroke volume was measured non-invasively utilizing Non-Invasive Cardiac Output Monitor (NICOM, Cheetah Medical). The waveform morphology was analyzed using novel PPG waveforms indices, including phase hemodynamic index (PHI) and amplitude hemodyamaic index and were evaluated from the ear PPG and finger PPG at different LBNP stages. Main results . The PHI, particularly the phase relationship between the second harmonic and the fundamental component of the ear PPG denoted as∇φ2,during the early stage of LBNP (-15 mmHg) in the HT and LT groups is statistically significantly different ( p value = 0.0033) with the area under curve 0.81 (CI: 0.616-0.926). The other indices are not significantly different. The 5 fold cross validation shows that∇φ2during the early stage of LBNP (-15 mmHg) as the single index could predict the tolerance of the subject with the sensitivity, specificity, accuracy and F 1 as 0.771 ± 0.192, 0.71 ± 0.107, 0.7 ± 0.1 and 0.771 ± 0.192 respectively. Significance . The ear's PPG PHI which compares the phases of the fundamental and second harmonic has the potential to be used as an early predictor of central hypovolemia., (© 2023 Institute of Physics and Engineering in Medicine.)

Central hypovolemia is accompanied by hemodynamic compensatory responses. Understanding the complex systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia-as induced by standing up and/or lower body negative pressure (LBNP)-in humans are important. LBNP has been widely used to understand the integrated physiological responses, which occur during sit to stand tests (orthostasis), different levels of hemorrhages (different levels of LBNP simulate different amount of blood loss) as well as a countermeasure against the cephalad fluid shifts which are seen during spaceflight. Additionally, LBNP application (used singly or together with head up tilt, HUT) is useful in understanding the physiology of orthostatic intolerance. The role seasonal variations in hormonal, autonomic and circulatory state play in LBNP-induced hemodynamic responses and LBNP tolerance as well as sex-based differences during central hypovolemia and the adaptations to exercise training have been investigated using LBNP. The data generated from LBNP studies have been useful in developing better models for prediction of orthostatic tolerance and/or for developing countermeasures. This review examines how LBNP application influences coagulatory parameters and outlines the effects of temperature changes on LBNP responses. Finally, the review outlines how LBNP can be used as innovative teaching tool and for developing research capacities and interests of medical students and students from other disciplines such as mathematics and computational biology., (© 2022. The Author(s).)

The photoplethysmographic (PPG) waveform contains hemodynamic information in its oscillations. We provide a new method for quantitative study of the waveform morphology and its relationship to the hemodynamics. A data adaptive modeling of the waveform shape is used to describe the PPG waveforms recorded from ear and finger. Several indices, based on the phase and amplitude information of different harmonics, are proposed to describe the PPG morphology. The proposed approach is illustrated by analyzing PPG waveforms recorded during a lower body negative pressure (LBNP) experiment. Different phase and amplitude dynamics are observed during the LBNP experiment. Specifically, we observe that the phase difference between the high order harmonics and fundamental components change more significantly when the PPG signal is recorded from the ear than the finger at the beginning of the study. In contrast, the finger PPG amplitude changes more when compared to the ear PPG during the recovery period. A more complete harmonic analysis of the PPG appears to provide new hemodynamic information when used during a LBNP experiment. We encourage other investigators who possess modulated clinical waveform data (e.g. PPG, arterial pressure, respiratory, and autonomic) to re-examine their data, using phase information and higher harmonics as a potential source of new insights into underlying physiologic mechanisms., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: 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., Materials and Methods: System's functionality assessment was conducted on eight male subjects (26 ± 4 years, normotensive and no history of cardiovascular risks) by perturbing pressure via short-term moderate lower body negative pressure (LBNP) intervention (-40 mmHg for 1 min). The ability of the system to capture dynamic responses of carotid pressure to LBNP was investigated and compared against the responses of peripheral pressure measured using a continuous BP monitor., Results: While 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 ( p  < .0001)., Conclusions: 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.

