Levels Of Lower Body Negative Pressure Research Articles

A Novel Method for Measurement of Cardiovascular Responses to Lower Body Negative Pressure in the Awake Instrumented Rat.

Lower body negative pressure (LBNP) has been used for decades in humans to model arterial baroreceptor unloading and represents a powerful tool for evaluating cardiovascular responses to orthostatic challenge. However, LBNP studies in animals have been limited to conditions of anesthesia or sedation, where cardiovascular reflexes are altered. Given the consequent uncertainties, the usefulness of LBNP studies in these preclinical models has been severely hampered. Here we developed an approach using a novel system to study LBNP responses in awake rats instrumented for telemetric blood pressure (BP) measurement. BP responses to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by measurements under various treatments. In awake untreated rats, BP was well maintained up to -15 mmHg LBNP, and there was a robust baroreceptor response in heart rate (HR). Under anesthesia with 3% isoflurane, BP was not maintained at LBNP below -3 mmHg, and baroreceptor responses in HR were completely blocked, confirming the limited usefulness of this method under anesthesia. Interrogation of the autonomic pathways involved in the response revealed that muscarinic (atropine) and β1-adrenergic (atenolol) blockade, separately or together, blocked the HR responses, but BP remained well maintained. α1-adrenergic blockade (prazosin) severely blunted the ability to maintain BP in response to LBNP. These data are consistent with findings in human subjects in that the vascular component of the orthostatic reflex predominates in preserving BP. Validation of this novel method provides a valuable tool for investigating orthostatic (in)tolerance in a facile preclinical model.

Effect of Lower Body Negative Pressure (LBNP) on Blood Pressure in Awake Rats and Effects of Anesthesia

Lower body negative pressure (LBNP) has been used for decades in a variety of settings and species to model orthostatic challenge (OC) and baroreceptor unloading. However, due to physical constraints, measurements of blood pressure (BP) during LBNP have always been made in anesthetized animals, where cardiovascular reflexes are blunted or even blocked. In terminal procedures, for example, urethane is often used in an attempt to preserve some measure of autonomic reflex function during OC. More recently, investigators have used isoflurane in animals fitted with BP telemeters in order to perform longitudinal studies, but the extent to which various cardiovascular reflexes may be preserved is unknown. Here we have developed a novel method to apply lower body negative pressure in awake rats instrumented for BP measurement. Rats were placed into a tubular restraining device (5 cm diameter X 21 cm length), that is divided into an upper and lower chamber by two adjacent latex septa with small holes (~ 2 cm). Rats were positioned so that the septa form a seal at the lower margin of the thorax, thereby creating independent upper and lower chambers. Negative pressure was then applied to the lower chamber using a high-volume vacuum and the pressure controlled using an adjustable damper. BP measurements in response to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by induction of anesthesia and repetition of the LBNP protocol. The effects of pentobarbital (50mg/kg), ketamine/xylazine (70/6 mg/kg) and isoflurane (3%) were determined on separate days. BP and heart rate (HR) responses are shown in the Table. We found that BP was remarkably preserved in awake rats up to at least -9 mmHg LBNP, and thereafter (at -12 and -15 mmHg) decreased modestly. There was a robust baroreceptor-mediated increase in HR beginning at -6 mmHg. By contrast, under each anesthetic, blood pressure decreased dramatically and progressively with increasing LBNP, and the reflex increases in HR were entirely blocked (and actually inverted). These data indicate that the awake rat has robust mechanisms to preserve cardiovascular function during OC, and that these mechanisms are severely compromised during anesthesia. University of Cincinnati College of Medicine Innovation Seed Grant. 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.

Effects of menstrual cycle on hemodynamic and autonomic responses to central hypovolemia.

