Lower Body Negative Pressure Protocol Research Articles

The correlation between carotid artery Doppler and stroke volume during central blood volume loss and resuscitation.

Using peripheral arteries to infer central hemodynamics is common among hemodynamic monitors. Doppler ultrasound of the common carotid artery has been used in this manner with conflicting results. We investigated the relationship between changing common carotid artery Doppler measures and stroke volume (SV), hypothesizing that more consecutively-averaged cardiac cycles would improve SV-carotid Doppler correlation. Twenty-seven healthy volunteers were recruited and studied in a physiology laboratory. Carotid artery Doppler pulse was measured with a wearable, wireless ultrasound during central hypovolemia and resuscitation induced by a stepped lower body negative pressure protocol. The change in maximum velocity time integral (VTI) and corrected flow time of the carotid artery (ccFT) were compared with changing SV using repeated measures correlation. In total, 73,431 cardiac cycles were compared across 27 subjects. There was a strong linear correlation between changing SV and carotid Doppler measures during simulated hemorrhage (repeated-measures linear correlation [Rrm ]=0.91 for VTI; 0.88 for ccFT). This relationship improved with larger numbers of consecutively-averaged cardiac cycles. For ccFT, beyond four consecutively-averaged cardiac cycles the correlation coefficient remained strong (i.e., Rrm of at least 0.80). For VTI, the correlation coefficient with SV was strong for any number of averaged cardiac cycles. For both ccFT and VTI, Rrm remained stable around 25 consecutively-averaged cardiac cycles. There was a strong linear correlation between changing SV and carotid Doppler measures during central blood volume loss. The strength of this relationship was dependent upon the number of consecutively-averaged cardiac cycles.

Sex Variations in Retinal Microcirculation Response to Lower Body Negative Pressure.

Lower body negative pressure (LBNP) is routinely used to induce central hypovolemia. LBNP leads to a shift in blood to the lower extremities. While the effects of LBNP on physiological responses and large arteries have been widely reported, there is almost no literature regarding how these cephalad fluid shifts affect the microvasculature. The present study evaluated the changes in retinal microcirculation parameters induced by LBNP in both males and females. Forty-four participants were recruited for the present study. The retinal measurements were performed at six time points during the LBNP protocol. To prevent the development of cardiovascular collapse (syncope) in the healthy participants, graded LBNP until a maximum of -40 mmHg was applied. A non-mydriatic, hand-held Optomed Aurora retinal camera was used to capture the retinal images. MONA Reva software (version 2.1.1) was used to analyze the central retinal arterial and venous diameter changes during the LBNP application. Repeated measures ANOVAs, including sex as the between-subjects factor and the grade of the LBNP as the within-subjects factor, were performed. No significant changes in retinal microcirculation were observed between the evaluated time points or across the sexes. Graded LBNP application did not lead to changes in the retinal microvasculature across the sexes. The present study is the first in the given area that attempted to capture the changes in retinal microcirculation caused by central hypovolemia during LBNP. However, further research is needed with higher LBNP levels, including those that can induce pre-fainting (presyncope), to fully understand how retinal microcirculation adapts during complete cardiovascular collapse (e.g., during hypovolemic shock) and/or during severe hemorrhage.

Non-invasive waveform analysis for emergency triage via simulated hemorrhage: An experimental study using novel dynamic lower body negative pressure model

The extent to which advanced waveform analysis of non-invasive physiological signals can diagnose levels of hypovolemia remains insufficiently explored. The present study explores the discriminative ability of a deep learning (DL) framework to classify levels of ongoing hypovolemia, simulated via novel dynamic lower body negative pressure (LBNP) model among healthy volunteers. We used a dynamic LBNP protocol as opposed to the traditional model, where LBNP is applied in a predictable step-wise, progressively descending manner. This dynamic LBNP version assists in circumventing the problem posed in terms of time dependency, as in real-life pre-hospital settings intravascular blood volume may fluctuate due to volume resuscitation. A supervised DL-based framework for ternary classification was realized by segmenting the underlying noninvasive signal and labeling segments with corresponding LBNP target levels. The proposed DL model with two inputs was trained with respective time–frequency representations extracted on waveform segments to classify each of them into blood volume loss: Class 1 (mild); Class 2 (moderate); or Class 3 (severe). At the outset, the latent space derived at the end of the DL model via late fusion among both inputs assists in enhanced classification performance. When evaluated in a 3-fold cross-validation setup with stratified subjects, the experimental findings demonstrated PPG to be a potential surrogate for variations in blood volume with average classification performance, AUROC: 0.8861, AUPRC: 0.8141, F1-score:72.16%, Sensitivity:79.06%, and Specificity:89.21%. Our proposed DL algorithm on PPG signal demonstrates the possibility to capture the complex interplay in physiological responses related to both bleeding and fluid resuscitation using this challenging LBNP setup.

Acute beetroot juice consumption does not alter cerebral autoregulation or cardiovagal baroreflex sensitivity during lower-body negative pressure in healthy adults.

