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Postural stress requires immediate autonomic nervous action to maintain blood pressure. We determined time-domain cardiac baroreflex sensitivity (BRS) and time delay (τ) between systolic blood pressure and interbeat interval variations during stepwise changes in the angle of vertical body axis (τ). The assumption was that with increasing postural stress, BRS becomes attenuated, accompanied by a shift in τ toward higher values. In 10 healthy young volunteers, α included 20 degrees head-down tilt (-20°), supine (0°), 30 and 70 degrees head-up tilt (300, 70°), and free standing (90°). Noninvasive blood pressures were analyzed over 6-mm periods before and after each change in a. The BRS was determined by frequency-domain analysis and with xBRS, a cross-correlation time-domain method. On average, between 28 (-20°) to 45 (90°) xBRS estimates per minute became available. Following a change in a, xBRS reached a different mean level in the first minute in 78% of the cases and in 93% after 6 mm. With increasing a, BRS decreased: BRS = -10.1·sin(α) + 18.7 (r² = 0.99) with tight correlation between xBRS and cross-spectral gain (r² = 0.97). Delay τ shifted toward higher values. In conclusion, in healthy subjects the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with sin(±), and the start of baroreflex adaptation to a physiological perturbation like postural stress occurs rapidly. The decreases of BRS and reduction of short τ may be the result of reduced vagal activity with increasing α. [ABSTRACT FROM AUTHOR]

Transient cardiovascular and cerebrovascular responses within the first minute of active standing provide the means to assess autonomic, cardiovascular and cerebrovascular regulation using a real-world everyday stimulus. Traditionally, these responses have been used to detect autonomic dysfunction, and to identify the hemodynamic correlates of patient symptoms and attributable causes of (pre)syncope and falls. This review addresses the physiology of systemic and cerebrovascular adjustment within the first 60 s after active standing. Mechanical factors induced by standing up cause a temporal mismatch between cardiac output and vascular conductance which leads to an initial blood pressure drops with a nadir around 10 s. The arterial baroreflex counteracts these initial blood pressure drops, but needs 2–3 s to be initiated with a maximal effect occurring at 10 s after standing while, in parallel, cerebral autoregulation buffers these changes within 10 s to maintain adequate cerebral perfusion. Interestingly, both the magnitude of the initial drop and these compensatory mechanisms are thought to be quite well-preserved in healthy aging. It is hoped that the present review serves as a reference for future pathophysiological investigations and epidemiological studies. Further experimental research is needed to unravel the causal mechanisms underlying the emergence of symptoms and relationship with aging and adverse outcomes in variants of orthostatic hypotension. [ABSTRACT FROM AUTHOR]

