Incremental Lower Body Negative Pressure Research Articles

Impaired cardiopulmonary baroreflex function and altered cardiovascular responses to hypovolemia in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is associated with autonomic dysregulation, which may be related to baroreflex dysfunction. Thus, we tested the hypothesis that cardiac and peripheral vascular responses to baroreflex activation via lower-body negative pressure (LBNP; -10, -20, -30, -40 mmHg) would be diminished in patients with HFpEF (n = 10, 71 ± 7 yr) compared with healthy controls (CON, n = 9, 69 ± 5 yr). Changes in heart rate (HR), mean arterial pressure (MAP, Finapres), forearm blood flow (FBF, ultrasound Doppler), and thoracic impedance (Z) were determined. Mild levels of LBNP (-10 and -20 mmHg) were used to specifically assess the cardiopulmonary baroreflex, whereas responses across the greater levels of LBNP represented an integrated baroreflex response. LBNP significantly increased in HR in CON subjects at -30 and -40 mmHg (+3 ± 3 and +6 ± 5 beats/min, P < 0.01), but was unchanged in patients with HFpEF across all LBNP levels. LBNP provoked progressive peripheral vasoconstriction, as quantified by changes in forearm vascular conductance (FVC), in both groups. However, a marked (40%-60%) attenuation in FVC responses was observed in patients with HFpEF (-6 ± 8, -15 ± 6, -16 ± 5, and -19 ± 7 mL/min/mmHg at -10, -20, -30, and -40 mmHg, respectively) compared with controls (-15 ± 10, -22 ± 6, -25 ± 10, and -28 ± 10 mL/min/mmHg, P < 0.01). MAP was unchanged in both groups. Together, these data provide new evidence for impairments in cardiopulmonary baroreflex function and diminished cardiovascular responsiveness during hypovolemia in patients with HFpEF, which may be an important aspect of the disease-related changes in autonomic cardiovascular control in this patient group.NEW & NOTEWORTHY Data from the current study demonstrate diminished cardiovascular responsiveness during hypovolemia induced by incremental lower-body negative pressure in patients with heart failure with preserved ejection fraction (HFpEF). These diminished responses imply impaired cardiopulmonary baroreflex function and altered autonomic cardiovascular regulation which may represent an important aspect of HFpEF pathophysiology.

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.

Effects of daily artificial gravity training on orthostatic tolerance following 60-day strict head-down tilt bedrest

PurposeOrthostatic intolerance commonly occurs following immobilization or space flight. We hypothesized that daily artificial gravity training through short-arm centrifugation could help to maintain orthostatic tolerance following head-down tilt bedrest, which is an established terrestrial model for weightlessness.MethodsWe studied 24 healthy persons (eight women; age 33.3 ± 9.0 years; BMI 24.3 ± 2.1 kg/m2) who participated in the 60-days head-down tilt bedrest (AGBRESA) study. They were assigned to 30 min/day continuous or 6 × 5 min intermittent short-arm centrifugation with 1Gz at the center of mass or a control group. We performed head-up tilt testing with incremental lower-body negative pressure until presyncope before and after bedrest. We recorded an electrocardiogram, beat-to-beat finger blood pressure, and brachial blood pressure and obtained blood samples from an antecubital venous catheter. Orthostatic tolerance was defined as time to presyncope. We related changes in orthostatic tolerance to changes in plasma volume determined by carbon dioxide rebreathing.ResultsCompared with baseline measurements, supine and upright heart rate increased in all three groups following head-down tilt bedrest. Compared with baseline measurements, time to presyncope decreased by 323 ± 235 s with continuous centrifugation, by 296 ± 508 s with intermittent centrifugation, and by 801 ± 354 s in the control group (p = 0.0249 between interventions). The change in orthostatic tolerance was not correlated with changes in plasma volume.ConclusionsDaily artificial gravity training on a short-arm centrifuge attenuated the reduction in orthostatic tolerance after 60 days of head-down tilt bedrest.

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.

Sex-specific improvement in cardiac phenotype in older females combining blood withdrawal and exercise training.

