Individualized Autoregulation-Derived Cerebral Perfusion Targets in Aneurysmal Subarachnoid Hemorrhage: A New Therapeutic Avenue?

Background: Cerebral perfusion pressure (CPP) is an important target in aneurysmal subarachnoid hemorrhage (aSAH), but it does not take into account autoregulatory disturbances. The pressure reactivity index (PRx) and the CPP with the optimal PRx (CPPopt) are new variables that may capture these pathomechanisms. In this study, we investigated the effect on the outcome of certain combinations of CPP or ΔCPPopt (actual CPP-CPPopt) with the concurrent autoregulatory status (PRx) after aSAH. Methods: This observational study included 432 aSAH patients, treated in the neurointensive care unit, at Uppsala University Hospital, Sweden. Functional outcome (GOS-E) was assessed 1-year postictus. Heatmaps of the percentage of good monitoring time (%GMT) of PRx/CPP and PRx/ΔCPPopt combinations in relation to GOS-E were created to visualize the association between these variables and outcome. Results: In the heatmap of the %GMT of PRx/CPP, the combination of lower CPP with higher PRx values was more strongly associated with lower GOS-E. The tolerance for lower CPP values increased with lower PRx values until a threshold of -0.50. However, for decreasing PRx below -0.50, there was a gradual reduction in the tolerance for lower CPP. In the heatmap of the %GMT of PRx/ΔCPPopt, the combination of negative ΔCPPopt with higher PRx values was strongly associated with lower GOS-E. In particular, negative ΔCPPopt together with PRx above +0.50 correlated with worse outcomes. In addition, there was a transition toward an unfavorable outcome when PRx went below -0.50, particularly if ΔCPPopt was negative. Conclusions: The PRx levels influenced the association between CPP/ΔCPPopt and outcome. Thus, this variable could be used to individualize a safe CPP-/ΔCPPopt-range.

The effects of cerebral pressure autoregulation status and CPP levels on cerebral metabolism in pediatric traumatic brain injury.

BACKGROUND: Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as marker of cerebral pressure autoregulation (CPA) and optimal CPP (CPPopt) may be assessed by identifying the CPP level with best (lowest) PRx. To evaluate the potential of CPPopt guided management in children with severe TBI, cerebral microdialysis (CMD) monitoring levels of lactate and the lactate/pyruvate ratio (LPR) (indicators of ischemia) were related to actual CPP levels, autoregulatory state (PRx) and deviations from CPPopt (ΔCPPopt). METHODS: Retrospective study of 21 children ≤ 17 years with severe TBI who had both ICP and CMD monitoring were included. CPP, PRx, CPPopt and ΔCPPopt where calculated, dichotomized and compared with CMD lactate and lactate-pyruvate ratio. RESULTS: Median age was 16 years (range 8-17) and median Glasgow coma scale motor score 5 (range 2-5). Both lactate (p = 0.010) and LPR (p = < 0.001) were higher when CPP ≥ 70 mmHg than when CPP < 70. When PRx ≥ 0.1 both lactate and LPR were higher than when PRx < 0.1 (p = < 0.001). LPR was lower (p = 0.012) when CPPopt ≥ 70 mmHg than when CPPopt < 70, but there were no differences in lactate levels. When ΔCPPopt > 10 both lactate (p = 0.026) and LPR (p = 0.002) were higher than when ΔCPPopt < -10. CONCLUSIONS: Increased levels of CMD lactate and LPR in children with severe TBI appears to be related to disturbed CPA (PRx). Increased lactate and LPR also seems to be associated with actual CPP levels ≥ 70 mmHg. However, higher lactate and LPR values were also seen when actual CPP was above CPPopt. Higher CPP appears harmful when CPP is above the upper limit of pressure autoregulation. The findings indicate that CPPopt guided CPP management may have potential in pediatric TBI.

Cerebrovascular reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury.

