Abstract Background and aims Stroke is a global health concern, requiring early and accurate diagnosis for effective treatment. Differentiating between ischemic stroke and hemorrhagic stroke is critical, as treatment strategies differ significantly. While neuroimaging is the gold standard for differential diagnosis of stroke code patients, blood biomarkers could be a promising and cost-effective diagnostic method for earlier diagnosis in the prehospital setting, where neuroimaging is unavailable. Studies demonstrate that the biomarker glial fibrillary acidic protein (GFAP) can distinguish ischemic and hemorrhagic stroke with high specificity, though sensitivity varies based on sampling timing and assay methodology. This narrative review explores the potential of GFAP as a diagnostic biomarkern severe strokes, and in identifying large vessel occlusions (LVOs). Methods We performed a narrative review by searching electronic databases, such as PubMed and Google Scholar, to identify relevant articles published up to July 2025. The search used combinations of the keywords “glial fibrillary acidic protein”, “stroke”, “blood biomarker”, and “diagnosis”. Articles were screened for relevance based on title and abstract, followed by full-text review. Results While studies suggest a correlation between higher GFAP levels and stroke severity in hemorrhagic stroke, evidence for this in ischemic stroke is inconclusive. Combining GFAP with clinical stroke scales and additional biomarkers has shown promise in identifying LVO. Conclusions Future research should focus on refining the diagnostic role of GFAP in severe strokes, optimizing sample timing, and including large cohorts representing the full spectrum of stroke severities. Conflict of interest Megan Gjordeni: nothing to disclose. Jakob Pansell: nothing to disclose. Eric P. Thelin: nothing to disclose. Michael V. Mazya: nothing to disclose. Kaveh Pourhamidi: nothing to disclose. Perttu J. Lindsberg: nothing to disclose. Olli S. Mattila: nothing to disclose. Charith Cooray: nothing to disclose.

BACKGROUND AND OBJECTIVES: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions. However, current evidence on postoperative outcomes exhibits variability due to small sample sizes, nonstandardized outcome assessment, and variations in surgical techniques. The aim of this study was to overcome these limitations by assessing standardized outcome measures after surgical intervention for CSDH at a high-volume population-based center favoring a uniform burr-hole craniotomy (BHC) approach. METHODS: Adult patients (≥15 years) who underwent surgical treatment of a CSDH at the Karolinska University Hospital from 2006 to 2022 were retrospectively included. Outcome measures included 6-month ipsilateral hematoma reoperation, postoperative complications categorized by the Landriel-Ibanez grading system, neurological function, and mortality. Predictors of outcomes were assessed using multivariable logistic regression models. RESULTS: In total, 2655 patients were included, with 2407 evacuated using BHC and 248 requiring a minicraniotomy. Reoperation for a hematoma recurrence occurred in 11%. Independent predictors of reoperation were male sex, diabetes, preoperative antithrombotic therapy, midline shift, and bilateral surgery. Postoperative complications occurred in 11% of cases, with 3.9% classified as moderate to severe. A complication leading to death was reported in 22 patients (0.8%). The most common postoperative complications were urinary tract infections (1.5%), subdural empyema (1.4%), and seizures (0.7%). Independent predictors of moderate-to-severe complications were higher preoperative Charlson Comorbidity Index and lower Glasgow Coma Scale score. The 1-year postoperative mortality rate was 12%. CONCLUSION: This study provided standardized outcome measures in a large cohort of patients treated for CSDH at a center where BHC was consistently used. Most postoperative complications were mild and either did not require intervention or were managed with pharmacological treatment. The identified predictors of CSDH reoperation and moderate-to-severe postoperative complications offer considerations for clinical management and patient care.

