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.

Cerebral physiologic insult burden in acute traumatic neural injury: a Canadian High Resolution-TBI (CAHR-TBI) descriptive analysis.

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 (PbtO2) only demonstrated a significant association with more time spent with CPP < 60 mmHg. Low regional oxygen saturation (rSO2) 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.

Critical thresholds of long-pressure reactivity index and impact of intracranial pressure monitoring methods in traumatic brain injury.

BACKGROUND: Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30%, resulting in acquired life-long disabilities in many survivors. To potentially improve outcomes in this TBI population, the management of secondary injuries, particularly the failure of cerebrovascular reactivity (assessed via the pressure reactivity index; PRx, a correlation between intracranial pressure (ICP) and mean arterial blood pressure (MAP)), has gained interest in the field. However, derivation of PRx requires high-resolution data and expensive technological solutions, as calculations use a short time-window, which has resulted in it being used in only a handful of centers worldwide. As a solution to this, low resolution (longer time-windows) PRx has been suggested, known as Long-PRx or LPRx. Though LPRx has been proposed little is known about the best methodology to derive this measure, with different thresholds and time-windows proposed. Furthermore, the impact of ICP monitoring on cerebrovascular reactivity measures is poorly understood. Hence, this observational study establishes critical thresholds of LPRx associated with long-term functional outcome, comparing different time-windows for calculating LPRx as well as evaluating LPRx determined through external ventricular drains (EVD) vs intraparenchymal pressure device (IPD) ICP monitoring. METHODS: The study included a total of n = 435 TBI patients from the Karolinska University Hospital. Patients were dichotomized into alive vs. dead and favorable vs. unfavorable outcomes based on 1-year Glasgow Outcome Scale (GOS). Pearson's chi-square values were computed for incrementally increasing LPRx or ICP thresholds against outcome. The thresholds that generated the greatest chi-squared value for each LPRx or ICP parameter had the highest outcome discriminatory capacity. This methodology was also completed for the segmentation of the population based on EVD, IPD, and time of data recorded in hospital stay. RESULTS: LPRx calculated with 10-120-min windows behaved similarly, with maximal chi-square values ranging at around a LPRx of 0.25-0.35, for both survival and favorable outcome. When investigating the temporal relations of LPRx derived thresholds, the first 4 days appeared to be the most associated with outcomes. The segmentation of the data based on intracranial monitoring found limited differences between EVD and IPD, with similar LPRx values around 0.3. CONCLUSION: Our work suggests that the underlying prognostic factors causing impairment in cerebrovascular reactivity can, to some degree, be detected using lower resolution PRx metrics (similar found thresholding values) with LPRx found clinically using as low as 10 min-by-minute samples of MAP and ICP. Furthermore, EVD derived LPRx with intermittent cerebrospinal fluid draining, seems to present similar outcome capacity as IPD. This low-resolution low sample LPRx method appears to be an adequate substitute for the clinical prognostic value of PRx and may be implemented independent of ICP monitoring method when PRx is not feasible, though further research is warranted.

ASA-score is associated with 90-day mortality after complicated mild traumatic brain injury - a retrospective cohort study.

PURPOSE: This study explores the association of the American Society of Anesthesiologists (ASA) score with 90-day mortality in complicated mild traumatic brain injury (mTBI) patients, and in trauma patients without a TBI. METHODS: This retrospective study was conducted using a cohort of trauma patients treated at a level III trauma center in Stockholm, Sweden from January to December 2019. The primary endpoint was 90-day mortality. The population was identified using the Swedish Trauma registry. The Trauma and Injury Severity Score (TRISS) was used to estimate the likelihood of survival. Trauma patients without TBI (NTBI) were used for comparison. Data analysis was conducted using R software, and statistical analysis included univariate and multivariate logistic regression. RESULTS: A total of 244 TBI patients and 579 NTBI patients were included, with a 90-day mortality of 8.2% (n = 20) and 5.4% (n = 21), respectively. Deceased patients in both cohorts were generally older, with greater comorbidities and higher injury severity. Complicated mTBI constituted 97.5% of the TBI group. Age and an ASA score of 3 or higher were independently associated with increased mortality risk in the TBI group, with odds ratios of 1.04 (95% 1.00-1.09) and 3.44 (95% CI 1.10-13.41), respectively. Among NTBI patients, only age remained a significant mortality predictor. TRISS demonstrated limited predictive utility across both cohorts, yet a significant discrepancy was observed between the outcome groups within the NTBI cohort. CONCLUSION: This retrospective cohort study highlights a significant association between ASA score and 90-day mortality in elderly patients with complicated mTBI, something that could not be observed in comparative NTBI cohort. These findings suggest the benefit of incorporating ASA score into prognostic models to enhance the accuracy of outcome prediction models in these populations, though further research is warranted.

