The lower limit of reactivity as a potential individualised cerebral perfusion pressure target in traumatic brain injury: a CENTER-TBI high-resolution sub-study analysis.

BACKGROUND: A previous retrospective single-centre study suggested that the percentage of time spent with cerebral perfusion pressure (CPP) below the individual lower limit of reactivity (LLR) is associated with mortality in traumatic brain injury (TBI) patients. We aim to validate this in a large multicentre cohort. METHODS: Recordings from 171 TBI patients from the high-resolution cohort of the CENTER-TBI study were processed with ICM+ software. We derived LLR as a time trend of CPP at a level for which the pressure reactivity index (PRx) indicates impaired cerebrovascular reactivity with low CPP. The relationship with mortality was assessed with Mann-U test (first 7-day period), Kruskal-Wallis (daily analysis for 7 days), univariate and multivariate logistic regression models. AUCs (CI 95%) were calculated and compared using DeLong's test. RESULTS: Average LLR over the first 7 days was above 60 mmHg in 48% of patients. %time with CPP < LLR could predict mortality (AUC 0.73, p = < 0.001). This association becomes significant starting from the third day post injury. The relationship was maintained when correcting for IMPACT covariates or for high ICP. CONCLUSIONS: Using a multicentre cohort, we confirmed that CPP below LLR was associated with mortality during the first seven days post injury.

Towards autoregulation-oriented management after traumatic brain injury: increasing the reliability and stability of the CPPopt algorithm.

PURPOSE: CPPopt denotes a Cerebral Perfusion Pressure (CPP) value at which the Pressure-Reactivity index, reflecting the global state of Cerebral Autoregulation, is best preserved. CPPopt has been investigated as a potential dynamically individualised CPP target in traumatic brain injury patients admitted in intensive care unit. The prospective bedside use of the concept requires ensured safety and reliability of the CPP recommended targets based on the automatically-generated CPPopt. We aimed to: Increase stability and reliability of the CPPopt automated algorithm by fine-tuning; perform outcome validation of the adjusted algorithm in a multi-centre TBI cohort. METHODS: ICM + software was used to derive CPPopt and fine-tune the algorithm. Parameters for improvement of the algorithm were selected based on qualitative and quantitative assessment of stability and reliability metrics. Patients enrolled in the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution cohort were included for retrospective validation. Yield and stability of the new algorithm were compared to the previous algorithm using Mann-U test. Area under the curves for mortality prediction at 6 months were compared with the DeLong Test. RESULTS: CPPopt showed higher stability (p < 0.0001), but lower yield compared to the previous algorithm [80.5% (70-87.5) vs 85% (75.7-91.2), p < 0.001]. Deviation of CPPopt could predict mortality with an AUC of [AUC = 0.69 (95% CI 0.59-0.78), p < 0.001] and was comparable with the previous algorithm. CONCLUSION: The CPPopt calculation algorithm was fine-tuned and adapted for prospective use with acceptable lower yield, improved stability and maintained prognostic power.

Individualized cerebral perfusion pressure in acute neurological injury: are we ready for clinical use?

PURPOSE OF REVIEW: Individualizing cerebral perfusion pressure based on cerebrovascular autoregulation assessment is a promising concept for neurological injuries where autoregulation is typically impaired. The purpose of this review is to describe the status quo of autoregulation-guided protocols and discuss steps towards clinical use. RECENT FINDINGS: Retrospective studies have indicated an association of impaired autoregulation and poor clinical outcome in traumatic brain injury (TBI), hypoxic-ischemic brain injury (HIBI) and aneurysmal subarachnoid hemorrhage (aSAH). The feasibility and safety to target a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) after TBI was recently assessed by the COGITATE trial. Similarly, the feasibility to calculate a MAP target (MAPopt) based on near-infrared spectroscopy was demonstrated for HIBI. Failure to meet CPPopt is associated with the occurrence of delayed cerebral ischemia in aSAH but interventional trials in this population are lacking. No level I evidence is available on potential effects of autoregulation-guided protocols on clinical outcomes. SUMMARY: The effect of autoregulation-guided management on patient outcomes must still be demonstrated in prospective, randomized, controlled trials. Selection of disease-specific protocols and endpoints may serve to evaluate the overall benefit from such approaches.

