This proposed project, the National Acute Brain Injury Study: Hypothermia II (NABIS:H In will be a multi-center, prospective, randomized Phase III clinical trial in which standard management at hypothermia (33 degrees C) for 48 hours is tested against standard management at normothermia in patients with severe brain injury (GCS<8), age 16-45 years, and with admission temperature less than or equal to 35 degrees C . The primary outcome measure will be the dichotomized Glasgow Outcome Scale at 6 months after injury (Good Recovery/Moderate Disability vs. Severe Disability/Vegetative/Dead). The sample size of 220 patients will detect an absolute difference of 17% in the percentage of poor outcomes in the two groups at a power of 80%. The selection of this population was based on findings from the original National Acute Brain Injury Study: Hypothermia (NABIS:H I). In that study, with a sample size of 392, hypothermia was induced beginning <6 hours after injury, reaching 33 degrees C by 8.4 + or - 3 hours after injury, and maintaining hypothermia for 48 hours. The null hypothesis was confirmed, with no difference in the percentage of patients making a poor recovery (Severe Disability, Vegetative, Dead) at 6 months after injury (Hypothermia 57%, Normothermia 57%, NS). In 52 patients age >45 years, there were more poor outcomes in the hypothermia group (Hypothermia 89%, Normothermia 69%, p=0.08) due to increased medical complications. However, in 81 patients (22% of 366 patients with complete data) who were age 16-45 years with admission temperature less than or equal to 35 C, maintenance of hypothermia was associated with a marked decrease in the percentage of poor outcomes (Hypothermia, 52%, Normothermia 76%, p=0.02) with no difference in complication rates. The effect was found in all of the 4 high-enrollment centers, and there were no confounding variables that could have explained the difference in outcomes. The entire treatment effect in this subgroup was to shift patients from Severe Disability (poor outcome) to Moderate Disability (good outcome). We believe that the finding is related to a very short treatment window for hypothermia induction. The proposed study prospectively tests whether maintenance of hypothermia present on admission results in better outcome than current management.
