Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation.

This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566-595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249-1261, 2004). Since then there has been a great deal of new research that has applied LBNP to investigate complex physiological responses to a variety of challenges including orthostasis, hemorrhage, and other important stressors seen in humans such as microgravity encountered during spaceflight. The LBNP stimulus has provided novel insights into the physiology underlying areas such as intolerance to reduced central blood volume, sex differences concerning blood pressure regulation, autonomic dysfunctions, adaptations to exercise training, and effects of space flight. Furthermore, approaching cardiovascular assessment using prediction models for orthostatic capacity in healthy populations, derived from LBNP tolerance protocols, has provided important insights into the mechanisms of orthostatic hypotension and central hypovolemia, especially in some patient populations as well as in healthy subjects. This review also presents a concise discussion of mathematical modeling regarding compensatory responses induced by LBNP. Given the diverse applications of LBNP, it is to be expected that new and innovative applications of LBNP will be developed to explore the complex physiological mechanisms that underline health and disease.

Comparing the compensatory reserve metric obtained from invasive arterial measurements and photoplethysmographic volume-clamp during simulated hemorrhage.

PURPOSE: The compensatory reserve metric (CRM) is a novel tool to predict cardiovascular decompensation during hemorrhage. The CRM is traditionally computed using waveforms obtained from photoplethysmographic volume-clamp (PPGVC), yet invasive arterial pressures may be uniquely available. We aimed to examine the level of agreement of CRM values computed from invasive arterial-derived waveforms and values computed from PPGVC-derived waveforms. METHODS: Sixty-nine participants underwent graded lower body negative pressure to simulate hemorrhage. Waveform measurements from a brachial arterial catheter and PPGVC finger-cuff were collected. A PPGVC brachial waveform was reconstructed from the PPGVC finger waveform. Thereafter, CRM values were computed using a deep one-dimensional convolutional neural network for each of the following source waveforms; (1) invasive arterial, (2) PPGVC brachial, and (3) PPGVC finger. Bland-Altman analyses were used to determine the level of agreement between invasive arterial CRM values and PPGVC CRM values, with results presented as the Mean Bias [95% Limits of Agreement]. RESULTS: The mean bias between invasive arterial- and PPGVC brachial CRM values at rest, an applied pressure of -45mmHg, and at tolerance was 6% [-17%, 29%], 1% [-28%, 30%], and 0% [-25%, 25%], respectively. Additionally, the mean bias between invasive arterial- and PPGVC finger CRM values at rest, applied pressure of -45mmHg, and tolerance was 2% [-22%, 26%], 8% [-19%, 35%], and 5% [-15%, 25%], respectively. CONCLUSION: There is generally good agreement between CRM values obtained from invasive arterial waveforms and values obtained from PPGVC waveforms. Invasive arterial waveforms may serve as an alternative for computation of the CRM.

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

BACKGROUND: Based on previous experiments in nonhuman primates, we hypothesized that DO2 crit in humans is 5-6 ml O2 ·kg-1  min-1 . STUDY DESIGN AND METHODS: 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. RESULTS: 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 5.3 ml 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. CONCLUSIONS: Average DO2 crit in humans is 5.3 ml 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.

Compensatory reserve and pulse character: Enhanced potential to predict urgency for transfusion and other life-saving interventions after traumatic injury.

