Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation.

Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure; 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO2)]; 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans); and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the interrelationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

Statistical Complexity Analysis of Neurovascular Coupling with Cognitive Stimulation in Healthy Subjects.

Neurovascular coupling (NVC) is the tight relationship between changes in cerebral blood flow and neural activation. NVC can be evaluated non-invasively using transcranial Doppler ultrasound (TCD)-measured changes in brain activation (cerebral blood velocity [CBv]) using different cognitive tasks and stimuli. This study used a novel approach to analyzing CBv changes occurring in response to 20 tasks from the Addenbrooke's Cognitive Examination III in 40 healthy individuals. The novel approach compared various information entropy families (permutation, Tsallis, and Rényi entropy) and statistical complexity measures based on disequilibrium. Using this approach, we found the majority of the attention, visuospatial, and memory tasks from the Addenbrooke's Cognitive Examination III that showed lower statistical complexity values when compared with the resting state. On the entropy-complexity (HC) plane, a receiver operating characteristic curve was used to distinguish between baseline and cognitive tasks using the area under the curve. Best area under the curve values were 0.91 ± 0.04, p = .001, to distinguish between resting and cognitively active states. Our findings show that brain hemodynamic signals captured with TCD can be used to distinguish between resting state (baseline) and cognitive effort (stimulation paradigms) using entropy and statistical complexity as an alternative method to traditional techniques such as coherent averaging of CBv signals. Further work should directly compare these analysis methods to identify the optimal method for analyzing TCD-measured changes in NVC.

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.

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.

A Comprehensive Perspective on Intracranial Pressure Monitoring and Individualized Management in Neurocritical Care: Results of a Survey with Global Experts.

BACKGROUND: Numerous trials have addressed intracranial pressure (ICP) management in neurocritical care. However, identifying its harmful thresholds and controlling ICP remain challenging in terms of improving outcomes. Evidence suggests that an individualized approach is necessary for establishing tolerance limits for ICP, incorporating factors such as ICP waveform (ICPW) or pulse morphology along with additional data provided by other invasive (e.g., brain oximetry) and noninvasive monitoring (NIM) methods (e.g., transcranial Doppler, optic nerve sheath diameter ultrasound, and pupillometry). This study aims to assess current ICP monitoring practices among experienced clinicians and explore whether guidelines should incorporate ancillary parameters from NIM and ICPW in future updates. METHODS: We conducted a survey among experienced professionals involved in researching and managing patients with severe injury across low-middle-income countries (LMICs) and high-income countries (HICs). We sought their insights on ICP monitoring, particularly focusing on the impact of NIM and ICPW in various clinical scenarios. RESULTS: From October to December 2023, 109 professionals from the Americas and Europe participated in the survey, evenly distributed between LMIC and HIC. When ICP ranged from 22 to 25 mm Hg, 62.3% of respondents were open to considering additional information, such as ICPW and other monitoring techniques, before adjusting therapy intensity levels. Moreover, 77% of respondents were inclined to reassess patients with ICP in the 18-22 mm Hg range, potentially escalating therapy intensity levels with the support of ICPW and NIM. Differences emerged between LMIC and HIC participants, with more LMIC respondents preferring arterial blood pressure transducer leveling at the heart and endorsing the use of NIM techniques and ICPW as ancillary information. CONCLUSIONS: Experienced clinicians tend to personalize ICP management, emphasizing the importance of considering various monitoring techniques. ICPW and noninvasive techniques, particularly in LMIC settings, warrant further exploration and could potentially enhance individualized patient care. The study suggests updating guidelines to include these additional components for a more personalized approach to ICP management.

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.

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.

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.

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).

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of PaCO2 , indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between PaCO2 and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of PaCO2 levels. ABSTRACT: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 ( PaCO2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO3- ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L-1 ; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3- , irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2 ; P = 0.151) reactivity to PaCO2 were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between PaCO2 and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of PaCO2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH.

Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. ABSTRACT: Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial PCO2 ( PaCO2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO3- ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

Vascular and haemodynamic issues of brain ageing.

The population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing "normal" ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.

Determinants of cerebral blood flow velocity change during squat-stand maneuvers.

The large changes in mean arterial blood pressure (MABP) and cerebral blood flow velocity (CBFV) induced by squat-stand maneuvers (SSM) make this approach particularly suited for studying dynamic cerebral autoregulation (CA). However, the role of other systemic determinants of CBFV has not been described and could provide alternative physiological interpretations of SSM results. In 32 healthy subjects (16 female), continuous recordings of MABP (Finometer), bilateral CBFV (transcranial Doppler, MCA), end-tidal CO2 (EtCO2; capnography), and heart rate (HR; electrocardiogram) were performed for 5 min standing at rest, and during 15 SSM at the frequency of 0.05 Hz. A time-domain, multivariate dynamic model estimated the CBFV variance explained by different inputs, corresponding to significant contributions from MABP (P < 0.00001), EtCO2 (P < 0.0001), and HR (P = 0.041). The autoregulation index (ARI; range 0-9) was estimated from the CBFV response to a step change in MABP. At rest, ARI values (typically 5.7) were independent of the number of model inputs, but during SSM, ARI was reduced compared with baseline (P < 0.0001), and the three input model yielded lower values for the right and left MCA (3.4 ± 1.2, 3.1 ± 1.3) when compared with the single-input MABP-CBFV model (4.1 ± 1.1, 3.9 ± 1.0; P < 0.0001). The high coherence of the MABP-CBFV transfer function at 0.05 Hz (typically 0.98) was considerably reduced (around 0.71-0.73; P < 0.0001) when the contribution of CBFV covariates was taken into account. Not taking into consideration other determinants of CBFV, in addition to MABP, could be misleading and introduce biases in physiological and clinical studies.

Cerebral perfusion pressure and autoregulation in eclampsia-a case control study.

BACKGROUND: Dynamic cerebral autoregulation and cerebral perfusion pressure are altered in pregnancies complicated by preeclampsia compared with normotensive pregnancies, but the connections of dynamic cerebral autoregulation, cerebral perfusion pressure, and cerebral complications in preeclampsia remain unclear. OBJECTIVE: This study aimed to assess dynamic cerebral autoregulation and cerebral perfusion pressure after delivery in women with eclampsia, in women with preeclampsia both with and without severe features, and in normotensive women. STUDY DESIGN: This was a prospective case control study at a large referral hospital in Cape Town, South Africa. The recruitment of participants was done at diagnosis (cases) or at admission for delivery (controls). Transcranial Doppler examinations with continuous noninvasive blood pressure measurements and end-tidal CO2 monitoring were conducted for cases and controls after delivery. Cerebral perfusion pressure and dynamic cerebral autoregulation index were calculated, and values were compared among groups. RESULTS: We included 16 women with eclampsia, 18 women with preeclampsia with severe features, 32 women with preeclampsia without severe features, and 21 normotensive women with uncomplicated pregnancies. Dynamic cerebral autoregulation was depressed in pregnant women with eclampsia; (autoregulation index, 3.9; interquartile range, 3.1-5.2) compared with all other groups (those with preeclampsia with severe features, autoregulation index, 5.6 [interquartile range, 4.4-6.8]; those with preeclampsia without severe features, autoregulation index, 6.8 [interquartile range, 5.1-7.4]; and normotensive controls, autoregulation index, 7.1 [interquartile range, 6.1-7.9]). Pregnant women with eclampsia had increased cerebral perfusion pressure (109.5 mm Hg; interquartile range, 91.2-130.9) compared with those with preeclampsia without severe features and those with normal blood pressure (84 mm Hg [interquartile range, 73.0-122.0] and 80.0 mm Hg [interquartile range, 67.5-92.0], respectively); furthermore, there was no difference in cerebral perfusion pressure between pregnant women with eclampsia and pregnant women with preeclampsia with severe features (109.5 mm Hg [interquartile range, 91.2-130.9] vs 96.5 mm Hg [interquartile range, 75.8-110.5]). CONCLUSION: Cerebral perfusion pressure and dynamic cerebral autoregulation are altered in eclampsia and may be important in the pathophysiological pathway and constitute a therapeutic target in the prevention of cerebral complications in preeclampsia.

Increasing Blood Pressure Variability Predicts Poor Functional Outcome Following Acute Stroke.

INTRODUCTION: Increasing blood pressure variability has been reported following acute stroke, but there is uncertainty about how best to measure it and about the impact on prognosis following acute ischaemic stroke and transient ischaemic attack. METHODS: Enhanced casual blood pressure and ambulatory blood pressure monitoring were completed at baseline (≤48 h post symptom onset). Blood pressure variability was defined by standard deviation and coefficient of variation of systolic, diastolic, mean arterial pressure, and pulse pressure. Modified Rankin scale score ≥3 described poor functional outcome assessed at 1- and 12-months post-stroke. Multivariable logistic regression models incorporating blood pressure variability measurement and other factors were performed, and odds ratio and 95% confidence intervals reported. RESULTS: 232 patients were recruited; 45 were dependent at 1-month, and 37 at 12-months. Dependent patients were more likely to be older, with a higher burden of pre-morbid conditions, and with increased blood pressure variability. Enhanced casual standard deviations of diastolic blood pressure [1.19 (1.02 to 1.39)] and mean arterial pressure [1.20 (1.00 to 1.43)] predicted dependency at 1-month. Predictors of 12-month dependency included: enhanced casual standard deviation of mean arterial pressure [1.21 (1.0-1.46)]; 24 h ambulatory monitor standard deviations of diastolic blood pressure [2.30 (1.08-4.90)] and mean arterial pressure [1.72 (1.09-2.72)], and the coefficient of variation of mean arterial pressure [1.76 (1.05-2.94)]; day-time ambulatory monitor coefficient of variation of systolic blood pressure [1.44 (1.02-2.03)] and mean arterial pressure [1.46 (1.02-2.08)]; and night-time ambulatory standard deviation of diastolic blood pressure [1.65 (1.03 -2.63)], and the coefficient of variation of mean arterial pressure and [1.38 (1.00- 1.90)] and pulse pressure [1.29 (1.00-1.65)]. CONCLUSION: Increasing blood pressure variability is independently and modestly associated with poor functional outcome at 1- and 12-months following acute stroke.

The critical closing pressure contribution to dynamic cerebral autoregulation in humans: influence of arterial partial pressure of CO2.

KEY POINTS: Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)-cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR). In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance-area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing. Transfer function analysis of the MAP-CBFV relationship can be extended to the MAP-RAP and MAP-CrCP relationships, to assess their contribution to the dynamic CA response. During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP-CBFV relationship. Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. ABSTRACT: Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra-cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21-70 years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end-tidal CO2 (capnography) and heart rate (ECG) were performed for 5 min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance-area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P < 0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70 ± 1.58 (normocapnia) to 4.14 ± 2.05 (hypercapnia; P < 0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies.

Pathophysiological and clinical considerations in the perioperative care of patients with a previous ischaemic stroke: a multidisciplinary narrative review.

With an ageing population and increasing incidence of cerebrovascular disease, an increasing number of patients presenting for routine and emergency surgery have a prior history of stroke. This presents a challenge for pre-, intra-, and postoperative management as the neurological risk is considerably higher. Evidence is lacking around anaesthetic practice for patients with vascular neurological vulnerability. Through understanding the pathophysiological changes that occur after stroke, insight into the susceptibilities of the cerebral vasculature to intrinsic and extrinsic factors can be developed. Increasing understanding of post-stroke systemic and cerebral haemodynamics has provided improved outcomes from stroke and more robust secondary prevention, although this knowledge has yet to be applied to our delivery of anaesthesia in those with prior stroke. This review describes the key pathophysiological and clinical considerations that inform clinicians providing perioperative care for patients with a prior diagnosis of stroke.

