Reduction In Central Blood Volume Research Articles

Daily use of veno-constrictive thigh cuffs during 30 days of strict 6° head-down tilt bedrest to reverse the headward fluid shift

Introduction: Chronic exposure to weightlessness induces a persistent headward fluid shift, which may contribute to the development of Spaceflight Associated Neuro-ocular Syndrome (SANS). Strict 6° head-down tilt bedrest (HDTBR) is a spaceflight analog that induces a headward fluid shift and development of SANS findings, enabling the evaluation of potential countermeasures. Lower body exercise can induce a sustained post-exercise hyperemia thereby shifting blood away from the central circulation. In addition, veno-constrictive thigh cuffs (VTC) can sequester blood volume in the legs. The purpose of this study was to determine whether 6 hours of daily VTC use following cycling exercise (Ex+VTC) could reverse the headward fluid shift during 30 days of strict 6° HDTBR. We hypothesized that Ex+VTC would sequester fluid in the legs leading to increased thigh circumference and reduced stroke volume (SV), cardiac output (CO), internal jugular vein (IJV) cross-sectional area (CSA) and pressure, and intraocular pressure (IOP). Methods: Participants were randomly assigned to a Control (n=12, 6 female) or Ex+VTC (n=12, 4 female) group and completed baseline data collection (BDC) in the seated and supine posture followed by 30 days of strict 6° HDTBR. The Ex+VTC group completed a maximal exercise test on a cycle ergometer in 6° HDT posture during BDC to establish work rates during HDTBR. The Ex+VTC group performed 10 minutes of light cycle exercise, cycled for 45 minutes at 45% of their max wattage, and then donned VTC to ~50 mmHg for 6 hours on 6 of 7 days per week during HDTBR. Data were collected before exercise and 30 minutes and 6 hours after exercise and donning VTCs on days 3, 17, and 29 of HDTBR. Controls were studied at similar time points. Days were nested within the models. Mixed models were used to determine differences between groups in the change in thigh circumference measured using a flexible tape measure, bilateral IOP measured using tonometry, CO measured using the inert gas rebreathe technique (Innocor), and ultrasound of bilateral IJV CSA and pressure from before to 30 min and 6 hours after use of the countermeasure. Left and right IJV and IOP data were nested within each participant. Results: The Ex+VTC group completed all exercise sessions followed by 6 hours of VTC use. Compared to Control, thigh circumference was greater after 30 minutes (+1.3 vs. -0.2 cm, p<0.001) and 6 hours of VTC use (+2.5 cm vs. -0.1 cm in controls, p<0.001). SV (-38 vs. 2 ml, p<0.001) and CO (-1.5 vs. 0.3 L/min, p<0.001) were reduced at 30 minutes and 6 hours of VTC use (SV: -30 vs. 5 ml, p<0.001; CO: -1.1 vs. 0.6 L/min, p<0.001) compared to Control. IJV CSA and pressure were reduced at 30 minutes (CSA, p<0.001; pressure, p=0.001) and 6 hours of VTC use (CSA, p<0.001; pressure, p=0.007). IOP was not different compared to Control. Conclusions:Use of VTC for 6 hours after 45 minutes of exercise successfully sequestered fluid in the legs, leading to a reduction in central blood volume, IJV CSA, and IJV pressure. Thus, an Ex+VTC countermeasure resulted in a partial fluid shift reversal. This research was supported by the NASA Human Research Program. 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.

Verification and Validation of Lower Body Negative Pressure as a Non-Invasive Bioengineering Tool for Testing Technologies for Monitoring Human Hemorrhage.