PURPOSE: Cerebral perfusion pressure (CPP) guidance by cerebral pressure autoregulation (CPA) status according to PRx (correlation mean arterial blood pressure (MAP) and intracranial pressure (ICP)) and optimal CPP (CPPopt = CPP with lowest PRx) is promising but little is known regarding this approach in elderly. The aim was to analyze PRx and CPPopt in elderly TBI patients. METHODS: A total of 129 old (≥ 65 years) and 342 young (16-64 years) patients were studied using monitoring data for MAP and ICP. CPP, PRx, CPPopt, and ΔCPPopt (difference between actual CPP and CPPopt) were calculated. Logistic regression analyses with PRx and ΔCPPopt as explanatory variables for outcome. The combined effects of PRx/CPP and PRx/ΔCPPopt on outcome were visualized as heatmaps. RESULTS: The elderly had higher PRx (worse CPA), higher CPPopt, and different temporal patterns. High PRx influenced outcome negatively in the elderly but less so than in younger patients. CPP close to CPPopt correlated to favorable outcome in younger, in contrast to elderly patients. Heatmap interaction analysis of PRx/ΔCPPopt in the elderly showed that the region for favorable outcome was centered around PRx 0 and ranging between both functioning and impaired CPA (PRx range - 0.5-0.5), and the center of ΔCPPopt was - 10 (range - 20-0), while in younger the center of PRx was around - 0.5 and ΔCPPopt closer to zero. CONCLUSIONS: The elderly exhibit higher PRx and CPPopt. High PRx influences outcome negatively in the elderly but less than in younger patients. The elderly do not show better outcome when CPP is close to CPPopt in contrast to younger patients.

Variations in Autoregulation-Based Optimal Cerebral Perfusion Pressure Determination Using Two Integrated Neuromonitoring Platforms in a Trauma Patient.

BACKGROUND: Neuromonitoring devices are often used in traumatic brain injury. The objective of this report is to raise awareness concerning variations in optimal cerebral perfusion pressure (CPPopt) determination using exploratory information provided by two neuromonitoring monitors that are part of research programs (Moberg CNS Monitor and RAUMED NeuroSmart LogO). METHODS: We connected both monitors simultaneously to a parenchymal intracranial pressure catheter and recorded the pressure reactivity index (PRx) and the derived CPPopt estimates for a patient with a severe traumatic brain injury. These estimates were available at the bedside and were updated at each minute. RESULTS: Using the Bland and Altman method, we found a mean variation of - 3.8 (95% confidence internal from - 8.5 to 0.9) mm Hg between the CPPopt estimates provided by the two monitors (limits of agreement from - 26.6 to 19.1 mm Hg). The PRx and CPPopt trends provided by the two monitors were similar over time, but CPPopt trends differed when PRx values were around zero. Also, almost half of the CPPopt estimates differed by more than 10 mm Hg. CONCLUSIONS: These wide variations recorded in the same patient are worrisome and reiterate the importance of understanding and standardizing the methodology and algorithms behind commercial neuromonitoring devices prior to incorporating them in clinical use.

Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

Time spent above optimal cerebral perfusion pressure is not associated with failure to improve in outcome in traumatic brain injury.

BACKGROUND: Optimal cerebral perfusion pressure (CPPopt) has emerged as a promising personalized medicine approach to the management of moderate-to-severe traumatic brain injury (TBI). Though literature demonstrating its association with poor outcomes exists, there is yet to be work done on its association with outcome transition due to a lack of serial outcome data analysis. In this study we investigate the association between various metrics of CPPopt and failure to improve in outcome over time. METHODS: CPPopt was derived using three different cerebrovascular reactivity indices; the pressure reactivity index (PRx), the pulse amplitude index (PAx), and the RAC index. For each index, % times spent with cerebral perfusion pressure (CPP) above and below its CPPopt and upper and lower limits of reactivity were calculated. Patients were dichotomized based on improvement in Glasgow Outcome Scale-Extended (GOSE) scores into Improved vs. Not Improved between 1 and 3 months, 3 and 6 months, and 1- and 6-month post-TBI. Logistic regression analyses were then conducted, adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. RESULTS: This study included a total of 103 patients from the Winnipeg Acute TBI Database. Through Mann-Whitney U testing and logistic regression analysis, it was found that % time spent with CPP below CPPopt was associated with failure to improve in outcome, while % time spent with CPP above CPPopt was generally associated with improvement in outcome. CONCLUSIONS: Our study supports the existing narrative that time spent with CPP below CPPopt results in poorer outcomes. However, it also suggests that time spent above CPPopt may not be associated with worse outcomes and is possibly even associated with improvement in outcome.

Focal brain oxygen, blood flow, and intracranial pressure measurements in relation to optimal cerebral perfusion pressure.