Background: Cerebral autoregulation (CA) continuously adjusts cerebrovascular resistance to maintain cerebral blood flow (CBF) constant despite changes in blood pressure. Also, CBF is proportional to changes in arterial carbon dioxide (CO 2 ) (cerebrovascular CO 2 reactivity). Hypercapnia elicits cerebral vasodilation that attenuates CA efficacy, while hypocapnia produces cerebral vasoconstriction that enhances CA efficacy. In this study, we quantified the influence of sevoflurane anesthesia on CO 2 reactivity and the CA-CO 2 relationship., Methods: We studied patients with type 2 diabetes mellitus (DM), prone to cerebrovascular disease, and compared them to control subjects. In 33 patients (19 DM, 14 control), end-tidal CO 2 , blood pressure, and CBF velocity were monitored awake and during sevoflurane-based anesthesia. CA, calculated with transfer function analysis assessing phase lead (degrees) between low-frequency oscillations in CBF velocity and mean arterial blood pressure, was quantified during hypocapnia, normocapnia, and hypercapnia., Results: In both control and DM patients, awake CO 2 reactivity was smaller (2.8%/mm Hg CO 2 ) than during sevoflurane anesthesia (3.9%/mm Hg; P <0.005). Hyperventilation increased CA efficacy more (3 deg./mm Hg CO 2 ) in controls than in DM patients (1.8 deg./mm Hg CO 2 ; P <0.001) in both awake and sevoflurane-anesthetized states., Conclusions: The CA-CO 2 relationship is impaired in awake patients with type 2 DM. Sevoflurane-based anesthesia does not further impair this relationship. In patients with DM, hypocapnia induces cerebral vasoconstriction, but CA efficacy does not improve as observed in healthy subjects., Competing Interests: B.J.P.v.d.S. is supported by an educational grant from Edwards Lifesciences (2010B0797). J.H. has received an investigator-initiated study grant from Novo Nordisk, a project grant from the European Society of Anaesthesiology , and a MarieCurie individual fellowship grant from H2020 EU programme. M.W.H. is Executive Section Editor Pharmacology with Anaesthesia & Analgesia and has provided consultancy for BBraun, Baxter, Fresenius, CSL Behring, Eurocept, ECHO Pharmaceuticals, and MSD. B.P. has received research funding from GE Healthcare, Edwards Lifesciences, Air Liquide France, and Novo Nordisk Netherlands. He is part of an advisory board for Laboratoire Aguettant, France, and has received lecture fees from Abbvie, The Netherlands and Orion Pharma BVBA, The Netherlands, as well as research grants from SCA, ESA, and ZonMW. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The first step to exercise is preceded by the required assumption of the upright body position, which itself involves physical activity. The gravitational displacement of blood from the chest to the lower parts of the body elicits a fall in central blood volume (CBV), which corresponds to the fraction of thoracic blood volume directly available to the left ventricle. The reduction in CBV and stroke volume (SV) in response to postural stress, post-exercise, or to blood loss results in reduced left ventricular filling, which may manifest as orthostatic intolerance. When termination of exercise removes the leg muscle pump function, CBV is no longer maintained. The resulting imbalance between a reduced cardiac output (CO) and a still enhanced peripheral vascular conductance may provoke post-exercise hypotension (PEH). Instruments that quantify CBV are not readily available and to express which magnitude of the CBV in a healthy subject should remains difficult. In the physiological laboratory, the CBV can be modified by making use of postural stressors, such as lower body "negative" or sub-atmospheric pressure (LBNP) or passive head-up tilt (HUT), while quantifying relevant biomedical parameters of blood flow and oxygenation. Several approaches, such as wearable sensors and advanced machine-learning techniques, have been followed in an attempt to improve methodologies for better prediction of outcomes and to guide treatment in civil patients and on the battlefield. In the recent decade, efforts have been made to develop algorithms and apply artificial intelligence (AI) in the field of hemodynamic monitoring. Advances in quantifying and monitoring CBV during environmental stress from exercise to hemorrhage and understanding the analogy between postural stress and central hypovolemia during anesthesia offer great relevance for healthy subjects and clinical populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van der Ster, Kim, Westerhof and van Lieshout.)

The human brain is constantly active and even small limitations to cerebral blood flow (CBF) may be critical for preserving oxygen and substrate supply, e.g., during exercise and hypoxia. Exhaustive exercise evokes a competition for the supply of oxygenated blood between the brain and the working muscles, and inability to increase cardiac output sufficiently during exercise may jeopardize cerebral perfusion of relevance for diabetic patients. The challenge in diabetes care is to optimize metabolic control to slow progression of vascular disease, but likely because of a limited ability to increase cardiac output, these patients perceive aerobic exercise to be more strenuous than healthy subjects and that limits the possibility to apply physical activity as a preventive lifestyle intervention. In this review, we consider the effects of functional activation by exercise on the brain and how it contributes to understanding the control of CBF with the limited exercise tolerance experienced by type 2 diabetic patients. Whether a decline in cerebral oxygenation and thereby reduced neural drive to working muscles plays a role for "central" fatigue during exhaustive exercise is addressed in relation to brain's attenuated vascular response to exercise in type 2 diabetic subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, van der Ster, Brassard, Secher and van Lieshout.)

Rationale: Assessing the relative contributions of cardioinhibition and vasodepression to the blood pressure (BP) decrease in tilt-induced vasovagal syncope requires methods that reflect BP physiology accurately., Objective: To assess the relative contributions of cardioinhibition and vasodepression to tilt-induced vasovagal syncope using novel methods., Methods and Results: We studied the parameters determining BP, that is, stroke volume (SV), heart rate (HR), and total peripheral resistance (TPR), in 163 patients with tilt-induced vasovagal syncope documented by continuous ECG and video EEG monitoring. We defined the beginning of cardioinhibition as the start of an HR decrease (HR) before syncope and used logarithms of SV, HR, and TPR ratios to quantify the multiplicative relation BP=SV·HR·TPR. We defined 3 stages before syncope and 2 after it based on direction changes of these parameters. The earliest BP decrease occurred 9 minutes before syncope. Cardioinhibition was observed in 91% of patients at a median time of 58 seconds before syncope. At that time, SV had a strong negative effect on BP, TPR a lesser negative effect, while HR had increased (all P <0.001). At the onset of cardioinhibition, the median HR was at 98 bpm higher than baseline. Cardioinhibition thus initially only represented a reduction of the corrective HR increase but was nonetheless accompanied by an immediate acceleration of the ongoing BP decrease. At syncope, SV and HR contributed similarly to the BP decrease ( P <0.001), while TPR did not affect BP., Conclusions: The novel methods allowed the relative effects of SV, HR, and TPR on BP to be assessed separately, although all act together. The 2 major factors lowering BP in tilt-induced vasovagal syncope were reduced SV and cardioinhibition. We suggest that the term vasodepression in reflex syncope should not be limited to reduced arterial vasoconstriction, reflected in TPR, but should also encompass venous pooling, reflected in SV.

