Progressive Central Hypovolemia 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.

Acute fasting reduces tolerance to progressive central hypovolemia in humans.

Potential health benefits of an acute fast include reductions in blood pressure and increases in vagal cardiac control. These purported health benefits could put fasted humans at risk for cardiovascular collapse when exposed to central hypovolemia. The purpose of this study was to test the hypothesis that an acute 24-h fast (vs. 3-h postprandial) would reduce tolerance to central hypovolemia induced via lower body negative pressure (LBNP). We measured blood ketones (β-OHB) to confirm a successful fast (n = 18). We recorded the electrocardiogram (ECG), beat-to-beat arterial pressure, muscle sympathetic nerve activity (MSNA; n = 7), middle cerebral artery blood velocity (MCAv), and forearm blood flow. Following a 5-min baseline, LBNP was increased by 15 mmHg until -60 mmHg and then increased by 10 mmHg in a stepwise manner until onset of presyncope. Each LBNP stage lasted 5-min. Data are expressed as means ± SE β-OHB increased (β-OHB; 0.12 ± 0.04 fed vs. 0.47 ± 0.11, P < 0.01 mmol/L fast). Tolerance to central hypovolemia was decreased by ∼10% in the fasted condition measured via total duration of negative pressure (1,370 [Formula: see text] 89 fed vs. 1,229 ± 94 s fast, P = 0.04), and was negatively associated with fasting blood ketones (R = -0.542, P = 0.02). During LBNP, heart rate and MSNA increased similarly, but in the fasted condition forearm vascular resistance was significantly reduced. Our results suggest that acute fasting reduces tolerance to central hypovolemia by blunting increases in peripheral resistance, indicating that prolonged fasting may hinder an individual's ability to compensate to a loss of blood volume.NEW & NOTEWORTHY An acute 24 h fasting reduces tolerance to central hypovolemia, and tolerance is negatively associated with blood ketone levels. Compared with a fed condition (3-h postprandial), fasted participants exhibited blunted peripheral vasoconstriction and greater reductions in stroke volume during stepwise lower body negative pressure. These findings suggest that a prolonged fast may lead to quicker decompensation during central hypovolemia.

Noninvasive Monitoring of Simulated Hemorrhage and Whole Blood Resuscitation

Hemorrhage is the leading cause of preventable death from trauma. Accurate monitoring of hemorrhage and resuscitation can significantly reduce mortality and morbidity but remains a challenge due to the low sensitivity of traditional vital signs in detecting blood loss and possible hemorrhagic shock. Vital signs are not reliable early indicators because of physiological mechanisms that compensate for blood loss and thus do not provide an accurate assessment of volume status. As an alternative, machine learning (ML) algorithms that operate on an arterial blood pressure (ABP) waveform have been shown to provide an effective early indicator. However, these ML approaches lack physiological interpretability. In this paper, we evaluate and compare the performance of ML models trained on nine ABP-derived features that provide physiological insight, using a database of 13 human subjects from a lower-body negative pressure (LBNP) model of progressive central hypovolemia and subsequent progressive restoration to normovolemia (i.e., simulated hemorrhage and whole blood resuscitation). Data were acquired at multiple repressurization rates for each subject to simulate varying resuscitation rates, resulting in 52 total LBNP collections. This work is the first to use a single ABP-based algorithm to monitor both simulated hemorrhage and resuscitation. A gradient-boosted regression tree model trained on only the half-rise to dicrotic notch (HRDN) feature achieved a root-mean-square error (RMSE) of 13%, an R2 of 0.82, and area under the receiver operating characteristic curve of 0.97 for detecting decompensation. This single-feature model's performance compares favorably to previously reported results from more-complex black box machine learning models. This model further provides physiological insight because HRDN represents an approximate measure of the delay between the ABP ejected and reflected wave and therefore is an indication of cardiac and peripheral vascular mechanisms that contribute to the compensatory response to blood loss and replacement.

Feature Importance Analysis for Compensatory Reserve to Predict Hemorrhagic Shock.