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., Level of Evidence: Diagnostic test or criteria; Level III., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Based on previous experiments in nonhuman primates, we hypothesized that DO 2 crit in humans is 5-6 ml O 2 ·kg -1  min -1 ., Study Design and Methods: We measured the compensatory reserve (CRM) and calculated oxygen delivery (DO 2 ) in 166 healthy, normotensive, nonsmoking subjects (97 males, 69 females) during progressive central hypovolemia induced by lower body negative pressure as a model of ongoing hemorrhage. Subjects were classified as having either high tolerance (HT; N = 111) or low tolerance (LT; N = 55) to central hypovolemia., Results: HT and LT groups were matched for age, weight, BMI, and vital signs, DO 2 and CRM at baseline. The CRM-DO 2 relationship was best fitted to a logarithmic model in HT subjects (amalgamated R 2  = 0.971) and a second-order polynomial model in the LT group (amalgamated R 2  = 0.991). Average DO 2 crit for the entire subject cohort was estimated at 5.3 ml O 2 ·kg -1  min -1 , but was ~14% lower in HT compared with LT subjects. The reduction in DO 2 from 40% CRM to 20% CRM was 2-fold greater in the LT compared with the HT group., Conclusions: Average DO 2 crit in humans is 5.3 ml O 2 ·kg -1  min -1 , but is ~14% lower in HT compared with LT subjects. The CRM-DO 2 relationship is curvilinear in humans, and different when comparing HT and LT individuals. The threshold for an emergent monitoring signal should be recalibrated from 30% to 40% CRM given that the decline in DO 2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM-DO 2 relationship., (© 2022 AABB. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during β-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I ) cranial, 10 cm below xiphoid process; II ) medial, half-way between cranial and caudal; III ) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank-Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume ( V 0 ), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.0 , which induces negative LV pressures and increases LV suction. Accordingly, LBNP-induced central hypovolemia is associated with increased DS. NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.

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., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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.

Head-up tilt (HUT)-induced gravitational stress causes collapse of the internal jugular vein (IJV) by decreasing central blood volume and through mass-effect from the surrounding tissues. Besides HUT, lower body negative pressure (LBNP) is used to stimulate orthostatic stress as an experimental model. Compared to HUT, LBNP has less of a gravitational effect because of the supine position; therefore, we hypothesized that LBNP causes less of a decrease in the cross-sectional area of the IJV compared to HUT. We tested the hypothesis by measuring the cross-sectional area of the IJV using B-mode ultrasonography while inducing orthostatic stress at levels of -40 mmHg LBNP and 60° HUT. The cross-sectional area of IJV decreased from the resting baseline during both LBNP and HUT trials, but the LBNP-induced decrease in the cross-sectional area of IJV was smaller than that of HUT (right, -45% ± 49% vs. -78% ± 27%, p = 0.008; left, -49% ± 27% vs. -78% ± 20%, p = 0.004). Since changes in venous outflow may affect cerebral arterial circulation, the findings of the present study suggest that orthostatic stress induced by different techniques modulates cerebral blood flow regulation through its effect on venous outflow., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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.

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 ± 15 mL, JVA: 0.56 ± 0.10 a.u.) to -40 mmHg suction (SV: 59 ± 18 mL, JVA: 0.47 ± 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.

Aim: To use a locally designed and simple lower-body negative-pressure (LBNP) device and 1.5 T magnetic resonance imaging (MRI) to demonstrate the ability to assess changes in cardiovascular function during preload reduction. These effects were evaluated on ventricular volumes and great vessel flow in healthy volunteers, for which there are limited published data., Material and Methods: After ethical review, 14 volunteers (mean age 33.9 ± 7 years, mean body mass index [BMI] 23.1 ± 2.5) underwent LBNP prospectively at 0, -5, -10, and -20 mmHg pressure, using a locally designed LBNP box. Expiratory breath-hold biventricular volumes, and free-breathing flow imaging of the ascending aorta and main pulmonary artery were acquired at each level of LBNP., Results: At -5 mmHg, there was no change in aortic flow or left ventricular volumes versus baseline. Right ventricular output (p=0.013) and pulmonary net flow (p=0.026) decreased. At -20 mmHg, aortic and pulmonary net flow (p<0.001) decreased, as were left and right ventricular end diastolic volume (p<0.001) and left and right end systolic volumes (p=0.038 and p=0.003 respectively)., Conclusions: Use of a MRI-compatible LBNP device is feasible to measure changes in ventricular volume and great arterial flow in the same experiment. This may enhance further research into the effects of preload reduction by MRI in a wide range of important cardiovascular pathologies., (Copyright © 2021. Published by Elsevier Ltd.)

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.

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.

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.

