Hg Lower Body Negative Pressure Research Articles

Impact of Daily Lower-Body Negative Pressure or Cycling Followed by Venous Constrictive Thigh Cuffs on Bedrest-Induced Orthostatic Intolerance.

Orthostatic intolerance occurs following immobilization in patients on Earth and in astronauts after spaceflight. Head-down tilt bedrest is a terrestrial model for weightlessness and induces orthostatic intolerance. We hypothesized that lower-body negative pressure (LBNP) or cycling followed by wearing venous constrictive thigh cuffs mitigates orthostatic intolerance after head-down tilt bedrest. We enrolled 47 healthy individuals (20 women, 35±9 years) to a 30-day strict head-down tilt bedrest study. During bedrest, they were assigned to 6 hours of 25 mm Hg LBNP (n=12) per day and 1 hour of supine cycling followed by 6 hours of venous constriction through thigh cuffs 6 days per week (n=12), 6 hours of daily upright sitting (positive control, n=11), or no countermeasure (negative control, n=12). We measured orthostatic tolerance as the time to presyncope during 80° head-up tilt testing with incremental LBNP before and immediately after bedrest. We determined plasma volume with carbon monoxide rebreathing before and at the end of bedrest. After bedrest, orthostatic tolerance decreased 540±457 seconds in the control group, 539±68 seconds in the cycling group, 217±379 seconds in the LBNP group, and 289±89 seconds in the seated group (P<0.0001 time point, P=0.009 for group differences). Supine and upright heart rate increased in all groups following bedrest. Plasma volume was only maintained in the cycling group but decreased in all others (interaction countermeasure×time point P<0.0001). Six hours of moderate LBNP training was as effective as sitting in attenuating orthostatic intolerance after 30 days of head-down tilt bedrest. Daily cycling exercise followed by 6 hours of wearing venous constrictive thigh cuffs, while maintaining plasma volume, did not improve orthostatic tolerance. URL: https://www.bfarm.de/EN; Identifiers: DRKS00027643 and DRKS00030848.

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.

Changes in Optic Nerve Head and Retinal Morphology During Spaceflight and Acute Fluid Shift Reversal

Countermeasures that reverse the headward fluid shift experienced in weightlessness have the potential to mitigate spaceflight-associated neuro-ocular syndrome. This study investigated whether use of the countermeasure lower-body negative pressure during spaceflight was associated with changes in ocular structure. To determine whether changes to the optic nerve head and retina during spaceflight can be mitigated by brief in-flight application of 25-mm Hg lower-body negative pressure. In the National Aeronautics and Space Administration's "Fluid Shifts Study," a prospective cohort study, optical coherence tomography scans of the optic nerve head and macula were obtained from US and international crew members before flight, in-flight, and up to 180 days after return to Earth. In-flight scans were obtained both under normal weightless conditions and 10 to 20 minutes into lower-body negative pressure exposure. Preflight and postflight data were collected in the seated, supine, and head-down tilt postures. Crew members completed 6- to 12-month missions that took place on the International Space Station. Data were analyzed from 2016 to 2021. Spaceflight and lower-body negative pressure. Changes in minimum rim width, optic cup volume, Bruch membrane opening height, peripapillary total retinal thickness, and macular thickness. Mean (SD) flight duration for the 14 crew members (mean [SD] age, 45 [6] years; 11 male crew members [79%]) was 214 (72) days. Ocular changes on flight day 150, as compared with preflight seated, included an increase in minimum rim width (33.8 μm; 95% CI, 27.9-39.7 μm; P < .001), decrease in cup volume (0.038 mm3; 95% CI, 0.030-0.046 mm3; P < .001), posterior displacement of Bruch membrane opening (-9.0 μm; 95% CI, -15.7 to -2.2 μm; P = .009), and decrease in macular thickness (fovea to 500 μm, 5.1 μm; 95% CI, 3.5-6.8 μm; P < .001). Brief exposure to lower-body negative pressure did not affect these parameters. Results of this cohort study suggest that peripapillary tissue thickening, decreased cup volume, and mild central macular thinning were associated with long-duration spaceflight. Acute exposure to 25-mm Hg lower-body negative pressure did not alter optic nerve head or retinal morphology, suggesting that longer durations of a fluid shift reversal may be needed to mitigate spaceflight-induced changes and/or other factors are involved.