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

Identifying critical DO2 with compensatory reserve during simulated hemorrhage in humans.

Based on previous experiments in nonhuman primates, we hypothesized that DO2 crit in humans is 5-6ml O2 ·kg-1 min-1 . We measured the compensatory reserve (CRM) and calculated oxygen delivery (DO2 ) 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. HT and LT groups were matched for age, weight, BMI, and vital signs, DO2 and CRM at baseline. The CRM-DO2 relationship was best fitted to a logarithmic model in HT subjects (amalgamated R2 =0.971) and a second-order polynomial model in the LT group (amalgamated R2 =0.991). Average DO2 crit for the entire subject cohort was estimated at 5.3ml O2 ·kg-1 min-1 , but was ~14% lower in HT compared with LT subjects. The reduction in DO2 from 40% CRM to 20% CRM was 2-fold greater in the LT compared with the HT group. Average DO2 crit in humans is 5.3ml O2 ·kg-1 min-1 , but is ~14% lower in HT compared with LT subjects. The CRM-DO2 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 DO2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM-DO2 relationship.

Identifying Critical DO2 with Compensatory Reserve during Simulated Hemorrhage in Humans

BackgroundHemorrhage is a leading cause of potentially‐survivable death in trauma. The basic principle for treatment of ongoing bleeding prior to hemorrhage control is that early detection and intervention will improve outcome. However, current monitoring technologies that rely on standard vital signs are unreliable in assessing the clinical status of trauma patients because of variability in the capacity of individuals to compensate for hypovolemia. A monitoring capability designed to measure changes in systemic oxygen delivery (DO2) would provide an earlier indicator of clinical status in patients with life‐threatening blood loss. Maintaining DO2 above the level associated with the onset of shock (i.e., DO2crit) until bleeding is controlled should be the aim of any hemorrhage intervention. But DO2crit has not been identified in humans. Over the past decade, measuring the physiological phenomenon of compensatory reserve (CRM) based on interrogation of arterial waveform morphology has provided a capability to assess the reduction in the capacity to compensate for ongoing progressive central hypovolemia. Based on non‐human primate hemorrhage experiments, we hypothesized that humans would demonstrate a linear relationship between CRM and DO2, allowing for the identification of a DO2crit in humans of ~5 to 6 ml O2·kg‐1·min‐1. We also hypothesized that individuals with high (HT) and low (LT) tolerance to hypovolemia (i.e., ‘good’ versus ‘poor’ compensators) would have similar CRM‐DO2 relationships and DO2crit.Study Design and MethodsCRM and calculated DO2 were measured in 166 healthy subjects (97 males, 69 females) with a mean ± SD age of 23 ± 4 years, height of 171 ± 11 cm, and weight of 69 ± 11 kg. All subjects underwent progressive central hypovolemia induced by lower body negative pressure as a model of ongoing hemorrhage to a physiological state of hemodynamic decompensation. Subjects were classified as having either high tolerance (HT; N = 111) or low tolerance (LT; N = 55) to central hypovolemia based on whether they completed 5 minutes at ‐60 mmHg LBNP.ResultsHT and LT groups were matched for age, weight, BMI, and vital signs, DO2 and CRM at baseline. The CRM‐DO2 relationship was best fitted to a logarithmic model in HT subjects (R2 = 0.971) and a polynomial model in the LT group (R2 = 0.991). Average DO2crit for the entire subject cohort was estimated at 5.3 ml O2·Kg‐1·min‐1, but was ~14% lower in HT compared to LT subjects. The reduction in DO2 from 40% CRM to 20% CRM was 2‐fold greater in the LT compared to the HT group.ConclusionsAverage DO2crit in humans is 5.3 ml O2·Kg‐1·min‐1, but is ~14% lower in HT compared to LT subjects. The CRM‐DO2 relationship is curvilinear in humans, and different when comparing HT and LT individuals. A threshold for an emergent monitoring signal should be set to 40% CRM given that the decline in DO2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM‐DO2 relationship.

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 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.

