Prognostic value of near-infrared spectroscopy regional oxygen saturation and cerebrovascular reactivity index in acute traumatic neural injury: a CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Cohort Study.

BACKGROUND: Near-infrared spectroscopy regional cerebral oxygen saturation (rSO2) has gained interest as a raw parameter and as a basis for measuring cerebrovascular reactivity (CVR) due to its noninvasive nature and high spatial resolution. However, the prognostic utility of these parameters has not yet been determined. This study aimed to identify threshold values of rSO2 and rSO2-based CVR at which outcomes worsened following traumatic brain injury (TBI). METHODS: A retrospective multi-institutional cohort study was performed. The cohort included TBI patients treated in four adult intensive care units (ICU). The cerebral oxygen indices, COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and arterial blood pressure) were calculated for each patient. Grand mean thresholds along with exposure-based thresholds were determined utilizing sequential chi-squared analysis and univariate logistic regression, respectively. RESULTS: In the cohort of 129 patients, there was no identifiable threshold for raw rSO2 at which outcomes were found to worsen. For both COx and COx_a, an optimal grand mean threshold value of 0.2 was identified for both survival and favorable outcomes, while percent time above - 0.05 was uniformly found to have the best discriminative value. CONCLUSIONS: In this multi-institutional cohort study, raw rSO2was found to contain no significant prognostic information. However, rSO2-based indices of CVR, COx and COx_a, were found to have a uniform grand mean threshold of 0.2 and exposure-based threshold of - 0.05, above which clinical outcomes markedly worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

Identifying the Cerebral Physiologic Response to Aerobic Exercise Following Concussion: A Scoping Review.

OBJECTIVE: The purpose of this study was to identify the cerebral physiologic response to aerobic exercise in individuals with a symptomatic concussion, highlighting available knowledge and knowledge gaps in the literature. DESIGN: A systematic scoping review was conducted and reported in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. A search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane libraries was conducted on June 15, 2023 (from database inception). An online systematic/scoping review management system was used to remove duplicates, and the remaining articles were screened for inclusion by 2 researchers. Inclusion criteria required articles to be original research published in peer-reviewed journals. Additionally, studies were required to have an aerobic exercise component, include a measure of cerebral physiology during a bout of aerobic exercise, exclude moderate and/or severe traumatic brain injury (TBI) populations, and be in the English language. Both human and animal studies were included, with participants of any age who were diagnosed with a mild TBI/concussion only (ie, Glasgow Coma Scale score ≥ 13). Studies could be of any design as long as a measure of cerebral physiologic response to a bout of aerobic exercise was included. RESULTS: The search resulted in 1773 articles to be screened and data from 3 eligible studies were extracted. CONCLUSIONS: There are currently too few studies investigating the cerebral physiologic response to aerobic exercise following concussion or mild TBI to draw definitive conclusions. Further research on this topic is necessary since understanding the cerebral physiologic response to aerobic exercise in the concussion and mild TBI populations could assist in optimizing exercise-based treatment prescription and identifying other targeted therapies.

Non-Invasive Estimation of Intracranial Pressure-Derived Cerebrovascular Reactivity Using Near-Infrared Spectroscopy Sensor Technology in Acute Neural Injury: A Time-Series Analysis.

The contemporary monitoring of cerebrovascular reactivity (CVR) relies on invasive intracranial pressure (ICP) monitoring which limits its application. Interest is shifting towards near-infrared spectroscopic regional cerebral oxygen saturation (rSO2)-based indices of CVR which are less invasive and have improved spatial resolution. This study aims to examine and model the relationship between ICP and rSO2-based indices of CVR. Through a retrospective cohort study of prospectively collected physiologic data in moderate to severe traumatic brain injury (TBI) patients, linear mixed effects modeling techniques, augmented with time-series analysis, were utilized to evaluate the ability of rSO2-based indices of CVR to model ICP-based indices. It was found that rSO2-based indices of CVR had a statistically significant linear relationship with ICP-based indices, even when the hierarchical and autocorrelative nature of the data was accounted for. This strengthens the body of literature indicating the validity of rSO2-based indices of CVR and potential greatly expands the scope of CVR monitoring.