Whilst both cardiac output (CO) and total peripheral resistance (TPR) determine mean arterial blood pressure (MAP), their relative importance in the pressor response to isometric exercise remains unclear. This study aimed to elucidate the relative importance of these two different factors by examining pressor responses during cardiopulmonary unloading leading to step-wise reductions in CO. Hemodynamics were investigated in 11 healthy individuals before, during and after two-minute isometric exercise during lower body negative pressure (LBNP; -20mmHg and -40mmHg). The blood pressure response to isometric exercise was similar during normal and reduced preload, despite a step-wise reduction in CO during LBNP (-20mmHg and -40mmHg). During -20mmHg LBNP, the decreased stroke volume, and consequently CO, was counteracted by an increased TPR, while heart rate (HR) was unaffected. HR was increased during -40 mmHg LBNP, although insufficient to maintain CO; the drop in CO was perfectly compensated by an increased TPR to maintain MAP. Likewise, transient application of LBNP (-20mmHg and -40mmHg) resulted in a short transient drop in MAP, caused by a decrease in CO, which was compensated by an increase in TPR. This study suggests that, in case of reductions of CO, changes in TPR are primarily responsible for maintaining the pressor response during isometric exercise. This highlights the relative importance of TPR compared to CO in mediating the pressor response during isometric exercise., Competing Interests: The authors have declared that no competing interests exist.

Key Points: Rapid alterations of gravitational stress during high-performance aircraft push-pull manoeuvres induce dramatic shifts in volume and pressure within the circulation system, which may result in loss of consciousness due to the rapid and significant reduction in cerebral perfusion. There are still no specific and effective countermeasures so far. We found that lower body negative pressure (LBNP), applied prior to and during -Gz and released at the subsequent transition to +Gz, could effectively counteract gravitational haemodynamic stress induced by a simulated push-pull manoeuvre and improve cerebral diastolic perfusion in human subjects. We developed a LBNP strategy that effectively protects cerebral perfusion at rapid -Gz to +Gz transitions via improving cerebral blood flow and blood pressure during push-pull manoeuvres and highlight the importance of the timing of the intervention. Our findings provide a systemic link of integrated responses between the peripheral and cerebral haemodynamic changes during push-pull manoeuvres., Abstract: The acute negative (-Gz) to positive (+Gz) gravity stress during high-performance aircraft push-pull manoeuvres dramatically reduces transient cerebral perfusion, which may lead to loss of vision or even consciousness. The aim of this study was to explore a specific and effective counteractive strategy. Twenty-three healthy young male volunteers (age 21 ± 1 year) were subjected to tilting-simulated push-pull manoeuvres. Lower body negative pressure (LBNP) of -40 mmHg was applied prior to and during -Gz stress (-0.50 or -0.87 Gz) and released at the subsequent transition to +1.00 Gz stress. Beat-to-beat cerebral and systemic haemodynamics were continuously recorded during the simulated push-pull manoeuvre in LBNP bouts and corresponding control bouts. During the rapid gravitational transition from -Gz to +Gz, the mean cerebral blood flow velocity decreased significantly in control bouts, while it increased in LBNP bouts (control vs. LBNP bouts, -6.6 ± 4.6 vs. 5.1 ± 6.8 cm s -1 for -0.50 Gz, and -7.4 ± 4.8 vs. 3.4 ± 4.6 cm s -1 for -0.87 Gz, P < 0.01), which was attributed mainly to the elevation of diastolic flow. The LBNP bouts showed much smaller reduction of mean arterial blood pressure at the brain level than control bouts (control bouts vs. LBNP bouts, -38 ± 12 vs. -23 ± 10 mmHg for -0.50 to +1.00 Gz, and -62 ± 16 vs. -43 ± 11 mmHg for -0.87 to +1.00 Gz, P < 0.01). LBNP applied at -Gz and released at subsequent +Gz had biphasic counteractive effects against the gravitational responses to the push-pull manoeuvre. These data demonstrate that this LBNP strategy could effectively protect cerebral perfusion with dominant improvement of diastolic flow during push-pull manoeuvres., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