Trial of Dexamethasone for Chronic Subdural Hematoma.

BACKGROUND: Chronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied. METHODS: We conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death). RESULTS: From August 2015 through November 2019, a total of 748 patients were included in the trial after randomization - 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, -6.4 percentage points [95% confidence interval, -11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group. CONCLUSIONS: Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.).

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.

Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study.

AIM: Perinatal asphyxia, resulting in hypoxic-ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long-term outcomes. METHODS: We prospectively enrolled 18-term born infants with HIE and 10-term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain-derived and inflammation associated proteins in their CSF. RESULTS: Increased CSF concentrations of several brain-specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha-II spectrin. The functional proteins included energy-related proteins like neuron-specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE. CONCLUSION: Brain-specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia.

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.

Cellular infiltration in traumatic brain injury.

Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site-segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points.

Alternative continuous intracranial pressure-derived cerebrovascular reactivity metrics in traumatic brain injury: a scoping overview.

BACKGROUND: Pressure reactivity index (PRx) has emerged as a means to continuously monitor cerebrovascular reactivity in traumatic brain injury (TBI). However, other intracranial pressure (ICP)-based continuous metrics exist, and may have advantages over PRx. The goal of this study was to perform a scoping overview of the literature on non-PRx ICP-based continuous cerebrovascular reactivity metrics in adult TBI. METHODS: We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019. Using a two-stage filtering of title/abstract, and then full manuscript, we identified pertinent articles. Data was abstracted to tables and each technique summarized, including pulse amplitude index (PAx), correlation between pulse amplitude of ICP and cerebral perfusion pressure (RAC), PRx55-15, and low-resolution metrics LAx and L-PRx. RESULTS: A total of 23 articles met the inclusion criteria, with the vast majority being retrospective in nature and based out of European centers. Sixteen articles focused on high-resolution metrics PAx, RAC, and PRx55-15, with 6 articles focusing on LAx and L-PRx. PAx may have a role in low ICP situations, where it appears to perform superior to PRx. RAC displays similar behavior to PRx, with a trend to stronger associations with favorable/unfavorable outcome at 6 months, and stronger parabolic relationship with CPP. PRx55-15 provides a focused assessment on the vasogenic frequency range associated with cerebral autoregulation, with preliminary data supporting a strong association with outcome in TBI. LAx and L-PRx display varying associations with 6-month outcome in TBI, depending on the window length of calculation, with shorter windows demonstrating stronger correlations with classical PRx. CONCLUSIONS: Non-PRx continuous ICP-based cerebrovascular reactivity metrics can be split into high-resolution and low-resolution measures. High-resolution indices include PAx, RAC, and PRx55-15, while low-resolution indices include L-PRx and LAx. The true role for these metrics beyond classic PRx remains unclear. Each displays situations where it may prove superior over PRx, given limitations with this currently widely accepted measure. Much future investigation into each of these alternative metrics is required prior to adoption into the clinical monitoring armamentarium in adult TBI.

Comparison of high versus low frequency cerebral physiology for cerebrovascular reactivity assessment in traumatic brain injury: a multi-center pilot study.

