To Örebro University

BACKGROUND: Whole blood transfusion (WBT) is associated with improved hemostasis and possibly mortality in patients with hemorrhagic shock after injury but there are no studies in patients with isolated severe traumatic brain injury (TBI). The objective of this investigation was to compare outcomes of balanced component therapy (BCT) versus WBT in patients with an isolated severe TBI.

METHODS: Adult patients (≥18 years) registered in the Trauma Quality Improvement Program (2016-2019) who suffered a blunt isolated severe TBI (head Abbreviated Injury Score ≥3 in the head and ≤1 in the remaining body regions) and who received a BCT (1-2:1 packed red blood cell (PRBC):fresh frozen plasma and 1-2:1 PRBC:platelets) or WBT were eligible for inclusion. Patients were matched, based on the transfusion received, using propensity score matching. The primary outcome of interest was in-hospital mortality.

RESULTS: A total of 217 patients received either WBT (n=82) or BCT (n=135). After propensity score matching, 50 matched pairs were analyzed. The rate of in-hospital mortality was significantly lower in the WBT compared with BCT group (43.1% vs 66.7%, p=0.025) corresponding to a relative risk (RR) reduction of 35% in in-hospital mortality (RR (CI 95%): 0.65 (0.43 to 0.97)). However, in subgroup analyses comparing those who were managed surgically and conservatively, this association only remained significant among patients who underwent neurosurgical intervention.

CONCLUSIONS: WBT in patients with severe isolated TBI is associated with better survival compared with BCT in patients who require neurosurgical intervention. Further investigation into this finding using an appropriately powered, prospective study design is warranted.

LEVEL OF EVIDENCE: Level III, therapeutic.

BACKGROUND AND OBJECTIVES: There is seemingly contradictory evidence concerning relationships between day-of-injury biomarkers and outcomes after mild traumatic brain injury (mTBI). To address this issue, we examined the association between a panel of biomarkers and multidimensional TBI outcomes.

METHODS: Participants with mTBI (Glasgow coma scores [GCSs] 13-15) were selected from Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury, a European observational study recruiting patients with TBI with indication for brain CT and presentation within 24 hours. Exclusion criteria for this secondary analysis were age younger than 16 years, incomplete biomarker panel, death, or no recorded outcomes. Participants were separated into 2 groups, CT-negative and CT-positive. Multivariable binary logistic regression was used to assess the relation between the log biomarker level (glial fibrillary acidic protein [GFAP], neurofilament light [NfL], neuron-specific enolase [NSE], S100 calcium-binding protein B [S100B], tau, ubiquitin C-terminal hydrolase L1 [UCH-L1]) and dichotomized 6-month outcomes (functional outcomes [GOSE score <8], health-related quality of life [HRQoL; Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS) score <52, Short-Form 12-Item Survey version 2 Mental Component Summary (SF12v2 MCS) score <40, Short-Form 12-Item Survey version 2 Physical Component Summary (SF12v2 PCS) score <40], persistent postconcussion symptoms [Rivermead Post-Concussion Symptoms Questionnaire score ≥16], anxiety disorder [Generalized Anxiety Disorder-7 (GAD-7) score ≥8], depression [Patient Health Questionnaire-9 (PHQ-9) score ≥10], and post-traumatic stress disorder [PTSD Checklist for DSM-5 (PCL-5) score ≥33]).

