Embracing uncertainty in cerebrospinal fluid dynamics: A Bayesian approach to analysing infusion studies.

Introduction: Cerebrospinal fluid (CSF) infusion test analysis allows recognizing and appropriately evaluating CSF dynamics in the context of normal pressure hydrocephalus (NPH), which is crucial for effective diagnosis and treatment. However, existing methodology possesses drawbacks that may compromise the precision and interpretation of CSF dynamics parameters. Research question: This study aims to circumvent these constraints by introducing an innovative analysis method grounded in Bayesian inference. Material and methods: A single-centre retrospective cohort study was conducted on 858 patients who underwent a computerized CSF infusion test between 2004 and 2020. We developed a Bayesian framework-based method for parameter estimation and compared the results to the current, gradient descent-based approach. We evaluated the accuracy and reliability of both methods by analysing erroneous prediction rates and curve fitting errors. Results: The Bayesian method surpasses the gradient descent approach, reflected in reduced inaccurate prediction rates and an improved goodness of model fit. On whole cohort level both techniques produced comparable results. However, the Bayesian method holds an added advantage by providing uncertainty intervals for each parameter. Sensitivity analysis revealed significance of the CSF production rate parameter and its interplay with other variables. The resistance to CSF outflow demonstrated excellent robustness. Discussion and conclusion: The proposed Bayesian approach offers a promising solution for improving robustness of CSF dynamics assessment in NPH, based on CSF infusion tests. Additional provision of the uncertainty measure for each diagnostic metric may perhaps help to explain occasional poor diagnostic performance of the test, offering a robust framework for improved understanding and management of NPH.

Cerebral autoregulation in paediatric and neonatal intensive care: A scoping review.

Deranged cerebral autoregulation (CA) is associated with worse outcome in adult brain injury. Strategies for monitoring CA and maintaining the brain at its 'best CA status' have been implemented, however, this approach has not yet developed for the paediatric population. This scoping review aims to find up-to-date evidence on CA assessment in children and neonates with a view to identify patient categories in which CA has been measured so far, CA monitoring methods and its relationship with clinical outcome if any. A literature search was conducted for studies published within 31st December 2022 in 3 bibliographic databases. Out of 494 papers screened, this review includes 135 studies. Our literature search reveals evidence for CA measurement in the paediatric population across different diagnostic categories and age groups. The techniques adopted, indices and thresholds used to assess and define CA are heterogeneous. We discuss the relevance of available evidence for CA assessment in the paediatric population. However, due to small number of studies and heterogeneity of methods used, there is no conclusive evidence to support universal adoption of CA monitoring, technique, and methodology. This calls for further work to understand the clinical impact of CA monitoring in paediatric and neonatal intensive care.

Pitfalls and possibilities of using Root SedLine for continuous assessment of EEG waveform-based metrics in intensive care research.

Objective.The Root SedLine device is used for continuous electroencephalography (cEEG)-based sedation monitoring in intensive care patients. The cEEG traces can be collected for further processing and calculation of relevant metrics not already provided. Depending on the device settings during acquisition, the acquired traces may be distorted by max/min value cropping or high digitization errors. We aimed to systematically assess the impact of these distortions on metrics used for clinical research in the field of neuromonitoring.Approach.A 16 h cEEG acquired using the Root SedLine device at the optimal screen settings was analyzed. Cropping and digitization error effects were simulated by consecutive reduction of the maximum cEEG amplitude by 2µV or by reducing the vertical resolution. Metrics were calculated within ICM+ using minute-by-minute data, including the total power, alpha delta ratio (ADR), and 95% spectral edge frequency. Data were analyzed by creating violin- or box-plots.Main Results.Cropping led to a continuous reduction in total and band power, leading to corresponding changes in variability thereof. The relative power and ADR were less affected. Changes in resolution led to relevant changes. While the total power and power of low frequencies were rather stable, the power of higher frequencies increased with reducing resolution.Significance.Care must be taken when acquiring and analyzing cEEG waveforms from Root SedLine for clinical research. To retrieve good quality metrics, the screen settings must be kept within the central vertical scale, while pre-processing techniques must be applied to exclude unacceptable periods.

Transmission of slow waves in Masimo O3 near infrared spectroscopy measures.

