Trials In Traumatic Brain Injury Research Articles

Diversity trends in traumatic brain injury clinical trials in the United States

ABSTRACT Background This study aims to understand the demographic representation of patients in Traumatic Brain Injury (TBI) clinical trials by evaluating the proportions of patients from various demographic categories amongst completed TBI clinical trials in the United States. Methods ClinicalTrials.gov was queried for active TBI clinical trials. One hundred and eight completed trials in the United States were selected based on inclusion criteria, and information regarding intervention, setting, age, sex, race, and ethnicity was extracted. 2002–2006 TBI incidence data was obtained from the CDC. Chi-squared testing was applied to analyze the relationship between distributions of race and sex in the collected clinical trials and the national TBI data, and logistic regression was conducted to identify variables that may predict reporting of race or ethnicity. Results About 53.7% of selected clinical trials reported racial data and 34.3% reported ethnicity data. Logistic regression identified that clinical trials in defined phases were more likely to report racial data (p = 0.047 [1.015, 9.603]). Conclusion Current TBI trials do not consistently report race or ethnicity data. Future efforts to ensure equitable representation in clinical trials may involve reform of recruitment processes and accountability measures implemented within the grant application process to ensure proper racial and ethnicity data reporting.

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis

Levetiracetam or Phenytoin as Prophylaxis for Status Epilepticus: Secondary Analysis of the "Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial" Dataset, 2014-2017.

To compare levetiracetam and phenytoin as prophylaxis for the short-term development of status epilepticus (SE) during care of pediatric patients with acute severe traumatic brain injury (TBI). Nonprespecified secondary analysis using propensity score matching. We used the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT NCT04077411) dataset (2014-2017). Patients less than 18 years old with Glasgow Coma Scale Score less than or equal to 8 who received levetiracetam or phenytoin as a prophylactic anticonvulsant therapy. None. Of the 516 total patients who qualified for the case-control study, 372 (72.1%) patients received levetiracetam, and 144 (27.9%) received phenytoin. After propensity score matching, the pair-matched analysis with 133 in each group failed to identify an association between levetiracetam versus phenytoin use and occurrent of SE (3.8% vs. 0.8%, p = 0.22), or mortality (i.e., in-hospital, 30-d and 60-d). However, on closer inspection of the statistical testing, we cannot exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with the following: up to a mean difference of 7.3% greater prevalence of SE; up to a mean difference of 13.9%, 12.1%, and 13.9% greater mortality during the hospital stay, and 30-, and 60-days after hospital arrival, respectively. Last, analysis of 6 months Glasgow Outcome Scale Extended score in those without premorbid comorbidities, there was an association between favorable outcomes and use of phenytoin rather than levetiracetam prophylaxis. In ADAPT, the decision to use prophylactic levetiracetam versus phenytoin failed to show an association with occurrence of subsequent SE, or mortality. However, we are unable to exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with greater prevalence of SE and mortality. We are unable to make any recommendation about one prophylactic anticonvulsant medication over the other, but recommend that further larger, contemporary studies in severe pediatric TBI are carried out.

Predicting Progression of Intracranial Hemorrhage in the Prehospital TXA for TBI Trial.