The upper frequency limit of dynamic cerebral autoregulation.

KEY POINTS: Dynamic cerebral autoregulation (CA) is expressed by the temporal pattern of cerebral blood flow (CBF) recovery following a sudden change in arterial blood pressure (BP). Transfer function analysis of BP as input and CBF velocity as output can express dynamic CA through its amplitude (or gain) and phase frequency responses. The upper frequency limit (FupLim ) at which dynamic CA can operate is of considerable physiological interest and can also provide additional information about worsening CA due to disease processes. In healthy subjects FupLim was strongly dependent on arterial PCO2 changes induced by four different breathing manoeuvres. The considerable intersubject variability in FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in studies of dynamic CA. ABSTRACT: Dynamic cerebral autoregulation (CA) can be expressed in the frequency domain by the amplitude and phase frequency responses calculated by transfer function analysis of arterial blood pressure (BP) and cerebral blood flow velocity (CBFV). We studied the effects of arterial PCO2 ( PaCO2 ) on the upper frequency limit (FupLim ) of these responses and its intersubject variability. Twenty-four healthy subjects (11 female, age 36.0 ± 13.4 years) were recruited. Recordings of CBFV (transcranial Doppler ultrasound), BP (Finometer) and end-tidal CO2 ( PETCO2 , capnography) were performed during 5 min at rest (normocapnia) and during four breathing manoeuvres: 5% and 8% CO2 in air and hyperventilation targeting reductions of 5 and 10 mmHg compared to normocapnia. FupLim was determined by the break point of the autoregulation index (ARI) curve as a function of frequency when the phase response was gradually set to zero. The five breathing conditions led to highly significant differences in PETCO2 (p < 0.0001), CBFV (P < 0.0001), ARI (p < 0.0001) and FupLim (p < 0.0001). FupLim ranged from 0.167 ± 0.036 Hz at the lowest values of hypocapnia (28.1 ± 1.9 mmHg) to 0.094 ± 0.040 Hz at the highest level of hypercapnia (41.7 ± 5.4 mmHg), showing a correlation of r = -0.53 (p < 0.001) with PETCO2 . These findings reinforce the key role of PaCO2 in CBF regulation. The considerable intersubject variability of FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in dynamic CA studies, and that the higher frequency band (0.20-0.40 Hz), in particular, does not contain relevant information about dynamic CA. Further investigations are needed to assess the information value of FupLim as a marker of dynamic CA efficiency in physiological and clinical studies.

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60 s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9 cm s-1 (11.1), old 51.7 (12.9) vs. 37.8 cm s-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7 mmHg (16.0), old 33.9 (13.5) vs. 39.3 mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09 mmHg cm s-1 (11.07), old 1.16 (0.34) vs. 1.34 mmHg cm s-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Alternative representation of neural activation in multivariate models of neurovascular coupling in humans.

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and PaCO2, rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. The simultaneous effects of neural stimulation, BP, and PaCO2 on CBFV were expressed with a dynamic multivariate model, using BP, EtCO2, and stimulation [s(t)] as inputs. Two versions of s(t) were considered: a gate function [sG(t)] or an orthogonal decomposition [sO(t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO2 reactivity [vasomotor reactivity step response (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO(t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10-5) and was correlated with the CBFV change (r = 0.73, P = 0.0001). The sO(t) explained a greater fraction of CBFV variance (~50%) than sG(t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for sG(t), and 6.9 and 7.4 for sO(t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO2 in response to sensorimotor stimulation, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO2 reactivity, and NVC in humans.NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 (PaCO2) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or PaCO2. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, PaCO2 and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions.