Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under ß-adrenergic blockade.

Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). ß-adrenergic blockade enhances BRS during rest, but its effect on BRS during acute psychological stress is unknown. This study tested the hypothesis that BRS is higher during acute psychological stress in healthy subjects under ß-adrenergic blockade. Twenty healthy novice male bungee jumpers were randomized and studied with (PROP, n=10) or without (CTRL, n=10) propranolol. BP and HR responses and BRS [cross-correlation time-domain (BRSTD) and cross-spectral frequency-domain (BRSFD) analysis] were evaluated from 30 min prior up to 2 h after the jump. HR, cardiac output and pulse pressure were lower in the PROP group throughout the study. Prior to the bungee jump, BRS was higher in the PROP group compared with the CTRL group [BRSTD: 28 (24-42) compared with 17 (16-28) ms·mmHg-1, P<0.05; BRSFD: 27 (20-34) compared with 14 (9-19) ms·mmHg-1, P<0.05; values are medians (interquartile range)]. BP declined after the jump in both groups, and post-jump BRS did not differ between the groups. In conclusion, during acute psychological stress, BRS is higher in healthy subjects treated with non-selective ß-adrenergic blockade with significantly lower HR but comparable BP.

Noninvasive cardiac output monitoring during exercise testing: Nexfin pulse contour analysis compared to an inert gas rebreathing method and respired gas analysis.

PURPOSE: Exercise testing is often used to assess cardiac function during physical exertion to obtain diagnostic information. However, this procedure is limited to measuring the electrical activity of the heart using electrocardiography and intermittent blood pressure (BP) measurements and does not involve the continuous assessment of heart functioning. In this study, we compared continuous beat-to-beat pulse contour analysis to monitor noninvasive cardiac output (CO) during exercise with inert gas rebreathing and respired gas analysis. METHODS: Nineteen healthy male volunteers were subjected to bicycle ergometry testing with increasing workloads. Cardiac output was deter- mined noninvasively by continuous beat-to-beat pulse contour analysis (Nexfin) and by inert gas rebreathing, and estimated using the respired gas analysis method. The effects of the rebreathing maneuver on heart rate (HR), stroke volume (SV), and CO were evaluated. RESULTS: The CO values derived from the Nexfin- and inert gas rebreathing methods were well correlated (r = 0.88, P < 0.01) and the limits of agreement were 30.3% with a measurement bias of 0.4 ± 1.8 L/min. Nexfin- and respired gas analysis-derived CO values correlated even better (r = 0.94, P < 0.01) and the limits of agreement were 21.5% with a measurement bias of -0.70 ± 1.6 L/min. At rest, the rebreathing maneuver increased HR by 13 beats/min (P < 0.01), SV remained unaffected (P = 0.7), while CO increased by 1.0 L/min (P < 0.01). Rebreathing did not affect these parameters during exercise. CONCLUSIONS: Nexfin continuous beat-to-beat pulse contour analysis is an appropriate method for noninvasive assessment of CO during exercise.

Impaired nocturnal blood pressure dipping in patients with type 2 diabetes mellitus.

Hypertension is a common comorbidity of type 2 diabetes mellitus (T2DM). Both conditions are associated with an increased cardiovascular risk, which is reduced by tight blood pressure (BP) and glycemic control. However, nondipping BP status continues to be an enduring cardiovascular risk factor in T2DM. Cardiovascular autonomic neuropathy and endothelial dysfunction have been proposed as potential mechanisms. This study tested the hypothesis that microvascular disease rather than cardiovascular autonomic neuropathy interferes with the physiological nocturnal BP reduction. Cardiovascular autonomic function and baroreflex sensitivity were determined in 22 type 2 diabetic patients with (DM+) and 23 diabetic patients without (DM-) manifest microvascular disease. BP dipping status was assessed from 24-hour ambulatory BP measurements. Sixteen nondiabetic subjects served as controls (CTRL). Cardiovascular autonomic function was normal in all subjects. Baroreflex sensitivity was lower in DM- compared with CTRL (7.7 ± 3.3 vs. 12.3 ± 8.3 ms·mm Hg-1; P < 0.05) and was further reduced in DM + (4.6 ± 2.0 ms·mm Hg-1; P < 0.01 vs. DM- and CTRL). The nocturnal decline in systolic and diastolic BP was blunted in DM- (12% and 14% vs. 17% and 19% in CTRL; P < 0.05) and even more so in DM+ (8% and 11%; P < 0.05 vs. DM- and P < 0.001 vs. CTRL). A nocturnal reduction in pulse pressure was observed in CTRL and DM- but not in DM+ (P < 0.05 vs. DM- and P < 0.01 vs. CTRL). In T2DM, progression of microvascular disease interferes with the normal nocturnal BP decline and coincides with a persistently increased pulse pressure and reduced baroreflex sensitivity, contributing to their increased cardiovascular risk.

