TXA in head injuries

A PEM adventure

Meet Polly, a 6-year-old girl with a penchant for shopping. Besides a few febrile convulsions when she was two, she’s a healthy 6-year-old. Having just bought the most gorgeous pair of red ballet pumps that would go delightfully with the red bow she bought in Harrods last week, she was skipping down Regent’s Street with her nanny.

As they crossed the front of Liberty, a huge letter L came plummeting down, crashing in front of her. By some miracle, the L missed Polly by a hair’s breadth, but startled by the experience, Polly stumbled sideways into the oncoming path of a cyclist. Incredibly, the cyclist swerved around Polly, managing to avoid hitting her. Calamity averted! But, Polly’s nanny, terrified for Polly’s life, grabbed her arm, pulled her to the pavement, and accidentally flung Polly into a street lamp. Polly collided head-first with the lamp post and instantly blacked out, waking to see crowds of onlookers peering on with concerned, yet curious, looks.

The nanny hailed the nearest black cab, and they set straight to our ED. En route, Polly vomited three times and started to become increasingly drowsy. Not liking the look of Polly one bit, the triage nurse took her straight into resus. Polly’s GCS is not great.

This is your assessment:

C – No catastrophic haemorrhage

A – is ok – airway’s patent, no stridor or stertor, sats 98% in air

C-spine – the SHO swoops into action and immobilises the neck manually with MILS

B – seems to be fine – RR 22, no bruising or external signs of injury, equal chest expansion, good air entry bilaterally, normal resonance to percussion bilaterally

C – No concerns – HR 120, BP 105/80, CRT <2sec centrally and peripherally, soft abdo, stable pelvis, no evidence of long bone fractures. Two IVs go in, one in each antecubital fossa.

D – here, we have a problem. Polly’s drowsy, and a formal GCS is 12 – E3, V4, M5. She has a right parietal-occipital region haematoma, and you think you might be able to feel a step – you’re pretty convinced she has a palpable skull fracture. Pupils are equal and reactive. 

E – Temp 37.2 C. Aside from the scalp haematoma, no other external stigmata of injury

It’s clear she needs a scan of her brain, and given her mechanism, you’d like to include her c-spine. You tell the team you’re worried about an intracranial bleed, but just as you’re about to phone the radiologist, your SHO asks –

“I’ve been reading about tranexamic acid in trauma. Should we give TXA to Polly?”

We want to stop any clot breakdown to try and slow any potential bleeding. During normal clot breakdown, plasminogen is converted to plasmin, and plasmin causes fibrinolysis and clot breakdown. TXA stops the conversion of plasminogen to plasmin and therefore stops clot busting. In theory, TXA should slow down or stop intracranial bleeding. But, there’s always been a worry that giving TXA could cause clotting in the cerebral vessels. This is not good.

So, how do you answer? “Yes, great idea, let’s give some TXA”, “No, I don’t give TXA to kids with isolated head injuries” or “That’s an interesting idea – do you want to tell me more about what you’ve been reading.”

There have been a couple of landmark trials.

CRASH 2, published in 2013 – was huge. It was an international multicentre randomised controlled trial comparing TXA with placebo in >20,000 adult trauma patients. The primary outcome was 28-day mortality – TXA improved survival with no increased risk of cerebral clots. The bottom line was that TXA, when given within 3 hours of injury, reduced mortality and didn’t cause harm, so it’s been widely adopted into trauma management.

And hot off the press… the international PATCH (Prehospital Antifibrinolytics to Trauma Coagulopathy and Haemorrhage) study (just published on 14th June 2023) compared a prehospital TXA bolus, followed by an eight-hour infusion with placebo in more than 1300 adult patients from 21 hospitals across three countries. Survival was better, both at 24 hours and six months, in the TXA group, although the primary outcome, a quality of life score at six months, called the Glasgow Outcome Scale Extended (GOS-E), was the same in both groups (53.7% in the TXA group vs 53.7% in the placebo group). Again, there was no increase in thrombotic stroke in the TXA group – TXA looks safe. This study moves trauma care beyond just ‘survival’.

What about head injury, though? The volume of blood bleeding into the brain is much smaller than in other traumatic haemorrhages. The skull can only fit a certain amount of blood in it. 