Progression of intracranial hemorrhage is a common, potentially devastating complication after moderate/severe traumatic brain injury (TBI). Clinicians have few tools to predict which patients with traumatic intracranial hemorrhage on their initial head computed tomography (hCT) scan will progress. The objective of this investigation was to identify clinical, imaging, and/or protein biomarkers associated with progression of intracranial hemorrhage (PICH) after moderate/severe TBI and to create an accurate predictive model of PICH based on clinical features available at presentation. We analyzed a subset of subjects from the phase II double-blind, multi-center, randomized "Prehospital Tranexamic Acid Use for TBI" trial. This subset was limited to the placebo arm of the parent trial with evidence of hemorrhage on the initial hCT and a follow-up hCT 6 h after. PICH was defined as an increase in hemorrhage size by 30% or more, or the development of new hemorrhage in the intra- and extra-axial intracranial vault between the initial and the follow-up hCT. Two independent radiologists evaluated each hCT, and conflicts were adjudicated by a third. Clinical and radiographic characteristics were collected, along with plasma protein biomarkers at admission. Principal component analysis (PCA) was performed, and each principal component (PC) was interrogated for its association with PICH. Finally, expert opinion and recursive feature extraction (RFE) were used to select input features for the construction of several supervised classification models. Their ability to predict PICH was quantified and compared. In this subset of subjects (n = 104), 46% (n = 48) demonstrated PICH. Univariate analyses showed no association between PICH and age, sex, admission Glasgow Coma Scale (GCS), GCS motor subscore, presence of midline shift, admission platelet count or admission INR. Radiographic severity scores (Marshall score [p = 0.007], Rotterdam score [p = 0.004]), and initial hematoma volume [p = 0.005] were associated with PICH. Higher levels of admission glial fibrillary acidic protein (p < 0.001) and MAP (p = 0.011) were also associated with PICH. Of the PCs, PC1 was significantly associated with PICH (p = 0.0125). Using multimodal data input, machine learning classifiers successfully discriminated patients with or without PICH. Models composed of machine-selected features performed better than models composed of expert-selected variables (reaching an average of 77% accuracy, AUC = 0.78 versus AUC = 0.68 for the expert-selected variables). Predictive models utilizing variables measured at admission can accurately predict PICH, confirmed by the 6-hour follow-up hCT. Our best-performing models must now be externally validated in a separate cohort of TBI patients with low GCS and initial hCT positive for hemorrhage.

The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: a subgroup analysis from the prehospital TXA for TBI trial.

In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. Therapeutic/Care Management, Level II.

445 Performance of the IMPACT and CRASH Prognostic Models for Traumatic Brain Injury in a Contemporary Multicenter Cohort: A TRACK-TBI Study

INTRODUCTION: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomisation After Significant Head Injury (CRASH) prognostic models for mortality and functional outcome in traumatic brain injury (TBI) were developed using historical data from 1984-2004. METHODS: The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury study enrolled participants aged = 17-years who presented to Level 1 trauma center and received head computed tomography (CT) scan &lt;24-hours of TBI. Data was extracted from participants meeting IMPACT (Glasgow Coma Scale (GCS) 3-12; completed 6-month Glasgow Outcome Scale-Extended (GOSE); N = 441) and CRASH criteria (GCS 3-14; completed 2-week and 6-month GOSE; N = 831). Original model coefficients were applied, and performances were assessed using discrimination (area under the receiver-operating characteristic curve (AUC)) and calibration (intercept; slope; [95% confidence interval]). RESULTS: IMPACT and CRASH models discriminated mortality (AUC = 0.77-0.81, 0.90-0.91, respectively) and unfavorable outcome (0.77-0.81; 0.83, respectively). The IMPACT Lab model overestimated mortality (intercept = -0.79 [-1.05, -0.53]; slope = 1.37 [1.05-1.69]) and acceptably estimated unfavorable outcome (intercept = 0.07 [-0.14, 0.29]; slope = 1.19 [0.96-1.42]). The CRASH CT model overestimated mortality (intercept = -1.06 [-1.36, -0.75]; slope = 0.96 [0.79-1.14]) and unfavorable outcome (intercept = -0.60 [-0.78, -0.41]; slope = 1.20 [1.03-1.37]). Calibration performance differences were observed across the 5 leading enrollment centers (IMPACT Lab model: intercept -1.66 to -0.35, slope 1.07-1.86; CRASH CT model: intercept -1.81 to -0.67, slope 0.67-1.56) and unfavorable outcome (IMPACT Lab model: intercept -0.57 to 0.34, slope 1.28-2.89; CRASH CT model: intercept -1.15 to -0.10, slope 1.02-1.44). CONCLUSIONS: IMPACT and CRASH models discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to develop prognostic models that incorporate contemporary changes in TBI casemix. Investigations to elucidate the relationships between increased survival, functional outcome, treatment intensity, and center-specific practices will be highly relevant.

