Effect of high-dose dexamethasone on outcome from severe head injury. A clinical retrospective and a double-blind study of betamethasone in severe closed brain injuries [proceedings]. Role of corticosteroids in the development of pneumonia in mechanically ventilated head-trauma victims. Effect of dexamethasone on nitrogen metabolism in brain-injured patients. Megadose steroids in severe head injury. Results of a prospective double-blind clinical trial. Steroids in severe head injury: A prospective randomized clinical trial. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Treatment of patients with severe head injury by triamcinolone: a prospective, controlled multicenter clinical trial of 396 cases. "Ultrahigh" dexamethasone in acute brain injury. Results from a prospective randomized double-blind multicenter trial (GUDHIS). German Ultrahigh Dexamethasone Head Injury Study Group. High dose glucocorticoids in the management of severe head injury.
The conflicting evidence concerning the influence of high-dose steroids on intracranial pressure (ICP) and outcome following severe head injury has led to the institution of the prospective double-blind controlled trial reported here. Severely head-injured patients admitted to intensive care during a 3-year period were randomly allocated to a dexamethasone- or placebo-treated group. Adults in the steroid group received dexamethasone, 50 mg intravenously, as a bolus on admission to the neurosurgical unit, then 100 mg on Days 1, 2, and 3, 50 mg on Day 4, and 25 mg on Day 5 on continuous intravenous infusion. Children received proportionate intravenous dosages calculated on a weight basis. Severity of head injury was assessed from admission Glasgow Coma Scale (GCS) scores and the appearance of the admission computerized tomography scan. Intracranial pressure (ICP) was monitored in all patients from the surface subarachnoid space. Outcome at 6 months was assessed using the Glasgow Outcome Scale. Steroid and placebo groups were similar in terms of admission GCS score, intracranial pathology, incidence of associated injuries, and time interval from injury to admission to intensive care. The ICP generally increased during the first 48 hours of intensive therapy; there was no difference in this trend between the steroid and placebo groups. A poorer outcome was observed in patients with elevated ICP who received steroids. No increase in the incidence of pulmonary, gastrointestinal, or other extracranial complications was seen in the steroid group. The 6-month outcome did not differ between the steroid and placebo groups. No advantage of high-dose dexamethasone on ICP trends or clinical outcome in the treatment of severe head injury has emerged from this study. nan The development of pneumonia was monitored in head-trauma patients requiring mechanical ventilation. Of the 66 patients studied, 15 (23%) developed pneumonia within 14 days after ICU admission. In each case the diagnosis was based on x-ray evidence and at least two of the following: increased white blood cell count, increased fever, and/or increased sputum production with a predominant organism on the sputum stain. Coagulase-positive Staphylococcus aureus was the most common etiologic agent. There was no difference in the occurrence of pneumonia between patients treated with no steroids or with low, moderate, or high steroid doses. Although there was an association between thiopental use and the development of pneumonia, dexamethasone treatment was not a significant risk factor in the development of pneumonia in this patient population. A randomized prospective clinical trial was conducted to determine the influence of dexamethasone therapy on nitrogen metabolism in patients with isolated head trauma without any pathologies. One group of 12 patients was not given steroids (groups NS). To the 12 patients of the second group, a dose of 0.36 mg/kg/day of dexamethasone was administered for the first nine days of stay (group S) in hospital. At the beginning of the study, between the two groups, there were no differences in age, sex, Glasgow Coma Scale Score, type of injury. In order to avoid bias, phenytoin, barbiturates and muscle-relaxant drugs were not given and the same caloric and protein intake was prefixed for both groups. The urea excretion, nitrogen output, nitrogen balance and cumulative nitrogen balance were not statistically different in the two groups throughout the period of study. Similar were also weight losses, blood glucose, blood urea nitrogen, albumin and creatinine levels. The outcome, evaluated at 3 months, was also similar. The incidence of sepsis, pulmonary and urinary infections, gastric reflux duration and quantity, was not higher in the steroid group compared with non-steroid treated patients. A prospective double-blind clinical trial was performed on 161 patients to determine the effectiveness of high-dose steroid therapy in patients admitted comatose after a non-missile-related head injury. Patients were randomized into a high-dose dexamethasone phosphate group and a placebo group. The initial dose of 100 mg of dexamethasone was administered within 6 hours of the accident. For statistical analysis, a sequential test was chosen, using survival at 1 month as a basic criterion of effectiveness. No significant difference was found in the 1-month survival rate or in the distribution of outcome after 6 months, either within the group as a whole, or in subgroups with varying severity of brain damage on admission. The authors conclude that dexamethasone in high doses has no statistically significant effect on morbidity or mortality in head-injured patients who are comatose on admission. This is a prospective randomized study of the efficacy of steroid therapy in patients with severe head injury. One hundred patients were randomized into two equal groups: the steroid group received 5 mg/kg/day of methylprednisolone, and the nonsteroid group received no drug. The groups were similar in their clinical features. All patients received a standardized therapeutic regimen. The patients were also classified as early responders or nonresponders to the overall treatment protocol without regard to steroid administration, on the basis of change in Glasgow Coma Scale score during the first 3 days of admission. There was no statistically significant difference in the outcome of the steroid and nonsteroid group at 6 months. Of the responders who were on steroids, 74% had good outcomes or were disabled, compared with 56% of the responders who did not receive steroids. In the nonresponder group, the patients on steroids were actually associated with a worse outcome than those who did not receive steroids: 75% of the nonresponders who received steroids were dead or vegetative, compared to 56% of those who were not receiving steroids. The data suggest that: 1) the effect of steroids may be different for different patient groups; 2) in order to identify these patients, a sensitive coma scale is needed; and 3) a rational approach to steroid therapy in head-injured patients may be to start all patients on steroids, but to discontinue their use in patients identified as not benefiting from steroid therapy. 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 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment.