RESULTS: A total of 1,589 participants (865 CT-negative, 724 CT-positive) were included (77% GCS 15, median age 52 years, 66% male). Higher biomarker levels were associated with a GOSE score <8: CT-negative: S100B (odds ratio [OR] 1.78, 95% CI 1.43-2.23) and UCH-L1 (OR 1.16, 95% CI 1.01-1.33); CT-positive: GFAP (OR 1.22, 95% CI 1.11-1.36), NfL (OR 1.30, 95% CI 1.11-1.52), S100B (OR 1.51, 95% CI 1.23-1.86), tau (OR 1.36, 95% CI 1.17-1.59), and UCH-L1 (OR 1.34, 95% CI 1.17-1.53). In CT-positive participants, positive association was seen between NfL (OR 1.3, 95% CI 1.06-1.60) and UCH-L1 (OR 1.28, 95% CI 1.07-1.54) with QOLIBRI-OS; S100B (OR 1.32, 95% CI 1.02-1.70) with SF12v2 PCS; and NSE (OR 1.52, 95% CI 1.06-2.18) and UCH-L1 (OR 1.21, 95% CI 1.01-1.46) with the GAD-7. However, in CT-negative participants only, negative associations were seen between GFAP and impairment on the QOLIBRI-OS (OR 0.76, 95% CI 0.66-0.88), SF12v2 MCS (OR 0.71, 95% CI 0.61-0.82), SF12v2 PCS (OR 0.79, 95% CI 0.68-0.91), GAD-7 (OR 0.80, 0.68-0.95), PHQ-9 (OR 0.80, 95% CI 0.68-0.93), and PCL-5 (OR 0.80, 95% CI 0.66-0.97). DISCUSSION: Participants with higher biomarker levels had greater odds of impaired functional recovery. However, in CT-negative participants, higher GFAP concentrations were associated with better HRQoL and less impaired mental health. Further exploration is required of the patient phenotypes that may explain the relationships observed in this analysis.

A 2022 report by the National Academies of Sciences, Engineering, and Medicine called for a Traumatic Brain Injury (TBI) Classification Workshop by the National Institutes of Health (NIH) to develop a more precise, evidence-based classification system. The workshop aimed to revise the Glasgow Coma Scale-based system by incorporating neuroimaging and validated blood biomarker tests. In December 2022, the National Institute for Neurological Disorders and Stroke formed six working groups of TBI experts to make recommendations for this revision. This report presents the findings and recommendations from the blood-based biomarker (BBM) working group, including feedback from the workshop and subsequent public review. The application of BBMs in a TBI classification system has potential to allow for a more adaptable and nuanced approach to triage, diagnosis, prognosis, and treatment. Current evidence supports the use of glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1, and S100B calcium-binding protein (S100B) to assist in reclassification of TBI at acute time points (0-24 h) primarily in emergency department settings, while neurofilament light chain (NfL), GFAP, and S100B have utility at subacute time points (1-30 days) in-hospital and intensive care unit settings. Blood levels of these biomarkers reflect the extent of structural brain injury in TBI and may be useful for describing the extent of structural brain injury in a classification system. While there is insufficient evidence to support a role for BBMs at chronic time points (>30 days), emerging evidence suggests that NfL and phosphorylated tau may have a potential future role in this regard. For inclusion in a revised TBI classification system, BBM assays must have appropriate age- and sex-specific reference ranges, be harmonized across platforms, and achieve high analytical precision, including accuracy, linearity, detection limits, selectivity, recovery, reproducibility, and stability. Improving transparency in BBM assay development can be achieved through large-scale data sharing of methods and results. Future research should focus on methods for promoting clinical adoption of BBM results, correlating BBMs with advanced neuroimaging, and on discovering new biomarkers for improved diagnosis and prognosis.

Background: Severe traumatic brain injury (TBI) leads t ochronic cognitive decline, imposing a significant societal burden. The regulation of cerebral blood flow (CBF) is critical for cognitive function, and acute disruptions in CBF regulation predict poor TBI outcomes. However, the long-term effects of TBI on CBF regulation and their association with cognitive function remain poorly understood.

Objective: This study aimed to investigate whether severe TBI results in chronic CBF dysregulation and whether this contributes to long-term cognitive deficits. Additionally, we examined the role of TBI-induced insulin-like growth factor 1 (IGF-1) deficiency in cerebrovascular dysfunction.

