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Corticosteroids in Head Injury

Worldwide, some millions of people are treated each year for serious head injury, of whom close to a million die, and a similar number are disabled, [Ref 1] often with profound effects on the subsequent quality of life of the affected individuals and their carers.[Ref 2] If a treatment as simple as short term corticosteroids produces just a moderate benefit, this could be worthwhile. For example, if corticosteroids reduced the risk of death by just 2% (e.g. from 15% to 13%), and reduced the risk of permanent disability by a similar amount, then treatment of 500,000 patients would avoid 10,000 deaths and prevent 10,000 permanent disabilities. But, such a benefit would be impossible to demonstrate reliably without large scale randomised evidence. If, for example, 10,000 patients were randomly allocated to receive a corticosteroid infusion and 10,000 a placebo infusion, then a reduction from 15% to 13% dead should be detectable - and a reduction from 15% to 12% would certainly be detectable. By contrast, a trial involving only 2,000 patients would probably miss such differences.

So far, all of the randomised trials of corticosteroids in head injury have been small: the largest included only a few hundred patients, and even in aggregate they have involved only about 2,000 patients (Figure 1).[Ref 3]  When all previous trials are combined, the risk of death in the corticosteroid treated group appears to be about 2% lower than in the control group, but the 95% confidence interval runs from 6% lower to 2% higher mortality. (This overall reduction from 39% dead to 37% dead corresponds to an 'odds ratio' of 0.91, with 95% confidence interval 0.74 to 1.12; the corresponding odds ratio for death or disability in those trials is 0.90, with 95% confidence interval 0.72 to 1.11.)  Hence, the overall result from the previous trials is compatible with there being no real benefit, but it is also easily compatible with a benefit of a few percent. However, the existing trials are too small to demonstrate or to refute either possibility.

Figure 1. Aggregate mortality results from 13 randomised trials of steroids in head injury published before 1997

  Steroid Control
Number of patients 1,061 1,087
Number of patients who died 396

Absolute benefit of steroids 2%, indicating 1 death prevented for every 50 patients treated: but these previous trial results are also statistically compatible with there being no real benefit at all (or even a small hazard).

Corticosteroids in Spinal Injury

Recent evidence of benefit from corticosteroids in acute spinal cord injury has renewed interest in their possible role in brain injury. The Second US National Acute Spinal Cord Injury Study (NASCIS 2) compared 24 hours of methylprednisolone (MP) vs placebo in 333 patients with acute spinal cord injury.[Ref 4]  At six months, patients who had received steroids rather than placebo appeared to have greater improvement in motor function, and in sensation to pinprick and touch. Similar results were reported in a Japanese trial of the same regimen.[Ref 5]  Recent trials of MP in acute spinal cord injury have indicated slightly more neurological recovery with 48 than with 24 hours of treatment.[Ref 6]


Dose Selection

Post-traumatic neuronal degeneration can involve lipid peroxidation,[Ref 7]  and in cats [Refs 8,9] and mice [Ref 10]  this can be inhibited by methylprednisolone,[Ref 11]  with 30 mg/kg needed for maximal effect. The dose of steroid used in previous head injury trials was, however, much lower than this,[Ref 3] and so a trial of the early administration of methylprednisolone in doses that are high enough to inhibit lipid peroxidation may produce slightly greater treatment effects than those in Figure 1. The CRASH trial has therefore been designed to determine reliably:


  • the effects of high dose corticosteroid infusion on death and on disability following significant head injury, and

  • the effects of such infusion on the risk of infection and of gastro-intestinal bleeding in this setting.