Introduction: Cerebral autoregulation (CA) dysfunction is a key complication following brain injury. CA assessment using near-infrared spectroscopy (NIRS) offers a promising alternative to the current non-invasive standard, cerebral blood flow velocity (CBFV) measured with transcranial Doppler. Research question: Can autoregulatory slow waves (frequency range 0.005-0.05 Hz) associated with spontaneous and induced changes in ABP in healthy volunteers be detected by parameters measured with the Masimo O3 NIRS device? Methods: ABP, CBFV and Masimo O3 parameters were measured in 10 healthy volunteers at baseline and during ABP oscillations induced by squat/stand manoeuvres. Transmission of slow waves was assessed with power spectral density and coherence analysis in NIRS signals and compared to that of CBFV. Results: At baseline, slow waves were detected with sufficient power that substantially exceeded the signals' measurement resolution in all parameters except cerebral oxygen saturation. During ABP oscillations in the 0.033 Hz range (induced by squat/stand), the power of slow waves increased in all parameters in a similar pattern, with total (cHb) and oxygenated (O2Hb) haemoglobin concentrations most closely mirroring CBFV (median standardised power [first-third quartile], baseline vs squat/stand: CBFV 0.35 [0.28-0.42] vs 0.50 [0.45-0.62], O2Hb 0.47 [0.33-0.68] vs 0.61 [0.59-0.69]). Coherence with ABP increased for both CBFV and NIRS measures from low at baseline (<0.4) to high during induced changes (>0.8). Conclusion: Spontaneous fluctuations in ABP can be observed in analysed Masimo O3 metrics to a varying degree. The clinical utility of Masimo O3 signals in CA assessment requires further investigation in brain injury patients.

Predicting outcome after aneurysmal subarachnoid hemorrhage by exploitation of signal complexity: a prospective two-center cohort study.

BACKGROUND: Signal complexity (i.e. entropy) describes the level of order within a system. Low physiological signal complexity predicts unfavorable outcome in a variety of diseases and is assumed to reflect increased rigidity of the cardio/cerebrovascular system leading to (or reflecting) autoregulation failure. Aneurysmal subarachnoid hemorrhage (aSAH) is followed by a cascade of complex systemic and cerebral sequelae. In aSAH, the value of entropy has not been established yet. METHODS: aSAH patients from 2 prospective cohorts (Zurich-derivation cohort, Aachen-validation cohort) were included. Multiscale Entropy (MSE) was estimated for arterial blood pressure, intracranial pressure, heart rate, and their derivatives, and compared to dichotomized (1-4 vs. 5-8) or ordinal outcome (GOSE-extended Glasgow Outcome Scale) at 12 months using uni- and multivariable (adjusted for age, World Federation of Neurological Surgeons grade, modified Fisher (mFisher) grade, delayed cerebral infarction), and ordinal methods (proportional odds logistic regression/sliding dichotomy). The multivariable logistic regression models were validated internally using bootstrapping and externally by assessing the calibration and discrimination. RESULTS: A total of 330 (derivation: 241, validation: 89) aSAH patients were analyzed. Decreasing MSE was associated with a higher likelihood of unfavorable outcome independent of covariates and analysis method. The multivariable adjusted logistic regression models were well calibrated and only showed a slight decrease in discrimination when assessed in the validation cohort. The ordinal analysis revealed its effect to be linear. MSE remained valid when adjusting the outcome definition against the initial severity. CONCLUSIONS: MSE metrics and thereby complexity of physiological signals are independent, internally and externally valid predictors of 12-month outcome. Incorporating high-frequency physiological data as part of clinical outcome prediction may enable precise, individualized outcome prediction. The results of this study warrant further investigation into the cause of the resulting complexity as well as its association to important and potentially preventable complications including vasospasm and delayed cerebral ischemia.

Association between EEG metrics and continuous cerebrovascular autoregulation assessment: a scoping review.