Changes in neurologic status after traumatic brain injury in the Resuscitation Outcomes Consortium Hypertonic Saline trial.

Traumatic brain injury (TBI) is an important public health problem resulting in significant death and disability. Emergency medical services (EMS) personnel often provide initial treatment for TBI, but only limited data describe the long-term course and outcomes of this care. We sought to characterize changes in neurologic status among adults with TBI patients enrolled in the Resuscitation Outcomes Consortium Hypertonic Saline (ROC-HS) trial. We used data from the TBI cohort of the ROC-HS trial. The trial included adults with TBI, with Glasgow Coma Scale (GCS) ≤8, and excluded those with shock (systolic blood pressure [SBP] ≤70 or SBP 71-90 with a heart rate [HR] ≥108). The primary outcome was Glasgow Outcome Scale-Extended (GOS-E; 1=dead, 8=no disability) determined at (a) hospital discharge and (b) 6-month follow-up. We assessed changes in GOS-E between hospital discharge and 6-month follow-up using descriptive statistics and Sankey graphs. Among 1279 TBI included in the analysis, GOS-E categories at hospital discharge were as follows: favorable (GOS-E 5-8) 220 (17.2%), unfavorable (GOS-E 2-4) 664 (51.9%), dead (GOS-E 1) 321 (25.1%), and missing 74 (5.8%). GOS-E categories at 6-month follow-up were as follows: favorable 459 (35.9%), unfavorable 279 (21.8%), dead 346 (27.1%), and missing 195 (15.2%). Among initial TBI survivors with complete GOS-E,>96% followed one of three neurologic recovery patterns: (1) favorable to favorable (20.0%), (2) unfavorable to favorable (40.3%), and (3) unfavorable to unfavorable (36.0%). Few patients deteriorated from favorable to unfavorable neurologic status, and there were few additional deaths. Among TBI receiving initial prehospital care in the ROC-HS trial, changes in 6-month neurologic status followed distinct patterns. Among TBI with unfavorable neurologic status at hospital discharge, almost half improved to favorable neurologic status at 6 months. Among those with favorable neurologic status at discharge, very few worsened or died at 6 months. These findings have important implications for TBI clinical care, research, and trial design.

Utility of in-session assessments during cognitive behavioral therapy for depression after traumatic brain injury: Results from arandomized controlled trial.

The development of depression after moderate to severe traumatic brain injury (TBI) is common. Cognitive-behavioral therapy (CBT) can be used to treat post-TBI depression, but the symptoms response is poorly described. This secondary analysis assessed: (1) the trajectory of depression symptoms up to 12 sessions of CBT, (2) which depressive symptom clusters were responsive to in-person and phone CBT, and (3) whether interim depression thresholds predict 16-week treatment response. This secondary analysis of the IRB-approved Life Improvement Following Traumatic Brain Injury trial included 100 adults with major depressive disorder (MDD) within ten years of moderate to severe traumatic brain injury from throughout the US. We used a combination of descriptive, graphical, and diagnostic accuracy methods. Cardinal and cognitive-affective symptom clusters improved most from CBT over 16 weeks. At 8 and 16 weeks, the most responsive individual symptoms were anhedonia, depressed mood, and fatigue; the least responsive were sleep and appetite. PHQ-9 thresholds with a Negative Predictive Value greater than 0.7 for sessions 6, 7, and 8 were, respectively: >15, >10, and >9. In-person and phone CBT led to similar symptom responses during treatment. Additionally, using PHQ-9 thresholds for predicting intervention response within eight sessions may help identify the need for treatment adjustments.

Evaluation of ChatGPT in Predicting 6-Month Outcomes After Traumatic Brain Injury.

