Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network (CARNet).

Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA.

Physiological Variability during Prehospital Stroke Care: Which Monitoring and Interventions Are Used?

Prehospital care is a fundamental component of stroke care that predominantly focuses on shortening the time between diagnosis and reaching definitive stroke management. With growing evidence of the physiological parameters affecting long-term patient outcomes, prehospital clinicians need to consider the balance between rapid transfer and increased physiological-parameter monitoring and intervention. This systematic review explores the existing literature on prehospital physiological monitoring and intervention to modify these parameters in stroke patients. The systematic review was registered on PROSPERO (CRD42022308991) and conducted across four databases with citation cascading. Based on the identified inclusion and exclusion criteria, 19 studies were retained for this review. The studies were classified into two themes: physiological-monitoring intervention and pharmacological-therapy intervention. A total of 14 included studies explored prehospital physiological monitoring. Elevated blood pressure was associated with increased hematoma volume in intracerebral hemorrhage and, in some reports, with increased rates of early neurological deterioration and prehospital neurological deterioration. A reduction in prehospital heart rate variability was associated with unfavorable clinical outcomes. Further, five of the included records investigated the delivery of pharmacological therapy in the prehospital environment for patients presenting with acute stroke. BP-lowering interventions were successfully demonstrated through three trials; however, evidence of their benefit to clinical outcomes is limited. Two studies investigating the use of oxygen and magnesium sulfate as neuroprotective agents did not demonstrate an improvement in patient's outcomes. This systematic review highlights the absence of continuous physiological parameter monitoring, investigates fundamental physiological parameters, and provides recommendations for future work, with the aim of improving stroke patient outcomes.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Depression of dynamic cerebral autoregulation during neural activation: The role of responders and non-responders.

Neurovascular coupling (NVC) interaction with dynamic cerebral autoregulation (dCA) remains unclear. We investigated the effect of task complexity and duration on the interaction with dCA. Sixteen healthy participants (31.6 ± 11.6 years) performed verbal fluency (naming-words (NW)) and serial subtraction (SS) paradigms, of varying complexity, at durations of 05, 30 and 60 s. The autoregulation index (ARI), was estimated from the bilateral middle cerebral artery blood velocity (MCAv) step response, calculated by transfer function analysis (TFA), for each paradigm during unstimulated (2 min) and neuroactivated (1 min) segments. Intraclass correlation (ICC) and coefficient of variation (CV) determined reproducibility for two visits and objective criteria were applied to classify responders (R) and non-responders (NoR) to task-induced MCAv increase. ICC values demonstrated fair reproducibility in all tasks. ARI decreased in right (RH) and left (LH) hemispheres, irrespective of paradigm complexity and duration (p < 0.0001). Bilateral ARI estimates were significantly decreased during NW for the R group only (p < 0.0001) but were reduced in both R (p < 0.0001) and NoR (p = 0.03) groups for SS tasks compared with baseline. The reproducible attenuation of dCA efficiency due to paradigm-induced NVC response, its interaction, and different behaviour in R and NoR, warrant further research in different physiological and clinical conditions.

Exploring Physiological Differences in Brain Areas Using Statistical Complexity Analysis of BOLD Signals.

The brain is a fundamental organ for the human body to function properly, for which it needs to receive a continuous flow of blood, which explains the existence of control mechanisms that act to maintain this flow as constant as possible in a process known as cerebral autoregulation. One way to obtain information on how the levels of oxygen supplied to the brain vary is through of BOLD (Magnetic Resonance) images, which have the advantage of greater spatial resolution than other forms of measurement, such as transcranial Doppler. However, they do not provide good temporal resolution nor allow for continuous prolonged examination. Thus, it is of great importance to find a method to detect regional differences from short BOLD signals. One of the existing alternatives is complexity measures that can detect changes in the variability and temporal organisation of a signal that could reflect different physiological states. The so-called statistical complexity, created to overcome the shortcomings of entropy alone to explain the concept of complexity, has shown potential with haemodynamic signals. The aim of this study is to determine by using statistical complexity whether it is possible to find differences between physiologically distinct brain areas in healthy individuals. The data set includes BOLD images of 10 people obtained at the University Hospital of Leicester NHS Trust with a 1.5 Tesla magnetic resonance imaging scanner. The data were captured for 180 s at a frequency of 1 Hz. Using various combinations of statistical complexities, no differences were found between hemispheres. However, differences were detected between grey matter and white matter, indicating that these measurements are sensitive to differences in brain tissues.

The effect of hypercapnia on the directional sensitivity of dynamic cerebral autoregulation and the influence of age and sex.

The cerebral circulation responds differently to increases in mean arterial pressure (MAP), compared to reductions in MAP. We tested the hypothesis that this directional sensitivity is reduced by hypercapnia. Retrospective analysis of 104 healthy subjects (46 male (44%), age range 19-74 years), with five minute recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), non-invasive MAP (Finometer) and end-tidal CO2 (capnography) at rest, during both poikilocapnia and hypercapnia (5% CO2 breathing in air) produced MCAv step responses allowing estimation of the classical Autoregulation Index (ARIORIG), and corresponding values for both positive (ARI+D) and negative (ARI-D) changes in MAP. Hypercapnia led to marked reductions in ARIORIG, ARI+D and ARI-D (p < 0.0001, all cases). Females had a lower value of ARIORIG compared to males (p = 0.030) at poikilocapnia (4.44 ± 1.74 vs 4.74 ± 1.48) and hypercapnia (2.44 ± 1.93 vs 3.33 ± 1.61). The strength of directional sensitivity (ARI+D-ARI-D) was not influenced by hypercapnia (p = 0.46), sex (p = 0.76) or age (p = 0.61). During poikilocapnia, ARI+D decreased with age in females (p = 0.027), but not in males. Directional sensitivity was not affected by hypercapnia, suggesting that its origins are more likely to be inherent to the mechanics of vascular smooth muscle than to myogenic pathways.

TCD assessment in fulminant hepatic failure: Improvements in cerebral autoregulation after liver transplantation.

INTRODUCTION AND OBJECTIVES: Acute liver failure, also known as fulminant hepatic failure (FHF), includes a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction and hepatic encephalopathy. The objective of this study was to assess cerebral autoregulation (CA) in 25 patients (19 female) with FHF and to follow up with seventeen of these patients before and after liver transplantation. PATIENTS AND METHODS: The mean age was 33.8 years (range 14-56, SD 13.1 years). Cerebral hemodynamics was assessed by transcranial Doppler (TCD) bilateral recordings of cerebral blood velocity (CBv) in the middle cerebral arteries (MCA). RESULTS: CA was assessed based on the static CA index (SCAI), reflecting the effects of a 20-30 mmHg increase in mean arterial blood pressure on CBv induced with norepinephrine infusion. SCAI was estimated at four time points: pretransplant and on the 1st, 2nd and 3rd posttransplant days, showing a significant difference between pre- and posttransplant SCAI (p = 0.005). SCAI peaked on the third posttransplant day (p = 0.006). Categorical analysis of SCAI showed that for most patients, CA was reestablished on the second day posttransplant (SCAI > 0.6). CONCLUSIONS: These results suggest that CA impairment pretransplant and on the 1st day posttransplant was re-established at 48-72 h after transplantation. These findings can help to improve the management of this patient group during these specific phases, thereby avoiding neurological complications, such as brain swelling and intracranial hypertension.

Measurement of resistance-area product by transcranial Doppler: An alternative tool for cognitive screening in hypertensive on drug treatment?

Introduction: Arterial hypertrophy and remodeling are adaptive responses present in systemic arterial hypertension that can result in silent ischemia and neurodegeneration, compromising brain connections and cognitive performance (CP). However, CP is affected differently over time, so traditional screening methods may become less sensitive in assessing certain cognitive domains. The study aimed to evaluate whether cerebrovascular hemodynamic parameters can serve as a tool for cognitive screening in hypertensive without clinically manifest cognitive decline. Methods: Participants were allocated into groups: non-hypertensive (n = 30) [group 1], hypertensive with systolic blood pressure (SBP) < 140 and diastolic blood pressure (DBP) < 90 mmHg (n = 54) [group 2] and hypertensive with SBP ≥ 140 or DBP ≥ 90 (n = 31) [group 3]. Measurements of blood pressure and middle cerebral artery blood flow velocity were obtained from digital plethysmography and transcranial Doppler. For the cognitive assessment, the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA) and a broad neuropsychological battery were applied. Results: Patients in groups 2 and 3 show no significant differences in most of the clinical-epidemiological variables or pulsatility index (p = 0.361), however compared to group 1 and 2, patients in group 3 had greater resistance-area product [RAP] (1.7 [±0.7] vs. 1.2 [±0.2], p < 0.001). There was a negative correlation between RAP, episodic memory (r = -0.277, p = 0.004) and cognitive processing speed (r = -0.319, p = 0.001). Conclusion: RAP reflects the real cerebrovascular resistance, regardless of the direct action of antihypertensive on the microcirculation, and seems to be a potential alternative tool for cognitive screening in hypertensive.

Point-Counterpoint: Cerebral perfusion pressure is a high-risk concept.

Cerebral perfusion pressure (CPP) is calculated as the difference between mean arterial blood pressure and mean intracranial pressure, being commonly applied in neurocritical care. This commentary discusses recent physiological advances in knowledge as well as bedside practice issues that in combination indicate considering CPP under this perspective may lead to inaccurate assumptions and potentially misleading decision making.

