Fast track — ArticlesEffect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial
Introduction
Every year, millions of people worldwide are treated for head injury. A substantial proportion die or are permanently disabled. Although much damage is done at the time of injury, post-traumatic inflammatory changes are believed to contribute to neuronal degeneration.1, 2 Corticosteroids have been used to treat head injury for more than 30 years. A survey of UK neurosurgical intensive-care units in 1996 showed that these drugs were used in 14% of units to treat head injuries,3 and a survey of intensive-care management of patients with a head injury in the USA reported that corticosteroids were used in 64% of trauma centres.4 Corticosteroids are also used for management of head injury in Asia.5
Previous randomised trials of corticosteroids in head injury have included no more than a few hundred patients, and altogether only about 2000 patients have been studied. In 1997, a systematic review of available trials suggested that the absolute risk of death in the corticosteroid-treated group was about 1–2% lower than in controls, but the 95% CI was from 6% fewer to 2% more deaths.6
The second US National Acute Spinal Cord Injury Study (NASCIS-2) compared 24 h of methylprednisolone with placebo in 333 patients with acute spinal-cord injury.7 At 6 months, people receiving methylprednisolone within 8 h of injury seemed to have greater improvement in motor function and sensation to pinprick and touch than did those given placebo. Similar results were reported in a Japanese trial of the same regimen.8 Results of NASCIS-3 indicated slightly more neurological recovery with 48 h of treatment than with 24 h.9 Use of corticosteroids to treat acute spinal-cord injury led to renewed interest in their role in the treatment of head injury.10
The CRASH trial (corticosteroid randomisation after significant head injury) is a large, international, randomised placebo-controlled trial of the effect of early administration of 48 h infusion of methylprednisolone on risk of death and disability after head injury. The trial aimed to inform clinical decision-making in an area of increasing global health importance. Reliable demonstration of even a small absolute benefit from corticosteroids would have the potential to avoid thousands of deaths and disabilities. Similarly, because corticosteroids are widely used to treat head injury, reliable refutation of any benefit would protect thousands of patients from possible side-effects and avoid unnecessary cost.
Section snippets
Patients and methods
The protocol for the CRASH trial has been published elsewhere (http://www.crash.lshtm.ac.uk). All collaborating investigators were required to secure local ethics or research committee approval before recruitment could begin. Patients with clinically significant head injury are unable to give valid informed consent. Local ethics committees set consent procedures for participating hospitals. Some allowed consent waiver and others consent from a legal representative. We always adhered to these
Results
Patients were enrolled in 239 hospitals from 49 countries: 2141 (21%) were enrolled by central telephone randomisation and 7867 (79%) were non-centrally randomised. The first patient was enrolled in April, 1999. In May, 2004, the data monitoring and ethics committee disclosed the unmasked results to the trial steering committee, which then stopped recruitment. 10 008 patients were randomised to corticosteroid or placebo infusions (figure 1): 62 were subsequently found to be younger than 16
Discussion
The results of the MRC CRASH trial of methylprednisolone treatment reliably refute any reduction in mortality in the 2 weeks after head injury: this treatment was associated with a significant rise in risk of death within 2 weeks. The apparent increase in mortality did not differ in the prespecified subgroups, although the hazard might be enhanced in patients presenting at a later time. Although the apparent hazard could be a statistical artifact, due in part to the data-dependent stopping of
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