To evaluate the capacity of ChatGPT, a widely accessible and uniquely popular artificial intelligence-based chatbot, in predicting the 6-month outcome following moderate-to-severe traumatic brain injury (TBI). Single-center observational retrospective study. Data are from a neuro-ICU from a level 1 trauma center. All TBI patients admitted to ICU between September 2021 and October 2022 were included in a prospective database. None. Based on anonymized clinical, imaging, and biological information available at the patients' hospital admission and extracted from the database, clinical vignettes were retrospectively submitted to ChatGPT for prediction of patients' outcomes. The predictions of two intensivists (one neurointensivist and one non-neurointensivist) both from another level 1 trauma center (Beaujon Hospital), were also collected as was the International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) scoring. Each intensivist, as well as ChatGPT, made their prognostic evaluations independently, without knowledge of the others' predictions and of the patients' actual management and outcome. Both the intensivists and ChatGPT were given access to the exact same set of information. The main outcome was a 6-month-functional status dichotomized into favorable (Glasgow Outcome Scale Extended [GOSE] ≥ 5) versus poor (GOSE < 5). Prediction of intracranial hypertension management, pulmonary infectious risk, and removal of life-sustaining therapies was also investigated as secondary outcomes. Eighty consecutive moderate-to-severe TBI patients were included. For the 6-month outcome prognosis, area under the receiver operating characteristic curve (AUC-ROC) for ChatGPT, the neurointensivist, the non-neurointensivist, and IMPACT were, respectively, 0.62 (0.50-0.74), 0.70 (0.59-0.82), 0.71 (0.59-0.82), and 0.81 (0.72-0.91). ChatGPT had the highest sensitivity (100%), but the lowest specificity (26%). For secondary outcomes, ChatGPT's prognoses were generally less accurate than clinicians' prognoses, with lower AUC values for most outcomes. This study does not support the use of ChatGPT for prediction of outcomes after TBI.

Performance of the IMPACT and CRASH prognostic models for traumatic brain injury in a contemporary multicenter cohort: a TRACK-TBI study.

The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization After Significant Head Injury (CRASH) prognostic models for mortality and outcome after traumatic brain injury (TBI) were developed using data from 1984 to 2004. This study examined IMPACT and CRASH model performances in a contemporary cohort of US patients. The prospective 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years 2014-2018) enrolled subjects aged ≥ 17 years who presented to level I trauma centers and received head CT within 24 hours of TBI. Data were extracted from the subjects who met the model criteria (for IMPACT, Glasgow Coma Scale [GCS] score 3-12 with 6-month Glasgow Outcome Scale-Extended [GOSE] data [n = 441]; for CRASH, GCS score 3-14 with 2-week mortality data and 6-month GOSE data [n = 831]). Analyses were conducted in the overall cohort and stratified on the basis of TBI severity (severe/moderate/mild TBI defined as GCS score 3-8/9-12/13-14), age (17-64 years or ≥ 65 years), and the 5 top enrolling sites. Unfavorable outcome was defined as GOSE score 1-4. Original IMPACT and CRASH model coefficients were applied, and model performances were assessed by calibration (intercept [< 0 indicated overprediction; > 0 indicated underprediction] and slope) and discrimination (c-statistic). Overall, the IMPACT models overpredicted mortality (intercept -0.79 [95% CI -1.05 to -0.53], slope 1.37 [1.05-1.69]) and acceptably predicted unfavorable outcome (intercept 0.07 [-0.14 to 0.29], slope 1.19 [0.96-1.42]), with good discrimination (c-statistics 0.84 and 0.83, respectively). The CRASH models overpredicted mortality (intercept -1.06 [-1.36 to -0.75], slope 0.96 [0.79-1.14]) and unfavorable outcome (intercept -0.60 [-0.78 to -0.41], slope 1.20 [1.03-1.37]), with good discrimination (c-statistics 0.92 and 0.88, respectively). IMPACT overpredicted mortality and acceptably predicted unfavorable outcome in the severe and moderate TBI subgroups, with good discrimination (c-statistic ≥ 0.81). CRASH overpredicted mortality in the severe and moderate TBI subgroups and acceptably predicted mortality in the mild TBI subgroup, with good discrimination (c-statistic ≥ 0.86); unfavorable outcome was overpredicted in the severe and mild TBI subgroups with adequate discrimination (c-statistic ≥ 0.78), whereas calibration was nonlinear in the moderate TBI subgroup. In subjects ≥ 65 years of age, the models performed variably (IMPACT-mortality, intercept 0.28, slope 0.68, and c-statistic 0.68; CRASH-unfavorable outcome, intercept -0.97, slope 1.32, and c-statistic 0.88; nonlinear calibration for IMPACT-unfavorable outcome and CRASH-mortality). Model performance differences were observed across the top enrolling sites for mortality and unfavorable outcome. The IMPACT and CRASH models adequately discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to update prognostic models to incorporate contemporary changes in TBI management and case-mix. Investigations to elucidate the relationships between increased survival, outcome, treatment intensity, and site-specific practices will be relevant to improve models in specific TBI subpopulations (e.g., older adults), which may benefit from the inclusion of blood-based biomarkers, neuroimaging features, and treatment data.