Slow sinusoidal tilt movements demonstrate the contribution to orthostatic tolerance of cerebrospinal fluid movement to and from the spinal dural space.

Standing up elicits a host of cardiovascular changes which all affect the cerebral circulation. Lowered mean arterial blood pressure (ABP) at brain level, change in the cerebral venous outflow path, lowered end-tidal PCO2 (PET CO2 ), and intracranial pressure (ICP) modify cerebral blood flow (CBF). The question we undertook to answer is whether gravity-induced blood pressure (BP) changes are compensated in CBF with the same dynamics as are spontaneous or induced ABP changes in a stable position. Twenty-two healthy subjects (18/4 m/f, 40 ± 8 years) were subjected to 30° and 70° head-up tilt (HUT) and sinusoidal tilts (SinTilt, 0°â†¨60° around 30° at 2.5-10 tilts/min). Additionally, at those three tilt levels, they performed paced breathing at 6-15 breaths/min to induce larger than spontaneous cardiovascular oscillations. We measured continuous finger BP and cerebral blood flow velocity (CBFv) in the middle cerebral artery by transcranial Doppler to compute transfer functions (TFs) from ABP- to CBFv oscillations. SinTilt induces the largest ABP oscillations at brain level with CBFv gains strikingly lower than for paced breathing or spontaneous variations. This would imply better autoregulation for dynamic gravitational changes. We demonstrate in a mathematical model that this difference is explained by ICP changes due to movement of cerebrospinal fluid (CSF) into and out of the spinal dural sack. Dynamic cerebrovascular autoregulation seems insensitive to how BP oscillations originate if the effect of ICP is factored in. CSF-movement in-and-out of the spinal dural space contributes importantly to orthostatic tolerance by its effect on cerebral perfusion pressure.

Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes.

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM- (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM-, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA V(mean) (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07-0.15 Hz), the phase lead of the MAP-to-MCA V(mean) transfer function was 52+/-10 degrees in CTRL subjects, reduced in subjects with DM- (40+/-6 degrees ; P<0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30+/-5 degrees ; P<0.01 compared with subjects with DM-), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA V(mean) to postural change was comparable for all groups (-12+/-6% in CTRL subjects, -15+/-6% in subjects with DM- and -15+/-7% in subjects with DM+). HbA(1c) (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.

Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest.

Central aortic pressure gives better insight into ventriculo-arterial coupling and better prognosis of cardiovascular complications than peripheral pressures. Therefore transfer functions (TF), reconstructing aortic pressure from peripheral pressures, are of great interest. Generalized TFs (GTF) give useful results, especially in larger study populations, but detailed information on aortic pressure might be improved by individualization of the TF. We found earlier that the time delay, representing the travel time of the pressure wave between measurement site and aorta is the main determinant of the TF. Therefore, we hypothesized that the TF might be individualized (ITF) using this time delay. In a group of 50 patients at rest, aged 28-66 yr (43 men), undergoing diagnostic angiography, ascending aortic pressure was 119 +/- 20/70 +/- 9 mmHg (systolic/diastolic). Brachial pressure, almost simultaneously measured using catheter pullback, was 131 +/- 18/67 +/- 9 mmHg. We obtained brachial-to-aorta ITFs using time delays optimized for the individual and a GTF using averaged delay. With the use of ITFs, reconstructed aortic pressure was 121 +/- 19/69 +/- 9 mmHg and the root mean square error (RMSE), as measure of difference in wave shape, was 4.1 +/- 2.0 mmHg. With the use of the GTF, reconstructed pressure was 122 +/- 19/69 +/- 9 mmHg and RMSE 4.4 +/- 2.0 mmHg. The augmentation index (AI) of the measured aortic pressure was 26 +/- 13%, and with ITF and GTF the AIs were 28 +/- 12% and 30 +/- 11%, respectively. Details of the wave shape were reproduced slightly better with ITF but not significantly, thus individualization of pressure transfer is not effective in resting patients.