Beetroot juice (BRJ) improves peripheral endothelial function and vascular compliance, likely due to increased nitric oxide bioavailability. It is unknown if BRJ alters cerebrovascular function and cardiovagal baroreflex control in healthy individuals. We tested the hypotheses that BRJ consumption improves cerebral autoregulation (CA) and cardiovagal baroreflex sensitivity (cBRS) during lower-body negative pressure (LBNP). Thirteen healthy adults (age: 26 ± 4 years; 5 women) performed oscillatory (O-LBNP) and static LBNP (S-LBNP) before (PRE) and 3 h after consuming 500 mL of BRJ (POST). Participants inhaled 3% CO2 (21% O2, 76% N2) during a 5 min baseline and throughout LBNP to attenuate reductions in end-tidal CO2 tension (PETCO2). O-LBNP was conducted at ∼0.02 Hz for six cycles (-70 mmHg), followed by a 3-min recovery before S-LBNP (-40 mmHg) for 7 min. Beat-to-beat middle cerebral artery blood velocity (MCAv) (transcranial Doppler) and blood pressure were continuously recorded. CA was assessed using transfer function analysis to calculate coherence, gain, and phase in the very-low-frequency (VLF; 0.020-0.070 Hz) and low-frequency bands (LF; 0.07-0.20 Hz). cBRS was calculated using the sequence method. Comparisons between POST vs. PRE are reported as mean ± SD. During O-LBNP, coherence VLF was greater at POST (0.55 ± 0.06 vs. 0.46 ± 0.08; P < 0.01), but phase VLF (P = 0.17) and gain VLF (P = 0.69) were not different. Coherence LF and phase LF were not different, but gain LF was lower at POST (1.03 ± 0.20 vs. 1.12 ± 0.30 cm/s/mmHg; P = 0.05). During S-LBNP, CA was not different in the VLF or LF bands (all P > 0.10). Up-cBRS and Down-cBRS were not different during both LBNP protocols. These preliminary data indicate that CA and cBRS during LBNP in healthy, young adults is largely unaffected by an acute bolus of BRJ.

The reciprocal relationship between cardiac baroreceptor sensitivity and cerebral autoregulation during simulated hemorrhage in humans.

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 -60mmHg LBNP stage, ≥20-min) or low tolerant (LT; did not complete -60mmHg 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.

Sympathetic transduction of blood pressure during graded lower body negative pressure

IntroductionCross‐sectional work has demonstrated that participants with high resting muscle sympathetic nerve activity (MSNA) have lower resting sympathetic transduction of blood pressure (BP), and a larger proportion of sympathetic bursts firing above the BP set‐point (or mean BP). However, to date, most of these observations have been evaluated between participants with different levels of resting MSNA. The objective of the current study is to evaluate the influence of acute elevations in MSNA on sympathetic transduction of BP in young healthy adults using graded lower body negative pressure (LBNP). We hypothesize that sympathetic transduction will decrease during acute elevations in MSNA due to an increased proportion of MSNA bursts firing above the BP set‐point.MethodsTen (1 female) young healthy participants underwent 8 minutes of quiet rest, followed by a graded LBNP protocol consisting of 8‐minute stages at ‐10, ‐20, and ‐30mmHg. Beat‐to‐beat heart rate and BP were quantified using single‐lead electrocardiography and finger photoplethysmography, respectively, while MSNA was quantified using fibular nerve microneurography. Sympathetic transduction was quantified in the time (signal‐averaging) and frequency (MSNA‐diastolic BP low frequency [LF: 0.04‐0.15 Hz] transfer function magnitude) domains. Tertiles of diastolic BP were determined for each participant, and the proportion of MSNA bursts firings within each BP tertile were quantified.ResultsMSNA burst frequency increased progressively during graded LBNP (from 15±7 to 17±7, 22±7, and 27±9 bursts/min; P&lt;0.01), while the proportion of MSNA bursts firing in the highest BP tertile remained stable (19±7, 18±9, 19±9, 19±7 %; P=0.72). Sympathetic transduction of BP was unchanged during LBNP (from 2.1±1.1 to 2.3±1.5, 2.1±1.2, and 2.0±1.1 mmHg; P=0.51), while the BP responses to non‐burst cardiac cycles decreased progressively (from ‐0.7±0.5 to ‐0.9±0.5, ‐1.0±0.4, and ‐1.4±0.7 mmHg; P&lt;0.01). The difference between burst and non‐burst cardiac cycles (from 2.8±1.4 to 3.2±1.9, 3.1±1.5, and 3.4±1.3 mmHg; P=0.26) and the MSNA‐diastolic BP transfer function magnitude (from 0.14±0.09 to 0.14±0.06, 0.14±0.06, and 0.13±0.07 au/mmHg; P=0.40) were also unchanged during LBNP. Lastly, the change in the proportion of MSNA bursts firing in the largest BP tertile was associated with the change in signal‐averaged sympathetic transduction across each stage of LBNP (r= ‐0.79, ‐0.78, ‐0.81; P≤0.01).ConclusionSympathetic transduction of diastolic BP is unchanged during graded LBNP due to the heterogenous inter‐individual responses in the gating of bursts to diastolic BP. The proportion of bursts firing at high BPs are associated with changes in sympathetic transduction of BP. The determinants of gating MSNA burst occurrence by the arterial baroreflex and its capacity for modulation warrant further study.