Chronic silent brain infarctions, detected as new white matter hyperintensities on magnetic resonance imaging (MRI) following transcatheter aortic valve implantation (TAVI), are associated with long-term cognitive deterioration. This is the first study to investigate to which extent the calcification volume of the native aortic valve (AV) measured with cardiac computed tomography angiography (CTA) predicts the increase in chronic white matter hyperintensity volume after TAVI. A total of 36 patients (79 ± 5 years, median EuroSCORE II 1.9%, Q 1 -Q 3 1.5-3.4%) with severe AV stenosis underwent fluid attenuation inversion recovery (FLAIR) MRI < 24 h prior to TAVI and at 3 months follow-up for assessment of cerebral white matter hyperintensity volume (mL). Calcification volumes (mm 3 ) of the AV, aortic arch, landing zone and left ventricle were measured on the CTA pre-TAVI. The largest calcification volumes were found in the AV (median 692 mm 3 ) and aortic arch (median 633 mm 3 ), with a large variation between patients (Q 1 -Q 3 482-1297 mm 3 and 213-1727 mm 3 , respectively). The white matter hyperintensity volume increased in 72% of the patients. In these patients the median volume increase was of 1.1 mL (Q 1 -Q 3 0.3-4.6 mL), corresponding with a 27% increase from baseline (Q 1 -Q 3 7-104%). The calcification volume in the AV predicted the increase of white matter hyperintensity volume (Δ%), with a 35% increase of white matter hyperintensity volume, per 100 mm 3 of AV calcification volume (SE 8.5, p < 0.001). The calcification volumes in the aortic arch, landing zone and left ventricle were not associated with the increase in white matter hyperintensity volume. In 72% of the patients new chronic white matter hyperintensities developed 3 months after TAVI, with a median increase of 27%. A higher calcification volume in the AV was associated with a larger increase in the white matter hyperintensity volume. These findings show the potential for automated AV calcium screening as an imaging biomarker to predict chronic silent brain infarctions.

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.

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., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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.

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.

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

Aim: The objective was to evaluate in treated heart failure (HF) patients whether multidrug therapy interferes with the cardiovascular autonomic response to postural stress., Methods and Results: Blood pressure (BP; Finapres), heart rate (HR), stroke volume, and total peripheral resistance (TPR) responses to standing up were measured in 33 HF patients and 10 healthy age-matched controls. Ten hypertensive (HT) patients treated with a similar combination of drugs but without heart failure served as reference subjects to account for use of medication. Frequency domain measures of HR and BP variability were calculated as correlates of cardiovascular autonomic function. Postural hypotension was found in 16 out of 33 HF patients independently from New York Heart Association functional class. In HF patients vs. HT patients and healthy controls the haemodynamic postural response was abnormal with a large initial BP fall and a slackened reflex increase in TPR resulting in inadequate BP recovery. HR and BP variability were normal in HT patients and healthy controls but attenuated in HF patients. The magnitude of the postural HR, stroke volume, and TPR responses as well as HR and BP variability was inversely related to the New York Heart Association class., Conclusions: In HF patients, the autonomic vasomotor response to postural stress is abnormal, more pronounced with increasing disease severity, and frequently associated with overt postural hypotension. These phenomena appear related to the cardiac condition rather than treatment.

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 (CBF v ) 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 CBF v 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 Pco 2 partial pressure (Pet CO 2 ) 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 CBF v during HUT vs. LBNP attributable to the pronounced reduction in Pet CO 2 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 Pco 2 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., (Copyright © 2017 the American Physiological Society.)