We hypothesised that vagal withdrawal and increased venous return interact in determining the rapid cardiac output (CO) response (phase I) at exercise onset. We used lower body negative pressure (LBNP) to increase blood distribution to the heart by muscle pump action and reduce resting vagal activity. We expected a larger increase in stroke volume (SV) and smaller for heart rate (HR) at progressively stronger LBNP levels, therefore CO response would remain unchanged. To this aim ten young, healthy males performed a 50 W exercise in supine position at 0 (Control), -15, -30 and -45 mmHg LBNP exposure. On single beat basis, we measured HR, SV, and CO. Oxygen uptake was measured breath-by-breath. Phase I response amplitudes were obtained applying an exponential model. LBNP increased SV response amplitude threefold from Control to -45 mmHg. HR response amplitude tended to decrease and prevented changes in CO response. The rapid response of CO explained that of oxygen uptake. The rapid SV kinetics at exercise onset is compatible with an increased venous return, whereas the vagal withdrawal conjecture cannot be dismissed for HR. The rapid CO response may indeed be the result of two independent yet parallel mechanisms, one acting on SV, the other on HR., Competing Interests: The authors declare no conflict of interest., (Eigentümer und Copyright ©Georg Thieme Verlag KG 2018.)

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.

Background: End stage renal disease (ESRD) is characterized by autonomic dysfunction. During orthostatic stress, sympathetic (SNS) activity increases and parasympathetic (PNS) activity decreases to maintain arterial blood pressure (BP). We hypothesized that ESRD patients have impaired ability to adjust cardiac SNS and PNS activity during orthostasis, which could contribute to increased blood pressure variability, orthostatic intolerance and falls., Methods: We measured beat-to-beat BP and Electrocardiography at baseline and during increasing lower body negative pressure (LBNP) in 20 ESRD patients and 18 matched controls (CON). Heart rate variability was quantified as total power (TP) and standard deviation of the N-N interval, reflecting both SNS and PNS; high frequency (HF), root mean square of successive differences of neighboring N-N intervals (RMSSD), and percent of consecutive N-N intervals differing >50 milliseconds (pNN50), reflecting cardiac PNS activity; and low frequency (LF) and LF/HF, reflecting sympoathovagal balance. BP variability was quantified as the standard deviation in systolic (SDSAP) and diastolic (SDDAP) BP., Results: Baseline HF, RMSSD, and pNN50 were significantly lower in ESRD (P < 0.05). While CON had a significant decrease in HF (P = 0.015), RMSSD (P = 0.003), and pNN50 (P = 0.005) during LBNP, there was no change in heart rate variability in ESRD. There was no significant difference in BP response, but ESRD had a significantly blunted heart rate response during graded LBNP compared to controls (P < 0.001). There was no significant difference in SDSAP or SDDAP during LBNP between groups (P > 0.05)., Conclusions: These data suggest that ESRD patients have impaired autonomic adjustments to orthostatic stress., (Copyright © 2019. Published by Elsevier Inc.)

The early detection of occult bleeding is a difficult problem for clinicians because physiological variables such as heart rate and blood pressure that are measured with standard patient monitoring equipment are insensitive to blood loss. In this study, the pulse arrival time (PAT) was investigated as an easily recorded, non-invasive indicator of hypovolemia. A lower body negative pressure (LBNP) study with a stepwise increase of negative pressure was conducted to induce central hypovolemia in a study population of 30 subjects. PAT values were extracted from simultaneous recordings of the electrocardiogram (ECG) and photoplethysmographic (PPG) recordings both from the index finger and from within the outer ear canal. Stroke volume (SV) was recorded as a reference measure by transthoracic echocardiography. An inter- and intra-individual correlation analysis between changes in SV and the PAT measurements was performed. Furthermore, it was assessed if PAT measurements can indicate a diminished SV in this scenario. It could be demonstrated that the measured PAT values are significantly increased at the lowest LBNP pressure level. A very strong intra-individual correlation (ρ ≥ 0.8) and a moderate inter-individual correlation (ρ ≥ 0.5) between PAT and SV measurements were found. Thus, PAT measurements could be a viable tool to monitor patient specific volemic trends. Further research is needed to investigate if PAT information can be utilized for a more robust inter-subject quantification of the degree of hypovolemia.

We propose a Deep Convolutional Neural Network (CNN) architecture for computing a Compensatory Reserve Metric (CRM) for trauma victims suffering from hypovolemia (decreased circulating blood volume). The CRM is a single health indicator value that ranges from 100% for healthy individuals, down to 0% at hemodynamic decompensation - when the body can no longer compensate for blood loss. The CNN is trained on 20 second blood pressure waveform segments obtained from a finger-cuff monitor of 194 subjects. The model accurately predicts CRM when tested on data from 22 additional human subjects obtained from Lower Body Negative Pressure (LBNP) emulation of hemorrhage, attaining a mean squared error (MSE) of 0.0238 over the full range of values, including those from subjects with both low and high tolerance to central hypovolemia.