Since hemorrhage is a leading cause of preventable death in both civilian and military settings, the development of advanced decision support monitoring capabilities is necessary to promote improved clinical outcomes. The emergence of lower body negative pressure (LBNP) has provided a bioengineering technology for inducing progressive reductions in central blood volume shown to be accurate as a model for the study of the early compensatory stages of hemorrhage. In this context, the specific aim of this study was to provide for the first time a systematic technical evaluation to meet a commonly accepted engineering standard based on the FDA-recognized Standard for Assessing Credibility of Modeling through Verification and Validation (V&V) for Medical Devices (ASME standard V&V 40) specifically highlighting LBNP as a valuable resource for the safe study of hemorrhage physiology in humans. As an experimental tool, evidence is presented that LBNP is credible, repeatable, and validated as an analog for the study of human hemorrhage physiology compared to actual blood loss. The LBNP tool can promote the testing and development of advanced monitoring algorithms and evaluating wearable sensors with the goal of improving clinical outcomes during use in emergency medical settings.

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.

Central Hypovolemia Detection During Environmental Stress-A Role for Artificial Intelligence?

The first step to exercise is preceded by the required assumption of the upright body position, which itself involves physical activity. The gravitational displacement of blood from the chest to the lower parts of the body elicits a fall in central blood volume (CBV), which corresponds to the fraction of thoracic blood volume directly available to the left ventricle. The reduction in CBV and stroke volume (SV) in response to postural stress, post-exercise, or to blood loss results in reduced left ventricular filling, which may manifest as orthostatic intolerance. When termination of exercise removes the leg muscle pump function, CBV is no longer maintained. The resulting imbalance between a reduced cardiac output (CO) and a still enhanced peripheral vascular conductance may provoke post-exercise hypotension (PEH). Instruments that quantify CBV are not readily available and to express which magnitude of the CBV in a healthy subject should remains difficult. In the physiological laboratory, the CBV can be modified by making use of postural stressors, such as lower body “negative” or sub-atmospheric pressure (LBNP) or passive head-up tilt (HUT), while quantifying relevant biomedical parameters of blood flow and oxygenation. Several approaches, such as wearable sensors and advanced machine-learning techniques, have been followed in an attempt to improve methodologies for better prediction of outcomes and to guide treatment in civil patients and on the battlefield. In the recent decade, efforts have been made to develop algorithms and apply artificial intelligence (AI) in the field of hemodynamic monitoring. Advances in quantifying and monitoring CBV during environmental stress from exercise to hemorrhage and understanding the analogy between postural stress and central hypovolemia during anesthesia offer great relevance for healthy subjects and clinical populations.

The design and use of a simple device for the MRI assessment of changes in cardiovascular function by lower-body negative-pressure-simulated reduction of central blood volume

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

Predictors of hemodynamic decompensation in progressive hypovolemia: Compensatory reserve versus heart rate variability.

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

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.

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.

Respiratory pump maintains cardiac stroke volume during hypovolemia in young, healthy volunteers.

Spontaneous breathing has beneficial effects on the circulation, since negative intrathoracic pressure enhances venous return and increases cardiac stroke volume. We quantified the contribution of the respiratory pump to preserve stroke volume during hypovolemia in awake, young, healthy subjects. Noninvasive stroke volume, cardiac output, heart rate, and mean arterial pressure (Finometer) were recorded in 31 volunteers (19 women), 19-30 yr old, during normovolemia and hypovolemia (approximating 450- to 500-ml reduction in central blood volume) induced by lower-body negative pressure. Control-mode noninvasive positive-pressure ventilation was employed to reduce the effect of the respiratory pump. The ventilator settings were matched to each subject's spontaneous respiratory pattern. Stroke volume estimates during positive-pressure ventilation and spontaneous breathing were compared with Wilcoxon matched-pairs signed-rank test. Values are overall medians. During normovolemia, positive-pressure ventilation did not affect stroke volume or cardiac output. Hypovolemia resulted in an 18% decrease in stroke volume and a 9% decrease in cardiac output ( P < 0.001). Employing positive-pressure ventilation during hypovolemia decreased stroke volume further by 8% ( P < 0.001). Overall, hypovolemia and positive-pressure ventilation resulted in a reduction of 26% in stroke volume ( P < 0.001) and 13% in cardiac output ( P < 0.001) compared with baseline. Compared with the situation with control-mode positive-pressure ventilation, spontaneous breathing attenuated the reduction in stroke volume induced by moderate hypovolemia by 30% (i.e., -26 vs. -18%). In the patient who is critically ill with hypovolemia or uncontrolled hemorrhage, spontaneous breathing may contribute to hemodynamic stability, whereas controlled positive-pressure ventilation may result in circulatory decompensation. NEW & NOTEWORTHY Maintaining spontaneous respiration has beneficial effects on hemodynamic compensation, which is clinically relevant for patients in intensive care. We have quantified the contribution of the respiratory pump to cardiac stroke volume and cardiac output in healthy volunteers during normovolemia and central hypovolemia. The positive hemodynamic effect of the respiratory pump was abolished by noninvasive, low-level positive-pressure ventilation. Compared with control-mode positive-pressure ventilation, spontaneous negative-pressure ventilation attenuated the fall in stroke volume by 30%.