Yoga Practitioners Exhibit Higher Parasympathetic Activity and Baroreflex Sensitivity and Better Adaptability to 40 mm Hg Lower-Body Negative Pressure.

Yoga has been shown to improve autonomic conditioning in humans, as evidenced by the enhancement of parasym-pathetic activity and baroreflex sensitivity. Therefore, we hypothesized that the experience of yoga may result in adaptation to acute hemodynamic changes. To decipher the long-term effects of yoga on cardiovascular variability, yoga practitioners were compared to yoga-naïve subjects during exposure to -40 mm Hg lower-body negative pressure (LBNP). A comparative study was conducted on 40 yoganaïve subjects and 40 yoga practitioners with an average age of 31.08 ± 7.31 years and 29.93 ± 7.57 years, respectively. Heart rate variability, blood pressure variability, baroreflex sensitivity, and correlation between systolic blood pressure and RR interval were evaluated at rest and during LBNP. In yoga practitioners, the heart rate was lower in supine rest (p = 0.011) and during LBNP (p = 0.043); the pNN50 measure of heart rate variability was higher in supine rest (p = 0.011) and during LBNP (p = 0.034). The yoga practitioners' standard deviation of successive beat-to-beat blood pressure intervals of systolic blood pressure variability was lower in supine rest (p = 0.034) and during LBNP (p = 0.007), with higher sequence baroreflex sensitivity (p = 0.019) and ~ high-frequency baroreflex sensitivity. Mean systolic blood pressure and RR interval were inversely correlated in the yoga group (r = -0.317, p = 0.049). The yoga practitioners exhibited higher parasympathetic activity and baroreflex sensitivity with lower systolic blood pressure variability, indicating better adaptability to LBNP compared to the yoga-naïve group. Our findings indicate that the yoga module was helpful in conditions of hypovolemia in healthy subjects; it is proposed to be beneficial in clinical conditions associated with sympathetic dominance, impaired barore-flex sensitivity, and orthostatic intolerance.

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

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

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.

Comparison of Compensatory Reserve Index during Lower Body Negative Pressure and Hemorrhage

A machine learning algorithm has been developed to detect reductions in central blood volume during lower body negative pressure (LBNP), a model of hemorrhage (Hem) which causes shifts in blood to the legs and elicits central hypovolemia. The algorithm calculates compensatory reserve index (CRI) where CRI=1 represents normovolemia and CRI=0 represents hypovolemia at the point of cardiovascular decompensation. The purpose of this study was to test the hypothesis that actual Hem and matching LBNP applications will elicit similar CRI values. This study compared CRI during Hem and matching LBNP in baboons. CRI was calculated from the arterial pressure waveform measured in baboons during Hem and LBNP (n=13). Blood was removed in four steps: 6.25%, 12.5%, 18.75%, and 25% of total blood volume. Shed blood was returned and the animals were allowed to recover. Four weeks after the Hem protocol, the same animals were subjected to four levels of LBNP which matched cardiovascular responses during Hem. Statistical analysis was performed using two way repeated measures ANOVA and linear regression analysis. Data are shown below as mean±95% confidence interval. CRI decreased significantly during each step of Hem and LBNP (p 蠄 0.003). CRI was not different between Hem and LBNP. Linear regression analysis between Hem CRI and LBNP CRI revealed slope of 1.03 and an adjusted R2 of 0.98. Hem Volume (ml/kg) Hem CRI LBNP (mm Hg) LBNP CRI 0 0.69 ± 0.10 0 0.76 ± 0.05 4.5 ± 0.1 0.57 ± 0.09 -22 ± 4 0.66 ± 0.08 9.1 ± 0.1 0.36 ± 0.08 -41 ± 4 0.36 ± 0.13 13.6 ± 0.2 0.16 ± 0.08 -54 ± 6 0.23 ± 0.11 17.8 ± 0.4 0.08 ± 0.03 -71 ± 5 0.14 ± 0.09 Conclusions Stepwise Hem and matching LBNP levels which are used as surrogates for actual blood loss elicited the same values of CRI. This study supports the validity of CRI as an index of central hypovolemia associated with Hem. FUNDING: US Army MRMC Combat Casualty Care Research Program

Evidence for a higher risk of hypovolemia-induced hemodynamic instability in females: implications for decision support during prehospital triage.