OBJECTIVE: Cerebrovascular autoregulation is defined as the capacity of cerebral blood vessels to maintain stable cerebral blood flow despite changing blood pressure. It is assessed using the pressure reactivity index (the correlation coefficient between mean arterial blood pressure and intracranial pressure). The objective of this scoping review is to describe the existing evidence concerning the association of EEG and cerebrovascular autoregulation in order to identify key concepts and detect gaps in the current knowledge. METHODS: Embase, MEDLINE, SCOPUS, and Web of Science were searched considering articles between their inception up to September 2023. Inclusion criteria were human (paediatric and adult) and animal studies describing correlations between continuous EEG and cerebrovascular autoregulation assessments. RESULTS: Ten studies describing 481 human subjects (67% adult, 59% critically ill) were identified. Seven studies assessed qualitative (e.g. seizures, epileptiform potentials) and five evaluated quantitative (e.g. bispectral index, alpha-delta ratio) EEG metrics. Cerebrovascular autoregulation was evaluated based on intracranial pressure, transcranial Doppler, or near infrared spectroscopy. Specific combinations of cerebrovascular autoregulation and EEG metrics were evaluated by a maximum of two studies. Seizures, highly malignant patterns or burst suppression, alpha peak frequency, and bispectral index were associated with cerebrovascular autoregulation. The other metrics showed either no or inconsistent associations. CONCLUSION: There is a paucity of studies evaluating the link between EEG and cerebrovascular autoregulation. The studies identified included a variety of EEG and cerebrovascular autoregulation acquisition methods, age groups, and diseases allowing for few overarching conclusions. However, the preliminary evidence for the presence of an association between EEG metrics and cerebrovascular autoregulation prompts further in-depth investigations.

Visualization of Cerebral Pressure Autoregulatory Insults in Traumatic Brain Injury.

OBJECTIVES: The first aim was to investigate the combined effect of insult intensity and duration of the pressure reactivity index (PRx) and deviation from the autoregulatory cerebral perfusion pressure target (∆CPPopt = actual CPP - optimal CPP [CPPopt]) on outcome in traumatic brain injury. The second aim was to determine if PRx influenced the association between intracranial pressure (ICP), CPP, and ∆CPPopt with outcome. DESIGN: Observational cohort study. SETTING: Neurocritical care unit, Cambridge, United Kingdom. PATIENTS: Five hundred fifty-three traumatic brain injury patients with ICP and arterial blood pressure monitoring and 6-month outcome data (Glasgow Outcome Scale [GOS]). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The insult intensity (mm Hg or PRx coefficient) and duration (minutes) of ICP, PRx, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In these plots, there was a transition from favorable to unfavorable outcome when PRx remained positive for 30 minutes and this was also the case for shorter durations when the intensity was higher. In a similar plot of ∆CPPopt, there was a gradual transition from favorable to unfavorable outcome when ∆CPPopt went below -5 mm Hg for 30-minute episodes of time and for shorter durations for more negative ∆CPPopt. Furthermore, the percentage of monitoring time with certain combinations of PRx with ICP, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In the combined PRx/ICP heatmap, ICP above 20 mm Hg together with PRx above 0 correlated with unfavorable outcome. In a PRx/CPP heatmap, CPP below 70 mm Hg together with PRx above 0.2-0.4 correlated with unfavorable outcome. In the PRx-/∆CPPopt heatmap, ∆CPPopt below 0 together with PRx above 0.2-0.4 correlated with unfavorable outcome. CONCLUSIONS: Higher intensities for longer durations of positive PRx and negative ∆CPPopt correlated with worse outcome. Elevated ICP, low CPP, and negative ∆CPPopt were particularly associated with worse outcomes when the cerebral pressure autoregulation was concurrently impaired.

Exploration of uncertainty of PRx time trends.

Introduction: PRx can be used as surrogate measure of Cerebral Autoregulation (CA) in traumatic brain injury (TBI) patients. PRx can provide means for individualising cerebral perfusion pressure (CPP) targets, such as CPPopt. However, a recent Delphi consensus of clinicians concluded that consensus could not be reached on the accuracy, reliability, and validation of any current CA assessment method. Research question: We aimed to quantify the short-term uncertainty of PRx time-trends and to relate this to other physiological measurements. Material and methods: Intracranial pressure (ICP), arterial blood pressure (ABP), end-tidal CO2 (EtCO2) high-resolution recordings of 911 TBI patients were processed with ICM + software. Hourly values of metrics that describe the variability within modalities derived from ABP, ICP and EtCO2, were calculated for the first 24h of neuromonitoring. Generalized additive models were used to describe the time trend of the variability in PRx. Linear correlations were studied for describing the relationship between PRx variability and the other physiological modalities. Results: The time profile of variability of PRx decreases over the first 12h and was higher for average PRx ∼0. Increased variability of PRx was not linearly linked with average ABP, ICP, or CPP. For coherence between slow waves of ABP and ICP >0.7, the variability in PRx decreased (R = -0.47, p < 0.001). Discussion and conclusion: PRx is a highly variable parameter. PRx short-term dispersion was not related to average ICP, ABP or CPP. The determinants of uncertainty of PRx should be investigated to improve reliability of individualised CA assessment in TBI patients.

Red solid line: Patterns of terminal loss of cerebrovascular reactivity at the bedside.