Disturbed cerebral autoregulation (represented by a positive pressure reactivity index [PRx]), elevated intracranial pressure (ICP), and decreased cerebral perfusion pressure (CPP) are key treatment targets following severe traumatic brain injury (sTBI). This study investigated neuroinflammation as a potential mechanism underlying these intracranial disturbances. Plasma samples from 11 sTBI patients (from a prior Phase II drug trial) were analyzed for 174 proteins using an antibody-based suspension bead array, with intervention effects accounted for where possible. Dimensionality reduction techniques, including principal component analysis (PCA) and supervised methods, were applied to protein data, informed by physiological variables (ICP, CPP, and PRx). PCA revealed distinct protein clustering patterns related to ICP >20 mmHg and PRx > 0, with PC1 linked to patient ID, time from injury, and intervention, and PC2/PC3 significantly associated with PRx dose (p < 0.001). Markers relating to inflammation of the vascular system comprised 20% of the top 50 proteins influencing PC2, implicating complement inflammation in these processes. Notably, MASP-2 (p = 0.027) and complement factor I (p = 0.039) were significantly associated with PRx dose in a mixed-effects model. These findings suggest that vascular inflammation, particularly complement activation, may contribute to intracranial physiological disturbances in sTBI, highlighting the complement pathway as a potential target for further investigation.

Coagulopathy following traumatic brain injury (TBI) is increasingly being recognized as a determinant of hematoma expansion and outcome. Unlike systemic trauma, where coagulopathy is often driven by hemorrhagic shock, TBI appears to induce a unique brain-derived hemostatic response. In this review, we discuss the mechanisms underlying TBI-induced coagulopathy, its diagnostic challenges, and association with hematoma expansion. We further evaluate evidence from randomized trials targeting coagulopathy in TBI, including interventions such as tranexamic acid, plasma, recombinant Factor VIIa, and fibrinogen. While several studies show proof of concept, clinical benefit remains inconsistent, likely due to issues of timing, heterogeneity, and underpowered study design. Moving forward, ultra-early and individualized approaches guided by real-time hemostatic monitoring may offer the most promising path. A better understanding of the temporal and mechanistic dynamics of coagulopathy will be essential for improving treatment strategies and patient outcomes.

Mild traumatic brain injury (mTBI) is a common cause of emergency department visits. Only a small percentage of mTBI patients develop an intracranial lesion (ICL) and even fewer will require neurosurgical intervention due to their injury. The Stockholm Score of Lesion Detection on Computed Tomography following Mild Traumatic Brain Injury (SELECT-TBI) study aims to provide a data-driven approach to estimate individualized risk for traumatic ICL and clinically significant lesions in mTBI patients. To provide a statistical analysis plan and pilot data analysis before completion of data collection, as pre-planned in the published study protocol. Retrospective study of patients ≥ 15 years old who underwent a computed tomography (CT) scan for their mTBI in Stockholm, Sweden, between 2015–2020. Up to 73 variables were collected for each patient. Data analysis of the first 5 000 patients in the cohort was conducted to develop preliminary prediction models using Lasso regression, general linear model and random forest and to perform an optimal population analysis to determine whether the final sample size would be sufficient. Six data selection strategies were tested, and area under the curve (AUC) receiver operator characteristic (ROC) curves were generated with a 4:1 training/validation data segmentation. The best-performing model was the Lasso regression model which achieved an AUC of 0.807 for any ICL and 0.903 for clinically significant ICL (accuracy of 70

Therapeutic management during the acute phase of traumatic brain injury (TBI) relies on continuous multimodal cerebral physiologic monitoring to detect and prevent secondary injury. These high-resolution data streams come from various invasive/non-invasive sensor technologies and challenge clinicians, as they are difficult to integrate into management algorithms and prognostic models. Data reduction techniques, like moving average filters, simplify data but may fail to address statistical autocorrelation and could introduce new properties, affecting model utility and interpretation. This study uses the CAnadian High-Resolution TBI (CAHR-TBI) dataset to examine the impact of temporal resolution changes (1 min to 24 h) on autoregressive integrated moving average (ARIMA) modeling for raw and derived cerebral physiologic signals. Stationarity tests indicated that the majority of the signals required first-order differencing to address persistent trends. A grid search identified optimal ARIMA parameters (p,d,q) for each signal and resolution. Subgroup analyses revealed population-specific differences in temporal structure, and small-scale forecasting using optimal parameters confirmed model adequacy. Variations in optimal structures across signals and patients highlight the importance of tailoring ARIMA models for precise interpretation and performance. Findings show that both raw and derived indices exhibit intrinsic ARIMA components regardless of resolution. Ignoring these features risks compromising the significance of models developed from such data. This underscores the need for careful resolution considerations in temporal modeling for TBI care.