Lower blood pressure, but not muscle sympathetic nerve activity, in female compared to male adults during progressive central hypovolemia

INTRODUCTIONRapid adjustments in cardiac output and sympathetically‐mediated vasoconstriction are critical to prevent blood pressure (BP) from falling during central hypovolemia. Female adults have a reduced ability to tolerate central hypovolemia (i.e., orthostatic hypotension), potentially due to reduced sympathetically‐mediated vasoconstriction. However, there are minimal data evaluating sex differences in muscle sympathetic nerve activity (MSNA) during pre‐syncopal limited central hypovolemia. Therefore, the purpose of this study was to compare autonomic cardiovascular responses during central hypovolemia between sexes. We tested the hypothesis that young healthy female, compared to male, adults would have a lower tolerance to progressive hypovolemia, accompanied by attenuated MSNA responses.METHODSTwenty‐eight female (28±8 years old, 170±7 cm, 75±8 kg, BMI: 26±3 kg/m2) and 31 male (age: 30±5 years old, height: 176±6 cm, mass: 82±9 kg, BMI: 26±3 kg/m2) adults completed a staged lower‐body negative pressure (LBNP) protocol. The LBNP protocol started at minus 40 mmHg (LBNP40) and was further reduced by 10 mmHg every 3 minutes until the participant reached pre‐syncope. MSNA (radial nerve), heart rate, and BP were collected continuously throughout the protocol. LBNP tolerance was quantified as a cumulative stress index (mmHg*min) and was compared between sexes using a two‐tailed Mann‐Whitney test. MSNA, heart rate, and BP responses during LBNP were compared between sexes (LBNP stage [repeated measure] x sex) using mixed‐model analysis of variance tests.RESULTSConsistent with prior findings, female adults had a lower tolerance to progressive LBNP (female: 513±283 vs. male: 929±357 mmHg*min, p&lt;0.0001). Due to more females reaching pre‐syncope sooner in the protocol, we compared responses during the early stages of LBNP. At these early LBNP stages (LBNP40 &amp; LBNP50), significant interactions for heart rate and BP were observed (heart rate: p&lt;0.0001, BP: p=0.0464). Post‐hoc analyses revealed a significantly higher heart rate (98±20 vs. 82±15 bpm, p&lt;0.0001) and lower mean BP (80±11 vs. 87±7 mmHg, p = 0.0343) in females at LBNP50. However, MSNA burst frequency responses were not different between sexes at the assessed time points (female vs. male; Baseline: 14±9 vs. 17±10, LBNP40: 29±14 vs. 34±12, LBNP50: 34±16 vs. 35±16 bursts/min; sex: p=0.2685, interaction: p=0.2334, stage: p&lt;0.0001).DISCUSSIONConsistent with previous reports, this study demonstrated a lower tolerance to progressive central hypovolemia in female compared to male adults. However, contrary to our hypothesis, there was no difference in MSNA burst frequency between sexes, despite lower BP in female adults during the early stages of LBNP. These findings support the need for future studies to explore other mechanisms contributing to sex differences in tolerance to central hypovolemia.

The Doppler shock index measured by a wearable ultrasound patch accurately detects moderate-to-severe central hypovolemia during lower body negative pressure.

ObjectiveModerate‐to‐severe hemorrhage is a life‐threatening condition, which is challenging to detect in a timely fashion using traditional vital signs because of the human body's robust physiologic compensatory mechanisms. Measuring and trending blood flow could improve diagnosis of clinically significant exsanguination. A lightweight, wireless, wearable Doppler ultrasound patch that captures and trends blood flow velocity could enhance hemorrhage detection.MethodsIn 11 healthy volunteers undergoing simulated hemorrhage and resuscitation during graded lower body negative pressure (LBNP) and release, we studied the relationship between stroke volume (SV) and common carotid artery velocity time integral (VTI) and corrected flow time (FTc). We assessed the diagnostic accuracy of 2 variations of a novel metric, the Doppler shock index (ie, the DSIVTI and DSIFTc), at capturing moderate‐to‐severe central hypovolemia defined as a 30% reduction in SV. The DSIVTI and DSIFTc are calculated as the heart rate divided by either the VTI or FTc, respectively.ResultsA total of 17,822 cardiac cycles were analyzed across 22 LBNP protocols. The average SV reduction to the lowest tolerated LBNP stage was 40%; there was no clinically significant fall in the mean arterial pressure. Correlations between changing SV and the common carotid artery VTI and FTc were strong (R 2 of 0.87, respectively) and concordant. The DSIVTI and DSIFTc accurately detected moderate‐to‐severe central hypovolemia with values for the area under the receiver operator curves of 0.96 and 0.97, respectively.ConclusionIn a human model of hemorrhage and resuscitation, measures from a wearable Doppler ultrasound patch correlated strongly with SV and identified moderate‐to‐severe central hypovolemia with excellent diagnostic accuracy.