Introduction: Continuous monitoring of the pressure reactivity index (PRx) provides an estimation of dynamic cerebral autoregulation (CA) at the bedside in traumatic brain injury (TBI) patients. Visualising the time-trend of PRx with a risk bar chart in ICM + software at the bedside allows for better real-time interpretability of the autoregulation status. When PRx>0.3 is sustained for long periods, typically of at least half an hour, the bar shows a pattern called "red solid line" (RSL). RSL was previously described to precede refractory intracranial hypertension and brain death. Research question: We aimed to describe pathophysiological changes in measured signals/parameters during RSL. Material and methods: Observation of time-trends of PRx, intracranial pressure, cerebral perfusion pressure, brain oxygenation and compensatory reserve of TBI patients with RSL. Results: Three pathophysiological patterns were identified: RSL precedes intracranial hypertension, RSL is preceded by intracranial hypertension, or RSL is preceded by brain hypoperfusion. In all cases, RSL was followed by death and the RSL onset was between 1 h and 1 day before the terminal event. Discussion and conclusion: RSL precedes death in intensive care and could represent a marker for terminal clinical deterioration in TBI patients. These findings warrant further investigations in larger cohorts to characterise pathophysiological mechanisms underlying the RSL pattern and whether RSL has a significant relationship with outcome after TBI.

Mathematical modelling of cerebral haemodynamics and their effects on ICP.

Introduction: Electrical-equivalence mathematical models that integrate vascular and cerebrospinal fluid (CSF) compartments perform well in simulations of dynamic cerebrovascular variations and their transient effects on intracranial pressure (ICP). However, ICP changes due to sustained vascular diameter changes have not been comprehensively examined. We hypothesise that changes in cerebrovascular resistance (CVR) alter the resistance of the bulk flow of interstitial fluid (ISF). Research question: We hypothesise that changes in CVR alter the resistance of the bulk flow of ISF, thus allowing simulations of ICP in response to sustained vascular diameter changes. Material and methods: A lumped parameter model with vascular and CSF compartments was constructed and converted into an electrical analogue. The flow and pressure responses to transient hyperaemic response test (THRT) and CSF infusion test (IT) were observed. Arterial blood pressure (ABP) was manipulated to simulate ICP plateau waves. The experiments were repeated with a modified model that included the ISF compartment. Results: Simulations of the THRT produced identical cerebral blood flow (CBF) responses. ICP generated by the new model reacted in a similar manner as the original model during ITs. Plateau pressure reached during ITs was however higher in the ISF model. Only the latter was successful in simulating the onset of ICP plateau waves in response to selective blood pressure manipulations. Discussion and conclusion: Our simulations highlighted the importance of including the ISF compartment, which provides mechanism explaining sustained haemodynamic influences on ICP. Consideration of such interactions enables accurate simulations of the cerebrovascular effects on ICP.

The Effect of Recruitment Maneuvers on Cerebrovascular Dynamics and Right Ventricular Function in Patients with Acute Brain Injury: A Single-Center Prospective Study.

BACKGROUND: Optimization of ventilatory settings is challenging for patients in the neurointensive care unit, requiring a balance between precise gas exchange control, lung protection, and managing hemodynamic effects of positive pressure ventilation. Although recruitment maneuvers (RMs) may enhance oxygenation, they could also exert profound undesirable systemic impacts. METHODS: The single-center, prospective study investigated the effects of RMs (up-titration of positive end-expiratory pressure) on multimodal neuromonitoring in patients with acute brain injury. Our primary focus was on intracranial pressure and secondarily on cerebral perfusion pressure (CPP) and other neurological parameters: cerebral autoregulation [pressure reactivity index (PRx)] and regional cerebral oxygenation (rSO2). We also assessed blood pressure and right ventricular (RV) function evaluated using tricuspid annular plane systolic excursion. Results are expressed as the difference (Δ) from baseline values obtained after completing the RMs. RESULTS: Thirty-two patients were enrolled in the study. RMs resulted in increased intracranial pressure (Δ = 4.8 mm Hg) and reduced CPP (ΔCPP = -12.8 mm Hg) and mean arterial pressure (difference in mean arterial pressure = -5.2 mm Hg) (all p < 0.001). Cerebral autoregulation worsened (ΔPRx = 0.31 a.u.; p < 0.001). Despite higher systemic oxygenation (difference in partial pressure of O2 = 4 mm Hg; p = 0.001) and unchanged carbon dioxide levels, rSO2 marginally decreased (ΔrSO2 = -0.5%; p = 0.031), with a significant drop in arterial content and increase in the venous content. RV systolic function decreased (difference in tricuspid annular plane systolic excursion = -0.1 cm; p < 0.001) with a tendency toward increased RV basal diameter (p = 0.06). Grouping patients according to ΔCPP or ΔPRx revealed that those with poorer tolerance to RMs had higher CPP (p = 0.040) and a larger RV basal diameter (p = 0.034) at baseline. CONCLUSIONS: In patients with acute brain injury, RMs appear to have adverse effects on cerebral hemodynamics. These findings might be partially explained by RM's impact on RV function. Further advanced echocardiography monitoring is required to prove this hypothesis.

