Dynamic Autoregulation Research Articles

Assessment of Dynamic Cerebral Autoregulation During Long-Term Exposure to High Altitude in Normal Subjects by Ultrasonography.

To evaluate changes in dynamic cerebral autoregulation (CA) during short-term and long-term exposure to high altitude with ultrasonography, and also study the sex differences in the response of CA to altitude. We assessed the differences in dynamic CA and measured with Doppler ultrasound of the bilateral internal carotid artery (ICA), vertebral artery (VA), and middle cerebral artery (MCA) and the values of basic information within 48 hours and at 2 years after arrival at Tibet in 65 healthy Han young Chinese volunteers, meanwhile, we compared the resistance index (RI) and pulsatility index (PI) of the right MCA at inhale oxygen 8 minutes when a newcomer with 2 years after arrival at Tibet. With 2 years of altitude exposure, the SaO2 of all subjects was above 90%, the mean PEF, DAP, and HR values decreased, HGB increased compared within 48 hours in same-gender groups. Comparisons of cerebral hemodynamics between before 2 years and after 2 years within male and female groups, the mean RI and PI values of bilateral MCA after 2 years were significantly higher than before 2 years, at the same time, the mean RI and PI values of bilateral ICA were significant differences (P < .05) between male groups, with regard to female groups, showed that the mean RI and PI values of bilateral VA were significant differences (P < .05). Comparisons of Right MCA hemodynamics between after oxygen uptake 8 minutes and 2 years, the mean RI and PI values were no significant difference within male and female groups (P > .05). Acute mountain sickness could result from an alteration of dynamic autoregulation of cerebral blood flow, but the impaired autoregulation may be corrected with the extension of time, furthermore, the response of CA to altitude in males and females are different.

Cerebral blood flow dynamics during cardiac surgery in infants.

In this pilot study, we investigated continuous cerebral blood flow velocity measurements to explore cerebrovascular hemodynamics in infants with congenital heart disease undergoing cardiac surgery. A non-invasive transfontanellar cerebral Doppler monitor (NeoDoppler) was used to monitor 15 infants (aged eight days to nine months) during cardiac surgery with cardiopulmonary bypass. Numerical and visual analyses were conducted to assess trends and events in Doppler measurements together with standard monitoring equipment. The mean flow index, calculated as the moving Pearson correlation between mean arterial pressure and time averaged velocity, was utilized to evaluate dynamic autoregulation. Two levels of impaired autoregulation were defined (Mean flow index >0.3/0.45), and percentage of time above these limits were calculated. High quality recordings were achieved during 90.6% of the monitoring period. There was a significant reduction in time averaged velocity in all periods of cardiopulmonary bypass. All patients showed a high percentage of time with impaired dynamic autoregulation, with Mean flow index >0.3 and 0.45: 73.71% ± 9.06% and 65.16% ± 11.27% respectively. Additionally, the system promptly detected hemodynamic events. Continuous transfontanellar cerebral Doppler monitoring could become an additional tool in enhancing cerebral monitoring in infants during cardiac surgery. This pilot study demonstrates the feasibility of continuous transfontanellar Doppler monitoring of cerebral blood flow velocities during cardiac surgery in infants. It also demonstrates a high proportion of time with impaired cerebral autoregulation during cardiac surgery based on the Mean flow index. Continuous transfontanellar Doppler could become a useful tool to improve cerebral monitoring and provide new pathophysiological insight.

Evaluation of dynamic cerebrovascular autoregulation during liver transplantation.