Time-Series Modeling and Forecasting of Cerebral Pressure-Flow Physiology: A Scoping Systematic Review of the Human and Animal Literature.

The modeling and forecasting of cerebral pressure-flow dynamics in the time-frequency domain have promising implications for veterinary and human life sciences research, enhancing clinical care by predicting cerebral blood flow (CBF)/perfusion, nutrient delivery, and intracranial pressure (ICP)/compliance behavior in advance. Despite its potential, the literature lacks coherence regarding the optimal model type, structure, data streams, and performance. This systematic scoping review comprehensively examines the current landscape of cerebral physiological time-series modeling and forecasting. It focuses on temporally resolved cerebral pressure-flow and oxygen delivery data streams obtained from invasive/non-invasive cerebral sensors. A thorough search of databases identified 88 studies for evaluation, covering diverse cerebral physiologic signals from healthy volunteers, patients with various conditions, and animal subjects. Methodologies range from traditional statistical time-series analysis to innovative machine learning algorithms. A total of 30 studies in healthy cohorts and 23 studies in patient cohorts with traumatic brain injury (TBI) concentrated on modeling CBFv and predicting ICP, respectively. Animal studies exclusively analyzed CBF/CBFv. Of the 88 studies, 65 predominantly used traditional statistical time-series analysis, with transfer function analysis (TFA), wavelet analysis, and autoregressive (AR) models being prominent. Among machine learning algorithms, support vector machine (SVM) was widely utilized, and decision trees showed promise, especially in ICP prediction. Nonlinear models and multi-input models were prevalent, emphasizing the significance of multivariate modeling and forecasting. This review clarifies knowledge gaps and sets the stage for future research to advance cerebral physiologic signal analysis, benefiting neurocritical care applications.

Optimal bispectral index exists in healthy patients undergoing general anesthesia: A validation study.

PURPOSE: Continuous cerebrovascular reactivity monitoring in both neurocritical and intra-operative care has gained extensive interest in recent years, as it has documented associations with long-term outcomes (in neurocritical care populations) and cognitive outcomes (in operative cohorts). This has sparked further interest into the exploration and evaluation of methods to achieve an optimal cerebrovascular reactivity measure, where the individual patient is exposed to the lowest insult burden of impaired cerebrovascular reactivity. Recent literature has documented, in neural injury populations, the presence of a potential optimal sedation level in neurocritical care, based on the relationship between cerebrovascular reactivity and quantitative depth of sedation (using bispectral index (BIS)) - termed BISopt. The presence of this measure outside of neural injury patients has yet to be proven. METHODS: We explore the relationship between BIS and continuous cerebrovascular reactivity in two cohorts: (A) healthy population undergoing elective spinal surgery under general anesthesia, and (B) healthy volunteer cohort of awake controls. RESULTS: We demonstrate the presence of BISopt in the general anesthesia population (96% of patients), and its absence in awake controls, providing preliminary validation of its existence outside of neural injury populations. Furthermore, we found BIS to be sufficiently separate from overall systemic blood pressure, this indicates that they impact different pathophysiological phenomena to mediate cerebrovascular reactivity. CONCLUSIONS: Findings here carry implications for the adaptation of the individualized physiologic BISopt concept to non-neural injury populations, both within critical care and the operative theater. However, this work is currently exploratory, and future work is required.

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.

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.

Associations between intracranial pressure thresholds and multimodal monitoring in acute traumatic neural injury: a scoping review.