Cerebral autoregulation derived blood pressure targets in elective neurosurgery.

Poor postoperative outcomes may be associated with cerebral ischaemia or hyperaemia, caused by episodes of arterial blood pressure (ABP) being outside the range of cerebral autoregulation (CA). Monitoring CA using COx (correlation between slow changes in mean ABP and regional cerebral O2 saturation-rSO2) could allow to individualise the management of ABP to preserve CA. We aimed to explore a continuous automated assessment of ABPOPT (ABP where CA is best preserved) and ABP at the lower limit of autoregulation (LLA) in elective neurosurgery patients. Retrospective analysis of prospectively collected data of 85 patients [median age 60 (IQR 51-68)] undergoing elective neurosurgery. ABPBASELINE was the mean of 3 pre-operative non-invasive measurements. ABP and rSO2 waveforms were processed to estimate COx-derived ABPOPT and LLA trend-lines. We assessed: availability (number of patients where ABPOPT/LLA were available); time required to achieve first values; differences between ABPOPT/LLA and ABP. ABPOPT and LLA availability was 86 and 89%. Median (IQR) time to achieve the first value was 97 (80-155) and 93 (78-122) min for ABPOPT and LLA respectively. Median ABPOPT [75 (69-84)] was lower than ABPBASELINE [90 (84-95)] (p < 0.001, Mann-U test). Patients spent 72 (56-86) % of recorded time with ABP above or below ABPOPT ± 5 mmHg. ABPOPT and ABP time trends and variability were not related to each other within patients. 37.6% of patients had at least 1 hypotensive insult (ABP < LLA) during the monitoring time. It seems possible to assess individualised automated ABP targets during elective neurosurgery.

Therapy Intensity Level Scale for Traumatic Brain Injury: Clinimetric Assessment on Neuro-Monitored Patients Across 52 European Intensive Care Units.

Intracranial pressure (ICP) data from traumatic brain injury (TBI) patients in the intensive care unit (ICU) cannot be interpreted appropriately without accounting for the effect of administered therapy intensity level (TIL) on ICP. A 15-point scale was originally proposed in 1987 to quantify the hourly intensity of ICP-targeted treatment. This scale was subsequently modified-through expert consensus-during the development of TBI Common Data Elements to address statistical limitations and improve usability. The latest 38-point scale (hereafter referred to as TIL) permits integrated scoring for a 24-h period and has a five-category, condensed version (TIL(Basic)) based on qualitative assessment. Here, we perform a total- and component-score analysis of TIL and TIL(Basic) to: 1) validate the scales across the wide variation in contemporary ICP management; 2) compare their performance against that of predecessors; and 3) derive guidelines for proper scale use. From the observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, we extract clinical data from a prospective cohort of ICP-monitored TBI patients (n = 873) from 52 ICUs across 19 countries. We calculate daily TIL and TIL(Basic) scores (TIL24 and TIL(Basic)24, respectively) from each patient's first week of ICU stay. We also calculate summary TIL and TIL(Basic) scores by taking the first-week maximum (TILmax and TIL(Basic)max) and first-week median (TILmedian and TIL(Basic)median) of TIL24 and TIL(Basic)24 scores for each patient. We find that, across all measures of construct and criterion validity, the latest TIL scale performs significantly greater than or similarly to all alternative scales (including TIL(Basic)) and integrates the widest range of modern ICP treatments. TILmedian outperforms both TILmax and summarized ICP values in detecting refractory intracranial hypertension (RICH) during ICU stay. The RICH detection thresholds which maximize the sum of sensitivity and specificity are TILmedian ≥ 7.5 and TILmax ≥ 14. The TIL24 threshold which maximizes the sum of sensitivity and specificity in the detection of surgical ICP control is TIL24 ≥ 9. The median scores of each TIL component therapy over increasing TIL24 reflect a credible staircase approach to treatment intensity escalation, from head positioning to surgical ICP control, as well as considerable variability in the use of cerebrospinal fluid drainage and decompressive craniectomy. Since TIL(Basic)max suffers from a strong statistical ceiling effect and only covers 17% (95% confidence interval [CI]: 16-18%) of the information in TILmax, TIL(Basic) should not be used instead of TIL for rating maximum treatment intensity. TIL(Basic)24 and TIL(Basic)median can be suitable replacements for TIL24 and TILmedian, respectively (with up to 33% [95% CI: 31-35%] information coverage) when full TIL assessment is infeasible. Accordingly, we derive numerical ranges for categorising TIL24 scores into TIL(Basic)24 scores. In conclusion, our results validate TIL across a spectrum of ICP management and monitoring approaches. TIL is a more sensitive surrogate for pathophysiology than ICP and thus can be considered an intermediate outcome after TBI.

