Optimizing Pharmacologic Treatment in Trauma

The CENTCOM Joint Theater Trauma System (JTTS) Clinical Practice Guideline (CPG) on damage control resuscitation at Level IIb/II treatment facilities strongly advocates the early use of the anti-fibrinolytic, tranexamic acid (TXA) in patients that are likely to require massive transfusion. This recommendation is based on the results of the two major studies that demonstrated a decrease in mortality in trauma patients that received TXA within three hours of injury. The CPG recommends a dose of 1 gram given intravenously over 10 minutes, followed by an additional gram over 8 hours. This dose is based on cardiac literature as no pharmacokinetic studies have been performed in the trauma population. 

In 2013, a committee of trauma management experts formed at the request of the Office of the Assistant Secretary of Defense for Health Affairs and the Joint Program Committee for Combat Casualty Care Research to develop research priorities for TXA identified “dosing” as a research priority. Specifically, they stated “All available data are based on one dosage regimen; could other regimens improve efficacy and safety or worsen efficacy and safety? How are pharmacokinetics affected by trauma?” 

We aim to develop a physiologically based pharmacokinetics (PBPK) model of tranexamic acid that will have the capability of predicting the impact of alterations in physiology on the time course of medications and have the ability to extrapolate to human clinical settings. To build this model we will first determine organ and tissue blood flow after grade I- IV hemorrhage in the swine using microsphere studies and determine organ and tissue partition coefficients at steady state plasma levels of TXA in the swine. We will then develop a PBPK model of TXA that includes elimination through hemorrhage and use the newly developed PBPK model as a tool to explore physiologic changes that have greatest influence on TXA disposition. We will test accuracy of PBPK model in isolated hemorrhage and polytrauma swine models and determine if existing dosing guidelines are optimal.

This study will provide rigorous scientific inquiry into the impact of physiological changes of hemorrhage on the disposition of tranexamic acid. It is in keeping with the American Nurses Association mandate to society to optimize health and wellbeing. The study addresses the priorities of TSNRP, specifically interventions that improve outcomes of the wounded warrior by optimizing pharmacologic therapy in trauma.