Dynamic cerebral autoregulation in Alzheimer's disease and mild cognitive impairment: A systematic review.

Dynamic cerebral autoregulation (dCA) is a key mechanism that regulates cerebral blood flow (CBF) in response to transient changes in blood pressure (BP). Impairment of dCA could increase vulnerability to hypertensive vascular damage, but also to BP lowering effects of antihypertensive treatment. The literature remains conflicted on whether dCA is altered in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We summarized available data on dCA in AD and MCI, by searching PubMed, Embase, PsycINFO and Web of Science databases (inception-January 2022). Eight studies (total n = 443) were included in the qualitative synthesis of which seven were eligible for meta-analysis. All studies used Transcranial Doppler (TCD) ultrasonography and transfer function analysis or the autoregulatory index to assess dCA during spontaneous or induced BP fluctuations. Meta-analysis indicated no significant difference between AD, MCI and healthy controls in dCA parameters for spontaneous fluctuations. For induced fluctuations, the available data were limited, but indicative of at least preserved and possibly better autoregulatory functioning in AD and MCI compared to controls. In summary, current evidence does not suggest poorer dCA efficiency in AD or MCI. Further work is needed to investigate dCA in dementia with induced fluctuations controlling for changes in end-tidal carbon dioxide.

Point/counterpoint: Cerebrovascular resistance is a flawed concept.

The relationship between cerebral blood flow and blood pressure is a critical part of investigation of cerebral autoregulation. Conventionally, cerebrovascular resistance (CVR) has been used to describe this relationship, but the underlying principles used for this method is flawed in real-world application for several reasons. Despite this, the use of CVR remains entrenched within current literature. This 'Point/Counterpoint' review provides a summary of the flaws in using CVR and explains the benefits of calculating the more accurate critical closing pressure (CrCP) and resistance-area product (RAP) parameters, with support of real-world data.

The role of the autonomic nervous system in cerebral blood flow regulation in stroke: A review.

Stroke is a pathophysiological condition which results in alterations in cerebral blood flow (CBF). The mechanism by which the brain maintains adequate CBF in presence of fluctuating cerebral perfusion pressure (CPP) is known as cerebral autoregulation (CA). Disturbances in CA may be influenced by a number of physiological pathways including the autonomic nervous system (ANS). The cerebrovascular system is innervated by adrenergic and cholinergic nerve fibers. The role of the ANS in regulating CBF is widely disputed owing to several factors including the complexity of the ANS and cerebrovascular interactions, limitations to measurements, variation in methods to assess the ANS in relation to CBF as well as experimental approaches that can or cannot provide insight into the sympathetic control of CBF. CA is known to be impaired in stroke however the number of studies investigating the mechanisms by which this occurs are limited. This literature review will focus on highlighting the assessment of the ANS and CBF via indices derived from the analyses of heart rate variability (HRV), and baroreflex sensitivity (BRS), and providing a summary of both clinical and animal model studies investigating the role of the ANS in influencing CA in stroke. Understanding the mechanisms by which the ANS influences CBF in stroke patients may provide the foundation for novel therapeutic approaches to improve functional outcomes in stroke patients.

Critical Closing Pressure and Cerebrovascular Resistance Responses to Intracranial Pressure Variations in Neurocritical Patients.

BACKGROUND: Critical closing pressure (CrCP) and resistance-area product (RAP) have been conceived as compasses to optimize cerebral perfusion pressure (CPP) and monitor cerebrovascular resistance, respectively. However, for patients with acute brain injury (ABI), the impact of intracranial pressure (ICP) variability on these variables is poorly understood. The present study evaluates the effects of a controlled ICP variation on CrCP and RAP among patients with ABI. METHODS: Consecutive neurocritical patients with ICP monitoring were included along with transcranial Doppler and invasive arterial blood pressure monitoring. Internal jugular veins compression was performed for 60 s for the elevation of intracranial blood volume and ICP. Patients were separated in groups according to previous intracranial hypertension severity, with either no skull opening (Sk1), neurosurgical mass lesions evacuation, or decompressive craniectomy (DC) (patients with DC [Sk3]). RESULTS: Among 98 included patients, the correlation between change (Δ) in ICP and the corresponding ΔCrCP was strong (group Sk1 r = 0.643 [p = 0.0007], group with neurosurgical mass lesions evacuation r = 0.732 [p < 0.0001], and group Sk3 r = 0.580 [p = 0.003], respectively). Patients from group Sk3 presented a significantly higher ΔRAP (p = 0.005); however, for this group, a higher response in mean arterial pressure (change in mean arterial pressure p = 0.034) was observed. Exclusively, group Sk1 disclosed reduction in ICP before internal jugular veins compression withholding. CONCLUSIONS: This study elucidates that CrCP reliably changes in accordance with ICP, being useful to indicate ideal CPP in neurocritical settings. In the early days after DC, cerebrovascular resistance seems to remain elevated, despite exacerbated arterial blood pressure responses in efforts to maintain CPP stable. Patients with ABI with no need of surgical procedures appear to remain with more effective ICP compensatory mechanisms when compared with those who underwent neurosurgical interventions.