BACKGROUND: Current moderate/severe traumatic brain injury (TBI) guidelines suggest the use of an intracranial pressure (ICP) treatment threshold of 20 mmHg or 22 mmHg. Over the past decade, the use of various cerebral physiology monitoring devices has been incorporated into neurocritical care practice and termed "multimodal monitoring." Such modalities include those that monitor systemic hemodynamics, systemic and brain oxygenation, cerebral blood flow (CBF), cerebral autoregulation, electrophysiology, and cerebral metabolism. Given that the relationship between ICP and outcomes is not yet entirely understood, a comprehensive review of the literature on the associations between ICP thresholds and multimodal monitoring is still needed. METHODS: We conducted a scoping review of the literature for studies that present an objective statistical association between ICP above/below threshold and any multimodal monitoring variable. MEDLINE, BIOSIS, Cochrane library, EMBASE, Global Health, and SCOPUS were searched from inception to July 2022 for relevant articles. Full-length, peer-reviewed, original works with a sample size of ≥50 moderate-severe TBI patients were included in this study. RESULTS: A total of 13 articles were deemed eligible for final inclusion. The included articles were significantly heterogenous in terms of their designs, demographics, and results, making it difficult to draw any definitive conclusions. No literature describing the association between guideline-based ICP thresholds and measures of brain electrophysiology, cerebral metabolism, or direct metrics of CBF was found. CONCLUSION: There is currently little literature that presents objective statistical associations between ICP thresholds and multimodal monitoring physiology. However, overall, the literature indicates that having ICP above guideline based thresholds is associated with increased blood pressure, increased cardiac decoupling, reduced parenchymal brain oxygen tension, and impaired cerebral autoregulation, with no association with CBF velocity within the therapeutic range of ICP. There was insufficient literature to comment on other multimodal monitoring measures.

Current state of high-fidelity multimodal monitoring in traumatic brain injury.

INTRODUCTION: Multimodality monitoring of patients with severe traumatic brain injury (TBI) is primarily performed in neuro-critical care units to prevent secondary harmful brain insults and facilitate patient recovery. Several metrics are commonly monitored using both invasive and non-invasive techniques. The latest Brain Trauma Foundation guidelines from 2016 provide recommendations and thresholds for some of these. Still, high-level evidence for several metrics and thresholds is lacking. METHODS: Regarding invasive brain monitoring, intracranial pressure (ICP) forms the cornerstone, and pressures above 22 mmHg should be avoided. From ICP, cerebral perfusion pressure (CPP) (mean arterial pressure (MAP)-ICP) and pressure reactivity index (PRx) (a correlation between slow waves MAP and ICP as a surrogate for cerebrovascular reactivity) may be derived. In terms of regional monitoring, partial brain tissue oxygen pressure (PbtO2) is commonly used, and phase 3 studies are currently ongoing to determine its added effect to outcome together with ICP monitoring. Cerebral microdialysis (CMD) is another regional invasive modality to measure substances in the brain extracellular fluid. International consortiums have suggested thresholds and management strategies, in spite of lacking high-level evidence. Although invasive monitoring is generally safe, iatrogenic hemorrhages are reported in about 10% of cases, but these probably do not significantly affect long-term outcome. Non-invasive monitoring is relatively recent in the field of TBI care, and research is usually from single-center retrospective experiences. Near-infrared spectrometry (NIRS) measuring regional tissue saturation has been shown to be associated with outcome. Transcranial doppler (TCD) has several tentative utilities in TBI like measuring ICP and detecting vasospasm. Furthermore, serial sampling of biomarkers of brain injury in the blood can be used to detect secondary brain injury development. CONCLUSIONS: In multimodal monitoring, the most important aspect is data interpretation, which requires knowledge of each metric's strengths and limitations. Combinations of several modalities might make it possible to discern specific pathologic states suitable for treatment. However, the cost-benefit should be considered as the incremental benefit of adding several metrics has a low level of evidence, thus warranting additional research.

Association between cerebrovascular reactivity in adult traumatic brain injury and improvement in patient outcome over time: an exploratory analysis.

BACKGROUND: Impaired cerebrovascular reactivity following moderate/severe traumatic brain injury (TBI) has emerged as a key potential driver of morbidity and mortality. However, the major contributions to the literature so far have been solely focused on single point measures of long-term outcome. Therefore, it remains unknown whether cerebrovascular reactivity impairment, during the acute phase of TBI, is associated with failure to improve in outcome across time. METHODS: Cerebrovascular reactivity was measured using three intracranial pressure-based surrogate metrics. For each patient, % time spent above various literature-defined thresholds was calculated. Patients were dichotomized based on outcome transition into Improved vs Not Improved between 1 and 3 months, 3 and 6 months, and 1 and 6 months, based on the Glasgow Outcome Scale-Extended (GOSE). Univariate and multivariable logistic regression analyses were performed, adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. RESULTS: Seventy-eight patients from the Winnipeg Acute TBI Database were included in this study. On univariate logistic regression analysis, higher % time with cerebrovascular reactivity metrics above clinically defined thresholds was associated with a lack of clinical improvement between 1 and 3 months and 1 and 6 months post injury (p < 0.05). These relationships held true on multivariable logistic regression analysis. CONCLUSION: Our study demonstrates that impaired cerebrovascular reactivity, during the acute phase of TBI, is associated with failure to improve clinically over time. These preliminary findings highlight the significance that cerebrovascular reactivity monitoring carries in outcome recovery association in moderate/severe TBI.