Current accepted cerebrovascular reactivity indices suffer from the need of high frequency data capture and export for post-acquisition processing. The role for minute-by-minute data in cerebrovascular reactivity monitoring remains uncertain. The goal was to explore the statistical time-series relationships between intra-cranial pressure (ICP), mean arterial pressure (MAP) and pressure reactivity index (PRx) using both 10-s and minute data update frequency in TBI. Prospective data from 31 patients from 3 centers with moderate/severe TBI and high-frequency archived physiology were reviewed. Both 10-s by 10-s and minute-by-minute mean values were derived for ICP and MAP for each patient. Similarly, PRx was derived using 30 consecutive 10-s data points, updated every minute. While long-PRx (L-PRx) was derived via similar methodology using minute-by-minute data, with L-PRx derived using various window lengths (5, 10, 20, 30, 40, and 60 min; denoted L-PRx_5, etc.). Time-series autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) models were created to analyze the relationship of these parameters over time. ARIMA modelling, Granger causality testing and VARIMA impulse response function (IRF) plotting demonstrated that similar information is carried in minute mean ICP and MAP data, compared to 10-s mean slow-wave ICP and MAP data. Shorter window L-PRx variants, such as L-PRx_5, appear to have a similar ARIMA structure, have a linear association with PRx and display moderate-to-strong correlations (r ~ 0.700, p < 0.0001 for each patient). Thus, these particular L-PRx variants appear closest in nature to standard PRx. ICP and MAP derived via 10-s or minute based averaging display similar statistical time-series structure and co-variance patterns. PRx and L-PRx based on shorter windows also behave similarly over time. These results imply certain L-PRx variants may carry similar information to PRx in TBI.

Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury.

Background Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls. Methods In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins. Results Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p < 0.0001, p < 0.0001, and p = 0.0008, respectively). In serum, tenascin-C concentration was higher and neurocan lower compared to healthy controls (p = 0.02 and p = 0.0009). Conclusions These findings indicate that levels of extracellular matrix proteins are associated with clinical outcome following TBI and may act as markers for different pathophysiology than currently used protein biomarkers.

Prognostic performance of computerized tomography scoring systems in civilian penetrating traumatic brain injury: an observational study.

BACKGROUND: The prognosis of penetrating traumatic brain injury (pTBI) is poor yet highly variable. Current computerized tomography (CT) severity scores are commonly not used for pTBI prognostication but may provide important clinical information in these cohorts. METHODS: All consecutive pTBI patients from two large neurotrauma databases (Helsinki 1999-2015, Stockholm 2005-2014) were included. Outcome measures were 6-month mortality and unfavorable outcome (Glasgow Outcome Scale 1-3). Admission head CT scans were assessed according to the following: Marshall CT classification, Rotterdam CT score, Stockholm CT score, and Helsinki CT score. The discrimination (area under the receiver operating curve, AUC) and explanatory variance (pseudo-R2) of the CT scores were assessed individually and in addition to a base model including age, motor response, and pupil responsiveness. RESULTS: Altogether, 75 patients were included. Overall 6-month mortality and unfavorable outcome were 45% and 61% for all patients, and 31% and 51% for actively treated patients. The CT scores' AUCs and pseudo-R2s varied between 0.77-0.90 and 0.35-0.60 for mortality prediction and between 0.85-0.89 and 0.50-0.57 for unfavorable outcome prediction. The base model showed excellent performance for mortality (AUC 0.94, pseudo-R2 0.71) and unfavorable outcome (AUC 0.89, pseudo-R2 0.53) prediction. None of the CT scores increased the base model's AUC (p > 0.05) yet increased its pseudo-R2 (0.09-0.15) for unfavorable outcome prediction. CONCLUSION: Existing head CT scores demonstrate good-to-excellent performance in 6-month outcome prediction in pTBI patients. However, they do not add independent information to known outcome predictors, indicating that a unique score capturing the intracranial severity in pTBI may be warranted.

