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Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80–1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91–1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74–1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90–1·33]). Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.

Recently, successful predictions using machine learning (ML) algorithms have been reported in various fields. However, in traumatic brain injury (TBI) cohorts, few studies have examined modern ML algorithms. To develop a simple ML model for TBI outcome prediction, we conducted a performance comparison of nine algorithms: ridge regression, least absolute shrinkage and selection operator (LASSO) regression, random forest, gradient boosting, extra trees, decision tree, Gaussian naïve Bayes, multi-nomial naïve Bayes, and support vector machine. Fourteen feasible parameters were introduced in the ML models, including age, Glasgow Coma Scale (GCS), systolic blood pressure (SBP), abnormal pupillary response, major extracranial injury, computed tomography (CT) findings, and routinely collected laboratory values (glucose, C-reactive protein [CRP], and fibrin/fibrinogen degradation products [FDP]). Data from 232 patients with TBI were randomly divided into a training sample (80%) for hyperparameter tuning and validation sample (20%). The bootstrap method was used for validation. Random forest demonstrated the best performance for in-hospital poor outcome prediction and ridge regression for in-hospital mortality prediction: the mean statistical measures were 100% sensitivity, 72.3% specificity, 91.7% accuracy, and 0.895 area under the receiver operating characteristic curve (AUC); and 88.4% sensitivity, 88.2% specificity, 88.6% accuracy, and 0.875 AUC, respectively. Based on the feature selection method using the tree-based ensemble algorithm, age, Glasgow Coma Scale, fibrin/fibrinogen degradation products, and glucose were identified as the most important prognostic factors for poor outcome and mortality. Our results indicate the relatively good predictive performance of modern ML for TBI outcome. Further external validation is required for more heterogeneous samples to confirm our results.

Background Elevated catecholamine levels might be associated with unfavorable outcome after traumatic brain injury (TBI). We investigated the association between catecholamine levels in the first 24 h post-trauma and functional outcome in patients with isolated moderate-to-severe TBI. Methods A cohort of 174 patients who sustained isolated blunt TBI was prospectively enrolled from three Level-1 Trauma Centers. Epinephrine (Epi) and norepinephrine (NE) concentrations were measured at admission (baseline), 6, 12 and 24 h post-injury. Outcome was assessed at 6 months by the extended Glasgow Outcome Scale (GOSE) score. Fractional polynomial plots and logistic regression models (fixed and random effects) were used to study the association between catecholamine levels and outcome. Effect size was reported as the odds ratio (OR) associated with one logarithmic change in catecholamine level. Results At 6 months, 109 patients (62.6%) had an unfavorable outcome (GOSE 5–8 vs. 1–4), including 51 deaths (29.3%). Higher admission levels of Epi were associated with a higher risk of unfavorable outcome (OR, 2.04, 95% CI: 1.31–3.18, p  = 0.002) and mortality (OR, 2.86, 95% CI: 1.62–5.01, p  = 0.001). Higher admission levels of NE were associated with higher risk of unfavorable outcome (OR, 1.59, 95% CI: 1.07–2.35, p  = 0.022) but not mortality (OR, 1.45, 95% CI: 0.98–2.17, p  = 0.07). There was no relationship between the changes in Epi levels over time and mortality or unfavorable outcome. Changes in NE levels with time were statistically associated with a higher risk of mortality, but the changes had no relation to unfavorable outcome. Conclusions Elevated circulating catecholamines, especially Epi levels on hospital admission, are independently associated with functional outcome and mortality after isolated moderate-to-severe TBI.

There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. ClinicalTrials.gov NCT01322009.