Cerebrovascular autoregulation in patients with acute and chronic liver failure is often impaired, yet an intact autoregulation is essential for the demand-driven supply of oxygenated blood to the brain. It is unclear, whether there is a connection between cerebrovascular autoregulation during liver transplantation (LTX) and the underlying disease, and if perioperative anesthesiologic consequences can result from this. In this prospective observational pilot study, data of twenty patients (35% female) undergoing LTX were analyzed. Cerebral blood velocity was measured using transcranial doppler sonography and was correlated with arterial blood pressure. The integrity of dynamic cerebrovascular autoregulation (dCA) was evaluated in the frequency domain through transfer function analysis (TFA). Standard clinical parameters were recorded. Mixed one-way ANOVA and generalized estimating equations were fitted to data involving repeated measurements on the same patient. For all other correlation analyses, Spearman's rank correlation coefficient (Spearman's-Rho) was used. Indications of impaired dCA are seen in frequency domain during different phases of LTX. No correlation was found between various parameter of dCA and primary disease, delirium, laboratory values, length of ICU or hospital stay, mortality or surgical technique. Although in most cases the dCA has been impaired during LTX, the heterogeneity of the underlying diseases seems to be too diverse to draw valid conclusions from this observational pilot study.

Developing a porcine model of severe traumatic brain injury induced by high amplitude rotational acceleration

IntroductionIt is unclear which pathophysiological processes initiate and drive dynamic cerebrovascular autoregulation (CA) impairment as seen in traumatic brain injury (TBI). This is not solely attributable to raised intracranial pressure (ICP), but also results from local tissue damage. Research questionIn order to investigate CA disturbing processes, a porcine model is needed that mimics severe TBI as seen in humans. This model requires high amplitude rotational acceleration. Material and methodsA customized device was built to produce a rotational impulse with high amplitude and short pulse duration. Following preparatory tests on cadaver piglets, six piglets of six weeks old were sedated, ventilated and subjected to rotational impulses of different magnitudes. The impulse was immediately followed by installment of invasive monitoring of ICP, PbO₂, Laser Doppler Flowmetry and arterial blood pressure. TBI was further characterized by magnetic resonance brain imaging. ResultsThe current setup enabled to reach sagittal head rotational maximal acceleration magnitudes up to 30 krad/s2. Half of the animals had an increase in ICP, measured shortly after the impulse. It has proved impossible so far to produce a sustained rise in ICP as seen in human severe TBI. MRI showed no anatomical abnormalities which would confirm severe TBI. Discussion and conclusionThe challenge to build a porcine model in which severe TBI with ICP raise and MRI changes as seen in humans can be reliably reproduced is still ongoing. It might be that higher peak rotational accelerations are needed.

A dynamic multiscale model of cerebral blood flow and autoregulation in the microvasculature

Models of the micro-circulatory blood flow in the brain can play a key role in understanding the variety of cerebrovascular diseases that occur in the microvasculature. These conditions are often linked to structural modifications in the vessel network, alterations in the blood flow patterns, as well as impairment in the autoregulatory response, all of which are pathological changes that the model should be able to address if it were to have any clinical value. Furthermore, if the model results were to be validated against clinical MRI data, the model simulations need to be computationally feasible when used on networks on the scale of an MRI voxel. This requires some form of an upscaling approach that bypasses the need for an explicit architectural representation of the whole network while maintaining the relevant anatomical connections. To this end, we developed a hybrid multiscale model of blood flow and autoregulation that traces the dynamic changes in blood flow, volume, and pressure in the cortical microvasculature, where the discrete topology of the penetrating vessels is preserved, and these are then appropriately coupled to the homogenised capillary bed by a spatially distributing support function in the terminal endings. In contrast to the other multiscale models, the model developed here accounts for the dynamic physiological phenomena of the blood flow and the autoregulation processes in the microvessels. We show how the adaptive meshing scheme for the capillary bed developed in this study can be employed to ensure a scale-invariant coupling formulation and numerically accurate simulations, all without compromising the computational feasibility of the model. A statistically accurate cortical network on the scale of an MRI voxel is generated, and the model parameter values are calibrated using a Monte Carlo Filtering analysis to ensure that the model results are physiologically informed. The model is found to be able to capture the steep pressure gradients that have been reported to occur at coupling interfaces. Furthermore, in response to an upstream pressure drop, the network is found to be able to recover cerebral blood flow while exhibiting the characteristic autoregulatory behaviour in terms of changes in vessel calibre and the biphasic flow response. Overall, the model developed here offers a high-quality characterisation of dynamic flow and autoregulation in the microvasculature at improved computational efficiency and lays the ground for whole-brain dynamic simulations.