Impact of Sleep Quality on Cardiovascular Responses to Simulated Hemorrhage in Humans

Introduction Sleep is an important determinant of cardiovascular health. Poor sleep quality, including sleep restriction, is associated with impairments in cardiovascular function, and may limit cardiovascular responsiveness to physiological stress. As hemorrhage is one of the leading causes of preventable civilian death, and a major cause of death from trauma in the military, it is important to assess the impact of sleep quality on cardiovascular responses to this stress. We hypothesize that human subjects who report poor sleep quality will be less tolerant to simulated hemorrhage, which will be associated with lower arterial pressure and cerebral blood flow, and higher heart rates compared to subjects who report good sleep quality. Methods Healthy human subjects (10F; 10M) participated in a graded pre-syncopal lower body negative pressure (LBNP) protocol to simulate hemorrhage. Sleep quality was assessed pre-experiment using the Pittsburgh Sleep Quality Index (PSQI). Subjects were categorized in two groups: POOR sleep quality (Global PSQI score ≥ 5) or GOOD sleep quality (Global PSQI score < 5). Arterial pressure, heart rate, stroke volume, and middle cerebral artery velocity (MCAv) were measured continuously throughout the LBNP protocol. The protocol was terminated if systolic arterial pressure was < 80 mmHg, or if subjects reported symptoms such as lightheadedness, nausea, dizziness, or vision disturbances. Results Of the 20 subjects tested, 5 were in the POOR sleep quality group (5M; 0F), and 15 were in the GOOD sleep quality group (5M; 10F). Sleep quality had no effect on tolerance to LBNP (POOR: 1453 ± 223 s vs. GOOD: 1535 ± 88 s; P = 0.34), and there were no differences in the magnitude of central hypovolemia at presyncope (%Δ stroke volume, POOR: -53 ± 8 % vs. GOOD: -49 ± 4 %; P = 0.32). However, there were differences in the magnitude of hypotension (%Δ mean arterial pressure, POOR: -18 ± 3 % vs. GOOD: -22 ± 2 %; P = 0.08), cerebral blood flow reduction (%Δ MCAv, POOR: -19 ± 6 % vs. GOOD: -28 ± 2 %; P = 0.03), and reflex tachycardia (% Δ heart rate, POOR: 103 ± 30 % vs. GOOD: 72 ± 9 %; P = 0.09). There was a moderate association between sleep quality and the magnitude of MCAv reduction at presyncope (r = 0.53; P = 0.02), where poorer sleep quality was associated with a smaller reduction in MCAv at presyncope. All 5 (100%) subjects in the POOR group terminated the experiment based on subjective symptoms (i.e., they did not reach the systolic arterial pressure threshold of 80 mmHg), compared to 2 of the 15 subjects (13%) in the GOOD group (P=0.001). Conclusion: Sleep quality did not affect tolerance to simulated hemorrhage in healthy human subjects. While there were differences in hemodynamic responses, this may be related to premature termination of the LBNP protocol based on the early onset of subjective presyncopal symptoms. A larger sample size may help to further investigate these observations.

Sympathetic Response to Resistance Breathing During Simulated Hemorrhage in Humans

Background Resistance breathing increases venous return and stroke volume by amplifying the respiratory pump during inspiration. Breathing with resistance devices augments reflex compensatory mechanisms to improve tolerance to hypovolemic stress, such as hemorrhage. We tested the hypothesis that protection of arterial pressure with resistance breathing during simulated hemorrhage is due to the mechanical effect of the respiratory pump, and not due to increases in sympathetic nervous system activity. Methods Lower body negative pressure (LBNP) was used to simulate hemorrhage in eight human subjects (4M, 3F; 27.5±1.6 y). Two experiments were conducted (randomized order): 1) a control condition in which ramp LBNP was applied at 3 mmHg/min until the onset of presyncope, and 2) a resistance breathing condition in which the same LBNP protocol was used, but subjects breathed through a resistance device during the final stages of the protocol. Mean arterial pressure and stroke volume were monitored continuously, and blood samples were collected every 5-min for measurement of plasma norepinephrine and epinephrine. Results There were no differences in the reduction in stroke volume (control, -36.9±13.8% vs. resistance breathing, -33.5±17.1%, P=0.31) or mean arterial pressure (control, -5.5±4.2% vs. resistance breathing, -6.3±7.4%, P=0.63) between conditions. LBNP induced increases in both norepinephrine (P=0.03) and epinephrine (P=0.003), but there was no main effect of resistance breathing on these responses (norepinephrine, P=0.8; epinephrine, P=0.48). Conclusion These data support the hypothesis that, based on circulating catecholamine responses, resistance breathing has no direct effect on sympathetic drive to compensate for central hypovolemia.

Internal Jugular Vein Volume Pulsatility during Head‐Down Tilt and Lower Body Negative Pressure

The objective of this study was to investigate the impact of internal jugular vein (IJV) distension on blood volume pulsatility. We hypothesized that pulsatility would be enhanced during cephalad fluid shifts and attenuated during caudal fluid shifts. Thirteen young healthy participants (8/5 male/female) were assessed during supine rest (repeated); 3 and 6 degrees of head-down tilt (HDT); and -20, -30, -40 mmHg of lower body negative pressure (LBNP) after at least 5 minutes in each condition. The order of the HDT and LBNP protocols was randomized. Right-side IJV blood volume was estimated using widefield near-infrared spectroscopy and quantified as jugular venous optical attenuation (JVA). Central venous pressure (CVP) was measured using a transducer attached to a catheter inserted into an antecubital vein in the right arm and corrected to the level of the heart. Participants were rightward tilted throughout to facilitate venous pressure measurements. Continuous signals were acquired for 30s in each condition and time-synced at 60Hz. Volume and pressure pulsatility were calculated as the differences between peak and nadir points along the cardiac cycle in JVA and CVP, respectively. Pressure-volume loops were created after ensemble averaging waveforms normalized to the cardiac cycle. Area of the pressure-volume loops and slope of the pressure-volume relationship during atrial filling (i.e., venous drainage) were assessed. Group mean JVA and CVP were highest during 6° HDT and lowest during -40 mmHg LBNP (see figure). Compared to baseline, JVA pulsatility was attenuated during -30 mmHg LBNP (P=0.048) and -40 mmHg LBNP (P=0.004) and was unchanged during each level of HDT (P>0.9). In contrast, CVP pulsatility was attenuated compared to baseline during -20, -30, and -40 mmHg LBNP (P<0.001) and was unchanged during each level of HDT (P>0.68). Area (P=0.088) and slope (P=0.269) of the pressure-volume loop were unchanged across all conditions. In multiple regression analysis, loop area was associated directly with pressure amplitude (P<0.001) but not volume amplitude (P=0.130); model r2=0.69. These data suggest that, while volume pulsatility did decrease when venous distension was reduced by higher levels of LBNP, this was primarily a function of changes in pressure pulsatilty. IJV compliance appeared to be unchanged across a wide range of venous distension. This work has relevance to states where venous pressure and distension are altered, including heart failure and hemorrhagic shock.

