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Double-blinded, placebo-controlled study of early tranexamic acid treatment in swine uncontrolled hemorrhage model

Sondeen, Jill L. PhD; Hanson, Margaret A. DVM; Prince, Malcolm D.; de Guzman, Rodolfo; Polykratis, Irene A.; Aden, James K. III PhD; Cap, Andrew P. MD, PhD; Dubick, Michael A. PhD

Journal of Trauma and Acute Care Surgery: January 2016 - Volume 80 - Issue 1 - p 81–88
doi: 10.1097/TA.0000000000000860
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BACKGROUND Tranexamic acid (TXA) is an antifibrinolytic drug that was shown to increase survival in trauma patients, but the mechanisms remain unclear. The purpose of this double-blinded, randomized placebo-controlled study was to determine if TXA with hypotensive resuscitation with Hextend (HEX) or fresh frozen plasma (FFP) reduced blood loss (BL) and improved survival in a model of uncontrolled hemorrhage.

METHODS Instrumented, anesthetized pigs (n = 11 per group) were subjected to 24-mL/kg controlled hemorrhage, followed by transection of the spleen. After 15 minutes of bleeding, TXA (1.43 mg/kg/min) or normal saline (NS) was given over 10 minutes, and then 15-mL/kg HEX or FFP was administered. At 90 minutes, a second infusion of TXA or NS was given. BL, coagulation status, and 5-hour survival were determined. Tissue plasminogen activator (tPA) was added to blood samples collected before and after TXA administration to confirm that the TXA inhibited fibrinolysis. In addition, a comparison of a dose response to tPA-induced fibrinolysis was made between swine and human plasma in vitro.

RESULTS TXA prevented the rise in d-dimers that occurred after spleen injury. However, there was no significant effect of TXA on survival or BL compared with NS with HEX (HEX + NS, 17 ± 2 mL/kg vs. HEX + TXA, 17 ± 2 mL/kg) or FFP (FFP + NS, 7 ± 2 mL/kg vs. FFP + TXA, 12 ± 3 mL/kg), while FFP significantly reduced BL and increased survival compared with HEX in the NS-treated animals. The tPA-induced fibrinolysis was inhibited in the blood from TXA-treated animals, yet in fibrinolysis sensitivity studies, human plasma was 30 times more sensitive to tPA-induced fibrinolysis than swine plasma.

CONCLUSION TXA did not reduce BL, even though TXA was antifibrinolytic in the pigs. The possibility remains that the pig is highly resistant to fibrinolysis and not a good model to study the effects of antifibrinolytics or that fibrinolysis is not a major factor in bleeding from splenic injury.

Supplemental digital content is available in the text.

From the US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas.

Submitted: April 16, 2015; Revised July 20, 2015; Accepted: July 22, 2015, Published online: October 30, 2015.

This study was presented as a poster at the 38th annual meeting of the Shock Society, June 6–9, 2015, in Denver, Colorado.

The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jtrauma.com).

Address for reprints: Michael Dubick, PhD, US Army Institute of Surgical Research San Antonio, TX 78234; email: Michael.a.dubick.civ@mail.mil.

© 2016 Lippincott Williams & Wilkins, Inc.