BACKGROUND:The cerebral compliance (or compensatory reserve) index, RAP, is a critical yet underutilized physiological marker in the management of moderate-to-severe traumatic brain injury (TBI). While RAP offers promise as a continuous bedside metric, its broader cerebral physiological context remains partly understood. This study aims to characterize the burden of impaired RAP in relation to other key components of cerebral physiology. METHODS:Archived data from 379 moderate-to-severe TBI patients were analyzed using descriptive and threshold-based methods across three RAP states (impaired, intact/transitional, and exhausted). Agglomerative hierarchical clustering, principal component analysis, and kernel-based clustering were applied to explore multivariate covariance structures. Then, high-frequency temporal analyses, including vector autoregressive integrated moving average impulse response functions (VARIMA IRF), cross-correlation, and Granger causality, were performed to assess dynamic coupling between RAP and other physiological signals. RESULTS:Impaired and exhausted RAP states were associated with elevated intracranial pressure (p = 0.021). Regarding AMP, impaired RAP was associated with elevated levels, while exhausted RAP was associated with reduced pulse amplitude (p = 3.94 × 10-9). These two RAP states were also associated with compromised autoregulation and diminished perfusion. Clustering analyses consistently grouped RAP with its constituent signals (ICP and AMP), followed by brain oxygenation parameters (brain tissue oxygenation (PbtO2) and regional cerebral oxygen saturation (rSO2)). Cerebral autoregulation (CA) indices clustered more closely with RAP under impaired autoregulatory states. Temporal analyses revealed that RAP exhibited comparatively stronger responses to ICP and arterial blood pressure (ABP) at 1-min resolution. Moreover, when comparing ICP-derived and near-infrared spectroscopy (NIRS)-derived CA indices, they clustered more closely to RAP, and RAP demonstrated greater sensitivity to changes in these ICP-derived CA indices in high-frequency temporal analyses. These trends remained consistent at lower temporal resolutions as well. CONCLUSION:RAP relationships with other parameters remain consistent and differ meaningfully across compliance states. Integrating RAP into patient trajectory modelling and developing predictive frameworks based on these findings across different RAP states can map the evolution of cerebral physiology over time. This approach may improve prognostication and guide individualized interventions in TBI management. Therefore, these findings support RAP's potential as a valuable metric for bedside monitoring and its prospective role in guiding patient trajectory modeling and interventional studies in TBI.

Overstimulation of the autonomic nervous system (ANS) in the acute phase after traumatic brain injury (TBI) may lead to paroxysmal sympathetic hyperactivity (PSH) syndrome. This study aimed to investigate the impact of the relationship between ANS activity and cerebral hemodynamics on the development of PSH syndrome. This retrospective study included 41 TBI patients admitted to Wroclaw University Hospital (Poland). Among them, 14 were classified as at risk for PSH based on the probabilistic Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM), with 10 rated as ‘possible’ and 4 as ‘probable’. High-resolution neuromonitoring data from the first 72 h post-injury included intracranial pressure (ICP), pressure reactivity index (PRx), baroreflex sensitivity (BRS), arterial blood pressure (ABP), and heart rate (HR). The correlation between ANS activity and cerebral hemodynamics was quantified using the mean, standard deviation, and zero-crossing rate (ZCR) across sliding windows of 3, 6, 12, and 24 h. Logistic regression was used to model PSH risk. The PSH risk model, including ZCR-based variability of ANS-cerebral hemodynamic correlations within a 3-h sliding window and adjusted by clinical metadata, achieved the highest performance (AUC 0.72 ± 0.27), outperforming the clinical metadata-only model (AUC 0.64 ± 0.18). Aggregated feature importance values indicated that the most predictive relationships were observed between HR–ICP and HR–PRx. Including the early post-injury interactions between ANS and cerebral hemodynamics in the clinical characteristics-based PSH risk model may improve its performance. Further studies in larger cohorts are necessary to validate these findings.