OBJECTIVE: Different paradigms for neurocritical care of traumatic brain injury (TBI) have emerged in conjunction with advanced neuromonitoring technologies and derived metrics. The priority for optimizing these metrics is not currently clear. The goal of this study was to determine whether achieving cerebral perfusion pressure (CPPopt) also improves other metrics like brain oxygenation and brain blood flow. METHODS: The authors performed a retrospective analysis of high-frequency data from patients with TBI who were treated at a single center and who had partial pressure of brain oxygen (PbtO2) measurements and/or brain blood flow measurements, while also undergoing intracranial pressure (ICP) monitoring. CPPopt was not calculated or targeted during patient care, but was retrospectively computed, as was the difference between the observed CPP and CPPopt. RESULTS: A total of 22 patients with ICP, PbtO2, and/or brain blood flow monitoring were included in the analysis, and 245.7 days of measurements obtained every second were analyzed including 6,748,866 PbtO2 measurements, 3,296,405 blood flow measurements, and 10,264,770 ICP measurements. The data obtained every second were averaged by minute for analysis. In summative data, PbtO2 measurements peaked near CPPopt and were not improved above CPPopt. Blood flow measurements remained stable near CPPopt, decreased below it, and increased when CPP exceeded CPPopt. ICP decreased linearly with CPP without a specific relationship with CPPopt. In an inverse analysis, the percentage of CPP values at CPPopt, although significantly higher on the favorable side of contemporary treatment thresholds of PbtO2, ICP, and blood flow, was not found to be strongly correlated with the mean values of the physiological measurements obtained every minute (r = 0.27, r = 0.11, and r = 0.47 for ICP, PbtO2, and blood flow, respectively; p < 0.0001). CONCLUSIONS: Although CPPopt was not targeted in the patients in this study, CPPopt was a physiologically significant value based on concurrent measurements of PbtO2 and blood flow. In summative data, achievement of CPPopt was associated with optimized PbtO2 and blood flow. Conversely, the correlation between achievement of CPPopt and the mean measurement value was not strong, strengthening the significance of CPPopt. In individual patients, achieving CPPopt is not always associated with optimal PbtO2 or blood flow. Further research should explore these relationships in treatment paradigms that specifically target CPPopt. These data do not support the premise that targeting and achieving CPPopt obviates the need for concurrent PbtO2 and blood flow monitoring. Although these data suggest that targeting CPPopt may be an appropriate initial treatment strategy, they do not provide evidence that CPPopt should be targeted with highest priority.

Interaction of Optimal Cerebral Perfusion Pressure with Early Brain Injury and its Impact on Ischemic Complications and Outcome Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Cerebral autoregulation is impaired early on after aneurysmal subarachnoid hemorrhage (aSAH). The study objective was to explore the pressure reactivity index (PRx) and cerebral perfusion pressure (CPP) in the earliest phase after aneurysm rupture and to address the question of whether an optimal CPP (CPPopt)-targeted management is associated with less severe early brain injury (EBI). METHODS: Patients with aSAH admitted between 2012 and 2020 were retrospectively included in this observational cohort study. The PRx was calculated as a correlation coefficient between intracranial pressure and mean arterial pressure. By plotting the PRx versus CPP, CPP correlating the lowest PRx value was identified as CPPopt. EBI was assessed by applying the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) on day 3 after ictus. An SEBES ≥ 3 was considered severe EBI. RESULTS: In 90 of 324 consecutive patients with aSAH, intracranial pressure monitoring was performed ≥ 7 days, allowing for PRx calculation and CPPopt determination. Severe EBI was associated with larger mean deviation of CPP from CPPopt 72 h after ictus (r = 0.22, p = 0.03). Progressive edema requiring decompressive hemicraniectomy was associated with larger deviation of CPP from CPPopt on day 2 (r = 0.23, p = 0.02). The higher the difference of CPP from CPPopt on day 3 the higher the mortality rate (r = 0.31, p = 0.04). CONCLUSIONS: Patients with CPP near to the calculated CPPopt in the early phase after aSAH experienced less severe EBI, less frequently received decompressive hemicraniectomy, and exhibited a lower mortality rate. A prospective evaluation of CPPopt-guided management starting in the first days after ictus is needed to confirm the clinical validity of this concept.

