Abstract and Commentary
Synopsis: There is an increase in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.
Source: Roberts I, et al. 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.
Traumatic brain injury (TBI) accounts for about 52,000 deaths yearly in the United States, and several million worldwide. Motor vehicle accidents are the major cause of TBI in young people; falls are the leading cause of death and disability in the elderly.
The most serious consequence of TBI is elevation of intracranial pressure (ICP), leading to lethal brain herniation. For the last 30 years, corticosteroids have been used to control elevated ICP in TBI patients. In 1997, a systematic review of published trial data suggested that the absolute risk of death in corticosteroid-treated patients was only about 1-2% lower than in controls. In 1998, the CRASH trial (Corticosteroid Randomization After Significant Head injury) was initiated to confirm or deny the effectiveness of corticosteroids in TBI.
The CRASH trial was a large, international, randomized, placebo-controlled trial of the effect of early administration of methylprednisolone on risk of death within 2 weeks and disability at 6 months after TBI. Adults with TBI were screened for inclusion within 8 hours of injury. Patients with a Glasgow Coma Scale (GCS) score of 14 or less, who were eligible for the study, were randomized to receive an intravenous infusion either of methylprednisolone (2g over 1 hour followed by a maintenance dose of 0.4g per hour) or of placebo for 48 hours.
Mortality data were collected at death, discharge, or at 2 weeks. Disability was assessed at 6 months, by a questionnaire that was mailed to patients or their caregivers, by telephone interview, or during a face-to-face interview.
The CRASH trial was powered to show a 2% difference in survival on an intention-to-treat basis, and Roberts and colleagues planned to enroll 20,000 patients. After 10,008 patients had been randomized, the data monitoring committee disclosed the unmasked results to the trial steering committee, which then stopped recruitment. The results were an unpleasant surprise: 21% of 4985 treated patients died within 2 weeks of randomization, compared with 18% of 4979 placebo patients. The relative risk of death from all causes in patients allocated to corticosteroids, compared with the placebo group, was 1.18 (95%, CI 1/09-1/27; P = 0.0001). The relative risk of death did not differ by severity of injury (P = 0.22) or time since injury (P = 0.05). There was no observed increase in complications with corticosteroid use. The effect of corticosteroids on disability at 6 months will be reported later.
The CRASH trial results show that corticosteroids should not be used to treat head injury, whatever the severity. In editorial comments, Saverland and Maegele2 point out that the CRASH trial left the unanswered, critical question of why corticosteroids significantly increased mortality. Therefore, clinicians are left to wonder how corticosteroids harmed TBI patients. The results of the CRASH trial will also raise doubts about the effectiveness of corticosteroid therapy in patients with traumatic spinal cord injury, where their use is well established. A recent critical review questioned the validity of existing trials of methylprednisolone in acute spinal cord injury.3
Roberts et al deserve our thanks and admiration for having completed one of the largest clinical trials in emergency patients with impaired consciousness. They have provided a definitive answer to an important therapeutic question. The use of corticosteroids in TBI now joins an ever-lengthening list of treatments that once were in widespread clinical use, but whose effectiveness could not be shown in large-scale, randomized trials. Goodbye to corticosteroid in TBI. — Igor Ougorets and John J. Caronna
Dr. Caronna, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.
1. Anderson P, et al. BMJ. 1997;314:1855-1859.
2. Saverland S, et al. Lancet. 2004;364:1291-1292.
3. Coleman WP, et al. J. Spinal Disord. 2000;13:185-199.