BACKGROUND: Field triage of trauma patients requires timely assessment of physiologic status to determine resuscitative needs. Vital signs and rudimentary assessments such as pulse character (PC) are used by first responders to guide decision making. The compensatory reserve measurement (CRM) has demonstrated utility as an easily interpretable method for assessing patient status. We hypothesized that the ability to identify injured patients requiring transfusion and other life-saving interventions (LSI) using a measurement of pulse character could be enhanced by the addition of the CRM. METHODS: We performed a prospective observational study on 300 trauma patients admitted to a level I trauma center. CRM was recorded continuously after device placement on arrival. Patient demographics, field and trauma resuscitation unit vital signs, therapeutic interventions, and outcomes were collected. A field SBP <100 mmHg was utilized as a surrogate for abnormal PC as previously validated. A patient with a CRM threshold value of <60% was considered clinically compromised with a risk of onset of decompensated shock. Data were analyzed to assess the capacity of CRM and pulse character separately or in combination to predict LSI defined as need for transfusion, intubation, tube thoracostomy, or operative/ angiographic hemorrhage control. RESULTS: An improvement in the predictive capability for LSI, transfusion, or a composite outcome was demonstrated by the combination of CRM and PC compared to either measure alone. CONCLUSIONS: Combining PC assessment with CRM has the potential to enhance the recognition of injured patients requiring life-saving intervention thus improving sensitivity of decision support for prehospital providers.

Wearable Sensors and Machine Learning for Hypovolemia Problems in Occupational, Military and Sports Medicine: Physiological Basis, Hardware and Algorithms.

Hypovolemia is a physiological state of reduced blood volume that can exist as either (1) absolute hypovolemia because of a lower circulating blood (plasma) volume for a given vascular space (dehydration, hemorrhage) or (2) relative hypovolemia resulting from an expanded vascular space (vasodilation) for a given circulating blood volume (e.g., heat stress, hypoxia, sepsis). This paper examines the physiology of hypovolemia and its association with health and performance problems common to occupational, military and sports medicine. We discuss the maturation of individual-specific compensatory reserve or decompensation measures for future wearable sensor systems to effectively manage these hypovolemia problems. The paper then presents areas of future work to allow such technologies to translate from lab settings to use as decision aids for managing hypovolemia. We envision a future that incorporates elements of the compensatory reserve measure with advances in sensing technology and multiple modalities of cardiovascular sensing, additional contextual measures, and advanced noise reduction algorithms into a fully wearable system, creating a robust and physiologically sound approach to manage physical work, fatigue, safety and health issues associated with hypovolemia for workers, warfighters and athletes in austere conditions.

AI-Enabled Advanced Development for Assessing Low Circulating Blood Volume for Emergency Medical Care: Comparison of Compensatory Reserve Machine-Learning Algorithms.

The application of artificial intelligence (AI) has provided new capabilities to develop advanced medical monitoring sensors for detection of clinical conditions of low circulating blood volume such as hemorrhage. The purpose of this study was to compare for the first time the discriminative ability of two machine learning (ML) algorithms based on real-time feature analysis of arterial waveforms obtained from a non-invasive continuous blood pressure system (Finometer®) signal to predict the onset of decompensated shock: the compensatory reserve index (CRI) and the compensatory reserve metric (CRM). One hundred ninety-one healthy volunteers underwent progressive simulated hemorrhage using lower body negative pressure (LBNP). The least squares means and standard deviations for each measure were assessed by LBNP level and stratified by tolerance status (high vs. low tolerance to central hypovolemia). Generalized Linear Mixed Models were used to perform repeated measures logistic regression analysis by regressing the onset of decompensated shock on CRI and CRM. Sensitivity and specificity were assessed by calculation of receiver-operating characteristic (ROC) area under the curve (AUC) for CRI and CRM. Values for CRI and CRM were not distinguishable across levels of LBNP independent of LBNP tolerance classification, with CRM ROC AUC (0.9268) being statistically similar (p = 0.134) to CRI ROC AUC (0.9164). Both CRI and CRM ML algorithms displayed discriminative ability to predict decompensated shock to include individual subjects with varying levels of tolerance to central hypovolemia. Arterial waveform feature analysis provides a highly sensitive and specific monitoring approach for the detection of ongoing hemorrhage, particularly for those patients at greatest risk for early onset of decompensated shock and requirement for implementation of life-saving interventions.

Compensatory reserve detects subclinical shock with more expeditious prediction for need of life-saving interventions compared to systolic blood pressure and blood lactate.