Lower body negative pressure (LBNP) simulates hemorrhage, and tolerance to LBNP (time to presyncope [TTP]) is indicative of tolerance to blood loss. The purpose of this study was to predict TTP based on demographic characteristics (sex, age, height, and body mass index) and physiological variables (heart rate [HR], systolic arterial pressure, diastolic arterial pressure [DAP], pulse pressure, stroke volume, total peripheral resistance [TPR], and baroreflex sensitivity [BRS]) at baseline, and during 2 levels of LBNP (-15, -30 mm Hg). Multiple linear regression analysis was used to create a model to predict TTP (range: 670 to 2516 seconds, n=187) based on demographic characteristics and physiological variables changes (Δ) from baseline to -30 mm Hg LBNP. The prediction model revealed that TTP (seconds)=1667.5+(5.1×Age)+(61.1×Sex)-(21.5×ΔHR)+(55.3×ΔDAP)-(88.2×ΔTPR)-(4.9×ΔBRS). Most significantly, our analysis demonstrated a lesser survival trajectory for females given the same rate and magnitude of hemorrhage compared to males. Young age and female sex are predictors of low tolerance to blood loss, and should be considered for early triage in the prehospital setting.

Peripheral Perfusion Index as an Early Predictor for Central Hypovolemia in Awake Healthy Volunteers

In healthy volunteers, we investigated the ability of the pulse oximeter-derived peripheral perfusion index (PPI) to detect progressive reductions in central blood volume. Twenty-five awake, spontaneously breathing, healthy male volunteers were subjected to progressive reductions in central blood volume by inducing stepwise lower body negative pressure (LBNP) with 20 mm Hg for 5 minutes per step, from 0 to -20, -40, -60, and back to 0 mm Hg. Throughout the procedure, stroke volume (SV), heart rate (HR), and mean arterial blood pressure were recorded using volume-clamp finger plethysmography. Assessment of the PPI was done by pulse oximetry. Additionally, the forearm-to-fingertip skin-temperature gradient was measured. Data are presented as mean±SE. PPI underwent log transformation and is presented as median (25th-75th). Of the 25 subjects, one did not complete the study because of cardiovascular collapse. After the first LBNP step (-20 mm Hg), PPI decreased from 2.2 (1.6-3.3) to 1.2 (0.8-1.6) (P=0.007) and SV decreased from 116±3.0 mL to 104±2.6 mL (P=0.02). The magnitude of the PPI decrease (41%±6.0%) was statistically different from that observed for SV (9%±1.3%) and HR (3%±1.9%). During progression of LBNP, SV decreased and HR increased progressively with the increased applied negative pressure, whereas the PPI remained low throughout the remainder of the protocol and returned to baseline values when LBNP was released. At -60 mm Hg LBNP, SV decreased and HR increased by 36%±0.9% and 33%±2.4% from baseline, respectively. Mean arterial blood pressure remained in the same range throughout the experiment. These results indicate that the pulse oximeter-derived PPI may be a valuable adjunct diagnostic tool to detect early clinically significant central hypovolemia, before the onset of cardiovascular decompensation in healthy volunteers.

Lightweight noninvasive trauma monitor for early indication of central hypovolemia and tissue acidosis

