Pharmacokinetics of Tranexamic Acid (TXA) Delivered by Expeditious Routes in a Swine Model of Polytrauma and Hemorrhagic Shock

Abstract

Objective

Hemorrhage is the leading cause of preventable death in civilian trauma centers and on the battlefield. One of the emerging treatment options for hemorrhage in austere environments is tranexamic acid (TXA). However, the landscape is not amenable to the current delivery standard. This study compared the pharmacokinetics of TXA via a standard 10-minute intravenous infusion (IV infusion), intravenous rapid push over 10 s (IV push), and intramuscular injection (IM) in a swine polytrauma and hemorrhagic shock model (trauma group) compared to uninjured controls (control group).

Methods

Thirty swine were randomized to the trauma or control group. Following anesthesia, the trauma group experienced a simulated blast injury and 40% controlled hemorrhage. Subjects in both groups were then randomized to receive 1 g/10 mL TXA via IV infusion, IV push, or IM. Animals were monitored for four hours with serial blood sampling. Serum TXA concentrations were measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and analyzed.

Results

The time to maximum TXA concentration (T_max) was not affected by trauma in IV infusion or IV push, but was affected in the IM administration with T_max significantly slower than the control group (p = 0.016). The minimum effective serum concentration of TXA (C_eff, 10 µg/mL) was reached in less than one minute with IV infusion and instantaneously with IV push. Despite lower bioavailability, the time to reach C_eff (T_eff) was achieved via IM administration in less than 10 min for both groups (6.4 min trauma vs. 2.1 min control).

Conclusions

In austere prehospital environments, an alternative to intravenous infusion of a life-saving medication is desired. Administration of TXA via all three methods reached the level needed to cause substantial inhibition of fibrinolysis within 10 min. The IV push method showed similar pharmacokinetics to IV infusion of TXA but can be delivered quickly without sacrificing an access site for 10 min.

Acknowledgments

The authors would like to thank and acknowledge LCDR Jared Verga and the Naval Medical Center Portsmouth animal facility staff for their efforts on this study.

Authorship Contributions

M.W. wrote the first draft and collected data. S.S. conceptualized the study concept, participated in protocol development, collected data, and contributed to manuscript creation. B.L. participated in data collection, data analysis, and manuscript creation. C.M., T.P., R.H., C.T., E.S., and L.G. participated in data collection. P.F. participated in protocol development. E.E.F. analyzed the data, finalized protocol development, and provided critical review of the manuscript. All authors read and approved the final manuscript.

Disclaimer

The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Mallori Wilson, Sean Stuart, Clyde Martin III, Timothy Parker Jr., Christopher Treager, Eric Sulava and Robert Healy are military service members. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.

Disclosure Statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by funding from RDT&E 6.6 funding in support of Clinical Infrastructure, Naval Medical Center Portsmouth and by the CIP1 Funds from the Navy Surgeon General Grant.