Purpose: The role of the autonomic nervous system in the genesis of atrial fibrillation (AF) has been well studied; however, the converse remains poorly understood. Pulmonary veins (PV) contain receptors important in cardiac reflexes. Here, we evaluated reflex responses in patients with paroxysmal AF (PAF) to lower body negative pressure (LBNP)., Methods: Thirty-four PAF patients (including 14 PAF patients post successful PV Isolation; PVI) were compared to 14 age and sex-matched controls. Mean arterial pressure (MAP), heart rate (HR), systemic vascular resistance index (SVRI), cardiac index (CI), and stroke volume index (SVI) were measured continuously during - 0, - 20, and - 40 mmHg LBNP. LBNP reduces venous return, deactivating atrial receptors, thereby eliciting a reflex increase in SVRI to maintain MAP., Results: AF patients have higher BMI than the controls (p = 0.02). In control subjects, LBNP did not alter MAP as SVRI increased. In PAF patients, LBNP resulted in a reduction in MAP (- 4.8%) with attenuated SVRI response (+ 4.2%) compared to controls (p < 0.05). However, in the post-PVI group, SVRI increase was similar to controls (p = 0.12) although that was insufficient to maintain MAP. In all patients, both reduction in SVI and CI and increase in HR were similar in response to LBNP., Conclusions: This study provides novel clinical evidence of autonomic dysfunction in PAF patients. Successful PVI results in partial recovery of the cardiac reflex. Therefore, not only does autonomic disturbance predispose to AF but it is also a consequence of AF; potentially contributing to disease progression. This could help explain the dictum "AF begets AF."

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 F 2 -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.

Cerebral Autoregulation (CA), defined as the ability of the cerebral vasculature to maintain stable levels of blood flow despite changes in systemic blood pressure, is a critical factor in neurophysiological health. Magnetic resonance imaging (MRI) is a powerful technique for investigating cerebrovascular function, offering high spatial resolution and wide fields of view (FOV), yet it is relatively underutilized as a tool for assessment of CA. The aim of this study was to demonstrate the potential of using MRI to measure changes in cerebrovascular resistance in response to lower body negative pressure (LBNP). A Pulsed Arterial Spin Labeling (PASL) approach with short inversion times (TI) was used to estimate cerebral arterial blood volume (CBV a ) in eight healthy subjects at baseline and -40mmHg LBNP. We estimated group mean CBV a values of 3.13 ± 1.00 and 2.70 ± 0.38 for baseline and lbnp respectively, which were the result of a differential change in CBV a during -40mmHg LBNP that was dependent on baseline CBV a . These data suggest that the PASL CBV a estimates are sensitive to the complex cerebrovascular response that occurs during the moderate orthostatic challenge delivered by LBNP, which we speculatively propose may involve differential changes in vascular tone within different segments of the arterial vasculature. These novel data provide invaluable insight into the mechanisms that regulate perfusion of the brain, and establishes the use of MRI as a tool for studying CA in more detail., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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 < 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., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

We investigated whether small reductions in skin temperature 60 s after the onset of a simulated hemorrhagic challenge would improve tolerance to lower body negative pressure (LBNP) after exercise heat stress. Eleven healthy subjects completed two trials (High and Reduced). Subjects cycled at ~55% maximal oxygen uptake wearing a warm water-perfused suit until core temperatures increased by ~1.2°C before lying supine and undergoing LBNP to presyncope. LBNP tolerance was quantified as cumulative stress index (CSI; product of each LBNP level multiplied by time; mmHg·min). Skin temperature was similarly elevated from baseline before LBNP and remained elevated 60 s after the onset of LBNP in both High (37.72 ± 0.52°C) and Reduced (37.95 ± 0.54°C) trials (both P < 0.0001). At 60%CSI skin temperature remained elevated in the High trial (37.51 ± 0.56°C) but was reduced to 34.97 ± 0.72°C by the water-perfused suit in the Reduced trial ( P < 0.0001 between trials). Cutaneous vascular conductance was not different between trials [High: 1.57 ± 0.43 vs. Reduced: 1.39 ± 0.38 arbitrary units (AU)/mmHg; P = 0.367] before LBNP but decreased to 0.67 ± 0.19 AU/mmHg at 60%CSI in the Reduced trial while remaining unchanged in the High trial ( P = 0.002 between trials). CSI was higher in the Reduced (695 ± 386 mmHg·min) relative to the High (441 ± 290 mmHg·min; P = 0.023) trial. Mean arterial pressure was not different between trials at presyncope (High: 62 ± 10 vs. Reduced: 62 ± 9 mmHg; P = 0.958). Small reductions in skin temperature after the onset of a simulated hemorrhagic challenge improve LBNP tolerance after exercise heat stress. This may have important implications regarding treatment of an exercise heat-stressed individual (e.g., soldier) who has experienced a hemorrhagic injury.