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.

Outcomes of Repeat Surgery in Pediatric Severe Traumatic Brain Injury: An Analysis from Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial

BackgroundEarly operative intervention, craniotomy (CO), and/or craniectomy (DC) are occasionally warranted in severe traumatic brain injury (TBI). Persistent increased intracranial pressure (ICP) or accumulation of intracranial hematoma post-surgery can result in higher mortality and morbidity. There is a gap in information regarding the outcome of repeat surgery (RS) in pediatric patients with severe TBI. MethodsAn observational cohort study titled Approaches and Decisions in Acute Pediatric Trial (ADAPT) of severe TBI data was obtained from the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System. All pediatric patients who underwent CO or DC, survived more than 44 hours and were found to have persistent elevated ICP >20 for two consecutive hours were included in the study. The purpose of the study was to find the outcomes of RS in pediatric severe TBI. Propensity based matching was used to find the outcomes. The primary outcome was 60-day mortality. ResultsOut of 1000 total patients enrolled in the ADAPT trial, 160 patients qualified for this study. Propensity score matching created 13 pairs of patients. There were no significant differences found between the groups who had RS vs. those who did not have repeat surgery (NRS). There were no significant differences found between the groups regarding 60-day mortality, median hospital days, median ICU days, and 6-month favorable outcome on Glasgow Outcome Scale Extended (GOS-E) score. ConclusionThere was no difference in mortality between patients who underwent a second surgery and patients who did not have to undergo a second surgery.

Identity Theft, Deep Brain Stimulation, and the Primacy of Post-trial Obligations.

Patient narratives from two investigational deep brain stimulation trials for traumatic brain injury and obsessive-compulsive disorder reveal that injury and illness rob individuals of personal identity and that neuromodulation can restore it. The early success of these interventions makes a compelling case for continued post-trial access to these technologies. Given the centrality of personal identity to respect for persons, a failure to provide continued access can be understood to represent a metaphorical identity theft. Such a loss recapitulates the pain of an individual's initial injury or illness and becomes especially tragic because it could be prevented by robust policy. A failure to fulfill this normative obligation constitutes a breach of disability law, which would view post-trial access as a means to achieve social reintegration through this neurotechnological accommodation.

Outcomes and physiologic responses associated with ketamine administration after traumatic brain injury in the United States and Canada: a retrospective analysis