High spatial and temporal resolution cerebrovascular reactivity for humans and large mammals: A technological description of integrated fNIRS and niABP mapping system.

Introduction: The process of cerebral vessels maintaining cerebral blood flow (CBF) fairly constant over a wide range of arterial blood pressure is referred to as cerebral autoregulation (CA). Cerebrovascular reactivity is the mechanism behind this process, which maintains CBF through constriction and dilation of cerebral vessels. Traditionally CA has been assessed statistically, limited by large, immobile, and costly neuroimaging platforms. However, with recent technology advancement, dynamic autoregulation assessment is able to provide more detailed information on the evolution of CA over long periods of time with continuous assessment. Yet, to date, such continuous assessments have been hampered by low temporal and spatial resolution systems, that are typically reliant on invasive point estimations of pulsatile CBF or cerebral blood volume using commercially available technology. Methods: Using a combination of multi-channel functional near-infrared spectroscopy and non-invasive arterial blood pressure devices, we were able to create a system that visualizes CA metrics by converting them to heat maps drawn on a template of human brain. Results: The custom Python heat map module works in "offline" mode to visually portray the CA index per channel with the use of colourmap. The module was tested on two different mapping grids, 8 channel and 24 channel, using data from two separate recordings and the Python heat map module was able read the CA indices file and represent the data visually at a preselected rate of 10 s. Conclusion: The generation of the heat maps are entirely non-invasive, with high temporal and spatial resolution by leveraging the recent advances in NIRS technology along with niABP. The CA mapping system is in its initial stage and development plans are ready to transform it from "offline" to real-time heat map generation.

Directional sensitivity of dynamic cerebral autoregulation during spontaneous fluctuations in arterial blood pressure at rest

Directional sensitivity, the more efficient response of cerebral autoregulation to increases, compared to decreases, in mean arterial pressure (MAP), has been demonstrated with repeated squat-stand maneuvers (SSM). In 43 healthy subjects (26 male, 23.1 ± 4.2 years old), five min. recordings of cerebral blood velocity (bilateral Doppler ultrasound), MAP (Finometer), end-tidal CO2 (capnograph), and heart rate (ECG) were obtained during sitting (SIT), standing (STA) and SSM. A new analytical procedure, based on autoregressive-moving average models, allowed distinct estimates of the autoregulation index (ARI) by separating the MAP signal into its positive (MAP+D) and negative (MAP−D) derivatives. ARI+D was higher than ARI−D (p < 0.0001), SIT: 5.61 ± 1.58 vs 4.31 ± 2.16; STA: 5.70 ± 1.24 vs 4.63 ± 1.92; SSM: 4.70 ± 1.11 vs 3.31 ± 1.53, but the difference ARI+D–ARI−D was not influenced by the condition. A bootstrap procedure determined the critical number of subjects needed to identify a significant difference between ARI+D and ARI−D, corresponding to 24, 37 and 38 subjects, respectively, for SSM, STA and SIT. Further investigations are needed on the influences of sex, aging and other phenotypical characteristics on the phenomenon of directional sensitivity of dynamic autoregulation.