Renal hypoxia is thought to be an important pathophysiological factor in the progression of chronic kidney disease (CKD) and the associated hypertension. In a previous study among CKD patients, supplementation with 100% oxygen reduced sympathetic nerve activity (SNA) and lowered blood pressure (BP). We aimed to assess the underlying haemodynamic modulation and hypothesized a decreased systemic vascular resistance (SVR). To that end, 19 CKD patients were studied during 15-min intervals of increasing partial oxygen pressure (ppO 2 ) from room air (0.21 ATA) to 1.0 ATA and further up to 2.4 ATA, while continuously measuring finger arterial blood pressure (Finapres). Off-line, we derived indexes of SVR, cardiac output (CO) and baroreflex sensitivity from the continuous BP recordings (Modelflow). During oxygen supplementation, systolic, and diastolic BP both increased dose-dependently from 128 ± 24 and 72 ± 19 mmHg respectively at baseline to 141 ± 23 ( p < 0.001) and 80 ± 21 mmHg ( p < 0.001) at 1.0 ATA oxygen. Comparing baseline and 1.0 ATA oxygen, SVR increased from 1440 ± 546 to 1745 ± 710 dyn·s/cm 5 ( p = 0.009), heart rate decreased from 60 ± 8 to 58 ± 6 bpm ( p < 0.001) and CO from 5.0 ± 1.3 to 4.6 ± 1.1 L/min ( p = 0.02). Baroreflex sensitivity remained unchanged (13 ± 13 to 15 ± 12 ms/mmHg). These blood pressure effects were absent in a negative control group of eight young healthy subjects. We conclude that oxygen supplementation in CKD patients causes a non-baroreflex mediated increased in SVR and blood pressure.

There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.

Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 ± 7 standard deviation (SD) yr, body mass index 45 ± 6 kg/m 2 ] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 ± 5 kg (10%, P < 0.001). Office BP decreased from 137 ± 10/86 ± 6 to 128 ± 12/81 ± 9 mmHg (P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 ± 14/80 ± 9 to 114 ± 10/73 ± 6 mmHg (P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 ± 13/66 ± 7 to 102 ± 9/62 ± 7 mmHg (P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 ± 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 ± 189 dyn·s·cm -5 , 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4-14.3] to 13.8 [8.5-19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate (R = -0.64, P = 0.02) and CO (R = -0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control., New & Noteworthy: The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients., (Copyright © 2017 the American Physiological Society.)

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.

Background: It would be desirable to safely and continuously measure blood pressure noninvasively under hyperbaric and/or hyperoxic conditions, in order to explore haemodynamic responses in humans under these conditions., Methods: A systematic analysis according to 'failure mode and effects analysis' principles of a commercially available beat-by-beat non-invasive blood pressure monitoring device was performed using specifications provided by the manufacturer. Possible failure modes related to pressure resistance and fire hazard in hyperbaric and oxygen-enriched environments were identified and the device modified accordingly to mitigate these risks. The modified device was compared to an unaltered device in five healthy volunteers under normobaric conditions. Measurements were then performed under hyperbaric conditions (243 kPa) in five healthy subjects., Results: Modifications required included: 1) replacement of the carbon brush motorized pump by pressurized air connected through a balanced pressure valve; 2) modification of the 12V power supply connection in the multiplace hyperbaric chamber, and 3) replacement of gas-filled electrolytic capacitors by solid equivalents. There was concurrence between measurements under normobaric conditions, with no significant differences in blood pressure. Measurements under pressure were achieved without problems and matched intermittent measurement of brachial arterial pressure., Conclusion: The modified system provides safe, stable, continuous non-invasive blood pressure trends under both normobaric and hyperbaric conditions.

The arterial baroreflex regulates blood pressure by modifying heart rate and systemic vascular resistance. Baroreflex sensitivity is expressed as the relation between changes in blood pressure and the resulting changes in reciprocal values of heart rate (cardBRS) and in reciprocal values of vascular resistance (vascBRS). This study investigated determinants of vascBRS and cardBRS and their relationship in a random population sample. Continuous noninvasive arterial pressure was analyzed in 105 adults (43 males) with a median age of 45 (range 18-95) years and body mass index of 24.5 (range 18.1-39.1) kg m⁻². Systolic and diastolic blood pressures were 130 (range 95-205) and 80 (range 47-141) mmHg, and heart rate was 66 (range 42-109) beats min⁻¹. Pulse contour (CO-trek)-determined vascular resistance was 1.37 (range 0.60-7.75) mmHg s ml⁻¹. The results of vascBRS and cardBRS were log-transformed; linear regression analysis revealed that age, resistance⁻¹, systolic and diastolic blood pressures were major determinants of log(vascBRS) explaining 30.5 % of the variance. Determinants of log(cardBRS) were age, body mass index, heart rate, systolic and diastolic blood pressures, explaining 70.4 % of the variance. Thus, some established determinants of cardBRS were not correlated with vascBRS. There was no correlation between log(cardBRS) and log(vascBRS) after correction for age, supporting that vascBRS is an independent description of baroreflex regulation. These findings suggest that vascBRS and cardBRS report different modalities of cardiovascular autonomic function.

Monitoring of continuous blood pressure and cardiac output is important to prevent hypoperfusion and to guide fluid administration, but only few patients receive such monitoring due to the invasive nature of most of the methods presently available. Noninvasive blood pressure can be determined continuously using finger cuff technology and cardiac output is easily obtained using a pulse contour method. In this way completely noninvasive continuous blood pressure and cardiac output are available for clinical use in all patients that would otherwise not be monitored. Developments and state of art in hemodynamic monitoring are reviewed here, with a focus on noninvasive continuous hemodynamic monitoring form the finger.