Wearable Sensors Incorporating Compensatory Reserve Measurement for Advancing Physiological Monitoring in Critically Injured Trauma Patients.

Vital signs historically served as the primary method to triage patients and resources for trauma and emergency care, but have failed to provide clinically-meaningful predictive information about patient clinical status. In this review, a framework is presented that focuses on potential wearable sensor technologies that can harness necessary electronic physiological signal integration with a current state-of-the-art predictive machine-learning algorithm that provides early clinical assessment of hypovolemia status to impact patient outcome. The ability to study the physiology of hemorrhage using a human model of progressive central hypovolemia led to the development of a novel machine-learning algorithm known as the compensatory reserve measurement (CRM). Greater sensitivity, specificity, and diagnostic accuracy to detect hemorrhage and onset of decompensated shock has been demonstrated by the CRM when compared to all standard vital signs and hemodynamic variables. The development of CRM revealed that continuous measurements of changes in arterial waveform features represented the most integrated signal of physiological compensation for conditions of reduced systemic oxygen delivery. In this review, detailed analysis of sensor technologies that include photoplethysmography, tonometry, ultrasound-based blood pressure, and cardiogenic vibration are identified as potential candidates for harnessing arterial waveform analog features required for real-time calculation of CRM. The integration of wearable sensors with the CRM algorithm provides a potentially powerful medical monitoring advancement to save civilian and military lives in emergency medical settings.

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.

Effect of Blood Volume Shift Simulated via Head-up Tilt on Photoplethysmography Morphology.

PPG can provide information on cardiovascular responses to fluid shifts from upper to lower part of body under the condition of orthostatic stress. The current study investigated ability of PPG derived LVET and other PPG derived features to identify progressive central hypovolemia induced by head up tilt (HUT) and evaluated potential use of LVET as early noninvasive indicator of blood loss. Continuous finger PPG, blood pressure, and electrocardiography were recorded simultaneously during 5-minutes of baseline and HUT of 20°, 40°, and 60° from 15 participants (age: 26.5 ± 3 years; height: 177 ± 8 cm; weight: 72 ± 10 kg, mean ± SD). Beat-by-beat pulse rate (PR), systolic amplitude (SA), systolic time (ST), diastolic time (DT), and PP Interval (PPI) and Ratio of pulse rate over systolic amplitude (PR/SA) were derived for each stage. LVET was derived from each stage. Friedman test followed by post-hoc analysis using Tukey-HSD was conducted to highlight the significance of changes induced by HUT. Application of 60° HUT (i.e. moderate category simulated hypovolemia) resulted in a significant change in PR (80±3 bpm vs 68±3 bpm, p=0.0008), DT (264±7 ms vs 303±4 ms, p=0.0008), ST (110±6 ms vs 117±7 ms, p=0.02), PP interval (764±39 ms vs 869±25 ms, p=0.0045), PR/SA (112±16 vs 82±21, p=0.012) , SA (0.875± 0.2 vs 1.69±0.6, p=0.012) and LVET(292 vs 351ms,p=0.0008) compared to baseline. LVET has a strong association with the change in central blood volume and may be used as a sensitive early marker of progressive hypovolemia. The findings of the study support the hypothesis of differentiating simulated hypovolemia based on PPG alone. Keywords: Hypovolemia, HUT, LVET.

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

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

Similar Hemostatic Responses to Hypovolemia in Hemorrhage and Lbnp Reveals a Hyperfibrinolytic Subset of Baboons