A High Salt Diet Does Not Alter the Kinetics or the Magnitude of Renal Blood Flow Autoregulation in Conscious Salt‐Resistant and Salt‐Sensitive Rats

Blood pressure (BP) salt‐sensitivity is a major public health problem that augments the risk of kidney disease. Both BP dependent and independent mechanisms are thought to contribute to the increased risk of kidney injury in salt‐sensitive (SS) populations. Previous studies have reported that high dietary salt intake impairs renal blood flow (RBF) autoregulation, which increases the susceptibility to hypertensive renal injury. However, in these studies, RBF autoregulation was assessed in anesthetized rats or in isolated renal resistance vessels, which do not fully characterize the dynamic nature of RBF autoregulation in the conscious state. Our group has recently developed novel analytical methods to characterize both the magnitude and kinetics of the RBF autoregulatory response to spontaneous BP fluctuations in conscious, chronically instrumented rats. The goal of this study was to assess the effects of a high salt diet on the dynamics of RBF autoregulation in conscious, salt‐resistant and SS rat strains. At 8‐13 weeks of age, male Sprague‐Dawley (SD), Dahl SS, Consomic SS.BN1, Spontaneously Hypertensive (SHR), and Stroke‐prone SHR (SHRsp) rats were instrumented with a BP radiotelemeter and an ultrasonic RBF probe was positioned on the left renal artery. Following 1 week of recovery, BP and RBF were assessed for 2‐3 hours/day over 2‐3 consecutive days while rats were maintained on normal salt diet (0.4‐1% NaCl). All rats were then administered a high salt diet (4‐8% NaCl) and 2‐3 days later, BP and RBF were assessed for 2‐3 hours/day over 3‐5 consecutive days. All recordings were divided into segments of varying length (0.5‐20 seconds), and adjacent segments which exhibited a BP difference of 5 mmHg or greater were used to calculate RBF autoregulatory indices (i.e., % change in RBF / % change in BP). Different segment lengths were used to infer the time required for the preglomerular vasculature to restore RBF to levels observed prior to the change in BP. As shown in Figure 1, BP was significantly different among strains during normal salt diet with SD &lt; SS.BN1 &lt; SS = SHR &lt; SHRsp. A high salt diet significantly increased BP in SS and SHR rats. No significant differences in RBF were found among all strains during normal or high salt intake, and a high salt diet did not significantly alter the RBF autoregulatory response in any strain (Figure 2). As also shown in Figure 2, all strains exhibited &gt; 60% RBF autoregulatory compensation by 2.5 seconds following a change in BP, and the response was significantly faster in SHRsp vs. SD, SS, and SS.BN1 strains. All strains except SS and SS.BN1 rats exhibited complete RBF compensation by 10‐20 seconds following a change in BP. We conclude that a high salt diet does not significantly alter RBF autoregulatory responses in the conscious state in the salt‐resistant or salt‐sensitive strains examined in this study. There are strain differences in the initial magnitude of the RBF autoregulatory response with those strains exhibiting higher ambient BP’s having a stronger RBF autoregulatory response. The implications of the weaker RBF autoregulatory responses at later time points (i.e., 10‐20 seconds) following a change in BP in SS and SS.BN1 rats requires further investigation.

Non-Invasive and Minimally-Invasive Cerebral Autoregulation Assessment: A Narrative Review of Techniques and Implications for Clinical Research.

The process of cerebral vessels regulating constant cerebral blood flow over a wide range of systemic arterial pressures is termed cerebral autoregulation (CA). Static and dynamic autoregulation are two types of CA measurement techniques, with the main difference between these measures relating to the time scale used. Static autoregulation looks at the long-term change in blood pressures, while dynamic autoregulation looks at the immediate change. Techniques that provide regularly updating measures are referred to as continuous, whereas intermittent techniques take a single at point in time. However, a technique being continuous or intermittent is not implied by if the technique measures autoregulation statically or dynamically. This narrative review outlines technical aspects of non-invasive and minimally-invasive modalities along with providing details on the non-invasive and minimally-invasive measurement techniques used for CA assessment. These non-invasive techniques include neuroimaging methods, transcranial Doppler, and near-infrared spectroscopy while the minimally-invasive techniques include positron emission tomography along with magnetic resonance imaging and radiography methods. Further, the advantages and limitations are discussed along with how these methods are used to assess CA. At the end, the clinical considerations regarding these various techniques are highlighted.