Methods: We assessed cognitive function, basal CBF (via phase contrast MRI), CBF autoregulation (via transcranial Doppler), and neurovascular coupling (NVC) in 33 TBI survivors (mean age: 37.6 years, ~10 years post-injury) and 21 age-matched healthy controls. Serum IGF-1 levels were also measured.

Results: TBI survivors exhibited significant impairments in memory and executive function compared to controls. While basal CBF and autoregulation remained intact, NVC responses were chronically impaired and correlated with cognitive deficits. However, IGF-1 levels did not differ between groups and were not associated with NVC impairment or cognitive function.

Conclusion: Our findings indicate that severe TBI results in chronic impairment of neurovascular coupling, which likely contributes to long-term cognitive deficits. These results highlight the need for further research to identify underlying neurovascular mechanisms and develop interventions to restore NVC and cognitive function in TBI survivors.

Severe traumatic brain injury (TBI) leads to chronic cognitive decline, imposing a significant societal burden. The regulation of cerebral blood flow (CBF) is critical for cognitive function, and acute disruptions in CBF regulation predict poor TBI outcomes. However, the long-term effects of TBI on CBF regulation and their association with cognitive function remain poorly understood. This study aimed to investigate whether severe TBI results in chronic CBF dysregulation and whether this contributes to long-term cognitive deficits. Additionally, we examined the role of TBI-induced insulin-like growth factor 1 (IGF-1) deficiency in cerebrovascular dysfunction. We assessed cognitive function, basal CBF (via phase contrast MRI), CBF autoregulation (via transcranial Doppler), and neurovascular coupling (NVC) in 33 TBI survivors (mean age 37.6 years, ~ 10 years post-injury) and 21 age-matched healthy controls. Serum IGF-1 levels were also measured. TBI survivors exhibited significant impairments in memory and executive function compared to controls. While basal CBF and autoregulation remained intact, NVC responses were chronically impaired and correlated with cognitive deficits. However, IGF-1 levels did not differ between groups and were not associated with NVC impairment or cognitive function. Our findings indicate that severe TBI results in chronic impairment of neurovascular coupling, which likely contributes to long-term cognitive deficits. These results highlight the need for further research to identify underlying neurovascular mechanisms and develop interventions to restore NVC and cognitive function in TBI survivors.

INTRODUCTION: As the world population is rapidly becoming older, the incidence of traumatic brain injury (TBI) is increasing among older adults with vast implications for brain health of older adults in Europe. Due to differences from younger patients, there are areas of uncertainty in the assessment, diagnosis and management of TBI in older adults.

RESEARCH QUESTION: To reach a consensus among experts on statements regarding the definition of old age, assessment, diagnosis and management of traumatic brain injury in older adults.

MATERIALS AND METHODS: A modified Delphi method consisting of two online rounds was organised, followed by an in-person meeting. Consensus was defined as >75 % agreement. In the second online round the experts were able to view their first assessment and the average of the group. Some statements were rephrased and presented again in the in-person meeting. Questions with numerical data could not be assessed by consensus and descriptive and non-parametric statistics were used to analyze them.

RESULTS: Experts (n = 72), from different nationalities (Europe, United States, Latin America, Africa and Asia) and specialities (Neurosurgery, Emergency Medicine, Intensive care medicine) responded on 62 statements. Consensus was finally reached on 44 statements regarding the definition of older adulthood, as well as the assessment, surgical and intensive care management, discharge, and rehabilitation of patients.

DISCUSSION AND CONCLUSIONS: This consensus reinforces the importance of this area for physicians and researchers interested in traumatic brain injury. It signals important areas of agreement as well as future topics for research and specific knowledge gaps.

