By Morte D, Lammers D, Bingham J, Kuckelman J, Eckert M, Martin M. Tranexamic acid administration following head trauma in a combat setting: Does tranexamic acid result in improved neurologic outcomes? J Trauma Acute Care Surg. 2019 Jul;87(1):125-129
Reviewed by Wazim Mohamed, MD
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Among trauma related deaths, hemorrhage accounts for approximately 30%, and trauma associated coagulopathy is a major contributor. Traumatic brain injury (TBI) is a common injury among patients with blast injuries leading to high mortality and morbidity rates, possibly related to progressive intracranial bleeding, cerebral edema and ischemia.
Tranexamic acid (TXA), an antifibrinolytic agent, has previously demonstrated hemostatic efficacy in preliminary studies, but effectiveness in specific populations or injury mechanisms is still unclear. This study hypothesized that TXA administration in trauma patients with concomitant TBI in a battlefield setting would lead to improved neurological outcomes. This was a retrospective review of combat trauma patients from the Joint Theater Trauma Registry (a prospectively collected dataset of all patients with traumatic injuries at facilities in Iraq and Afghanistan) between 2008 and 2015. Data fields included patient characteristics, clinical presentation, mechanism of injury, injury severity score (ISS), anatomic abbreviated severity scale, transfusion requirements and need for surgical interventions.
All patients with a documented Head Abbreviated Injury Scale (AIS) were included. Severity of TBI was based on the presenting GCS: mild, moderate or severe. Propensity score matching in a 1:1 ratio was used to create two groups (TXA administered and non-TXA administered patients) with similar characteristics. This included adjustment for age, sex, mechanism of injury, ISS, anatomic AIS, vital signs, GCS score on initial presentation, baseline laboratory values, early and total transfusion requirements, emergent operations, and neurosurgical interventions.
As per the Combat Casualty Care Data guidelines, TXA dosing was standardized to 1 gm bolus within 3 hours of injury followed by 1 gm infusion over the next 8 hours. The indications for TXA administration included resuscitation for hemorrhage and for patients likely to require massive transfusion. Primary outcomes included discharge severity of TBI, change in GCS from presentation to discharge and mortality. Secondary outcomes included prolonged respiratory failure and rates of thromboembolic events. Descriptive analysis was used for continuous data and percentages for categorical data. Comparative analysis was completed used Fishers exact tests and two-tailed t-tests. Nonparametric data were evaluated using chi-square and Mann-Whitney U tests. Statistical significance was defined as p value less than 0.05.
The initial cohort consisted of 4476 patients and the propensity model evaluated 92 patients who were equally distributed among the two groups. The mean age was 25 years with almost 100% males. In the unmatched cohorts, the baseline characteristics demonstrated patients that received TXA having significantly higher rates of penetrating injury, higher ISS, higher head abbreviated injury score >3, lower presenting GCS, higher transfusion requirement, higher rate of emergent operation, and higher rate of neurosurgical intervention.
After the propensity score matching, there were no statistically significant differences between the matched groups. These groups were tested for primary and secondary outcomes. Severe TBI occurred in 39% of TXA patients and 47% of non-TXA patients (p=0.515), and moderate TBI occurred in 10% of TXA patients and 6% of non-TXA patients (p=0.515). Neurosurgical interventions were required in 26.1% of patients (8% TXA and 17% non-TXA, p=0.218). The TXA group was associated with a significant improvement in discharge outcomes. All patients in the TXA group had a GCS of 14 or more at the time of discharge. The authors infer this as complete neurological recovery or mild TBI. The non-TXA group had 87% of patients with GCS 14 or more at discharge. Mortality was significantly higher in the non-TXA group (10.1% vs. 0%; p=0.03). Patients that remained intubated at discharge (0% vs. 2.2%; p=0.47) and thromboembolic events (4.3% vs. 2.2%; p=0.59), among the TXA and non-TXA groups respectively, were not statistically significant.
The authors conclude that TXA administration in trauma patients with TBI, specifically in combat casualties, is associated with improved neurological outcomes at discharge and reduced early mortality. These results support the numerous prior studies that have shown an association between TXA and improved outcomes in trauma patients.
However, there are some limitations to the current study. This includes the retrospective nature of the study and the potential for remaining confounding variables, which the study sought to eliminate through propensity matching. Individual cohorts were less than 50 patients and may not have been adequately powered to demonstrate some of the secondary outcomes.
The administration of TXA is a binary record in the registry without further information regarding timing, dosage and duration of administration; the study assumes adherence to the Combat Casualty Care Data guidelines to infer the administration of TXA. The lack of CT scanners at many initial treatment sites made the diagnosis of TBI difficult. The study demographics were confined to young males and therefore may not translate to the general trauma population or TBI.
With the inability to review CT scans, the authors were also not able to quantify ICH or monitor for expansion. One significant limitation of the study not noted by the authors is the definition of complete neurological recovery as a GCS of 14 or more. This definition of good outcome limits measurement of cognitive and functional outcomes; prior studies on TXA and trauma used more nuanced scales, such as the Glasgow Outcomes Score. Furthermore, the non-TXA matched cohort had double the number of neurosurgical interventions, raising the question of acuity of illness in this group. And while there was no statistical significance in neurosurgical interventions between the groups, the study may have been underpowered to detect this.
There were no differences among the secondary outcomes including respiratory failure and rates of thromboembolism. TXA has been of immense interest recently, and preliminary trials, including the CRASH 2 trial, suggest a decrease in bleeding and mortality in trauma patients. The current study supports this. The CRASH 3 trial (Clinical Randomization of an Antifibrinolytic in Significant Head injury) has concluded enrollment in January 2019, and those results will add to those of these authors to help determine optimum treatment of TBI patients moving forward.
Wazim Mohamed, MD
Assistant Professor of Neurology
Division of Neurotrauma and Critical Care Neurology
Wayne State University