Purpose: Ketamine has historically been contraindicated in traumatic brain injury (TBI) due to concern for raising intracranial pressure. However, it is increasingly being used in TBI due to the favorable respiratory and hemodynamic properties. To date, no studies have evaluated whether ketamine administered in subjects with TBI is associated with patient survival or disability. Methods: We performed a retrospective analysis of data from the multicenter Prehospital Tranexamic Acid Use for Traumatic Brain Injury trial, comparing ketamine-exposed and ketamine-unexposed TBI subjects to determine whether an association exists between ketamine administration and mortality, as well as secondary outcome measures.Results: We analyzed 841 eligible subjects from the original study, of which 131 (15.5%) received ketamine. Ketamine-exposed subjects were younger (37.3±16.9 years vs. 42.0±18.6 years, P=0.037), had a worse initial Glasgow Coma Scale score (7±3 vs. 8±4, P=0.003), and were more likely to be intubated than ketamine-unexposed subjects (88.5% vs. 44.2%, P&lt;0.001). Overall, there was no difference in mortality (12.2% vs. 15.5%, P=0.391) or disability measures between groups. Ketamine-exposed subjects had significantly fewer instances of elevated intracranial pressure (ICP) compared to ketamine-unexposed subjects (56.3% vs. 82.3%, P=0.048). In the very rare outcomes of cardiac events and seizure activity, seizure activity was statistically more likely in ketamine-exposed subjects (3.1% vs. 1.0%, P=0.010). In the intracranial hemorrhage subgroup, cardiac events were more likely in ketamine-exposed subjects (2.3% vs. 0.2%, P=0.025). Ketamine exposure was associated with a smaller increase in TBI protein biomarker concentrations.Conclusions: Ketamine administration was not associated with worse survival or disability despite being administered to more severely injured subjects. Ketamine exposure was associated with reduced elevations of ICP, more instances of seizure activity, and lower concentrations of TBI protein biomarkers.

Selection of a statistical analysis method for the Glasgow Outcome Scale-Extended endpoint for estimating the probability of favorable outcome in future severe TBI clinical trials.

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.

The effect of recombinant erythropoietin on long-term outcome after moderate-to-severe traumatic brain injury

PurposeRecombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown.MethodsWe conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010–2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5–8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI.ResultsOf 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47–1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI - 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2–22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome.ConclusionEPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI.

A map of evidence using transcranial direct current stimulation (tDCS) to improve cognition in adults with traumatic brain injury (TBI).

Cognition impairments often occur after a traumatic brain injury and occur at higher rates in military members. Cognitive symptoms impair daily function, including balance and life quality, years after the TBI. Current treatments to regain cognitive function after TBI, including medications and cognitive rehabilitation, have shown limited effectiveness. Transcranial direct current stimulation (tDCS) is a low-cost, non-invasive brain stimulation intervention that improves cognitive function in healthy adults and people with neuropsychologic diagnoses beyond current interventions. Despite the available evidence of the effectiveness of tDCS in improving cognition generally, only two small TBI trials have been conducted based on the most recent systematic review of tDCS effectiveness for cognition following neurological impairment. We found no tDCS studies that addressed TBI-related balance impairments. A scoping review using a peer-reviewed search of eight databases was completed in July 2022. Two assessors completed a multi-step review and completed data extraction on included studies using a priori items recommended in tDCS and TBI research guidelines. A total of 399 results were reviewed for inclusion and 12 met the criteria and had data extracted from them by two assessors using Google Forms. Consensus on combined data results included a third assessor when needed. No studies using tDCS for cognition-related balance were found. Guidelines and technology measures increase the identification of brain differences that alter tDCS effects on cognition. People with mild-severe and acute-chronic TBI tolerated and benefited from tDCS. TBI-related cognition is understudied, and systematic research that incorporates recommended data elements is needed to advance tDCS interventions to improve cognition after TBI weeks to years after injury.

Glasgow coma scale pupil score (GCS-P) and the hospital mortality in severe traumatic brain injury: analysis of 1,066 Brazilian patients.

