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Abstract & Commentary
Source: CRASH trial collaborators. Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH trial): Randomized placebo-controlled trial. Lancet 2004; 364:1321-1328.
A total of 10,008 adults with clinically significant head injury were randomized to receive either a 48-hour infusion of methylprednisolone or placebo in this multicenter international trial. Inclusion criteria included age 16 or older and a Glasgow Coma Scale score of 14 or less within 8 hours of injury. Patients were not randomized if there was either a clear indication or contraindication for corticosteroids. All patients received a fixed dose of 2 g methylprednisolone over 1 hour in a 100 mL infusion, followed by 0.4 g per hour for 48 hours in a 20 mL per hour infusion.
The primary outcomes were death within two weeks of injury, and death or disability at six months. All analyses were performed on an intention-to-treat basis. An interim analysis supplied to the independent monitoring committee resulted in the trial being halted before reaching the planned enrollment of 20,000 patients.
The risk of death from all causes within two weeks was higher in the group allocated corticosteroids (21% deaths) when compared with the placebo group (18% deaths). The relative risk of death from all causes in patients allocated corticosteroids compared with placebo was 1.18 (95%, CI 1.09-1.27; p = 0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity or time since injury. In addition, risk of death at two weeks was not different in any of eight computed tomographic scan diagnosis subgroups or in patients with and without major extracranial injury.
Commentary by Stephany Abbuhl, MD, FACEP
The authors report that a 1995 survey showed that 64% of trauma centers in the United States used corticosteroids more than half the time in the intensive care management of head injury patients,1 and they also mention documented use of steroids in England and Asia.
The background that led to steroid use in certain centers for head injury patients is interesting. First, there is the argument that post-inflammatory changes and swelling contribute to neuronal degeneration. Second, although controversial, the standard of care has been to treat acute blunt spinal cord injury with methylprednisolone since the National Acute Spinal Cord Injury Studies showed slight neurologic improvement with this treatment, and there probably was some transferring of the evidence to head trauma. Finally, there were data from a few underpowered studies that suggested a small benefit in the corticosteroid group in head injury patients. The surprising results of this trial not only refute any reduction in mortality with corticosteroids in the two weeks after head injury, but the treatment was associated with a significant rise in risk of death.
Globally, the results from this trial potentially could protect many thousands of patients from increased risk of death associated with corticosteroid use. It also is likely that these results will further the debate on the evidence and use of steroids in spinal cord injury.
One significant limitation of this trial was that the protocol did not collect data on the cause of death. However, data were collected on complications, and although there was evidence of a small increase in the relative risk of infections and gastrointestinal bleeding within two weeks, it still remains unclear why patients allocated to corticosteroid treatment had a higher mortality rate. The effect of corticosteroids at six months was not reported in this publication, but will be reported later and may shed some light on this issue.
Dr. Abbuhl, Medical Director, Department of Emergency Medicine, The Hospital of the University of Pennsylvania; Associate Professor of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, is on the Editorial Board of Emergency Medicine Alert.
1. Ghajar J, et al. Survey of critical care management of comatose, head-injured patients in the United States. Crit Care Med 1995;23:560567.