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Three Part Question

In [patients requiring trauma resuscitation] is a [single dose of tranexamic acid administered by intramuscular injection] as effective as [intravenous administration] for [reversal of trauma-induced coagulopathy]?

Clinical Scenario

A 32-year-old patient presents to the emergency department following a high-speed motor vehicle accident. He is hypotensive and has obvious ecchymosis on the abdomen with a “seatbelt sign.” Paramedics were unable to administer tranexamic acid (TXA) due to difficulty in establishing IV access. You wonder if IM would be effective alternative to an IV route for administering TXA in bleeding trauma patients.

Search Strategy

Medline 1966-08/21 using PubMed, Cochrane Library (2021), and Embase

[(tranexamic acid) AND (intramuscular)]. LIMIT to English language.

Search Outcome

30 studies were identified; 5 studies addressed the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
DeSoucy ES, et al. Winter 2019 USA	15 swine bled of 35% blood volume and randomized to single 1g dose of IV, IO, or IM TXA	Randomized controlled animal study	Changes to baseline hemodynamics or blood loss	No significant difference in baseline hemodynamics or blood loss between groups	Non-human; small sample size; all patients received TXA
			Drug concentration at different time points	Peak concentration was significantly higher in IV/IO routes. IO and IM routes are practical alternatives when IV access is unavailable.
Spruce MW, et al. June 2020 USA	12 swine bled of 35% blood volume and randomized to receive 1g IV TXA, 1g IM TXA, or placebo	Randomized controlled animal study	Pharmacokinetics	Pharmacokinetics were similar between IV and IM TXA. IV TXA reached higher serum concentration only during the infusion.	Non-human; small sample size; IV TXA given as bolus as opposed to current regimen of bolus and slow infusion.
			Reversal of in vitro hyperfibrinolysis	Both routes corrected in vitro hyperfibrinolysis.
Grassin-Delyle S, et al. January 2021 France and UK	30 adult trauma patients who received 1g IV TXA per protocol were eligible for a second 1g TXA given IM	Prospective observational study	Pharmacokinetics of IM TXA	IM TXA was well tolerated, rapidly absorbed, and reached therapeutic concentrations within 15 minutes.	Small sample size; uneven distribution of sex (26 males vs 4 females); all patients received TXA; target therapeutic concentrations were obtained from in vitro studies.
Puigdellívol E, et al. June 1985 Spain	3 health male volunteers given 500 mg TXA both IV and IM on separate occasions	Crossover study	Bioavailability measured as peak plasma concentrations	Bioavailability of IM TXA was fast and complete	Small sample size, non-trauma patients, clinical outcomes not considered
Kane Z, et al. Sept 2021 France and UK	48 healthy volunteers given PO, IM and SG single dose regimens The model was verified using separate IV and oral validation datasets (n = 26 participants).	Pharmacokinetics (PK) study	PK data for PO, IM and SG single dose regimens	intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures.	Small sample size, non-trauma patients, clinical outcomes not considered
			Plasma levels following an IM dose of 1000 mg TXA	Intramuscular administration of 1000 mg TXA is predicted to achieve >15 mg/L in plasma in <15 min and exceed this level for approximately 3 h post dose.

Comment(s)

All studies are limited by small sample sizes. Two studies were performed on animals. Of the three human studies, only one study included traumatically injured patients. All of the studies focused on pharmacokinetics and assumed that there is a correlation between peak concentration and bioavailability and clinical outcome. None of these studies analyzed coagulation markers, blood product resuscitation, or patient outcome (dead or living). While IM TXA seems to be a promising alternative to IV TXA in the setting of difficult vascular access, larger randomized controlled studies are needed to determine if these two routes are actually equivalent on a clinical level.

Clinical Bottom Line

Treatment with IM TXA resulted in nearly 100% bioavailability and reached target concentration levels. No adverse events have been reported in the literature. IM TXA is likely equivalent to IV TXA on a pharmacokinetic level, but further studies are needed to determine clinical relevance.

References

1. DeSoucy ES, Davidson AJ, Hoareau GL, Simon MA, Tibbits EM, Ferencz SE, Grayson JK, Galante JM. Pharmacokinetics of Tranexamic Acid via Intravenous, Intraosseous, and Intramuscular Routes in a Porcine (Sus scrofa) Hemorrhagic Shock Model. J Spec Oper Med 2019 Winter;19(4):80-84
2. Spruce MW, Beyer CA, Caples CM, DeSoucy ES, Kashtan HW, Hoareau GL, Grayson JK, Johnson MA. Pharmacokinetics of Tranexamic Acid Given as an Intramuscular Injection Compared to Intravenous Infusion in a Swine Model of Ongoing Hemorrhage Shock 2020 Jun;53(6):754-760
3. Grassin-Delyle S, Shakur-Still H, Picetti R, Frimley L, Jarman H, Davenport R, McGuinness W, Moss P, Pott J, Tai N, Lamy E, Urien S, Prowse D, Thayne A, Gilliam C, Pynn H, Roberts I. Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: A clinical trial. Br J Anaesth 2021 Jan;126(1):201-209.
4. Puigdellívol E, Carral ME, Moreno J, Plà-Delfina JM, Jané F. Pharmacokinetics and absolute bioavailability of intramuscular tranexamic acid in man Int J Clin Pharmacol Ther Toxicol 1985 Jun;23(6):298-301.
5. Kane Z, Picetti R, Wilby A, Standing JF, Grassin-Delyle S, Roberts I, Shakur-Still H. Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers Eur J Pharm Sci 2021 Sep 1;164:105893