Visualization of Intracranial Pressure Insults After Severe Traumatic Brain Injury: Influence of Individualized Limits of Reactivity.

Cerebral perfusion pressure (CPP) lower limits of reactivity can be determined almost continuously after severe traumatic brain injury (TBI), and deviation below the lower limit carries important prognostic information. In this study, we used a recently derived coloured contour method for visualizing intracranial pressure (ICP) insults to describe the influence of having a CPP above the CPP lower limits of reactivity after severe TBI. In a cohort of 729 patients, we examined the relationship between ICP insults and the 6-month Glasgow Outcome Scale score, using colour-coded plots, as described previously. We then assessed this relationship when ICP insults were above or below the CPP lower limit of reactivity. We found a curvilinear relationship whereby even prolonged durations of low-intensity ICP insults were not associated with poor outcomes but short durations of high-intensity insults were. When only ICP insults with a CPP below the CPP lower limit of reactivity were considered, a much lower intensity of ICP insults could be tolerated. A CPP above the lower limits of reactivity exerts a protective effect, whereas a CPP below the lower reactivity limits renders the patient vulnerable to increased morbidity from intracranial hypertension.

Patient's Clinical Presentation and CPPopt Availability: Any Association?

BACKGROUND: The 'optimal' CPP (CPPopt) concept is based on the vascular pressure reactivity index (PRx). The feasibility and effectiveness of CPPopt guided therapy in severe traumatic brain injury (TBI) patients is currently being investigated prospectively in the COGiTATE trial. At the moment there is no clear evidence that certain admission and treatment characteristics are associated with CPPopt availability (yield). OBJECTIVE: To test the relation between patients' admission and treatment characteristics and the average CPPopt yield. METHODS: Retrospective analysis of 230 patients from the CENTER-TBI high-resolution database with intracranial pressure (ICP) measured using an intraparenchymal probe. CPPopt was calculated using the algorithm set for the COGiTATE study. CPPopt yield was defined as the percentage of CPP monitored time (%) when CPPopt is available. The variables in the statistical model included age, admission Glasgow Coma Scale (GCS), gender, pupil response, hypoxia and hypotension at the scene, Marshall computed tomography (CT) score, decompressive craniectomy, injury severity score score and 24-h therapeutic intensity level (TIL) score. RESULTS: The median CPPopt yield was 80.7% (interquartile range 70.9-87.4%). None of the selected variables showed a significant statistical correlation with the CPPopt yield. CONCLUSION: In this retrospective multicenter study, none of the selected admission and treatment variables were related to the CPPopt yield.

Semi-automated Computed Tomography Volumetry as a Proxy for Intracranial Pressure in Patients with Severe Traumatic Brain Injury: Clinical Feasibility Study.

INTRODUCTION: Traumatic brain injury (TBI) is associated with high mortality due to intracranial pressure (ICP). Whether computed tomography (CT) scanning of the brain within the first 24 h is indicative of intracranial hypertension is largely unknown. We assessed the feasibility of semi-automated CT segmentation in comparison with invasive ICP measurements. RELEVANCE: CT volumetry of the brain might provide ICP data when invasive monitoring is not possible or is undesirable. METHODS: We identified 33 patients with TBI who received a CT scan at admission and ICP monitoring within 24 h. Semi-automated segmentation of CT images in Matlab yielded cerebrospinal fluid (CSF) and intracranial volume (ICV) data. The ratio CSF/ICV × 100 (expressed as a percentage) was used as a proxy for ICP. The association between invasive ICP and the CSF/ICV ratio was evaluated using a simple linear regression model and a mono-exponential function derived from previous research in animals. RESULTS: ICP is moderately but significantly associated with the CSF/ICV ratio (r = -0.44, p = 0.01). The mono-exponential function provided a better fit of the relationship between ICP and the CSF/ICV ratio than the linear model. CONCLUSION: Our feasibility TBI data show that cross-sectional volumetric CT measures are associated with ICP. This non-invasive method can be used in future studies to monitor patients who are not candidates for invasive monitoring or to evaluate therapy effects objectively.

Optimal Cerebral Perfusion Pressure Assessed with a Multi-Window Weighted Approach Adapted for Prospective Use: A Validation Study.