Detecting central hypovolemia in simulated hypovolemic shock by automated feature extraction with principal component analysis.

Assessment of the volume status by blood pressure (BP) monitoring is difficult, since baroreflex control of BP makes it insensitive to blood loss up to about one liter. We hypothesized that a machine learning model recognizes the progression of central hypovolemia toward presyncope by extracting information of the noninvasive blood pressure waveform parametrized through principal component analysis. This was tested in healthy volunteers exposed to simulated hemorrhage by lower body negative pressure (LBNP). Fifty-six healthy volunteers were subjected to progressive central hypovolemia. A support vector machine was trained on the blood pressure waveform. Three classes of progressive stages of hypovolemia were defined. The model was optimized for the number of principal components and regularization parameter for penalizing misclassification (cost): C. Model performance was expressed as accuracy, mean squared error (MSE), and kappa statistic (inter-rater agreement). Forty-six subjects developed presyncope of which 41 showed an increase in model classification severity from baseline to presyncope. In five of the remaining nine subjects (1 was excluded) it stagnated. Classification of samples during baseline and end-stage LBNP had the highest accuracy (95% and 50%, respectively). Baseline and first stage of LBNP demonstrated the lowest MSE (0.01 respectively 0.32). Model MSE and accuracy did not improve for C values exceeding 0.01. Adding more than five principal components did not further improve accuracy or MSE. Increment in kappa halted after 10 principal components had been added. Automated feature extraction of the blood pressure waveform allows modeling of progressive hypovolemia with a support vector machine. The model distinguishes classes between baseline and presyncope.

Modeling Arterial Pulse Pressure From Heart Rate During Sympathetic Activation by Progressive Central Hypovolemia.

Heart rate (HR) has an impact on the central blood pressure (BP) wave shape and is related to pulse wave velocity and therefore to timing and duration of systole and diastole. This study tested the hypothesis that in healthy subjects both in rest and during sympathetic stimulation the relation between HR and pulse pressure (PP) is described by a linear effect model. Forty-four healthy volunteers were subjected to sympathetic stimulation by continuous lower body negative pressure (LBNP) until the onset of pre-syncopal symptoms. Changes in PP and HR were tracked non-invasively and modeled by linear mixed effect (LME) models. The dataset was split into two groups: the first was used for creating a model and the second for its evaluation. Models were created on the data obtained during LBNP. Model performance was expressed as absolute median error (1st; 3rd quantiles) and bias with limits of agreement (LOA) between modeled and measured PP. From rest to sympathetic stimulation, mean BP was maintained while HR increased (~30%) and PP decreased gradually (~20%). During baseline, PP could be modeled with an absolute error of 6 (4; 10) mm Hg and geometric mean ratio of the bias was 0.97 (LOA: 0.8-1.1). During LBNP, absolute median model error was 5 (4; 8) mmHg with geometric mean ratio 1.02 (LOA: 0.8-1.3). In conclusion, both during rest and during sustained sympathetic outflow induced by progressive central hypovolemia, a LME model of HR provides for an estimate of PP in healthy young adults.

Myocardial preload alters central pressure augmentation through changes in the forward wave.

OBJECTIVE: Augmentation index (AIx) is often used to quantify the contribution of wave reflection to central pulse pressure. Recent studies have challenged this view by showing how contractility-induced changes in the forward pressure wave can markedly impact AIx. We hypothesized that changes in preload will also affect AIx through changes in the forward wave and studied this in two experiments. METHODS: Noninvasively obtained aortic pressure was used to study central haemodynamics and wave morphology. In the first experiment, we examined the effects of head-up tilt with and without unilateral thigh cuff in 12 young healthy volunteers (mean age 26 years, 50% men). In the second experiment, we examined the effects of active standing in 31 middle-aged patients (mean age 57 years, 65% men) before and after phlebotomy. RESULTS: Head-up tilt or active standing significantly decreased AIx [-17.7 ±â€Š10.4 percentage point (pp) in the young population, -4.7 ±â€Š12.3 pp in the middle-aged population, both P < 0.05]. The fall in AIx was associated with increases in HR, diastolic pressure and systemic vascular resistance and a decrease in stroke volume (all P < 0.05). Inflation of a unilateral thigh cuff reduced the decrease in AIx by 10.7 pp, whereas 500 ml of blood loss augmented the fall in AIx by 5.9 pp (both P < 0.05). The changes in AIx were related to a preload-induced change in forward pressure wave shape (earlier peaking and steeper downstroke). CONCLUSION: Next to inotropic and chronotropic effects, preload emerges as another myocardial factor that obscures the relation between wave reflection and AIx.

Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort.

OBJECTIVE: Experimental evidence indicates that maternal undernutrition during gestation may program hypertension in the offspring. We investigated whether maternal undernutrition leads to increased arterial stiffness. METHODS: We measured carotid artery lumen diameter (LD), distensibility (DC), stiffness (beta), and compliance (CC) by M-mode ultrasound in 673 individuals, aged 56-61 years, who had been born as term singletons around the time of the 1944-45 Dutch famine. RESULTS: Maternal famine exposure had no effect on any of the measures of carotid size or stiffness in the offspring. Low maternal weight at the end of pregnancy and low birth weight were associated with decreased LD (0.01 mm/kg maternal weight, sex-adjusted P < 0.001; 0.1 mm/kg birth weight, sex-adjusted P = 0.08) and CC (0.002 mm2/kPa per kg maternal weight, sex-adjusted P = 0.001; 0.03 mm2/kPa per kg birth weight, sex-adjusted P = 0.03), but neither was associated with increased beta, or decreased DC. These effects were not attenuated by adjusting for maternal protein/carbohydrate ratio in the third trimester. The association of low birth weight with increased CC diminished after adjusting for maternal weight. The association of maternal weight with CC was smaller when adjusted for LD. CONCLUSION: Our findings suggest that small maternal size, not poor maternal diet, in late gestation programs decreased arterial compliance in the adult offspring by affecting vessel size rather than vessel wall stiffness.

Aging modifies the effect of cardiac output on middle cerebral artery blood flow velocity.

An association between cerebral blood flow (CBF) and cardiac output (CO) has been established in young healthy subjects. As of yet it is unclear how this association evolves over the life span. To that purpose, we continuously recorded mean arterial pressure (MAP; finger plethysmography), CO (pulse contour; CO-trek), mean blood flow velocity in the middle cerebral artery (MCAV; transcranial Doppler ultrasonography), and end-tidal CO2 partial pressure (PetCO2) in healthy young (19-27 years), middle-aged (51-61 years), and elderly subjects (70-79 years). Decreases and increases in CO were accomplished using lower body negative pressure and dynamic handgrip exercise, respectively. Aging in itself did not alter dynamic cerebral autoregulation or cerebrovascular CO2 reactivity. A linear relation between changes in CO and MCAVmean was observed in middle-aged (P < 0.01) and elderly (P = 0.04) subjects but not in young (P = 0.45) subjects, taking concurrent changes in MAP and PetCO2 into account. These data imply that with aging, brain perfusion becomes increasingly dependent on CO.

Support Vector Machine Based Monitoring of Cardio-Cerebrovascular Reserve during Simulated Hemorrhage.

