Central Hypovolemia Research Articles

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y-Ca2+-Activated Potassium Channel-Nitric Oxide Mediated Mechanism.

BackgroundPostmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory.Methods and ResultsFemale Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB‐OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the OVX groups (P<0.05), with significant impairments in the AB‐OVX group (P<0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the AB‐OVX group (P<0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups (P<0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB‐OVX group (P<0.05), and vasodilation to the Ca2+‐activated potassium channel α‐subunit agonist NS‐1619 was impaired in both AB groups (P<0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca2+‐activated potassium channel α‐subunit protein was increased in AB groups (P<0.05).ConclusionsMechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca2+‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.

Non-linear Heart Rate and Blood Pressure Interaction in Response to Lower-Body Negative Pressure.

Early detection of hemorrhage remains an open problem. In this regard, blood pressure has been an ineffective measure of blood loss due to numerous compensatory mechanisms sustaining arterial blood pressure homeostasis. Here, we investigate the feasibility of causality detection in the heart rate and blood pressure interaction, a closed-loop control system, for early detection of hemorrhage. The hemorrhage was simulated via graded lower-body negative pressure (LBNP) from 0 to −40 mmHg. The research hypothesis was that a significant elevation of causal control in the direction of blood pressure to heart rate (i.e., baroreflex response) is an early indicator of central hypovolemia. Five minutes of continuous blood pressure and electrocardiogram (ECG) signals were acquired simultaneously from young, healthy participants (27 ± 1 years, N = 27) during each LBNP stage, from which heart rate (represented by RR interval), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were derived. The heart rate and blood pressure causal interaction (RR↔SBP and RR↔MAP) was studied during the last 3 min of each LBNP stage. At supine rest, the non-baroreflex arm (RR→SBP and RR→MAP) showed a significantly (p < 0.001) higher causal drive toward blood pressure regulation compared to the baroreflex arm (SBP→RR and MAP→RR). In response to moderate category hemorrhage (−30 mmHg LBNP), no change was observed in the traditional marker of blood loss i.e., pulse pressure (p = 0.10) along with the RR→SBP (p = 0.76), RR→MAP (p = 0.60), and SBP→RR (p = 0.07) causality compared to the resting stage. Contrarily, a significant elevation in the MAP→RR (p = 0.004) causality was observed. In accordance with our hypothesis, the outcomes of the research underscored the potential of compensatory baroreflex arm (MAP→RR) of the heart rate and blood pressure interaction toward differentiating a simulated moderate category hemorrhage from the resting stage. Therefore, monitoring baroreflex causality can have a clinical utility in making triage decisions to impede hemorrhage progression.

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.

A machine-learning based analysis for the recognition of progressive central hypovolemia

Objective: Traditional patient monitoring during surgery includes heart rate (HR), blood pressure (BP) and peripheral oxygen saturation. However, their use as predictors for central hypovolemia is limited, which may lead to cerebral hypoperfusion. The aim of this study was to develop a monitoring model that can indicate a decrease in central blood volume (CBV) at an early stage. Approach: Twenty-eight healthy subjects (aged 18–50 years) were included. Lower body negative pressure (−50 mmHg) was applied to induce central hypovolemia until the onset of pre-syncope. Ten beat-to-beat and four discrete parameters were measured, normalized, and filtered with a 30 s moving window. Time to pre-syncope was scaled from 100%–0%. A total of 100 neural networks with 5, 10, 15, 20, or 25 neurons in their respective hidden layer were trained by 10, 20, 40, 80, 160, or 320 iterations to predict time to pre-syncope for each subject. The network with the lowest average slope of a fitted line over all subjects was chosen as optimal. Main results: The optimal generalized model consisted of 10 hidden neurons, trained using 80 iterations. The slope of the fitted line on the average prediction was −0.64 (SD 0.35). The model recognizes in 75% of the subjects the need for intervention at >200 s before pre-syncope. Significance: We developed a neural network based on a set of physiological variables, which indicates a decrease in CBV even in the absence of HR and BP changes. This should allow timely intervention and prevent the development of symptomatic cerebral hypoperfusion.