BACKGROUND: Pressure reactivity index (PRx)-cerebral perfusion pressure (CPP) relationships over a given time period can be used to detect a value of CPP at which PRx shows the best autoregulation (optimal CPP, or CPPopt). Algorithms for continuous assessment of CPPopt in traumatic brain injury (TBI) patients reached the desired high yield with a multi-window approach (CPPopt_MA). However, the calculations were tested on retrospective manually cleaned datasets. Moreover, CPPopt false-positive values can be generated from non-physiological variations of intracranial pressure (ICP) and arterial blood pressure (ABP). Therefore, the algorithm robustness was improved, making it suitable for prospective bedside application (COGiTATE trial). OBJECTIVE: To validate the CPPopt revised algorithm in a large single-centre retrospective cohort of TBI patients. METHODS: 840 TBI patients were included. CPPopt yield, stability and ability to discriminate outcome groups were compared to CPPopt_MA and the Brain Trauma Foundation (BTF) guideline reference. RESULTS: CPPopt yield was lower than CPPopt_MA yield (85% and 90%, p < 0.001), but, importantly, with increased stability (p < 0.0001). The ∆(CPP-CPPopt) could distinguish the mortality and survival outcome (t = -6.7, p < 0.0001) with a statistical significance higher than the ∆CPP calculated with the guideline reference (CPP-60) (t = -4.5, p < 0.0001). CONCLUSION: This study validates, on a large cohort of patients, the new algorithm proposed for prospective use of CPPopt as a CPP target at bedside.

An Update on the COGiTATE Phase II Study: Feasibility and Safety of Targeting an Optimal Cerebral Perfusion Pressure as a Patient-Tailored Therapy in Severe Traumatic Brain Injury.

INTRODUCTION: Monitoring of cerebral autoregulation (CA) in patients with a traumatic brain injury (TBI) can provide an individual 'optimal' cerebral perfusion pressure (CPP) target (CPPopt) at which CA is best preserved. This potentially offers an individualized precision medicine approach. Retrospective data suggest that deviation of CPP from CPPopt is associated with poor outcomes. We are prospectively assessing the feasibility and safety of this approach in the COGiTATE [CPPopt Guided Therapy: Assessment of Target Effectiveness] study. Its primary objective is to demonstrate the feasibility of individualizing CPP at CPPopt in TBI patients. The secondary objectives are to investigate the safety and physiological effects of this strategy. METHODS: The COGiTATE study has included patients in four European hospitals in Cambridge, Leuven, Nijmegen, and Maastricht (coordinating centre). Patients with severe TBI requiring intracranial pressure (ICP)-directed therapy are allocated into one of two groups. In the intervention group, CPPopt is calculated using a published (modified) algorithm. In the control group, the CPP target recommended in the Brain Trauma Foundation guidelines (CPP 60-70 mmHg) is used. RESULTS: Patient recruitment started in February 2018 and will continue until 60 patients have been studied. Fifty-one patients (85% of the intended total) have been recruited in October 2019. The first results are expected early 2021. CONCLUSION: This prospective evaluation of the feasibility, safety and physiological implications of autoregulation-guided CPP management is providing evidence that will be useful in the design of a future phase III study in severe TBI patients.

Cerebral and Limb Tissue Oxygenation During Peripheral Venoarterial Extracorporeal Life Support.