Prospective Pilot Clinical Study of Noninvasive Cerebrovascular Autoregulation Monitoring in Open-Angle Glaucoma Patients and Healthy Subjects.

PurposeTo analyze the cerebrovascular autoregulation (CA) dynamics in patients with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) as well as healthy subjects using noninvasive ultrasound technologies for the first time.MethodsThe CA status of 10 patients with NTG, 8 patients with HTG, and 10 healthy subjects was assessed, using an innovative noninvasive ultrasonic technique, based on intracranial blood volume slow-wave measurements. Identified in each participant were intraocular pressure, ocular perfusion pressure, and CA-related parameter volumetric reactivity index (VRx), as well as the duration and doses of the longest cerebral autoregulation impairment (LCAI). In addition, we calculated the associations of these parameters with patients’ diagnoses.ResultsThe VRx value, the LCAI dose, and duration in healthy subjects were significantly lower than in patients with NTG (P < 0.05). However, no significant differences were noted in these parameters between healthy subjects and HTG and between NTG and HTG groups.ConclusionsNTG is associated with the disturbed cerebral blood flow and could be diagnosed by performing noninvasive CA assessments.Translational RelevanceThe VRx monitoring method can be applied to a wider range of patient groups, especially patients with normal-tension glaucoma.

Dynamic cerebrovascular autoregulation in patients prone to postural syncope: Comparison of techniques assessing the autoregulation index from spontaneous variability series.

Three approaches to the assessment of cerebrovascular autoregulation (CA) via the computation of the autoregulation index (ARI) from spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV) were applied: 1) a time domain method (TDM); 2) a nonparametric method (nonPM); 3) a parametric method (PM). Performances were tested over matched and surrogate unmatched pairs. Data were analyzed at supine resting (REST) and during the early phase of 60° head-up tilt (TILT) in 13 subjects with previous history of postural syncope (SYNC, age: 28±9yrs.; 5 males) and 13 control individuals (noSYNC, age: 27±8yrs.; 5 males). Analysis was completed by computing autonomic markers from heart period (HP) and systolic arterial pressure (SAP) variability series via spectral approach. HP and SAP spectral indexes suggested that noSYNC and SYNC groups exhibited different autonomic responses to TILT. ARI analysis indicated that: i) all methods have a sufficient statistical power to separate matched from unmatched pairs with the exception of nonPM applied to impulse response; ii) ARI estimates derived from different methods might be uncorrelated and, even when correlated, might exhibit a significant bias; iii) orthostatic stressor did not induce any evident ARI change in either noSYNC or SYNC individuals; iv) this conclusion held regardless of the method. Methods for the ARI estimation from spontaneous variability provide different ARIs but none indicate that noSYNC and SYNC subjects have different dynamic component of CA.

Experimental high thoracic spinal cord injury impairs the cardiac and cerebrovascular response to orthostatic challenge in rats.

Spinal cord injury (SCI) impairs the cardiovascular responses to postural challenge, leading to the development of orthostatic hypotension (OH). Here, we apply lower body negative pressure (LBNP) to rodents with high-level SCI to demonstrate the usefulness of LBNP as a model for experimental OH studies, and to explore the effect of simulated OH on cardiovascular and cerebrovascular function following SCI. Male Wistar rats (n = 34) were subjected to a sham or T3-SCI surgery and survived into the chronic period postinjury (i.e., 8 wk). Cardiac function was tracked via ultrasound pre- to post-SCI to demonstrate the clinical utility of our model. At study termination, we conducted left-ventricular (LV) catheterization and insonated the middle cerebral artery to investigate the hemodynamic, cardiac, and cerebrovascular response to a mild dose of LBNP that is sufficient to mimic clinically defined OH in rats with T3-SCI but not sham animals. In response to mimicked OH, there was a greater decline in stroke volume, cardiac output, maximal LV pressure, and blood pressure in SCI compared with sham (P < 0.034), whereas heart rate was increased in sham but decreased in SCI (P < 0.029). SCI animals also had an exaggerated reduction in peak, minimum and mean middle cerebral artery flow, for a given change in blood pressure, in response to LBNP (P < 0.033), implying impaired dynamic cerebral autoregulation. Using a preclinical SCI model of OH, we demonstrate that complete high thoracic SCI impairs the cardiac response to OH and disrupts dynamic cerebral autoregulation.NEW & NOTEWORTHY This is the first use of LBNP to interrogate the cardiac and cerebrovascular responses to simulated OH in a preclinical study of SCI. Here, we demonstrate the utility of our simulated OH model and use it to demonstrate that SCI impairs the cardiac response to simulated OH and disrupts dynamic cerebrovascular autoregulation.