Prehospital plasma administration improves survival in injured patients at risk for hemorrhagic shock and transported by air ambulance. Traumatic brain injury (TBI) is a leading cause of death following trauma, but few early interventions improve outcomes. To assess the association between prehospital plasma and survival in patients with TBI. The Prehospital Air Medical Plasma (PAMPer) trial was a pragmatic, multicenter, phase 3, cluster randomized clinical trial involving injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center. The trial was conducted at 6 US sites with 9 level-I trauma centers (comprising 27 helicopter emergency services bases). The original trial analyzed 501 patients, including 230 patients who were randomized to receive plasma and 271 randomized to standard care resuscitation. This secondary analysis of a predefined subgroup included patients with TBI. Data analysis was performed from October 2019 to February 2020. Patients were randomized to receive standard care fluid resuscitation or 2 units of thawed plasma. The primary outcome was mortality at 30 days. Patients with TBI were prespecified as a subgroup for secondary analysis and for measurement of markers of brain injury. The 30-day survival benefit of prehospital plasma in subgroups with and without TBI as diagnosed by computed tomography was characterized using Kaplan-Meier survival analysis and Cox proportional hazard regression. In total, 166 patients had TBI (median [interquartile range] age, 43.00 [25.00-59.75] years; 125 men [75.3%]). When compared with the 92 patients who received standard care, the 74 patients with TBI who received prehospital plasma had improved 30-day survival even after adjustment for multiple confounders and assessment of the degree of brain injury with clinical variables and biomarkers (hazard ratio [HR], 0.55; 95% CI, 0.33-0.94; P = .03). Receipt of prehospital plasma was associated with improved survival among patients with TBI with a prehospital Glasgow Coma Scale score of less than 8 (HR, 0.56; 95% CI, 0.35-0.91) and those with polytrauma (HR, 0.50; 95% CI, 0.28-0.89). Patients with TBI transported from the scene of injury had improved survival following prehospital plasma administration (HR, 0.45; 95% CI, 0.26-0.80; P = .005), whereas patients who were transferred from an outside hospital showed no difference in survival for the plasma intervention (HR, 1.00; 95% CI, 0.33-3.00; P = .99). These findings are exploratory, but they suggest that receipt of prehospital plasma is associated with improved survival in patients with computed tomography-positive TBI. The prehospital setting may be a critical period to intervene in the care of patients with TBI. Future studies are needed to confirm the clinical benefits of early plasma resuscitation following TBI and concomitant polytrauma. ClinicalTrials.gov Identifier: NCT01818427.

Background The occurrence of traumatic brain injury (TBI) has been progressively increasing over the years, mainly due to factors such as driving accidents and falls. Globally, TBI is now considered a significant cause of death and disability, particularly among young adults. TBI leads to inflammation and oxidative stress, significantly contributing to increased mortality and long-term complications. The importance of early therapeutic interventions in patients with TBI has been highlighted in several studies. The impact of trehalose as an anti-inflammatory and antioxidant on TBI has been well documented in animal models; however, this effect remains inconclusive in humans. This study aims to assess the effects of trehalose on inflammatory markers, oxidative stress, clinical outcomes, and mortality in TBI patients. Method In this double-blind randomized controlled trial, we will recruit 80 patients aged 18 to 65 years with TBI from Al-Zahra Hospital, Isfahan, Iran, and randomly allocate them at the individual level into two groups of 40. One group will receive 10 g of trehalose daily (intervention group), while the other will receive 10 g of maltodextrin (placebo group) for 7 days. Primary outcomes include inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6)), oxidative stress markers (total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA)), clinical scores (sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), Nutrition Risk In Critically Ill (NUTRIC)), mortality (days 28, 60, 90), and hospital stay (day). Discussion Given the anti-inflammatory and antioxidant effects of trehalose observed in preclinical TBI models, its supplementation in patients with TBI may potentially improve the outcomes.

Background The prognostication of long-term functional outcomes remains challenging in patients with traumatic brain injury (TBI). Our aim was to demonstrate that intensive care unit (ICU) variables are not efficient to predict 6-month functional outcome in survivors with moderate to severe TBI (msTBI) but are mostly associated with mortality, which leads to a mortality bias for models predicting a composite outcome of mortality and severe disability. Methods We analyzed the data from the multicenter randomized controlled Continuous Hyperosmolar Therapy in Traumatic Brain-Injured Patients trial and developed predictive models using machine learning methods and baseline characteristics and predictors collected during ICU stay. We compared our models’ predictions of 6-month binary Glasgow Outcome Scale extended (GOS-E) score in all patients with msTBI (unfavorable GOS-E 1–4 vs. favorable GOS-E 5–8) with mortality (GOS-E 1 vs. GOS-E 2–8) and binary functional outcome in survivors with msTBI (severe disability GOS-E 2–4 vs. moderate to no disability GOS-E 5–8). We investigated the link between ICU variables and long-term functional outcomes in survivors with msTBI using predictive modeling and factor analysis of mixed data and validated our hypotheses on the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Results Based on data from 370 patients with msTBI and classically used ICU variables, the prediction of the 6-month outcome in survivors was inefficient (mean area under the receiver operating characteristic 0.52). Using factor analysis of mixed data graph, we demonstrated that high-variance ICU variables were not associated with outcome in survivors with msTBI ( p  = 0.15 for dimension 1, p  = 0.53 for dimension 2) but mostly with mortality ( p  < 0.001 for dimension 1), leading to a mortality bias for models predicting a composite outcome of mortality and severe disability. We finally identified this mortality bias in the IMPACT model. Conclusions We demonstrated using machine learning–based predictive models that classically used ICU variables are strongly associated with mortality but not with 6-month outcome in survivors with msTBI, leading to a mortality bias when predicting a composite outcome of mortality and severe disability.