Femoral access in extracorporeal life support (ECLS) has been associated with regional variations in arterial oxygen saturation, potentially predisposing the patient to ischemic tissue damage. Current monitoring techniques, however, are limited to intermittent bedside evaluation of capillary refill among other factors. The aim of this study was to assess whether cerebral and limb regional tissue oxygen saturation (rSO2) values reflect changes in various patient-related parameters during venoarterial ECLS (VA-ECLS). This retrospective observational study included adults assisted by femorofemoral VA-ECLS. Bifrontal cerebral and bilateral limb tissue oximetry was performed for the entire duration of support. Hemodynamic data were analyzed parallel to cerebral and limb rSO2. A total of 23 patients were included with a median ECLS duration of 5 [1-20] days. Cardiac arrhythmias were observed in 12 patients, which was associated with a decreased mean rSO2 from 61%±11% to 51%±10% during atrial fibrillation and 67%±9% to 58%±10% during ventricular fibrillation (P<0.001 for both). A presumably sudden increase in cardiac output due to myocardial recovery (n=8) resulted in a significant decrease in mean cerebral rSO2 from 73%±7% to 54%±6% and from 69%±9% to 53%±8% for the left and right cerebral hemisphere, respectively (P=0.012 for both hemispheres). Also, right radial artery partial gas pressure for oxygen decreased from 15.6±2.8 to 8.3±1.9 kPa (P=0.028). No differences were found in cerebral desaturation episodes between patients with and without neurologic complications. In six patients, limb rSO2 increased from on average 29.3±2.7 to 64.0±5.1 following insertion of a distal cannula in the femoral artery (P=0.027). Likewise, restoration of flow in a clotted distal cannula inserted in the femoral artery was necessary in four cases and resulted in increased limb rSO2 from 31.3±0.8 to 79.5±9.0; P=0.068. Non-invasive tissue oximetry adequately reflects events influencing cerebral and limb perfusion and can aid in monitoring tissue perfusion in patients assisted by ECLS.

Improving Prediction of Favourable Outcome After 6 Months in Patients with Severe Traumatic Brain Injury Using Physiological Cerebral Parameters in a Multivariable Logistic Regression Model.

BACKGROUND/OBJECTIVE: Current severe traumatic brain injury (TBI) outcome prediction models calculate the chance of unfavourable outcome after 6 months based on parameters measured at admission. We aimed to improve current models with the addition of continuously measured neuromonitoring data within the first 24 h after intensive care unit neuromonitoring. METHODS: Forty-five severe TBI patients with intracranial pressure/cerebral perfusion pressure monitoring from two teaching hospitals covering the period May 2012 to January 2019 were analysed. Fourteen high-frequency physiological parameters were selected over multiple time periods after the start of neuromonitoring (0-6 h, 0-12 h, 0-18 h, 0-24 h). Besides systemic physiological parameters and extended Corticosteroid Randomisation after Significant Head Injury (CRASH) score, we added estimates of (dynamic) cerebral volume, cerebral compliance and cerebrovascular pressure reactivity indices to the model. A logistic regression model was trained for each time period on selected parameters to predict outcome after 6 months. The parameters were selected using forward feature selection. Each model was validated by leave-one-out cross-validation. RESULTS: A logistic regression model using CRASH as the sole parameter resulted in an area under the curve (AUC) of 0.76. For each time period, an increased AUC was found using up to 5 additional parameters. The highest AUC (0.90) was found for the 0-6 h period using 5 parameters that describe mean arterial blood pressure and physiological cerebral indices. CONCLUSIONS: Current TBI outcome prediction models can be improved by the addition of neuromonitoring bedside parameters measured continuously within the first 24 h after the start of neuromonitoring. As these factors might be modifiable by treatment during the admission, testing in a larger (multicenter) data set is warranted.

Continuous Assessment of "Optimal" Cerebral Perfusion Pressure in Traumatic Brain Injury: A Cohort Study of Feasibility, Reliability, and Relation to Outcome.

BACKGROUND: Guidelines recommend maintaining cerebral perfusion pressure (CPP) between 60 and 70 mmHg in patients with severe traumatic brain injury (TBI), but acknowledge that optimal CPP may vary depending on cerebral blood flow autoregulation. Previous retrospective studies suggest that targeting CPP where the pressure reactivity index (PRx) is optimized (CPPopt) may be associated with improved recovery. METHODS: We performed a retrospective cohort study involving TBI patients who underwent PRx monitoring to assess issues of feasibility relevant to future interventional studies: (1) the proportion of time that CPPopt could be detected; (2) inter-observer variability in CPPopt determination; and (3) agreement between manual and automated CPPopt estimates. CPPopt was determined for consecutive 6-h epochs during the first week following TBI. Sixty PRx-CPP tracings were randomly selected and independently reviewed by six critical care professionals. We also assessed whether greater deviation between actual CPP and CPPopt (ΔCPP) was associated with poor outcomes using multivariable models. RESULTS: In 71 patients, CPPopt could be manually determined in 985 of 1173 (84%) epochs. Inter-observer agreement for detectability was moderate (kappa 0.46, 0.23-0.68). In cases where there was consensus that it could be determined, agreement for the specific CPPopt value was excellent (weighted kappa 0.96, 0.91-1.00). Automated CPPopt was within 5 mmHg of manually determined CPPopt in 93% of epochs. Lower PRx was predictive of better recovery, but there was no association between ΔCPP and outcome. Percentage time spent below CPPopt increased over time among patients with poor outcomes (p = 0.03). This effect was magnified in patients with impaired autoregulation (defined as PRx > 0.2; p = 0.003). CONCLUSION: Prospective interventional clinical trials with regular determination of CPPopt and corresponding adjustment of CPP goals are feasible, but measures to maximize consistency in CPPopt determination are necessary. Although we could not confirm a clear association between ΔCPP and outcome, time spent below CPPopt may be particularly harmful, especially when autoregulation is impaired.

