Tranexamic Acid (TXA) is a mainstay of trauma management. CRASH 2 (2) demonstrated its effectiveness in bleeding patients and CRASH 3 (1,5) (in my opinion) showed that we should also be using it in mild/moderate head injury. In both trials there is evidence that it is a time critical intervention for patients and that it should therefore be administered as soon as possible via the IV route. Not everyone agrees on this (and that’s fine), but there seems to be no more divisive drug in emergency medicine/critical care than TXA, with well respected commentators coming to different conclusions to myself and others (7,8,9). There is also a North-Atlantic split with a higher proportion of proponents to the East as compared to North America.
The dosage in both trials was 1g bolus followed by an 8-hour infusion of a further 1g. However, that regime was not really evidence based. I’ve spoken with the CRASH 2 team about where this came from and the theory was that patients needed an initial boost (the bolus) and that following this in a ‘bleeding’ patient it might be lost (through blood loss) and therefore an infusion is required to keep levels therapeutic. The same logic would follow for the WOMAN trial (PPH)(3) and HALT-IT trials (GI bleeding) (4). In CRASH 3 (head injury) they could have arguably have abandoned the infusion as few if any of these patients were actively bleeding, but presumably for consistency they kept the bolus + infusion regimen.
However, gaining IV access may be tricky in the prehospital/ED environment and it takes valuable time to prepare and deliver the drugs. In some prehospital settings, such as tactical environments or in mass casualty settings, IV drug delivery and infusions may be especially difficult to deliver. Once in hospital, TXA infusions may not complete or may be interrupted to facilitate patient care.
What if TXA could be given IM though? In theory that would offer many practical advantages and thus may make this life saving drug available to a greater number of patients, and at an early stage of their journey, thus perhaps making it more effective.
This week the British Journal of Anaesthesia published a paper on the use of IM TXA, (10) and whilst this is an early and relatively small trial it’s worthy of a look as it may be the beginning of a change in trauma care.
You can listen to a podcast with one of the authors, Ian Roberts, below. We also discuss different TXA regimens, fraud, meta-analysis, data sharing and TXA in head injury.
The abstract is below, but as always we strongly recommend that you read the full paper yourself and make your own conclusions.
What type of study is this?
This is an open label pharmokinetic study that seeks to examine how a drug (in this case TXA) behaves in humans. We don’t cover a lot of these studies on the blog, but in essence this is a method of determining whether a drug is likely to perform clinically based on the measurement over time of drug concentration.
Who did they study?
Adult trauma patients who had received their initial bolus of TXA were eligible if in the opinion of the treating clinicians a second dose was needed. They managed to recruit 30 patients. There is limited data on injury severity or physiological compromise although it looks as though 60% were clinically shocked at the time of enrolment.
What was the intervention?
Patients in the trial were then given a 1g bolus of IM TXA (in 2x5ml doses in separate sites). Blood samples were then taken at 10min, 45min, 90min, 3h, 6h and 10h later. These samples were then analysed for TXA concentration. The authors state that a therapeutic TXA level is 5-10mg/L and so it is the time needed to get to that level and stay at that level that is arguably the ‘outcome’ for this paper.
What did they find?
The headline data is that all the patients showed effective absorbtion of TXA through the IM route. The authors state that the time to reach therapeutic concentrations (5 or 10 mg L1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively.
The reason for the broad values given is that it is based on the variability within the observed data and then also on a statistical model that builds in factors such as age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates.
Combining the data for the combined pharmokinetic model is shown in Figure 2 in the paper (and in the tweet below). This demonstrates that TXA can reach therapeutic levels easily within the first few hours of use which is when most bleeding deaths occur.
There were no serious systemic or local adverse reactions from TXA.
There is also an element of #dogmalysis here. I’ve always been taught that the IM route is a no-go in the shocked patient. That was not the case in this study with good absorption of TXA. Even more surprising is that drug levels rose faster in the shocked patients! Drug levels are a feature of both absorption and elimination and it is mooted that shocked patients have lower elimination rates thus faster and more prolonged therapeutic levels.
This study is promising. It is a detailed analysis of pharmokinetics amongst a group of patients with significant trauma, but as with all studies there are caveats.
It’s a fairly small group of patients. Although the results are notably consistent between patients it is possible that a small number of patients not captured in this trial may have a different response.
It’s not an RCT with a patient-orientated outcome which would be our gold standard. Perhaps a non-inferiority trial design would be a higher level of evidence to support a change in practice but that would require very large numbers of patients and is unlikely to happen anytime soon.
Patients in this study had already received an IV bolus of 1g TXA and whilst the authors argue that this would have been unlikely to have influenced the results we should be cautious in extrapolating these findings to how TXA would perform as the initial dose.
It would be useful to compare and contrast the pharmokinetics of patients receiving IM TXA vs. the usual infusion.
So should we all use IM TXA from now on then?
Perhaps not if the IV route is available and if we have the time and resources to administer it. However, that’s not always the case especially in some LMIC and tactical settings. In those environments and in the absence of alternatives the IM route should be considered an option. With trauma being one of the biggest killers in the world, especially in LMICs then the implications may be considerable.
Similarly, the option of giving IM TXA prehospital could save time and effort in obtaining IV access in all settings and thus could change practice in all health economies. Arguably it is the pre-hospital setting where this may have the biggest impact.
I am aware that work is ongoing to develop an auto-injector for tactical use of TXA, with one commentator even suggesting that it could be used prophylactically on the battlefield. An interesting claim, not supported by the evidence here, but interesting none the less.
Another issue is whether we need the infusion at all. I am aware of UK trauma centres that changed practice to give a second 1g bolus of TXA as opposed to the infusion. The Royal London Hospital approach is shown below which I believe is based on their work on the long running ACIT study. In practical terms two bolus doses is a preferable option, but we have to remember that the best evidence, from CRASH 2 and 3 is from the use of a bolus followed by infusion.
The bottom line
This paper demonstrates that TXA can be given IM and that it reaches therapeutic levels quite quickly and for several hours. This may be an option in settings where IV infusions are unavailable, unaffordable or impractical.
- Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext
- 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 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60835-5/fulltext
- Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30638-4/fulltext
- Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30848-5/fulltext
- Simon Carley, “JC: Tranexamic Acid (TXA) in Head Injury. The CRASH-3 results. St Emlyn’s,” in St.Emlyn’s, October 14, 2019, https://www.stemlynsblog.org/jc-tranexamic-acid-txa-in-head-injury-the-crash-3-results-st-emlyns/.
- Chris Gray, “JC: Halt! It’s not time for TXA! Or is it? HALT-IT results at St Emlyn’s,” in St.Emlyn’s, June 23, 2020, https://www.stemlynsblog.org/halt-it-st-emlyns/.
- Justin Morgenstern, “CRASH 3: TXA is no wonder drug”, First10EM blog, October 28, 2019. Available at: https://first10em.com/crash-3/.
- SGEM#270: CRASH-3 TXA FOR TRAUMATIC HEAD BLEEDS? https://thesgem.com/2019/10/sgem270-crash-3-txa-for-traumatic-head-bleeds/
- CRASH-3: TXA for ICH? https://rebelem.com/crash-3-txa-for-ich/
- Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial https://bjanaesthesia.org/article/S0007-0912(20)30682-6/fulltext