INTRODUCTION: We conducted a prospective observational study on 205 trauma patients at a level I trauma facility to test the hypothesis that a compensatory reserve measurement (CRM) would identify higher risk for progression to shock and/or need a life-saving interventions (LSIs) earlier than systolic blood pressure (SBP) and blood lactate (LAC). METHODS: A composite outcome metric included blood transfusion, procedural LSI, and mortality. Discrete measures assessed as abnormal (ab) were SBP <90 mmHg, CRM <60%, and LAC >2.0. A graded categorization of shock was defined as: no shock (normal [n] SBP [n-SBP], n-CRM, n-LAC); sub-clinical shock (ab-CRM, n-SBP, n-LAC); occult shock (n-SBP, ab-CRM, ab-LAC); or overt shock (ab-SBP, ab-CRM, ab-LAC). RESULTS: Three patients displayed overt shock, 53 displayed sub-clinical shock, and 149 displayed no shock. After incorporating lactate into the analysis, 86 patients demonstrated no shock, 25 were classified as sub-clinical shock, 91 were classified as occult shock, and 3 were characterized as overt shock. Each shock subcategory revealed a graded increase requiring LSI and transfusion. Initial CRM was associated with progression to shock (odds ratio = 0.97; p < .001) at an earlier time than SBP or LAC. CONCLUSIONS: Initial CRM uncovers a clinically relevant subset of patients who are not detected by SBP and LAC. Our results suggest CRM could be used to more expeditiously identify injured patients likely to deteriorate to shock, with requirements for blood transfusion or procedural LSI.

Efficacy of the compensatory reserve measurement in an emergency department trauma population.

BACKGROUND: The Compensatory Reserve Measurement (CRM) is a novel method used to provide early assessment of shock based on arterial wave form morphology changes. We hypothesized that (1) CRM would be significantly lower in those trauma patients who received life-saving interventions compared with those not receiving interventions, and (2) CRM in patients who received interventions would recover after the intervention was performed. STUDY DESIGN AND METHODS: We captured vital signs along with analog arterial waveform data from trauma patients meeting major activation criteria using a prospective study design. Study team members tracked interventions throughout their emergency department stay. RESULTS: Ninety subjects met inclusion with 13 receiving a blood product and 10 a major airway intervention. Most trauma was blunt (69%) with motor vehicle collisions making up the largest proportion (37%) of injury mechanism. Patients receiving blood products had lower CRM values just prior to administration versus those who did not (50% versus 58%, p = .045), and lower systolic pressure (SBP; 95 versus 123 mmHg, p = .005), diastolic (DBP; 62 versus 79, p = .007), and mean arterial pressure (MAP; 75 versus 95, p = .006), and a higher pulse rate (HR; 101 versus 89 bpm, p = .039). Patients receiving an airway intervention had lower CRM values just prior to administration versus those who did not (48% versus 58%, p = .062); however, SBP, DBP, MAP, and HR were not statistically distinguishable (p ≥ .645). CONCLUSIONS: Our results support our hypotheses that the CRM distinguished those patients who received blood or an airway intervention from those who did not, and increased appropriately after interventions were performed.

The compensatory reserve: potential for accurate individualized goal-directed whole blood resuscitation.

Hemorrhagic shock can be mitigated by timely and accurate resuscitation designed to restore adequate delivery of oxygen (DO2 ). Current doctrine of using systolic blood pressure (SBP) as a guide for resuscitation can be associated with increased morbidity. The compensatory reserve measurement (CRM) is a novel vital sign based on the recognition that the sum of all mechanisms that contribute to the compensatory response to hemorrhage reside in features of the arterial pulse waveform. CRM can be assessed continuously and non-invasively in real time. Compared to standard vital signs, CRM provides an early, as well as more sensitive and specific, indicator of patient hemorrhagic status since the activation of compensatory mechanisms occurs immediately at the onset of blood loss. Recent data obtained from our laboratory experiments on non-human primates have demonstrated that CRM is linearly related to DO2 during controlled progressive hemorrhage and subsequent whole blood resuscitation. We used this relationship to determine that the time of hemodynamic decompensation (i.e., CRM = 0%) is defined by a critical DO2 at approximately 5.3 mL O2 ∙kg-1 ∙min-1 . We also demonstrated that a target CRM of 35% during whole blood resuscitation only required replacement of 40% of the total blood volume loss to adequately sustain a DO2 more than 50% (i.e., 8.1 mL O2 ∙kg-1 ∙min-1 ) above critical DO2 (i.e., threshold for decompensated shock) while maintaining hypotensive resuscitation (i.e., SBP at ~90 mmHg). Consistent with our hypothesis, specific values of CRM can be used to accurately maintain DO2 thresholds above critical DO2 , avoiding the onset of hemorrhagic shock with whole blood resuscitation.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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.

