Should pre-hospital intramuscular tranexamic acid be given to trauma patients at risk of significant haemorrhage?

Clinical scenario

A paramedic crew attends a patient who has fallen from a third-storey balcony. No other pre-hospital teams are available to assist. The patient has a deformed femur and apparent pelvic asymmetry. He is alert with a heart rate of 114 bpm and blood pressure of 115/80 mmHg. Adequate analgesia is achieved with inhaled methoxyflurane to facilitate the application of a pelvic binder and Kendrick Traction Device. The crew wish to give tranexamic acid (TXA) but are unable to gain intravenous (IV) access. The patient declines intraosseous (IO) access and is conveyed to the nearest major trauma centre where a cannula is placed under ultrasound guidance and IV TXA is administered. The crew subsequently discuss the case with colleagues, who inform them that the latest update to the JRCALC guidelines ¹ allows intramuscular (IM) administration of TXA as an alternative to IV/IO. They wonder whether the patient may have benefitted from this.

Three-part question

In [adults at risk of significant haemorrhage], does [pre-hospital IM administration of TXA vs IV administration in hospital] improve [morbidity and mortality]?

Search strategy

On 6th November 2022, the MEDLINE, Embase and Cochrane Library databases were searched.

Title and abstract: Tranexamic AND (intramuscular OR prehospital OR pre-hospital).

The search was limited to papers published after 2010.

Search outcome

Results were identified for title and abstract screening (MEDLINE: 154, Embase: 570 and Cochrane Library: 69).

No systematic review, clinical trial or observational study was found comparing the effectiveness of IM TXA vs IV TXA or IM TXA vs placebo.

Three systematic reviews examining the effect of pre-hospital IV TXA were identified. The primary studies included in these reviews overlapped and the findings were similar. The review with the most recent evidence and largest number of patients is included.

One further observational study, published after that systematic review, was identified and included.

One observational study examining the effect of pre-hospital TXA on the timing of administration was identified.

One pharmacokinetic study of IM TXA in human trauma patients was identified. The included studies are summarised in Table 1.

Comment

A subgroup analysis of the CRASH-2 trial ⁶ showed that the beneficial effect of TXA in reducing deaths due to bleeding was only seen when the first dose was administered within 3 h of injury and the effect was probably greater still when it was given within 1 h. Li et al. ⁷ performed a subgroup analysis of the STAAMP trial ⁸ and found that the survival of shocked trauma patients was significantly improved if pre-hospital IV TXA was administered within one hour of injury but not if it was delayed. Finally, Gayet-Ageron et al. ⁹ combined the results of the CRASH-2 trial and the WOMAN trial, which examined the effect of TXA on survival in post-partum haemorrhage. They found ‘Immediate [IV] TXA improved survival by more than 70% (OR 1·72, 95% CI 1·42–2·10; p < 0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit.’

NICE guideline NG39 ¹⁰ recommends ‘Use IV TXA as soon as possible in patients with major trauma and active or suspected active bleeding. Do not use IV TXA more than 3 h after injury in patients with major trauma unless there is evidence of hyperfibrinolysis.’

Pre-hospital TXA availability appears to reduce the time to administration following injury and reduce mortality by a similar amount as would be expected from the CRASH-2 data, which is based on patients in hospital. A further randomised placebo-controlled trial is currently underway with a target recruitment of 1316 patients at risk of traumatic coagulopathy based on a Coagulopathy in Severe Trauma score ≥3. ¹¹ Like the STAAMP trial, it seeks to compare the effectiveness of IV TXA initiated pre-hospital vs placebo.

IM TXA administration is associated with rapid absorption even in shocked trauma patients and has minimal side effects. IM TXA is now recognised as an alternative to IV/IO administration for patients at risk of haemorrhage in the most recent update to the JRCALC guidelines¹ for pre-hospital practitioners.

Given its increased effectiveness, avenues should be explored to facilitate patients receiving TXA as soon as possible after injury. This has led some to propose that the potential use of IM autoinjectors should be investigated in certain settings.^12,13 Even if IM TXA were less effective than TXA via the IV route, this may be more than compensated for by the potential benefit of earlier administration in situations where IV/IO access and administration may be delayed.

Clinical trials to investigate the potential for IM TXA to reduce morbidity and mortality could include a randomised placebo-controlled trial or a non-inferiority trial vs IV/IO administration.

Clinical bottom line

Current guidelines support early pre-hospital administration of TXA in trauma patients. If there is likely to be a significant delay in IV/IO administration, then patients may benefit from IM administration. This should be guided by clinician judgement.

Table 1.

Summary of included studies.

Author, date and country	Patient group	Study type	Outcomes	Key results	Study weaknesses
Almuwallad et al., 2021, UK 2	Total of 2347 adult trauma patients from 4 studies receiving pre-hospital IV TXA vs no pre-hospital TXA	Systematic review and meta-analysis	Mortality and venous thromboembolic events (VTE)	Four studies included: Three cohort studies: Pre-hospital TXA vs no pre-hospital TXA with no restriction on treatment in hospital. One randomised control trial (RCT): TXA initiated pre-hospital vs placebo (placebo group then received second dose of placebo in hospital) Mortality at 24 h was reduced in those receiving pre-hospital TXA (OR 0.60; 95% CI 0.37–0.99; p = 0.05) Mortality at 28–30 days: OR 0.69 (95% CI 0.47–1.02)	Small number of studies included Mostly observational data Patients in placebo arm of RCT did not receive TXA in-hospital
Imach et al., 2021, Germany 3	2275 matched pairs of injured patients at risk of bleeding receiving pre-hospital IV TXA vs no pre-hospital TXA	Retrospective match-pair analysis	Mortality and transfusion requirements	Pre-hospital TXA administration significantly reduced mortality at 6 h after hospital admission (6.8% CI 5.8–7.8 vs 9.1% CI 8.0–10.3, p = 0.004) Significantly more TXA patients were transfused (33.9% CI 32.0–35.9 vs 30.7%, CI 28.8–32.6, p = 0.022). If transfused, the average amount was significantly lower (6.0 units, CI 5.5–6.5 vs 7.6 units, CI 6.9–8.3, p < 0.001)	Retrospective analysis of registry data
Marsden et al., 2019, UK 4	661 patients from TARN database receiving TXA either pre-hospital or in-hospital	Retrospective observational notes review	Time from injury to documented administration of TXA	The median time to TXA administration when given pre-hospital was 51 min (IQR 39–72). If given in-hospital it was 112 min (IQR 84–160) (p < 0.001) Patients who received pre-hospital TXA had a higher probability of receiving it within 3 h (OR 36.02; 95% CI 8.69–149.33) and within 1 h (OR 12.47; 95% CI 8.23–18.88) of injury	Retrospective review relying on accurate documentation of timings
Grassin-Delyle et al., 2021, UK 5	30 adult trauma patients receiving second dose of IM TXA in-hospital	Pharmacokinetic study	Time to target therapeutic concentrations	IM TXA is rapidly absorbed, even in shocked patients. Plasma concentrations >5 mg/l were achieved in about 4 min IM TXA is well tolerated with only mild and transient injection site reactions	Small number of patients No patient-centred outcome. Target therapeutic concentration based on in vitro studies

IM: intramuscular; IV: intravenous; TXA: tranexamic acid.