Estrogen and progesterone levels undergo changes throughout the menstrual cycle. Existing literature regarding the effect of menstrual phases on cardiovascular and autonomic regulation during central hypovolemia is contradictory. This study aims to explore the influence of menstrual phases on cardiovascular and autonomic responses in both resting and during the central hypovolemia induced by lower body negative pressure (LBNP). This is a companion paper, in which data across the menstrual phases from healthy young females, whose results are reported in Shankwar et al. (2023), were further analysed. The study protocol consisted of three phases: (1) 30 min of supine rest; (2) 16 min of four LBNP levels; and (3) 5 min of supine recovery. Hemodynamic and autonomic responses (assessed via heart rate variability, HRV) were measured before-, during-, and after-LBNP application using Task Force Monitor® (CNSystems, Graz, Austria). Blood was also collected to measure estrogen and progesterone levels. In this companion paper, we have exclusively assessed 14 females from the previous study (Shankwar et al., 2023): 8 in the follicular phase of the menstrual cycle (mean age 23.38 ± 3.58 years, height 166.00 ± 5.78 cm, weight 57.63 ± 5.39 kg and BMI of 20.92 ± 1.96 25 kg/m2) and 6 in the luteal phase (mean age 22.17 ± 1.33 years, height 169.83 ± 5.53 cm, weight 62.00 ± 7.54 kg and BMI of 21.45 ± 2.63 kg/m2). Baseline estrogen levels were significantly different from the follicular phase as compared to the luteal phase: (33.59 pg/ml, 108.02 pg/ml, respectively, p < 0.01). Resting hemodynamic variables showed no difference across the menstrual phases. However, females in the follicular phase showed significantly lower resting values of low-frequency (LF) band power (41.38 ± 11.75 n.u. and 58.47 ± 14.37 n.u., p = 0.01), but higher resting values of high frequency (HF) band power (58.62 ± 11.75 n.u. and 41.53 ± 14.37 n.u., p = 0.01), as compared to females in the luteal phase. During hypovolemia, the LF and HF band powers changed only in the follicular phase F(1, 7) = 77.34, p < 0.0001 and F(1, 7) = 520.06, p < 0.0001, respectively. The menstrual phase had an influence on resting autonomic variables, with higher sympathetic activity being observed during the luteal phase. Central hypovolemia leads to increased cardiovascular and autonomic responses, particularly during the luteal phase of the menstrual cycle, likely due to higher estrogen levels and increased sympathetic activity.

Sex Variations in Retinal Microcirculation Response to Lower Body Negative Pressure.

Lower body negative pressure (LBNP) is routinely used to induce central hypovolemia. LBNP leads to a shift in blood to the lower extremities. While the effects of LBNP on physiological responses and large arteries have been widely reported, there is almost no literature regarding how these cephalad fluid shifts affect the microvasculature. The present study evaluated the changes in retinal microcirculation parameters induced by LBNP in both males and females. Forty-four participants were recruited for the present study. The retinal measurements were performed at six time points during the LBNP protocol. To prevent the development of cardiovascular collapse (syncope) in the healthy participants, graded LBNP until a maximum of -40 mmHg was applied. A non-mydriatic, hand-held Optomed Aurora retinal camera was used to capture the retinal images. MONA Reva software (version 2.1.1) was used to analyze the central retinal arterial and venous diameter changes during the LBNP application. Repeated measures ANOVAs, including sex as the between-subjects factor and the grade of the LBNP as the within-subjects factor, were performed. No significant changes in retinal microcirculation were observed between the evaluated time points or across the sexes. Graded LBNP application did not lead to changes in the retinal microvasculature across the sexes. The present study is the first in the given area that attempted to capture the changes in retinal microcirculation caused by central hypovolemia during LBNP. However, further research is needed with higher LBNP levels, including those that can induce pre-fainting (presyncope), to fully understand how retinal microcirculation adapts during complete cardiovascular collapse (e.g., during hypovolemic shock) and/or during severe hemorrhage.

Cerebral blood flow autoregulation assessment by correlation analysis between mean arterial blood pressure and transcranial doppler sonography or near infrared spectroscopy is different: A pilot study.

