Elsevier

The Lancet

Volume 364, Issue 9442, 9–15 October 2004, Pages 1321-1328
The Lancet

Fast track — Articles
Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(04)17188-2Get rights and content

Summary

Background

Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1–2%. The CRASH trial—a multicentre international collaboration—aimed to confirm or refute such an effect by recruiting 20 000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment.

Methods

10 008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797.

Findings

Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21·1%] vs 893 [17·9%] deaths; relative risk 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 (p=0·22) or time since injury (p=0·05).

Interpretation

Our results show there is no reduction 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.

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

References (22)

  • G Teasdale et al.

    Assessment of coma and impaired consciousness: a practical scale

    Lancet

    (1974)
  • B Jennett et al.

    Assessment of outcome after severe brain damage: a practical scale

    Lancet

    (1975)
  • S Pocock et al.

    Trials stopped early: too good to be true?

    Lancet

    (1999)
  • DK Menon

    Cerebral protection in severe brain injury: physiological determinants of outcome and their optimisation

    Br Med Bull

    (1999)
  • MC Morganti-Kossmann et al.

    Inflammatory response in acute traumatic brain injury: a double-edged sword

    Curr Opin Crit Care

    (2002)
  • DR Jeevaratnum et al.

    Survey of intensive care of severely head injured patients in the United Kingdom

    BMJ

    (1996)
  • J Ghajar et al.

    Survey of critical care management of comatose head injured patients in the United States

    Crit Care Med

    (1995)
  • Z Wang et al.

    Current status of trauma care in China

    Trauma Q

    (1999)
  • P Alderson et al.

    Corticosteroids in acute traumatic brain injury: a systematic review of randomised trials

    BMJ

    (1997)
  • MB Bracken et al.

    A randomised controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

    N Engl J Med

    (1990)
  • K Otani et al.

    Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury [Japanese]

    Sekitsui Sekizui J

    (1994)
  • Cited by (845)

    • Management of Head Trauma

      2024, Surgical Clinics of North America
    View all citing articles on Scopus

    Listed at end of report

    View full text