Effects of transjugular intrahepatic portosystemic shunt (TIPS) on blood volume distribution in patients with cirrhosis

BackgroundCirrhosis is accompanied by portal hypertension with splanchnic and systemic arterial vasodilation, and central hypovolaemia.A transjugular intrahepatic portosystemic shunt (TIPS) alleviates portal hypertension, but also causes major haemodynamic changes. AimsTo investigate effects of TIPS on regional blood volume distribution, and systemic haemodynamics. MethodsThirteen cirrhotic patients had their regional blood volume distribution determined with gamma-camera technique before and after TIPS. Additionally, we measured systemic haemodynamics during liver vein and right heart catheterization. Central and arterial blood volume (CBV) and cardiac output (CO) were determined with indicator dilution technique. ResultsAfter TIPS, the thoracic blood volume increased (+10.4% of total blood volume (TBV), p<0.01), whereas the splanchnic blood volume decreased (−11.9% of TBV, p<0.001). CO increased (+22%, p<0.0001), and systemic vascular resistance decreased (−26%, p<0.001), whereas CBV did not change. Finally, right atrial pressure and mean pulmonary artery pressure increased after TIPS (+50%, p<0.005; +40%, p<0.05, respectively). ConclusionsTIPS restores central hypovolaemia by an increase in thoracic blood volume and alleviates splanchnic vascular congestion. In contrast, CBV seems unaltered. The improvement in central hypovolaemia is therefore based on an increase in thoracic blood volume that includes both the central venous and arterial blood volume. This is supported by an increase in preload, combined with a decrease in afterload.

Cerebral oxygenation and regional cerebral perfusion responses with resistance breathing during central hypovolemia.

Resistance breathing improves tolerance to central hypovolemia induced by lower body negative pressure (LBNP), but this is not related to protection of anterior cerebral blood flow [indexed by mean middle cerebral artery velocity (MCAv)]. We hypothesized that inspiratory resistance breathing improves tolerance to central hypovolemia by maintaining cerebral oxygenation (ScO2), and protecting cerebral blood flow in the posterior cerebral circulation [indexed by posterior cerebral artery velocity (PCAv)]. Eight subjects (4 male/4 female) completed two experimental sessions of a presyncopal-limited LBNP protocol (3 mmHg/min onset rate) with and without (Control) resistance breathing via an impedance threshold device (ITD). ScO2 (via near-infrared spectroscopy), MCAv and PCAv (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Hemodynamic responses were analyzed between the Control and ITD condition at baseline (T1) and the time representing 10 s before presyncope in the Control condition (T2). While breathing on the ITD increased LBNP tolerance from 1,506 ± 75 s to 1,704 ± 88 s (P = 0.003), both mean MCAv and mean PCAv were similar between conditions at T2 (P ≥ 0.46), and decreased by the same magnitude with and without ITD breathing (P ≥ 0.53). ScO2 also decreased by ~9% with or without ITD breathing at T2 (P = 0.97), and there were also no differences in deoxygenated (dHb) or oxygenated hemoglobin (HbO2) between conditions at T2 (P ≥ 0.43). There was no evidence that protection of regional cerebral blood velocity (i.e., anterior or posterior cerebral circulation) nor cerebral oxygen extraction played a key role in the determination of tolerance to central hypovolemia with resistance breathing.

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.