Blood flow (BF) increases with increasing exercise intensity in skeletal, respiratory, and cardiac muscle. In humans during maximal exercise intensities, 85% to 90% of total cardiac output is distributed to skeletal and cardiac muscle. During exercise BF increases modestly and heterogeneously to brain and decreases in gastrointestinal, reproductive, and renal tissues and shows little to no change in skin. If the duration of exercise is sufficient to increase body/core temperature, skin BF is also increased in humans. Because blood pressure changes little during exercise, changes in distribution of BF with incremental exercise result from changes in vascular conductance. These changes in distribution of BF throughout the body contribute to decreases in mixed venous oxygen content, serve to supply adequate oxygen to the active skeletal muscles, and support metabolism of other tissues while maintaining homeostasis. This review discusses the response of the peripheral circulation of humans to acute and chronic dynamic exercise and mechanisms responsible for these responses. This is accomplished in the context of leading the reader on a tour through the peripheral circulation during dynamic exercise. During this tour, we consider what is known about how each vascular bed controls BF during exercise and how these control mechanisms are modified by chronic physical activity/exercise training. The tour ends by comparing responses of the systemic circulation to those of the pulmonary circulation relative to the effects of exercise on the regional distribution of BF and mechanisms responsible for control of resistance/conductance in the systemic and pulmonary circulations., (© 2012 American Physiological Society)

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.

The enhanced heart rate and blood pressure soon after awaking increases cardiac oxygen demand, and has been associated with the high incidence of acute myocardial infarction in the morning. The behavior of cardiac oxygen supply is unknown. We hypothesized that oxygen supply decreases in the morning and to that purpose investigated cardiac oxygen demand and oxygen supply at night and after awaking. We compared hypertensive to normotensive subjects and furthermore assessed whether pressures measured non-invasively and intra-arterially give similar results. Aortic pressure was reconstructed from 24-h intra-brachial and simultaneously obtained non-invasive finger pressure in 14 hypertensives and 8 normotensives. Supply was assessed by Diastolic Time Fraction (DTF, ratio of diastolic and heart period), demand by Rate-Pressure Product (RPP, systolic pressure times heart rate, HR) and supply/demand ratio by A(dia)/A(sys), with A(dia) and A(sys) diastolic and systolic areas under the aortic pressure curve. Hypertensives had lower supply by DTF and higher demand by RPP than normotensives during the night. DTF decreased and RPP increased in both groups after awaking. The DTF of hypertensives decreased less becoming similar to the DTF of normotensives in the morning; the RPP remained higher. A(dia)/A(sys) followed the pattern of DTF. Findings from invasively and non-invasively determined pressure were similar. The cardiac oxygen supply/demand ratio in hypertensive patients is lower than in normotensives at night. With a smaller night-day differences, the hypertensives' risk for cardiovascular events may be more evenly spread over the 24 h. This information can be obtained noninvasively.

Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). β-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 β-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 β-adrenergic blockade with significantly lower HR but comparable BP.

Sickle cell disease (SCD) is associated with a high incidence of ischemic stroke. SCD is characterized by hemolytic anemia, resulting in reduced nitric oxide-bioavailability, and by impaired cerebrovascular hemodynamics. Cerebrovascular CO2 responsiveness is nitric oxide dependent and has been related to an increased stroke risk in microvascular diseases. We questioned whether cerebrovascular CO2 responsiveness is impaired in SCD and related to hemolytic anemia. Transcranial Doppler-determined mean cerebral blood flow velocity (V(mean)), near-infrared spectroscopy-determined cerebral oxygenation, and end-tidal CO2 tension were monitored during normocapnia and hypercapnia in 23 patients and 16 control subjects. Cerebrovascular CO2 responsiveness was quantified as Delta% V(mean) and Deltamicromol/L cerebral oxyhemoglobin, deoxyhemoglobin, and total hemoglobin per mm Hg change in end-tidal CO2 tension. Both ways of measurements revealed lower cerebrovascular CO2 responsiveness in SCD patients versus controls (V(mean), 3.7, 3.1-4.7 vs 5.9, 4.6-6.7 Delta% V(mean) per mm Hg, P < .001; oxyhemoglobin, 0.36, 0.14-0.82 vs 0.78, 0.61-1.22 Deltamicromol/L per mm Hg, P = .025; deoxyhemoglobin, 0.35, 0.14-0.67 vs 0.58, 0.41-0.86 Deltamicromol/L per mm Hg, P = .033; total-hemoglobin, 0.13, 0.02-0.18 vs 0.23, 0.13-0.38 Deltamicromol/L per mm Hg, P = .038). Cerebrovascular CO2 responsiveness was not related to markers of hemolytic anemia. In SCD patients, impaired cerebrovascular CO2 responsiveness reflects reduced cerebrovascular reserve capacity, which may play a role in pathophysiology of stroke.