Abstract Purpose This study aimed to investigate whether incorporating pre-injury health status, measured by the American Society of Anesthesiologists (ASA) score, improves outcome prediction models for moderate-to-severe traumatic brain injury (msTBI) patients. Methods We conducted a retrospective single-center study of msTBI patients (2005–2021). The primary outcome was 1-year Glasgow Outcome Scale (GOS, dichotomized as GOS1-3 (unfavorable) vs. 4–5 (favorable)), and secondary outcome was 90-day mortality. Logistic regression evaluated the contribution of ASA score to the International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) core + CT outcome prediction model incorporating age, admission GCS, pupillary reactivity, Marshall CT classification, hypoxia, hypotension, epidural hematoma, and subarachnoid hemorrhage. Results Among the 720 adult patients that were included 51% had an unfavorable GOS at 1 year. The 90-day mortality was 19%. ASA score and TRISS were independently associated with both outcomes (p < 0.001). Incorporating the ASA score to our IMPACT model significantly enhanced its explanatory value of dichotomized GOS (35% vs. 32% variance explained, p < 0.001) and improved the model’s prognostic accuracy. Conclusion In this retrospective single-center cohort study, we found that ASA score improves existing prognostic models for msTBI. Incorporating this simple comorbidity measure could enhance outcome prediction and support more personalized acute management. Future prospective studies are needed to validate these results.

It has been demonstrated that patient-specific intracranial pressure (ICP) thresholds are possible to derive using the function intersectionality between ICP and cerebrovascular reactivity (CVR). Such individualized ICP (iICP) thresholds represent a potential personalized medicine approach to neurocritical care management. However, it is currently unknown how various CVR thresholds compare in regard to deriving iICP. Here we attempt to identify the CVR thresholds that are best suited for iICP derivation. Leveraging 365 patient data sets from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative, iICP was derived using three ICP-based CVR indices: the pressure reactivity index (PRx); the pulse amplitude index (PAx); and the RAC index, and thresholds ranging from − 1 to + 1, in 0.05 increments. Patients were dichotomized based on 6-month outcome scores into Alive vs. Dead and Favorable vs. Unfavorable outcome. 2 × 2 tables were created for each threshold, grouping patients by outcome and whether their mean ICP was greater or less than their calculated iICP. Chi-squares were calculated for each table and subsequently plotted. The thresholds that produced the largest Chi-square values were identified as those able to derive the iICP with the greatest ability to predict outcomes. Next, Spearman rank correlation testing was used to evaluate associations between iICP, for each threshold, and measures of cerebral physiologic insult burden. With consideration of yield data, ability to predict outcome, and association with cerebral physiologic insult burden, a threshold of + 0.05 was identified for PRx. No optimal threshold could be identified for PAx or RAC.

Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6-12 months post-injury, dichotomized into unfavorable (GOS <= 3) or favorable (GOS >= 4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1-8.3 mL) and 100% (IQR 10-530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p = 0.003). For dichotomized CE, absolute cutoffs of 1-10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.

Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which is commonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.