Face Cooling Increases Blood Pressure during Simulated Blood Loss

IntroductionBlood loss causes central hypovolemia and in severe instances, it can decrease blood pressure and lead to cardiovascular decompensation. Simple and quick interventions that can be used to prevent cardiovascular decompensation in pre‐hospital settings could be a valuable tool for first responsders. Cooling the forehead and cheeks using an ice/water slurry mixture has been shown to increase blood pressure for over 15 minutes. Therefore, face cooling could be used to mitigate decreases in blood pressure during blood loss.PurposeWe tested the hypothesis that face cooling during simulated blood loss will increase blood pressure.MethodsTen healthy participants (22 ± 2 years, 3 women) completed two randomized trials on separate days. Both trials began with 30 mmHg of lower body negative pressure (LBNP) to simulate blood loss for 6 minutes. Then, either a 2.5 L plastic bag of an ice/water slurry mixture (0 ± 0°C) (LBNP+FC) or a 2.5 L plastic bag of thermoneutral water (34 ± 1°C) (LBNP+SHAM) was placed on the forehead and eyes and 30 mmHg of LBNP was maintained for an additional 15 minutes. We continuously measured blood pressure (Penaz method), heart rate (ECG), stroke volume (Model flow), cardiac output, total peripheral resistance, and forehead temperature throughout the protocol.ResultsForehead temperature did not change from LBNP (34.2 ± 0.6°C) to LBNP+SHAM (33.9 ± 1.4°C, P &gt; 0.999) and decreased from LBNP (34.4 ± 0.5°C) to LBNP+FC (11.0 ± 1.6°C, P &lt; 0.001). Mean arterial pressure did not change from LBNP (82 ± 10 mmHg) to LBNP+SHAM (80 ± 8 mmHg, P = 0.978), but markedly increased during LBNP+FC. The peak increase from LBNP (77 ± 9 mmHg) was observed after 3 minutes of LBNP+FC (98 ± 15 mmHg, P &lt; 0.001). Heart rate during LBNP (76 ± 14 bpm, P = 0.978) was not different from LBNP+SHAM (75 ± 13 bpm). Heart rate was lower throughout LBNP+FC beginning at 2 minutes of FC (60 ± 16 bpm) versus LBNP (80 ± 19 bpm, P &lt; 0.001). Stroke volume did not change from LBNP (72 ± 15 mL) to LBNP+SHAM (67 ± 18 mL, P = 0.857). However, stroke volume increased from LBNP (78 ± 16 mL) to LBNP+FC, and peaked after 5 minutes of FC (97 ± 32 mL, P &lt; 0.001). Cardiac output did not change from LBNP (5.4 ± 1.0 L/min) to LBNP+SHAM (4.9 ± 1.0 L/min, P &gt; 0.415). Cardiac output slightly decreased from LBNP (6.2 ± 1.5 L/min) to 2 minutes of LBNP+FC (5.3 ± 1.6 L/min, P = 0.038). Total peripheral resistance did not change from LBNP (15.6 ± 3.7 mmHg/L/min) to LBNP+SHAM (17.3 ± 3.2 mmHg/L/min, P = 0.613). Total peripheral resistance throughout LBNP+FC was greater than LBNP. The peak increase in total peripheral resistance was observed after 2 minutes of LBNP+FC (20.0 ± 6.2 mmHg/L/min) versus LBNP (13.2 ± 3.9 mmHg/L/min, P &lt; 0.001).ConclusionsFace cooling during simulated moderate blood loss increases blood pressure through an increase in total peripheral resistance. Although more research is warranted, face cooling during blood loss is a potential simple and quick intervention that could delay cardiovascular decompensation.Support or Funding InformationUniversity at Buffalo IMPACT Award

Epinephrine Does Not Influence Baroreflex Sensitivity During Lower Body Negative Pressure to Physiological Tolerance