Hemostatic responses to exercise, dehydration, and simulated bleeding in heat-stressed humans.

Heat stress followed by an accompanying hemorrhagic challenge may influence hemostasis. We tested the hypothesis that hemostatic responses would be increased by passive heat stress, as well as exercise-induced heat stress, each with accompanying central hypovolemia to simulate a hemorrhagic insult. In aim 1, subjects were exposed to passive heating or normothermic time control, each followed by progressive lower-body negative pressure (LBNP) to presyncope. In aim 2 subjects exercised in hyperthermic environmental conditions, with and without accompanying dehydration, each also followed by progressive LBNP to presyncope. At baseline, pre-LBNP, and post-LBNP (<1, 30, and 60 min), hemostatic activity of venous blood was evaluated by plasma markers of hemostasis and thrombelastography. For aim 1, both hyperthermic and normothermic LBNP (H-LBNP and N-LBNP, respectively) resulted in higher levels of factor V, factor VIII, and von Willebrand factor antigen compared with the time control trial (all P < 0.05), but these responses were temperature independent. Hyperthermia increased fibrinolysis [clot lysis 30 min after the maximal amplitude reflecting clot strength (LY30)] to 5.1% post-LBNP compared with 1.5% (time control) and 2.7% in N-LBNP ( P = 0.05 for main effect). Hyperthermia also potentiated increased platelet counts post-LBNP as follows: 274 K/µl for H-LBNP, 246 K/µl for N-LBNP, and 196 K/µl for time control ( P < 0.05 for the interaction). For aim 2, hydration status associated with exercise in the heat did not affect the hemostatic activity, but fibrinolysis (LY30) was increased to 6-10% when subjects were dehydrated compared with an increase to 2-4% when hydrated ( P = 0.05 for treatment). Central hypovolemia via LBNP is a primary driver of hemostasis compared with hyperthermia and dehydration effects. However, hyperthermia does induce significant thrombocytosis and by itself causes an increase in clot lysis. Dehydration associated with exercise-induced heat stress increases clot lysis but does not affect exercise-activated or subsequent hypovolemia-activated hemostasis in hyperthermic humans. Clinical implications of these findings are that quickly restoring a hemorrhaging hypovolemic trauma patient with cold noncoagulant fluids (crystalloids) can have serious deleterious effects on the body's innate ability to form essential clots, and several factors can increase clot lysis, which should therefore be closely monitored.

Unmasking the Hypovolemic Shock Continuum: The Compensatory Reserve.

Hypovolemic shock exists as a spectrum, with its early stages characterized by subtle pathophysiologic tissue insults and its late stages defined by multi-system organ dysfunction. The importance of timely detection of shock is well known, as early interventions improve mortality, while delays render these same interventions ineffective. However, detection is limited by the monitors, parameters, and vital signs that are traditionally used in the intensive care unit (ICU). Many parameters change minimally during the early stages, and when they finally become abnormal, hypovolemic shock has already occurred. The compensatory reserve (CR) is a parameter that represents a new paradigm for assessing physiologic status, as it comprises the sum total of compensatory mechanisms that maintain adequate perfusion to vital organs during hypovolemia. When these mechanisms are overwhelmed, hemodynamic instability and circulatory collapse will follow. Previous studies involving CR measurements demonstrated their utility in detecting central blood volume loss before hemodynamic parameters and vital signs changed. Measurements of the CR have also been used in clinical studies involving patients with traumatic injuries or bleeding, and the results from these studies have been promising. Moreover, these measurements can be made at the bedside, and they provide a real-time assessment of hemodynamic stability. Given the need for rapid diagnostics when treating critically ill patients, CR measurements would complement parameters that are currently being used. Consequently, the purpose of this article is to introduce a conceptual framework where the CR represents a new approach to monitoring critically ill patients. Within this framework, we present evidence to support the notion that the use of the CR could potentially improve the outcomes of ICU patients by alerting intensivists to impending hypovolemic shock before its onset.

