Effects of tranexamic acid on neuropathology, electroencephalography, and cerebral fibrin deposition in a rat model of polytrauma with concomitant penetrating traumatic brain injury.

Several studies have demonstrated the clinical utility of Tranexamic Acid (TXA) for use in trauma patients presenting with significant hemorrhage. TXA is an antifibrinolytic that inhibits plasminogen activation and plasmin activity has been shown to mitigate blood loss and reduce all-cause mortality in the absence of adverse vascular occlusive events. Recent clinical developments indicate TXA is safe to use in patients with concomitant traumatic brain injury (TBI); however, the pre-hospital effects are not well understood. Importantly, TXA has been associated with seizure activity. Therefore, this study sought to evaluate the effects of early administration of TXA on neurological recovery and electroencephalogram (EEG) abnormalities following penetrating TBI with concomitant hypoxemia and hemorrhagic shock (PHH). We hypothesized that early administration of TXA will provide hemodynamic stabilization and reduce intracerebral hemorrhage which will result in improved neurological function. To test this hypothesis, Sprague-Dawley rats received a unilateral, frontal penetrating ballistic-like brain injury by inserting a probe into the frontal cortex of the anesthetized rat. Five minutes following brain injury, animals underwent 30 minutes of respiratory distress and 30 minutes of hemorrhage. Upon completion of the hemorrhage phase, animals received the initial dose of drug intravenously over 10 minutes after which the pre-hospital phase was initiated. During the pre-hospital phase, animals received autologous shed whole blood as needed to maintain a MAP of 65 mmHg. After 90 minutes, "in-hospital" resuscitation was performed by administering the remaining shed whole blood providing 100% oxygen for 15 minutes. Upon recovery from surgery, animals were administered their second dose of vehicle or TXA intravenously over 8 hours. TXA induced an early improvement in neurologic deficit, which was statistically significant compared to vehicle at 24 h, 48 h, and 72 h at three doses tested. Analysis of cerebral hemoglobin content and intracerebral lesion progression revealed 100 mg/kg provided the optimal effects for improvement of neuropathology and was continued for determination of adverse treatment effects. We observed no exacerbation of cerebral thrombosis but TXA treatment caused an increased risk of EEG abnormalities. These results suggest that TXA following polytrauma with concomitant brain injury may provide mild neuroprotective effects by preventing lesion progression but this may be associated with an increased risk of abnormal EEG patterns. This risk may be associated with TXA inhibition of glycine receptors and may warrant additional considerations during the use of TXA in severe TBI patients.