Introduction: In the initial phase of hypovolemic shock, mean blood pressure (BP) is maintained by sympathetically mediated vasoconstriction rendering BP monitoring insensitive to detect blood loss early. Late detection can result in reduced tissue oxygenation and eventually cellular death. We hypothesized that a machine learning algorithm that interprets currently used and new hemodynamic parameters could facilitate in the detection of impending hypovolemic shock. Method: In 42 (27 female) young [mean (sd): 24 (4) years], healthy subjects central blood volume (CBV) was progressively reduced by application of -50 mmHg lower body negative pressure until the onset of pre-syncope. A support vector machine was trained to classify samples into normovolemia (class 0), initial phase of CBV reduction (class 1) or advanced CBV reduction (class 2). Nine models making use of different features were computed to compare sensitivity and specificity of different non-invasive hemodynamic derived signals. Model features included: volumetric hemodynamic parameters (stroke volume and cardiac output), BP curve dynamics, near-infrared spectroscopy determined cortical brain oxygenation, end-tidal carbon dioxide pressure, thoracic bio-impedance, and middle cerebral artery transcranial Doppler (TCD) blood flow velocity. Model performance was tested by quantifying the predictions with three methods: sensitivity and specificity, absolute error, and quantification of the log odds ratio of class 2 vs. class 0 probability estimates. Results: The combination with maximal sensitivity and specificity for classes 1 and 2 was found for the model comprising volumetric features (class 1: 0.73-0.98 and class 2: 0.56-0.96). Overall lowest model error was found for the models comprising TCD curve hemodynamics. Using probability estimates the best combination of sensitivity for class 1 (0.67) and specificity (0.87) was found for the model that contained the TCD cerebral blood flow velocity derived pulse height. The highest combination for class 2 was found for the model with the volumetric features (0.72 and 0.91). Conclusion: The most sensitive models for the detection of advanced CBV reduction comprised data that describe features from volumetric parameters and from cerebral blood flow velocity hemodynamics. In a validated model of hemorrhage in humans these parameters provide the best indication of the progression of central hypovolemia.

The cerebrovascular response to lower-body negative pressure vs. head-up tilt.

Lower-body negative pressure (LBNP) has been proposed as a MRI-compatible surrogate for orthostatic stress. Although the effects of LBNP on cerebral hemodynamic behavior have been considered to reflect those of orthostatic stress, a direct comparison with actual orthostasis is lacking. We assessed the effects of LBNP (-50 mmHg) vs. head-up tilt (HUT; at 70°) in 10 healthy subjects (5 female) on transcranial Doppler-determined cerebral blood flow velocity (CBFv) in the middle cerebral artery and cerebral perfusion pressure (CPP) as estimated from the blood pressure signal (finger plethysmography). CPP was maintained during LBNP but decreased after 2 min in response to HUT, leading to an ~15% difference in CPP between LBNP and HUT (P ≤ 0.020). Mean CBFv initially decreased similarly in response to LBNP and for HUT, but, from minute 3 on, the decline became ~50% smaller (P ≤ 0.029) during LBNP. The reduction in end-tidal Pco2 partial pressure (PetCO2 ) was comparable but with an earlier return toward baseline values in response to LBNP but not during HUT (P = 0.008). We consider the larger decrease in CBFv during HUT vs. LBNP attributable to the pronounced reduction in PetCO2 and to gravitational influences on CPP, and this should be taken into account when applying LBNP as an MRI-compatible orthostatic stress modality.NEW & NOTEWORTHY Lower-body negative pressure (LBNP) has the potential to serve as a MRI-compatible surrogate of orthostatic stress but a comparison with actual orthostasis was lacking. This study showed that the pronounced reduction in end-tidal Pco2 together with gravitational effects on the brain circulation lead to a larger decline in cerebral blood flow velocity in response to head-up tilt than during lower-body negative pressure. This should be taken into account when employing lower-body negative pressure as MRI-compatible alternative to orthostatic stress.

Changes in finger-aorta pressure transfer function during and after exercise.

Noninvasive finger blood pressure has become a surrogate for central blood pressure under widely varying circumstances. We tested the validity of finger-aorta transfer functions (TF) to reconstruct aortic pressure in seven cardiac patients before, during, and after incremental bicycle exercise. The autoregressive exogenous model method was used for calculating finger-aorta TFs. Finger pressure was measured noninvasively using Finapres and aortic pressure using a catheter-tip manometer. When applying the individual TFs found during rest for reconstruction of aortic pressure during all workloads, systolic pressure was increasingly underestimated, with large variation between subjects: +4.0 to -18.1 mmHg. In most subjects, diastolic pressure was overestimated: -3.9 to +5.5 mmHg. Pulse pressure estimation varied between +4.5 and -21.9 mmHg. In all cases, wave distortion was present. Postexercise, error in reconstructed aortic systolic pressure slowly declined, and diastolic pressure was overestimated. During rest, the TF gain had a minimum between 3.65 and 4.85 Hz (Fmin). During exercise, Fmin shifted to frequencies between 4.95 and 7.15 Hz at the maximum workload, with no change in gain. Postexercise, gain in most subjects shifted to values closer to unity, whereas Fmin did not return to resting values. Within each subject, aorta-Finapres travel time was linearly related to mean pressure. During exercise, Fmin was linearly related to both delay and heart rate. We conclude that, during increasing exercise, rest TFs give an increasingly unreliable reconstruction of aortic pressure, especially at higher heart rates.

