The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury

BACKGROUND: Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. METHODS: Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). RESULTS: 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. CONCLUSION: This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128

Penetrating civilian craniocerebral gunshot wounds: a protocol of delayed surgery

Objective: Several factors have led to our unique approach of delayed definitive débridement. We wanted to evaluate the effectiveness of our management and compare it with the existing data in the literature. Methods: We retrospectively reviewed the records of 194 patients presenting between January 1996 and October 2003 with penetrating craniocerebral gunshot wounds. After exclusion criteria, 125 patients qualified. Results: Of the patients, 88.8% were male. The mean age was 24.9 ± 10.9 years. In 70.4% of patients, the presenting Glasgow Coma Scale (GCS) score was 3 to 8. Only 38 (30.4%) of the 125 patients survived, with poor outcome in 2 and good outcome in 36. Bilaterally fixed and dilated pupils and bihemispheric tract on computed tomographic scan were significantly related to poor outcome. There were 49 surgical procedures performed on 27 of the patients, with a mortality rate of 7.4%. Of the 38 survivors, 13 underwent no surgery. Average time to surgery was 11.04 days. Total rate of infection was 8%, and it did not influence outcome. No patient presenting with a GCS score of 3 or 4 survived. Seventeen patients attended follow-up, for a total of 3609 days (average, 212 d) and very few late complications. Conclusion: Our supportive care of patients is not optimal. We should have saved more of our patients who presented with GCS scores of 14 and 15 who subsequently died. We have been able to report unconventionally late surgical management of two-thirds of survivors, with no surgery in one-third of survivors. Despite a high rate of infectious complications, infection did not lead to death or disability. Our protocol rarely leads to patients surviving in a permanently vegetative state. In the future, we would perform early surgery for patients who present awake and continue our current management for poor-grade patients. In this way, we will improve the number of good outcomes without increasing the population of severely damaged and dependent survivors

Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months

MRC CRASH is a randomised controlled trial (ISRCTN74459797) of the effect of corticosteroids on death and disability after head injury. We randomly allocated 10,008 adults with head injury and a Glasgow Coma Scale score of 14 or less, within 8 h of injury, to a 48-h infusion of corticosteroid (methylprednisolone) or placebo. Data at 6 months were obtained for 9673 (96.7%) patients. The risk of death was higher in the corticosteroid group than in the placebo group (1248 [25.7%] vs 1075 [22.3%] deaths; relative risk 1.15, 95% CI 1.07-1.24; p=0.0001), as was the risk of death or severe disability (1828 [38.1%] vs 1728 [36.3%] dead or severely disabled; 1.05, 0.99-1.10; p=0.079). There was no evidence that the effect of corticosteroids differed by injury severity or time since injury. These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury