Cerebrovascular Pressure Autoregulation Research Articles

Cerebral Blood Flow Monitoring in High-Risk Fetal and Neonatal Populations.

Cerebrovascular pressure autoregulation promotes stable cerebral blood flow (CBF) across a range of arterial blood pressures. Cerebral autoregulation (CA) is a developmental process that reaches maturity around term gestation and can be monitored prenatally with both Doppler ultrasound and magnetic resonance imaging (MRI) techniques. Postnatally, there are key advantages and limitations to assessing CA with Doppler ultrasound, MRI, and near-infrared spectroscopy. Here we review these CBF monitoring techniques as well as their application to both fetal and neonatal populations at risk of perturbations in CBF. Specifically, we discuss CBF monitoring in fetuses with intrauterine growth restriction, anemia, congenital heart disease, neonates born preterm and those with hypoxic-ischemic encephalopathy. We conclude the review with insights into the future directions in this field with an emphasis on collaborative science and precision medicine approaches.

Distortion of the Intracranial Pressure Waveform by Extraventricular Drainage System.

To investigate whether intracranial pressure (ICP) waveform measurements obtained from extraventricular drainage (EVD) systems are suitable for the calculation of intracranial elastance (ICE) or cerebrovascular pressure autoregulation (PAR) indices. The transfer characteristic of an EVD system is investigated by its step and frequency responses with focus on the low frequency (LF) range from 0.02 to 0.065Hz (important in PAR) and the location of the system's first resonance frequency (important for ICE). The effects of opening the distal end of the EVD for drainage of cerebrospinal fluid and the presence of trapped air bubbles are also investigated. The EVD system exhibits a first resonant frequency below 4Hz, resulting in significant distortion of the measured ICP waveform. The frequency response in the LF range only remains flat when the EVD is closed. Opening the drain results in drops in magnitude and phase along the entire frequency range above DC. Air bubbles close to the EVD catheter tip affect the LF range while an air bubble close to the pressure transducer further decreases the first resonant frequency. Tests with actual ICP waveforms confirmed EVD-induced waveform distortions that can lead to erroneous ICE estimation. EVD-based ICP measurements distort the waveform morphology. PAR indices based on LF information are only valid if the EVD is closed. EVD-based ICE estimation is to be avoided. ICP waveform analyses to derive information about ICE and PAR should be critically questioned if only EVD derived ICP signals are at hand.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia

Introduction: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. Methods: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. Results: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO₂), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. Conclusion: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO₂ and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

Neonatal cerebrovascular autoregulation.

Cerebrovascular pressure autoregulation is the physiologic mechanism that holds cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure (CPP). Cerebral vasoreactivity refers to the vasoconstriction and vasodilation that occur during fluctuations in arterial blood pressure (ABP) to maintain autoregulation. These are vital protective mechanisms of the brain. Impairments in pressure autoregulation increase the risk of brain injury and persistent neurologic disability. Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic-ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and infants requiring extracorporeal membrane oxygenation (ECMO). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. We will review neonatal pressure autoregulation and autoregulation monitoring techniques with a focus on brain protection. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Adjuvant treatments that support and optimize autoregulation may improve neurologic outcomes.

Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation.

