Collaborative European NeuroTrauma Effectiveness Research Research Articles

Prognostic models for depression and post-traumatic stress disorder symptoms following traumatic brain injury: a CENTER-TBI study

BackgroundTraumatic brain injury (TBI) is associated with an increased risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). We aimed to identify predictors and develop models for the...

Association of Blood-Based Biomarkers and 6-Month Patient-Reported Outcomes in Patients With Mild TBI: A CENTER-TBI Analysis.

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. 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]). 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). 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.

Validation of the GCS-Pupil Scale in Traumatic Brain Injury: Incremental Prognostic Value of Pupillary Reactivity with GCS in the Prospective Observational Cohorts CENTER-TBI and TRACK-TBI.

To compare the incremental prognostic value of pupillary reactivity captured as part of the Glasgow Coma Scale-Pupils (GCS-P) score or added as separate variable to the GCS+P, in traumatic brain injury (TBI). We analyzed patients enrolled between 2014 and 2018 in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, n = 3521) and the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI, n = 1439) cohorts. Logistic regression was utilized to quantify the prognostic performances of GCS-P (GCS minus number of unreactive pupils) and GCS+P versus GCS alone according to Nagelkerke's R2. End-points were mortality and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-4) at 6 month post-injury. We estimated 95% confidence intervals (CIs) with bootstrap resampling to summarize the improvement in prognostic capability. In a meta-analysis of CENTER-TBI and TRACK-TBI, GCS as a linear score had a R2 of 25% (95% CI 19-31%) for mortality and 33% (4-41%) for unfavorable outcome. Pupillary reactivity as a separate variable improved the R2 by an absolute value of 6% (4.0-7.7%) and 2% (1.2-3.0%) for mortality and unfavorable outcome, respectively, while comparatively half of this improvement was captured by the GCS-P score (3% [2.1-3.3%], 1% [1-1.7%], respectively). GCS-P showed a stronger association with 6-month outcome after TBI than GCS alone and provides a single integrated score. However, this comes at a loss of clinical and prognostic information compared with GCS+P. For prognostic models, inclusion of GCS and pupillary reactivity as separate factors may be preferable to using a GCS-P summary score.

Disparities in casemix, acute interventions, discharge destinations and mortality of patients with traumatic brain injury between Europe and India.

Traumatic brain injury (TBI) is a major global health problem that disproportionally affects low- and middle-income countries. The needs for patients with TBI therefore may differ between levels of national development. We aimed to describe differences in epidemiology and acute care provision of TBI between India and Europe. We used data from two prospective observational registry studies - the Collaborative Indian NeuroTrauma Effectiveness Research in TBI (CINTER-TBI) and the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI), which included TBI patients with an indication for brain CT-scan presenting to 65 centres across Europe and Israel and two trauma centres in India. We performed descriptive analyses of demographic, injury, and treatment characteristics and used random-effects logistic regression with covariate adjustment to examine the likelihood of acute neurosurgical interventions and in-hospital mortality. We included 22 849 patients from CENTER-TBI and 3904 from CINTER-TBI. The median age in Europe was 55 years (IQR = 32-76) compared to 27 years (IQR = 18-40) in India. The most common cause of TBI in Europe were falls (n = 12150 (53%), while traffic incidents predominated in India (n = 2130 (55%)). The proportion of patients with severe TBI was higher in India (n = 867 (22%)) than in Europe (n = 1661 (7%). Professional pre-hospital care involving ambulance service was utilised by three-fourths (n = 17203 (75%)) of European and less than a one-tenth (n = 224 (6%)) of Indian patients in our sample. Patients with severe TBI were more likely to undergo surgical contusion/haematoma evacuation in India compared to Europe (OR = 2.0; 95% CI = 1.7-2.5) and Indian patients had higher odds of undergoing intracranial pressure monitor placement (OR = 2.3; 95% CI = 2.0-2.7). A primary decompressive craniectomy was likewise more often performed in the Indian cohort (OR = 5.1; 95% CI = 3.5-7.5). Discharge destinations in Europe included rehabilitation centres (n = 1261 (6%)) or nursing homes (n = 1208 (5%)), which was rarely the case in India (n = 13 (0%) and n = 9 (0%), respectively). Substantial disparities between India and Europe exist along the neurotrauma care chain, with both systems being likely to face unique features and challenges in the future.

Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury

The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E]≤4) were used for hierarchical clustering to identify patients with similar signatures. Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Association of early blood-based biomarkers and six-month functional outcomes in conventional severity categories of traumatic brain injury: capturing the continuous spectrum of injury

Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively. Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Clinical and Imaging Characteristics, Care Pathways, and Outcomes of Traumatic Epidural Hematomas: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study.

Guideline recommendations for surgical management of traumatic epidural hematomas (EDHs) do not directly address EDHs that co-occur with other intracranial hematomas; the relative rates of isolated vs nonisolated EDHs and guideline adherence are unknown. We describe characteristics of a contemporary cohort of patients with EDHs and identify factors influencing acute surgery. This research was conducted within the longitudinal, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury cohort study which prospectively enrolled patients with traumatic brain injury from 65 hospitals in 18 European countries from 2014 to 2017. All patients with EDH on the first scan were included. We describe clinical, imaging, management, and outcome characteristics and assess associations between site and baseline characteristics and acute EDH surgery, using regression modeling. In 461 patients with EDH, median age was 41 years (IQR 24-56), 76% were male, and median EDH volume was 5 cm3 (IQR 2-20). Concomitant acute subdural hematomas (ASDHs) and/or intraparenchymal hemorrhages were present in 328/461 patients (71%). Acute surgery was performed in 99/461 patients (21%), including 70/86 with EDH volume ≥30 cm3 (81%). Larger EDH volumes (odds ratio [OR] 1.19 [95% CI 1.14-1.24] per cm3 below 30 cm3), smaller ASDH volumes (OR 0.93 [95% CI 0.88-0.97] per cm3), and midline shift (OR 6.63 [95% CI 1.99-22.15]) were associated with acute surgery; between-site variation was observed (median OR 2.08 [95% CI 1.01-3.48]). Six-month Glasgow Outcome Scale-Extended scores ≥5 occurred in 289/389 patients (74%); 41/389 (11%) died. Isolated EDHs are relatively infrequent, and two-thirds of patients harbor concomitant ASDHs and/or intraparenchymal hemorrhages. EDHs ≥30 cm3 are generally evacuated early, adhering to Brain Trauma Foundation guidelines. For heterogeneous intracranial pathology, surgical decision-making is related to clinical status and overall lesion burden. Further research should examine the optimal surgical management of EDH with concomitant lesions in traumatic brain injury, to inform updated guidelines.

Imaging Findings in Acute Traumatic Brain Injury: a National Institute of Neurological Disorders and Stroke Common Data Element-Based Pictorial Review and Analysis of Over 4000 Admission Brain Computed Tomography Scans from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

In 2010, the National Institute of Neurological Disorders and Stroke (NINDS) created a set of common data elements (CDEs) to help standardize the assessment and reporting of imaging findings in traumatic brain injury (TBI). However, as opposed to other standardized radiology reporting systems, a visual overview and data to support the proposed standardized lexicon are lacking. We used over 4000 admission computed tomography (CT) scans of patients with TBI from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study to develop an extensive pictorial overview of the NINDS TBI CDEs, with visual examples and background information on individual pathoanatomical lesion types, up to the level of supplemental and emerging information (e.g., location and estimated volumes). We documented the frequency of lesion occurrence, aiming to quantify the relative importance of different CDEs for characterizing TBI, and performed a critical appraisal of our experience with the intent to inform updating of the CDEs. In addition, we investigated the co-occurrence and clustering of lesion types and the distribution of six CT classification systems. The median age of the 4087 patients in our dataset was 50 years (interquartile range, 29-66; range, 0-96), including 238 patients under 18 years old (5.8%). Traumatic subarachnoid hemorrhage (45.3%), skull fractures (37.4%), contusions (31.3%), and acute subdural hematoma (28.9%) were the most frequently occurring CT findings in acute TBI. The ranking of these lesions was the same in patients with mild TBI (baseline Glasgow Coma Scale [GCS] score 13-15) compared with those with moderate-severe TBI (baseline GCS score 3-12), but the frequency of occurrence was up to three times higher in moderate-severe TBI. In most TBI patients with CT abnormalities, there was co-occurrence and clustering of different lesion types, with significant differences between mild and moderate-severe TBI patients. More specifically, lesion patterns were more complex in moderate-severe TBI patients, with more co-existing lesions and more frequent signs of mass effect. These patients also had higher and more heterogeneous CT score distributions, associated with worse predicted outcomes. The critical appraisal of the NINDS CDEs was highly positive, but revealed that full assessment can be time consuming, that some CDEs had very low frequencies, and identified a few redundancies and ambiguity in some definitions. Whilst primarily developed for research, implementation of CDE templates for use in clinical practice is advocated, but this will require development of an abbreviated version. In conclusion, with this study, we provide an educational resource for clinicians and researchers to help assess, characterize, and report the vast and complex spectrum of imaging findings in patients with TBI. Our data provides a comprehensive overview of the contemporary landscape of TBI imaging pathology in Europe, and the findings can serve as empirical evidence for updating the current NINDS radiologic CDEs to version 3.0.