Hemodialysis Induces an Acute Decline in Cerebral Blood Flow in Elderly Patients.

The initiation of hemodialysis is associated with an accelerated decline of cognitive function and an increased incidence of cerebrovascular accidents and white matter lesions. Investigators have hypothesized that the repetitive circulatory stress of hemodialysis induces ischemic cerebral injury, but the mechanism is unclear. We studied the acute effect of conventional hemodialysis on cerebral blood flow (CBF), measured by [15O]H2O positron emission tomography-computed tomography (PET-CT). During a single hemodialysis session, three [15O]H2O PET-CT scans were performed: before, early after the start of, and at the end of hemodialysis. We used linear mixed models to study global and regional CBF change during hemodialysis. Twelve patients aged ≥65 years (five women, seven men), with a median dialysis vintage of 46 months, completed the study. Mean (±SD) arterial BP declined from 101±11 mm Hg before hemodialysis to 93±17 mm Hg at the end of hemodialysis. From before the start to the end of hemodialysis, global CBF declined significantly by 10%±15%, from a mean of 34.5 to 30.5 ml/100g per minute (difference, -4.1 ml/100 g per minute; 95% confidence interval, -7.3 to -0.9 ml/100 g per minute; P=0.03). CBF decline (20%) was symptomatic in one patient. Regional CBF declined in all volumes of interest, including the frontal, parietal, temporal, and occipital lobes; cerebellum; and thalamus. Higher tympanic temperature, ultrafiltration volume, ultrafiltration rate, and pH significantly associated with lower CBF. Thus, conventional hemodialysis induces a significant reduction in global and regional CBF in elderly patients. Repetitive intradialytic decreases in CBF may be one mechanism by which hemodialysis induces cerebral ischemic injury.

Optimal Cerebral Perfusion Pressure in Centers With Different Treatment Protocols.

OBJECTIVES: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed "optimal cerebral perfusion pressure." DESIGN: Retrospective analysis of prospectively collected data. SETTING: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. PATIENTS: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70 mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70 mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. CONCLUSIONS: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment.

Visualisation of the 'Optimal Cerebral Perfusion' Landscape in Severe Traumatic Brain Injury Patients.

OBJECTIVE: An 'optimal' cerebral perfusion pressure (CPPopt) can be defined as the point on the CPP scale corresponding to the greatest autoregulatory capacity. This can be established by examining the pressure reactivity index PRx-CPP relationship, which is approximately U-shaped but suffers from noise and missing data. In this paper, we present a method for plotting the whole PRx-CPP relationship curve against time in the form of a colour-coded map depicting the 'landscape' of that relationship extending back for several hours and to display this robustly at the bedside.This is a short version of a full paper recently published in Critical Care Medicine (2016) containing some new insights and details of a novel bedside implementation based on a presentation during Intracranial Pressure 2016 Symposium in Boston. METHODS: Recordings from routine monitoring of traumatic brain injury patients were processed using ICM+. Time-averaged means for arterial blood pressure, intracranial pressure, cerebral perfusion pressure (CPP) and pressure reactivity index (PRx) were calculated and stored with time resolution of 1 min. ICM+ functions have been extended to include not just an algorithm of automatic calculation of CPPopt but also the 'CPPopt landscape' chart. RESULTS: Examining the 'CPPopt landscape' allows the clinician to differentiate periods where the autoregulatory range is narrow and needs to be targeted from periods when the patient is generally haemodynamically stable, allowing for more relaxed CPP management. This information would not have been conveyed using the original visualisation approaches. CONCLUSIONS: We describe here a natural extension to the concept of autoregulatory assessment, providing the retrospective 'landscape' of the PRx-CPP relationship extending over the past several hours. We have incorporated such visualisation techniques online in ICM+. The proposed visualisation may facilitate clinical evaluation and use of autoregulation-guided therapy.