Face cooling increases blood pressure during central hypovolemia.

A reduction in central blood volume can lead to cardiovascular decompensation (i.e., failure to maintain blood pressure). Cooling the forehead and cheeks using ice water raises blood pressure. Therefore, face cooling (FC) could be used to mitigate decreases in blood pressure during central hypovolemia. We tested the hypothesis that FC during central hypovolemia induced by lower-body negative pressure (LBNP) would increase blood pressure. Ten healthy participants (22 ± 2 yr, three women, seven men) completed two randomized LBNP trials on separate days. Trials began with 30 mmHg of LBNP for 6 min. Then, a 2.5-liter plastic bag of ice water (0 ± 0°C) (LBNP+FC) or thermoneutral water (34 ± 1°C) (LBNP+Sham) was placed on the forehead, eyes, and cheeks during 15 min of LBNP at 30 mmHg. Forehead temperature was lower during LBNP+FC than LBNP+Sham, with the greatest difference at 21 min of LBNP (11.1 ± 1.6 vs. 33.9 ± 1.4°C, P < 0.001). Mean arterial pressure was greater during LBNP+FC than LBNP+Sham, with the greatest difference at 8 min of LBNP (98 ± 15 vs. 80 ± 8 mmHg, P < 0.001). Cardiac output was higher during LBNP+FC than LBNP+Sham with the greatest difference at 18 min of LBNP (5.9 ± 1.4 vs. 4.9 ± 1.0 liter/min, P = 0.005). Forearm cutaneous vascular resistance was greater during LBNP+FC than LBNP+Sham, with the greatest difference at 15 min of LBNP (7.2 ± 3.4 vs. 4.9 ± 2.7 mmHg/perfusion units (PU), P < 0.001). Face cooling during LBNP increases blood pressure through increases in cardiac output and vascular resistance.

Wearable technology for compensatory reserve to sense hypovolemia.

Traditional monitoring technologies fail to provide accurate or early indications of hypovolemia-mediated extremis because physiological systems (as measured by vital signs) effectively compensate until circulatory failure occurs. Hypovolemia is the most life-threatening physiological condition associated with circulatory shock in hemorrhage or sepsis, and it impairs one's ability to sustain physical exertion during heat stress. This review focuses on the physiology underlying the development of a novel noninvasive wearable technology that allows for real-time evaluation of the cardiovascular system's ability to compensate to hypovolemia, or its compensatory reserve, which provides an individualized estimate of impending circulatory collapse. Compensatory reserve is assessed by real-time changes (sampled millions of times per second) in specific features (hundreds of features) of arterial waveform analog signals that can be obtained from photoplethysmography using machine learning and feature extraction techniques. Extensive experimental evidence employing acute reductions in central blood volume (using lower-body negative pressure, blood withdrawal, heat stress, dehydration) demonstrate that compensatory reserve provides the best indicator for early and accurate assessment for compromises in blood pressure, tissue perfusion, and oxygenation in resting human subjects. Engineering challenges exist for the development of a ruggedized wearable system that can measure signals from multiple sites, improve signal-to-noise ratios, be customized for use in austere conditions (e.g., battlefield, patient transport), and be worn during strenuous physical activity.