Genetic Variation and Impact on Outcome in Traumatic Brain Injury: an Overview of Recent Discoveries.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) has a significant burden of disease worldwide and outcomes vary widely. Current prognostic tools fail to fully account for this variability despite incorporating clinical, radiographic, and biochemical data. This variance could possibly be explained by genotypic differences in the patient population. In this review, we explore single nucleotide polymorphism (SNP) TBI outcome association studies. RECENT FINDINGS: In recent years, SNP association studies in TBI have focused on global, neurocognitive/neuropsychiatric, and physiologic outcomes. While the APOE gene has been the most extensively studied, other genes associated with neural repair, cell death, the blood-brain barrier, cerebral edema, neurotransmitters, mitochondria, and inflammatory cytokines have all been examined for their association with various outcomes following TBI. The results have been mixed across studies and even within genes. SNP association studies provide insight into mechanisms by which outcomes may vary following TBI. Their individual clinical utility, however, is often limited by small sample sizes and poor reproducibility. In the future, they may serve as hypothesis generating for future therapeutic targets.

Usability of Noninvasive Counterparts of Traditional Autoregulation Indices in Traumatic Brain Injury.

The pressure reactivity index (PRx) and the pulse amplitude index (PAx) are invasively determined parameters that are commonly used to describe autoregulation following traumatic brain injury (TBI). Using a transcranial Doppler ultrasound (TCD) technique, it is possible to approximate cerebral arterial blood volume (CaBV) solely from cerebral blood flow velocities, and further, to calculate non-invasive markers of autoregulation. In this brief study, we aimed to investigate whether the estimation of relative CaBV with different models could describe the cerebrovascular reactivity of TBI patients. PRx, PAx and their non-invasive counterparts (nPRx and nPAx) were calculated retrospectively from data collected during the monitoring of TBI patients. CaBV, an essential parameter for the calculation of nPRx and nPAx, was determined with both a continuous flow forward (CFF) model-considering a non-pulsatile blood outflow from the brain-and a pulsatile flow forward (PFF) model, presuming a pulsatile outflow. We found that the estimated CaBV demonstrates good coherence with ICP and that nPRx and nPAx can describe cerebrovascular reactivity similarly to PRx and PAx. Continuous monitoring with TCD is difficult, so the usability of PRx and PAx is limited. However, they might become useful for clinicians in the near future owing to rapid advances in these technologies.

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.

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.

Cerebrovascular Consequences of Elevated Intracranial Pressure After Traumatic Brain Injury.

We compared various descriptors of cerebral hemodynamics in 517 patients with traumatic brain injury (TBI) who had, on average, elevated (>23 mmHg) or normal (<15 mmHg) intracranial pressure (ICP). In a subsample of 193 of those patients, transcranial Doppler ultrasound (TCD) recordings were made. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), cerebral autoregulation indices based on TCD (the mean flow index (Mx; the coefficient of correlation between the the cerebral perfusion pressure CPP and flow velocity) and the autoregulation index (ARI)), and the pressure reactivity index (PRx) were compared between groups. We also analyzed the TCD-based cerebral blood flow (CBF) index (diastolic CBFV/mean CBFV), the spectral pulsatility index (sPI), and the critical closing pressure (CrCP). Finally, we also looked at brain tissue oxygenation (cerebral oxygen partial tension (PbtO2)) in 109 patients. The mean cerebral perfusion pressure (CPP) was lower in the group with elevated ICP (p < 0.01), despite a higher mean arterial pressure (MAP) (p < 0.005) and worse autoregulation (as assessed with the Mx, ARI, and PRx indices), greater CrCP, a lower CBF index, and a higher sPI (all with p values of <0.001). Neither the mean CBFV nor PbtO2 reached significant differences between groups. Mortality in the group with elevated ICP was almost three times greater than that in the group with normal ICP (45% versus 17%). Elevated ICP affects cerebral autoregulation. When autoregulation is not working properly, the brain is exposed to ischemic insults whenever CPP falls.

