What is the role of methylprednisolone in the management of acute traumatic brain injury, particularly in light of the CRASH (Corticosteroid Randomisation After Significant Head injury) II trial?

CRASH II and CRASH III Trials: Corticosteroids in Traumatic Brain Injury

Direct Answer

Corticosteroids, specifically methylprednisolone, should NOT be used in traumatic brain injury (TBI) management, as the CRASH trial definitively demonstrated increased mortality without any functional benefit. 1, 2

Evidence from the CRASH Trial

The CRASH (Corticosteroid Randomisation After Significant Head injury) trial was a landmark study that fundamentally changed TBI management:

CRASH Trial Design and Results

• 10,008 adults with head injury (Glasgow Coma Scale ≤14) were randomized within 8 hours of injury to receive either a 48-hour infusion of methylprednisolone or placebo 3, 4
• Primary finding: Corticosteroids significantly increased mortality with a relative risk of death of 1.18 (95% CI: 1.09-1.27, p=0.0001) 1, 3
• At 2 weeks: 21.1% died in the steroid group versus 17.9% in placebo (1,052 vs 893 deaths) 4
• At 6 months: 25.7% died in the steroid group versus 22.3% in placebo (1,248 vs 1,075 deaths) 3
• No benefit for disability: The risk of death or severe disability was also higher in the corticosteroid group (38.1% vs 36.3%) 3

Consistency Across Subgroups

• The harmful effect of corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05) 4
• This means steroids are harmful across all TBI severities - mild, moderate, and severe 4

Current Clinical Guidelines

Strong Recommendations Against Steroid Use

The Brain Trauma Foundation explicitly recommends against giving steroids in TBI, with a Grade 1- (strong negative recommendation) and strong expert agreement. 1, 2

• High-dose steroids are specifically listed among therapies to be avoided in critically ill TBI patients 2
• The FDA does not approve methylprednisolone for TBI treatment 5

Mechanism of Harm

• Increased infection rates 2
• Hyperglycemia 2
• Gastrointestinal bleeding 2
• The exact mechanism of increased mortality within 2 weeks remains unclear but is consistently demonstrated 4

Critical Pitfalls to Avoid

Do Not Extrapolate from Spinal Cord Injury Protocols

The American Association of Neurological Surgeons explicitly advises against extrapolating from spinal cord injury treatment protocols (such as NASCIS methylprednisolone protocols) to TBI management. 1

• While methylprednisolone has been used in spinal cord injury (though controversially), this does NOT apply to brain injury 5
• Even in thoracolumbar spinal cord injury, the Congress of Neurological Surgeons found insufficient evidence to recommend methylprednisolone, noting that "the complication profile should be carefully considered" 5

"Stress Dose" Steroids Also Show No Benefit

• The use of "stress dose" steroids in acute TBI shows no benefit for death or disability, with a pooled relative risk of 0.95 1
• This means even lower doses of steroids should be avoided 1

CRASH III Trial Context

While the user question mentions CRASH III, the provided evidence focuses on CRASH II (the main CRASH trial for TBI). CRASH III examined tranexamic acid (an antifibrinolytic agent, NOT a steroid) in TBI patients with intracranial bleeding - this is a completely different intervention and should not be confused with the corticosteroid findings from CRASH II 6, 3, 4.

What to Do Instead for Cerebral Edema Management

First-Line Approaches

• Ensure proper ventilation with tracheal intubation and mechanical ventilation, monitoring end-tidal CO2 to maintain appropriate levels 2
• Consider external ventricular drainage for persistent intracranial hypertension after sedation and correction of secondary brain insults 2
• Maintain serum glucose between normal levels in severe TBI patients 2

Second-Line Approaches

• Consider decompressive craniectomy for refractory intracranial hypertension after multidisciplinary discussion 2
• Avoid prolonged hypernatremia when controlling intracranial pressure 2

Important Distinction

Do not confuse TBI-related edema management with tumor-associated edema or spinal cord compression, where dexamethasone has established benefits. 2 The pathophysiology is fundamentally different.