Pupil reactivity and the Glasgow Coma Scale (GCS) score are the most clinically relevant information to predict the survival of traumatic brain injury (TBI) patients. We evaluated the accuracy of the GCS-Pupil score (GCS-P) as a prognostic index to predict hospital mortality in Brazilian patients with severe TBI and compare it with a model combining GCS and pupil response with additional clinical and radiological prognostic factors. Data from 1,066 patients with severe TBI from 5 prospective studies were analyzed. We determined the association between hospital mortality and the combination of GCS, pupil reactivity, age, glucose levels, cranial computed tomography (CT), or the GCS-P score by multivariate binary logistic regression. Eighty-five percent (n = 908) of patients were men. The mean age was 35 years old, and the overall hospital mortality was 32.8%. The area under the receiver operating characteristic curve (AUROC) was 0.73 (0.70-0.77) for the model using the GCS-P score and 0.80 (0.77-0.83) for the model including clinical and radiological variables. The GCS-P score showed similar accuracy in predicting the mortality reported for the patients with severe TBI derived from the International Mission for Prognosis and Clinical Trials in TBI (IMPACT) and the Corticosteroid Randomization After Significant Head Injury (CRASH) studies. Our results support the external validation of the GCS-P to predict hospital mortality following a severe TBI. The predictive value of the GCS-P for long-term mortality, functional, and neuropsychiatric outcomes in Brazilian patients with mild, moderate, and severe TBI deserves further investigation.

Evaluating the Performance of the IMPACT Model in the Prehospital TXA for TBI Trial (P14-7.001)

<h3>Objective:</h3> To test the IMPACT model’s performance in a contemporary clinical trial population. <h3>Background:</h3> The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) prognostic model predicts functional outcome after moderate-severe traumatic brain injury (TBI). Our previous work suggested that glial fibrillary acidic protein (GFAP) may improve the discrimination of outcome when added to prognostic models. <h3>Design/Methods:</h3> We analyzed data from a subset subjects from the phase II double-blind, multicenter randomized controlled trial, “Prehospital Tranexamic Acid Use for Traumatic Brain Injury.” This subset was limited to subjects in the placebo arm of the parent trial with evidence of hemorrhage on initial head computed tomographic (CT) scan. All 3 versions (core, extended, lab) of the IMPACT model were evaluated against 6-month mortality, plus an exploratory 4^th version (lab+GFAP). We compared our results to previously published validation results from the CENTER-TBI cohort. <h3>Results:</h3> Within the subset (n=166), 127 subjects had complete 6-month outcome data. Predictor variables were missing &lt;10% (0–9.4%) of cases, and were imputed (GCS motor score, pupillary reactivity, serum glucose, serum hemoglobin, hypoxia, and Marshall CT score). GFAP was associated with mortality (p=0.004). The core model discriminated poorly in the subset (AUC 0.60 [95% CI: 0.48–0.71], p=0.096). The extended model discriminated well (AUC 0.73 [95% CI: 0.64–0.82], p&lt;0.001). The lab model discriminated non-significantly better (AUC 0.76 [95% CI: 0.66–0.86], p=0.167). Adding GFAP to the lab model improved discrimination further (AUC 0.83 [95% CI: 0.76–0.90], p=0.004). All 4 models overestimated mortality compared with the observed rate (n=31, 24% v. 26–82%). <h3>Conclusions:</h3> In comparison with the observational CENTER-TBI validation cohort, the IMPACT models (core/extended/lab) discriminated mortality less well in a subset of the TXA trial. The addition of GFAP improved discrimination for mortality, but further work is needed to optimize its addition to the lab model. <b>Disclosure:</b> Dr. Hinson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UCSF. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. Shannon McWeeney has nothing to disclose. Adam Ferguson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Spine X Inc. Adam Ferguson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuronasal Inc.. The institution of Adam Ferguson has received research support from NIH/NINDS. The institution of Adam Ferguson has received research support from VA RR&amp;D. The institution of Adam Ferguson has received research support from VA BLR&amp;D. The institution of Adam Ferguson has received research support from Wings for Life Foundation/Craig H Neilsen Foundation. The institution of Adam Ferguson has received research support from Wings for Life Foundation. The institution of Adam Ferguson has received research support from DoD/CDMRP. The institution of Adam Ferguson has received research support from DARPA. The institution of Adam Ferguson has received research support from DoE. Adam Ferguson has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with NIH/CSR. Dr. Schreiber has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for CSL Behring. Dr. Schreiber has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Harmonetics. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tricol. Dr. Schreiber has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Trauma Textbook. Dr. Schreiber has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Lawyers. The institution of Dr. Schreiber has received research support from DoD. Dr. Rowell has nothing to disclose.