Hemorrhage is a major cause of soldier death; it must be quickly identified and appropriately treated. We developed a prototype patient monitor that noninvasively and continuously determines muscle oxygen saturation (SmO₂), muscle pH (pHm), and a regional assessment of blood volume (HbT) using near-infrared spectroscopy. Previous demonstration in a model of progressive, central hypovolemia induced by lower body negative pressure (LBNP) showed that SmO₂ provided an early indication of impending hemodynamic instability in humans. In this review, we expand the number of subjects and provide an overview of the relationship between the muscle and sublingual microcirculation in this model of compensated shock. Healthy human volunteers (n = 30) underwent progressive LBNP in 5-minute intervals. Standard vital signs, along with stroke volume (SV), total peripheral resistance, functional capillary density, SmO₂, HbT, and pHm were measured continuously throughout the study. SmO₂ and SV significantly decreased during the first level of central hypovolemia (-15 mm Hg LBNP), whereas vital signs were later indicators of impending cardiovascular collapse. SmO₂ declined with SV and inversely with total peripheral resistance throughout LBNP. HbT was correlated with declining functional capillary density, suggesting vasoconstriction as a cause for decreased SmO₂ and subsequently decreased pHm. CLINICAL TRANSLATION: The monitor has been miniaturized to a 58-g solid-state sensor that is currently being evaluated on patients with dengue hemorrhagic fever. Early results demonstrate significant decreases in SmO₂ similar to those observed with progressive reductions in central blood volume. As such, this technology has the potential to (1) provide a monitoring capability for both nontraumatic and traumatic hemorrhage and (2) help combat medics triage casualties and monitor patients during lengthy transport from combat areas.

Central Hypervolemia with Hemodilution Impairs Dynamic Cerebral Autoregulation

Frequent changes in the perioperative central blood volume could affect cerebral autoregulation through alterations in sympathetic nerve activity, cardiac output, blood viscosity, and cerebral vasomotor tone. However, the effect of dynamic cerebral autoregulation has not been studied during acute wide-ranging changes in central blood volume, especially with respect to central hypervolemia with hemodilution. We evaluated dynamic cerebral autoregulation during central hypovolemia and central hypervolemia with hemodilution using spectral and transfer function analysis between mean arterial blood pressure (MBP) and cerebral blood flow (CBF) velocity variability in 12 individuals. Rapid changes in central blood volume were achieved using two levels of lower body negative pressure (-15 and -30 mm Hg) and two discrete infusions of normal saline (15 mL/kg and total 30 mL/kg). We then estimated changes in central blood volume as central venous pressure (CVP) and/or cardiac output using impedance cardiography. Steady-state CBF velocity and cardiac output decreased at -30 mm Hg lower body negative pressure (changes of CVP approximately -4 mm Hg) or were increased by each saline infusion (changes of CVP 4-6 mm Hg), without a significant change in MBP. However, transfer function gain (magnitude of transfer) between MBP and CBF velocity variability significantly increased only after saline infusion, suggesting an increased magnitude of transfer from MBP oscillations to CBF fluctuations during central hypervolemia with hemodilution. Our results suggest that, although steady-state CBF velocity changes under both central hypervolemia and hypovolemia, only hypervolemic hemodilution impairs dynamic cerebral autoregulation.

The Effects of Aging and Physical Activity on Doppler Measures of Diastolic Function

Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70+/-4 years) and 12 fit Masters athlete (68+/-3 years) seniors were recruited. Twelve young healthy (32+/-9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p<0.001), TDI Emean (p<0.001), and propagation velocity of mitral inflow (p<0.001) and an increase in IVRT (p=0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p=0.212), IVRT (p=0.546), or propagation velocity of mitral inflow (p=1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p=0.012) and during maximal lower body negative pressure (p=0.036), but not during saline solution infusion (p=0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.

R‐wave Amplitude in Lead II of an Electrocardiograph Correlates with Central Hypovolemia in Human Beings

Previous animal and human experiments have suggested that reduction in central blood volume either increases or decreases the amplitude of R waves in various electrocardiograph (ECG) leads depending on underlying pathophysiology. In this investigation, we used graded central hypovolemia in adult volunteer subjects to test the hypothesis that moderate reductions in central blood volume increases R-wave amplitude in lead II of an ECG. A four-lead ECG tracing, heart rate (HR), estimated stroke volume (SV), systolic blood pressure, diastolic blood pressure, and mean arterial pressure were measured during baseline supine rest and during progressive reductions of central blood volume to an estimated volume loss of >1,000 mL with application of lower-body negative pressure (LBNP) in 13 healthy human volunteer subjects. Lower-body negative pressure resulted in a significant progressive reduction in central blood volume, as indicated by a maximal decrease of 65% in SV and maximal elevation of 56% in HR from baseline to -60 mm Hg LBNP. R-wave amplitude increased (p < 0.0001) linearly with progressive LBNP. The amalgamated correlation (R2) between average stroke volume and average R-wave amplitude at each LBNP stage was -0.989. These results support our hypothesis that reduction of central blood volume in human beings is associated with increased R-wave amplitude in lead II of an ECG.