Near-infrared spectroscopy (NIRS) assesses cerebral oxygen saturation (Sco2) as a balance between cerebral oxygen delivery and consumption. In 71 patients, we evaluated whether marked reduction in mean arterial pressure (MAP) during propofol-fentanyl anesthesia induction affects frontal lobe Sco2. The NIRS-determined arm muscle oxygenation (Smo2), heart rate (HR), and cardiac output (CO) were monitored, endtidal carbon dioxide tension was controlled at 3.5 to 4.5 kPa, and central blood volume was maintained. Before anesthesia, the median (range) MAP, HR, and CO were 93 mm Hg (61-126 mm Hg), 76 beats/min (50-96 beats/min), and 5.3 L/min (2.4-9.0 L/min), respectively, but immediately following intravenous administration of fentanyl and propofol, MAP decreased to 63 mm Hg (37-109 mm Hg), HR to 63 beats/min (40-103 beats/min), and CO to 4.1 L/min (7.9-70 L/min) (P < .05). When blood pressure decreased, the median (range) NIRS-determined Smo2 also decreased (73% [54%-94%] to 71% [52%-87%]), whereas Sco2 increased from 67% (46%-93%) to 74% (48%-95%) (P < .05), independent of age and gender. After anesthesia induction, variables recovered and remained at preanesthetic levels during surgery. The findings implicate that even an approximately 30% drop in MAP at the induction of anesthesia does not typically affect cerebral oxygenation.

Background and Purpose: Sickle cell disease (SCD) is associated with cerebral hyperperfusion and an increased risk of stroke. Also, both recurrent microvascular obstruction and chronic hemolysis affect endothelial function, potentially interfering with systemic and cerebral blood flow control. We addressed the question whether cerebrovascular control in patients with SCD is affected and related to hemolysis., Methods: Systemic and cerebrovascular control were studied in 18 patients with SCD and 10 healthy subjects. Dynamic cerebral autoregulation was evaluated by transfer function analysis assessing the relationship between mean cerebral blood flow velocity and mean arterial pressure., Results: Normal baroreflex sensitivity and postural cardiovascular reflex responses indicated integrity of systemic cardiovascular control. In the low- (0.07 to 0.15 Hz) frequency region, mean arterial pressure variability was comparable for both groups, but a larger mean cerebral blood flow velocity variability in SCD (6.1 [4.6 to 7.0] versus 4.2 [2.6 to 5.2] [cm x s(-1)](2) x Hz(-1); P<0.05) indicated a reduced capacity to buffer the transfer of blood pressure surges to the cerebral tissue. Impairment of dynamic cerebrovascular control was confirmed by a reduced mean arterial pressure-to-mean cerebral blood flow velocity transfer function phase lead in SCD versus healthy subjects (32+/-17 degrees versus 50+/-19 degrees , P<0.05) that was unrelated to the severity of hemolysis., Conclusions: In patients with SCD, dynamic cerebral autoregulation is impaired but appears unrelated to hemolysis.

In this study, we compared continuous cardiac output (CO) obtained from the femoral arterial pressure by simulation of an aortic input impedance model [model-simulated cardiac output (MCO)] to thermodilution cardiac output (TDCO) determined by bolus injection during liver transplantation. Both variables were measured in 39 adult patients (13 females) every 10th minute during liver transplant surgery. Paired measurements were compared during the 4 phases of surgery-dissection, anhepatic phase, early reperfusion (the first 15 minutes after reperfusion), and late reperfusion (15-60 minutes after reperfusion)-without the detection of any significant difference between the 2 estimates of CO. TDCO ranged from 2.3 to 17.2 L/minute, and the bias (the mean difference between MCO and TDCO) prior to calibration was -0.4 +/- 1.6 L/minute (mean +/- standard deviation; 1309 paired measurements; 95% limits of agreement: -3.4 to 2.6 L/minute). After calibration of the first determined MCO by the simultaneously determined TDCO, the bias was 0.1 +/- 1.5 L/minute, with 57% (n = 744) of the comparisons being less than 1 L/minute and 35% (n = 453) being less than 0.5 L/minute; this was independent of the level of CO, and the mutual correlation coefficient was 0.812 (P < 0.001). This study indicates that during liver transplantation surgery, MCO reflects TDCO throughout the operation. Thus, for CO, this less invasive method appears to provide a reliable uninterrupted measurement during orthotopic liver transplantation.