BackgroundThe baroreflex plays an integral role in blood pressure maintenance by altering heart rate and sympathetic activity in response to changes in arterial pressure. Baroreflex sensitivity (BRS) has been shown to decrease linearly during progressive exposure to central hypovolemia as induced by lower body negative pressure (LBNP), and can be used as an index of decompensation status during hemorrhage. Circulating epinephrine is significantly elevated during high stress situations such as hemorrhage; however, it is unclear whether epinephrine influences BRS during progressive exposure to central hypovolemia. Based on previous work, we hypothesized epinephrine would attenuate any reduction in spontaneous cardiac baroreflex sensitivity during LBNP.MethodsTen young (35±3 yrs), healthy (BMI 24±1 kg/m2) men and women (6M/4F) underwent LBNP protocols on 2 separate days consisting of a 10‐min pre‐infusion baseline, 15‐min infusion period (randomized to saline or epinephrine, 0.1 μg/kg/min), 10‐min post‐infusion baseline, and 5 minutes of LBNP at −15, −30, −45, −60, −70, and −80 mmHg until the onset of presyncope (range= −30 to −80 mmHg). Presyncope was defined as a rapid decrease in systolic blood pressure greater than 15 mmHg, 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. Spontaneous cardiac BRS was determined using the sequence method (WinCPRS). Data are reported from both 10‐min baselines and from 1 minute at 20, 40, 60, 80, and 100 percent of each individual's total LBNP exposure time.ResultsWe observed no significant differences in total exposure time (1475±150 vs. 1415±79s; p=0.69) or cumulative stress index (820±135 vs. 699±69 min*mmHg; p=0.37) between saline and epinephrine visits, respectively. Baroreflex sensitivity did not change during post‐infusion baselines (ΔDown‐Down =−2±1 vs. −2±2 ms/mmHg; saline vs. epinephrine, respectively; p=0.09). Baroreflex sensitivity was significantly reduced with LBNP (p&lt;0.01 main effect of LBNP). There was no difference between the change in baroreflex sensitivity during LBNP with saline or epinephrine infusion (ΔDown‐Down =−14±4 vs. −8±4 ms/mmHg, p=0.17).ConclusionsConsistent with previous work, spontaneous cardiac baroreflex sensitivity fell during LBNP. Contrary to our hypothesis, epinephrine infusion did not attenuate the fall in spontaneous cardiac baroreflex sensitivity observed during simulated blood loss. Because epinephrine did not alter the effect of LBNP on BRS, these data suggest that BRS may accurately reflect decompensation status during traumatic hemorrhage independent of elevated circulating epinephrine.Support or Funding InformationUS Army Medical Research and Materiel Command Contract W81XWH‐13‐2‐0038

Measurement of the Compensatory Reserve Predicts Racial Differences in Orthostatic Tolerance

The Compensatory Reserve Index (CRI) has recently been established to accurately measure the body's integrated capacity to compensate for physiological conditions of reduced central blood volume, and predict hemodynamic decompensation. We previously demonstrated that African American (AA) women have a higher tolerance to orthostatic stress. Therefore, we tested the hypothesis that the CRI would identify racial differences in orthostatic tolerance prior to the onset of traditional signs and symptoms. We measured beat‐by‐beat blood pressure (BP) and heart rate (HR) in 23 AA (22 ± 1 years; 24 ± 1 kg/m2) and 31 Caucasian women (20 ± 1 years; 23 ± 1 kg/m2) during progressive lower body negative pressure (LBNP) to presyncope. Blood pressure waveforms were analyzed using a machine‐learning algorithm to derive the CRI at each LBNP stage; stroke volume (SV) was derived from the Finometer (Model flow). Resting mean arterial BP (AA, 78 ± 3 vs. Caucasian, 74 ± 2 mmHg) and HR (AA, 68 ± 2 vs. Caucasian, 65 ± 2 bpm) were similar between groups. The CRI progressively decreased during LBNP in both groups, however the CRI in Caucasian women was 4% lower than AA women at −15 mmHg LBNP and decreased to 21% lower at −50 mmHg LBNP (P&lt;0.05). The rate of decline in SV during LBNP was greater in Caucasian women (ANOVA P&lt;0.05), and differences were noted as early as −20 mmHg. However changes in BP and HR during LBNP were not different between groups. At presyncope, mean arterial BP (AA, 66 ± 3 vs. white, 65 ± 4 mmHg) and HR (AA, 102 ± 4 vs. white, 97 ± 3 bpm) were similar between groups, as was the change in SV (AA, Δ −33 ± 2 vs. white, Δ −35 ± 3 mL). Finally, the time to presyncope was 1.6 minutes longer in AA women. These data support the notion that greater tolerance to the orthostatic stress induced by LBNP in AA women can be explained by their greater reserve to compensate for progressive central hypovolemia compared to Caucasian women. An important clinical translation is that the CRI provides a more sensitive and specific measure for early assessment of differences in orthostatic tolerance in comparison to traditional vital signs and symptoms or changes in hemodynamics.Support or Funding InformationResearch supported by funding from the Combat Casualty Care Research Program of the US Army Medical Research and Materiel Command and NIH HL071159.