Vasoconstrictor Reserve and Sympathetic Neural Control of Orthostasis

We tested the hypothesis that individual variability in orthostatic tolerance is dependent on the degree of neural and vasomotor reserve available for vasoconstriction. Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in 12 healthy young volunteers during 60 degrees head-up tilt (HUT), followed by a cold pressor test (CPT) in HUT. Orthostatic tolerance was determined by progressive lower-body negative pressure (LBNP) to presyncope. The same protocols were performed randomly in normovolemic and hypovolemic conditions. We found that mean arterial pressure increased and stroke volume decreased, whereas heart rate (HR), MSNA, and total peripheral resistance (TPR) increased during HUT (all P<0.01). Application of the CPT in HUT did not increase HR or decrease stroke volume further but elevated mean arterial pressure (P<0.01) and increased MSNA and TPR in some subjects. There was a positive correlation between the time to presyncope from -50 mm Hg LBNP (equivalent to 60 degrees HUT alone) and the changes in MSNA produced by the CPT under both conditions (r=0.442, P=0.039). Those who had greater increases in MSNA had greater increases in TPR during the CPT and longer time to presyncope (both P<0.05). One subject had dramatic increases in MSNA but small increases in TPR during the CPT, which indicates a disassociation between sympathetic activity and the increase in peripheral vascular resistance. These results support our hypothesis and suggest that vasoconstrictor capability is a contributor to orthostatic tolerance in humans. Vasoconstrictor reserve therefore may be one mechanism underlying individual variability in orthostatic intolerance.

Spectral and cross-spectral autoregressive analysis of cardiovascular variables in subjects with different degrees of orthostatic tolerance.

The mechanisms leading to vasovagal syncope are still unclear. A simple discriminating test for the identification of syncope-prone subjects is not presently available. Fifty-two subjects had a stepwise orthostatic test with 60 degrees tilt and -20 and -40 mm Hg lower-body negative pressure before the appearance of impending syncope symptoms. Spectral and cross-spectral analyses of heart period and systolic pressure time series were performed to estimate the power of the high-frequency (approximately equals 0.25 Hz) and low-frequency (approximately equals 0.1 Hz) oscillations, the coherence between heart period and systolic pressure, and the mean low-frequency and high-frequency central frequency, phase shift, and transfer function at maximal coherence. According to time to presyncope, the 52 subjects were divided into two groups: 25 with normal orthostatic tolerance, and 27 with poor orthostatic tolerance. In the supine positions, the mean central low-frequency was significantly lower in poor-tolerance group than in normal-tolerance group, discriminating poor from normal orthostatic tolerance with 80% specificity and 83% sensitivity, and was significantly correlated to time to presyncope. In the 2 to 3 minutes preceding syncope, subjects with poor orthostatic tolerance had less tachycardia, lower low-frequency power of systolic pressure, higher respiratory frequency, and a less negative phase shift in high-frequency range. In presyncope, sympathetic activation is reduced in subjects with poor orthostatic tolerance. In addition, the higher breathing frequency and the smaller negativity of phase shift in high-frequency range, which may indicate an inadequate engagement of the baroreflex, suggest a causal role of respiration in the development of syncope. Supine central values of low frequency may be proposed as a valuable clinical index of orthostatic intolerance.

Electric analog model of the aortic valve for calculation of continuous beat-to-beat aortic flow using a pressure gradient.

The objective was to develop a technique for calculating continuous, beat-to-beat aortic flow (AoF) using only left ventricular pressure (LVP) and aortic pressure (AoP). An electric analog model of the aortic valve was developed that includes resistance (R), inertance (L), and compliance (C) parameters, and resulting second order differential equations were derived. Aortic flow, AoP, and LVP recorded in eight subjects during a 5 day period and during lower body negative pressure (LBNP) were used to validate the model. Resistance, L, and C were estimated using a least-squares fit to the measured AoF on day 0 and during 0 mm Hg LBNP. For days 1-4, AoF was calculated using measured values of AoP and LVP and the R, L, and C values from day 0. Similarly, for LBNP, AoF was calculated using measured values of AoP and LVP, and the R, L, and C values from 0 mm Hg LBNP. The calculated and measured AoF were compared. Differences in cardiac output between the calculated and measured flows were less than 13.1+/-17% across days and under minor altered physiologic conditions (LBNP). Waveform morphology for the calculated AoF also agreed well with the measured AoF. Spectral analysis showed differences in magnitude and phase between measured and calculated aortic flow for the first five harmonics across days, less than 20+/-6% and 25+/-14 degrees, respectively. Preliminary evaluation indicates that our model works well for calculating flow through a biologic valve using LVP and AoP. We speculate that it may perform better for a mechanical valve, and if so it may be possible to develop an instrumented mechanical valve capable of continuous LVP, AOP, and AoF measurements.