                10008 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.
                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).
                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. The present studies were conducted to test whether the outcome of severe head injury is improved by early administration of the synthetic corticosteroid triamcinolone. In a prospective, double-blind, multicenter clinical trial, 396 patients with severe head injury were randomized to a steroid group (n = 187) receiving 200 mg triamcinolone acetonide (Volon A soluble) i.v. within 4 h after trauma, followed by 3 x 40 mg/day i.v. for 4 days, and 3 x 20 mg/day i.v. for a further 4 days, and a placebo group (n = 209) receiving injections which did not contain any active drug. The placebo group was subjected to the same standard treatment procedures. Clinical features were not different between the groups upon admission to hospital. Subdural hematoma, epidural hematoma, and focal supratentorial contusion were among the most frequent diagnoses. The result of treatment with triamcinolone was assessed at discharge from the hospital and at 1 year after trauma, using the Glasgow Outcome Scale. Differences in favor of steroid treatment could be detected with regard to the patients' condition at discharge (P = 0.0634). More patients with steroids had a good recovery (49.2% vs 40.7%), and fewer died (16.0% vs 21.5%). Differences in outcome were even more pronounced (P < 0.0145) in patients with a focal lesion and a Glasgow Coma Score on admission of < 8 (n = 93). In this group, 34.8% of the patients made a good recovery, as against 21.3% of the placebo group; mortality was also lower in the verum group (19.6% vs 38.3%). The results indicate that a major subgroup of patients with severe head injury benefits from early administration of triamcinolone. Efficacy of the treatment can be expected, in particular, in patients with a focal cerebral lesion and a Glasgow Coma Score of < 8 on admission. Administration of steroids beginning at the scene of an accident would therefore be beneficial in these cases. In a prospective randomized double-blind multicenter trial, the efficacy and safety of a 51-hour ultra-high intravenous dexamethasone dosing regimen was investigated in patients with moderate and severe head injury. 300 patients between 15 and 55 years of age were randomized to receive either placebo or dexamethasone: 500 mg intravenous infusion within 3 h after trauma initially, followed by 200 mg after 3 h, thereafter 8 times 200 mg at 6 hourly intervals, resulting in a total administered dose of 2,3 g in 51 hours. Primary end points for assessment of efficacy were: Modified Glasgow Coma Scale (grading 3-16) on Day 5, modified Glasgow Outcome Scale (grading 1-6) 10-14 months after injury, and the time interval until consciousness improved above a level of modified GCS > or = 8. Secondary endpoints were CT results and neurological and laboratory data. The two groups were well matched with respect to important prognostic variables, such as age, severity of trauma, and interval between trauma and application of the drug. 269 patients (89.7%) were available for final examination after 10-14 months. Results were surprisingly favourable in both groups: Lethality in the dexamethasone and placebo group was 14.3 and 15.4%, respectively, and 61.7 and 57.4%, respectively, achieved social and professional rehabilitation after 10-14 months (outcome scale 6). No statistical difference was seen between the dexamethasone and the placebo group in any of the primary end points of efficacy and safety (incidence of upper gastrointestinal bleeding, infection, and thrombosis).(ABSTRACT TRUNCATED AT 250 WORDS) Eighty-eight patients with a Glasgow coma score of 8 or less 6 hours after nonpenetrating head trauma were given either high dose methylprednisolone sodium succinate (30 mg/kg q6h X2, then 250 mg q6h X6, then tapering over 8 days), low dose methylprednisolone (1.5 mg/kg q6h X2, then 25 mg q6h X6, then tapering over 8 days), or placebo. Standard care including the removal of traumatic hematomas, assisted ventilation, and intracranial pressure monitoring and control was carried out. Follow-up assessments were performed on all surviving patients at 6 months and were graded according to the Glascow outcome scale. No statistically significant difference in outcome was seen between the low dose group and the placebo group. The high dose group experienced a mortality of 39% as compared to a 52% mortality in the low dose and placebo groups (P less than 0.05). Mortality differences were most marked in patients less than 40 years old, with the high dose group experiencing a mortality of 6% as compared to a 43% mortality for the low dose and placebo groups (P less than 0.05). For patients under 50 years old, the incidence of recovery of speech was 62% compared to 36% in the low dose and placebo groups (P less than 0.5). The increased survival in those treated with high dose corticoids, however, was associated with an increase in the poorer outcome categories.
In the absence of a meta-analysis, we feel most weight should be placed on the result of the largest trial. The increase in mortality with steroids in this trial suggest that steroids should no longer be routinely used in people with traumatic head injury.