Intercenter variance in clinical trials of head trauma - experience of theNational Acute Brain Injury Study: Hypothermia

Object. In a recently conducted trial of hypothermia in patients with sever e brain injury, differences were found in the effects of hypothermia treatm ent among various centers. This analysis explores the reasons for such diff erences. Methods. The authors reviewed data obtained in 392 patients treate d for severe brain injury. Prerandomization variables, critical physiologic al variables, treatment variables, and accrual methodologies were investiga ted among various centers. Hypothermia was found to be detrimental in patie nts older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effe ct in those in whom normothermia was documented on admission. Marginally si gnificant differences (p < 0.054) in the intercenter outcomes of hypothermi a-treated patients were likely the result of wide differences in the percen tage of patients older than 45 years of age and in the percentage of patien ts in whom hypotheimia was present on admission among centers. The trial se nsitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral per-fusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not in tracranial pressure (ICP) greater than 25 min Hg (not significant) among pa tients in the various centers. Hours of vasopressor usage (p < 0.03) and mo rphine dose (p < 0.001) and the percentage of dehydrated patients varied si gnificantly among centers (p < 0.001). The participation of small centers i ncreased intercenter variance and diminished the quality of data. Conclusio ns. For Phase LH clinical trials we recommend: 1) a detailed protocol speci fying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.