The Reciprocal Relationship Between Cardiac Baroreceptor Sensitivity and Cerebral Autoregulation During Simulated Hemorrhage in Humans

Tolerance to reduced central blood volume (e.g., via hemorrhage) depends upon cardiovascular and cerebrovascular mediated compensatory mechanisms to preserve cerebral perfusion. Prior studies have demonstrated a reciprocal relationship between the arterial baroreflex and cerebral autoregulation (CA) at rest and in response to acute hypotension. It is unknown if this reciprocal relationship persists during progressive and sustained hypotension simulating hemorrhage. We hypothesized that the reciprocal relationship between cardiac baroreceptor sensitivity (BRS) and CA would be maintained during a simulated hemorrhage induced by maximal 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, 26 ± 4 y) completed a step-wise LBNP protocol until the onset of presyncope. Subjects were classified as high tolerant (HT) if they completed at least the -60 mmHg stage of LBNP (≥ 20-min), and low tolerant (LT) if they became presyncopal prior to completing the -60 mmHg stage of LBNP (< 20-min), as previously defined by our group. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), and middle cerebral artery velocity (MCAv) were measured continuously. The absolute change from baseline to presyncope (Δ) was calculated for each variable. Cardiac BRS was calculated as ΔHR divided by ΔMAP, and CA was calculated as ΔMCAv divided by ΔMAP. The relationship between BRS and CA was assessed with Pearson's correlation coefficients for the entire group of 51 subjects, and within the HT and LT sub-groups. Absolute change values for the hemodynamic responses were also compared between the two tolerance groups. By design, tolerance to LBNP was different between the groups (HT (n=30): 1775 ± 225 s vs. LT (n=21): 1184 ± 253 s; P<0.0001). Accordingly, HT subjects demonstrated a greater ΔSV (HT: -51 ± 17 ml vs. LT: -41 ± 13 ml; P=0.03) and a greater ΔHR (HT: +56 ± 17 bpm vs. LT: +34 ± 20 bpm; P<0.0001) in response to maximal LBNP. Interestingly, ΔMAP (HT: -18 ± 7 mmHg vs. LT: -19 ± 9 mmHg; P=0.51), ΔMCAv (HT: -17 ± 8 cm/s vs. LT: -19 ± 10 cm/s; P=0.52), BRS (HT: 4 ± 3 bpm/mmHg vs. LT: 3 ± 4 bpm/mmHg; P=0.24), and CA (HT: 1.2 ± 0.9 cm/s.mmHg-1 vs. LT: 1.5 ± 1.8 cm/s.mmHg-1; P=0.45) were similar between HT and LT subjects. In support of our hypothesis, there was a strong reciprocal relationship (R=0.77; P<0.0001) between BRS and CA in the group of 51 subjects. When independently assessing this relationship within each tolerance group, however, there was a stronger relationship in LT subjects (R=0.94; P<0.0001) compared to HT subjects (R=0.57; P<0.001). In support of our hypothesis, the reciprocal relationship between cardiac BRS and CA was maintained during sustained and progressive hypotension, but this relationship was stronger in subjects with lower tolerance to this stress. These findings suggest that despite a strong overall relationship in the interaction between BRS and CA, it may not be a primary compensatory mechanism that dictates tolerance to simulated hemorrhage in young healthy adults.

Time‐Frequency Analysis of Hemodynamics Oscillations during Presyncopal Lower Body Negative Pressure (LBNP)

