Progressive Lower Body Negative Pressure Research Articles

Sublingual sufentanil does not decrease tolerance to progressive central hypovolemia

Hemorrhage is a leading cause of death in both civilian and battlefield settings. Since pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic responses beneficial to maintaining arterial blood pressure and thus organ perfusion. Sublingual sufentanil is currently available for administration on the battlefield, but its effect on hemorrhage tolerance is unknown. This study tested the hypothesis that sufentanil impairs tolerance to progressive central hypovolemia in awake humans. METHODS: 29 participants, 15 males and 14 females (aged: 29 ± 5, weight: 74 ± 8 kg, BMI: 25 ± 2 kg/m2) participated in this double-blinded, randomized, placebo-controlled trial. Following sublingual administration of sufentanil (30 μg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) protocol starting at 40 mmHg that was further reduced by 10 mmHg every three minutes until presyncope. Presyncope was defined as: continued reports of feeling faint and/or nauseous, a rapid decline in blood pressure resulting in systolic blood pressure <80 mmHg, and/or relative bradycardia accompanied by a narrowing of pulse pressure. Tolerance to LBNP, quantified as cumulative stress index (mmHg*min), was compared between sufentanil and placebo trials using a Wilcoxon Signed rank test. Arterial blood pressure, heart rate, and plasma catecholamine concentrations were compared using mixed effects models (LBNP stage x Drug). RESULTS: Tolerance to LBNP was not different between trials (sufentanil: 518 ± 203 vs. placebo: 594 ± 267, p = 0.495). Mean blood pressure decreased similarly between the two trials during LBNP (sufentanil: -23 ± 9 mmHg vs. placebo: -22 ± 10 mmHg, p< 0.001), with no main effect of drug (p = 0.498) or interaction (p = 0.935). Increases in heart rate with LBNP were similar between the two trials (sufentanil: 44 ± 25 bpm vs. placebo: 52 ± 23 bpm, time: p < 0.001) with no main effect of drug (p=0.626) or interaction (p = 0.424). Epinephrine (drug: p = 0.004, time: p < 0.001, interaction: p = 0.031) and norepinephrine (drug: p = 0.017, time: p < 0.001, interaction: p = 0.161), concentrations increased to LBNP, with post hoc analysis revealing that epinephrine concentrations were higher at LBNP 50 and presyncope (p ≤ 0.05) with sufentanil. CONCLUSION: These data demonstrate that sublingual sufentanil does not impair tolerance to simulated hemorrhage or alter the assessed mechanisms responsible for maintaining arterial blood pressure. W81XWH-22-C-0004. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Sympathetic Responses to Lower-Body Negative Pressure.

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. 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). 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). 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.

Hemodynamic effects of supplemental oxygen versus air in simulated blood loss in healthy volunteers: a randomized, controlled, double-blind, crossover trial

BackgroundTrauma patients frequently receive supplemental oxygen, but its hemodynamic effects in blood loss are poorly understood. We studied the effects of oxygen on the hemodynamic response and tolerance to simulated blood loss in healthy volunteers.MethodsFifteen healthy volunteers were exposed to simulated blood loss by lower body negative pressure (LBNP) on two separate visits at least 24 h apart. They were randomized to inhale 100% oxygen or medical air on visit 1, while inhaling the other on visit 2. To simulate progressive blood loss LBNP was increased every 3 min in levels of 10 mmHg from 0 to 80 mmHg or until hemodynamic decompensation. Oxygen and air were delivered on a reservoired face mask at 15 L/min. The effect of oxygen compared to air on the changes in cardiac output, stroke volume and middle cerebral artery blood velocity (MCAV) was examined with mixed regression to account for repeated measurements within subjects. The effect of oxygen compared to air on the tolerance to blood loss was measured as the time to hemodynamic decompensation in a shared frailty model. Cardiac output was the primary outcome variable.ResultsOxygen had no statistically significant effect on the changes in cardiac output (0.031 L/min/LBNP level, 95% confidence interval (CI): − 0.015 to 0.077, P = 0.188), stroke volume (0.39 mL/LBNP level, 95% CI: − 0.39 to 1.2, P = 0.383), or MCAV (0.25 cm/s/LBNP level, 95% CI: − 0.11 to 0.61, P = 0.176). Four subjects exhibited hemodynamic decompensation when inhaling oxygen compared to 10 when inhaling air (proportional hazard ratio 0.24, 95% CI: 0.065 to 0.85, P = 0.027).ConclusionsWe found no effect of oxygen compared to air on the changes in cardiac output, stroke volume or MCAV during simulated blood loss in healthy volunteers. However, oxygen had a favorable effect on the tolerance to simulated blood loss with fewer hemodynamic decompensations. Our findings suggest that supplemental oxygen does not adversely affect the hemodynamic response to simulated blood loss.Trial registration This trial was registered in ClinicalTrials.gov (NCT05150418) December 9, 2021

The Effect of Supine Cycling and Progressive Lower Body Negative Pressure on Cerebral Blood Velocity Responses.