Cerebral Blood Flow Deviations in Critically Ill Patients: Potential Insult Contributing to Ischemic and Hyperemic Injury.

Background: Ischemic and hyperemic injury have emerged as biologic mechanisms that contribute to cognitive impairment in critically ill patients. Spontaneous deviations in cerebral blood flow (CBF) beyond ischemic and hyperemic thresholds may represent an insult that contributes to this brain injury, especially if they accumulate over time and coincide with impaired autoregulation.Methods: We used transcranial Doppler to measure the proportion of time that CBF velocity (CBFv) deviated beyond previously reported ischemic and hyperemic thresholds in a cohort of critically ill patients with respiratory failure and/or shock within 48 h of ICU admission. We also assessed whether these CBFv deviations were more common during periods of impaired dynamic autoregulation, and whether they are explained by concurrent variations in mean arterial pressure (MAP) and end-tidal PCO2 (PetCO2).Results: We enrolled 12 consecutive patients (three females) who were monitored for a mean duration of 462.6 ± 39.8 min. Across patients, CBFv deviated by more than 20–30% from its baseline for 17–24% of the analysis time. These CBFv deviations occurred equally during periods of preserved and impaired autoregulation, while concurrent variations in MAP and PetCO2 explained only 13–21% of these CBFv deviations.Conclusion: CBFv deviations beyond ischemic and hyperemic thresholds are common in critically ill patients with respiratory failure or shock. These deviations occur irrespective of the state of dynamic autoregulation and are not explained by changes in MAP and CO2. Future studies should explore mechanisms responsible for these CBFv deviations and establish whether their cumulative burden predicts poor neurocognitive outcomes.

BP Fluctuations and the Real-Time Dynamics of Renal Blood Flow Responses in Conscious Rats.

Renal autoregulation maintains stable renal function despite BP fluctuations and protects glomerular capillaries from hypertensive injury. However, real-time dynamics of renal autoregulation in conscious animals have not been characterized. To develop novel analytic methods for assessing renal autoregulation, we recorded concurrent BP and renal blood flow in conscious rats, comparing animals with renal autoregulation that was intact versus impaired (from 3/4 nephrectomy), before and after additional impairment (from the calcium channel blocker amlodipine). We calculated autoregulatory indices for adjacent short segments of increasing length (0.5, 1, 2.5, 5, 10, and 20 seconds) that exhibited a mean BP difference of at least 5 mm Hg. Autoregulatory restoration of renal blood flow to baseline after BP changes in conscious rats occurs rapidly, in 5-10 seconds. The response is significantly slower in states of impaired renal autoregulation, enhancing glomerular pressure exposure. However, in rats with severe renal autoregulation impairment (3/4 nephrectomy plus amlodipine), renal blood flow in conscious animals (but not anesthetized animals) was still restored to baseline, but took longer (15-20 seconds). Consequently, the ability to maintain overall renal blood flow stability is not compromised in conscious rats with impaired renal autoregulation. These novel findings show the feasibility of renal autoregulation assessment in conscious animals with spontaneous BP fluctuations and indicate that transient increases in glomerular pressure may play a greater role in the pathogenesis of hypertensive glomerulosclerosis than previously thought. These data also show that unidentified mechanosensitive mechanisms independent of known renal autoregulation mechanisms and voltage-gated calcium channels can maintain overall renal blood flow and GFR stability despite severely impaired renal autoregulation.