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.

Contribution of intracranial pressure to human dynamic cerebral autoregulation after acute brain injury.

Cerebral perfusion pressure (CPP) is normally expressed by the difference between mean arterial blood pressure (MAP) and intracranial pressure (ICP) but comparison of the separate contributions of MAP and ICP to human cerebral blood flow autoregulation has not been reported. In patients with acute brain injury (ABI), internal jugular vein compression (IJVC) was performed for 60 s. Dynamic cerebral autoregulation (dCA) was assessed in recordings of middle cerebral artery blood velocity (MCAv, transcranial Doppler), and invasive measurements of MAP and ICP. Patients were separated according to injury severity as having whole/undamaged skull, large fractures, or craniotomies, or following decompressive craniectomy. Glasgow coma score was not different for the three groups. IJVC induced changes in MCAv, MAP, ICP, and CPP in all three groups. The MCAv response to step changes in MAP and ICP expressed the dCA response to these two inputs and was quantified with the autoregulation index (ARI). In 85 patients, ARI was lower for the ICP input as compared with the MAP input (2.25 ± 2.46 vs. 3.39 ± 2.28; P < 0.0001), and particularly depressed in the decompressive craniectomy (DC) group (n = 24, 0.35 ± 0.62 vs. 2.21 ± 1.96; P < 0.0005). In patients with ABI, the dCA response to changes in ICP is less efficient than corresponding responses to MAP changes. These results should be taken into consideration in studies aimed to optimize dCA by manipulation of CPP in neurocritical patients.

Antihypertensives in dementia: Good or bad for the brain?

Hypertension is associated with both ageing and dementia. Despite this, optimal blood pressure targets in dementia remain unclear. Both high and low blood pressure are associated with poorer cognition. Changes in vascular physiology in dementia may increase the vulnerability of the brain to hypoperfusion associated with antihypertensives. We discuss the potential risks of antihypertensives in the context of altered cerebral haemodynamics, and evidence from antihypertensive trials in dementia. We suggest that individualised blood pressure targets should be the focus for antihypertensive therapy in dementia, rather than strict control to uniform targets extrapolated from trials in cognitively healthy individuals.

Point-Counterpoint: Transfer function analysis of dynamic cerebral autoregulation: To band or not to band?

Transfer function analysis (TFA) is the most frequently adopted method for assessing dynamic cerebral autoregulation (CA) with continuously recorded arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Conventionally, values of autoregulatory metrics (e.g., gain and phase) derived from TFA are averaged within three frequency bands separated by cut-off frequencies at 0.07 Hz and 0.20 Hz, respectively, to represent the efficiency of dynamic CA. However, this is of increasing concerns, as there remains no solid evidence for choosing these specific cut-off frequencies, and the rigid adoption of these bands can stifle further developments in TFA of dynamic CA. In this 'Point-Counterpoint' mini-review, we provide evidence against the fixed banding, indicate possible alternatives, and call for awareness of the risk of the 'one-size-fits-all' banding becoming dogmatic. We conclude that we need to remain open to the multiple possibilities offered by TFA to realize its full potential in studies of human dynamic CA.

Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.

Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

Detection of Blood CO2 Influences on Cerebral Hemodynamics Using Transfer Entropy.

Cerebral hemodynamics describes an important physiological system affected by components such as blood pressure, CO2 levels, and endothelial factors. Recently, novel techniques have emerged to analyse cerebral hemodynamics based on the calculation of entropies, which quantifies or describes changes in the complexity of this system when it is affected by a pathological or physiological influence. One recently described measure is transfer entropy, which allows for the determination of causality between the various components of a system in terms of their flow of information, and has shown positive results in the multivariate analysis of physiological signals. This study aims to determine whether conditional transfer entropy reflects the causality in terms of entropy generated by hypocapnia on cerebral hemodynamics. To achieve this, non-invasive signals from 28 healthy individuals who undertook a hyperventilation maneuver were analyzed using conditional transfer entropy to assess the variation in the relevance of CO2 levels on cerebral blood velocity. By employing a specific method to discretize the signals, it was possible to differentiate the influence of CO2 levels during the hyperventilation phase (22.0% and 20.3% increase for the left and right hemispheres, respectively) compared to normal breathing, which remained higher during the recovery phase (15.3% and 15.2% increase, respectively).