Extracellular vesicles: pathogenetic, diagnostic and therapeutic value in traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Accurate classification according to injury-specific and patient-specific characteristics is critical to help informed clinical decision-making and to the pursuit of precision medicine in TBI. Reliable biomarker signatures for improved TBI diagnostics are required but still an unmet need. Areas covered: Extracellular vesicles (EVs) represent a new class of biomarker candidates in TBI. These nano-sized vesicles have key roles in cell signaling profoundly impacting pathogenic pathways, progression and long-term sequelae of TBI. As such EVs might provide novel neurobiological insights, enhance our understanding of the molecular mechanisms underlying TBI pathophysiology and recovery, and serve as biomarker signatures and therapeutic targets and delivery systems. Expert commentary: EVs are fast gaining momentum in TBI research, paving the way for new transformative diagnostic and treatment approaches. Their potential to sort out TBI variability and active involvement in the mechanisms underpinning different clinical phenotypes point out unique opportunities for improved classification, risk-stratification ad intervention, harboring promise of predictive, personalized, and even preemptive therapeutic strategies. Although a great deal of progress has been made, substantial efforts are still required to ensure the needed rigorous validation and reproducibility for clinical implementation of EVs.

Positive blood alcohol level in severe traumatic brain injury is associated with better long-term functional outcome.

OBJECTIVE: To investigate the association between positive blood alcohol level (BAL) and functional outcome in patients suffering severe traumatic brain injury. STUDY DESIGN: The brain trauma registry of an academic trauma centre was queried for patients admitted between January 2007 and December 2011. All patients (≥ 18 years) with a neurosurgical intensive care length of stay beyond 2 days were included. Patient demographics, clinical characteristics, injury profile, laboratory test and outcomes were abstracted for analysis. Primary outcome was unfavourable functional outcome defined as Glasgow Outcome Score (GOS) ≤ 3. Multivariable regression models were used for analysis. RESULTS: Of the 352 patients, 39% were BAL (+) at admission. Patients with (+) BAL were significantly younger with less co-morbidities. The cohorts exhibited no significant difference in the severity of the intra-cranial injury and the use of intra-cranial monitoring or surgical interventions. Further, the groups presented no difference in in-hospital mortality (p = 0.1) or 1-year mortality (p = 0.5). There was a worse long-term functional outcome in (-) BAL patients compared to their BAL (+) counterparts after adjustment for confounders (GOS ≤ 3: AOR = 2.0, 95% CI = 1.1-3.5, p = 0.02). CONCLUSION: Positive BAL on admission is associated with a better long-term functional outcome in patients suffering severe traumatic brain injury.

The Effect of ß-blockade on Survival After Isolated Severe Traumatic Brain Injury.

BACKGROUND: Several North American studies have observed survival benefit in patients exposed to ß-blockers following traumatic brain injury (TBI). The purpose of this study was to evaluate the effect of ß-blockade on mortality in a Swedish cohort of isolated severe TBI patients. METHODS: The trauma registry of an urban academic trauma center was queried to identify patients with an isolated severe TBI between 1/2007 and 12/2011. Isolated severe TBI was defined as an intracranial injury with an Abbreviated Injury Scale (AIS)≥3 excluding extra-cranial injuries AIS≥3. Multivariable logistic regression analysis was used to determine the effect of ß-blocker exposure on mortality. Also, a subgroup analysis was performed to investigate the risk of mortality in patients on pre-admission ß-blocker versus not and the effect of specific type of ß-blocker on the overall outcome. RESULTS: Overall, 874 patients met the study criteria. Of these, 33% (n=287) were exposed to ß-blockers during their hospital admission. The exposed patients were older (62±16 years vs. 49±21 years, p<0.001), and more severely injured based on their admission GCS, ISS, and head AIS scores (GCS≤8: 32% vs. 28%, p=0.007; ISS≥16: 71% vs. 59%, p=0.001; head AIS≥4: 60% vs. 45%, p<0.001). The crude mortality was higher in patients who did not receive ß-blockers (17% vs. 11%, p=0.007) during their admission. After adjustment for significant confounders, the patients not exposed to ß-blockers had a 5-fold increased risk of in-hospital mortality (AOR 5.0, CI 95% 2.7-8.5, p=0.001). No difference in survival was noted in regards to the type of ß-blocker used. Subgroup analysis revealed a higher risk of mortality in patients naive to ß-blockers compared to those on pre-admission ß-blocker therapy (AOR 3.0 CI 95% 1.2-7.1, p=0.015). CONCLUSIONS: ß-blocker exposure after isolated severe traumatic brain injury is associated with significantly improved survival. We also noted decreased mortality in patients on pre-admission ß-blocker therapy compared to patients naive to such treatment. Further prospective studies are warranted.