Early versus delayed cranioplasty after decompressive craniectomy in traumatic brain injury: a multicenter observational study within CENTER-TBI and Net-QuRe.

The aim of this study was to compare the outcomes of early (≤ 90 days) and delayed (> 90 days) cranioplasty following decompressive craniectomy (DC) in patients with traumatic brain injury (TBI). The authors analyzed participants enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and the Neurotraumatology Quality Registry (Net-QuRe) studies who were diagnosed with TBI and underwent DC and subsequent cranioplasty. These prospective, multicenter, observational cohort studies included 5091 patients enrolled from 2014 to 2020. The effect of cranioplasty timing on functional outcome was evaluated with multivariable ordinal regression and with propensity score matching (PSM) in a sensitivity analysis of functional outcome (Glasgow Outcome Scale-Extended [GOSE] score) and quality of life (Quality of Life After Brain Injury [QOLIBRI] instrument) at 12 months following DC. Among 173 eligible patients, 73 (42%) underwent early cranioplasty and 100 (58%) underwent delayed cranioplasty. In the ordinal logistic regression and PSM, similar 12-month GOSE scores were found between the two groups (adjusted odds ratio [aOR] 0.87, 95% CI 0.61-1.21 and 0.88, 95% CI 0.48-1.65, respectively). In the ordinal logistic regression, early cranioplasty was associated with a higher risk for hydrocephalus than that with delayed cranioplasty (aOR 4.0, 95% CI 1.2-16). Postdischarge seizure rates (early cranioplasty: aOR 1.73, 95% CI 0.7-4.7) and QOLIBRI scores (β -1.9, 95% CI -9.1 to 9.6) were similar between the two groups. Functional outcome and quality of life were similar between early and delayed cranioplasty in patients who had undergone DC for TBI. Neurosurgeons may consider performing cranioplasty during the index admission (early) to simplify the patient's chain of care and prevent readmission for cranioplasty but should be vigilant for an increased possibility of hydrocephalus. Clinical trial registration nos.: CENTER-TBI, NCT02210221 (clinicaltrials.gov); Net-QuRe, NTR6003 (trialsearch.who.int) and NL5761 (onderzoekmetmensen.nl).

Frequency and predictors of headache in the first 12 months after traumatic brain injury: results from CENTER-TBI

BackgroundHeadache is a prevalent and debilitating symptom following traumatic brain injury (TBI). Large-scale, prospective cohort studies are needed to establish long-term headache prevalence and associated factors after TBI. This study aimed to assess the frequency and severity of headache after TBI and determine whether sociodemographic factors, injury severity characteristics, and pre- and post-injury comorbidities predicted changes in headache frequency and severity during the first 12 months after injury.MethodsA large patient sample from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study was used. Patients were stratified based on their clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU) in the acute phase. Headache was assessed using a single item from the Rivermead Post-Concussion Symptoms Questionnaire measured at baseline, 3, 6 and 12 months after injury. Mixed-effect logistic regression analyses were applied to investigate changes in headache frequency and associated predictors.ResultsA total of 2,291 patients responded to the headache item at baseline. At study enrolment, 59.3% of patients reported acute headache, with similar frequencies across all strata. Female patients and those aged up to 40 years reported a higher frequency of headache at baseline compared to males and older adults. The frequency of severe headache was highest in patients admitted to the ICU. The frequency of headache in the ER stratum decreased substantially from baseline to 3 months and remained from 3 to 6 months. Similar trajectory trends were observed in the ICU and ADM strata across 12 months. Younger age, more severe TBI, fatigue, neck pain and vision problems were among the predictors of more severe headache over time. More than 25% of patients experienced headache at 12 months after injury.ConclusionsHeadache is a common symptom after TBI, especially in female and younger patients. It typically decreases in the first 3 months before stabilising. However, more than a quarter of patients still experienced headache at 12 months after injury. Translational research is needed to advance the clinical decision-making process and improve targeted medical treatment for headache.Trial registrationClinicalTrials.gov NCT02210221.