The Effect of Aging and Rapid Saline Infusion on Compensatory Reserve during Whole‐Body Passive Heat Stress

The compensatory reserve is defined as the physiological capacity to compensate for reductions in central blood volume. It is measured by a machine learning algorithm, called CRI, which analyzes continuous changes in the features of a photoplethysmographic signal obtained by finger pulse oximetry. The purpose of this study was 2‐fold. First, we examined the effect of healthy aging on compensatory reserve during normothermic and heat stress conditions. Second, we examined the effect of rapid saline infusion during heat stress on compensatory reserve. Eleven young (6 males/5 females; mean ± SD: age, 25 ± 4 years; height, 165 ± 6 cm; weight, 63 ± 9 kg) and ten aged (4 males/6 females; age, 69 ± 4 years; height, 165 ± 9 cm; weight, 68 ± 9 kg) adults were exposed to central hypovolemia via 15 and 30 mmHg of lower‐body negative pressure (LBNP) under normothermic and heat stress (increase in core temperature of 1.5°C) conditions. Approximately 10 min after the heat stress LBNP challenge, warm saline was rapidly infused (15 ml/kg in ~6 min) while subjects remained hyperthermic. Absolute CRI values (Table) range between 0 and 1, where 0 represents little to no reserve for cardiovascular compensation and 1 represents maximal physiological reserve to compensate for central hypovolemia. Under normothermic conditions, an age × LBNP level interaction was observed (P&lt;0.01). Relative to baseline, CRI was reduced during 15 mmHg LBNP in young (P&lt;0.01) but not aged (P=0.21) adults. During 30 mmHg LBNP, CRI was reduced in both groups (P≤0.01). During whole‐body passive heat stress, CRI was lower relative to normothermic baseline in both groups (P&lt;0.01). During subsequent LBNP, CRI was further reduced in young adults during 15 and 30 mmHg (P&lt;0.01). In aged adults, CRI was further reduced at 30 mmHg during heating (P=0.06), but not at 15mmHg (P=0.27). Relative to heat stress, rapid saline infusion did not affect CRI in young (P=0.47) or aged (P=0.99) adults. These results demonstrate that CRI responses at low levels of central hypovolemia (i.e. 15 mmHg ≈ 250 ml) differ between young and aged adults under normothermic and heat stress conditions. Furthermore, CRI is unaffected by rapid saline infusion performed under heat stress conditions in both young and aged adults.Support or Funding InformationFunded by the Department of Defense (W81XWH‐12‐1‐0152). CRI responses in young and aged adults. Normothermic baseline LBNP15 LBNP30 Heat stress LBNP15 LBNP30 Infusion Young 0.88±0.06 0.77±0.11* 0.53±0.17* 0.43±0.27* 0.31±0.20† 0.18±0.13† 0.40±0.18 Aged 0.84±0.20 0.79±0.21 0.67±0.24* 0.45±0.20* 0.40±0.20 0.35±0.23† 0.41±0.15 Values are mean ± SD. different from baseline at P≤0.05; different from heat stress at P≤0.06.