Secondary peaks of S100B in serum relate to subsequent radiological pathology in traumatic brain injury.

INTRODUCTION: Patients suffering from severe traumatic brain injury (TBI) often develop secondary brain lesions that may worsen outcome. S100B, a biomarker of brain damage, has been shown to increase in response to secondary cerebral deterioration. The aim of this study was to analyze the occurrence of secondary increases in serum levels of S100B and their relation to potential subsequent radiological pathology present on CT/MRI-scans. METHODS: Retrospective study from a trauma level 1 hospital, neuro-intensive care unit. 250 patients suffering from TBI were included. Inclusion required a minimum of two radiological examinations and at least three serum samples of S100B, with at least one >48 h after trauma. RESULTS: Secondary pathological findings on CT/MRI, present in 39 % (n = 98) of the patients, were highly correlated to secondary increases of ≥0.05 µg/L S100B (P < 0.0001, pseudo-R (2) 0.532). Significance remained also after adjusting for known important TBI predictors. In addition, secondary radiological findings were significantly correlated to outcome (Glasgow Outcome Score, GOS) in uni-(P < 0.0001, pseudo-R (2) 0.111) and multivariate analysis. The sensitivity and specificity of detecting later secondary radiological findings was investigated at three S100B cut-off levels: 0.05, 0.1, and 0.5 µg/L. A secondary increase of ≥0.05 µg/L had higher sensitivity (80 %) but lower specificity (89 %), compared with a secondary increase of ≥0.5 µg/L (16 % sensitivity, 98 % specificity), to detect secondary radiological findings. CONCLUSIONS: Secondary increases in serum levels of S100B, even as low as ≥0.05 µg/L, beyond 48 h after TBI are strongly correlated to the development of clinically significant secondary radiological findings.

Intracranial Pressure-Derived Cerebrovascular Reactivity Indices and Their Critical Thresholds: A Canadian High Resolution-Traumatic Brain Injury Validation Study.

Current neurointensive care guidelines recommend intracranial pressure (ICP) and cerebral perfusion pressure (CPP) centered management for moderate-severe traumatic brain injury (TBI) because of their demonstrated associations with patient outcome. Cerebrovascular reactivity metrics, such as the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC index, have also demonstrated significant prognostic capabilities with regard to outcome. However, critical thresholds for cerebrovascular reactivity indices have only been identified in two studies conducted at the same center. In this study, we aim to determine the critical thresholds of these metrics by leveraging a unique multi-center database. The study included a total of 354 patients from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative. Based on 6-month Glasgow Outcome Scores, patients were dichotomized into alive versus dead and favorable versus unfavorable. Chi-square values were then computed for incrementally increasing values of each physiological parameter of interest against outcome. The values that generated the greatest chi-squares for each parameter were considered to be the thresholds with the greatest outcome discriminatory capacity. To confirm that the identified thresholds provide prognostic utility, univariate and multivariable logistical regression analyses were performed adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. Through the chi-square analysis, a lower limit CPP threshold of 60 mm Hg and ICP thresholds of 18 mm Hg and 22 mm Hg were identified for both survival and favorable outcome predictions. For the cerebrovascular reactivity metrics, different thresholds were identified for the two outcome dichotomizations. For survival prediction, thresholds of 0.35, 0.25, and 0 were identified for PRx, PAx, and RAC, respectively. For favorable outcome prediction, thresholds of 0.325, 0.20, and 0.05 were found. Univariate logistical regression analysis demonstrated that the time spent above/below thresholds were associated with outcome. Further, multivariable logistical regression analysis found that percent time above/below the identified thresholds added additional variance to the IMPACT core model for predicting both survival and favorable outcome. In this study, we were able to validate the results of the previous two works as well as to reaffirm the ICP and CPP guidelines from the Brain Trauma Foundation (BTF) and the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).