Early vs Late Fixation of Extremity Fractures Among Adults With Traumatic Brain Injury

The optimal timing for fixation of extremity fractures after traumatic brain injury (TBI) remains controversial. To investigate whether patients who underwent extremity fixation within 24 hours of TBI experienced worse outcomes than those who had the procedure 24 hours or more after TBI. This cohort study used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Patients 16 years or older with TBI who underwent internal extremity fixation met inclusion criteria. To compare outcomes, patients who underwent the procedure within 24 hours were propensity score matched with those who underwent it 24 hours or later. Patients were treated from December 9, 2014, to December 17, 2017. Data analysis was conducted between August 1, 2022, and December 25, 2023. The primary outcome was an unfavorable functional status at 6 months (Glasgow Outcome Scale-Extended [GOSE] score ≤4). A total of 253 patients were included in this study. The median age was 41 (IQR, 27-57) years, and 184 patients (72.7%) were male. The median Injury Severity Score (ISS) was 41 (IQR, 27-49). Approximately half of the patients (122 [48.2%]) had a mild TBI while 120 (47.4%) had moderate to severe TBI. Seventy-four patients (29.2%) underwent an internal extremity fixation within 24 hours, while 179 (70.8%) had the procedure 24 hours or later. At 6 months, 86 patients (34.0%) had an unfavorable functional outcome. After propensity score matching, there were no statistically significant differences in unfavorable functional outcomes at 6 months (odds ratio [OR], 1.12 [95% CI, 0.51-1.99]; P = .77) in patients with TBI of any severity. Similar results were observed in patients with mild TBI (OR, 0.71 [95% CI, 0.22-2.29]; P = .56) and moderate to severe TBI (OR, 1.08 [95% CI, 0.32-3.70]; P = .90). The outcomes of extremity fracture fixation performed within 24 hours after TBI appear not to be worse than those of procedures performed 24 hours or later. This finding suggests that early fixation after TBI could be considered in patients with mild head injuries.

Early systemic insults following traumatic brain injury: association with biomarker profiles, therapy for intracranial hypertension, and neurological outcomes—an analysis of CENTER-TBI data

PurposeWe analysed the impact of early systemic insults (hypoxemia and hypotension, SIs) on brain injury biomarker profiles, acute care requirements during intensive care unit (ICU) stay, and 6-month outcomes in patients with traumatic brain injury (TBI).MethodsFrom patients recruited to the Collaborative European neurotrauma effectiveness research in TBI (CENTER-TBI) study, we documented the prevalence and risk factors for SIs and analysed their effect on the levels of brain injury biomarkers [S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and protein Tau], critical care needs, and 6-month outcomes [Glasgow Outcome Scale Extended (GOSE)].ResultsAmong 1695 TBI patients, 24.5% had SIs: 16.1% had hypoxemia, 15.2% had hypotension, and 6.8% had both. Biomarkers differed by SI category, with higher S100B, Tau, UCH-L1, NSE and NfL values in patients with hypotension or both SIs. The ratio of neural to glial injury (quantified as UCH-L1/GFAP and Tau/GFAP ratios) was higher in patients with hypotension than in those with no SIs or hypoxia alone. At 6 months, 380 patients died (22%), and 759 (45%) had GOSE ≤ 4. Patients who experienced at least one SI had higher mortality than those who did not (31.8% vs. 19%, p < 0.001).ConclusionThough less frequent than previously described, SIs in TBI patients are associated with higher release of neuronal than glial injury biomarkers and with increased requirements for ICU therapies aimed at reducing intracranial hypertension. Hypotension or combined SIs are significantly associated with adverse 6-month outcomes. Current criteria for hypotension may lead to higher biomarker levels and more negative outcomes than those for hypoxemia suggesting a need to revisit pressure targets in the prehospital settings.