Cerebral autoregulation monitoring using the cerebral oximetry index after neonatal cardiac surgery: A single-center retrospective cohort study.

OBJECTIVE: To investigate whether cerebral autoregulation is impaired after neonatal cardiac surgery and whether changes in autoregulation metrics are associated with different congenital heart defects or the incidence of postoperative neurologic events. METHODS: This is a retrospective observational study of neonates undergoing monitoring during the first 72 hours after cardiac surgery. Archived data were processed to calculate the cerebral oximetry index (COx) and derived metrics. Acute neurologic events were identified by an electronic medical record review. The Skillings-Mack test and the Wilcoxon signed-rank test were used to analyze the evolution of autoregulation metrics over time; the Mann-Whitney U test was used for comparison between groups. RESULTS: We included 28 neonates, 7 (25%) with hypoplastic left heart syndrome and 21 (75%) with transposition of the great arteries. Overall, the median percentage of time spent with impaired autoregulation, defined as percentage of time with a COx >0.3, was 31.6% (interquartile range, 21.1%-38.3%). No differences in autoregulation metrics between different cardiac defects subgroups were observed. Seven patients (25%) experienced a postoperative acute neurologic event. Compared to the neonates without an acute neurologic event, those with an acute neurologic event had a higher COx (0.16 vs 0.07; P = .035), a higher percentage of time with a COx >0.3 (39.4% vs 29.2%; P = .017), and a higher percentage of time with a mean arterial pressure below the lower limit of autoregulation (13.3% vs 6.9%; P = .048). CONCLUSIONS: COx monitoring after cardiac surgery allowed for the detection of impaired cerebral autoregulation, which was more frequent in neonates with postoperative acute neurologic events.

Inaugural State of the Union: Continuous Cerebral Autoregulation Monitoring in the Clinical Practice of Neurocritical Care and Anesthesia.

How continuous cerebral autoregulation (CCA) knowledge should be optimally gained and interpreted is still an active area of research and refinement. We now experience a unique situation of having indices clinically available before definitive evidence of benefit or practice guidelines, in a moment when high rates of institutional variability exist both in the application of monitoring as well as in monitoring-guided treatments. Responses from 47 international clinicians, experts in this field, were collected with polling and discussion of the results. The clinical use of CCA in critical illness was not universal among experts, with 34% not using it. Of those who use a CCA index in clinical practice, 64% use intracranial pressure-based Pressure Reactivity index (PRx). There seems to exist a considerable trust in the physiologic plausibility of CCA to guide individual arterial blood pressure and cerebral perfusion pressure therapy and provide benefit, regardless of the difficulty of proving this. A total of 59% feel the need for phase II and III prospective studies but would continue to use CCA information in their practice even if randomized controlled trials (RCTs) did not show clear clinical benefit. There was nearly universal interest to participate in an RCT, with agreement that the research community must together determine end points and interventions to reduce wasted effort and time, and that investigations should include the following: the most appropriate way of inclusion of CCA into the clinical workflow; whether CCA-guided interventions should be prophylactic, proactive; or reactive; and whether a CCA-centric (unimodal) or a multimodal monitoring-integrated tiered therapy approach should be adopted. Pediatric and neonatal populations were highlighted as having urgent need and even more plausibility than adults. On the whole, the initiative was enthusiastically embraced by the experts, with the general feeling that a strong push should be now made by the community to convert the plausible benefits of CCA monitoring, already implemented in some centers, into a more standardized and RCT-validated clinical reality.