Cerebrovascular pressure reactivity monitoring using wavelet analysis in traumatic brain injury patients: A retrospective study.

BACKGROUND: After traumatic brain injury (TBI), the ability of cerebral vessels to appropriately react to changes in arterial blood pressure (pressure reactivity) is impaired, leaving patients vulnerable to cerebral hypo- or hyperperfusion. Although, the traditional pressure reactivity index (PRx) has demonstrated that impaired pressure reactivity is associated with poor patient outcome, PRx is sometimes erratic and may not be reliable in various clinical circumstances. Here, we introduce a more robust transform-based wavelet pressure reactivity index (wPRx) and compare its performance with the widely used traditional PRx across 3 areas: its stability and reliability in time, its ability to give an optimal cerebral perfusion pressure (CPPopt) recommendation, and its relationship with patient outcome. METHODS AND FINDINGS: Five hundred and fifteen patients with TBI admitted in Addenbrooke's Hospital, United Kingdom (March 23rd, 2003 through December 9th, 2014), with continuous monitoring of arterial blood pressure (ABP) and intracranial pressure (ICP), were retrospectively analyzed to calculate the traditional PRx and a novel wavelet transform-based wPRx. wPRx was calculated by taking the cosine of the wavelet transform phase-shift between ABP and ICP. A time trend of CPPopt was calculated using an automated curve-fitting method that determined the cerebral perfusion pressure (CPP) at which the pressure reactivity (PRx or wPRx) was most efficient (CPPopt_PRx and CPPopt_wPRx, respectively). There was a significantly positive relationship between PRx and wPRx (r = 0.73), and wavelet wPRx was more reliable in time (ratio of between-hour variance to total variance, wPRx 0.957 ± 0.0032 versus PRx and 0.949 ± 0.047 for PRx, p = 0.002). The 2-hour interval standard deviation of wPRx (0.19 ± 0.07) was smaller than that of PRx (0.30 ± 0.13, p < 0.001). wPRx performed better in distinguishing between mortality and survival (the area under the receiver operating characteristic [ROC] curve [AUROC] for wPRx was 0.73 versus 0.66 for PRx, p = 0.003). The mean difference between the patients' CPP and their CPPopt was related to outcome for both calculation methods. There was a good relationship between the 2 CPPopts (r = 0.814, p < 0.001). CPPopt_wPRx was more stable than CPPopt_PRx (within patient standard deviation 7.05 ± 3.78 versus 8.45 ± 2.90; p < 0.001). Key limitations include that this study is a retrospective analysis and only compared wPRx with PRx in the cohort of patients with TBI. Prior prospective validation is required to better assess clinical utility of this approach. CONCLUSIONS: wPRx offers several advantages to the traditional PRx: it is more stable in time, it yields a more consistent CPPopt recommendation, and, importantly, it has a stronger relationship with patient outcome. The clinical utility of wPRx should be explored in prospective studies of critically injured neurological patients.

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

OBJECTIVES: 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. DESIGN: Single-center retrospective analysis of prospectively collected data. SETTING: The neurocritical care unit at a tertiary academic medical center. PATIENTS: 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. INTERVENTIONS: None. METHODS AND MAIN RESULTS: 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). CONCLUSIONS: 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.

Enhanced Visualization of Optimal Cerebral Perfusion Pressure Over Time to Support Clinical Decision Making.

OBJECTIVE: Cerebrovascular reactivity can provide a continuously updated individualized target for management of cerebral perfusion pressure, termed optimal cerebral perfusion pressure. The objective of this project was to find a way of improving the optimal cerebral perfusion pressure methodology by introducing a new visualization method. DATA SOURCES: Four severe traumatic brain injury patients with intracranial pressure monitoring. DATA EXTRACTION: Data were collected and pre-processed using ICM+ software. DATA SYNTHESIS: Sequential optimal cerebral perfusion pressure curves were used to create a color-coded maps of autoregulation - cerebral perfusion pressure relationship evolution over time. CONCLUSIONS: The visualization method addresses some of the main drawbacks of the original methodology and might bring the potential for its clinical application closer.

