Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers.

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1ß, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1ß, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = - 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28-30, 2024, in Estoril, Lisbon, Portugal.

Seizure Prophylaxis in Young Patients Following Traumatic Brain Injury.

Introduction: Phenytoin is one of the commonly used anti.seizure medications in nontraumatic seizures. However, its utility and safety in young patients with traumatic brain injury (TBI) for the prevention of early-onset seizures (EOS) are debatable. We sought to explore the use of phenytoin as a seizure prophylaxis following TBI. We hypothesized that administering phenytoin is not effective in preventing EOS after TBI. Methods: This was a retrospective observational study conducted on adult TBI patients. EOS was defined as a witnessed seizure within a week postinjury. Data were compared as phenytoin versus no-phenytoin use, EOS versus no-EOS, and among TBI severity groups. Results: During 1 year, 639 TBI patients were included with a mean age of 32 years; of them, 183 received phenytoin as seizure prophylaxis, and 453 received no prophylaxis medication. EOS was documented in 13 (2.0%) patients who received phenytoin, and none had EOS among the nonphenytoin group. The phenytoin group was more likely to have a higher Marshall Score (P = 0.001), lower Glasgow Coma Scale (GCS) (P = 0.001), EOS (P = 0.001), and higher mortality (P = 0.001). Phenytoin was administrated for 15.2%, 43.2%, and 64.5% of mild, moderate, and severe TBI patients, respectively. EOS and no-EOS groups were comparable for age, gender, mechanism of injury, GCS, Marshall Score, serum phenytoin levels, liver function levels, hospital stay, and mortality. Multivariable logistic regression analysis showed that low serum albumin (odds ratio [OR] 0.81; 95% confidence interval [CI] 0.676.0.962) and toxic phenytoin level (OR 43; 95% CI 2.420.780.7) were independent predictors of EOS. Conclusions: In this study, the prophylactic use of phenytoin in TBI was ineffective in preventing EOS. Large-scale matched studies and well-defined hospital protocols are needed for the proper utility of phenytoin post-TBI.

Efficacy and safety of the second in-hospital dose of tranexamic acid after receiving the prehospital dose: double-blind randomized controlled clinical trial in a level 1 trauma center.

BACKGROUND: Prehospital administration of tranexamic acid (TXA) to injured patients is increasing worldwide. However, optimal TXA dose and need of a second infusion on hospital arrival remain undetermined. We investigated the efficacy and safety of the second in-hospital dose of TXA in injured patients receiving 1 g of TXA in the prehospital setting. We hypothesized that a second in-hospital dose of TXA improves survival of trauma patients. METHODS: A prospective, double-blind, placebo-controlled randomized, clinical trial included adult trauma patients receiving 1 g of TXA in the prehospital settings. Patients were then blindly randomized to Group I (second 1-g TXA) and Group II (placebo) on hospital arrival. The primary outcome was 24-h (early) and 28-day (late) mortality. Secondary outcomes were thromboembolic events, blood transfusions, hospital length of stay (HLOS) and organs failure (MOF). RESULTS: A total of 220 patients were enrolled, 110 in each group. The TXA and placebo groups had a similar early [OR 1.000 (0.062-16.192); p = 0.47] and late mortality [OR 0.476 (95% CI 0.157-1.442), p = 0.18].The cause of death (n = 15) was traumatic brain injury (TBI) in 12 patients and MOF in 3 patients. The need for blood transfusions in the first 24 h, number of transfused blood units, HLOS, thromboembolic events and multiorgan failure were comparable in the TXA and placebo groups. In seriously injured patients (injury severity score > 24), the MTP activation was higher in the placebo group (31.3% vs 11.10%, p = 0.13), whereas pulmonary embolism (6.9% vs 2.9%, p = 0.44) and late mortality (27.6% vs 14.3%, p = 0.17) were higher in the TXA group but did not reach statistical significance. CONCLUSION: The second TXA dose did not change the mortality rate, need for blood transfusion, thromboembolic complications, organ failure and HLOS compared to a single prehospital dose and thus its routine administration should be revisited in larger and multicenter studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03846973.

Beta blocker use in traumatic brain injury based on the high-sensitive troponin status (BBTBBT): methodology and protocol implementation of a double-blind randomized controlled clinical trial.

BACKGROUND: Beta-adrenergic receptor blockers (BB) play an important role in the protection of organs that are susceptible for secondary injury due to stress-induced adrenergic surge. However, the use of BB in traumatic brain injury (TBI) patients is not yet the standard of care which necessitates clear scientific evidence to be used. The BBTBBT study aims to determine whether early administration of propranolol based on the high-sensitive troponin T(HsTnT) status will improve the outcome of TBI patients. We hypothesized that early propranolol use is effective in reducing 10- and 30-day mortality in TBI patients. Secondary outcomes will include correlation between serum biomarkers (troponin, epinephrine, cytokines, enolase, S100 calcium binding protein B) and the severity of injury and the impact of BB use on the duration of hospital stay and functional status at a 3-month period. METHODS: The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status. All enrolled patients will be tested for HsTnT at the first 4 and 6 h post-injury. Patients with positive HsTnT will receive BB if there is no contraindication (group 1). Patients with negative HsTnT will be randomized to receive either propranolol (group 2) or placebo (group 3). The time widow for receiving the study treatment is the first 24 h post-injury. DISCUSSION: Early BB use may reduce the catecholamine storm and subsequently the cascade of immune and inflammatory changes associated with TBI. HsTnT could be a useful fast diagnostic and prognostic tool in TBI patients. This study will be of great clinical interest to improve survival and functional outcomes of TBI patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04508244. Registered on 7 August 2020. Recruitment started on 29 December 2020 and is ongoing.