Lung Injury Risk in Traumatic Brain Injury Managed With Optimal Cerebral Perfusion Pressure Guided-Therapy.

Introduction: Management of traumatic brain injury (TBI) has to counterbalance prevention of secondary brain injury without systemic complications, namely lung injury. The potential risk of developing acute respiratory distress syndrome (ARDS) leads to therapeutic decisions such as fluid balance restriction, high PEEP and other lung protective measures, that may conflict with neurologic outcome. In fact, low cerebral perfusion pressure (CPP) may induce secondary ischemic injury and mortality, but disproportionate high CPP may also increase morbidity and worse lung compliance and hypoxia with the risk of developing ARDS and fatal outcome. The evaluation of cerebral autoregulation at bedside and individualized (optimal CPP) CPPopt-guided therapy, may not only be a relevant measure to protect the brain, but also a safe measure to avoid systemic complications. Aim of the study: We aimed to study the safety of CPPopt-guided-therapy and the risk of secondary lung injury association with bad outcome. Methods and results: Single-center retrospective analysis of 92 severe TBI patients admitted to the Neurocritical Care Unit managed with CPPopt-guided-therapy by PRx (pressure reactivity index). During the first 10 days, we collected data from blood gas, ventilation and brain variables. Evolution along time was analyzed using linear mixed-effects regression models. 86% were male with mean age 53±21 years. 49% presented multiple trauma and 21% thoracic trauma. At hospital admission, median GCS was 7 and after 3-months GOS was 3. Monitoring data was CPP 86±7mmHg, CPP-CPPopt -2.8±10.2mmHg and PRx 0.03±0.19. The average PFratio (PaO2/FiO2) was 305±88 and driving pressure 15.9±3.5cmH2O. PFratio exhibited a significant quadratic dependence across time and PRx and driving pressure presented significant negative association with PFRatio. CPP and CPPopt did not present significant effect on PFratio (p=0.533; p=0.556). A significant positive association between outcome and the difference CPP-CPPopt was found. Conclusion: Management of TBI using CPPopt-guided-therapy was associated with better outcome and seems to be safe regarding the development of secondary lung injury.

Evaluation and application of ultra-low-frequency pressure reactivity index in pediatric traumatic brain injury patients.

PURPOSE: While clinical practice suggests that knowing the cerebral autoregulation (CA) status of traumatic brain injury (TBI) patients is crucial in assessing the best treatment, evidence in pediatric TBI (pTBI) is limited. The pressure reactivity index (PRx) is a surrogate method for the continuous estimation of CA in adults; however, calculations require continuous, high-resolution monitoring data. We evaluate an ultra-low-frequency pressure reactivity index (UL-PRx), based on data sampled at ∼5-min periods, and test its association with 6-month mortality and unfavorable outcome in a cohort of pTBI patients. METHODS: Data derived from pTBI patients (0-18 years) requiring intracranial pressure (ICP) monitoring were retrospectively collected and processed in MATLAB using an in-house algorithm. RESULTS: Data on 47 pTBI patients were included. UL-PRx mean values, ICP, cerebral perfusion pressure (CPP), and derived indices showed significant association with 6-month mortality and unfavorable outcome. A value of UL-PRx of 0.30 was identified as the threshold to better discriminate both surviving vs deceased patients (AUC: 0.90), and favorable vs unfavorable outcomes (AUC: 0.70) at 6 months. At multivariate analysis, mean UL-PRx and % time with ICP > 20 mmHg, remained significantly associated with 6-month mortality and unfavorable outcome, even when adjusted for International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-Core variables. In six patients undergoing secondary decompressive craniectomy, no significant changes in UL-PRx were found after surgery. CONCLUSIONS: UL-PRx is associated with a 6-month outcome even if adjusted for IMPACT-Core. Its application in pediatric intensive care unit could be useful to evaluate CA and offer possible prognostic and therapeutic implications in pTBI patients. CLINICALTRIALS: GOV: NCT05043545, September 14, 2021, retrospectively registered.

Cerebral pressure autoregulation and optimal cerebral perfusion pressure during neurocritical care of children with traumatic brain injury.

