The use of steroids is not recommended for improving outcome or reducing intracranial pressure (ICP). In patients with moderate or severe traumatic brain injury (TBI), high-dose methylprednisolone is associated with increased mortality and is contraindicated.

Steroids were introduced in the early 1960s as a treatment for brain edema. Experimental evidence accumulated that steroids were useful in the restoration of altered vascular permeability in brain edema, reduction of cerebrospinal fluid production,26 attenuation of free radical production, and other beneficial effects in experimental models. The administration of glucocorticoids to patients with brain tumors often resulted in marked clinical improvement and glucocorticoids were found to be beneficial when administered in the perioperative period to patients undergoing brain tumor surgery. French and Galicich reported a strong clinical benefit of glucocorticoids in cases of brain edema and found glucocorticoids especially beneficial in patients with brain tumors. Renauldin et al. in 1973 reported a beneficial effect of high-dose glucocorticoids in patients with brain tumors who were refractory to conventional doses.

Glucocorticoids became commonly administered to patients undergoing a variety of neurosurgical procedures and became commonplace in the treatment of severe TBI. In 1976 Gobiet et al. compared low- and high-dose Decadron to a previous control group of severe TBI patients and reported it to be of benefit in the high-dose group. Also in 1976, Faupel et al. performed a double blind trial and reported a favorable dose-related effect on mortality in TBI patients using glucocorticoid treatment. Subsequently, six major studies of glucocorticoid in severe TBI were conducted that evaluated clinical outcome, ICP, or both. None of these studies showed a substantial benefit of glucocorticoid therapy in these patients. Trials in TBI patients have been completed using the synthetic glucocorticoid, triamcinolone, the 21-aminosteroid tirilazad, a trial using ultra-high-dose dexamethasone, and a trial using highdose methylprednisolone. None of these trials has indicated an overall beneficial effect of steroids on outcome, and one trial was halted before completion when an interim analysis showed increased mortality with steroid administration. Moreover, a meta-analysis of trials of steroids in TBI revealed no overall beneficial effect on outcome.

For this update, Medline was searched from 1996 through April of 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 14 potentially relevant studies, 2 were added to the existing table and used as evidence for this question (Evidence Table I).

In 1979, Cooper et al. reported a prospective, doubleblind study of dexamethasone in patients with severe TBI. Ninety-seven patients were stratified for severity and treated with placebo, low-dose dexamethasone 60 mg/day, or high-dose dexamethasone 96 mg/day. Seventy-six patients were available for clinical follow-up, and ICP was measured in 51. The results showed no difference in outcome, ICP, or serial neurologic examinations among the groups.

Saul et al. reported a randomized clinical trial in 100 patients. One group received methylprednisolone 5 mg/kg/day versus a control group that received no drug. There was no statistically significant difference in outcome between the treated and non-treated groups at 6 months. A subgroup analysis indicated that, in patients who improved during the first 3 days after TBI, the steroid-treated group had better outcomes than the placebo group.

Gianotta et al. reported a double blind clinical trial of 88 patients comparing placebo; low-dose methylprednisolone 1.5 mg/kg loading, followed by a tapering dose; and high-dose methylprednisolone 30 mg/kg loading, followed by a tapering dose. The data did not show a beneficial effect of either low-dose or high-dose methylprednisolone compared with placebo. Subgroup analysis revealed an increased survival and improved speech function in patients under age 40 when the high dose was compared with the low dose and placebo groups combined.

Gaab et al. reported the results of a randomized double-blind multicenter trial of the efficacy and safety of ultra-high-dose dexamethasone in patients with moderate and severe TBI. The trial enrolled 300 patients, randomized to placebo or dexamethasone: 500 mg within 3h of injury, followed by 200 mg after 3 h, then 200 mg every 6 h for eight doses for a total dexamethasone dose of 2.3 g, given within 51 h. Glasgow Outcome Scale (GOS) score at 10-14 months following injury, and also time from injury until Glasgow Coma Scale (GCS) score reached 8 or greater were used as primary endpoints. The results of the trial revealed no differences between placebo and drug-treated patients in either primary endpoints. This trial has the advantage of having a large number of patients who were treated early following injury and with very high doses of medication.

Marshall et al. reported the results of a large randomized controlled trial (RCT) of the synthetic 21-amino steroid, tirilazad mesylate, on outcome for patients with severe TBI19 There is experimental evidence that this compound may be more effective than glucocorticoids against specific mechanisms that occur in brain injury, and higher doses can be used without glucocorticoid side effects. The trial enrolled 1,170 patients; no overall benefit on outcome in TBI patients was detected. The same outcome was demonstrated in a similar trial conducted in Europe and Australia that included nontrauma patients.

More recently, Watson et al., using an existing prospective database, conducted a retrospective comparison of occurrence of first late seizures between TBI patients (GCS ≤ 10) who received glucocorticoids (n = 125) and those who did not (n = 279). The treatment group was further divided into those who received the treatment within 24 h of injury (n = 105) and those who received it between days 2 and 7 post-injury. Patients were followed for 2 years. Authors used multivariate analysis to control for seizure risk and injury severity. They found a 74% increase in risk of developing first late seizures for patients who received glucocorticoids within 24 h of injury over those who did not (p = 0.04; hazard ratio = 1.74; CI 1.01-2.98). There was no significant difference between groups in the development of second late seizures, or in mortality. However, the evidence is Level III due to lack of information about GCS, hypotension, and hypoxia in the different groups, as well as to the possibility of bias in the selection of patients who received the treatment.

Alderson et al. in 1997 reported the results of a systematic review of RCTs of corticosteroids in acute traumatic brain injury. Many of the trials mentioned above, as well as additional unpublished data, were included in this analysis. The data presented indicates no evidence for a beneficial effect of steroids to improve outcome in TBI patients. Analysis of the trials with the best blinding of groups revealed the summary odds ratio for death was 1.04 (0.83-1.30), and for death and disability was 0.97 (0.77-1.23). The authors stated that a lack of benefit from steroids remained uncertain, and recommended that a larger trial of greater than 20,000 patients be conducted to detect a possible beneficial effect of steroids.

The CRASH (Corticosteroid Randomization After Significant Head Injury) trial collaborators in 2004 reported the results of an international RCT of methylprednisolone in patients with TBI. 10,008 patients from 239 hospitals in 49 countries were randomized to receive either 2g IV methylprednisolone followed by 0.4 mg/h for 48 h, or placebo. Inclusion criteria were age 16 years or greater, GCS 14 or less, and admission to hospital within 8 h of injury. Exclusion criteria included any patient with clear indications or contraindications for corticosteroids as interpreted by the referring or admitting physicians. The study was halted by the data monitoring committee, after approximately 5 years and 2 months of enrollment, when interim analysis showed a deleterious effect of methylprednisolone. Specifically, 2-week mortality in the steroid group was 21% versus 18% in controls, with a 1.18 relative risk of death in the steroid group (95% CI 1.09-1.27, p = 0.0001). This increase in risk was no different when patients were adjusted for the presence of extracranial injuries. The authors stated that the cause of the increase in mortality was unclear, but was not due to infections or gastrointestinal bleeding.

The majority of available evidence indicates that steroids do not improve outcome or lower ICP in severe TBI. There is strong evidence that steroids are deleterious; thus their use is not recommended for TBI.

Currently, there is little enthusiasm for re-examining the use of existing formulations of steroids for treatment of patients with TBI. If new compounds with different mechanisms of actions are discovered, further study may be justified.