Recently, cerebral autoregulation indices based on moving correlation indices between mean arterial pressure (MAP) and cerebral oximetry (NIRS, ORx) or transcranial Doppler (TCD)-derived middle cerebral artery flow velocity (Mx) have been introduced to clinical practice. In a pilot study, we aimed to evaluate the validity of these indices using incremental lower body negative pressure (LBNP) until presyncope representing beginning cerebral hypoperfusion as well as lower body positive pressure (LBPP) with added mild hypoxia to induce cerebral hyperperfusion in healthy subjects. Five male subjects received continuous hemodynamic, TCD and NIRS monitoring. Decreasing levels of LBNP were applied in 5-minute steps until subjects reached presyncope. Increasing levels of LBPP were applied stepwise up to 20 or 25 mmHg. Normobaric hypoxia was added until an oxygen saturation of 84% was reached. This was continued for 10 minutes. ORx and Mx indices were calculated using previously described methods. Both Indices showed an increase > 0.3 indicating impaired cerebral autoregulation during presyncope. However, there was no significant difference in Mx at presyncope compared to baseline (p = 0.168). Mean arterial pressure and cardiac output decreased only in presyncope, while stroke volume was decreased at the last pressure level. Neither Mx nor ORx showed significant changes during LBPP or hypoxia. Agreement between Mx and ORx was poor during the LBNP and LBPP experiments (R2 = 0.001, p = 0.3339). Mx and ORx represent impaired cerebral autoregulation, but in Mx this may not be distinguished sufficiently from baseline. LBPP and hypoxia are insufficient to reach the upper limit of cerebral autoregulation as indicated by Mx and ORx.

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.

Acute regulation of erythropoietin via lower body negative pressure: Influence of sex and age.

The regulation of erythropoiesis via hemodynamic stimuli such as reduced central blood volume (CBV) remains uncertain in women and elderly individuals. This study assessed the acute effects of lower body negative pressure (LBNP) on key endocrine biomarkers regulating erythropoiesis, that is, erythropoietin (EPO) and copeptin, in young and older women and men (n= 87). Transthoracic echocardiography and hemodynamics were assessed throughout incremental LBNP levels for 1hour, or until presyncope, with established methods. Venous blood samples were collected at baseline and immediately after termination of the orthostatic tolerance (OT) test for subsequent hormone analyses. The average age of young women and men (33.1± 6.0 vs. 29.5± 6.9yr) and older women and men (63.8± 8.0 vs. 65.3± 8.9yr) as well as their physical activity levels were matched within each age and sex group. CBV, as determined by right atrial volume, was reduced in all individuals at the end of the OT test (p< 0.001). The average OT time ranged from 50.1 to 58.1min in all individuals. LBNP increased circulating EPO in young women (p= 0.023) but not in young men or older individuals. Copeptin was increased in all individuals with LBNP but was exclusively associated with EPO in men (r= 0.39, p= 0.013). The present study indicates that the acute hemodynamic regulation of EPO production is both sex- and age-dependent.

Impact of Increasing Lower Body Negative Pressure and Its Abrupt Release on Left Ventricular Hemodynamics in Anesthetized Pigs.

Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from −15 to −45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure–volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.

Cardiovascular Responses to Mild Lower Body Negative Pressure during Spaceflight

IntroductionWeightlessness during spaceflight causes a chronic cephalad fluid shift that has been hypothesized to underlie numerous risks associated with spaceflight, including the development of ocular structural and functional changes and in rare cases venous thrombosis. Acute use of 25 mmHg lower body negative pressure (LBNP) during spaceflight can partially reverse this headward fluid shift and thus, may represent a promising countermeasure. However, there are limited data on how the cardiovascular system responds to sustained use of mild LBNP during spaceflight when cardiovascular deconditioning and adaptation may cause crewmembers to be more susceptible to orthostatic stressors than they would have been on Earth.PurposeThe purpose of this study was to quantify the heart rate (HR) and blood pressure response throughout ~60 minutes of exposure to 25 mmHg LBNP during spaceflight and determine if this response was augmented at later time points during 6‐month spaceflight missions.HypothesisWe hypothesized that crewmembers would experience an increase in HR during LBNP that would be sufficient to maintain mean arterial pressure (MAP) and this would not be augmented later in spaceflight.MethodsBrachial arterial pressure and HR were measured before and throughout ~60 min of 25 mmHg LBNP after ~45 days (FD45) and ~150 days (FD150) of spaceflight in 12 crewmembers. Total LBNP session times varied slightly due to logistical constraints. MAP and HR changes from baseline with LBNP exposure were analyzed with splines models. Marginal means were used for estimation and statistical comparisons across time and between flight days.ResultsBefore LBNP use, HR was 59 beats per min (BPM 95% CI: 56 – 62) and MAP was 93 mmHg (95% CI: 90 – 96). During LBNP exposure on FD45, HR increased by 9 BPM (95% CI: +7 – +10) at 15 min of exposure, and increased further to +10 BPM (95% CI: +8 – +12) at 30 min, and +11 BPM (95% CI: +9 – +14) at 45 min. On FD150, HR increased by 8 BPM (95% CI: +5 – +11) at 15 min of exposure but plateaued thereafter. MAP decreased by 5 mmHg (95% CI: ‐8 – ‐2) at 15 min and remained lower thereafter. MAP responses during ~60 min of LBNP exposure were not statistically different between FD45 and FD150. A total of 46 sessions of LBNP were successfully completed, and only a single case of mild hypotensive symptoms was reported, and this session was completed.ConclusionThese data suggest that the cardiovascular system can accommodate up to 60 min of sustained use of mild levels of LBNP during long‐duration spaceflight. There was a single report of mild hypotensive symptoms during use of LBNP by an individual who had low blood pressure prior to the start of the LBNP session. Thus, the absolute arterial blood pressure should be taken into consideration when determining if an LBNP session will be a potential challenge to the cardiovascular system during spaceflight.