Circulating biomarkers might improve the prediction of outcomes in patients with traumatic brain injury (TBI) beyond current approaches. Robust and up-to-date evidence is required to support their clinical utility and integration into medical practice to guide decision-making. Our objective was to critically appraise the existing evidence for six core blood-based TBI biomarkers (S100 calcium-binding protein B, glial fibrillary acidic protein [GFAP], neuron-specific enolase, ubiquitin C-terminal hydrolase-L1 [UCH-L1], tau and neurofilament proteins), in predicting outcome after TBI. Electronic databases, including Medline and Embase, were searched for articles published from their inception to October 2023. Studies were included if they evaluated the accuracy of blood biomarker concentrations at hospital presentation for outcome prediction in adult patients with TBI. Outcomes assessed were mortality, Glasgow Outcome Scale (GOS)/GOS extended (GOS-E), or the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Study selection, data extraction, and quality assessment using the modified Quality Assessment of Prognostic Accuracy Studies tool were performed by two authors independently, with disagreements being resolved through discussion or arbitration. If appropriate, a meta-analysis was conducted by calculating the weighted summary area under the curve (AUC) and using a bivariate regression model. Of 12,792 retrieved records, 32 articles, including 7481 patients with TBI, were selected as relevant. Two biomarkers showed strong associations with in-hospital and 6-month mortality: GFAP (unadjusted pooled AUC 0.81 [95% confidence interval [CI] 0.75-0.87] and 0.82 [0.80-0.85], respectively) and UCH-L1 (0.80 [0.74-0.85] and 0.83 [0.77-0.88]). Their addition to models that included established risk factors consistently improved the predictive value, though models and performance varied substantially across studies. In four studies measuring both markers, UCH-L1 outperformed GFAP in improving risk stratification when added to established prediction models. At similar to 1.5 ng/mL (five studies), the summary sensitivity of GFAP for predicting mortality was 78% (95% CI 67-85%), and the summary specificity was 79% (95% CI 64-89%). The other assessed biomarkers had fair to good performance in mortality prediction with unclear added benefits. Neurofilament light (NfL) (three studies) demonstrated the strongest association in predicting a 6-month poor outcome (GOS-E <= 4; GOS <= 3) (unadjusted pooled AUC 0.81 [95% CI 0.75-0.87]), whereas the other assessed biomarkers had a fair performance with unclear or irrelevant added value. All core biomarkers had only marginal or no association with incomplete recovery and post-concussion symptoms/syndrome, as assessed by RPQ. Serious problems were found in the design and analysis of many of the studies. We conclude that admission measurements of core blood TBI biomarkers, in particular GFAP and UCH-L1, are strongly associated with mortality. There remains little evidence that any of these markers are ready for clinical implementation for prognostic purposes. Future work focused on the intended use and applying unbiased rigorous analysis methods is necessary to demonstrate that the biomarker test results are "prognostically actionable."

INTRODUCTION: Reversal treatment is commonly used for managing oral anticoagulant (OAC)-associated intracranial haemorrhages. Its effects on mortality are still understudied, particularly in various subtypes of intracranial haemorrhages. This systematic review and meta-analysis aims to synthesise the available data to study the impact of reversal therapies on mortality following various OAC-associated acute intracranial haemorrhages.

METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Protocols, and the final review will be reported in accordance with the PRISMA reporting guidelines. This systematic review and meta-analysis will include studies that assess contemporary reversal treatment in comparison to no reversal treatment, in cases of OAC-associated intracranial haemorrhage. Stratification will be performed for the types of bleeding as well as OAC at bleeding onset. Preliminary searches to determine search term inclusions were conducted in May-August 2024 in the electronic databases Embase, PubMed, Scopus and Web of Science without language and publication date restrictions. Randomised controlled studies, non-randomised controlled trials, and observational studies will be considered for the final meta-analysis. Three reviewers (MT, JOS and AB) will screen titles and abstracts, and one reviewer (MT) will subsequently conduct full-text screening. Risks of bias will be assessed by MT using tools such as Risk of Bias 2, Risk Of Bias In Non-randomised Studies - of Interventions and the Newcastle-Ottawa Scale. Heterogeneity among the study results will be assessed using the I² statistic. If appropriate, a random-effects meta-analysis model will be performed. Subgroup analyses and meta-regression (if applicable) will be performed to assess sources of heterogeneity among (1) intracranial haemorrhage types, (2) OAC drugs and (3) study types, with randomised controlled trials being the primary focus.