Introduction Greater low frequency (LF) oscillations (~0.1 Hz) in mean arterial pressure (MAP) and cerebral blood flow (indexed by middle cerebral artery velocity; MCAv) have been associated with higher tolerance to central hypovolemia. As the fast Fourier transform approach was used in these prior studies, measuring exact timing of oscillatory amplitude was not possible. In the present study, the continuous wavelet transform was used for time localization and measurement of the magnitude of LF oscillations during application of lower body negative pressure (LBNP) to presyncope to reduce cerebral perfusion. We hypothesized that the magnitude of LF oscillations in MAP and MCAv would be higher in subjects with greater tolerance to this stress. We also hypothesized that the time of instantaneous maximum magnitude of LF oscillations would be further from baseline for high tolerant subjects. Methods 31 healthy human subjects (14 F: 17 M; 25.1 ± 3.0 y) underwent a stepwise LBNP protocol to presyncope. Subjects were classified as high tolerant (HT) if they completed the -60 mmHg stage of LBNP, and low tolerant (LT) if they did not. Continuous beat-to-beat MAP and mean MCAv were recorded. The continuous wavelet transform was used to extract magnitude of oscillations within the LF range (0.07-0.15 Hz) over time for both MAP and mean MCAv. The instantaneous maximum magnitude of LF oscillations was then extracted. Pearson's correlation was calculated for instantaneous LF magnitude of MAP and mean MCAv versus presyncopal time. A t-test was then used to compare magnitude and relative time of LF oscillations between HT and LT subjects. Results The maximum magnitude of MAP LF oscillations was positively correlated with presyncopal time (R = 0.39, P = 0.03). The maximum magnitude of MCAv LF oscillations, however, was not correlated with presyncopal time (R = -0.03, P = 0.86). When assessing HT and LT subjects, no differences were observed for maximum magnitude of LF oscillations in MAP (HT 4.3 ± 1.0, LT 3.7 ± 1.2, P=0.15) or MCAv (HT 3.1 ± 0.9, LT 3.1 ± 0.7, P=0.91). Time to maximum magnitude of LF oscillations was greater in high tolerant subjects for both MAP (HT 1384.5 ± 329.6 s, LT 798.6 ± 416.8 s, P<0.01) and MCAv (HT 1064.3 ± 431.6 s, LT 662.4 ± 380.1 s, P=0.01). When expressing the time of maximum amplitude as a percent of presyncopal time, the average time in all subjects for MAP was 73.6 ± 22.0 % and 59.6 ± 26.1 % for MCAv, and there were no differences between tolerance groups in either MAP (HT 79.5 ± 14.0 %, LT 67.4 ± 27.3 %, P=0.14) or MCAv (HT 61.8 ± 24.8 %, LT 57.3 ± 28.1 %, P=0.64). Conclusions Using wavelet analysis, only the maximum magnitude of MAP LF oscillations was modestly correlated to presyncopal time. Contrary to previous measures using fast Fourier transform, there was no difference in instantaneous maximum magnitude of oscillations in MAP and mean MCAv between high and low tolerant subjects indicating that both groups could mount similar responses. Interestingly, the relative timing of maximum magnitude of oscillations in MAP and MCAv was no different between tolerance groups.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

A comparison of protocols for simulating hemorrhage in humans: step versus ramp lower body negative pressure.

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 (ScO2), and end-tidal CO2 (etCO2) 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, ScO2, and etCO2 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.

The effect of hypercapnia on regional cerebral blood flow regulation during progressive lower-body negative pressure.

Previous work indicates that dynamic cerebral blood flow (CBF) regulation is impaired during hypercapnia; however, less is known about the impact of resting hypercapnia on regional CBF regulation during hypovolemia. Furthermore, there is disparity within the literature on whether differences between anterior and posterior CBF regulation exist during physiological stressors. We hypothesized: (a) lower-body negative pressure (LBNP)-induced reductions in cerebral blood velocity (surrogate for CBF) would be more pronounced during hypercapnia, indicating impaired CBF regulation; and (b) the anterior and posterior cerebral circulations will exhibit similar responses to LBNP. In 12 healthy participants (6 females), heart rate (electrocardiogram), mean arterial pressure (MAP; finger photoplethosmography), partial pressure of end-tidal carbon dioxide (PETCO2), middle cerebral artery blood velocity (MCAv) and posterior cerebral artery blood velocity (PCAv; transcranial Doppler ultrasound) were measured. Cerebrovascular conductance (CVC) was calculated as MCAv or PCAv indexed to MAP. Two randomized incremental LBNP protocols were conducted (-20, -40, -60 and -80mmHg; three-minute stages), during coached normocapnia (i.e., room air), and inspired 5% hypercapnia (~ + 7mmHg PETCO2 in normoxia). The main findings were: (a) static CBF regulation in the MCA and PCA was similar during normocapnic and hypercapnic LBNP trials, (b) MCA and PCA CBV and CVC responded similarly to LBNP during normocapnia, but (c) PCAv and PCA CVC were reduced to a greater extent at -60mmHg LBNP (P = 0.029; P < 0.001) during hypercapnia. CBF regulation during hypovolemia was preserved in hypercapnia, and regional differences in cerebrovascular control may exist during superimposed hypovolemia and hypercapnia.

The Influence of Acute Beetroot Juice Consumption on Cerebral Autoregulation during Orthostatic Stress