This study determined whether an intervention combining hematological and exercise stimuli may overcome the prevailing limitations to improve the cardiac phenotype and orthostatic tolerance (OT) of females with advanced age. Healthy females (n = 15) and males (n = 14) matched by age (63.7 ± 7.0 vs. 63.6 ± 8.7 yr) and moderate physical activity were recruited. OT, transthoracic echocardiography, and central hemodynamics were assessed during incremental lower body negative pressure (LBNP) levels (up to -50 mmHg) for 1 h or until presyncope, prior to and after an intervention comprising standard (10%) blood withdrawal and an 8-wk exercise training program designed to maximize central hemodynamic adaptations. OT time was lower in females compared with males (48.1 ± 10.6 vs. 57.0 ± 4.8 min, P = 0.008) before the intervention. Improved OT time (+11%) in females (48.1 ± 10.6 vs. 53.5 ± 6.1 min, P = 0.021) but not in males (57.0 ± 4.8 vs. 56.7 ± 5.6 min, P = 0.868) was found following the intervention, resulting in similar OT time between females and males (P = 0.156). The intervention induced improvements in left ventricular (LV) diastolic function (+13% for myocardial e') along with increased LV mass (+13%) in females (P ≤ 0.039) but not in males (P ≥ 0.257). During the initial LBNP stages (0 to -20 mmHg), LV stroke volume and cardiac output were exclusively increased in females after the intervention (P ≤ 0.034). In conclusion, the cardiac phenotype of females with advanced age can be structurally and functionally modified in parallel to improved OT via short-term hematological and central hemodynamic stimuli.NEW & NOTEWORTHY Based on previous studies, main features of the cardiac phenotype in females with advanced age are generally unresponsive to lifestyle interventions. The present findings reveals that the cardiac phenotype of middle-age and older females is amenable to large modification in a short-term period when hematological stimuli are combined with those induced by exercise training. The same intervention only induced minor adaptations in males matched by age and potential confounding factors.

Effects of short-term hypercaloric nutrition on orthostatic tolerance in healthy individuals: a randomized controlled crossover study

Reduced-caloric intake lowers blood pressure through sympathetic inhibition, and worsens orthostatic tolerance within days. Conversely, hypercaloric nutrition augments sympathetic activity and blood pressure. Because dietary interventions could be applied in patients with syncope, we tested the hypothesis that short-term hypercaloric dieting improves orthostatic tolerance. In a randomized crossover trial, 20 healthy individuals (7 women, 26.7 ± 8 years, 22.6 ± 2 kg/m2) followed a 4-day hypercaloric (25% increase of energy intake by fat) or normocaloric nutritional plan, with a washout period of at least 23 days between interventions. We then performed head-up tilt table testing with incremental lower body negative pressure while recording beat-by-beat blood pressure and heart rate. The primary endpoint was orthostatic tolerance defined as time to presyncope. Time to presyncope during combined head-up tilt and lower body negative pressure did not differ between hypercaloric and normocaloric dieting (median 23.19 versus 23.04 min, ratio of median 1.01, 95% CI of ratio 0.5–1.9). Heart rate, blood pressure, heart rate variability, and blood pressure variability in the supine position and during orthostatic testing did not differ between interventions. We conclude that 4 days of moderate hypercaloric nutrition does not significantly improve orthostatic tolerance in healthy individuals. Nevertheless, given the important interaction between energy balance and cardiovascular autonomic control in the brain, caloric intake deserves more attention as a potential contributor and treatment target for orthostatic intolerance.

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.

Graded lower body negative pressure induces intraventricular negative pressures and incremental diastolic suction: a pressure-volume study in a porcine model.

Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during β-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank-Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, LBNP-induced central hypovolemia is associated with increased DS.NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.

Sex Differences in Orthostatic Tolerance Are Mainly Explained by Blood Volume and Oxygen Carrying Capacity.

The reduced orthostatic tolerance (OT) that is characteristic of the female sex may be explained by multiple phenotypic differences between sexes. This study aimed to elucidate the mechanistic role of blood volume (BV) and oxygen carrying capacity on sex differences in OT. Experimental intervention. University of Calgary, Main Campus, Calgary, AB, Canada. Healthy women and men (n = 90) throughout the adult lifespan (20-89 yr) matched by age and physical activity. Incremental lower body negative pressure (LBNP) in all individuals. Blood withdrawal and oxygen carrying capacity reduction in men to match with women's levels. Transthoracic echocardiography and central blood pressures were assessed throughout incremental LBNP for 1 hour or until presyncope. Blood uniformization resulted in a precise sex match of BV and oxygen carrying capacity (p ≥ 0.598). A third of women (14/45) and two thirds of men (31/45) prior to blood uniformization completed the orthostatic test without presyncopal symptoms (p-for-sex < 0.001). After blood uniformization, seven out of 45 men completed the test (p-for-sex = 0.081). Left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) were progressively reduced with LBNP in both sexes, with women showing markedly lower volumes than men (p < 0.001). Blood uniformization did not eliminate sex differences in LVEDV and SV. Sex differences in OT are not present when BV and oxygen carrying capacity are experimentally matched between sexes throughout the adult lifespan.