Dynamic Autoregulation is Impaired in Circulatory Shock.

Circulatory shock is a life-threatening disorder that is associated with high mortality, with a state of systemic and tissue hypoperfusion that can lead to organ failure, including the brain, where altered mental state is often observed. We hypothesized that cerebral autoregulation (CA) is impaired in patients with circulatory shock. Adult patients with circulatory shock and healthy controls were included. Cerebral blood flow velocity (CBFV, transcranial Doppler ultrasound) and arterial blood pressure (BP, Finometer or intra-arterial line) were continuously recorded during 5 min in both groups. Autoregulation Index (ARI) was estimated from the CBFV response to a step change in BP, derived by transfer function analysis; ARI ≤ 4 was considered impaired CA. The relationship between organ dysfunction, assessed with the Sequential Organ Failure Assessment (SOFA) score and the ARI, was assessed with linear regression. Twenty-five shock patients and 28 age-matched healthy volunteers were studied. The mean ± SD SOFA score was 10.8 ± 4.3. Shock patients compared with control subjects had lower ARI values (4.0 ± 2.1 vs. 5.9 ± 1.5, P = 0.001). Impaired CA was more common in shock patients (44.4% vs. 7.1%, P = 0.003). There was a significant inverse relationship between the ARI and the SOFA score (R = -0.63, P = 0.0008). These results suggest that circulatory shock is often associated with impaired CA and that the severity of CA alterations is correlated with the degree of multiple organ failure, reinforcing the need to monitor cerebral hemodynamics in patients with circulatory shock.

Cerebrovascular Dynamics During Continuous Motor Task.

We investigated the cerebral autoregulation (CA) dynamics parameter phase and gain change when exposed to a longlasting motor task. 25 healthy subjects (mean age ± SE, 38±2.6 years, 13 females) underwent simultaneous recordings of spontaneous fluctuations in blood pressure (BP), cerebral blood flow velocity (CBFV), and end-tidal CO(2) (ETCO(2)) over 5 min of rest followed by 5 min of left elbow flexion at a frequency of 1 Hz. Tansfer function gain and phase between BP and CBFV were assessed in the frequency ranges of very low frequencies (VLF, 0.02-0.07 Hz), low frequencies (LF, 0.07-0.15), and high frequencies (HF, >0.15). CBFV increased on both sides rapidly to maintain an elevated steady state until movement stopped. Cerebrovascular resistance fell on the right side (rest 1.35±0.06, movement 1.28±0.06, p<0.01), LF gain decreased from baseline (right side 0.97±0.07 %/mm Hg, left 1.01±0.09) to movement epoch (right 0.73±0.08, left 0.76±0.06, p</=0.01). VLF phase decreased from baseline (right 1.03±0.05 radians, left 1.10±0.06) to the movement epoch (right 0.81±0.07, left 0.82±0.10, p?0.05). CA regulates continuous motor efforts by changes in resistance, gain and phase.