Acute Fasting Decreases Tolerance to Lower Body Negative Pressure

Potential health benefits of an acute fast include reductions in blood pressure and increases in vagal cardiac control. These purported health benefits could put fasted humans at risk for cardiovascular collapse when exposed to central hypovolemia. Intense lower body negative pressure (LBNP) induces reproducible and reversible central hypovolemia. The purpose of this study was to investigate the influence of an acute 24‐hour fast on tolerance to severe LBNP. We tested the hypothesis that fasting would reduce tolerance to severe LBNP. Ours was a randomized, crossover design with an LBNP tolerance test occurring 3‐hrs postprandial (fed) and 24‐hrs postprandial (fast). A standardized meal was provided for both conditions. Criteria for termination of LBNP was; 1) a drop in systolic pressure of 15 mmHg or greater for 10 s and/or 2) sudden bradycardia. Eighteen young (23±0.7 yrs), normotensive, non‐obese (25±0.8 BMI), participants were brought to presyncope. We measured blood glucose (GLU), ketones (β‐OHB), and triglycerides (TRG) to confirm a successful fast. With subjects in a supine position, we recorded the ECG, beat‐to‐beat arterial pressure (finger plethysmography), muscle sympathetic nerve activity (MSNA; N=7), and forearm blood flow via venous occlusion plethysmography (VOP; N=12). Following a 5‐min baseline, LBNP was increased in 15 mmHg increments every 5 min in a stepwise manner until onset of presyncope. LBNP levels eliciting presyncope were denoted as 100% tolerance, data were assessed relative to this normalized maximal tolerance by expressing LBNP as 80, 40, and 0% (baseline) of maximal tolerance. Data are expressed as means ± SE. P‐values ≤ 0.05 were considered statistically significant and indicated by an (*). Changes in TRG, GLU and β‐OHB with fasting were consistent with expectations: TRG and GLU decreased (TRG; 130±16 fed vs. 78±9* mg/dL fast) (GLU; 100±3 fed vs. 81±2* mg/dL fast), and β‐OHB increased (β‐OHB; 0.12±.04 fed vs. 0.47±.11* mmol/L fast). Our participants were similarly hydrated, measured via urine specific gravity, (1.0168±.002 fed vs. 1.0122±.003 a.u. fast) and weight stable (77.8±3.6 fed vs. 76.9±3.4 kg fast) between conditions. Tolerance to central hypovolemia was decreased by ~10% in the fasted condition measured via total duration of negative pressure (1370±89 fed vs. 1229±94* s fast). At each normalized time point, heart rate and MSNA increased similarly in both conditions. Additionally, systolic blood pressure and stroke volume decreased similarly in both conditions. Both forearm blood flow (FBF) and forearm vascular resistance (FVR) are expressed as a percent change from 0 to 100%. ΔFBF significantly decreased in the fed condition at 100% (‐45.8±4.8 fed vs. ‐23.5±8.1* % fast) and ΔFVR increased in the fed condition at 100% (141.6±34.5 fed vs. 67.1±24.8* % fast). Our results suggest that acute fasting reduces tolerance to central hypovolemia by blunting increases in peripheral vascular resistance, and could lead to earlier decompensation when compared to the normal, fed state.