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.

Methodological Consideration on Monitoring Refractory Intracranial Hypertension and Autonomic Nervous System Activity.

Refractory intracranial hypertension (RIH) refers to a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment and leads to patient death. Detrimental sequelae of raised ICP in acute brain injury (ABI) are unclear because the underlying physiopathological mechanisms of raised ICP have not been sufficiently investigated. Recent reports have shown that autonomic activity is altered during changes in ICP. The aim of our study was to evaluate the feasibility of assessing autonomic activity during RIH with our adopted methodology. We selected 24 ABI patients for retrospective review who developed RIH. They were monitored based on ICP, arterial blood pressure, and electrocardiogram using ICM+ software. Secondary parameters reflecting autonomic activity were computed in time and frequency domains through the continuous measurement of heart rate variability and baroreflex sensitivity. The results of the analysis will be presented later in a full paper. This preliminary analysis shows the feasibility of the adopted methodology.

Lower Limit of Reactivity Assessed with PRx in an Experimental Setting.

In traumatic brain injury, longer time spent with a cerebral perfusion pressure (CPP) below the pressure reactivity index (PRx)-derived lower limit of reactivity (LLR) has been shown to be statistically associated with higher mortality. We set out to scrutinise the behaviour of LLR and the methods of its estimation in individual cases by performing retrospective analysis of intracranial pressure (ICP), arterial blood pressure (ABP) and laser Doppler flow (LDF) signals recorded in nine piglets undergoing controlled, terminal hypotension. We focused on the sections of the recordings with stable experimental conditions where a clear breakpoint of LDF/CPP characteristic (LLA) could be identified.In eight of the nine experiments, when CPP underwent a monotonous decrease, the relationship PRx/CPP showed two breakpoints (1 - when PRx starts to rise; 2 - when PRx saturates at PRx > 0.3), with LDF-based LLA sitting between them. LLR (CPP at PRx reaching 0.3 in the error bar chart) was close to the lower LLR breakpoint.In conclusion, when CPP has a monotonous decrease, PRx starts worsening before CPP crosses the LLA. A further decrease in CPP below LLA would cause a decrease in CBF, even if the pressure reactivity is not completely lost. This pattern should be taken into account when PRx is used to detect LLA continuously.

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.

The Limited Impact of Current Therapeutic Interventions on Cerebrovascular Reactivity in Traumatic Brain Injury: A Narrative Overview.

Current intensive care unit (ICU) treatment strategies for traumatic brain injury (TBI) care focus on intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-directed therapeutics, dictated by guidelines. Impaired cerebrovascular reactivity in moderate/severe TBI is emerging as a major associate with poor outcome and appears to dominate the landscape of physiologic derangement over the course of a patient's ICU stay. Within this article, we review the literature on the known drivers of impaired cerebrovascular reactivity in adult TBI, highlight the current knowledge surrounding the impact of guideline treatment strategies on continuously monitored cerebrovascular reactivity, and discuss current treatment paradigms for impaired reactivity. Finally, we touch on the areas of future research, as we strive to develop specific therapeutics for impaired cerebrovascular reactivity in TBI. There exists limited literature to suggest advanced age, intracranial injury patterns of diffuse injury, and sustained ICP elevations may drive impaired cerebrovascular reactivity. To date, the literature suggests there is a limited impact of such ICP/CPP guideline-based therapies on cerebrovascular reactivity, with large portions of a given patients ICU period spent with impaired cerebrovascular reactivity. Emerging treatment paradigms focus on the targeting individualized CPP and ICP thresholds based on cerebrovascular reactivity, without directly targeting the pathways involved in its dysfunction. Further work involved in uncovering the molecular pathways involved in impaired cerebrovascular reactivity is required, so that we can develop therapeutics directed at its prevention and treatment.