Background: Lower body negative pressure (LBNP) has been established in human studies as an alternative method to blood removal (HEM) to study central hypovolemia. In a baboon model, LBNP also mimics the cardiovascular response of HEM. Hemostatic responses, including platelet activation, coagulation and fibrinolysis in response to LBNP and HEM in this baboon model are reported here. A previous meeting report from this study focused on hemostatic interactions; this report expands the assay of fibrinolytic proteins and includes detailed post-hoc analysis of interactions. Methods: Thirteen anesthetized baboons were exposed to progressive central hypovolemia by HEM and, four weeks later, by LBNP. Whole blood cell counts were determined; pro-coagulant and fibrinolytic activity was evaluated by plasma markers, thrombelastography, flow cytometry and platelet aggregometry at baseline (BL), intermediate hypovolemia (MID), presyncope or maximal hypovolemia (MAX) and after recovery (REC). Results: Baseline values for HEM (day 0) and LBNP (day 28) were indistinguishable for most analyzed parameters; however platelet number, maximal clotting (MA), Protein C, TAT, TAFI-activity, plasma renin, angiotensin and epinephrine were all significantly different (p&amp;lt;0.05). Central hypovolemia induced by both methods activated coagulation; TEG revealed decreased clotting time (R) and increased maximal clotting (MA) at MID, MAX and REC over BL. No differences during developing central hypovolemia were observed between HEM and LBNP. Platelets displayed activation markers on flow cytometry; absolute numbers and functional aggregometry were unchanged. At MAX hypovolemia, there was a modest hemodilution for HEM and a modest hemoconcentration for LBNP; red blood cell count decreased 5.8%±5.5%, p=0.0007 with HEM and increased 5.3±5.9%, p=0.0056 with LBNP. Coagulation factors were significantly increased with LBNP at MAX compared to HEM; fibrinolysis proteins were more varied. No hyper-fibrinolysis developed with progressive hypovolemia by either method; instead hyper-fibrinolysis already existed at BL with significant variance in TEG fibrinolysis at 30 min (LY30) values. Post hoc analysis separated study subjects into low lysis (LY30BL&amp;lt;2) or high lysis (LY30BL&amp;gt;2) whose fibrinolytic state matched at both HEM and LBNP BL. High lysis samples (n=8) showed a strong correlation (r=0.95; p&amp;lt;0.001) of tissue plasminogen activator (tPA) to LY30 at BL that was absent in low lysis samples (n=6). Thrombin activatable fibrinolysis inhibitor (TAFI) activity correlated with tPA levels for low lysis subjects (r=0.88) with no correlation for high lysis subjects (r=.08). Conclusions: Central hypovolemia resulted in activation of coagulation by either LBNP or HEM; thus LBNP is a powerful model for studying hemorrhage. This study also revealed a subset of baboons with baseline activation of fibrinolysis which was strongly coupled to tPA and uncoupled from TAFI activity. The methods demonstrated hemodilution with blood removal and hemoconcentration with LBNP, as has been observed in humans, but these modest changes had no significant effect on coagulation parameters. Unexpectedly, this study demonstrated that the effects of blood removal were sustained 28 days later on baseline parameters. Overall, these results in large primates suggest that baseline differences between apparently healthy and superficially homogeneous individuals may determine outcomes in studies of hemostasis. Disclosures No relevant conflicts of interest to declare.

Heart Rate Variability Analysis During Lower Body Negative Pressure Test Induced Central Hypovolemia

Abstract In clinical patient monitoring scenarios, the detection of hemorrhage is still a major problem. Traditional vital signs like heart rate and blood pressure are insensitive to blood loss due to compensatory mechanisms in the body that can sustain these parameters until shortly before cardiovascular collapse. These compensatory mechanisms during blood loss are primarily driven by the autonomic nervous system. Heart rate variability analysis is a viable tool in the quantitative analysis of the autonomic nervous system and shows promising results in the context of hypovolemia detection. In order to investigate if HRV parameters suitably reflect a mild to moderate blood volume reduction, we conducted a lower body negative pressure test study with 30 volunteering participants thereby simulating progressive central hypovolemia. Here, HRV parameters from the time domain (mean HR, SDNN, RMSSD, rSDRM, pNN50), the frequency domain (VLF, LF, HF, LF/HF), non-linear HRV parameters (SD1, SD2, SD1/SD2, SampEn, ApEn) and the respiratory rate (RR) were collected. The changes of the evaluated parameters as a consequence of the reduced blood volume were statistically evaluated. A statistically significant deviation from their baseline values could be found for RMSSD, rSDRM, pNN50, HF, LF/HF, SD1 and SD1/SD2 at a chamber pressures starting at −30 mmHg. Therefore, we support the proposition that heart rate variability analysis can help in detecting otherwise occult hypovolemia.