Time course of compensatory physiological responses to central hypovolemia in high- and low-tolerant human subjects.

Lower body negative pressure (LBNP) simulates hemorrhage in human subjects. Most subjects (67%) exhibited high tolerance (HT) to hypovolemia, while the remainder (33%) had low tolerance (LT). To investigate the mechanisms for decompensation to central hypovolemia in HT and LT subjects, we characterized the time course of total peripheral resistance (TPR), heart rate (HR), and muscle sympathetic nerve activity (MSNA) during LBNP to tolerance determined by the onset of decompensation (presyncope, PS). We hypothesized that 1) maximum (Max) TPR, HR, and MSNA would coincide, and 2) PS would result from simultaneous decreases in TPR, HR, and MSNA in LT and HT subjects but occur earlier in LT than in HT subjects. Max TPR was lower and occurred earlier in LT ( n = 59) than in HT ( n = 113) subjects (LT: 24 ± 1 mmHg·min·1-1 at 756 ± 31 s; HT: 28 ± 1 mmHg·min·1-1 at 1,265 ± 37 s, P < 0.01). Max TPR occurred several minutes before PS. During subsequent decrease in TPR, HR and MSNA continued to increase. Max HR (LT: 111 ± 2 beat/min at 923 ± 27 s; HT: 130 ± 2 beats/min at 1489 ± 23 s, P < 0.01) occurred several seconds before PS. Higher MSNA ( P < 0.01) was attained in HT ( n = 10; 51 ± 5 bursts/min at max TPR; 54 ± 5 bursts/min at max HR) than LT subjects ( n = 4; 41 ± 8 bursts/min at max TPR; 39 ± 8 bursts/min at max HR). The onset of cardiovascular decompensation is a biphasic process in which vasodilation occurs before bradycardia and sympathetic withdrawal. This pattern was similar in LT and HT but occurred earlier in LT subjects. We conclude that sudden bradycardia plays a critical role in the determination of tolerance to central hypovolemia.

Tolerance to a haemorrhagic challenge during heat stress is improved with inspiratory resistance breathing.

NEW FINDINGS: What is the central question of this study? Does inspiratory resistance breathing improve tolerance to simulated haemorrhage in individuals with elevated internal temperatures? What is the main finding and its importance? The main finding of this study is that inspiratory resistance breathing modestly improves tolerance to a simulated progressive haemorrhagic challenge during heat stress. These findings demonstrate a scenario in which exploitation of the respiratory pump can ameliorate serious conditions related to systemic hypotension. ABSTRACT: Heat exposure impairs human blood pressure control and markedly reduces tolerance to a simulated haemorrhagic challenge. Inspiratory resistance breathing enhances blood pressure control and improves tolerance during simulated haemorrhage in normothermic individuals. However, it is unknown whether similar improvements occur with this manoeuvre in heat stress conditions. In this study, we tested the hypothesis that inspiratory resistance breathing improves tolerance to simulated haemorrhage in individuals with elevated internal temperatures. On two separate days, eight subjects performed a simulated haemorrhage challenge [lower-body negative pressure (LBNP)] to presyncope after an increase in internal temperature of 1.3 ± 0.1°C. During one trial, subjects breathed through an inspiratory impedance device set at 0 cmH2 O of resistance (Sham), whereas on a subsequent day the device was set at -7 cmH2 O of resistance (ITD). Tolerance was quantified as the cumulative stress index. Subjects were more tolerant to the LBNP challenge during the ITD protocol, as indicated by a > 30% larger cumulative stress index (Sham, 520 ± 306 mmHg min; ITD, 682 ± 324 mmHg min; P < 0.01). These data indicate that inspiratory resistance breathing modestly improves tolerance to a simulated progressive haemorrhagic challenge during heat stress.