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 vasodilation. 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 years; 19 females) completed a stepwise maximal-exercise test to determine each participant's wattage associated with their exercise-induced maximal CBv increase. During the second visit, 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 (MCAv), 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 to resting-supine baseline, averaged MCAv was elevated during 0 and -20 Torr LBNP (q-value>7.73; p<0.001); 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 were 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 concussion recovery.

Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status.

Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. We measured HR, SBP, and CRM in 172 human subjects (19-55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater ( p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94-0.97) compared with 0.91 (0.89-0.94) for SI ( p = 0.0002). Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. Diagnostic Test or Criteria; Level III.

Using the ear photoplethysmographic waveform as an early indicator of central hypovolemia in healthy volunteers utilizing LBNP induced hypovolemia model

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 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 during the early stage of LBNP (−15 mmHg) as the single index could predict the tolerance of the subject with the sensitivity, specificity, accuracy and F1 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.

Cardio-respiratory interactions in response to lower-body negative pressure

The relationship between heart rate and blood pressure, as well as cardiorespiratory coupling, play a critical role in maintaining blood pressure and organ perfusion during conditions of blood loss. Traditional vital signs such as blood pressure, breathing rate, and oxygen saturation are poor markers of blood loss, making it difficult for medics to assess the severity of central hypovolemia. Monitoring hemorrhage is further complicated by the fact that some patients have a low tolerance to hemorrhage and would reach the point of cardiovascular collapse in less time than high tolerant individuals. Therefore, this study aimed to investigate the potential of the physiological interaction between heart rate and blood pressure, and cardiorespiratory coupling to track the progression of simulated hemorrhage, as well as distinguish individuals with low tolerance (LT) from the ones with high tolerance (HT) to hypovolemia. Nineteen subjects (age: 28 ± 6 years; height: 170 ± 7 cm; weight: 68 ± 10 kg) underwent a progressive lower body negative pressure (LBNP) protocol in which the participant was supine inside the chamber for 12 min (baseline) before 12 min of chamber decompression at –20, –30, –40, –50 and –60 mmHg followed by a 12 min recovery period. Twelve subjects reached presyncope before or during –60 mmHg LBNP stage and were considered low tolerant (LT, 12 participants), while the ones who completed –60 mmHg were considered high tolerant (HT, 7 participants). Continuous blood pressure (BP), respiration (RSP), and electrocardiogram (ECG) signals were acquired simultaneously during baseline and each LBNP stage. RR interval was calculated using ECG, while systolic blood pressure (SBP), and pulse pressure were derived from BP waveform. Wavelet transform coherence and convergent cross-mapping techniques were employed to study the physiological interdependence and the causal relationship between heart rate, blood pressure, and respiration. The interaction between blood pressure and heart rate in terms of gain, active gain, and fraction time active to maintain homeostasis was higher in the LT group during baseline, and LBNP simulated mild, moderate, and severe hemorrhage. The significant time of interaction between SBP and RSP, and the causal effect of blood pressure on respiration were higher in the HT group during baseline compared to the LT group. HT participants also had a higher causal effect of respiration on blood pressure during –30 and –40 mmHg compared to LT. Moreover, the HT group displayed a higher causal drive of respiratory-related changes in heart rate and heart rate mediated changes in respiration during severe simulated hemorrhage (–40 mmHg) compared to the LT group. The calculated metrics to distinguish between individual LT from HT subjects achieved a sensitivity of 58%–83%, an accuracy of 63%–84%, and an area under the ROC curve of 74%–86%, while the overlap of LT individual responses with HT was 0%–33%. These results indicate the potential of cardiorespiratory coupling, and heart rate and blood pressure interaction toward tracking the progression of hemorrhage and distinguishing individuals with low tolerance to hypovolemia from those with high tolerance. Measurements of such interactions could improve clinical outcomes for patients with low tolerance to hypovolemia and therefore reduce morbidity and mortality through early implementation of life-saving interventions.

Comparing the Effects of Low-Dose Ketamine, Fentanyl, and Morphine on Hemorrhagic Tolerance and Analgesia in Humans

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73–139], fentanyl (n = 28): 95 [68–130], morphine (n = 30): 62 [35–85]; values expressed as a % of the respective placebo trial’s CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

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.

Low-dose morphine reduces tolerance to central hypovolemia in healthy adults without affecting muscle sympathetic outflow.

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

Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.

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

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.