Vasovagal syncope is the most common cause of transient loss of consciousness, and recurrent vasovagal fainting has a profound impact on quality of life. Physical countermaneuvers are applied as a means of tertiary prevention but have so far only proven useful at the onset of a faint. This placebo-controlled crossover study tested the hypothesis that leg crossing increases orthostatic tolerance. Nine naïve healthy subjects [6 females, median age 25 yr (range 20-41 yr), mean body mass index 23 (SD 2)] were subjected to passive head-up tilt combined with a graded lower body negative pressure challenge (20, 40, and 60 mmHg) determining orthostatic tolerance thrice, in randomized order: 1) control, 2) with leg crossing, and 3) with oral placebo. Blood pressure (Finometer), heart rate, and changes in thoracic blood volume (impedance), stroke volume, and cardiac output (Modelflow) were followed during orthostatic stress. Primary outcome was time to presyncope (systolic blood pressure /=140 beats/min). With leg crossing, orthostatic tolerance increased from 26 +/- 2 to 34 +/- 2 min (placebo 23 +/- 3 min, P < 0.001). During leg crossing, mean arterial pressure (81 vs. 81 mmHg) and cardiac output (95 vs. 94% supine) remained unchanged; heart rate increase was lower (13 vs. 18 beats/min, P < 0.05); stroke volume was higher (79 vs. 74% supine, P < 0.05); and there was a trend toward lower thoracic impedance. Leg crossing increases orthostatic tolerance in healthy human subjects. As a measure of prevention, it is a worthwhile addition to the management of vasovagal syncope.

Background and Purpose: We addressed whether dynamic cerebral autoregulation (dCA) is affected in middle cerebral artery (MCA) territory (MCAS) and lacunar ischemic stroke (LS)., Methods: Blood pressure (MAP) and MCA velocity (V) were measured in 10 patients with large MCAS (National Institutes of Health Stroke score, 17+/-2; mean+/-SEM), in 10 with LS (score, 9+/-1), and in 10 reference subjects. dCA was evaluated in time (delay of the MCA Vmean counter-regulation during changes in MAP) and frequency domains (cross-spectral MCA Vmean-to-MAP phase lead)., Results: In reference subjects, latencies for MAP increments (5.3+/-0.5 seconds) and decrements (5.6+/-0.5 seconds) were comparable, and low frequency MCA Vmean-to-MAP phase lead was 56+/-5 and 59+/-5 degrees (left and right hemisphere). In MCAS, these latencies were 4.6+/-0.7 and 5.6+/-0.5 seconds in the nonischemic hemisphere and not detectable in the ischemic hemisphere. In the unaffected hemisphere, phase lead was 61+/-6 degrees versus 26+/-6 degrees on the ischemic side (P<0.05). In LS, no latency and smaller phase lead bilaterally (32+/-6 and 33+/-5 degrees) conformed to globally impaired dCA., Conclusions: In large MCAS infarcts, dynamic cerebral autoregulation was impaired in the affected hemisphere. In LS, dynamic cerebral autoregulation was impaired bilaterally, a finding consistent with the hypothesis of bilateral small vessel disease in patients with lacunar infarcts.

1. The intravenous administration of fluid and blood has to balance the danger of unexpected death in response to a reduction of central blood volume (CBV) against that of developing pulmonary and/or peripheral oedema. 2. The initial cardiovascular response to haemorrhage is similar to that developed in response to standing. In the upright position, adults are subjected to a reduction of CBV of approximately 0.5 L and can therefore tolerate a blood loss of approximately 1 L when supine. 3. However, volume administration directed by cardiovascular variables is seldom precise, even with integration of the bradycardia and hypotension developed when CBV decreases by approximately 30%. Immediate intervention is needed because such a reduction in CBV raises the lower limit of cerebral autoregulation to approximately 80 mmHg compared with the commonly considered value of approximately 60 mmHg with an associated risk of developing brain ischaemia and irreversible shock. 4. Alternatively, the volume load can be monitored both directly and accurately by means of thoracic electrical admittance. A functional definition of normovolaemia may be the filling of the heart that ensures cardiac output and oxygen delivery. From that perspective, supine humans are normovolaemic in that a maximal venous oxygen saturation (Svo2) is established. 5. Conversely, Svo2 decreases in the upright position and, with a blood loss of approximately 100 mL, Svo2 is reduced by 1%. It is suggested that, in supine humans and guided by Svo2, normovolaemia may be established to an accuracy of approximately 100 mL and that its adequacy is controlled by recording cerebral oxygenation.