OBJECTIVE: The management of cerebral perfusion pressure (CPP) is a challenge in children with traumatic brain injury (TBI) because the normal blood pressure is age dependent and the role of cerebral pressure autoregulation (CPA) is unclear. In this study, the authors aimed to examine the pressure reactivity index (PRx), CPP, optimal CPP (CPPopt), and deviations from CPPopt (ΔCPPopt) in a series of children with TBI generally and regarding age relations, temporal changes, and the influence on outcome. METHODS: Intracranial pressure (ICP) and mean arterial pressure (MAP) monitoring data were collected during neurointensive care in 57 children who sustained a TBI and were ≤ 17 years of age. CPP, PRx, CPPopt, and ΔCPPopt (actual CPP - CPPopt) were calculated. Clinical outcomes at 6 months postinjury were dichotomized into favorable outcomes (Glasgow Outcome Scale [GOS] score 4 or 5) and unfavorable outcomes (GOS scores 1-3). RESULTS: The median patient age was 15 (range 0.5-17) years, and the median Glasgow Coma Scale motor score at admission was 5 (range 2-5). Forty-nine (86%) of the 57 patients had favorable outcomes. For the entire group, lower PRx (better preserved CPA) was associated with a more favorable outcome (p = 0.023, ANCOVA adjusted for age). When the children were divided into age groups, this finding was statistically significant in children ≤ 15 years of age (p = 0.016), but not in children ≥ 16 years (p = 0.528). In children ≤ 15 years, a lower proportion of time with ΔCPPopt < -10% was significantly associated with a favorable outcome (p = 0.038), but not in the older age group. Temporal analysis indicated that PRx was higher (more impaired CPA) from day 4 and CPPopt was higher from day 6 in the unfavorable outcome group compared with the favorable outcome group, although those findings were not significant. CONCLUSIONS: Impaired CPA is related to poor outcome, particularly in children ≤ 15 years of age. In that age group, actual CPP below the CPPopt level contributed significantly to unfavorable outcome, while levels close to or above the CPPopt were unrelated to outcome. CPPopt appears to be higher during the time period when CPA is most impaired.

Neurocritical care management supported by multimodal brain monitoring after acute brain injury / Abordagem de cuidados neurocríticos apoiada por monitorização cerebral multimodal após lesão cerebral aguda

ABSTRACT Objective: To evaluate the association between different intensive care units and levels of brain monitoring with outcomes in acute brain injury. Methods: Patients with traumatic brain injury and subarachnoid hemorrhage admitted to intensive care units were included. Neurocritical care unit management was compared to general intensive care unit management. Patients managed with multimodal brain monitoring and optimal cerebral perfusion pressure were compared with general management patients. A good outcome was defined as a Glasgow outcome scale score of 4 or 5. Results: Among 389 patients, 237 were admitted to the neurocritical care unit, and 152 were admitted to the general intensive care unit. Neurocritical care unit management patients had a lower risk of poor outcome (OR = 0.228). A subgroup of 69 patients with multimodal brain monitoring (G1) was compared with the remaining patients (G2). In the G1 and G2 groups, 59% versus 23% of patients, respectively, had a good outcome at intensive care unit discharge; 64% versus 31% had a good outcome at 28 days; 76% versus 50% had a good outcome at 3 months (p < 0.001); and 77% versus 58% had a good outcome at 6 months (p = 0.005). When outcomes were adjusted by SAPS II severity score, using good outcome as the dependent variable, the results were as follows: for G1 compared to G2, the OR was 4.607 at intensive care unit discharge (p < 0.001), 4.22 at 28 days (p = 0.001), 3.250 at 3 months (p = 0.001) and 2.529 at 6 months (p = 0.006). Patients with optimal cerebral perfusion pressure management (n = 127) had a better outcome at all points of evaluation. Mortality for those patients was significantly lower at 28 days (p = 0.001), 3 months (p < 0.001) and 6 months (p = 0.001). Conclusion: Multimodal brain monitoring with autoregulation and neurocritical care unit management were associated with better outcomes and should be considered after severe acute brain injury.