Differences in Sympathetic Nervous Stimulation of Brown Adipose Tissue Between the Young and Old, and the Lean and Obese.

UNLABELLED: Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold. METHODS: This was a prospective observational study. We included 10 young obese, 11 old lean, and 14 young lean healthy men. All subjects underwent (18)F-FDG PET/CT and (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT/CT after an overnight fast and 2 h of cold exposure. Metabolic BAT activity was expressed as volume and as SUVmax of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG). RESULTS: SUVmax, BAT volume, and SQUVmax were significantly different between young and old (SUVmax, 7.9 [range, 4.2-17.3] vs. 2.9 [range, 0.0-4.0]; volume, 124.8 [range, 10.9-338.8] vs. 3.4 [range, 0.0-10.9]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 0.0 [range, 0.0-2.2], respectively) (all P < 0.01) but not between lean and obese (SUVmax, 7.9 [range, 4.2-17.3] vs. 4.0 [range, 0.0-13.5] [P = 0.69]; volume, 124.8 [range, 10.9-338.8] vs. 11.8 [range, 0.0-190.2] [P = 0.64]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 1.7 [range, 0-3.5] [P = 0.69], respectively). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT-positive subjects (ρ = 0.82, P < 0.01). CONCLUSION: Both sympathetic drive and BAT activity are lower in older but not in obese men.

Cardiovascular Response Patterns to Sympathetic Stimulation by Central Hypovolemia.

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

Arterial Pressure Variation as a Biomarker of Preload Dependency in Spontaneously Breathing Subjects - A Proof of Principle.

OBJECTIVE: Pulse (PPV) and systolic pressure variation (SPV) quantify variations in arterial pressure related to heart-lung interactions and have been introduced as biomarkers of preload dependency to guide fluid treatment in mechanically ventilated patients. However, respiratory intra-thoracic pressure changes during spontaneous breathing are considered too small to affect preload and stroke volume sufficiently for the detection by PPV and/or SPV. This study addressed the effects of paced breathing and/or an external respiratory resistance on PPV and SPV in detecting preload dependency in spontaneously breathing subjects. METHODS: In 10 healthy subjects, hemodynamic and respiratory parameters were evaluated during progressive central hypovolemia (head-up tilt). Breathing conditions were varied by manipulating breathing frequency and respiratory resistance. Subjects responding with a reduction in stroke volume index ≥15% were classified as having developed preload dependency. The ability for PPV and SPV to predict preload dependency was expressed by the area under the ROC curve (AUC). RESULTS: A breathing frequency at 6/min increased the PPV (16±5% vs. 10±3%, p<0.001) and SPV (9±3% vs. 5±2%, p<0.001) which was further enhanced by an expiratory resistance (PPV: 19±3%, p = 0.025 and SPV: 10±2%, p = 0.047). These respiratory modifications, compared to free breathing, enhanced the predictive value of PPV with higher accuracy (AUC: 0.92 vs. 0.46). CONCLUSION: Under conditions of progressive central hypovolemia, the application of an external respiratory resistance at a breathing frequency of 6/min enhanced PPV and SPV and is worth further study for detection of preload dependency from arterial pressure variations in non-ventilated subjects.

Time-domain cross-correlation baroreflex sensitivity: performance on the EUROBAVAR data set.

OBJECTIVE: To test a new method (cross-correlation baroreflex sensitivity, xBRS) for the computation of time-domain baroreflex sensitivity on spontaneous blood pressure and heart interval variability using the EUROBAVAR data set. METHODS: We applied xBRS to the 42 records in the EUROBAVAR data set, obtained from 21 patients in the lying and standing positions. One patient had a recent heart transplant and one was diabetic with evident cardiac autonomic neuropathy. xBRS computes the correlation between beat-to-beat systolic blood pressure and R-R interval, resampled at 1 Hz, in a sliding 10 s window, with delays of 0-5 s for interval. The delay with the greatest positive correlation is selected and, when significant at P = 0.01, slope and delay are recorded as one xBRS value. Each 1 s of the recording is the start of a new computation. Non-parametric tests are used. RESULTS: With patients in the lying position, xBRS yielded a value of 12.4 ms/mmHg compared with the EUROBAVAR sequential 16.2 ms/mmHg, and for the standing positions the respective values were 6.2 and 6.7 ms/mmHg, giving lying to standing ratios of 1.96 and 2.10, respectively. xBRS yielded results for all files, with 20 values per minute on average at a lower within-patient variance. Best delays were 0, 1 and 2 s, and the delay increased by 102 ms when the patient was in the standing position. The xBRS method was successful in the patients with diabetes and the heart transplant. CONCLUSION: The xBRS method should be considered for experimental and clinical use, because it yielded values that correlated strongly with and were close to the EUROBAVAR averages, yielded more values per minute, had lower within-patient variance and measured baroreflex delay.