Accurate measurement of traumatic intracranial hematoma volume is important for assessing disease progression and prognosis, as well as for serving as an important end-point in clinical trials aimed at preventing hematoma expansion. While the ABC/2 formula has traditionally been used for volume estimation in spontaneous intracerebral hemorrhage, its adaptation to traumatic hematomas lacks validation. This study aimed to compare the accuracy of ABC/2 with computer-assisted volumetric analysis (CAVA) in estimating the volumes of traumatic intracranial hematomas. We performed a dual-center observational study that included adult patients with moderate-to-severe traumatic brain injury. Volumes of intracerebral, subdural (SDHs), and epidural hematomas from admission computed tomography scans were measured using ABC/2 and CAVA, and compared using the Wilcoxon signed-rank test, Spearman's rank correlation, Lin's concordance correlation coefficient (CCC), and Bland-Altman plots. Prognostic significance for outcomes was evaluated through logistic and linear regression models. In total, 1,179 patients with 1,543 hematomas were included. Despite a high correlation (Spearman coefficients between 0.95 and 0.98) and excellent concordance (Lin's CCC from 0.89 to 0.96) between ABC/2 and CAVA, ABC/2 overestimated hematoma volumes compared with CAVA, in some instances exceeding 50 ml. Bland-Altman analysis highlighted wide limits of agreement, especially in SDH. While both methods demonstrated comparable accuracy in predicting outcomes, CAVA was slightly better at predicting craniotomies and midline shift. We conclude that while ABC/2 provides a generally reliable volumetric assessment suitable for descriptive purposes and as baseline variables in studies, CAVA should be the gold standard in clinical situations and studies requiring more precise volume estimations, such as those using hematoma expansion as an outcome.

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol-1sec-1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism-the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

Adult neural stem cells (NSC) are a potential source for the regeneration of damaged tissue during neuropathological conditions, but much remains unexplored. In an attempt to study the influence of neuroinflammation on NSCs, we generated a transgenic reporter rat strain that expresses the Discosoma sp . red (DsRed) fluorophore in NSCs and subjected it to traumatic brain injury (TBI). Transcriptomic analysis of NSCs isolated from TBI revealed an enrichment of stress response genes that pertained to endoplasmic reticulum (ER) stress and integrated stress response (ISR). Downstream analysis on NSC cultures pinpointed IL-1α as a trigger of ISR in these cells. At concentration levels similar to the ones measured post-TBI in rats, IL-1α induced the translation of activating transcription factor 4 (ATF4), an ISR master regulator. Further, ATF4 was necessary for the IL-1α -dependent induction of a senescent profile in NSCs, which included a metabolic shift towards glycolysis, induction of senescence-associated secretory phenotype, SASP, and cell cycle arrest. In summary, the ISR/ATF4 pathway seems to play a major role in NSC function during neuroinflammation and provides a therapeutic tool for protecting the NSC pool during these conditions.### Competing Interest StatementL.B. has received travel grants and lecture fees from Sanofi/ Genzyme, Biogen, Amirall, and MedDay. L.B. has participated in advisory boards for Genzyme, Sanofi, Biogen, Amirall and Merck. The other authors declare no conflict of interest.

Abstract Background Mild traumatic brain injury (mTBI), i.e. a TBI with an admission Glasgow Coma Scale (GCS) of 13–15, is a common cause of emergency department visits. Only a small fraction of these patients will develop a traumatic intracranial hemorrhage (tICH) with an even smaller subgroup suffering from severe outcomes. Limitations in existing management guidelines lead to overuse of computed tomography (CT) for emergency department (ED) diagnosis of tICH which may result in patient harm and higher healthcare costs. Objective To perform a systematic review and meta-analysis to characterize known and potential novel risk factors that impact the risk of tICH in patients with mTBI to provide a foundation for improving existing ED guidelines. Methods The literature was searched using MEDLINE, EMBASE and Web of Science databases. Reference lists of major literature was cross-checked. The outcome variable was tICH on CT. Odds ratios (OR) were pooled for independent risk factors. Results After completion of screening, 17 papers were selected for inclusion, with a pooled patient population of 26,040 where 2,054 cases of tICH were verified through CT (7.9%). Signs of a skull base fracture (OR 11.71, 95% CI 5.51–24.86), GCS < 15 (OR 4.69, 95% CI 2.76–7.98), loss of consciousness (OR 2.57, 95% CI 1.83–3.61), post-traumatic amnesia (OR 2.13, 95% CI 1.27–3.57), post-traumatic vomiting (OR 2.04, 95% CI 1.11–3.76), antiplatelet therapy (OR 1.54, 95% CI 1.10–2.15) and male sex (OR 1.28, 95% CI 1.11–1.49) were determined in the data synthesis to be statistically significant predictors of tICH. Conclusion Our meta-analysis provides additional context to predictors associated with high and low risk for tICH in mTBI. In contrast to signs of a skull base fracture and reduction in GCS, some elements used in ED guidelines such as anticoagulant use, headache and intoxication were not predictive of tICH. Even though there were multiple sources of heterogeneity across studies, these findings suggest that there is potential for improvement over existing guidelines as well as a the need for better prospective trials with consideration for common data elements in this area. PROSPERO registration number CRD42023392495.

