What is the role of tranexamic acid (TXA) in the management of traumatic brain injury, as demonstrated by the CRASH 2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2) trial?

CRASH-2 Trial: Tranexamic Acid in Traumatic Hemorrhage

Core Trial Findings and Impact

The CRASH-2 trial definitively established that tranexamic acid (TXA) administered as 1g IV over 10 minutes followed by 1g infusion over 8 hours significantly reduces all-cause mortality (14.5% vs 16.0%, RR 0.91) and bleeding deaths (4.9% vs 5.7%, RR 0.85) in trauma patients with significant hemorrhage. 1

Mortality Reduction by Timing

The trial revealed critical time-dependent effects that fundamentally changed trauma care protocols:

• Treatment within 1 hour: Greatest mortality reduction with bleeding deaths decreasing from 7.7% to 5.3% (RR 0.68,95% CI 0.57-0.82, P<0.0001) 1
• Treatment between 1-3 hours: Still effective, reducing bleeding deaths from 6.1% to 4.8% (RR 0.79,95% CI 0.64-0.97, P=0.03) 1
• Treatment after 3 hours: HARMFUL - increased risk of death due to bleeding from 3.1% to 4.4% (RR 1.44,95% CI 1.12-1.84, P=0.004) 1

Effectiveness decreases by 10% for every 15-minute delay in administration, making pre-hospital administration critical. 1

Standard Dosing Protocol from CRASH-2

The evidence-based regimen that should be used universally:

• Loading dose: 1g IV over 10 minutes 2, 1
• Maintenance infusion: 1g IV over 8 hours 2, 1

This achieves therapeutic plasma levels of 10 μg/ml necessary to inhibit systemic fibrinolysis, with a plasma half-life of 120 minutes. 1

Implementation Strategy Based on Trial Evidence

Administer TXA to ALL trauma patients with significant bleeding or at risk of significant hemorrhage as soon as possible, ideally en route to the hospital. 2, 1 The European guideline explicitly recommends pre-hospital administration to ensure treatment within the critical 3-hour window. 2

Critical Clinical Algorithm

1. Identify bleeding trauma patient - any significant hemorrhage or risk thereof 2
2. Assess time from injury - must be within 3 hours 2, 1
3. Administer immediately - do not await viscoelastic assessment results 2
4. Give loading dose - 1g IV over 10 minutes 2, 1
5. Continue maintenance - 1g over 8 hours 2, 1

Safety Profile from CRASH-2

No increase in thrombotic events was observed - in fact, myocardial infarction rates were lower with TXA. 1 This finding from over 20,000 patients has been consistently replicated, with meta-analyses of 125,550 participants showing no evidence of increased thromboembolic risk. 1

Important Safety Caveat

Higher doses beyond the CRASH-2 protocol (≥4g/24h) are associated with increased seizure risk, particularly in cardiac surgery, without proven additional benefit. 1 Stick to the CRASH-2 dosing regimen.

Extension to Traumatic Brain Injury: CRASH-3 Trial

While CRASH-2 focused on extracranial bleeding, the subsequent CRASH-3 trial (n=12,737) evaluated TXA specifically in traumatic brain injury patients. 2, 3, 4

TBI-Specific Findings

In patients with mild to moderate TBI treated within 3 hours, TXA reduced head injury-related death (RR 0.78,95% CI 0.64-0.95), but showed no benefit in severe head injury (RR 0.99,95% CI 0.91-1.7). 2, 5, 3

The European trauma guidelines now recommend TXA for TBI patients when administered within 3 hours of injury using the same CRASH-2 dosing regimen. 2, 5

Cost-Effectiveness Evidence

The CRASH-2 trial demonstrated exceptional cost-effectiveness across all economic settings:

• Tanzania: $48 per life-year gained 1
• India: $66 per life-year gained 1
• UK: $64 per life-year gained 1

This makes TXA one of the most cost-effective interventions in trauma care globally. 1

Critical Pitfalls to Avoid

Never delay TXA administration beyond 3 hours - this converts benefit to harm, with increased bleeding death risk after the 3-hour window. 2, 1

Do not restrict use to only massive transfusion protocols - CRASH-2 showed benefit across all trauma patients with significant bleeding, and only 40% of preventable deaths occur in the highest-risk group. 1 Broader application prevents more deaths.

Do not use alternative dosing regimens - the CRASH-2 protocol (1g + 1g) is the only regimen with proven mortality benefit. 2, 1 Higher doses increase seizure risk without additional benefit. 1

Do not await laboratory results - the European guideline explicitly states that TXA administration should not await viscoelastic assessment results, as early administration is critical. 2

Renal Impairment Consideration

TXA is renally excreted and accumulates in renal failure, requiring dose adjustment in patients with severe renal impairment. 2, 5 However, in the acute trauma setting with life-threatening hemorrhage, the mortality benefit outweighs this concern when standard dosing is used.