Comparison of compensatory reserve during lower-body negative pressure and hemorrhage in nonhuman primates.

Compensatory reserve was measured in baboons (n = 13) during hemorrhage (Hem) and lower-body negative pressure (LBNP) using a machine-learning algorithm developed to estimate compensatory reserve by detecting reductions in central blood volume during LBNP. The algorithm calculates compensatory reserve index (CRI) from normovolemia (CRI = 1) to cardiovascular decompensation (CRI = 0). The hypothesis was that Hem and LBNP will elicit similar CRI values and that CRI would have higher specificity than stroke volume (SV) in predicting decompensation. Blood was removed in four steps: 6.25%, 12.5%, 18.75%, and 25% of total blood volume. Four weeks after Hem, the same animals were subjected to four levels of LBNP that was matched on the basis of their central venous pressure. Data (mean ± 95% confidence interval) indicate that CRI decreased (P < 0.001) from baseline during Hem (0.69 ± 0.10, 0.57 ± 0.09, 0.36 ± 0.10, 0.16 ± 0.08, and 0.08 ± 0.03) and LBNP (0.76 ± 0.05, 0.66 ± 0.08, 0.36 ± 0.13, 0.23 ± 0.11, and 0.14 ± 0.09). CRI was not different between Hem and LBNP (P = 0.20). Linear regression analysis between Hem CRI and LBNP CRI revealed a slope of 1.03 and a correlation coefficient of 0.96. CRI exhibited greater specificity than SV in both Hem (92.3 vs. 82.1) and LBNP (94.8 vs. 83.1) and greater ROC AUC in Hem (0.94 vs. 0.84) and LBNP (0.94 vs. 0.92). These data support the hypothesis that Hem and LBNP elicited the same CRI response, suggesting that measurement of compensatory reserve is superior to SV as a predictor of cardiovascular decompensation.

White blood cell concentrations during lower body negative pressure and blood loss in humans.

NEW FINDINGS: What is the central question of this study? Is lower body negative pressure a useful surrogate to study white blood cell responses to haemorrhage in humans? What is the main finding and its importance? We found that lower body negative pressure appears to be a useful surrogate to study the early white blood cell mobilization response during blood loss. Hypovolaemia has been associated with an immune response that might be secondary to sympathoexcitation. We tested the hypothesis that simulated hypovolaemia using lower body negative pressure (LBNP) and real hypovolaemia induced via experimental blood loss (BL) cause similar increases in the white blood cell concentration ([WBC]). We measured [WBC] and catecholamine concentrations in 12 men who underwent an LBNP and a BL protocol in a randomized order. We compared 45 mmHg of LBNP with 1000 ml of BL; therefore, [WBC] and catecholamine concentrations were plotted against central venous pressure to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Mean regression line slopes were similar for total [WBC] (LBNP 183 ± 4 µl-1  mmHg-1 versus BL 155 ± 109 µl-1  mmHg-1 , P = 0.15), neutrophils (LBNP 110 ± 2 µl-1  mmHg-1 versus BL 96 ± 72 µl-1  mmHg-1 , P = 0.15) and lymphocytes (LBNP 65 ± 21 µl-1  mmHg-1  versus BL 59 ± 38 µl-1  mmHg-1 , P = 0.90). Mean regression line slopes for adrenaline were similar (LBNP 15 ± 5 pg ml-1  mmHg-1 versus BL 16 ± 4 pg ml-1  mmHg-1 , P = 0.84) and were steeper during LBNP for noradrenaline (LBNP 28 ± 6 pg ml-1  mmHg-1 versus BL 9 ± 6 pg ml-1  mmHg-1 , P = 0.01). These data indicate that central hypovolaemia elicits a relative leucocytosis with a predominantly neutrophil-based response. Additionally, our results indicate that LBNP models the stimulus-response relationship between central venous pressure and [WBC] observed during BL.