Physiological Mechanisms Mediating the Coupling between Heart Period and Arterial Pressure in Response to Postural Changes in Humans.

The upright posture strengthens the coupling between heart period (HP) and systolic arterial pressure (SAP) consistently with a greater contribution of the arterial baroreflex to cardiac control, while paradoxically decreasing cardiac baroreflex sensitivity (cBRS). To investigate the physiological mechanisms that mediate the coupling between HP and SAP in response to different postures, we analyzed the cross-correlation functions between low-frequency HP and SAP fluctuations and estimated cBRS with the sequence technique in healthy male subjects during passive head-up tilt test (HUTT, n = 58), during supine wakefulness, supine slow-wave sleep (SWS), and in the seated and active standing positions (n = 8), and during progressive loss of 1 L blood (n = 8) to decrease central venous pressure in the supine position. HUTT, SWS, the seated, and the standing positions, but not blood loss, entailed significant increases in the positive correlation between HP and the previous SAP values, which is the expected result of arterial baroreflex control, compared with baseline recordings in the supine position during wakefulness. These increases were mirrored by increases in the low-frequency variability of SAP in each condition but SWS. cBRS decreased significantly during HUTT, in the seated and standing positions, and after blood loss compared with baseline during wakefulness. These decreases were mirrored by decreases in the RMSSD index, which reflects cardiac vagal modulation. These results support the view that the cBRS decrease associated with the upright posture is a byproduct of decreased cardiac vagal modulation, triggered by the arterial baroreflex in response to central hypovolemia. Conversely, the greater baroreflex contribution to cardiac control associated with upright posture may be explained, at least in part, by enhanced fluctuations of SAP, which elicit a more effective entrainment of HP fluctuations by the arterial baroreflex. These SAP fluctuations may result from enhanced fluctuations of vascular resistance specific to the upright posture, and not be driven by the accompanying central hypovolemia.

Muscle oxygen saturation increases during head-up tilt-induced (pre)syncope.

To evaluate whether muscle vasodilatation plays a role for hypotension developed during central hypovolaemia, muscle oxygenation (Sm O2 ) was examined during (pre)syncope induced by head-up tilt (HUT). Skin blood flow (SkBF) and oxygenation (Sskin O2 ) were determined because evaluation of Sm O2 may be affected by superficial tissue oxygenation. Furthermore, we evaluated cerebral oxygenation (Sc O2 ) and middle cerebral artery mean blood flow velocity (MCAvmean ). Twenty healthy male volunteers (median age 24 years; range 19-38) were subjected to passive 50° HUT for 1 h or until (pre)syncope. Sc O2 and Sm O2 (near-infrared spectroscopy), MCAvmean (transcranial Doppler) along with mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) (Modelflow® ) were determined. (Pre)syncopal symptoms appeared in 17 subjects after 11 min (median; range 2-34) accompanied by a decrease in MAP, SV, CO and TPR, while HR remained elevated. During (pre)syncope, Sc O2 decreased [73% (71-76; mean and 95% CI) to 68% (65-71), P < 0.0001] along with MCAvmean [40 (37-43) to 32 (29-35) cm s-1 , P < 0.0001]. In contrast, Sm O2 increased [63 (56-69)% to 71% (65-78), P < 0.0001], while Sskin O2 [64% (58-69) to 53% (47-58), P < 0.0001] and SkBF [71 (44-98) compared to a baseline of 99 (72-125) units, P = 0.020] were reduced. We confirm that the decrease in MAP during HUT is associated with a reduction in indices of cerebral perfusion. (Pre)syncope was associated with an increase in Sm O2 despite reduced Sskin O2 and SkBF, supporting that muscle vasodilation plays an important role in the circulatory events leading to hypotension during HUT.

Plasma hyperosmolality improves tolerance to combined heat stress and central hypovolemia in humans.