Increasing SUR1-related pathway activity with increasing injury severity in immune and neurovascular cells after murine TBI (P8-1.006)

<h3>Objective:</h3> To evaluate cell-specific changes in sulfonylurea-receptor-1 (SUR1)-transient receptor melastatin-4 (TRPM4) related pathway gene expression activity and biological processes by single-cell RNA sequencing (scRNA-Seq) across increasing severity of murine traumatic brain injury (TBI). <h3>Background:</h3> SUR1-TRPM4 inhibition is being evaluated in a phase-II TBI trial, however genes upstream/downstream of this channel may also be impacted differentially across cell types at the injury site. We hypothesized that SUR1-TRPM4 pathway gene expression and biological processes vary with severity, particularly in immune-cells subtypes. <h3>Design/Methods:</h3> Murine TBI models of increasing severity included naïve, mild-repetitive-TBI (mrTBI), Controlled-Cortical Impact (CCI). Dissociated single-cell suspensions from peri-injured tissue 24h post-TBI underwent scRNA-Seq (10X-Genomics, Illumina), pre-processing (CellRanger) and quality-control (Seurat). A network of 202 SUR1-related genes was developed and used to evaluate SUR1-pathway activity (AUCell). Gene expression, biological pathways, gene-ontology network, cell-communication and pseudotime analyses were assessed (R-packages). <h3>Results:</h3> 79,764 cells were sequenced (naïve=26,851, mrTBI=27,380, CCI=25,533), consisting of 11 cell-types and several subtypes. SUR1-pathway activity was absent in naïve myeloid cells, mildly increased in some cells after mrTBI, and markedly increased after CCI particularly in monocyte, microglia, macrophage and neutrophil subtypes. In B- and T-cells, SUR1-pathway activity was only noted after CCI. Increased SUR1-pathway activity was seen in several astrocyte- and endothelial-subtypes (limited to CCI). Only one neuronal subtype demonstrated increased SUR1-pathway activity after CCI. In immune cells S100a8, S100a9, Cxcl2, and Il1b displayed the highest correlation to SUR1-pathway activity. In astrocytes this was AQP4. Pseudotime analysis identified lineages specific for higher SUR1-pathway activity in several cell types. Biological processes associated with SUR1-pathway activity (chemotaxis, differentiation, apoptosis) were highly variable between cell types. <h3>Conclusions:</h3> SUR1-pathway activity and associated biological processes varied greatly with TBI severity (maximal in severe TBI), and cell type. These differences should be leveraged to develop cell-specific biomarkers and targeted pathway modulation/treatment. <b>Disclosure:</b> Mr. Sneiderman has nothing to disclose. Dr. Xiong has nothing to disclose. Dr. Rajasundaram has nothing to disclose. Dr. Simon has nothing to disclose. Dr. Catapano has nothing to disclose. Mrs. Mihaljevic has nothing to disclose. Dr. Shahjouei has nothing to disclose. Dr. Raikwar has nothing to disclose. Dr. Rani has nothing to disclose. Miss Trivedi has nothing to disclose. Mr. Rulney has nothing to disclose. Dr. Winkler has nothing to disclose. Ms. Miller has nothing to disclose. Mr. Lim has nothing to disclose. Ms. Feldman has nothing to disclose. Vincent Vagni has nothing to disclose. The institution of Dr. Kohanbash has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Johns Hopkins Health System. The institution of Patrick M. Kochanek, MD, MCCM has received research support from Chuck Noll Foundation. The institution of Patrick M. Kochanek, MD, MCCM has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received publishing royalties from a publication relating to health care. Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. An immediate family member of Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Legal fees. The institution of Dr. Jha has received research support from NIH/NINDS, Chuck Noll Foundation, University of Pittsburgh, Barrow Neurological Foundation.