Sex-Specific Effect of Blood Oxygen-Carrying Capacity on Orthostatic Tolerance in Older Individuals.

Blood oxygen (O2)-carrying capacity is reduced with aging and has been previously linked with the capacity to withstand the upright posture, that is, orthostatic tolerance (OT). This study experimentally tested the hypothesis that a definite reduction in blood O2-carrying capacity via hemoglobin manipulation differently affects the OT of older women and men as assessed by lower body negative pressure (LBNP). Secondary hemodynamic parameters were determined with transthoracic echocardiography throughout incremental LBNP levels for 1 hour or until presyncope in healthy older women and men (total n = 26) matched by age (64 ± 7 vs 65 ± 8 years, p < .618) and physical activity levels. Measurements were repeated within a week period after a 10% reduction of blood O2-carrying capacity via carbon monoxide rebreathing and analyzed via 2-way analysis of covariance. In the assessment session, OT time was similar between women and men (53.5 ± 6.1 vs 56.4 ± 6.0 minutes, p = .238). Following a 10% reduction of blood O2-carrying capacity, OT time was reduced in women compared with men (51.3 ± 7.0 vs 58.2 ± 2.8 minutes, p = .003). The effect of reduced O2-carrying capacity on OT time differed between sexes (mean difference [MD] = -5.30 minutes, p = .010). Prior to presyncope, reduced O2-carrying capacity resulted in lower left ventricular end-diastolic volume (MD = -8.11 mL∙m-2, p = .043) and stroke volume (MD = -8.04 mL∙m-2, 95% confidence interval = -14.36, -1.71, p = .018) in women relative to men, even after adjusting for baseline variables. In conclusion, present results suggest that reduced blood O2-carrying capacity specifically impairs OT and its circulatory determinants in older women.

Internal Jugular Vein Volume Pulsatility during Head‐Down Tilt and Lower Body Negative Pressure

The objective of this study was to investigate the impact of internal jugular vein (IJV) distension on blood volume pulsatility. We hypothesized that pulsatility would be enhanced during cephalad fluid shifts and attenuated during caudal fluid shifts. Thirteen young healthy participants (8/5 male/female) were assessed during supine rest (repeated); 3 and 6 degrees of head-down tilt (HDT); and -20, -30, -40 mmHg of lower body negative pressure (LBNP) after at least 5 minutes in each condition. The order of the HDT and LBNP protocols was randomized. Right-side IJV blood volume was estimated using widefield near-infrared spectroscopy and quantified as jugular venous optical attenuation (JVA). Central venous pressure (CVP) was measured using a transducer attached to a catheter inserted into an antecubital vein in the right arm and corrected to the level of the heart. Participants were rightward tilted throughout to facilitate venous pressure measurements. Continuous signals were acquired for 30s in each condition and time-synced at 60Hz. Volume and pressure pulsatility were calculated as the differences between peak and nadir points along the cardiac cycle in JVA and CVP, respectively. Pressure-volume loops were created after ensemble averaging waveforms normalized to the cardiac cycle. Area of the pressure-volume loops and slope of the pressure-volume relationship during atrial filling (i.e., venous drainage) were assessed. Group mean JVA and CVP were highest during 6° HDT and lowest during -40 mmHg LBNP (see figure). Compared to baseline, JVA pulsatility was attenuated during -30 mmHg LBNP (P=0.048) and -40 mmHg LBNP (P=0.004) and was unchanged during each level of HDT (P>0.9). In contrast, CVP pulsatility was attenuated compared to baseline during -20, -30, and -40 mmHg LBNP (P<0.001) and was unchanged during each level of HDT (P>0.68). Area (P=0.088) and slope (P=0.269) of the pressure-volume loop were unchanged across all conditions. In multiple regression analysis, loop area was associated directly with pressure amplitude (P<0.001) but not volume amplitude (P=0.130); model r2=0.69. These data suggest that, while volume pulsatility did decrease when venous distension was reduced by higher levels of LBNP, this was primarily a function of changes in pressure pulsatilty. IJV compliance appeared to be unchanged across a wide range of venous distension. This work has relevance to states where venous pressure and distension are altered, including heart failure and hemorrhagic shock.