Beetroot juice (BRJ) supplementation improves cerebrovascular function during exercise. Breathing a mild hypercapnic gas transiently reduces cerebral autoregulation in healthy participants. However, it is unknown if acute BRJ consumption improves cerebral autoregulation while breathing a mild hypercapniac gas.PurposeWe tested the hypothesis that acute BRJ consumption improves cerebral autoregulation while breathing a mild hypercapnic gas during oscillatory lower body negative pressure (LBNP).MethodsEight healthy participants (age: 27±5 y, 3 F) completed a 5 min baseline (BL) followed by 6 min of LBNP intervals (30s at −70 mmHg, 30s at 0 mmHg) while breathing a mild hypercapnic gas (3% CO2, 21% O2, 76% N2). LBNP was performed pre (PRE) and 3 hours after consuming 500 mL of BRJ (BRJ). Mean arterial pressure (MAP), heart rate (HR), end‐tidal carbon dioxide tension (PETCO2), and middle cerebral artery blood velocity (MCAv) were continuously recorded. Cerebral vascular conductance (CVC) was calculated as MCAv divided by MAP. The magnitude of change in MAP, HR, PETCO2, MCAv, and CVC due to LBNP were calculated from the mean change from BL (Δ) obtained during each interval throughout the LBNP protocols. Cerebral autoregulation (i.e., gain and phase) was assessed throughout the LBNP protocols using Fourier transformation and is reported for BL and as the change from BL (Δ). Values are reported as Δ mean±SD.ResultsThere were no differences between conditions at BL for MAP (PRE: 99±8 vs. BRJ: 95±7 mmHg; P=0.10), HR (PRE: 65±9 vs. BRJ: 65±10 bpm; P=0.40), PETCO2 (PRE: 48±3 vs. BRJ: 49±3 mmHg; P=0.30), CVC (PRE: 0.86±0.18 vs. BRJ: 0.83±0.13 cm/s/mmHg; P=0.16) gain (PRE: 0.96±0.29 vs. BRJ: 0.93±0.22 cm/s/mmHg; P=0.31), or phase (PRE: 7±5 vs. BRJ: 10±6°; P=0.19). At BL, MCAv was lower with BRJ (PRE: 84±14 vs. BRJ: 79±11 cm/s; P&lt;0.01). The ΔMAP during −70 mmHg did not differ with BRJ (PRE: −8±5 vs. BRJ: −6±6 mmHg; P=0.51). The ΔMAP did not differ from BL during 0 mmHg PRE (P=0.44) but the ΔMAP was greater during 0 mmHg with BRJ (PRE: 1±3 vs. BRJ: 4±2 mmHg; P=0.03). The ΔHR was greater during −70 mmHg with BRJ (PRE: 13±10 vs. BRJ: 16±11 bpm; P=0.05) but the ΔHR during 0 mmHg did not differ with BRJ (PRE: −5±4 vs. BRJ: −3±3 bpm; P=0.29). The ΔPETCO2 did not differ between PRE and BRJ during −70 mmHg (PRE: −3±1 vs. BRJ: −3±2 mmHg; P=0.91) or 0 mmHg (PRE: −1±1 vs. BRJ: −1±2 mmHg; P=0.91). ΔMCAv did not differ from BL or between PRE and BRJ during −70 mmHg (PRE: −5±18 vs. BRJ: −4±16 cm/s; P=0.76) and 0 mmHg (PRE: −2±14 vs. BRJ: −1±13 cm/s; P=0.76). The ΔCVC did not differ with BRJ during −70 mmHg (PRE: −0.01±0.11 vs. BRJ: −0.03±0.08 cm/s/mmHg; P=0.20) but was greater with BRJ during 0 mmHg (PRE: −0.07±0.05 vs. BRJ: −0.11±0.08 cm/s/mmHg; P=0.02). During LBNP, there were no differences between conditions for Δgain (PRE: −0.03±0.18 vs. BRJ −0.05±0.10 cm/s/mmHg; P=0.41) or Δphase (PRE: −1±5 vs. BRJ: −3±8.2°; P=0.34).ConclusionsThese preliminary data indicate that acute BRJ does not alter cerebral autoregulation during an orthostatic stressor while healthy participants breathed a mild hypercapnic gas. Further investigations are warranted to determine if chornic BRJ ingestion affects cerebral autoregulation.

Epinephrine Increases Middle Cerebral Artery Blood Velocity in Response to Progressive Central Hypovolemia in Healthy Humans

ObjectivesWe aimed to determine if epinephrine played a beneficial role on middle cerebral artery velocity (MCAv) during physiologically stressful stimuli prior to cardiovascular collapse. MCAv was assessed during lower body negative pressure (LBNP) under conditions of a saline or epinephrine infusion. We hypothesized that (1) epinephrine would augment the change in MCAv from baseline to LBNP tolerance, (2), epinephrine would increase MCAv for a given LBNP stimulus, (3) at a given percent of LBNP tolerance epinephrine and saline will be similar and (4) that epinephrine would improve LBNP tolerance.MethodsNine participants (35±9yrs, n=5 male, 4 female) underwent a LBNP protocol to physiological tolerance during two study visits, performed at least two weeks apart, and randomized to saline or epinephrine (dose=0.1μg/kg/min) infusions (peripherally‐ inserted central catheter). Blood pressure (radial artery catheter) and middle cerebral artery velocity (transcranial Doppler) were assessed. MCAv and cerebrovascular conductance index (CvCi) were analyzed during baseline (three minutes), physiological tolerance (one minute), during LBNP at a given stimulus (three minutes; −15, −30, −45 mmHg of LBNP), and during relative percentages of LBNP tolerance [three minutes; 20, 40, 60, and 80% of LBNP tolerance time (s)]. Baseline was defined as measures taken after 15 minutes of saline or epinephrine infusion.ResultsIn both saline and epinephrine conditions, MCAv and CvCi decreased from baseline to tolerance (Saline MCAv: 69.7±7.5 vs 44.9±4.9 cm/s, p&lt;0.05; Epinephrine MCAv: 80.9±5.9 vs 56.5±6.7 cm/s, p&lt;0.05; Saline CvCi: 0.69±0.06 vs 0.58±0.067 cm/s/mmHg, p&gt;0.05; Epinephrine CvCi: 0.80±0.06 vs 0.70±0.078 cm/s/mmHg, p&lt;0.05). Epinephrine augmented MCAv at a given LBNP stimulus from baseline to −15, −30, and −45 mmHg (MCAv: Treatment effect: p&lt;0.05; CvCi: Treatment effect: p=0.05). At a relative percent of LBNP tolerance, epinephrine increased MCAv, but when blood pressure was controlled for with CvCi there was no treatment effect between epinephrine and saline (MCAv: Treatment effect: p&lt;0.05; CvCi: Treatment effect: p&gt;0.05). Time to tolerance was not significantly different between saline and epinephrine conditions (1469±168 vs. 1445±82s, p=0.88).ConclusionsEpinephrine increased MCAv during LBNP. These data suggest that epinephrine plays a beneficial role during stressful physiological stimuli such as hemorrhage in humans by augmenting cerebral blood flow prior to cardiovascular collapse. However, epinephrine did not improve LBNP tolerance.Support or Funding InformationThe United States Department of Defense W81XWH‐13‐2‐0038