In severe traumatic brain injury, cerebral perfusion pressure management based on cerebrovascular pressure reactivity index has the potential to provide a personalized treatment target to improve patient outcomes. So far, the methods have focused on identifying "one" autoregulation-guided cerebral perfusion pressure target-called "cerebral perfusion pressure optimal". We investigated whether a cerebral perfusion pressure autoregulation range-which uses a continuous estimation of the "lower" and "upper" cerebral perfusion pressure limits of cerebrovascular pressure autoregulation (assessed with pressure reactivity index)-has prognostic value. Single-center retrospective analysis of prospectively collected data. The neurocritical care unit at a tertiary academic medical center. Data from 729 severe traumatic brain injury patients admitted between 1996 and 2016 were used. Treatment was guided by controlling intracranial pressure and cerebral perfusion pressure according to a local protocol. None. Cerebral perfusion pressure-pressure reactivity index curves were fitted automatically using a previously published curve-fitting heuristic from the relationship between pressure reactivity index and cerebral perfusion pressure. The cerebral perfusion pressure values at which this "U-shaped curve" crossed the fixed threshold from intact to impaired pressure reactivity (pressure reactivity index = 0.3) were denoted automatically the "lower" and "upper" cerebral perfusion pressure limits of reactivity, respectively. The percentage of time with cerebral perfusion pressure below (%cerebral perfusion pressure < lower limit of reactivity), above (%cerebral perfusion pressure > upper limit of reactivity), or within these reactivity limits (%cerebral perfusion pressure within limits of reactivity) was calculated for each patient and compared across dichotomized Glasgow Outcome Scores. After adjusting for age, initial Glasgow Coma Scale, and mean intracranial pressure, percentage of time with cerebral perfusion pressure less than lower limit of reactivity was associated with unfavorable outcome (odds ratio %cerebral perfusion pressure < lower limit of reactivity, 1.04; 95% CI, 1.02-1.06; p < 0.001) and mortality (odds ratio, 1.06; 95% CI, 1.04-1.08; p < 0.001). Individualized autoregulation-guided cerebral perfusion pressure management may be a plausible alternative to fixed cerebral perfusion pressure threshold management in severe traumatic brain injury patients. Prospective randomized research will help define which autoregulation-guided method is beneficial, safe, and most practical.

Static cerebrovascular pressure autoregulation remains intact during deep hypothermia.

Clinical studies measuring cerebral blood flow in infants during deep hypothermia have demonstrated diminished cerebrovascular pressure autoregulation. The coexistence of hypotension in these cohorts confounds the conclusion that deep hypothermia impairs cerebrovascular pressure autoregulation. We sought to compare the lower limit of autoregulation and the static rate of autoregulation between normothermic and hypothermic piglets. Twenty anesthetized neonatal piglets (5-7days old; 10 normothermic and 10 hypothermic to 20°C) had continuous measurements of cortical red cell flux using laser Doppler flowmetry, while hemorrhagic hypotension was induced without cardiopulmonary bypass. Lower limit of autoregulation was determined for each subject using piecewise regression and SRoR was determined above and below each lower limit of autoregulation as (%change cerebrovascular resistance/%change cerebral perfusion pressure). The estimated difference in lower limit of autoregulation was 1.4mmHg (lower in the hypothermic piglets; 95% C.I. -10 to 14mmHg; P=0.6). The median lower limit of autoregulation in the normothermic group was 39mmHg [IQR 38-51] vs 35mmHg [31-50] in the hypothermic group. Intact steady-state pressure autoregulation was defined as static rate of autoregulation >0.5 and was demonstrated in all normothermic subjects (static rate of autoregulation=0.72 [0.65-0.87]) and in 9/10 of the hypothermic subjects (static rate of autoregulation=0.65 [0.52-0.87]). This difference in static rate of autoregulation of 0.06 (95% C.I. -0.3 to 0.1) was not significant (P=0.4). Intact steady-state cerebrovascular pressure autoregulation is demonstrated in a swine model of profound hypothermia. Lower limit of autoregulation and static rate of autoregulation were similar in hypothermic and normothermic subjects.

The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased with Elevations in Intracranial Pressure.

The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. We sought to delineate the ULA in a neonatal swine model. Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF; n = 10), controlled cortical impact (CCI; n = 10), or impact + infusion (CCI + INF; n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flux recordings during arterial hypertension until lethality. An increase in red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression and static rates of autoregulation (SRoRs) were determined above and below this inflection. When identified, the ULA (median [interquartile range]) was as follows: sham group: 102 mmHg (97-109), INF group: 75 mmHg (52-84), CCI group: 81 mmHg (69-101), and CCI + INF group: 61 mmHg (52-57; p = 0.01). Both groups with interventricular infusion had significantly lower ULA compared with the sham group. Neonatal piglets without intracranial pathological conditions tolerated acute hypertension, with minimal perturbation of cerebral blood flow. Piglets with acutely elevated intracranial pressure, with or without trauma, demonstrated loss of autoregulation when subjected to arterial hypertension.

A New Monitor of Pressure Autoregulation: What Does It Add?

Cerebrovascular pressure autoregulation is a vital, protective mechanism that constrains cerebral blood flow during changes in arterial blood pressure. Pressure autoregulation is known to fail during profound hypotension, and the so-called lower limit of autoregulation (LLA) is diverse for different subjects. 1 The measurement and monitoring of pressure autoregulation is specifically useful to discriminate safe from harmful blood pressure: when arterial blood pressure is within range to render normal pressure autoregulation measurements, the brain is protected; when arterial blood pressure is too low and pressure autoregulation measurements show impairment, the brain is vulnerable. 2,3 In the present study, Hori et al. 4 present a novel method to measure pressure autoregulation using the Ornim UT-light technology (Ornim, Inc., Kfar Saba, Israel), rendered as a cerebral flow velocity index (CFVx). The UT-light method is proprietary and quantifies relative tissue blood movement from the Doppler shift of near-infrared light caused by red cells in motion. It is an uncalibrated, surrogate measure of cerebral blood flow. How does this measure autoregulation? How is this to be evaluated and validated? Not fewer than 15 metrics purported to measure autoregulation have infused the medical literature within hundreds of manuscripts in the past 2 decades. 5 It would be instructive to know how these metrics are related and to consider the evidentiary burden required to deploy them clinically. Pressure autoregulation is distinct from, but often confused with, other servomechanisms that contribute to the homeostasis of cerebral blood flow. Examples include neurovascular coupling (or metabolic autoregulation), which rapidly matches cerebral blood flow to local metabolic demands 6 ; the systemic vasoconstrictive response to shock, which diverts cardiac output from sympathetic, angiotensin, and vasopressin-reactive vascular beds to the brain and heart, which respond differently to these neurohormonal cues 7–9 ; and cerebral vasodilatory and constrictive responses caused by changes in arterial carbon dioxide. 10 Each of these operates at the same point of action, that is to affect a change or to prevent a change in cerebral blood flow. The pressure autoregulation mechanism can be measured even when cerebral blood flow is influenced by the other mechanisms listed if the metric used is attuned to the proper frequency. Three components are needed to construct a metric of autoregulation:

The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased With Elevations in Intracranial Pressure

The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. To delineate the ULA in an infant swine model. Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF) (n = 10), controlled cortical impact (CCI) (n = 10), or CCI + INF (n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flowmetry recordings during arterial hypertension to lethality using an aortic balloon catheter. An increase of red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression, and static rates of autoregulation were determined above and below this inflection. The ULA was rendered as the first instance of an upward deflection of Doppler flux causing a static rate of autoregulation decrease greater than 0.5. ULA was identified in 55% of piglets after sham surgery, 70% after INF, 70% after CCI, and 91% after CCI with INF (P = .36). When identified, the median (interquartile range) ULA was as follows: sham group, 102 mm Hg (97-109 mm Hg); INF group, 75 mm Hg (52-84 mm Hg); CCI group, 81 mm Hg (69-101 mm Hg); and CCI + INF group, 61 mm Hg (52-57 mm Hg) (P = .01). In post hoc analysis, both groups with interventricular INF had significantly lower ULA than that observed in the sham group. Neonatal piglets without intracranial pathology tolerated acute hypertension with minimal perturbation of cerebral blood flow. Piglets with acutely increased intracranial pressure with or without trauma demonstrated loss of autoregulation when subjected to arterial hypertension.

The ontogeny of cerebrovascular pressure autoregulation in premature infants.

To quantify cerebrovascular autoregulation as a function of gestational age (GA) and across the phases of the cardiac cycle. The present study is a hypothesis-generating re-analysis of previously published data. Premature infants (n=179) with a GA range of 23 to 33 weeks were monitored with umbilical artery catheters and transcranial Doppler insonation of the middle cerebral artery for 1-h sessions over the first week of life. Autoregulation was quantified by three methods, as a moving correlation coefficient between: (1) systolic arterial blood pressure (ABP) and systolic cerebral blood flow (CBF) velocity (Sx); (2) mean ABP and mean CBF velocity (Mx); and (3) diastolic ABP and diastolic CBF velocity (Dx). Comparisons of individual and cohort cerebrovascular pressure autoregulation were made across GA for each aspect of the cardiac cycle. Systolic, mean and diastolic ABP increased with GA (r=0.3, 0.4 and 0.4; P<0.0001). Systolic CBF velocity was pressure-passive in infants with the lowest GA, and Sx decreased with advancing GA (r=-0.3; P<0.001), indicating increased capacity for cerebral autoregulation during systole during development. By contrast, Dx was elevated, indicating dysautoregulation, in all subjects and showed minimal change with advancing GA (r=-0.06; P=0.05). Multivariate analysis confirmed that both GA (P<0.001) and 'effective cerebral perfusion pressure' (ABP minus critical closing pressure (CrCP); P<0.01) were associated with Sx. Premature infants have low and usually pressure-passive diastolic CBF velocity. By contrast, the regulation of systolic CBF velocity by pressure autoregulation developed in this cohort between 23 and 33 weeks GA. Elevated effective cerebral perfusion pressure derived from the CrCP was associated with dysautoregulation.