Measurement of net whole-body transcapillary fluid transport and effective vascular compliance in humans.

Net whole-body transcapillary fluid transport (TFT) between the circulation and the interstitial (extravascular) space may be calculated as: IV - deltaPV - UV - IL, where IV=infused or ingested volume (when applicable), deltaPV = change in plasma volume, UV=urine volume, and IL=insensible loss. Infusion of 30 mL/kg isotonic saline over 25 minutes increased supine TFT from a basal capillary reabsorption of -106+/-24 mL/h (mean+/-SE) to a net filtration of 1,229+/-124 mL/h. One hour after infusion, reabsorption of -236+/-102 mL/h was seen, and control reabsorption levels returned by 3 hours. Four hours of 30 mm Hg lower body negative pressure (LBNP) elicited no net TFT, probably because of upper body reabsorptive compensation for lower body capillary filtration. When ingestion of 1 L of isotonic saline accompanied LBNP, filtration of 145+/-10 mL/h occurred. Reabsorption of extravascular fluid into the circulation always followed LBNP. Application of this technique could aid understanding of physiologic conditions, experimental interventions, disease states, and therapies that cause or are influenced by fluid shifts between intravascular and interstitial compartments.

Diastolic ventricular interaction in chronic heart failure: relation to heart rate variability and neurohumoral status.

It is likely that abnormal baroreflex control mechanisms are at least partially responsible for autonomic dysfunction in chronic heart failure. We recently demonstrated that diastolic ventricular interaction is associated with impaired baroreflex control of vascular resistance in heart failure. We reasoned that by constraining left ventricular filling, such interaction would decrease baroreflex activity and, thereby, increase sympathetic and decrease parasympathetic outflow. We hypothesized, therefore, that diastolic ventricular interaction in chronic heart failure patients would be associated with autonomic dysfunction. We used radionuclide ventriculography to measure changes in left and right ventricular end-diastolic volumes during acute volume unloading achieved by -30 mm Hg lower-body negative pressure in 30 patients with chronic heart failure. An increase in left ventricular volume in association with a reduction in right ventricular volume indicates diastolic ventricular interaction (a larger increase indicating a greater degree of interaction). We also measured heart rate variability (n = 23) and resting venous plasma norepinephrine (n = 24), epinephrine (n = 24), and atrial natriuretic peptide (ANP) (n = 14). During lower-body negative pressure, while right ventricular volume decreased in all patients (P < 0.001), left ventricular end-diastolic volume increased (from 152 +/- 25 to 157 +/- 36 ml/m2, P = 0.01). The change in left ventricular volume was positively correlated with resting plasma norepinephrine (P < 0.01) and ANP (P < 0.005), and negatively correlated with the standard deviation of normal to normal R-R intervals (P < 0.005), the root-mean-square of differences between successive normal to normal R-R intervals (P < 0.05), total power (P < 0.01), low-frequency power (P < 0.01), and high-frequency power (P < 0.05). Diastolic ventricular interaction in patients with chronic heart failure is associated with sympathetic nervous system activation evidenced by increased plasma norepinephrine and reduced heart rate variability.

Effects of ANF infusion on the renal responses to lower-body negative pressure in humans.