Are Spontaneous Low Frequency Oscillations in Arterial Pressure and Cerebral Blood Flow Associated with the Protection of Cerebral Tissue Oxygenation during Simulated Hemorrhage?

IntroductionPrior studies have independently demonstrated that subjects with higher tolerance to simulated hemorrhage elicited by lower body negative pressure (LBNP) exhibit maintenance of cerebral tissue oxygenation, and higher amplitude in spontaneously generated low frequency (~0.1 Hz) oscillations in arterial pressure and cerebral blood flow. We hypothesized that these two independent observations are related, wherein subjects with higher tolerance to LBNP would exhibit increased low frequency power in arterial pressure and cerebral blood flow, which may contribute to the protection of cerebral tissue oxygenation.MethodsHealthy male (n=19, 25±1 y) and female (n=13, 28±1 y) subjects participated in a stepwise LBNP protocol to pre‐syncope. Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), cerebral tissue oxygen saturation (ScO2), and end tidal CO2 (etCO2) were measured continuously. Subjects were classified as high tolerant if they completed the −60 mmHg step of LBNP. Low frequency oscillations in MAP and MCAv were assessed in the 0.04–0.15 Hz range. Both time and frequency domain data were analyzed using a linear mixed model analysis of variance with Tukey post hoc tests. Comparisons were made at baseline across LBNP stages (−15, −30, −45, and −60 mmHg).ResultsOf the 32 subjects tested, 20 were classified as high tolerant and 12 as low tolerant. No differences were observed between high and low tolerant subjects in MAP (P=0.28), low frequency power of MAP (P=0.13), or low frequency power of MCAv (P=0.24) during LBNP. However, high tolerant subjects exhibited greater protection against reductions in ScO2 (P&lt;0.01), MCAv (P&lt;0.01), and etCO2 (P&lt;0.01) compared to low tolerant subjects during LBNP.ConclusionContrary to our hypothesis, low frequency oscillations in MAP and MCAv did not account for the observed protection in ScO2 for high tolerant subjects. Rather, maintenance of oxygen delivery (indexed via MCAv) appeared to account for the protection in cerebral oxygenation in this cohort of young, healthy subjects.Support or Funding InformationFunding for this study was provided by the U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐2‐0137, and a contract with Pendar Medical LLC. The content is solely the responsibility of the authors and does not necessarily represent the official views the US Department of Defense.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Efficacy of fluid loading as a countermeasure to the hemodynamic and hormonal changes of 28-h head-down bed rest.

After exposure to microgravity, or head‐down bed rest (HDBR), fluid loading is often used with the intent of increasing plasma volume and maintaining mean arterial pressure during orthostatic stress. Nine men (aged 18–32 years) underwent three randomized trials with lower body negative pressure (LBNP) before and after: (1) 4‐h of sitting with fluid loading (1 g sodium chloride/125 mL of water starting 2.5‐h before LBNP), (2) 28‐h of 6‐degree HDBR without fluid loading, and (3) 28‐h of 6‐degree HDBR with fluid loading. LBNP was progressive from 0 to −40 mmHg. After 28‐h HDBR, fluid loading did not protect against the loss of plasma volume (−280 ± 64 mL without fluid loading, −207 ± 86 with fluid loading, P = 0.472) nor did it protect against a drop of mean arterial pressure (P = 0.017) during LBNP (Post‐28 h HDBR response from 0 to −40 mmHg LBNP: 88 ± 4 to 85 ± 4 mmHg without fluid loading and 93 ± 4 to 88 ± 5 mmHg with fluid loading, P = 0.557 between trials). However, fluid loading did protect against the loss of stroke volume index and central venous pressure observed after 28‐h HDBR. Fluid loading also attenuated the increase of angiotensin II seen after 28‐h HDBR and throughout the LBNP protocol (Post‐28 h HDBR response from 0 to −40 mmHg LBNP: 16.6 ± 3.4 to 23.7 ± 5.0 pg/mL without fluid loading and 6.1 ± 0.8 to 12.2 ± 2.3 pg/mL with fluid loading, P < 0.001 between trials). Our results indicate that fluid loading did not protect against plasma volume loss due to HDBR or change blood pressure responses to LBNP. However, changes in central venous pressure, stroke volume and fluid regulatory hormones could potentially influence longer duration studies and those with more severe orthostatic stress.