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.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage]×drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360mmHg‧min, p=0.77). Increases in MSNA burst frequency (time: P<0.01, trial: p=0.27, interaction: p=0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P<0.01, trial: P<0.01, interaction: p=0.01) and heart rate (time: P<0.01, trial: P<0.01, interaction: P<0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P<0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Evidence for misleading decision support in characterizing differences in tolerance to reduced central blood volume using measurements of tissue oxygenation.

The physiological response to hemorrhage includes vasoconstriction in an effort to shunt blood to the heart and brain. Hemorrhaging patients can be classified as "good" compensators who demonstrate high tolerance (HT) or "poor" compensators who manifest low tolerance (LT) to central hypovolemia. Compensatory vasoconstriction is manifested by lower tissue oxygen saturation (StO2 ), which has propelled this measure as a possible early marker of shock. The compensatory reserve measurement (CRM) has also shown promise as an early indicator of decompensation. Fifty-one healthy volunteers (37% LT) were subjected to progressive lower body negative pressure (LBNP) as a model of controlled hemorrhage designed to induce an onset of decompensation. During LBNP, CRM was determined by arterial waveform feature analysis. StO2 , muscle pH, and muscle H+ concentration were calculated from spectrum using near-infrared spectroscopy (NIRS) on the forearm. These values were statistically indistinguishable between HT and LT participants at baseline (p ≥ 0.25). HT participants exhibited lower (p = 0.01) StO2 at decompensation compared to LT participants. Lower StO2 measured in patients during low flow states associated with significant hemorrhage does not necessarily translate to a more compromised physiological state, but may reflect a greater resistance to the onset of shock. Only the CRM was able to distinguish between HT and LT participants early in the course of hemorrhage, supported by a significantly greater ROC AUC (0.90) compared with STO2 (0.68). These results support the notion that measures of StO2 could be misleading for triage and resuscitation decision support.

An assessment of hypercapnia-induced elevations in regional cerebral perfusion during combined orthostatic and heat stresses

We investigated that the effects of hypercapnia-induced elevations in cerebral perfusion during a heat stress on global cerebrovascular responses to an orthostatic challenge. Seven volunteers completed a progressive lower-body negative pressure (LBNP) challenge to presyncope during heat stress, with or without breathing a hypercapnic gas mixture. Administration of the hypercapnic gas mixture increased the partial pressure of end-tidal CO2 greater than pre-heat stress alone, and increased both internal carotid artery (ICA) and vertebral artery (VA) blood flows (P < 0.05). During LBNP, both ICA and VA blood flows with the hypercapnic gas mixture remained elevated relative to the control trial (P < 0.05). However, at the end of LBNP due to pre-syncopal symptoms, both ICA and VA blood flows decreased to similar levels between trials. These findings suggest that hypercapnia-induced cerebral vasodilation is insufficient to maintain cerebral perfusion at the end of LBNP due to pre-syncope in either the anterior or posterior vascular beds.

Exogenous Infusion of Epinephrine Augments Cardiac Output during Simulated Hemorrhage in Humans

BackgroundLower body negative pressure (LBNP) simulates hemorrhage, evoking compensatory cardiovascular mechanisms of increased heart rate (HR) while stroke volume (SV) and cardiac output (CO) progressively decline, ultimately leading to presyncope. Previous work has shown that circulating levels of plasma epinephrine are elevated during LBNP; however, the role of early administration of epinephrine in compensatory cardiovascular mechanisms to simulated hemorrhage is not well understood.PurposeWe hypothesized that during simulated hemorrhage, a low‐dose exogenous infusion of epinephrine in humans would: 1) augment HR response, 2) attenuate the decline of SV and CO, and 3) prolong time to tolerance.MethodsNine healthy subjects (5M/4F, 35±9yrs, BMI 25±1 kg·m−2) participated in LBNP on two separate study days. Protocols on each day consisted of a 10‐minute pre‐infusion baseline, 15‐minute infusion period (randomized to saline or epinephrine, dose = 0.1 μg·kg−1·min−1, delivered through a peripherally inserted central catheter), 10‐minute post‐infusion baseline, and 5 minute stages of progressive LBNP with stepwise increases of 10–15 mmHg negative pressure until tolerance (systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms). Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Cardiovascular function (HR, SV, CO, and systemic vascular resistance (SVR)) was determined using arterial waveform analysis. Data were analyzed via percent tolerance using repeated measures ANOVA with student method for pairwise comparisons.ResultsInfusion of exogenous epinephrine lowered MAP (p&lt;0.01) and diastolic blood pressure (DBP; p&lt;0.001), but raised systolic blood pressure (SBP; p=0.019) throughout all stages of LBNP. Epinephrine compared to saline augmented mean HR, SV and CO to the penultimate stage of LBNP (p≤0.01 for all cardiac measures) and concurrently reduced SVR (p=0.002). However, time to tolerance was not significantly different between epinephrine and saline conditions (1415 ± 79 vs. 1475 ± 150s, respectively; p=0.69).DiscussionOur findings suggest that during simulated hemorrhage exogenous epinephrine can augment cardiac function without increasing tolerance to progressive central hypovolemia. During the epinephrine infusion, benefits to cardiac function may have been limited by reduced vascular resistance.Support or Funding InformationThe United States Department of Defense W81XWH‐13‐2‐0038