To investigate the role of atrial natriuretic factor (ANF) in renal responses to a decrease in central blood volume, we examined the effects of ANF infusion on renal function and hormones during prolonged lower-body negative pressure (LBNP). Ten healthy volunteers participated in two experimental sequences, each comprising a 120-min baseline period followed by the application of -20 mm Hg LBNP for 90 min. During one of the two sequences, ANF was infused throughout LBNP application at the constant rate of 2.5 ng/kg/min. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by using inulin and p-aminohippuric acid clearance techniques. LBNP induced a significant decrease in ERPF (534 +/- 28 to 457 +/- 26 ml/min; p < 0.05), GFR (120 +/- 2.5 to 112 +/- 2.5 ml/min; p < or = 0.01), in urine excretion (12 +/- 0.9 to 5.6 +/- 0.5 ml/min; p < 0.001), in sodium excretion (0.36 +/- 0.03 to 0.30 +/- 0.02 mmol/min; p < 0.05), and in plasma ANF (19 +/- 3 to 11 +/- 2 pg/ml; p = 0.001) concomitant with an increase in plasma renin activity (PRA; 0.48 +/- 0.09 to 0.87 +/- 0.16 ng/ml/h; p = 0.01) and of forearm vascular resistance (FVR; p < 0.05). The combination of ANF infusion with LBNP led to a slight increase in plasma ANF from baseline (from 20 +/- 2 to 28 +/- 3 pg/ml; p < 0.05). Compared with values obtained during LBNP with saline vehicle infusion, values obtained during LBNP with ANF infusion were similar for ERPF (463 +/- 23 vs. 457 +/- 26 ml/min), for GFR (111 +/- 2 vs. 112 +/- 2 ml/min), and for urine excretion (7 +/- 0.6 vs. 5.6 +/- 0.5 ml/min; p = 0.07), but greater for fractional excretion of sodium (2.38 +/- 0.25% vs. 1.91 +/- 0.11%; p < 0.05) and FVR (p < 0.05), and smaller for PRA (0.49 +/- 0.1 vs. 0.87 +/- 0.16 ng/ml/h; p < 0.01). These data show that ANF infusion attenuates the antinatriuretic effect of low-level LBNP and its PRA-increasing effects without altering renal hemodynamic responses to LBNP, although there is a decrease in the LBNP-induced forearm vasoconstriction. These results were obtained with plasma ANF levels slightly higher than those in baseline. They support the hypothesis that a decrease in ANF secretion might contribute to the antinatriuretic effect of LBNP.

Diastolic ventricular interaction: a possible mechanism for abnormal vascular responses during volume unloading in heart failure.

Baroreflex dysfunction is common in chronic heart failure and contributes to the associated sympathoexcitation. Baroreceptor activity normally decreases during volume unloading, causing an increase in sympathetic outflow and resulting in forearm vasoconstriction. Some heart failure patients develop attenuated vasoconstriction or paradoxical vasodilation. The mechanism for this is unknown. We have recently demonstrated diastolic ventricular interaction in some patients with chronic heart failure as evidenced by increases in left ventricular (LV) end-diastolic volume in association with decreases in right ventricular (RV) volume during volume unloading. We reasoned that such an increase in LV volume, by increasing LV mechanoreceptor activity, would decrease sympathetic outflow and could therefore explain the abnormal vascular responses seen in such patients. We assessed changes in forearm vascular resistance (FVR) during application of -20 and -30 mm Hg lower-body negative pressure (LBNP) in 24 patients with chronic heart failure and 16 control subjects. Changes in LV and RV end-diastolic volumes were assessed during -30 mm Hg LBNP in all heart failure patients. Diastolic ventricular interaction was demonstrated in 12 patients as evidenced by increases in LV end-diastolic volume in association with decreases in RV end-diastolic volume during LBNP. Changes in FVR during LBNP (-20 and -30 mm Hg) were markedly attenuated in these 12 patients (-1.6+/-11.2 and -0.9+/-12.5 U) compared with both the remaining patients (11.9+/-10.0 and 17.0+/-12.3 U) and the control subjects (16.5+/-9.5 and 23.1+/-13.9 U) (P<.01 for both comparisons at each level of LBNP). FVR decreased in 5 of these 12 patients during -30 mm Hg LBNP, a response seen in none of the remaining patients (P=.01). Diastolic ventricular interaction in patients with chronic heart failure is associated with attenuated forearm vasoconstriction or paradoxical vasodilation during LBNP. This may explain the apparent derangement in baroreflex control of sympathetic outflow during acute volume unloading in heart failure.