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.

Abstract P192: Orthostatic Tolerance Before And After 60 Days Of Strict Head Down Tilt Bedrest With And Without Daily Artificial Gravity Training

Background: Orthostatic intolerance occurs after space flight, immobilization and in patients with autonomic diseases, so there is a need for more effective countermeasures. We hypothesized that daily artificial gravity elicited through short-arm centrifugation attenuates plasma volume loss and orthostatic intolerance following 60 days of HDTBR, which models cardiovascular responses to weightlessness. Methods: We studied 24 healthy persons (8 women, 33.4±9.3 yr, 24.3±2.1 kg/m2) exposed to 60d HDTBR. Subjects were assigned to 30 min/d continuous short arm centrifugation (cAG), 6x5 min short arm centrifugation (iAG), or a control group (ctr, no countermeasures). Head-up tilt testing (15 min of 80°) followed by incremental lower body negative pressure (-10 mmHg every 3 min) until presyncope was performed before and at the end of HDTBR. Plasma volume was measured (CO rebreathing) 12-2 days before and after 56d of HDTBR. Stroke volume was measured by cMRI. Norepinephrine, epinephrine, aldosterone, and renine plasma levels were measured before and after HDTBR. Results: Time to presyncope decreased in all groups following bedrest (ctr: 22:56 min pre and 9:35 min post, cAG 15:34 min pre and 10:11 min post; iAG 14:56 min pre and 10:00 min post, p&lt;0.001). The significant interaction (p=0.025) between bedrest and intervention was explained by greater baseline orthostatic tolerance time in the ctr. AG Data was pooled analysis. The reduction in stroke volume (ctr, pre: 93±19 ml, HDTBR: 69±13 ml, AG, pre: 88±20 ml, HDTBR: 67±17 ml) and plasma volume was similar (ctr, pre: 4155±1085 ml, HDTBR: 3855±1087 ml, AG, pre: 4114±1250 ml, HDTBR: 3674± 1313 ml). Catechols and aldosterone did not change significantly during bedrest. The increase in renine was similar between groups (ctr pre: 18±12 mE/L, HDTBR: 21±8 mE/L, AG pre: 21±10 mE/L, HDTBR: 31±12 mE/L). Conclusions: 30 min daily AG didn’t prevent a reduction in orthostatic tolerance following 60d HDTBR. Whether numerically smaller reductions in orthostatic tolerance in the AG groups indicate efficacy or result from baseline differences can’t be ascertained. A stronger AG stimulus or combination with other countermeasures might be required to maintain orthostatic tolerance and to attenuate the volume reduction.

The effect of hypercapnia on regional cerebral blood flow regulation during progressive lower-body negative pressure.

Previous work indicates that dynamic cerebral blood flow (CBF) regulation is impaired during hypercapnia; however, less is known about the impact of resting hypercapnia on regional CBF regulation during hypovolemia. Furthermore, there is disparity within the literature on whether differences between anterior and posterior CBF regulation exist during physiological stressors. We hypothesized: (a) lower-body negative pressure (LBNP)-induced reductions in cerebral blood velocity (surrogate for CBF) would be more pronounced during hypercapnia, indicating impaired CBF regulation; and (b) the anterior and posterior cerebral circulations will exhibit similar responses to LBNP. In 12 healthy participants (6 females), heart rate (electrocardiogram), mean arterial pressure (MAP; finger photoplethosmography), partial pressure of end-tidal carbon dioxide (PETCO2), middle cerebral artery blood velocity (MCAv) and posterior cerebral artery blood velocity (PCAv; transcranial Doppler ultrasound) were measured. Cerebrovascular conductance (CVC) was calculated as MCAv or PCAv indexed to MAP. Two randomized incremental LBNP protocols were conducted (-20, -40, -60 and -80mmHg; three-minute stages), during coached normocapnia (i.e., room air), and inspired 5% hypercapnia (~ + 7mmHg PETCO2 in normoxia). The main findings were: (a) static CBF regulation in the MCA and PCA was similar during normocapnic and hypercapnic LBNP trials, (b) MCA and PCA CBV and CVC responded similarly to LBNP during normocapnia, but (c) PCAv and PCA CVC were reduced to a greater extent at -60mmHg LBNP (P = 0.029; P < 0.001) during hypercapnia. CBF regulation during hypovolemia was preserved in hypercapnia, and regional differences in cerebrovascular control may exist during superimposed hypovolemia and hypercapnia.