Measures of Compensatory Reserve are More Sensitive and Specific than Heart Rate Variability as Early Predictors of Hemodynamic Decompensation

BackgroundHemorrhage remains the leading cause of death following traumatic injury in both civilian and military settings. Heart rate variability (HRV) and complexity (HRC) have been recognized as potential “new vital signs” for monitoring trauma patients, although their benefit for triage decision support remains unclear. Another new paradigm, the compensatory reserve measurement (CRM), represents the integration of all mechanisms responsible for compensation during blood loss, designed to identify current physiologic status by estimating the progression toward hemodynamic decompensation. We hypothesized that CRM would provide greater sensitivity and specificity to detect progressive reductions in central circulating blood volume and onset of decompensation as compared to measurements of HRV and HRC.MethodsContinuous, noninvasive measurements of CRM and electrocardiogram (ECG) were made on 101 healthy volunteers (59 males, 42 females; mean±SD age 28±8 years) during stepwise progressive central hypovolemia to the point of decompensation. Lower body negative pressure (LBNP) was used to simulate hemorrhage by inducing the onset and progression of central hypovolemia. Time‐domain measures of HRV were taken from ECG signal data including R‐to‐R Interval Standard Deviation in milliseconds (ms), Root Mean Square Standard Deviation, percentage of RRI that vary by at least 50 ms, and amplitude measures of High Frequency Oscillations and Low Frequency Oscillations (CDMLF) obtained from the complex demodulation method. Measures of HRC included Sample Entropy, Fractal Dimension by Dispersion Analysis, Stationarity and Detrended Fluctuation Analysis. Data were analyzed using generalized estimating equations with compound symmetry covariance structures for longitudinal correlated data analysis of continuous variables, the results of which were used to report least‐square means with 95% confidence intervals at each LBNP level.ResultsCRM demonstrated superior ROC AUC (0.93) compared with all measures of HRV (≤ 0.84), and HRC (≤ 0.86). Sensitivity and specificity values at the ROC optimal thresholds were greater for CRM (SENS=0.84; SPEC=0.84) than HRV (SENS ≤ 0.78; SPEC ≤ 0.77) and HRC (SENS ≤ 0.79; SPEC ≤ 0.77). With standardized values across all levels of LBNP, CRM had a steeper decline, less variability, and explained a greater proportion of the variation in the data than both HRV and HRC during progressive hypovolemia.ConclusionConsistent with our hypothesis, CRM had greater sensitivity and specificity in detecting progressive reductions in circulating blood volume and decompensation than HRV and HRC. These findings add to the growing body of literature describing the advantages of CRM for detecting reductions in central blood volume. Most importantly, these results provide further support for the potential use of CRM in the triage and monitoring of patients at risk of circulatory shock following blood loss.Support or Funding InformationStudy funding was provided by a grant from the US Army Combat Casualty Care Research Program (D‐009‐2014‐USAISR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Differentiating compensatory mechanisms associated with low tolerance to central hypovolemia in women.

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

Detecting central hypovolemia in simulated hypovolemic shock by automated feature extraction with principal component analysis.