382 ± 145 mmHg × min, P = 0.04). However, no differences in mean arterial pressure (P = 0.10), heart rate (P = 0.09), or muscle sympathetic nerve activity (P = 0.60, n = 6) were observed between conditions. When individual data were assessed, LBNP tolerance improved ≥25% in eight subjects but remained unchanged in the remaining four subjects. In subjects who exhibited improved LBNP tolerance, plasma hyperosmolality resulted in elevated mean arterial pressure (ISO: 62 ± 10 vs. 72 ± 9 mmHg, P < 0.01) and a greater increase in heart rate (ISO: +12 ± 24 vs. HYPER: +23 ± 17 beats/min, P = 0.05) before presyncope. No differences in these variables were observed between conditions in subjects that did not improve LBNP tolerance (all P ≥ 0.55). These results suggest that plasma hyperosmolality improves tolerance to central hypovolemia during heat stress in most, but not all, individuals.

Effect of Aerobic Fitness on Hemodynamic Responses to Upright Tilting

The purpose of this study was to examine the influence of aerobic fitness on heart rate, systolic and diastolic blood pressure, mean arterial pressure, and pulse pressure responses to upright tilting in 10 below-average (BA Group) and 10 above-average (AA Group) aerobically fit adults. Aerobic fitness levels were predicted using the Astrand and Ryhming submaximal exercise test. Mean predicted maximal aerobic capacities were significantly higher (p less than .05) for the AA Group (46.0 +/- 6.0 mL.kg-1.min-1) compared with the BA Group (31.0 +/- 4.8 mL.kg-1.min-1) subjects. Heart rate and blood pressure responses were obtained at rest (supine position for 30 minutes) and during 5 minutes of upright tilting to 70 degrees (electric tilt table). A two-factor analysis of variance indicated that the increase in heart rate to upright tilting was significant (p less than .05) (significant treatment effect). More importantly, the study revealed a significant treatment x group interaction (p less than .05), indicating that the heart rate response for the BA Group was significantly greater than for the AA Group. Similar results occurred for blood pressure responses. A separate analysis of variance demonstrated significant changes in hemodynamic responses to upright tilting and significant treatment x group interactions. These results demonstrated significantly smaller (p less than .05) changes in blood pressure and heart rate to upright tilting for the AA Group compared with the BA Group. The results, therefore, indicate that reflex responses to central hypovolemia are different between above-average and below-average aerobically fit adults.

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

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 45mmHg of LBNP with 1000ml 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±4μl-1 mmHg-1 versus BL 155±109μl-1 mmHg-1 , P=0.15), neutrophils (LBNP 110±2μl-1 mmHg-1 versus BL 96±72μl-1 mmHg-1 , P=0.15) and lymphocytes (LBNP 65±21μl-1 mmHg-1 versus BL 59±38μl-1 mmHg-1 , P=0.90). Mean regression line slopes for adrenaline were similar (LBNP 15±5pgml-1 mmHg-1 versus BL 16±4 pgml-1 mmHg-1 , P=0.84) and were steeper during LBNP for noradrenaline (LBNP 28±6pgml-1 mmHg-1 versus BL 9±6pgml-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.

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.

Cardiovascular Response Patterns to Sympathetic Stimulation by Central Hypovolemia.

In healthy subjects, variation in cardiovascular responses to sympathetic stimulation evoked by submaximal lower body negative pressure (LBNP) is considerable. This study addressed the question whether inter-subject variation in cardiovascular responses coincides with consistent and reproducible responses in an individual subject. In 10 healthy subjects (5 female, median age 22 years), continuous hemodynamic parameters (finger plethysmography; Nexfin, Edwards Lifesciences), and time-domain baroreflex sensitivity (BRS) were quantified during three consecutive 5-min runs of LBNP at −50 mmHg. The protocol was repeated after 1 week to establish intra-subject reproducibility. In response to LBNP, 5 subjects (3 females) showed a prominent increase in heart rate (HR; 54 ± 14%, p = 0.001) with no change in total peripheral resistance (TPR; p = 0.25) whereas the other 5 subjects (2 females) demonstrated a significant rise in TPR (7 ± 3%, p = 0.017) with a moderate increase in HR (21 ± 9%, p = 0.004). These different reflex responses coincided with differences in resting BRS (22 ± 8 vs. 11 ± 3 ms/mmHg, p = 0.049) and resting HR (57 ± 8 vs. 71 ± 12 bpm, p = 0.047) and were highly reproducible over time. In conclusion, we found distinct cardiovascular response patterns to sympathetic stimulation by LBNP in young healthy individuals. These patterns of preferential autonomic blood pressure control appeared related to resting cardiac BRS and HR and were consistent over time.