ETHICS AND DISSEMINATION: Ethical approval is not needed as this project involves previously published data. We intend to publish the results in a peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42024556420.

This article explores the diagnostic performance of a panel of six biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], neuron-specific enolase [NSE], S100 calcium-binding protein B [S100B], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) in the context of the "2023 UK National Institute for Health and Care Excellence (NICE) Head Injury: Assessment and early management (NG232)" guideline. Emphasis is placed on subjects where clinical equipoise remains concerning the decision for head computed tomography (CT), medium-risk subjects. All adult subjects from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) dataset with a complete biomarker profile and interpretable CT scan within 24 h of injury were classified as high, medium, and low-risk according to the NICE NG232 Clinical Decision Rule (CDR) for CT head imaging following head injury. In subjects classified as medium-risk, the area under the receiver operating characteristic curve (AUC) was used to assess the diagnostic performance of biomarkers to identify those with (1) CT abnormality or (2) potential neurosurgical lesion, with CT considered the gold standard diagnosis. A time-to-biomarker sub-analysis was performed in subjects with a time from injury to sampling within 6 h, in keeping with current clinical usage of biomarkers. Among 1979 CENTER-TBI participants with sufficient clinical information to facilitate classification, 385 subjects were classified as medium-risk. Biomarker concentrations were significantly higher in those with traumatic CT abnormalities as compared with those without for all biomarkers aside from NSE (all p < 0.05). When sampled within 24 h of injury, GFAP demonstrated the best diagnostic performance for CT abnormality (AUC 0.81 [0.77-0.86]), with NFL, t-tau, and UCH-L1 showing moderate performance. At a threshold to provide a 95% sensitivity, GFAP, NFL, t-tau, and UCH-L1 demonstrated specificities ranging from 18% to 33% corresponding to a potential reduction of total CT images performed in these subjects by 14-23%. S100B and UCH-L1 showed improved performance when biomarker sampling time was limited to 6 h following injury. In intoxicated subjects with a persistent Glasgow Coma Score of 13-14, biomarker levels were significantly higher in subjects with CT abnormality as compared with those without. In conclusion, serum biomarkers demonstrate potential for the reduction in CT scan requirements in those classified as medium-risk in reference to the NG232 CDR criteria. These results highlight a need for further prospective studies on the use of diagnostic TBI biomarkers in current emergency medicine practice, with future consideration given to the integration of biomarkers in the NICE NG232 head injury guidelines.

Introduction: Traumatic Brain Injury (TBI) is a global health concern and a leading cause of trauma-related death worldwide. Computed tomography (CT) scan is the gold standard for screening for intracranial bleeding following TBI. Most cases of TBI are mild, with negative CT scans. Different instruments and guidelines are employed to better predict which patients need a CT scan and to minimise unnecessary radiation exposure and save resources. One such instrument is the Scandinavian Neurotrauma Committee guidelines.

Research question: To validate and examine adherence to the Scandinavian Neurotrauma Committee guidelines in Region Örebro County.

Material and methods: We executed a retrospective study with review of patient records and data analysis. Descriptive and comparative statistics were used, along with binary logistic regression analysis to account for confounding factors.

Results: A total of 505 cases were reviewed. Sensitivity of the guidelines was measured at 95% with specificity at 29%. The positive and negative predictive values were 0.77 and 0.69, respectively. A total of 17 false negative cases were found. One case required surgery, during which a chronic subdural hematoma was identified. Adherence to guidelines was 56%, with the lack of analysis of S100B primarily accounting for non-adherence. A total of 54 CT scans were performed outside of guideline indications.

Discussion and conclusions: The guidelines can effectively predict which patients need a CT scan. Increased adherence could potentially decrease the number of CT scans, while inclusion of older age limit as an independent rule-in law for CT scans would increase patient safety.