Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 30 and 60 Minutes of Traumatic Brain Injury.

Importance: Data on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking. Objectives: To examine the performance of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein 2 (MAP-2) within 30 and 60 minutes of TBI in identifying intracranial lesions on computed tomography (CT) scan, need for neurosurgical intervention (NSI), and clinically important early outcomes (CIEO). Design, Setting, and Participants: This cohort study is a biomarker analysis of a multicenter prehospital TBI cohort from the Prehospital Tranexamic Acid Use for TBI clinical trial conducted across 20 centers and 39 emergency medical systems in North America from May 2015 to March 2017. Prehospital hemodynamically stable adult patients with traumatic injury and suspected moderate to severe TBI were included. Blood samples were measured for GFAP, UCH-L1, and MAP-2. Data were analyzed from December 1, 2023, to March 15, 2024. Main Outcomes and Measures: The presence of CT lesions, diffuse injury severity on CT, NSI within 24 hours of injury, and CIEO (composite outcome including early death, neurosurgery, or prolonged mechanical ventilation ≥7 days) within 7 days of injury. Results: Of 966 patients enrolled, 804 patients (mean [SD] age, 41 [19] years; 418 [74.2%] male) had blood samples, including 563 within 60 minutes and 375 within 30 minutes of injury. Among patients with blood drawn within 30 minutes of injury, 212 patients (56.5%) had CT lesions, 61 patients (16.3%) had NSI, and 112 patients (30.0%) had CIEO. Among those with blood drawn within 60 minutes, 316 patients (56.1%) had CT lesions, 95 patients (16.9%) had NSI, and 172 patients (30.6%) had CIEO. All biomarkers showed significant elevations with worsening diffuse injury on CT within 30 and 60 minutes of injury. Among blood samples taken within 30 minutes, GFAP had the highest area under the receiver operating characteristic curve (AUC) to detect CT lesions, at 0.88 (95% CI, 0.85-0.92), followed by MAP-2 (AUC, 0.78; 95% CI, 0.73-0.83) and UCH-L1 (AUC, 0.75; 95% CI, 0.70-0.80). Among blood samples taken within 60 minutes, AUCs for CT lesions were 0.89 (95% CI, 0.86-0.92) for GFAP, 0.76 (95% CI, 0.72-0.80) for MAP-2, and 0.73 (95% CI, 0.69-0.77) for UCH-L1. Among blood samples taken within 30 minutes, AUCs for NSI were 0.78 (95% CI, 0.72-0.84) for GFAP, 0.75 (95% CI, 0.68-0.81) for MAP-2, and 0.69 (95% CI, 0.63-0.75) for UCH-L1; and for CIEO, AUCs were 0.89 (95% CI, 0.85-0.93) for GFAP, 0.83 (95% CI, 0.78-0.87) for MAP-2, and 0.77 (95% CI, 0.72-0.82) for UCH-L1. Combining the biomarkers was no better than GFAP alone for all outcomes. At GFAP of 30 pg/mL within 30 minutes, sensitivity for CT lesions was 98.1% (95% CI, 94.9%-99.4%) and specificity was 34.4% (95% CI, 27.2%-42.2%). GFAP levels greater than 6200 pg/mL were associated with high risk of NSI and CIEO. Conclusions and Relevance: In this cohort study of prehospital patients with TBI, GFAP, UCH-L1, and MAP-2 measured within 30 and 60 minutes of injury were significantly associated with traumatic intracranial lesions and diffuse injury severity on CT scan, 24-hour NSI, and 7-day CIEO. GFAP was the strongest independent marker associated with all outcomes. This study sets a precedent for the early utility of GFAP in the first 30 minutes from injury in future clinical and research endeavors.

Intravenous Versus Intraosseous Use of Tranexamic Acid in Patients With Traumatic Brain Injury.

INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic drug that has been demonstrated to reduce head injury-related mortality when given within 2 h of injury in patients with traumatic brain injury and intracranial hemorrhage. It is usually administered via intravenous (IV) access, which can be difficult to obtain in prehospital and austere settings. Intraosseous (IO) access is fast and offers an alternative when IV access proves challenging; however, TXA administration via IO access has never been studied in humans. We sought to determine if the total drug exposure of TXA given in the prehospital setting in patients with moderate or severe brain injury differs based on route of administration. METHODS: We performed a retrospective analysis of prospectively collected data from the prehospital TXA for traumatic brain injury trial (NCT01990768). Participants who received TXA via IO administration were compared to those who received TXA via IV administration and stratified by renal function category based on the Kidney Disease Improving Global Outcomes criteria. The area under the plasma drug concentration-time curve (AUC) was calculated using the trapezoidal rule (Phoenix WinNonlin 8.3, Certara, Princeton NJ) to obtain total drug exposure. The inverse variance method was used to combine observations within strata and calculate mean differences. RESULTS: Of the 966 participants enrolled in the trial, 345 participants received a 2-g TXA prehospital bolus (11 IO, 334 IV); 312 participants received a 1-g TXA prehospital bolus followed by a 1-g TXA infusion in-hospital over 8 h (13 IO, 299 IV). After exclusion because of missing data and extreme estimated AUC, 233 IV and eight IO participants in the 2-g bolus arm and 152 IV and eight IO participants in the 1-g bolus 1-g infusion arm remained. Participants did not differ by age, sex, race, ethnicity, body mass index, serum creatinine, estimated glomerular filtration rate, or clot lysis at 30 min on thromboelastography. No difference in the mean AUCs were observed between IV and IO for either the 2-g bolus group (-2.6 µ g/mL/h [IO] compared to IV, 95% confidence interval: -28.4 to 23.3 µ g/mL/h) or the 1-g bolus/1-g infusion group (-13.0 µ g/mL/h [IO] compared to IV, 95% confidence interval: -236.2 to 210.3 µ g/mL/h). CONCLUSIONS: These preliminary data suggest that the administration of TXA via IO and IV routes may result in similar total drug exposure. Further studies incorporating larger numbers with clinical outcomes are needed to confirm this finding.

The Association Between Tranexamic Acid and Seizures in Moderate or Severe Traumatic Brain Injury.

INTRODUCTION: Tranexamic acid (TXA) administered within 2 h of injury reduces mortality in traumatic brain injury (TBI) with intracranial hemorrhage. TXA also reduces the seizure threshold in a dose-dependent manner. We examined whether a 2-g bolus of prehospital TXA administered in moderate or severe TBI is associated with seizure activity within 72 h of injury. METHODS: Patients from the prehospital TXA for TBI trial with Glasgow Coma Scale < 13, blunt head injury, and time-of-seizure data were included in this analysis. The original trial randomized patients with suspected TBI to placebo, 1-g TXA bolus + 1-g 8-h TXA infusion, or 2-g TXA bolus within 2 h of injury. In this secondary analysis, multivariable logistic regression was performed to examine the association of treatment group with seizure incidence. The model controlled for age, Glasgow Coma Scale, Injury Severity Score, intracranial hemorrhage, Abbreviated Injury Scale-head, and home antiseizure medication use. RESULTS: Of the 786 patients who met the inclusion criteria, 19 had seizures within 72 h (five in placebo, two in 1-g bolus/1-g infusion, and 12 in 2-g bolus). The 2-g TXA bolus was not associated with increased seizures compared to placebo (odds ratio 0.41, 95% confidence interval 0.12-1.18, P = 0.12). Home antiseizure medication use was associated with increased seizures (odds ratio 15.95, 95% confidence interval 3.79-60.57, P < 0.001). CONCLUSIONS: A prehospital 2-g TXA bolus in moderate or severe TBI was not associated with increased seizure activity during the first 72 h after injury; however, limited power, limited use of continuous electroencephalography, and unavailable seizure prophylaxis data highlight the need for further study.

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.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.

Tranexamic Acid, Mortality, and Intracranial Hemorrhage Type in Moderate or Severe Traumatic Brain Injury.

This cohort study examines the association of tranexamic acid administration with intracranial hemorrhage type, neurologic outcomes, and mortality in patients with traumatic brain injury.