Along came the CRASH 3 trial, another huge study looking specifically at TXA in traumatic brain injury. Another international multicentre randomised controlled trial, TXA, was compared with placebo in >12,000 adult trauma patients with a GCS of 12 (or confirmed intracranial haemorrhage on CT), with no significant other non-head injury bleeding. Adults were randomised to receive a loading dose of TXA plus an infusion over 8 hours or saline. The team was interested in 28-day head injury-related mortality. 18.5% of patients in the TXA group died from their head injuries, compared to 19.8% in the placebo group – this was not statistically significant. Even if they excluded patients with a GCS of 3 or unreactive pupils at enrollment, outcomes were not better in the TXA group (12.5% mortality in the TXA group v 14.0% in the placebo group – not statistically significant). TXA conferred no survival benefit in adult patients with isolated head injuries. 

But that’s not where it ends. There were two key take-homes…

Safety. As in CRASH-2, TXA did not show a significant increase in thrombotic events or seizures. Giving TXA didn’t make the situation worse.

Subgroup analysis threw up some interesting results. When patients were separated into those with a GCS <9, or GCS 9-12, giving TXA to those with a lower GCS didn’t make any difference to survival. But, in patients with GCS 9 or above, what the authors called mild to moderate head injury, TXA significantly improved outcomes. The risk of death from a mild-moderate head injury was reduced when TXA was given (a decent relative risk reduction of 0.78). Giving TXA earlier (<3h) conferred a greater benefit. 

So, CRASH-3 has some important data. TXA results in better outcomes if given early in patients with mild to moderate TBI and does not cause harm.

“But,” says the SHO, “that data is in adults. Can you apply it to Polly?”

How do you respond? “Sure, we can try – let’s go with TXA”, “No – I’m not convinced the evidence is that good” or “I’m not sure – let’s do a quick PubMed search for some paediatric-specific evidence.”

The evidence is interesting.

First is PED-TRAX, the Paediatric Trauma and Tranexamic Acid Study, a retrospective review of >750 paediatric trauma admissions to Camp Bastion in Afghanistan. They found that the more injured a child was (higher ISS, hypotension, acidosis or coagulopathy), the more likely they were to receive TXA. Interestingly, even though kids who received TXA were much more severely injured, the children who received TXA had better survival outcomes than those who didn’t, with no complications.

Next of interest is a secondary analysis of the MATIC study – the MAssive Transfusion In Children study, published in 2022. MATIC was a prospective observational study of children with life-threatening bleeding – an international data set of 450 children with life-threatening haemorrhage who needed >40mL/kg of blood products. Just under half of the children had bleeding secondary to trauma, and the authors found children who received TXA, or other antifibrinolytics, had better survival outcomes at 6 and 24 hours—another win for TXA.

So this sounds very interesting – TXA sounds beneficial in paediatric trauma.

But it’s not all rosy. 

Last year, Kornelson et al. looked through all the evidence around TXA in paediatric trauma and published a systematic review and meta-analysis. Based on the 14 included studies, TXA only seemed to improve survival in children injured in combat and didn’t improve survival in injured civilian children.

But – these findings are all from observational cohort studies with small numbers and significant heterogeneity, especially regarding the dosing of TXA. 

The SHO interjects – “So the evidence isn’t clear cut. The question is, if it might work, should we give it anyway? Or is there a risk TXA could cause harm?”

Well, one study in Kornelson’s systematic review and meta-analysis is interesting. A retrospective cohort study in Japan by Maeda et al., published in 2018, looked at 1900 matched pairs of injured children under 12, half of whom received TXA. There was a small increased risk of seizures in the TXA group – 0.3% (7 children) of the 1900 children in the TXA group vs none of the 1900 children in the non-TXA group. 

But the evidence is a bit contrary – the systematic review and meta-analysis found no increased risk of seizures in the 14 included studies.

“The evidence is a mixed bag. Should we give TXA?”

While you’ve been having this lengthy debate, Polly has dropped her GCS to 11.

Rolling their eyes at your time-wasting evidence-based debate, the anaesthetist has initiated neuroprotective measures – head of the bed up, good temperature and glucose control, and has called CT, who are ready to receive Polly. 

Brakes off. She’s wheeled to radiology.

“You know what,” says your SHO as you roll Polly along the corridor, “we’re going to have the answer to our question in the next couple of years.”

The TIC-TOC trial, a large-scale, prospective, multicentre, randomised controlled trial from the PECARN network, is on the horizon. It’s a double-blinded RCT randomising severely injured children to receive either (1) TXA 15 mg/kg bolus + 2 mg/kg/h infusion over eight hours, (2) double this – TXA 30 mg/kg bolus dose + 4 mg/kg/h infusion over eight hours, or (3) normal saline placebo bolus + infusion.