Association Between Early External Ventricular Drain Insertion and Functional Outcomes 6 Months Following Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading global cause of morbidity and mortality. Intracranial hypertension following moderate-to-severe TBI (m-sTBI) is a potentially modifiable secondary cerebral insult and one of the central therapeutic targets of contemporary neurocritical care. External ventricular drain (EVD) insertion is a common therapeutic intervention used to control intracranial hypertension and attenuate secondary brain injury. However, the optimal timing of EVD insertion in the setting of m-sTBI is uncertain and practice variation is widespread. Therefore, we aimed to assess if there is an association between timing of EVD placement and functional neurological outcome at 6 months post m-sTBI. We pooled individual patient data for all relevant harmonizable variables from the Erythropoietin in Traumatic Brain Injury (EPO-TBI) and Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomized control trials, and the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) Core Study version 3.0 and Australia-Europe NeuroTrauma Effectiveness Research in TBI (Oz-ENTER) prospective observational studies to create a combined dataset. The Glasgow Coma Scale (GCS) score was used to define TBI severity and we included all patients admitted to an intensive care unit with a GCS ≤12, who were 15 years or older and underwent EVD placement within 7 days of injury. We used hierarchical multi-variable logistic regression models to study the association between EVD insertion within 24 h of injury (early) compared with EVD insertion more than 24 h after injury (late) and 6-month functional neurological outcome measured using the Glasgow Outcome Score Extended (GOSE). In total, 2536 patients were assessed. Of these, 502 (20%) underwent early EVD insertion and 145 (6%) underwent late EVD insertion. Following adjustment for the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) score extended (Core + CT), sex, injury severity score, study and treatment site, patients receiving a late EVD had higher odds of death or severe disability (GOSE 1-4) at 6 months follow-up than those receiving an early EVD adjusted odds ratio; 95% confidence interval, 2.14; 1.22-3.76; p = 0.008. Our study suggests that in patients with m-sTBI where an EVD is needed, early (≤ 24 h post-injury) insertion may result in better long-term functional outcomes. This finding supports future prospective investigation in this area.

Development of a Multimodal Machine Learning-Based Prognostication Model for Traumatic Brain Injury Using Clinical Data and Computed Tomography Scans: A CENTER-TBI and CINTER-TBI Study.

Computed tomography (CT) is an important imaging modality for guiding prognostication in patients with traumatic brain injury (TBI). However, because of the specialized expertise necessary, timely and dependable TBI prognostication based on CT imaging remains challenging. This study aimed to enhance the efficiency and reliability of TBI prognostication by employing machine learning (ML) techniques on CT images. A retrospective analysis was conducted on the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) data set (n = 1016). An ML-driven binary classifier was developed to predict favorable or unfavorable outcomes at 6 months post-injury. The prognostic performance was assessed using the area under the curve (AUC) over fivefold cross-validation and compared with conventional models that depend on clinical variables and CT scoring systems. An external validation was performed using the Comparative Indian Neurotrauma Effectiveness Research in Traumatic Brain Injury (CINTER-TBI) data set (n = 348). The developed model achieved superior performance without the necessity for manual CT assessments (AUC = 0.846 [95% CI: 0.843-0.849]) compared with the model based on the clinical and laboratory variables (AUC = 0.817 [95% CI: 0.814-0.820]) and established CT scoring systems requiring manual interpretations (AUC = 0.829 [95% CI: 0.826-0.832] for Marshall and 0.838 [95% CI: 0.835-0.841] for International Mission for Prognosis and Analysis of Clinical Trials in TBI [IMPACT]). The external validation demonstrated the prognostic capacity of the developed model to be significantly better (AUC = 0.859 [95% CI: 0.857-0.862]) than the model using clinical variables (AUC = 0.809 [95% CI: 0.798-0.820]). This study established an ML-based model that provides efficient and reliable TBI prognosis based on CT scans, with potential implications for earlier intervention and improved patient outcomes.