Assessment of the volume status by blood pressure (BP) monitoring is difficult, since baroreflex control of BP makes it insensitive to blood loss up to about one liter. We hypothesized that a machine learning model recognizes the progression of central hypovolemia toward presyncope by extracting information of the noninvasive blood pressure waveform parametrized through principal component analysis. This was tested in healthy volunteers exposed to simulated hemorrhage by lower body negative pressure (LBNP).Fifty‐six healthy volunteers were subjected to progressive central hypovolemia. A support vector machine was trained on the blood pressure waveform. Three classes of progressive stages of hypovolemia were defined. The model was optimized for the number of principal components and regularization parameter for penalizing misclassification (cost): C. Model performance was expressed as accuracy, mean squared error (MSE), and kappa statistic (inter‐rater agreement).Forty‐six subjects developed presyncope of which 41 showed an increase in model classification severity from baseline to presyncope. In five of the remaining nine subjects (1 was excluded) it stagnated. Classification of samples during baseline and end‐stage LBNP had the highest accuracy (95% and 50%, respectively). Baseline and first stage of LBNP demonstrated the lowest MSE (0.01 respectively 0.32). Model MSE and accuracy did not improve for C values exceeding 0.01. Adding more than five principal components did not further improve accuracy or MSE. Increment in kappa halted after 10 principal components had been added. Automated feature extraction of the blood pressure waveform allows modeling of progressive hypovolemia with a support vector machine. The model distinguishes classes between baseline and presyncope.

Measurement of compensatory reserve predicts racial differences in tolerance to simulated hemorrhage in women.

The compensatory reserve measurement (CRM) has been established to accurately measure the body's total integrated capacity to compensate for physiologic states of reduced central blood volume and predict hemodynamic decompensation associated with inadequate tissue oxygenation. We previously demonstrated that African American (AA) women have a higher tolerance to reductions in central blood volume. Therefore, we tested the hypothesis that the CRM would identify racial differences during simulated hemorrhage, before the onset of traditional signs/symptoms. We performed a retrospective analysis during simulated hemorrhage using lower-body negative pressure (LBNP) in 23 AA (22 ± 1 years; 24 ± 1 kg/m) and 31 white women (WW) (20 ± 1 years; 23 ± 1 kg/m). Beat-by-beat blood pressure (BP) and heart rate (HR) were recorded during progressive lower body negative pressure to presyncope. The BP waveforms were analyzed using a machine-learning algorithm to derive the CRM at each lower body negative pressure stage. Resting mean arterial BP (AA, 78 ± 3 mm Hg vs. WW, 74 ± 2 mm Hg) and HR (AA, 68 ± 2 bpm vs. WW, 65 ± 2 bpm) were similar between groups. The CRM progressively decreased during LBNP in both groups; however, the rate of decline in the CRM was less (p < 0.05) in AA. The CRM was 4% higher in AA at -15 mm Hg LBNP and progressively increased to 21% higher at -50 mm Hg LBNP (p < 0.05). However, changes in BP and HR were not different between groups. These data support the notion that the greater tolerance to simulated hemorrhage induced by LBNP in AA women can be explained by their greater capacity to protect the reserve to compensate for progressive central hypovolemia compared with WW, independent of standard vital signs. Diagnostic test, level II.

Modeling Arterial Pulse Pressure From Heart Rate During Sympathetic Activation by Progressive Central Hypovolemia.

Heart rate (HR) has an impact on the central blood pressure (BP) wave shape and is related to pulse wave velocity and therefore to timing and duration of systole and diastole. This study tested the hypothesis that in healthy subjects both in rest and during sympathetic stimulation the relation between HR and pulse pressure (PP) is described by a linear effect model. Forty-four healthy volunteers were subjected to sympathetic stimulation by continuous lower body negative pressure (LBNP) until the onset of pre-syncopal symptoms. Changes in PP and HR were tracked non-invasively and modeled by linear mixed effect (LME) models. The dataset was split into two groups: the first was used for creating a model and the second for its evaluation. Models were created on the data obtained during LBNP. Model performance was expressed as absolute median error (1st; 3rd quantiles) and bias with limits of agreement (LOA) between modeled and measured PP. From rest to sympathetic stimulation, mean BP was maintained while HR increased (~30%) and PP decreased gradually (~20%). During baseline, PP could be modeled with an absolute error of 6 (4; 10) mm Hg and geometric mean ratio of the bias was 0.97 (LOA: 0.8–1.1). During LBNP, absolute median model error was 5 (4; 8) mmHg with geometric mean ratio 1.02 (LOA: 0.8–1.3). In conclusion, both during rest and during sustained sympathetic outflow induced by progressive central hypovolemia, a LME model of HR provides for an estimate of PP in healthy young adults.