RESUMO Objetivo: Avaliar a associação entre diferentes tipos de unidades de cuidados intensivos e os níveis de monitorização cerebral com desfechos na lesão cerebral aguda. Métodos: Foram incluídos doentes com traumatismo craniencefálico e hemorragia subaracnoide internados em unidades de cuidados intensivos. A abordagem na unidade de cuidados neurocríticos foi comparada à abordagem na unidade de cuidados intensivos polivalente geral. Os doentes com monitorização cerebral multimodal e pressão de perfusão cerebral ótima foram comparados aos que passaram por tratamento geral. Um bom desfecho foi definido como pontuação de 4 ou 5 na Glasgow outcome scale. Resultados: Dos 389 doentes, 237 foram admitidos na unidade de cuidados neurocríticos e 152 na unidade de cuidados intensivos geral. Doentes com abordagem em unidades de cuidados neurocríticos apresentaram menor risco de um mau desfecho (Odds ratio = 0,228). Um subgrupo de 69 doentes com monitorização cerebral multimodal (G1) foi comparado aos demais doentes (G2). Em G1 e G2, respectivamente, 59% e 23% dos doentes apresentaram bom desfecho na alta da unidade de cuidados intensivos; 64% e 31% apresentaram bom desfecho aos 28 dias; 76% e 50% apresentaram bom desfecho aos 3 meses (p < 0,001); e 77% e 58% apresentaram bom desfecho aos 6 meses (p = 0,005). Quando os desfechos foram ajustados para o escore de gravidade do SAPS II, usando o bom desfecho como variável dependente, os resultados foram os seguintes: para o G1, em comparação ao G2, a odds ratio foi de 4,607 na alta da unidade de cuidados intensivos (p < 0,001), 4,22 aos 28 dias (p = 0,001), 3,250 aos 3 meses (p = 0,001) e 2,529 aos 6 meses (p = 0,006). Os doentes com abordagem da pressão de perfusão cerebral ótima (n = 127) apresentaram melhor desfecho em todos os momentos de avaliação. A mortalidade desses doentes foi significativamente menor aos 28 dias (p = 0,001), aos 3 meses (p < 0,001) e aos 6 meses (p = 0,001). Conclusão: A monitorização cerebral multimodal com autorregulação e abordagem na unidade de cuidados neurocríticos foi associado a melhores desfechos e deve ser levado em consideração após lesão cerebral aguda grave.

Targeting Autoregulation-Guided Cerebral Perfusion Pressure after Traumatic Brain Injury (COGiTATE): A Feasibility Randomized Controlled Clinical Trial.

Managing traumatic brain injury (TBI) patients with a cerebral perfusion pressure (CPP) near to the cerebral autoregulation (CA)-guided "optimal" CPP (CPPopt) value is associated with improved outcome and might be useful to individualize care, but has never been prospectively evaluated. This study evaluated the feasibility and safety of CA-guided CPP management in TBI patients requiring intracranial pressure monitoring and therapy (TBIicp patients). The CPPopt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) parallel two-arm feasibility trial took place in four tertiary centers. TBIicp patients were randomized to either the Brain Trauma Foundation (BTF) guideline CPP target range (control group) or to the individualized CA-guided CPP targets (intervention group). CPP targets were guided by six times daily software-based alerts for up to 5 days. The primary feasibility end-point was the percentage of time with CPP concordant (±5 mm Hg) with the set CPP targets. The main secondary safety end-point was an increase in therapeutic intensity level (TIL) between the control and intervention group. Twenty-eight patients were randomized to the control and 32 patients to the intervention group. CPP in the intervention group was in the target range for 46.5% (interquartile range, 41.2-58) of the monitored time, significantly higher than the feasibility target specified in the published protocol (36%; p < 0.001). There were no significant differences between groups for TIL or for other safety end-points. Conclusively, targeting an individual and dynamic CA-guided CPP is feasible and safe in TBIicp patients. This encourages a prospective trial powered for clinical outcomes.

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.

Influence of Patient Demographics on Optimal Cerebral Perfusion Pressure Following Traumatic Brain Injury.

The relationship between optimal cerebral perfusion pressure (CPPopt) and patient characteristics has yet to be defined but could have significant implications for future guidelines recommending cerebral perfusion pressure (CPP) targets.Data from 36 traumatic brain injured patients admitted to neurological intensive care were analysed retrospectively. Linear mixed effects (LME) analysis was performed using an unadjusted-adjusted approach.Clinical characteristics with p < 0.10 were included in the adjusted model. A second adjusted model which included all variables of interest was created. Model fit was assessed using the root-mean-square error (RMSE).The adjusted model included time from initiation of intracranial pressure (ICP) monitoring (estimate = 0.00292, p < 0.001), age (estimate = -0.211, p = 0.0750) and the presence of diffuse axonal injury (DAI) (estimate = -35.5, p < 0.001). The RMSE of this model was 8.11 mmHg. The RMSE of the model containing all variables was 8.09 mmHg.Time, age and the presence of DAI may be important predictors of CPPopt. The models were too inaccurate at predicting CPPopt for employment in clinical practice but warrant further investigation. CPPopt is a dynamic measurement influenced by many factors, supporting the utility of investigating the feasibility of CPPopt-guided therapy.