Analgesics in the Pre‐Hospital Setting: Simulated Hemorrhagic Tolerance in Humans is not Impaired by Ketamine Administration

Hemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a hemorrhagic injury on the battlefield is virtually always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial towards the maintenance of blood pressure and vital organ blood flow during that hemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a hemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anesthetized animals. Specifically, the influence of ketamine, one of three analgesics employed in the pre‐hospital setting by the US Army, on hemorrhagic tolerance in humans is entirely unknown. Thus, the purpose of this study is to test the hypothesis that ketamine will impair the capacity for a conscious human to tolerate a simulated hemorrhagic insult. Twelve subjects (4 females, 29±7 years old, 181±6 cm, 84±10 kg) participated in this double‐blinded, randomized, placebo‐controlled investigation. Tolerance to a simulated hemorrhage was performed using a progressive lower body negative pressure (LBNP) protocol to pre‐syncope following intravenous administration of Ketamine (20 mg—consistent with the US Army's CoTCCC guidelines) or placebo (saline). Tolerance was quantified as a cumulative stress index (CSI, mmHg•min). Tolerance to the LBNP challenge was not different between the ketamine and placebo trials (CSI: 746±368 mmHg•min and 795±316 mmHg•min respectively, P=0.61). These data, the first to be obtained in conscious humans, demonstrate that administration of ketamine does not compromise tolerance to a simulated hemorrhagic insult. These findings may be insightful in choosing the most suitable analgesic medication in the pre‐hospital setting during a hemorrhagic insult.Support or Funding InformationFunding: Department of Defense – US Army, W81XWH1820012This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The dynamics of cerebral blood flow leading up to pre‐syncope in heat stressed humans

Whole‐body heat stress reduces tolerance to lower‐body negative pressure (LBNP). Lucas et al. (Am J Physiol, 2013) previously showed that elevating cerebral perfusion early in LBNP challenge (via breathing a hypercapnic gas mixture) did not restore LBNP tolerance. However, that study only evaluated blood velocity responses from the middle cerebral artery (MCA). Given regional differences in CO2 responsiveness in the cerebral circulation, that work may not accurately reflect global cerebral perfusion responses to LBNP, as it did not account for perfusion from the anterior or posterior cerebral arteries. To address this deficit, seven healthy volunteers performed progressive LBNP to presyncope during passive heat stress, with or without breathing a hypercapnic gas mixture (5% CO2, 21% O2, balanced N2) prior to the onset of LBNP; the order of the trials were randomized and performed on separate days. Internal carotid artery (ICA) and vertebral artery (VA) blood flows were measured throughout LBNP. External canal temperature increased by ~1.4 °C during heat stress (via water‐perfused suit) and was maintained during LBNP in both trials. Heat stress decreased end‐tidal CO2 (PETCO2) by ~3mmHg. Administration of the hypercapnic gas increased PETCO2to a level greater than pre‐heat stress values (43.0±2.4 to 49.3±3.6mmHg), and PETCO2 remained at or above pre‐heat stress baseline (43.7±3.6mmHg) at the end of LBNP. LBNP tolerance, evaluated by cumulative stress index, was similar between trials. Heat stress slightly decreased both ICA and VA blood flows, and subsequent inhalation of the hypercapnic gas increased both by 125±37% and133±33%, respectively, from pre‐heat stress baseline. Of note, during LBNP, both ICA and VA blood flows in the hypercapnic trial were greater relative to the respective blood flows during the control LBNP trial (all P&lt;0.05). However, at the termination of LBNP, due to pre‐syncopal symptoms, ICA and VA blood flows decreased to similar levels between the hypercapnic and control LBNP trials. These findings suggested that hypercapnia‐induced cerebral vasodilation is insufficient to maintain cerebral blood flow, resulting in a failure to improvement in LBNP tolerance in heat stressed humans.Support or Funding Information18H03166 JSPS KAKENHI Grant‐in‐AidThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sympathetic activation by lower body negative pressure decreases kidney perfusion without inducing hypoxia in healthy humans

PurposeThere 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.MethodsEight 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.ResultsWith 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).ConclusionThe 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.