Guidance Document Regarding the Pre-Hospital Use of Tranexamic Acid for Injured Patients

Endorsed By American College of Surgeons: Committee on Trauma, American College of Emergency

List authors from writing group

Tranexamic acid (TXA) is a synthetic lysine analog that competitively inhibits the activation of
plasminogen to plasmin. It was approved by the US Food and Drug Administration in 1986 for short-
term use as an injection to reduce or prevent bleeding during tooth extraction in hemophilia patients.
The oral form is approved to treat menorrhagia. All other uses are off-label.

TXA has the potential benefit of decreasing fibrinolysis in the injured bleeding patient. The 2010
results of the Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial
showed a decrease in all-cause mortality of 1.5% and a decrease in risk of death secondary to
hemorrhage of 0.8% in patients receiving TXA. While CRASH-2 was the largest randomized study to date,
many are critical of the findings, such as the lack of modern resuscitative practices in many of the
participating centers. Retrospective studies, such as the Military Application of Tranexamic Acid in
Trauma Emergency Resuscitation (MATTERs) study, also showed a mortality benefit in patients receiving
TXA, but suggested an increase in thromboembolic events.

A subgroup analysis of the CRASH-2 study examined the timing of administration. In bleeding
patients, a significant reduction in mortality resulted from TXA administration within 1 hour of injury.
This benefit continued up to 3 hours post-injury, but after 3 hours, TXA administration was found to be
harmful. Some in the prehospital community have embraced this finding, suggesting that an early
administration approach is most beneficial to the patient and thus the drug is ideal for the prehospital
environment. Our organizations recognize that TXA is being administered already in many prehospital
air and ground systems. We recognize that insufficient evidence exists to support or refute the
prehospital administration of TXA and are awaiting the results of several prehospital studies currently in
progress before making a recommendation regarding prehospital use of this agent. Therefore, we have
created this document to aid agencies and systems in best practices for TXA administration based on
currently available best evidence.

System integration is paramount

Definitive hemorrhage control and rapid transport to a trauma center is the key to survival in
the bleeding patient. TXA administration should never delay transport. Furthermore, TXA
administration involves a bolus dose followed by an infusion over 8 hours. The receiving center should
endorse the prehospital use to not only ensure the infusion is initiated but also to avoid a repeat bolus.
EMS agencies are encouraged to engage with their leading regional trauma centers to agree on
protocols for prehospital TXA use. It is also encouraged that a clear hand-off of care report be given by
EMS providers specifically noting that the TXA bolus has been given during transport so that the infusion
is begun at the receiving center.

Administration to bleeding patients

Limited evidence suggests that more venous thromboembolic events (VTE) occur when TXA is
given to patients not requiring massive transfusion. This discrimination can be difficult in the field
where rapid decisions must be made with minimal diagnostics or time for evaluation. Objective
measurements should be used to guide prehospital TXA administration protocols. The focus for
management of compressible, external bleeding should be on pressure dressings, hemostatic agents,
wound packing, or tourniquets. Evidence of injury consistent with non-compressible hemorrhage (e.g.
penetrating thoracoabdominal trauma, unstable pelvis fractures) along with heart rate > 120 bpm and
SBP < 90 mmHg are suggested criteria. Agencies may consider vital sign adjustments for the geriatric
population.

Transport to a trauma center

Compressible bleeding should be managed with pressure dressings, hemostatic agents, wound
packing, or tourniquets. Prehospital TXA should be administered only to patients with non-compressible
bleeding. Thus, definitive surgical control at a trauma center is essential. Patients receiving prehospital
TXA should be preferentially transported to a Level I or II trauma center if available. If geographic or
other factors preclude direct trauma center transport, the first receiving hospital should be capable of
continuing the TXA infusion and implementing hemorrhage control procedures.

Monitoring and Quality Improvement

Given the lack of data available, our organizations recommend prehospital TXA administration
be monitored closely in a prehospital and/or trauma registry. Administration should be reviewed and
protocols improved to avoid unnecessary or incomplete doses, inappropriate patient selection, or lack
of infusion following the initial bolus. TXA dosing, timing, blood transfusion requirements, and any
adverse events should be included in the registry. If TEG is being used to guide resuscitation, fibrinolysis
as measured by %LY30 should be collected in the trauma registry for future research.

Caution in cases of known anticoagulation

The effect of administering TXA in conjunction with other medications to reverse anticoagulants,
such as 4-factor Prothombin Concentrate Complex (PCC) is unknown and could potentially lead to more
thrombotic complications. In the case of trauma patients known to be on chronic anticoagulants,
medical control should be consulted prior to TXA administration if specific protocols for this situation
have not been developed.

Communication is key

Repeat bolus doses of TXA should be avoided. Prehospital TXA administration should be clearly
communicated with the next receiving provider. Simple adjuncts, such as stickers or wristbands applied
to patients, may be used to aid in the information transfer.

Pediatrics

Children were excluded from the CRASH-2 Trial. The best studies of TXA efficacy in children to
date are in craniofacial surgery, where there is Level I evidence that TXA decreases transfusion
requirements. An acknowledged risk of TXA is seizures, which has been seen mainly in the pediatric
cardiac surgery population. With the extremely limited information concerning TXA use in pediatric
trauma, prehospital TXA use is not currently recommended outside of a research study.
Don’t Forget the Basics

In the bleeding patient, hemorrhage control and appropriate resuscitation are still priority.
Prehospital TXA use should never supersede field bleeding control techniques, rapid transport to a
trauma center, or the administration of blood or plasma.

References:

CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H,
Gogichaishvili T, Gupta S, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood
transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-
controlled trial. Lancet. 2010;376:23.

CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G,
Hunt BJ, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an
exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096-1101.

Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma
Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147:113-119

Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: How should
we use it? J Trauma Acute Care Surg. 2013;74:1575-86.

Faraoni D and Goobie SM. The efficacy of antifibrinolytic drugs in children undergoing noncardiac
surgery: a systematic review of the literature. Anesth Analg 2014;118:628–36. PMID: 24557107

Goobie SM, Meier PM, Sethna NF, Soriano SG, Zurakowski D, Samant S, et al. Population
pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery. Clin
Pharmacokinet 2013;52:267–276. PMID: 23371895