CRASH 3 and Traumatic Brain Injury

Posted by Jeremy Windsor on Jan 01, 2021

Each year traumatic brain injury (TBI) is responsible for more than 50 million deaths. In the UK it is the most common cause of death in the under 40's. Unfortunately, effective treatments are short on the ground. Tranexamic Acid is a cheap and easily administered drug that's recently been studied by researchers from the London School of Hygiene and Tropical Medicine. David Cambray-Deakin, one of our new Mountain Medicine Fellows at Chesterfield Royal Hospital, decided to take a look at their results...

The recently published CRASH-3 randomised controlled trial compared tranexamic acid (TXA) with placebo in the management of TBI. TXA is an anti-fibrinolytic drug that reduces bleeding by inhibiting the enzymatic breakdown of blood clots. To a limited extent, this works. In the preceding CRASH-2 study, TXA was shown to reduce the risk of death in bleeding trauma patients. In particular, subgroup analysis showed that those who also had a TBI experienced fewer intracerebral haemorrhages on TXA. Therefore hopes were high that TXA could reduce death from TBI in a larger, more focused trial.

Over the course of almost 7 years, CRASH-3 recruited an extraordinary 12,737 patients from no fewer than 175 hospitals across 29 countries. The patients had all suffered a traumatic brain injury (TBI) with evidence of bleeding on their CT scan or a GCS of 12 or lower. The patients were randomised to receive either tranexamic acid (TXA) or placebo (PLA). The primary outcome was head injury related death within 28 days. Of the 9,202 patients who were treated within 3 hours, there was no difference in the primary outcome between the 2 groups - TXA 855 (18.5%) vs PLA 892 (19.8%). However the story doesn't end there! Given such a large number of patients, it's well worth delving into the sub-group analysis. These results revealed that the severity of injury and timing of treatment made an enormous difference to the primary outcome. 

To ensure that the drug could be administered as easily as possible, the trial protocol sets out to give only 2 doses - an initial 1g IV over 10 minutes followed by a further 1g IV over 8 hours


Whilst TXA made no difference to patients with a severe TBI (GCS 3-8), those with a mild to moderate injury (GCS 9-15) were 22% less likely to suffer a head injury related death at 28 days - 166/2846 (TXA) vs 207/2769 (PLA). In a similar way, timing made no difference to those with a severe TBI. However deaths were fewer in those with a mild to moderate injury if they received TXA within 1 hour of injury. Put simply, TXA works best if given quickly to those with a mild to moderate brain injury. Or as one commentator pithily put it, "tranexamic acid reduces brain injury, but it can’t raise the dead". 

A final important finding that's worth mentioning is that TXA is safe. For many years there has been suspicions that TXA might cause life threatening complications such as pulmonary embolism or ischaemic stroke. It doesn't - the enormous population recruited to CRASH-3 shows this with some confidence! In fact, there's some evidence to suggest that it may even reduce gastrointestinal bleeding.

Given the growing evidence to support the use of TXA in TBI we asked those involved in pre-hospital care what they thought. Here's what they wrote...

Stuart Allan - GP and MRT Doctor - "Mountain Rescue England and Wales have TXA on their National Formulary and have had for some time. This is on Section 3 - that is, recommended for use by doctors and other suitably trained personnel. In other words those familiar with the drug and its administration. Officially, this was included following CRASH-2 and not CRASH-3 but has recently been the source of much discussion amongst members of the Lake District Search and Mountain Rescue Association (LDSAMRA)*. Ultimately, we still need to focus upon getting the basics done right, such as effective ABCDE and rapid evacuation, however it is another useful weapon in our armamentarium".

*It's worth noting that in the current England and Wales MRT Drug Formulary, TXA is not recommended for use in isolated head injuries. The formulary can be found here.

Dave Gregory - Paramedic and MRT Member - "In the North West Ambulance Service we've been using TXA since October 2020 for patients with a TBI. Patients need to be over 18, have a GCS of 12 or less and present within 3 hours of injury. We don't have access to a pump so we're giving it as a slow bolus over 10 minutes. The second dose is then given in hospital".

David Hillebrandt - GP and Pre-Hospital Care Doctor - "It now just feels routine to us all in BASICS Devon to give TXA to these patients. I'm not sure what paramedic protocol is followed but it seems it is often given prior to our arrival. My one worry is that some people will see this drug as a panacea for all ills and fail to do the basic things right such as dressing, splinting and packaging patients".

Steve Rowe - Anaesthetist and Deputy Leader of Edale MRT - "We've been carrying TXA since CRASH 2 was published, and have given it plenty of times (usually at the bottom of Stanage!) to patients who may be bleeding following trauma.

Whilst we've read CRASH 3 and the infographics, we haven't jumped at it for moderate head injuries in isolation as the trial didn't actually reach significance, but demonstrated "a signal" towards significance. 

Team members don't have cannulation skills, but seeing as the team has a number of professional medics and often works in conjunction with air ambulance services, we are happy with this situation currently.

I note with interest an encouraging paper published in the British Journal of Anaesthesia that looks at the successful use of intramuscular TXA. This could easily be given by non-professional medics as it requires a lesser skill set than cannulation.

Still waiting for the sub-group follow on papers from CRASH 3 - maybe they'll convince me..."

Up until now my experience of TXA in clinical use has mostly been during my F1 posts in General Surgery and Acute Medicine, where it was sometimes used in the management of acute upper gastrointestinal bleeds. I saw a more uncommon use (though a highly effective one!) when I was an F2 in Clinical Oncology. TXA was used successfully as a mouthwash preparation for a patient with a bleeding tongue cancer following radiotherapy. Now reading the CRASH-3 trial and finding out about it I’ve learnt so much. I'm really looking forward to using TXA in the future!

Thanks to David and all those who contributed to this post.

Interested in a Scottish climbing adventure? Take a look at this! Perhaps cragging in Wales instead?

Have you ever thought about how someone with an artificial heart would cope in the mountains? Why not read this

Have you ever had a non-freezing cold injury (NFCI)? There's a good chance that you have! Read more about NFCI here.

If you would like to find out more about mountain medicine why not join the British Mountain Medicine Society? See this link for details.

Have something to say? Comment on this post