Hemodynamic Stability to Surface Warming and Cooling During Sustained and Continuous Simulated Hemorrhage in Humans.

One in 10 deaths worldwide is caused by traumatic injury, and 30% to 40% of those trauma-related deaths are due to hemorrhage. Currently, warming a bleeding victim is the standard of care due to the adverse effects of combined hemorrhage and hypothermia on survival. We tested the hypothesis that heating is detrimental to the maintenance of arterial pressure and cerebral perfusion during hemorrhage, while cooling is beneficial to victims who are otherwise normothermic. Twenty-one men (31 ± 9 y) were examined under two separate protocols designed to produce central hypovolemia similar to hemorrhage. Following 15 min of supine rest, 10 min of 30 mm Hg of lower body negative pressure (LBNP) was applied. On separate randomized days, subjects were then exposed to skin surface cooling (COOL), warming (WARM), or remained thermoneutral (NEUT), while LBNP continued. Subjects remained in these thermal conditions for either 40 min of 30 mm Hg LBNP (N = 9), or underwent a continuous LBNP ramp until hemodynamic decompensation (N = 12). Arterial blood pressure during LBNP was dependent on the thermal perturbation as blood pressure was greater during COOL (P >0.001) relative to NEUT and WARM for both protocols. Middle cerebral artery blood velocity decreased (P <0.001) from baseline throughout sustained and continuous LBNP, but the magnitude of reduction did not differ between thermal conditions. Contrary to our hypothesis, WARM did not reduce cerebral blood velocity or LBNP tolerance relative to COOL and NEUT in normothermic individuals. While COOL increased blood pressure, cerebral perfusion and time to presyncope were not different relative to NEUT or WARM during sustained or continuous LBNP. Warming an otherwise normothermic hemorrhaging victim is not detrimental to hemodynamic stability, nor is this stability improved with cooling.

White Blood Cell Counts during Lower Body Negative Pressure vs. Blood Loss in Humans

Hypovolemia‐induced sympathoexcitation might initiate an immune response through an increase in circulating epinephrine and splenic demargination. We tested the hypothesis that lower body negative pressure (LBNP) and blood loss (BL) result in comparable increases in white blood cell counts (WBCs). We determined WBCs and epinephrine levels in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of suction. BL included 5 minutes at baseline and following three stages of 333 mL of blood removal (up to 1000 mL total). Blood draws were performed at baseline and after the last stage of each protocol. LBNP to −45mmHg was a greater central hypovolemic stimulus vs. BL, therefore WBCs and epinephrine concentrations were plotted against central venous pressure (CVP) to obtain stimulus‐response relationships using the linear regression line slopes for both protocols. Paired tests were used to determine if the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes fell on similar trajectories for total WBC (LBNP 183±46 vs. BL 155±109 mcL−1 *mmHg−1, p=0.15), neutrophils (LBNP 110±29 vs. BL 96±72 mcL−1 *mmHg−1, p=0.15) and lymphocytes (LBNP 65±21 vs. BL 59±38 mcL−1 *mmHg−1, p=0.90). Mean regression line slopes for epinephrine were similar as well (LBNP 15±5 vs. BL 16±4 pg *mL−1 *mmHg−1, p=0.84). Our results indicate that LBNP models the stimulus‐response relationship between CVP and WBCs observed during BL. Central hypovolemia, induced by LBNP or BL, elicits a relative leukocytosis with a predominantly neutrophil‐based response.Support or Funding InformationUS Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823