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.

Ground Reaction Forces generated by a Lower Body Negative Pressure Exercise Device for Space Flight

Loss of bone and muscle are leading concerns among astronauts during prolonged space flight. Lower body negative pressure (LBNP) chambers generate gravitational and cardiovascular stresses to maintain musculoskeletal strength and fitness by means of suction pressure. Ground reaction forces (GRFs) generated underneath the user’s feet are directly proportional to the level of negative pressure applied. However, the exact mechanism of GRF generation remains unresolved. We hypothesize that increasing the cross‐sectional area (CSA) of the user’s waist in contact with a flexible waist seal will increase the GRFs generated at a given vacuum pressure. To test our hypothesis, we collected GRFs generated by 6 healthy subjects under two conditions: original (unchanged) CSA of their waist and a greater waist CSA using expanded cushioning around waist of the same subjects. GRFs were measured with LBNP levels ranging from 0 (ambient pressure) to 50 mmHg with subjects lying in supine position to simulate microgravity. The original CSA of 467.7 cm2 ± 69.0 cm2 generated 118 % ± 31 % body weight at −50 mmHg. However, the larger CSA of 1,451.0 cm2 ± 331.0 cm2 generated a mean GRF of 146 % ± 31% body weight at −50 mmHg. A one‐way ANOVA test resulted in p‐values &lt; 0.05 for all pressures, denoting statistically significant increases in larger compared with original CSA GRF. The GRF generated with larger CSA followed this equation GRF = −1.8211 (LBNP) + 0.7899 while the GRF generated with original CSA followed the equation: GRF = −1.5079 (LBNP) + 0.3995. These data support our hypothesis that GRFs generated by LBNP are directly proportional to the waist CSA. Using this new concept, astronauts may generate GRFs at lower LBNP levels to prevent pre‐syncopal symptoms during exercise in space.Support or Funding InformationSupported by NASA grants NNX13AJ12G and NSSC19K0409.Average weight measurements with varying pressures for six volunteers; red is original CSA of subject's waist and blue is larger CSA.Figure 1

Cardiovascular Responses During Graded Lower‐Body Negative Pressure in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) represents approximately half of the known cases of heart failure in the United States, with equally poor outcomes and rising prevalence compared to heart failure with reduced ejection fraction (HFrEF). While changes in autonomic nervous system function is a well‐known feature of HFrEF pathophysiology, whether patients with HFpEF experience a similar decrement remains unknown. Therefore, we sought to evaluate the reflex cardiovascular responses to baroreflex unloading achieved via graded levels of lower‐body negative pressure (LBNP) in patients with HFpEF compared to healthy, age‐matched controls (CON). In six participants (three HFpEF (1 male, 70±3 yrs) and three CON (2 male, 74±2 yrs)), we assessed forearm blood flow (FBF; Doppler ultrasound), mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram) and forearm vascular conductance (FVC) at rest and throughout graded levels of LBNP (−10, −20, −30 and −40 mmHg). At rest, there were no significant differences between HFpEF and CON in FBF (109±32 vs. 85±29 ml/min), MAP (90±4 vs. 96±3 mmHg), HR (60±5 vs. 61±5 bpm), or FVC (1.19±0.33 vs. 0.89±0.28 ml/min/mmHg). The reflex tachycardic response to baroreflex unloading induced by LBNP was similar between patients with HFpEF and CON. Vasoconstriction in response to LBNP decreased FBF to a similar level in both HFpEF and CON (−10: 102±31 vs. 88±28 ml/min; −20: 95±30 vs. 76±25 ml/min; −30: 91±30 vs. 78±28 ml/min; −40: 91±33 vs. 71±21 ml/min, HFpEF vs. CON), with similar changes in FVC. Together, these preliminary data suggest that baroreflex‐mediated cardiac and vascular responses are not altered in patients with HFpEF, suggesting an absence of overt autonomic dysfunction is this patient group.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313, R56AG057584, T32HL139451) and the U.S. Department of Veterans Affairs (I01RX001311, I01RX001697, I01RX002323, I01RX000182).

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.

Effect of Lower Body Negative Pressure on Phase I Cardiovascular Responses at Exercise Onset.

We hypothesised that vagal withdrawal and increased venous return interact in determining the rapid cardiac output (CO) response (phase I) at exercise onset. We used lower body negative pressure (LBNP) to increase blood distribution to the heart by muscle pump action and reduce resting vagal activity. We expected a larger increase in stroke volume (SV) and smaller for heart rate (HR) at progressively stronger LBNP levels, therefore CO response would remain unchanged. To this aim ten young, healthy males performed a 50 W exercise in supine position at 0 (Control), −15, −30 and −45 mmHg LBNP exposure. On single beat basis, we measured HR, SV, and CO. Oxygen uptake was measured breath-by-breath. Phase I response amplitudes were obtained applying an exponential model. LBNP increased SV response amplitude threefold from Control to −45 mmHg. HR response amplitude tended to decrease and prevented changes in CO response. The rapid response of CO explained that of oxygen uptake. The rapid SV kinetics at exercise onset is compatible with an increased venous return, whereas the vagal withdrawal conjecture cannot be dismissed for HR. The rapid CO response may indeed be the result of two independent yet parallel mechanisms, one acting on SV, the other on HR.

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.

Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

Effect of Graded Sympathetic Activation on Regional Cerebral Vascular Conductance

The role of sympathetic nervous system in cerebral blood flow regulation remains poorly characterized. Previous studies have shown heterogeneity in regional cerebral circulation in response to various stimuli such as exercise, hypoxia, hypocapnia, etc. Recently, Ogoh et al. demonstrated that a moderate level (−50 Torr) of lower body negative pressure (LBNP) caused a significant reduction in internal carotid artery (ICA) blood flow, whereas vertebral artery (VA) blood flow remained unchanged, albeit trending towards a lower blood flow. Although a moderate increase in sympathetic nerve activity (SNA) occurs at −50 LBNP, it has been shown that SNA increases progressively with higher levels of LBNP. Whether VA blood flow is protected at higher levels of LBNP remains unknown. In this study, we tested the hypothesis that greater reflex‐mediated sympathetic activation via a higher level of LBNP will reduce conductance and blood flow to both the ICA and VA. In 9 young, healthy men, heart rate (ECG), arterial blood pressure (brachial sphygmomanometer), VA, ICA, and brachial artery blood flow (duplex Doppler ultrasound), middle cerebral artery (MCA) blood velocity (transcranial Doppler) and end‐tidal CO2 (ETCO2; capnograph) were measured at rest, and during 3–5 min of low, moderate and high LBNP (−30, −50, and −70 Torr, respectively). Conductance was calculated as blood flow of the respective artery/mean arterial pressure. Brachial artery blood flow and conductance were significantly reduced during all LBNP trials, indicating reflex‐mediated sympathetic vasoconstriction. Neither ETCO2 (Δ −1.9 ± 1.3 mmHg relative to baseline, p=0.18) nor any of the cerebral blood vessel measures were affected during −30 Torr LBNP. At −50 Torr LBNP, a reduction in ETCO2 (Δ −5.3 ± 1.6 mmHg relative to baseline, p=0.01) was accompanied by a reduction in ICA conductance (Δ −17.0 ± 8.4% baseline, p=0.057) whereas VA conductance remained unchanged (Δ −8.6 ± 5.6% baseline, p=0.24). Interestingly, with a similar reduction in ETCO2 at −70 Torr LBNP (Δ −4.3 ± 1.3 mmHg relative to baseline, p=0.04), there was a significant reduction in both ICA (Δ −13.1 ± 3.1% baseline, p=0.017) and VA conductance (Δ −20.4 ± 5.3% baseline, p=0.019). Thus, VA conductance was unaffected during low and moderate levels of LBNP however, high levels of LBNP induced a significant reduction in VA conductance and blood flow and this reduction appeared to be independent of the decrease in ETCO2. Collectively, these preliminary findings suggest that large increases in reflex‐mediated sympathetic activation via high levels of LBNP causes significant reductions in both ICA and VA conductance and blood flow.Support or Funding Information1 RO1 HL 127071This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.