Contrasting Characteristics and Outcomes of Sports-Related and Non–Sports-Related Traumatic Brain Injury

Exposure to traumatic brain injury (TBI) has raised widespread concern over participation in sports, particularly over possible long-term consequences. However, little is known about the outcomes of individuals presenting to hospitals with sports-related TBI. To compare the characteristics and outcomes of individuals presenting to hospitals with sports-related and non-sports-related TBI. The CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) observational cohort study was conducted at hospitals in 18 countries. The study enrolled 4509 patients who had TBI and had an indication for computed tomography (CT), of whom 4360 were 16 years or older. Outcomes were assessed at 3 and 6 months, and groups were compared using regression analyses adjusting for clinical and demographic differences. Data were collected between December 9, 2014, and December 17, 2017, and analyzed from August 2022 to March 2023. Sports-related and non-sports-related TBI with subgroups selected by severity of injury. The main outcome was the Glasgow Outcome Scale-Extended (GOSE) at 6 months, with secondary outcomes covering postconcussion symptoms, health-related quality of life, and mental health. A total of 4360 patients were studied, including 256 (6%) with sports-related TBI (mean [SD] age, 38.9 [18.1] years; 161 [63%] male) and 4104 with non-sports-related TBI (mean [SD] age, 51.0 [20.2] years; 2773 [68%] male). Compared with patients with non-sports-related TBI, patients with sports-related TBI were younger, more likely to have tertiary education, more likely to be previously healthy, and less likely to have a major extracranial injury. After adjustment, the groups did not differ in incomplete recovery (GOSE scores <8) at 6 months (odds ratio [OR], 1.27; 95% CI, 0.90-1.78; P = .22 for all patients; OR, 1.20; 95% CI, 0.83-1.73; P = .34 for those with mild TBI; and OR, 1.19; 95% CI, 0.74-1.92; P = .65 for those with mild TBI and negative CT findings). At 6 months, there was incomplete recovery in 103 of 223 patients (46%) with outcomes in the sports-related TBI group, 65 of 168 (39%) in those with mild sports-related TBI, and 30 of 98 (31%) in those with mild sports-related TBI and negative CT findings. In contrast, at 6 months, the sports-related TBI group had lower prevalence of anxiety, depression, posttraumatic stress disorder, and postconcussion symptoms than the non-sports-related group. In this cohort study of 4360 patients with TBI, functional limitations 6 months after injury were common after sports-related TBI, even mild sports-related TBI. Persisting impairment was evident in the sports-related TBI group despite better recovery compared with non-sports-related TBI on measures of mental health and postconcussion symptoms. These findings caution against taking an overoptimistic view of outcomes after sports-related TBI, even if the initial injury appears mild.

The crisis of the third day in intracranial pressure dynamics following traumatic brain injury, fact or fiction?

IntroductionIn 1960, Lazorthes and Campman introduced the concept of a ‘crisis of the third day’, which gained prominence in the field of traumatic brain injury (TBI), where it relates to neurological deterioration on the third day after injury. However, evidence regarding this phenomenon remains scarce. Research questionThis study aimed to analyze posttraumatic intracranial pressure (ICP) patterns in a large European cohort to investigate the existence of a third-day crisis and its impact on 12-month functional outcomes. Materials and methodsData were analyzed from the prospective Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Patients with TBI admitted to ICUs in 65 European centers who received ICP monitoring were included. ICP measurements, averaged per day, were analyzed using mixed models. The association between ICP peak timing and functional outcome was examined with multivariable logistic regression. ResultsThe study included 886 patients. Average ICP trajectories showed no significant changes over the first seven days post-injury, without elevation around the third day. Among 563 patients with ICP >20 during the first week, 45% reached their highest ICP after the third day. Elevated ICP (>20 mmHg) during the first week was associated with unfavorable 12-month outcomes, but the timing of ICP peak was not linked to functional outcomes. Discussion and conclusionThis multicenter study challenges the ‘crisis of the third day’ concept. No distinct ICP or TIL elevations were observed around the third day. Elevated ICP remains a prognostic indicator, but ICP peak timing does not correlate with functional outcomes.

Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): a multicentre observational cohort study

Patients with traumatic brain injury are a heterogeneous population, and the most severely injured individuals are often treated in an intensive care unit (ICU). The primary injury at impact, and the harmful secondary events that can occur during the first week of the ICU stay, will affect outcome in this vulnerable group of patients. We aimed to identify clinical variables that might distinguish disease trajectories among patients with traumatic brain injury admitted to the ICU. We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. We included patients aged 18 years or older with traumatic brain injury who were admitted to the ICU at one of the 65 CENTER-TBI participating centres, which range from large academic hospitals to small rural hospitals. For every patient, we obtained pre-injury data and injury features, clinical characteristics on admission, demographics, physiological parameters, laboratory features, brain biomarkers (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], S100 calcium-binding protein B [S100B], tau, neurofilament light [NFL], glial fibrillary acidic protein [GFAP], and neuron-specific enolase [NSE]), and information about intracranial pressure lowering treatments during the first 7 days of ICU stay. To identify clinical variables that might distinguish disease trajectories, we applied a novel clustering method to these data, which was based on a mixture of probabilistic graph models with a Markov chain extension. The relation of clusters to the extended Glasgow Outcome Scale (GOS-E) was investigated. Between Dec 19, 2014, and Dec 17, 2017, 4509 patients with traumatic brain injury were recruited into the CENTER-TBI core dataset, of whom 1728 were eligible for this analysis. Glucose variation (defined as the difference between daily maximum and minimum glucose concentrations) and brain biomarkers (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were consistently found to be the main clinical descriptors of disease trajectories (ie, the leading variables contributing to the distinguishing clusters) in patients with traumatic brain injury in the ICU. The disease trajectory cluster to which a patient was assigned in a model was analysed as a predictor together with variables from the IMPACT model, and prediction of both mortality and unfavourable outcome (dichotomised GOS-E ≤4) was improved. First-day ICU admission data are not the only clinical descriptors of disease trajectories in patients with traumatic brain injury. By analysing temporal variables in our study, variation of glucose was identified as the most important clinical descriptor that might distinguish disease trajectories in the ICU, which should direct further research. Biomarkers of brain injury (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were also top clinical descriptors over time, suggesting they might be important in future clinical practice. European Union 7th Framework program, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation, and NeuroTrauma Sciences.

Therapy Intensity Level Scale for Traumatic Brain Injury: Clinimetric Assessment on Neuro-Monitored Patients Across 52 European Intensive Care Units.

Intracranial pressure (ICP) data from traumatic brain injury (TBI) patients in the intensive care unit (ICU) cannot be interpreted appropriately without accounting for the effect of administered therapy intensity level (TIL) on ICP. A 15-point scale was originally proposed in 1987 to quantify the hourly intensity of ICP-targeted treatment. This scale was subsequently modified-through expert consensus-during the development of TBI Common Data Elements to address statistical limitations and improve usability. The latest 38-point scale (hereafter referred to as TIL) permits integrated scoring for a 24-h period and has a five-category, condensed version (TIL(Basic)) based on qualitative assessment. Here, we perform a total- and component-score analysis of TIL and TIL(Basic) to: 1) validate the scales across the wide variation in contemporary ICP management; 2) compare their performance against that of predecessors; and 3) derive guidelines for proper scale use. From the observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, we extract clinical data from a prospective cohort of ICP-monitored TBI patients (n = 873) from 52 ICUs across 19 countries. We calculate daily TIL and TIL(Basic) scores (TIL24 and TIL(Basic)24, respectively) from each patient's first week of ICU stay. We also calculate summary TIL and TIL(Basic) scores by taking the first-week maximum (TILmax and TIL(Basic)max) and first-week median (TILmedian and TIL(Basic)median) of TIL24 and TIL(Basic)24 scores for each patient. We find that, across all measures of construct and criterion validity, the latest TIL scale performs significantly greater than or similarly to all alternative scales (including TIL(Basic)) and integrates the widest range of modern ICP treatments. TILmedian outperforms both TILmax and summarized ICP values in detecting refractory intracranial hypertension (RICH) during ICU stay. The RICH detection thresholds which maximize the sum of sensitivity and specificity are TILmedian ≥ 7.5 and TILmax ≥ 14. The TIL24 threshold which maximizes the sum of sensitivity and specificity in the detection of surgical ICP control is TIL24 ≥ 9. The median scores of each TIL component therapy over increasing TIL24 reflect a credible staircase approach to treatment intensity escalation, from head positioning to surgical ICP control, as well as considerable variability in the use of cerebrospinal fluid drainage and decompressive craniectomy. Since TIL(Basic)max suffers from a strong statistical ceiling effect and only covers 17% (95% confidence interval [CI]: 16-18%) of the information in TILmax, TIL(Basic) should not be used instead of TIL for rating maximum treatment intensity. TIL(Basic)24 and TIL(Basic)median can be suitable replacements for TIL24 and TILmedian, respectively (with up to 33% [95% CI: 31-35%] information coverage) when full TIL assessment is infeasible. Accordingly, we derive numerical ranges for categorising TIL24 scores into TIL(Basic)24 scores. In conclusion, our results validate TIL across a spectrum of ICP management and monitoring approaches. TIL is a more sensitive surrogate for pathophysiology than ICP and thus can be considered an intermediate outcome after TBI.