Comparison of Compensatory Reserve Index Before and After Analgesia

BACKGROUNDPrehospital assessment of cardiovascular stability during hemorrhage is unpredictable because standard vital signs do not predict cardiovascular shock until it is too late for the medic to respond with a life‐saving intervention. In an effort to improve survival from hemorrhage, a machine learning algorithm has been developed as an early predictor of cardiovascular shock. The algorithm is able to detect reductions in central blood volume during blood loss, and assess the individual's capacity to compensate for blood loss by calculating beat‐ to‐beat compensatory reserve index (CRI) from a finger photoplethysmography waveform. CRI=100 represents normovolemia and CRI=0 represents hypovolemia at the point of cardiovascular decompensation. The algorithm has been validated in blood loss studies in animals and humans; however these studies were conducted in the absence of other confounding factors associated with blood loss such as trauma and pain. The current study was designed to determine if pain, in the absence of trauma, affects CRI by comparing CRI before and after epidural anesthesia to provide analgesia during childbirth. The purpose of this study was to test the hypothesis that pain or analgesia does not affect CRI.METHODSThis study was conducted in healthy pregnant women (n=20) during the labor phase of childbirth. CRI was calculated from a finger pulse oximeter placed on the patient's index finger and connected to the DataOx™ CRI monitor. CRI was recorded for 1 hour before and 1 hour after epidural anesthesia.RESULTSCRI (mean ± SD) before analgesia was 83±11. CRI at 10, 20, 30, 40, 50, and 60 minutes after analgesia was 77±13, 80±13, 77±15, 81±16, 83±13, and 84±15, respectively. Repeated measures ANOVA revealed no statistical difference in CRI values before and after epidural anesthesia (p = 0.085). Pain scale scores before and after analgesia were 7±2 and 1±2, respectively.CONCLUSIONSThese results indicate that pain, as an independent factor (in the absence of blood loss or trauma), does not affect compensatory reserve, and provide preliminary evidence that pain associated with trauma may not affect the body's ability to compensate for blood loss. This study supports the use of pain management on the battlefield, and supports the utility of assessing compensatory reserve in the prehospital setting to improve survivability from combat trauma.Support or Funding InformationFUNDING: ­­­US Army MRMC Combat Casualty Care Research Program

Specificity of Compensatory Reserve vs SMO2, Lactate and ETCO2 as Early Predictors of Tolerance to Progressive Reductions in Central Blood Volume

Circulatory shock resulting from acute uncontrolled hemorrhage remains a leading cause of death in both military and civilian trauma. Early, accurate and reliable prediction of decompensation is associated with effective intervention and improved clinical outcomes. Individual tolerance to reduced central blood volume can serve as a model to assess the sensitivity and specificity of vital sign measurements. The compensatory reserve (CR) is a measurement of this capacity. Measurements of muscle oxygen saturation (SmO2), lactate and end tidal CO2 (ETCO2) have recently gained attention as potentially superior prognostic tools for early assessment of the status of patients with progressive hemorrhage, but fail to identify individual tolerance. We hypothesized that CR would be able to better predict hemodynamic compensation and provide greater specificity and sensitivity than SmO2, lactate, or ETCO2. To test this hypothesis, we employed lower body negative pressure (LBNP) on healthy human subjects until symptoms of presyncope were evident. Receiver operating characteristic area under the curve (ROC AUC), sensitivity and specificity were used to evaluate the ability of CRI and SmO2, lactate and ETCO2 to predict hemodynamic decompensation. CR had the superior ability to predict decompensation compared to SM02, lactate and ETCO2 (ROC AUC: 0.91 vs. 0.68; 0.54; 0.70 p&lt;0.0007), respectively. Similarly, CR also exhibited a greater sensitivity (0.87 vs. 0.65; .85, .89; p&lt;0.05) and specificity (0.80 vs. 0.63, 0.29, 0.54, p&lt;0.05). These findings support the notion that CR provides superior detection of hemodynamic compensation compared to measurements of tissue oxygenation, lactate and ETCO2.Support or Funding InformationUS Army MRMC Combat Casualty Care Research Program

Integrated Compensatory Responses in a Human Model of Hemorrhage.

Hemorrhage is the leading cause of trauma-related deaths, partly because early diagnosis of the severity of blood loss is difficult. Assessment of hemorrhaging patients is difficult because current clinical tools provide measures of vital signs that remain stable during the early stages of bleeding due to compensatory mechanisms. Consequently, there is a need to understand and measure the total integration of mechanisms that compensate for reduced circulating blood volume and how they change during ongoing progressive hemorrhage. The body's reserve to compensate for reduced circulating blood volume is called the 'compensatory reserve'. The compensatory reserve can be accurately evaluated with real-time measurements of changes in the features of the arterial waveform measured with the use of a high-powered computer. Lower Body Negative Pressure (LBNP) has been shown to simulate many of the physiological responses in humans associated with hemorrhage, and is used to study the compensatory response to hemorrhage. The purpose of this study is to demonstrate how compensatory reserve is assessed during progressive reductions in central blood volume with LBNP as a simulation of hemorrhage.

Specificity of Compensatory Reserve and Tissue Oxygenation as Early Predictors of Tolerance to Progressive Reductions in Central Blood Volume.

We previously reported that measurements of muscle oxygen saturation (SmO2) and the compensatory reserve index (CRI) provided earlier indication of reduced central blood volume than standard vital signs (e.g., blood pressure, heart rate, arterial oxygen saturation). In the present study, we hypothesized that the CRI would provide greater sensitivity and specificity to detect progressive decrease in central circulating blood volume compared with SmO2. Continuous noninvasive measures of CRI (calculated from feature changes in the photoplethysmographic arterial waveforms) were collected from 55 healthy volunteer subjects before and during stepwise lower body negative pressure (LBNP) to the onset of hemodynamic decompensation. Near infrared spectroscopy was used on the forearm to obtain deep SmO2, hydrogen ion concentration ([H]), and hemoglobin volume (HbT; decreases reflect vasoconstriction). CRI decreased by 97% in a linear fashion across progressive blood volume loss, with no clinically significant alterations in vital signs. The receiver operating characteristic (ROC) area under the curve (AUC) for the CRI was 0.91, with a sensitivity of 0.87 and specificity of 0.80, when predicting decompensation at progressive levels of LBNP. In comparison, SmO2, [H], and HbT had significantly lower ROC AUC, sensitivity and specificity values for detecting the same outcome. Consistent with our hypothesis, CRI detected central hypovolemia with significantly greater specificity than measures of tissue metabolism. Single measurement of CRI may enable more accurate triage, while CRI monitoring may allow for earlier detection of casualty deterioration.

The efficacy of novel anatomical sites for the assessment of muscle oxygenation during central hypovolemia

Muscle tissue oxygenation (SmO2) can track central blood volume loss associated with hemorrhage. Traditional peripheral measurement sites (e.g., forearm) may not be practical due to excessive movement or injury (e.g., amputation). The aim of this study was to evaluate the efficacy of three novel anatomical sites for the assessment of SmO2 under progressive central hypovolemia. 10 male volunteers were exposed to stepwise prone lower body negative pressure to decrease central blood volume, while SmO2 was assessed at four sites-the traditional site of the flexor carpi ulnaris (ARM), and three novel sites not previously investigated during lower body negative pressure, the deltoid, latissimus dorsi, and trapezius. SmO2 at the novel sites was compared to the ARM sensor and to stroke volume responses. A reduction in SmO2 was detected by the ARM sensor at the first level of lower body negative pressure (-15 mmHg; P = 0.007), and at -30 (the deltoid), -45 (latissimus dorsi), and -60 mmHg lower body negative pressure (trapezius) at the novel sites (P ≤ 0.04). SmO2 responses at all novel sites were correlated with responses at the ARM (R ≥ 0.89), and tracked the reduction in stroke volume (R ≥ 0.87); the latissimus dorsi site exhibited the strongest linear correlations (R ≥ 0.96). Of the novel sensor sites, the latissimus dorsi exhibited the strongest linear associations with SmO2 at the ARM, and with reductions in central blood volume. These findings have important implications for detection of hemorrhage in austere environments (e.g., combat) when use of a peripheral sensor may not be ideal, and may facilitate incorporation of these sensors into uniforms.

The Effect of Passive Heat Stress and Exercise-Induced Dehydration on the Compensatory Reserve During Simulated Hemorrhage

Compensatory reserve represents the proportion of physiological responses engaged to compensate for reductions in central blood volume before the onset of decompensation. We hypothesized that compensatory reserve would be reduced by hyperthermia and exercise-induced dehydration, conditions often encountered on the battlefield. Twenty healthy males volunteered for two separate protocols during which they underwent lower-body negative pressure (LBNP) to hemodynamic decompensation (systolic blood pressure <80 mm Hg). During protocol #1, LBNP was performed following a passive increase in core temperature of ∼1.2°C (HT) or a normothermic time-control period (NT). During protocol #2, LBNP was performed following exercise during which: fluid losses were replaced (hydrated), fluid intake was restricted and exercise ended at the same increase in core temperature as hydrated (isothermic dehydrated), or fluid intake was restricted and exercise duration was the same as hydrated (time-match dehydrated). Compensatory reserve was estimated with the compensatory reserve index (CRI), a machine-learning algorithm that extracts features from continuous photoplethysmograph signals. Prior to LBNP, CRI was reduced by passive heating [NT: 0.87 (SD 0.09) vs. HT: 0.42 (SD 0.19) units, P <0.01] and exercise-induced dehydration [hydrated: 0.67 (SD 0.19) vs. isothermic dehydrated: 0.52 (SD 0.21) vs. time-match dehydrated: 0.47 (SD 0.25) units; P <0.01 vs. hydrated]. During subsequent LBNP, CRI decreased further and its rate of change was similar between conditions. CRI values at decompensation did not differ between conditions. These results suggest that passive heating and exercise-induced dehydration limit the body's physiological reserve to compensate for further reductions in central blood volume.

Variability in integration of mechanisms associated with high tolerance to progressive reductions in central blood volume: the compensatory reserve.

High tolerance to progressive reductions in central blood volume has been associated with higher heart rate (HR), peripheral vascular resistance (PVR), sympathetic nerve activity (SNA), and vagally mediated cardiac baroreflex sensitivity (BRS). Using a database of 116 subjects classified as high tolerance to presyncopal‐limited lower body negative pressure (LBNP), we tested the hypothesis that subjects with greater cardiac baroreflex withdrawal (i.e., BRS > 1.0) would demonstrate greater LBNP tolerance associated with higher HR, PVR, and SNA. Subjects underwent LBNP to presyncope. Mean and diastolic arterial pressure (MAP; DAP) was measured by finger photoplethysmography and BRS (down sequence) was autocalculated (WinCPRS) as ∆R‐R Interval/∆DAP. DownBRS (ms/mmHg) was used to dichotomize subjects into two groups (Group 1 = DownBRS > 1.0, N = 49, and Group 2 = DownBRS < 1.0, N = 67) at the time of presyncope. Muscle SNA was measured directly from the peroneal nerve via microneurography (N = 19) in subjects from Groups 1 (n = 9) and 2 (n = 10). Group 1 (DownBRS > 1.0) had lower HR (107 ± 19 vs. 131 ± 20 bpm), higher stroke volume (45 ± 15 vs. 36 ± 15 mL), less SNA (45 ± 13 vs. 53 ± 7 bursts/min), and less increase in PVR (4.1 ± 1.3 vs. 4.5 ± 2.6) compared to Group 2 (DownBRS < 1.0). Both groups had similar tolerance times (1849 ± 260 vs. 1839 ± 253 sec), MAP (78 ± 11 vs. 79 ± 12 mmHg), compensatory reserve index (CRI) (0.10 ± 0.03 vs. 0.09 ± 0.01), and cardiac output (4.5 ± 1.2 vs. 4.7 ± 1.1 L/min) at presyncope. Contrary to our hypothesis, higher HR, PVR, SNA, and BRS were not associated with greater tolerance to reduced central blood volume. These data are the first to demonstrate the variability and uniqueness of individual human physiological strategies designed to compensate for progressive reductions in central blood volume. The sum total of these integrated strategies is accurately reflected by the measurement of the compensatory reserve.