Optimal Cerebral Perfusion Pressure Based on Intracranial Pressure-Derived Indices of Cerebrovascular Reactivity: Which One Is Better for Outcome Prediction in Moderate/Severe Traumatic Brain Injury?

Intracranial pressure (ICP)-derived indices of cerebrovascular reactivity (e.g., PRx, PAx, and RAC) have been developed to improve understanding of brain status from available neuromonitoring variables. These indices are moving correlation coefficients between slow-wave vasogenic fluctuations in ICP and arterial blood pressure. In this retrospective analysis of neuromonitoring data from 200 patients admitted with moderate/severe traumatic brain injury (TBI), we evaluate the predictive value of CPPopt based on these ICP-derived indices of cerebrovascular reactivity. Valid CPPopt values were obtained in 92.3% (PRx), 86.7% (PAX), and 84.6% (RAC) of the monitoring periods, respectively. In multivariate logistic analysis, a baseline model that includes age, sex, and admission Glasgow Coma Score had an area under the receiver operating curve of 0.762 (P < 0.0001) for dichotomous outcome prediction (dead vs. good recovery). When adding time/dose of CPP below CPPopt, all multivariate models (based on PRx, PAx, and RAC) predicted the dichotomous outcome measure, but additional value of the prediction was only significantly added by the PRx-based calculations of time spent with CPP below CPPopt and dose of CPP below CPPopt.

Autoregulatory or Fixed Cerebral Perfusion Pressure Targets in Traumatic Brain Injury: Determining Which Is Better in an Energy Metabolic Perspective.

Current guidelines in traumatic brain injury (TBI) recommend a cerebral perfusion pressure (CPP) within the fixed interval of 60-70 mm Hg. However, the autoregulatory, optimal CPP target (CPPopt) might yield better cerebral blood flow (CBF) regulation. In this study, we investigated fixed versus autoregulatory CPP targets in relation to cerebral energy metabolism and clinical outcome after TBI. Ninety-eight non-craniectomized patients with severe TBI treated in the neurointensive care unit, Uppsala University Hospital, Sweden, 2008-2018, were included. Data from cerebral microdialysis (MD), intracranial pressure (ICP), pressure autoregulation, CPP and CPPopt55-15 (a variant of CPPopt based on filtered slow waves from 15-55 sec range) were analyzed the first 10 days. The good monitoring time (GMT %) below/within/above the fixed and autoregulatory CPP targets were calculated. CPPopt55-15 was >70 mm Hg 74% of the time the first 10 days. Higher GMT (%) ΔCPPopt55-15 ± 10 mm Hg correlated with lower lactate/pyruvate ratio (LPR) on day 1 and lower cerebral glycerol on days 6-10, and predicted favorable clinical outcome. Higher GMT (%) CPP within 60-70 mm Hg correlated with lower cerebral glucose on days 2-10 and higher LPR on days 6-10, but predicted favorable clinical outcome. Higher GMT (%) CPP >70 mm Hg had the opposite associations; that is, with higher cerebral glucose and lower LPR, but unfavorable clinical outcome. Autoregulatory CPP targets may be beneficial, because patients with CPP values close to the optimal CPP had both better cerebral energy metabolism and better clinical outcome, but this needs to be evaluated in randomized trials.

Optimal Cerebral Perfusion Pressure: Targeted Treatment for Severe Traumatic Brain Injury.