In this paper we review recent developments in the methodology of non-invasive finger arterial pressure measurement and the information about arterial flow that can be obtained from it. Continuous measurement of finger pressure based on the volume-clamp method was introduced in the early 1980s both for research purposes and for clinical medicine. Finger pressure tracks intra-arterial pressure but the pressure waves may differ systematically both in shape and magnitude. Such bias can, at least partly, be circumvented by reconstruction of brachial pressure from finger pressure by using a general inverse anti-resonance model correcting for the difference in pressure waveforms and an individual forearm cuff calibration. The Modelflow method as implemented in the Finometer computes an aortic flow waveform from peripheral arterial pressure by simulating a non-linear three-element model of the aortic input impedance. The methodology tracks fast changes in stroke volume (SV) during various experimental protocols including postural stress and exercise. If absolute values are required, calibration against a gold standard is needed. Otherwise, Modelflow-measured SV is expressed as change from control with the same precision in tracking. Beat-to-beat information on arterial flow offers important and clinically relevant information on the circulation beyond what can be detected by arterial pressure.

A 33-year old male patient, with Marfan's syndrome, reported symptoms of orthostatic intolerance and fatigue as a longstanding problem. Orthostatic cardiovascular examination showed poor orthostatic tolerance, with a rise in heart rate and a fall in arterial blood pressure and cerebral blood flow velocity. Self-discovered physical counterpressure manoeuvers improved symptoms, related to a substantial increase in arterial pressure and cerebral perfusion. When orthostatic complaint are reported by patients with Marfan's syndrome, physical counterpressure manoeuvers should be advised to reduce symptoms of postural hypotension.

The proper understanding of the cardiovascular mechanisms involved in complaints of short-lasting dizziness and the evaluation of unexplained recurrent syncope requires continuous monitoring of cardiac stroke volume (SV) in addition to blood pressure and heart rate. The primary aim of the present study was to evaluate a pulse wave analysis method that calculates beat-to-beat flow from non-invasive arterial pressure by simulating a non-linear, time-varying model of human aortic input impedance (Modelflow; MF), by comparing MF stroke volume (SV(MF)) to Doppler ultrasound (US) flow velocity SV (SV(US)). A second purpose was to compare the two methods under two different conditions: the supine and head-up tilt (30 degrees ) position. SV(US) and SV(MF) with non-invasive arterial pressure (Finapres) as input to the aortic model were measured beat-to-beat during spontaneous supine breathing and in the passive 30 degrees head-up tilt (HUT30) position in six normotensive healthy humans [three females, mean age 24 (21-26) years]. There were variations in supine SV track between the two methods with zero difference and a SD of the beat-to-beat difference (MF-US) of 4.2%. HUT30 induced a systematic difference of 10.5% and an increase in SD to 6.9%, which was reproducible. Beat-to-beat changes in SV in the supine resting condition were equally well assessed by both methods. Systematic differences appear during HUT30 and show opposite signs. The difference between the two methods upon a change in body position may be attributed to limitations in each method.

The cardiovascular derangement that results from the administration of endotoxin in healthy subjects is qualitatively similar to what is observed in patients in septic shock. The biological response to endotoxin is attributed in part to cytokine release. In experimental endotoxemia, recombinant bactericidal/permeability increasing protein (rBPI(23)) has shown a protective effect by binding endotoxin with the subsequent inhibition of the endotoxin-induced cytokine release and of neutrophil activation. In a controlled, blinded crossover study the early cardiovascular effects of rBPI(23) were investigated in an experimental endotoxemia model in humans. The beat-to-beat changes in arterial pressure and cardiac output following infusion of endotoxin (40 EU/kg body weight) and rBPI(23) (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg) were studied for 2 hours in 8 healthy male adults. Endotoxin or rBPI(23) alone did not induce significant cardiovascular changes. Endotoxin following rBPI(23) infusion elicited a fall in total peripheral resistance with its nadir after 4 minutes to 40% (range 16-53; P <.001) of control level. Mean arterial pressure showed little change, and the fall in total peripheral resistance was associated with a reflex increase in heart rate and cardiac output (32%; range 43-106). Changes in cardiovascular variables in the subsequent 2 hours were not significant. In vitro activation of the contact system by, respectively, rBPI(23), LPS, and LPS-rBPI(23) complexes was assessed. Following incubation with rBPI(23), LPS, and LPS-rBPI(23) complexes, complex levels were generated at levels comparable to those observed in the buffer control. The rapid vasodilatation by endotoxin administered concomitantly with rBPI(23) is not mediated by complement or contact system activation. The early vasodilatation is compensated by an increase in cardiac output, which therefore does not result in arterial hypotension. The monitoring of continuous cardiac output allows for the detection of rapid effects on systemic flow and conductance that go unnoticed in a recording of arterial pressure.