Factorial validity and comparability of the six translations of the Rivermead Post-Concussion Symptoms Questionnaire translations: results from the CENTER-TBI study

BackgroundComparison of patient-reported outcomes in multilingual studies requires evidence of the equivalence of translated versions of the questionnaires. The present study examines the factorial validity and comparability of six language versions of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) administered to individuals following traumatic brain injury (TBI) in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) study.MethodsSix competing RPQ models were estimated using data from Dutch (n = 597), English (n = 223), Finnish (n = 213), Italian (n = 268), Norwegian (n = 263), and Spanish (n = 254) language samples recruited six months after injury. To determine whether the same latent construct was measured by the best-fitting model across languages and TBI severity groups (mild/moderate vs. severe), measurement invariance (MI) was tested using a confirmatory factor analysis framework.ResultsThe results did not indicate a violation of the MI assumption. The six RPQ translations were largely comparable across languages and were able to capture the same construct across TBI severity groups. The three-factor solution comprising emotional, cognitive, and somatic factors provided the best fit with the following indices for the total sample: χ2 (101) = 647.04, {chi }^{2}/df= 6.41, p < 0.001, CFI = 0.995, TLI = 0.994, RMSEA = 0.055, CI90%[0.051, 0.059], SRMR = 0.051.ConclusionThe RPQ can be used in international research and clinical settings, allowing direct comparisons of scores across languages analyzed within the full spectrum of TBI severity. To strengthen the aggregated applicability across languages, further analyses of the utility of the response scale and comparisons between different translations of the RPQ at the item level are recommended.

Prognostic Value of Serum Biomarkers in Patients With Moderate-Severe Traumatic Brain Injury, Differentiated by Marshall Computer Tomography Classification.

Prognostication is challenging in patients with traumatic brain injury (TBI) in whom computed tomography (CT) fails to fully explain a low level of consciousness. Serum biomarkers reflect the extent of structural damage in a different way than CT does, but it is unclear whether biomarkers provide additional prognostic value across the range of CT abnormalities. This study aimed to determine the added predictive value of biomarkers, differentiated by imaging severity. This prognostic study used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (2014-2017). The analysis included patients aged ≥16 years with a moderate-severe TBI (Glasgow Coma Scale [GCS] <13) who had an acute CT and serum biomarkers obtained ≤24h of injury. Of six protein biomarkers (GFAP, NFL, NSE, S100B, Tau, UCH-L1), the most prognostic panel was selected using lasso regression. The performance of established prognostic models (CRASH and IMPACT) was assessed before and after the addition of the biomarker panel and compared between patients with different CT Marshall scores (Marshall score <3 vs. Marshall score ≥3). Outcome was assessed at six months post-injury using the extended Glasgow Outcome Scale (GOSE), and dichotomized into favorable and unfavorable (GOSE <5). We included 872 patients with moderate-severe TBI. The mean age was 47 years (range 16-95); 647 (74%) were male and 438 (50%) had a Marshall CT score <3. The serum biomarkers GFAP, NFL, S100B and UCH-L1 provided complementary prognostic information; NSE and Tau showed no added value. The addition of the biomarker panel to established prognostic models increased the area under the curve (AUC) by 0.08 and 0.03, and the explained variation in outcome by 13-14% and 7-8%, for patients with a Marshall score of <3 and ≥3, respectively. The incremental AUC of biomarkers for individual models was significantly greater when the Marshall score was <3 compared with ≥3 (p < 0.001). Serum biomarkers improve outcome prediction after moderate-severe TBI across the range of imaging severities and especially in patients with a Marshall score <3.