Recent investigations have challenged the reliability of estimating sympathetic autonomic outflow from heart rate variability (HRV) analysis. Towards overcoming this long-lasting challenge, in this study we propose a new formulation for the assessment of autonomic nervous system activity on the heart based on two separate indices: the Sympathetic Activity Index (SAI) and the Parasympathetic Activity Index (PAI). Specifically, considering the RR interval series as an input, we properly combine the output of orthonormal Laguerre filters to disentangle the overlapping contribution of sympathetic and parasympathetic activities on HRV spectra. Adaptive Kalman predictions account for a time-varying SAI and PAI estimation from exemplary data gathered from 35 healthy subjects under-going a lower-body negative pressure (LBNP) protocol. Results show a defined characteristic increase (reduction) of the SAI (PAI) dynamics during LBNP with respect to the resting state condition, demonstrating the reliability of the proposed measures for a non-invasive autonomic assessment in the healthy without the need of individual model calibration. Comparison with standard HRV metrics defined in the frequency domain, as well as prospective endeavours for cardiovascular assessments in pathological states, are also discussed.

Lower body negative pressure (LBNP) is a method derived from space medicine, which in recent years has been increasingly used by clinicians to assess the efficiency of the cardiovascular regulatory mechanisms. LBNP with combined tilt testing is considered as an effective form of training to prevent orthostatic intolerance. We have developed a prototype system comprising a tilt table and LBNP chamber, and tested it in the context of the feasibility of the device for assessing the pilots' efficiency. The table allows for controlled tilting in the range from -45 to +80° at the maximum change rate of 45°/s. The LBNP value can smoothly be adjusted down to -100 mmHg at up to 20 mmHg/s. 17 subjects took part in the pilot study. A 24-minute scenario included -100 mmHg supine LBNP, head up tilt (HUT) and -60 mmHg LBNP associated with HUT, separated by resting phases. The most noticeable changes were observed in stroke volume (SV). During supine LBNP, HUT and the combined stimulus, a decrease of the SV value by 20%, 40% and below 50%, respectively, were detected. The proposed system can map any pre-programed tilt and LBNP profiles, and the pilot study confirmed the efficiency of performing experimental procedures.