Identification of individual therapy targets is critical for traumatic brain injury (TBI) patients. Clinical outcomes depend on cerebrovascular autoregulation (CA) impairment. Here, we compare the effectiveness of optimal cerebral perfusion pressure (CPPopt)-targeted therapy in younger (<45 years of age) and elderly (≥45 years of age) TBI patients. Single-center multi-modal invasive arterial blood pressure(t), intracranial pressure (ICP)(t), cerebral perfusion pressure CPP(t), and CPPopt(t) monitoring (n = 81) was performed. ICM+ software was used for continuous CPPopt(t) status assessment by identification of pressure reactivity index (PRx). The most significant prognostic factors were age, Glasgow Coma Scale, serum glucose, and duration of longest CA ompairment event (LCAI) when PRx(t) >0.5 within 24 h after admission. The modeled accuracies for favorable and unfavorable outcome prediction were 86.5% and 90.9%, respectively. Age above 45 years and averaged ICP during all monitoring time above 21.3 mm Hg was associated with unfavorable outcome of an individual patient. Averaged CPP values close to CPPopt were associated with a better outcome in younger patients. Averaged ΔCPPopt <-5.0 mm Hg, averaged PRx >0.36, and LCAI >100 min were significantly associated with mortality for the younger patients. The critical values of averaged PRx >0.26 and LCAI >61 min were significantly associated with mortality for the elderly group. Autoregulation-guided treatment was important for individual TBI management, especially in younger patients. Further randomized multi-center studies are needed to prove final benefit.

Noninvasive Monitoring of Dynamic Cerebrovascular Autoregulation and 'Optimal Blood Pressure' in Normal Adult Subjects.

BACKGROUND: Cerebrovascular autoregulation can be continuously monitored from slow fluctuations of arterial blood pressure (ABP) and regional cerebral oxygen saturation (rSO2). The purpose of this study was to evaluate the index of dynamic cerebrovascular autoregulation (TOx) and the associated 'optimal' ABP in normal adult healthy subjects. METHODS: Twenty-eight healthy volunteers were studied. TOx was calculated as the moving correlation coefficient between spontaneous fluctuations of ABP and rSO2. ABP was measured with the Finometer photoplethysmograph. The ABP with optimal autoregulation (ABPOPT) was also determined as the ABP level with the lowest associated TOx (opt-TOx). RESULTS: Average rSO2 and TOx was 72.3 ± 2.9% and 0.05 ± 0.18, respectively. Two subjects had impaired autoregulation with a TOx > 0.3. The opt-TOx was - 0.1 ± 0.26. ABPOPT was 87.0 ± 16.7 mmHg. The difference between ABP and ABPOPT was - 0.3 ± 7.5 mmHg. In total, 44% of subjects had a deviation of ABP from ABPOPT exceeding 5 mmHg. ABPOPT ranged from 57 to 117 mmHg. CONCLUSIONS: TOx in healthy volunteers on average displays intact autoregulation and ABP close to ABPOPT. However, some subjects have possible autoregulatory dysfunction or a significant deviation of ABP from ABPOPT, which may confer a susceptibility to neurological injury.

Is There a Relationship Between Optimal Cerebral Perfusion Pressure-Guided Management and PaO2/FiO2 Ratio After Severe Traumatic Brain Injury?

OBJECTIVE: Severe traumatic brain injury (TBI) management has been associated with adult respiratory distress syndrome (ARDS) in previous literature. We aimed to investigate the relationships between optimal CPP-guided management, ventilation parameters over time and outcome after severe TBI. MATERIALS AND METHODS: We performed retrospective analysis of recorded data from 38 patients admitted to the NCCU after severe TBI, managed with optimal cerebral perfusion pressure (CPPopt)-guided therapy, calculated using pressure reactivity index (PRx). All patients were sedated and ventilated with lung protective criteria (Peep > 5, tidal volume 6-8 ml/kg and airway pressure < 30 cmH2O). RESULTS: Daily mean CPPopt varied between a minimum of 84 mmHg and a maximum of 91 mmHg with an all period mean value of 88 mmHg. The mean value for the difference between CPP and CPPopt was -1.9 mmHg. Daily mean P/F ratio decreased and varied between 253 and 387 with an all-period mean of 294 mmHg. During the 10 days of recording data, five patients (13%) developed criteria of severe ARDS, but only two patients died due to severe ARDS (5%). PaO2/FiO2 (P/F) ratio did not correlate with CPPopt, but showed a strong correlation with tidal volume (p = 0.000) and driving pressure (p = 0.000). CONCLUSIONS: Although CPPopt-guided therapy may induce a decrease in P/F ratio over time during the first 10 days, we could not find an association with worst outcome, which may be influenced by lung protective ventilation strategies and preservation of cerebral autoregulation.