Clinical and Physiological Events That Contribute to the Success Rate of Finding "Optimal" Cerebral Perfusion Pressure in Severe Brain Trauma Patients.

OBJECTIVE: Recently, a concept of an individually targeted level of cerebral perfusion pressure that aims to restore impaired cerebral vasoreactivity has been advocated after traumatic brain injury. The relationship between cerebral perfusion pressure and pressure reactivity index normally is supposed to have a U-shape with its minimum interpreted as the value of "optimal" cerebral perfusion pressure. The aim of this study is to investigate the relation between the absence of the optimal cerebral perfusion pressure curve and physiological variables, clinical factors, and interventions. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Neurocritical care units in two university centers. PATIENTS: Between May 2012 and December 2013, a total of 48 traumatic brain injury patients were studied with real-time annotation of predefined clinical events. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients had continuous monitoring of arterial blood pressure, intracranial pressure, and cerebral perfusion pressure, with real-time calculations of pressure reactivity index and optimal cerebral perfusion pressure using ICM+ software (Cambridge Enterprise, University of Cambridge, Cambridge, UK). Selected clinical events were inserted on a daily basis, including changes in physiological variables, sedativeanalgesic drugs, vasoactive drugs, and medical/surgical therapies for intracranial hypertension. The collected data were divided into 4-hour periods, with the primary outcome being absence of the optimal cerebral perfusion pressure curve. For every period, mean values (± SDs) of arterial blood pressure, intracranial pressure, pressure reactivity index, and other physiological variables were calculated; clinical events were organized using predefined scales. In 28% of all 1,561 periods, an optimal cerebral perfusion pressure curve was absent. A generalized linear mixed model with binary logistic regression was fitted. Absence of slow arterial blood pressure waves (odds ratio, 2.7; p < 0.001), higher pressure reactivity index values (odds ratio, 2.9; p < 0.001), lower amount of sedative-analgesic drugs (odds ratio, 1.9; p = 0.03), higher vasoactive medication dose (odds ratio, 3.2; p = 0.02), no administration of maintenance neuromuscular blockers (odds ratio, 1.7; p < 0.01), and following decompressive craniectomy (odds ratio, 1.8; p < 0.01) were independently associated with optimal cerebral perfusion pressure curve absence. CONCLUSIONS: This study identified six factors that were independently associated with absence of optimal cerebral perfusion pressure curves.

Observation of Autoregulation Indices During Ventricular CSF Drainage After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study.

BACKGROUND: Cerebral autoregulation is increasingly recognized as a factor that requires evaluation when managing poor grade aneurysmal subarachnoidal hemorrhage (aSAH) patients. In this single center pilot study, we investigated whether intraventricular intracranial pressure (ICP) derived when extraventricular drain (EVD) is open can be used to calculate dynamic autoregulation estimates in ICU aSAH patients. METHODS: Ten patients with the diagnosis of aSAH as confirmed by computed tomography (CT) and CT-angiography were enrolled. ICP was monitored via a transducer connected to the most proximal side exit of the EVD catheter. From at least 30 min periods of brain monitoring before, during, and after temporarily EVD closure, commonly used indexes of dynamic cerebral autoregulation were calculated. RESULTS: Preserved pulsatile ICP signals were seen with open EVD. There were no significant changes in parameters describing cerebral autoregulation between EVD open and closed conditions. Power spectra of ABP and ICP showed no significant changes for the selected frequency ranges. There was a small significant increase in absolute ICP [2.4 (3.8) mmHg, p < 0.001] upon short-term EVD closure. Cerebral spinal reserve capacity (RAP index) worsened significantly by short-term EVD closure. CONCLUSIONS: Due to preserved slow fluctuations in the ICP signal, an open EVD system can be used to calculate dynamic autoregulation indices in aSAH patients requiring intensive care monitoring with the pressure measurement from the most proximal part of drain. If these results are confirmed in larger study, this technique can open the way for investigating the role of autoregulation disturbance in aSAH patients.