The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. We tested the hypothesis that acute hypoxemia during simulated blood loss in humans would cause impairments in cerebral blood flow control. Ten healthy subjects (32 ± 6 years, BMI 27 ± 2 kg·m -2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 min at 0, -15, -30, and -45 mmHg) during both normoxia and hypoxia (F i O 2  = 0.12-0.15 O 2 titrated to an SaO 2 of ~85%). Physiological responses during both protocols were expressed as absolute changes from baseline, one subject was excluded from analysis due to presyncope during the first stage of LBNP during hypoxia. LBNP induced greater reductions in mean arterial pressure during hypoxia versus normoxia (MAP, at -45 mmHg: -20 ± 3 vs. -5 ± 3 mmHg, P < 0.01). Despite differences in MAP, middle cerebral artery velocity responses (MCAv) were similar between protocols (P = 0.41) due to increased cerebrovascular conductance index (CVCi) during hypoxia (main effect, P = 0.04). Low frequency MAP (at -45 mmHg: 17 ± 5 vs. 0 ± 5 mmHg 2 , P = 0.01) and MCAv (at -45 mmHg: 4 ± 2 vs. -1 ± 1 cm·s -2 , P = 0.04) spectral power density, as well as low frequency MAP-mean MCAv transfer function gain (at -30 mmHg: 0.09 ± 0.06 vs. -0.07 ± 0.06 cm·s -1 ·mmHg -1 , P = 0.04) increased more during hypoxia versus normoxia. Contrary to our hypothesis, these findings support the notion that cerebral blood flow control is not impaired during exposure to acute hypoxia and progressive central hypovolemia despite lower MAP as a result of compensated increases in cerebral conductance and flow variability., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The microgravity ocular syndrome (MOS) results in significant structural and functional ophthalmic changes during 6-mo spaceflight missions consistent with an increase in cerebrospinal fluid (CSF) pressure compared with the preflight upright position. A ground-based study was performed to assess two of the major hypothesized contributors to MOS, headward fluid shifting and increased ambient CO 2 , on intracranial and periorbital CSF. In addition, lower body negative pressure (LBNP) was assessed as a countermeasure to headward fluid shifting. Nine healthy male subjects participated in a crossover design study with five head-down tilt (HDT) conditions: -6, -12, and -18° HDT, -12° HDT with -20 mmHg LBNP, and -12° HDT with a 1% CO 2 environment, each for 5 h total. A three-dimensional volumetric scan of the cranium and transverse slices of the orbita were collected with MRI, and intracranial CSF volume and optic nerve sheath diameter (ONSD) were measured after 4.5 h HDT. ONSD increased during -6° ( P < 0.001), -12° ( P < 0.001), and -18° HDT ( P < 0.001) and intracranial CSF increased during -12° HDT ( P = 0.01) compared with supine baseline. Notably, LBNP was able to reduce the increases in ONSD and intracranial CSF during HDT. The addition of 1% CO 2 during HDT, however, had no further effect on ONSD, but rather ONSD increased from baseline in a similar magnitude to -12° HDT with ambient air ( P = 0.001). These findings demonstrate the ability of LBNP, a technique that targets fluid distribution in the lower limbs, to directly influence CSF and may be a promising countermeasure to help reduce increases in CSF. NEW & NOTEWORTHY This is the first study to demonstrate the ability of lower body negative pressure to directly influence cerebrospinal fluid surrounding the optic nerve, indicating potential use as a countermeasure for increased cerebrospinal fluid on Earth or in space., (Copyright © 2017 the American Physiological Society.)

High cerebral pressure and flow fluctuations could be a risk for future cerebrovascular disease. This study aims to determine whether acute systemic vasoconstriction affects the dynamic pulsatile hemodynamic transmission from the aorta to the brain. We applied a stepwise lower body negative pressure (LBNP) (-10, -20, and -30 mmHg) in 15 young men to induce systemic vasoconstriction. To elucidate the dynamic relationship between the changes in aortic pressure (AoP; estimated from the radial arterial pressure waveforms) and the cerebral blood flow velocity (CBFV) at the middle cerebral artery (via a transcranial Doppler), frequency-domain analysis characterized the beat-to-beat slow oscillation (0.02-0.30 Hz) and the intra-beat rapid change (0.78-9.69 Hz). The systemic vascular resistance gradually and significantly increased throughout the LBNP protocol. In the low-frequency range (LF: 0.07-0.20 Hz) of a slow oscillation, the normalized transfer function gain of the steady-state component (between mean AoP and mean CBFV) remained unchanged, whereas that of the pulsatile component (between pulsatile AoP and pulsatile CBFV) was significantly augmented during -20 and -30 mmHg of LBNP (+28.8% and +32.4% vs. baseline). Furthermore, the relative change in the normalized transfer function gain of the pulsatile component at the LF range correlated with the corresponding change in systemic vascular resistance ( r  = 0.41, P = 0.005). Regarding the intra-beat analysis, the normalized transfer function gain from AoP to CBFV was not significantly affected by the LBNP stimulation ( P = 0.77). Our findings suggest that systemic vasoconstriction deteriorates the dampening effect on the pulsatile hemodynamics toward the brain, particularly in slow oscillations (e.g., 0.07-0.20 Hz). NEW & NOTEWORTHY We characterized the pulsatile hemodynamic transmission from the heart to the brain by frequency-domain analysis. The low-frequency transmission was augmented with a mild LBNP stimulation partly due to the elevated systemic vascular resistance. A systemic vasoconstriction deteriorates the dampening effect on slow oscillations of pulsatile hemodynamics toward the brain., (Copyright © 2017 the American Physiological Society.)