Background Neurocritical diseases such as subarachnoid hemorrhage, traumatic brain injury, and cerebral hemorrhage are the main cause of death and long-term disability. Red blood cell (RBC) transfusion can improve the oxygen supply to the brain, but may lead to complications such as cerebral vasospasm. The optimal threshold is unknown. We conducted a randomized trial to explore the optimal RBC transfusion strategy for neurocritical patients based on perioperative blood protection: liberal RBC transfusion strategy or restrictive RBC transfusion strategy. Methods This is a single-center, prospective, randomized, controlled trial. A total of 234 neurocritical patients will be randomly assigned to the liberal RBC transfusion strategy (90 g/L) group and the restrictive RBC transfusion strategy (70 g/L) group in a 1:1 ratio. The primary outcome is the neurological outcome at discharge. Further safety and efficacy parameters include the Glasgow Outcome Scale extended score at 6 months after surgery, in-hospital mortality, the incidence of transfusion reactions, and the incidence of systemic complications. Discussion This is a prospective randomized controlled study to investigate the effect of a liberal RBC transfusion strategy (90 g/L) versus a restrictive RBC transfusion strategy (70 g/L) on the outcome of neurocritical patients. Transfusion strategies for neurocritical patients with impaired autoregulation of cerebral blood flow have been controversial, so it is necessary to explore transfusion strategies that are more suitable for these patients. This study will be carried out on the basis of blood protection, that is, intraoperative autotransfusion will be used during the surgery, which was not involved in previous studies. The results of this study will provide a theoretical basis for the use of blood products in neurocritical patients. Trial registration This study conforms to the principles of the Helsinki Declaration. This trial is registered at the Chinese Clinical Trial Registry (ChiCTR2400083713) on April 30, 2024. Before the study started, it was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (KY2023-116-03).

Background Multiple trauma scores have been developed and validated, including the Revised Trauma Score (RTS) and the Mechanism, Glasgow Coma Scale, Age, and Arterial Pressure (MGAP) score. However, these scores are complex to calculate or have low prognostic abilities for trauma mortality. Therefore, we aimed to develop and validate a trauma score that is easier to calculate and more accurate than the RTS and the MGAP score. Methods The study was a retrospective prognostic study. Data from patients registered in the Japan Trauma Databank (JTDB) were dichotomized into derivation and validation cohorts. Patients’ data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial were assigned to another validation cohort. We obtained age and physiological variables at baseline, created ordinal variables from continuous variables, and defined integer weighting coefficients. Score performance to predict all-cause in-hospital death was assessed using the area under the curve in receiver operating characteristics (AUROC) analyses. Results Based on the JTDB derivation cohort ( n  = 99,867 with 12.5% mortality), the novel score ranged from 0 to 14 points, including 0–2 points for age, 0–6 points for the Glasgow Coma Scale, 0–4 points for systolic blood pressure, and 0–2 points for respiratory rate. The AUROC of the novel score was 0.932 for the JTDB validation cohort ( n  = 76,762 with 10.1% mortality) and 0.814 for the CRASH-2 cohort ( n  = 19,740 with 14.6% mortality), which was superior to RTS (0.907 and 0.808, respectively) and MGAP score (0.918 and 0.774, respectively) results. Conclusions We report an easy-to-use trauma score with better prognostication ability for in-hospital mortality compared to the RTS and MGAP score. Further studies to test clinical applicability of the novel score are warranted.

In our prospective, multi-center, randomized controlled trial (RCT)—the Brain Hypothermia (B-HYPO) study—we could not show any difference on neurological outcomes in patients probably because of the heterogeneity in the severity of their traumatic condition. We therefore aimed to clarify and compare the effectiveness of the two therapeutic temperature management regimens in severe (Abbreviated Injury Scale [AIS] 3–4) or critical trauma patients (AIS 5). In the present post hoc B-HYPO study, we re-evaluated data based on the severity of trauma as AIS 3–4 or AIS 5 and compared Glasgow Outcome Scale score and mortality at 6 months by per-protocol analyses. Consequently, 135 patients were enrolled. Finally, 129 patients, that is, 47 and 31 patients with AIS 3–4 and 36 and 15 patients with AIS 5 were allocated to the mild therapeutic hypothermia (MTH) and fever control groups, respectively. No significant intergroup differences were observed with regard to age, gender, scores on head computed tomography (CT) scans, and surgical operation for traumatic brain injury (TBI), except for Injury Severity Score (ISS) in AIS 5. The fever control group demonstrated a significant reduction of TBI-related mortality compared with the MTH group (9.7% vs. 34.0%, p = 0.02) and an increase of favorable neurological outcomes (64.5% vs. 51.1%, p = 0.26) in patients with AIS 3–4, although the latter was not statistically significant. There was no difference in mortality or favorable outcome in patients with AIS 5. Fever control may be considered instead of MTH in patients with TBI (AIS 3–4).