Background Over the recent decades, continuous multi-modal monitoring of cerebral physiology has gained increasing interest for its potential to help minimize secondary brain injury following moderate-to-severe acute traumatic neural injury (also termed traumatic brain injury; TBI). Despite this heightened interest, there has yet to be a comprehensive evaluation of the effects of derangements in multimodal cerebral physiology on global cerebral physiologic insult burden. In this study, we offer a multi-center descriptive analysis of the associations between deranged cerebral physiology and cerebral physiologic insult burden. Methods Using data from the Canadian High-Resolution TBI (CAHR-TBI) Research Collaborative, a total of 369 complete patient datasets were acquired for the purposes of this study. For various cerebral physiologic metrics, patients were trichotomized into low, intermediate, and high cohorts based on mean values. Jonckheere-Terpstra testing was then used to assess for directional relationships between these cerebral physiologic metrics and various measures of cerebral physiologic insult burden. Contour plots were then created to illustrate the impact of preserved vs impaired cerebrovascular reactivity on these relationships. Results It was found that elevated intracranial pressure (ICP) was associated with more time spent with cerebral perfusion pressure (CPP) < 60 mmHg and more time with impaired cerebrovascular reactivity. Low CPP was associated with more time spent with ICP > 20 or 22 mmHg and more time spent with impaired cerebrovascular reactivity. Elevated cerebrovascular reactivity indices were associated with more time spent with CPP < 60 mmHg as well as ICP > 20 or 22 mmHg. Low brain tissue oxygenation (PbtO(2)) only demonstrated a significant association with more time spent with CPP < 60 mmHg. Low regional oxygen saturation (rSO(2)) failed to produce a statistically significant association with any particular measure of cerebral physiologic insult burden. Conclusions Mean ICP, CPP and, cerebrovascular reactivity values demonstrate statistically significant associations with global cerebral physiologic insult burden; however, it is uncertain whether measures of oxygen delivery provide any significant insight into such insult burden.

INTRODUCTION: Dysfunctional cerebrovascular reactivity (CVR)/autoregulation contributes to secondary injury following traumatic brain injury (TBI). Currently, monitoring of CVR relies on intracranial pressure (ICP) monitoring and has known thresholds at which outcomes worsen. Interest has shifted to less invasive near infrared spectroscopic (NIRS) regional cerebral oxygen saturation (rSO2) based measures of CVR. However, threshold levels at which outcomes worsen have not yet been determined for these indices. METHODS: A retrospective multi-institutional cohort study utilizing the CAnadian High Resolution TBI (CAHR-TBI) Research Collaborative database was performed. The cohort included TBI patients with ICP, arterial blood pressure (ABP), and rSO2 monitoring treated in adult intensive care units (ICU). COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and ABP) were calculated for each subject as the rSO2 based indices of CVR. 2 x 2 tables were created grouping patients by alive/dead and favorable/unfavorable outcomes at various thresholds of COx and COx_a as well as rSO2 itself. Chi-square values were calculated and the threshold producing the highest value was identified as providing the best discriminative value. RESULTS: A total of 129 patients were included. For both COx and COx_a an optimal threshold value of 0.2 was identified for both survival (χ 2 = 9.57, p = 0.0020; χ 2 = 13.04, p = 0.0003 respectively) and favorable outcomes (χ 2 = 5.98, p = 0.0145; χ 2 = 8.94, p = 0.0028 respectively) with values above this associated with worse outcomes. Notably, there was no identifiable threshold for raw rSO2 values at which outcomes were identified to worsen. CONCLUSIONS: In this multi-institutional cohort study, COx and COx_a were found to have a uniform threshold of 0.2, above which clinical outcomes worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

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.