Continuous Monitoring of Cerebrovascular Pressure Reactivity After Traumatic Brain Injury in Children

We hypothesized that pressure reactivity index (PRx) values indicating preserved cerebrovascular pressure autoregulation would be associated with survival in children with traumatic brain injury (TBI). This hypothesis was tested in a prospective, blinded, observational, pilot study. Twenty-one children admitted between May 2006 and September 2008 with severe TBI necessitating invasive intracranial pressure monitoring were enrolled in this study. The PRx was continuously monitored as a moving, linear correlation coefficient between low-frequency waves of intracranial and arterial blood pressures. Positive values of PRx approaching 1 indicate impaired cerebrovascular pressure reactivity, whereas negative PRx values or values close to 0 indicate preserved cerebrovascular pressure reactivity. Survival was the primary outcome and was compared with the average PRx value obtained during the intracranial pressure-monitoring period. PRx was associated with survival in this cohort; survivors (N = 15) had a mean PRx +/- SD of 0.08 +/- 0.19, and nonsurvivors (N = 6) had a mean PRx of 0.69 +/- 0.21 (P = .0009). In this sample, continuous PRx monitoring suggested impaired cerebrovascular pressure reactivity at low levels of cerebral perfusion pressure (CPP) and intact cerebrovascular pressure reactivity at higher levels of CPP. Intact cerebrovascular pressure reactivity quantified with the PRx is associated with survival after severe head trauma in children. The PRx is CPP dependent in children. The PRx may be useful for defining age-specific and possibly patient-specific optimal targets for CPP after TBI.

Identification of Pressure Passive Cerebral Perfusion and Its Mediators after Infant Cardiac Surgery

Cerebrovascular pressure autoregulation (CPA) regulates cerebral blood flow (CBF) in relation to changes in mean arterial blood pressure (MAP). Identification of a pressure-passive cerebral perfusion and the potentially modifiable physiologic factors underlying it has been difficult to achieve in sick infants. We previously validated the near-infrared spectroscopy-derived hemoglobin difference (HbD) signal (cerebral oxyhemoglobin - deoxyhemoglobin) as a reliable measure of changes in CBF in animal models. We now sought to determine whether continuous measurements of DeltaHbD would correlate to middle cerebral artery flow velocity (CBFV), allow identification and quantification of pressure-passive state, and help to delineate potentially modifiable factors. We enrolled 43 infants (2 d to 7 mo old) who were undergoing open cardiac surgery and cardiopulmonary bypass. At 6 and 20 h after surgery, we measured changes in HbD, CBFV (by transcranial Doppler), and MAP at different end-tidal CO(2) levels. We assigned a pressure-passive index (PPI) to each study on the basis of the relative duration of significant coherence between DeltaMAP and DeltaHbD. We found a significant relationship between DeltaHbD and DeltaCBFV at both time points. At 6 h after surgery, we showed high concordance (coherence > 0.5; PPI > or = 41%) between DeltaMAP and DeltaHbD, consistent with disturbed CPA in 13% of infants. End-tidal CO(2) values > or = 40 mm Hg and higher MAP variability both were associated with increased odds (p < 0.001) of autoregulatory failure. This approach provides a means to identify and quantify disturbances of CPA. High CO(2) levels and fluctuating MAP are two important preventable factors associated with disturbed CPA.

The Effects of Large-dose Propofol on Cerebrovascular Pressure Autoregulation in Head-injured Patients

The Effects of Large-dose Propofol on Cerebrovascular Pressure Autoregulation in Head-injured Patients