Coagulation changes during lower body negative pressure and blood loss in humans.

We tested the hypothesis that markers of coagulation activation are greater during lower body negative pressure (LBNP) than those obtained during blood loss (BL). We assessed coagulation using both standard clinical tests and thrombelastography (TEG) in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5-min stages at 0, -15, -30, and -45 mmHg of suction. BL included 5 min at baseline and following three stages of 333 ml of blood removal (up to 1,000 ml total). Arterial blood draws were performed at baseline and after the last stage of each protocol. We found that LBNP to -45 mmHg is a greater central hypovolemic stimulus versus BL; therefore, the coagulation markers were plotted against central venous pressure (CVP) to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Paired t-tests were used to determine whether the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes for coagulation markers versus CVP fell on similar trajectories during both protocols, except for TEG α° angle (-0.42 ± 0.96 during LBNP vs. -2.41 ± 1.13°/mmHg during BL; P < 0.05). During both LBNP and BL, coagulation was accelerated as evidenced by shortened R-times (LBNP, 9.9 ± 2.4 to 6.2 ± 1.1; BL, 8.7 ± 1.3 to 6.4 ± 0.4 min; both P < 0.05). Our results indicate that LBNP models the general changes in coagulation markers observed during BL.

Fluid restriction during exercise in the heat reduces tolerance to progressive central hypovolaemia.

NEW FINDINGS: What is the central question of this study? Interactions between dehydration, as occurs during exercise in the heat without fluid replacement, and hyperthermia on the ability to tolerate central hypovolaemia are unknown. What is the main finding and its importance? We show that inadequate fluid intake during exercise in the heat can impair tolerance to central hypovolaemia even when it elicits only mild dehydration. These findings suggest that hydration during physical work in the heat has important military and occupational relevance for protection against the adverse effects of a subsequent haemorrhagic injury. This study tested the hypothesis that dehydration induced via exercise in the heat impairs tolerance to central hypovolaemia. Eleven male subjects (32 ± 7 years old, 81.5 ± 11.1 kg) walked (O2 uptake 1.7 ± 0.4 l min(-1) ) in a 40°C, 30% relative humidity environment on three occasions, as follows: (i) subjects walked for 90 min, drinking water to offset sweat loss (Hydrated, n = 11); (ii) water intake was restricted, and exercise was terminated when intestinal temperature increased to the same level as in the Hydrated trial (Isothermic Dehydrated, n = 11); and (iii) water intake was restricted, and exercise duration was 90 min (Time Match Dehydrated, n = 9). For each trial, tolerance to central hypovolaemia was determined following exercise via progressive lower body negative pressure and quantified as time to presyncope. Increases in intestinal temperature prior to lower body negative pressure were not different (P = 0.91) between Hydrated (1.1 ± 0.4°C) and Isothermic Dehydrated trials (1.1 ± 0.4°C), but both were lower than in the Time Match Dehydrated trial (1.7 ± 0.5°C, P < 0.01). Prior to lower body negative pressure, body weight was unchanged in the Hydrated trial (-0.1 ± 0.2%), but was reduced in Isothermic Dehydrated (-0.9 ± 0.4%) and further so in Time Match Dehydrated trial (-1.9 ± 0.6%, all P < 0.01). Time to presyncope was greater in Hydrated (14.7 ± 3.2 min) compared with Isothermic Dehydrated (11.9 ± 3.3 min, P < 0.01) and Time Match Dehydrated trials (10.2 ± 1.6 min, P = 0.03), which were not different (P = 0.19). These data indicate that inadequate fluid intake during exercise in the heat reduces tolerance to central hypovolaemia independent of increases in body temperature.