Outcomes will include those specifically associated with traumatic brain injury – immediate survivability and longer-term sequelae, including quality of life at one week, one month, three months and six months, with longer-term neurocognitive follow-up.

We’ve high hopes for some results soon that will answer the question of whether we should be using TXA in paediatric trauma, including children with isolated head injuries.

Polly’s CT shows a small subdural bleed. Just as you’re finishing a swift neurosurgical referral, you’re called back to resus for another incoming trauma…

Polly showed us that there’s evidence that early TXA might improve survival in mild to moderate head injury, although this is adult-centric data. It’s unclear if there’s a benefit in children, but the evidence suggests TXA does not cause harm, so the risk of giving it is low. The TIC-TOC trial will give us more answers. But remember – although the academic debate is great fun, don’t let it delay neuro-protective measures while debating the evidence!

This post is part of the PEM Adventure at NEPTUNE 2023, hosted by Dani, Kat, Costas and Sarah. NEPTUNE 2023 was inaugural UK PEM trauma conference, hosted by Nottingham University Hospitals Trust, one of the largest major trauma centres in the UK.

Selected references

CRASH-3 trial collaborators. 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. Lancet. 2019 Nov 9;394(10210):1713-1723. doi: 10.1016/S0140-6736(19)32233-0. Epub 2019 Oct 14. Erratum in: Lancet. 2019 Nov 9;394(10210):1712. PMID: 31623894; PMCID: PMC6853170.

Eckert MJ, Wertin TM, Tyner SD, Nelson DW, Izenberg S, Martin MJ. Tranexamic acid administration to pediatric trauma patients in a combat setting: the pediatric trauma and tranexamic acid study (PED-TRAX). J Trauma Acute Care Surg. 2014 Dec;77(6):852-8; discussion 858. doi: 10.1097/TA.0000000000000443. PMID: 25423534.

Kornelsen E, Kuppermann N, Nishijima DK, Ren LY, Rumantir M, Gill PJ, Finkelstein Y. Effectiveness and safety of tranexamic acid in pediatric trauma: A systematic review and meta-analysis. Am J Emerg Med. 2022 May;55:103-110. doi: 10.1016/j.ajem.2022.01.069. Epub 2022 Feb 7. PMID: 35305468.

Maeda T, Michihata N, Sasabuchi Y, Matsui H, Ohnishi Y, Miyata S, Yasunaga H. Safety of Tranexamic Acid During Pediatric Trauma: A Nationwide Database Study. Pediatr Crit Care Med. 2018 Dec;19(12):e637-e642. doi: 10.1097/PCC.0000000000001724. PMID: 30199511.

Nishijima, DK, VanBuren, JM, Linakis, SW, et al. Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): A pilot randomized trial. Acad Emerg Med. 2022; 29: 862– 873. doi: 10.1111/acem.14481

PATCH-Trauma Investigators and the ANZICS Clinical Trials Group; Gruen RL, Mitra B, Bernard SA, McArthur CJ, Burns B, Gantner DC, Maegele M, Cameron PA, Dicker B, Forbes AB, Hurford S, Martin CA, Mazur SM, Medcalf RL, Murray LJ, Myles PS, Ng SJ, Pitt V, Rashford S, Reade MC, Swain AH, Trapani T, Young PJ. Prehospital Tranexamic Acid for Severe Trauma. N Engl J Med. 2023 Jun 14. doi: 10.1056/NEJMoa2215457. Epub ahead of print. PMID: 37314244.

Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, Cook L, Kawahara T, Perel P, Prieto-Merino D, Ramos M, Cairns J, Guerriero C. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013 Mar;17(10):1-79. doi: 10.3310/hta17100. PMID: 23477634; PMCID: PMC4780956.

Spinella, Philip C. MD1; Leonard, Julie C. MD, MPH2; Gaines, Barbara A. MD3; Luther, James F. MA4; Wisniewski, Stephen R. PhD4; Josephson, Cassandra D. MD5; Leeper, Christine M. MD, MS6;  for the MAssive Transfusion epidemiology and outcomes In Children (MATIC) Investigators and BloodNet. Use of Antifibrinolytics in Pediatric Life-Threatening Hemorrhage: A Prospective Observational Multicenter Study. Critical Care Medicine 50(4):p e382-e392, April 2022. | DOI: 10.1097/CCM.0000000000005383