Elevated resting heart rate and reduced orthostatic tolerance in obese humans

Obesity is linked with numerous physiological impairments; however, its impact on orthostatic tolerance (OT) remains unknown. This study tested the hypothesis that OT is reduced in obese individuals, and that reduced heart rate (HR) reserve and impaired cerebral autoregulation contribute to impaired OT. Eleven obese (8 females) and 22 non-obese (10 females) individuals were exposed to incremental lower body negative pressure (LBNP) to presyncope while HR, arterial blood pressure, and cerebral perfusion (middle cerebral artery blood velocity; MCA V mean) were measured. OT was quantified with a cumulative stress index (CSI). OT was reduced in obese subjects, and there was an inverse relationship between body mass index (BMI) and OT (R=-0.47). HR was higher at rest and during each level of LBNP completed by all subjects. Similar peak HR (HRpeak) during LBNP between obese and non-obese subjects resulted in obese having a higher %peak HR at rest and at each stage of LBNP compared. Relationships existed for BMI and resting %HRpeak (R=0.45) and resting %HRpeak and CSI (R=-0.52). Despite lower CSI in obese, MCA V mean and indices of cerebral autoregulation were similar between groups at all time points. These data suggest that OT is reduced in obese and a higher resting HR, but not impaired regulation of cerebral perfusion, may contribute to this reduction.

Short-term variability of blood pressure: effects of lower-body negative pressure and long-duration bed rest

Mild lower-body negative pressure (LBNP) has been utilized to selectively unload cardiopulmonary baroreceptors, but there is evidence that arterial baroreceptors can be transiently unloaded after the onset of mild LBNP. In this paper, a black box mathematical model for the prediction of diastolic blood pressure (DBP) variability from multiple inputs (systolic blood pressure, R-R interval duration, and central venous pressure) was applied to interpret the dynamics of blood pressure maintenance under the challenge of LBNP and in long-duration, head-down bed rest (HDBR). Hemodynamic recordings from seven participants in the WISE (Women's International Space Simulation for Exploration) Study collected during an experiment of incremental LBNP (-10 mmHg, -20 mmHg, -30 mmHg) were analyzed before and on day 50 of a 60-day-long HDBR campaign. Autoregressive spectral analysis focused on low-frequency (LF, ~0.1 Hz) oscillations of DBP, which are related to fluctuations in vascular resistance due to sympathetic and baroreflex regulation of vasomotor tone. The arterial baroreflex-related component explained 49 ± 13% of LF variability of DBP in spontaneous conditions, and 89 ± 9% (P < 0.05) on day 50 of HDBR, while the cardiopulmonary baroreflex component explained 17 ± 9% and 12 ± 4%, respectively. The arterial baroreflex-related variability was significantly increased in bed rest also for LBNP equal to -20 and -30 mmHg. The proposed technique provided a model interpretation of the proportional effect of arterial baroreflex vs. cardiopulmonary baroreflex-mediated components of blood pressure control and showed that arterial baroreflex was the main player in the mediation of DBP variability. Data during bed rest suggested that cardiopulmonary baroreflex-related effects are blunted and that blood pressure maintenance in the presence of an orthostatic stimulus relies mostly on arterial control.

Postpartum Assessment of the Renin Angiotensin System in Women with Previous Severe, Early-Onset Preeclampsia

Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. Physiological assessments were conducted at an academic center. Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). Response to LBNP and ANG II was evaluated. RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

Use Of Non-invasive Markers For Early And Accurate Detection Of Traumatic Hemorrhage