2032 - DYNAMICS QUANTIFICATION OF TRANSCRIPTION FACTOR SWITCHES IN HSPC LINEAGE CHOICE

Transcription factor (TF) networks regulate the lineage choice of hematopoietic stem and progenitor cells (HSPCs). Previous studies suggested a functional antagonism between the core hematopoietic TFs PU.1 and GATA1, and their autoregulation as the basis for a cell-intrinsic stochastic switch regulating PU.1 expression in lineage choice of HSPCs. Using long-term quantitative time-lapse imaging of HSCs from the PU.1eYFP/GATA1mCherry reporter mouse line, we previously showed that a random PU.1 and GATA1 switch does not initiate myeloid lineage choice. To further analyze the regulation of PU.1, we generated a novel mouse line with an inducible PU.1-ERT2 allele co-expressed with the PU.1eYFP/GATA1mCherry reporter alleles. Using single-cell reprogramming assays, microfluidics facilitated reversible PU.1 induction by TNF and single-cell quantification in response to transgenic PU.1-ERT2 activation, we quantified PU.1 expression in thousands of single HSPCs to measure the short- and long- term autoregulation dynamics. Surprisingly, we do not observe direct autoregulation of PU.1 at many different stages of hematopoietic differentiation. We find PU.1 autoregulation not to be involved in initiating differentiation, but to be an indirect consequence of it. Finally, to dissect the molecular triad of PU.1, GATA1 and GATA2 in regulating HSC lineage choice, we have generated a novel reporter mouse line for GATA2 protein and continuously quantify its expression dynamics, simultaneous with that of GATA1 in living HSPCs along the megakaryocyte-erythrocyte and granulocyte-monocyte differentiation trajectories. These data disprove several previous assumptions about the regulation of HSPC fate control, identify novel regulators, and demonstrate vacancy for other cell-extrinsic and -intrinsic players in regulating hematopoietic TFs specifically and lineage choice of HSCs in general.

Impaired dynamic cerebral autoregulation in trained breath-hold divers.

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breath-hold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-to-stand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (∆CVRi/∆T)/∆BP]. The BHD demonstrated slower RoR than controls (P ≤ 0.001, d = 1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls (P = 0.004, d = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls (P = 0.01, d = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia.

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 PCO 2 (PETCO 2), 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°↨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.

Patient-specific management of severe TBI depending on age and cerebrovascular autoregulation status

Determination of proper choice of patient-specific management methodology is crucial for patients with traumatic brain injury (TBI). The treatment outcomes of TBI patients depend on cerebral blood flow autoregulation impairments which can also be affected by patients’ age, brain injury grade or pharmacological influences (anaesthetics, sedation, etc.). The objective of the prospective study was to explore the influence of various factors (dynamics of cerebrovascular autoregulation (CA) status, cerebral perfusion pressure (CPP) declination from optimal CPP value (ΔCPPopt), TBI severity, age, glucose level in blood, etc.) on the TBI patients' outcome. Multimodal ABP, ICP, CPP and CA monitoring of 81 TBI patients has been performed in Republic Vilnius University Hospital (Lithuania). ICM+ software (Cambridge, UK) was used for continuous CA status assessment by calculating Pressure Reactivity Index (PRx) and for identification of patient-specific optimal CPP (optCPP). The post-hoc analysis of associations between the patients' outcome and complex influence monitored parameters was performed by creating multifactorial model of predicting TBI patient's outcome and determining the most important factors affecting outcome. The multifactorial logistic regression model showed that the most significant factors affecting TBI patient's outcome are age, Glasgow Coma Scale (GCS), glucose level in blood serum samples (determined within 24 hours after admission), Helsinki CT (HCT) score and duration of longest CA impairment when PRx(t) > 0.5 within 24 hours after admission. The modelled accuracies for mortality and unfavorable outcome prediction were 82% and 86% respectively. The age > 45 years (P = 0.034, χ2 = 17.48) and HCT > 7 (P = 0.14, χ2 = 15.13) were found statistically significantly associated with unfavorable outcome or mortality. OptCPP-targeted management was found statistically significantly associated with better outcome for younger patients (age 0.36 and duration of LCAI > 100 min (P = 0.043, χ2 = 18.00) were found associated with mortality for younger patients group ( 0.26 (P = 0.005, χ2 = 7.80) and duration of LCAI > 61 min (P = 0.019, χ2 = 5.44) were founded associated with mortality for elderly patients group (> 45 years). The main factors affecting TBI treatment outcomes are patient's age, HCT, GCS, blood glucose level and the CA status during first day after patient admission. The optCPP-targeted patient-specific management is useful for stabilizing CA in severe TBI patients as well as for improving outcome for younger patients with age