Tilt table design for rapid and sinusoidal posture change with minimal vestibular stimulation.

INTRODUCTION: Cardiovascular response to fast posture change can be used to model individual orthostatic response under normal circumstances and after spaceflight. We set out to construct a computer-controlled tilt table suitable for repeated sinusoidal tilt motion as well as fast, single head-up tilt (HUT). The movement profile of the table was designed to prevent muscle tensing and limit vestibular stimulation. METHODS: On the new table, 20 healthy subjects underwent a protocol of fast HUT and sinusoidal tilt motion at 2.5 tilts per minute. BP was measured non-invasively (Finapres). Time domain dynamic response to HUT and frequency domain response to sinusoidal tilts were derived from the beat-to-beat BP and from interbeat-interval (IBI) series. RESULTS: Tilt motion did not induce dizziness and was experienced by all subjects as smooth. The systolic BP response to fast HUT correlated mildly with the systolic BP spectral power at the sinusoidal tilt frequency (R = 0.47). The IBI response to fast HUT correlated well with the IBI power at the sinusoidal tilt frequency (R = 0.74). DISCUSSION: In this study we presented a computer controlled tilt table capable of fast posture change and sinusoidal tilts. An exploratory protocol demonstrated that the table is suitable for obtaining cardiovascular response to posture change for modeling purposes.

Arterial pressure variations as parameters of brain perfusion in response to central blood volume depletion and repletion.

RATIONALE: A critical reduction in central blood volume (CBV) is often characterized by hemodynamic instability. Restoration of a volume deficit may be established by goal-directed fluid therapy guided by respiration-related variation in systolic- and pulse pressure (SPV and PPV). Stroke volume index (SVI) serves as a surrogate end-point of a fluid challenge but tissue perfusion itself has not been addressed. OBJECTIVE: To delineate the relationship between arterial pressure variations, SVI and regional brain perfusion during CBV depletion and repletion in spontaneously breathing volunteers. METHODS: This study quantified in 14 healthy subjects (11 male) the effects of CBV depletion [by 30 and 70 degrees passive head-up tilt (HUT)] and a fluid challenge (by tilt back) on CBV (thoracic admittance), mean middle cerebral artery (MCA) blood flow velocity (Vmean), SVI, cardiac index (CI), PPV, and SPV. RESULTS: PPV (103 ± 89%, p < 0.05) and SPV (136 ± 117%, p < 0.05) increased with progression of central hypovolemia manifested by a reduction in thoracic admittance (11 ± 5%, p < 0.001), SVI (28 ± 6%, p < 0.001), CI (6 ± 8%, p < 0.001), and MCAVmean (17 ± 7%, p < 0.05) but not in arterial pressure. The reduction in MCAVmean correlated to the fall in SVI (R (2) = 0.52, p < 0.0001) and inversely to PPV and SPV [R (2) = 0.46 (p < 0.0001) and R (2) = 0.45 (p < 0.0001), respectively]. PPV and SPV predicted a ≥15% reduction in MCAVmean and SVI with comparable sensitivity (67/67% vs. 63/68%, respectively) and specificity (89/94 vs. 89/94%, respectively). A rapid fluid challenge by tilt-back restored all parameters to baseline values within 1 min. CONCLUSION: In spontaneously breathing subjects, a reduction in MCAVmean was related to an increase in PPV and SPV during graded CBV depletion and repletion. Specifically, PPV and SPV predicted changes in both SVI and MCAVmean with comparable sensitivity and specificity, however the predictive value is limited in spontaneously breathing subjects.