Acute hemorrhage and subsequent circulatory collapse (shock) account for approximately 50% of the deaths on the battlefield and the forward operating table, a statistic that has remained relatively unchanged since World War I. Hemorrhage is defined as the escape of blood from a vessel and is the most common cause of hypovolemic shock. Current and classic techniques available to battlefield medics for triage and are focused on the traditional vital sign markers. Similarly, monitoring shock in the civilian trauma patient has also focused on the clinical "gold standard" assessments of Blood Pressure (BP), arterial O2 saturation or simple pulse palpation. However, these standard vital sign measurements fail to predict death or identify reductions in central blood volume until cardiovascular collapse has already occurred. About 10 percent of the total blood volume can be removed with almost no effect on either arterial pressure or cardiac output. PURPOSE: To develop and demonstrate a system that rapidly and non-invasively tracks vital sign markers throughout the progression of hemorrhage. METHODS: Orbital Research Inc (ORI) and Kent State University (KSU) used an incremental lower body negative pressure (LBNP) routine to safely educe physiologic changes like those typical to hemorrhage. Six research subjects have completed the study. An instrumented glove (developed by Orbital Research) collected vital signs intermittently and non-invasively during the experiment. Standards measure of metabolism; ECG and cardiac output were collected continuously. RESULTS: Using the instrumented glove to collect cardiovascular metrics, differences in R-R interval variability and Lf/Hf ratio are were detected during the LBNP sequence. Cardiac output, stroke volume and blood pressure data verified the physiologic compensations in response to the LBNP. CONCLUSIONS: Heart Rate Variability (HRV) has also shown promise and correlation to early reductions in central blood volume when blood pressures and SpO2 have not yet changed. This project demonstrated feasibility of using instrumented to glove to rapidly collect cardiovascular markers indicative of the onset of hemorrhage.

Combined head-up tilt and lower body negative pressure as an experimental model of orthostatic syncope.

The combination of head-up tilt and incremental lower body negative pressure has shown promise in the diagnosis of orthostatic hypotension and neurocardiogenic syncope, although prior methodologies limited conclusions as to the reproducibility of the test. The aim of this study was to assess the efficacy and reproducibility of a protocol combining tilt and stages of incremental lower body negative pressure. Ten volunteers (6 men and 4 women; mean age 21 +/- 1 years) participated in the study, which was composed of three sessions, 1 month apart, each consisting of 60 degrees tilt followed by lower body suction in incremental levels of -10 mmHg for 5 minutes at each level. The primary outcome variable was the time to presyncope. Secondary variables were the levels of heart rate, blood pressure, cerebral blood flow, and end-tidal CO2 at each level of the test. Presyncope could be achieved in all subjects. The mean times to presyncope were 24.6 +/- 1.4 minutes, 26.2 +/- 1.8 minutes, and 31.8 +/- 1.6 minutes and were not different across tests (P = 0.3). Intrasubject variability was assessed by determining the mean average deviation from the mean, which was 3.2 +/- 2.0 minutes. Changes in heart rate, blood pressure, end-tidal CO2, and cerebral blood flow were consistent with repeat testing. Lower body negative pressure combined with head-up tilt in a staged protocol can safely and reliably induce presyncope in all normal subjects tested. The test is a potent and reproducible investigational tool for inducing hypotension and transient cerebral hypoperfusion.

Variation in the renin angiotensin system throughout the normal menstrual cycle.

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

Effect of oral contraceptives on the renin angiotensin system and renal function.

We examined the effect of oral contraceptive (OC) usage on the renin angiotensin system (RAS) in two related experiments. In the first experiment, subjects were 34 healthy, normotensive, premenopausal women, 15 OC users and 19 OC nonusers, mean age 25 +/- 1 yr, ingesting a controlled sodium diet. We assessed arterial pressure, glomerular filtration rate, effective renal plasma flow, renal vascular resistance (RVR), and filtration fraction (FF) using inulin and p-aminohippurate clearance techniques, both at baseline and in response to the ANG II receptor blocker losartan. In the second experiment, in similar subjects, 10 OC users and 10 nonusers, we examined circulating RAS components [angiotensinogen, ANG II, aldosterone, plasma renin activity (PRA), and active renin] in response to incremental lower body negative pressure (LBNP), to determine whether renin secretion is suppressed by OC usage. OC users exhibited elevations in systolic blood pressure, RVR, and FF compared with nonusers, which were partially corrected by losartan. In the LBNP phase of the study, baseline measures of PRA, angiotensinogen, ANG II, and aldosterone were all increased in the OC group compared with the control group. Active renin levels did not differ between groups. Incremental LBNP resulted in increased circulating levels of RAS components in both groups. We conclude that the RAS is activated in women using OCs. There was no evidence that decreases in renin secretion result in normalization of the RAS as a whole.

Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6+/-1.0 versus 7.2+/-1.2 mmHg; means+/-S.E.M., P<0.02), HR (59+/-2 versus 66+/-3 beats/min, P<0.05) and MSNA burst frequency (29.0+/-2.4 versus 39.0+/-3.5 bursts/min, P<0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2+/-0.6 versus 8.8+/-1.4 bursts/100 heart beats per mmHg; P<0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.