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Alan M. Haltiner, David W. Newell, Nancy R. Temkin, Sureyya S. Dikmen, and H. Richard Winn

Object. The goals of this study were to determine if the use of phenytoin to prevent early posttraumatic seizures following head injury was associated with significant adverse side effects and also to determine if the reduction in early posttraumatic seizures after phenytoin administration was associated with a change in mortality rates in head-injured patients.

Methods. The authors performed a secondary analysis of the data obtained in a prospective double-blind placebo-controlled study of 404 patients who were randomly assigned to receive phenytoin or placebo for the prevention of early and late posttraumatic seizures. The incidence of adverse drug effects during the first 2 weeks of treatment, however, was low and not significantly different between the treated and placebo groups. Hypersensitivity reactions occurred in 0.6% of the patients in the phenytoin-treated group compared with 0% in the placebo group (p = 1.0) during week 1, and in 2.5% of phenytoin-treated compared with 0% of placebo-treated patients (p = 0.12) for the first 2 weeks of treatment. Mortality rates were also similar in both groups. Although the mortality rate was higher in patients who developed seizures, this increase was related to the greater severity of the injuries sustained by these patients at the time of the original trauma.

Conclusions. The results of this study indicate that the incidence of early posttraumatic seizure can be effectively reduced by prophylactic administration of phenytoin for 1 or 2 weeks without a significant increase in drug-related side effects. Reduction in posttraumatic seizure during the 1st week, however, was not associated with a reduction in the mortality rate.

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Nancy R. Temkin, Sureyya S. Dikmen, Gail D. Anderson, Alan J. Wilensky, Mark D. Holmes, Wendy Cohen, David W. Newell, Pamela Nelson, Asaad Awan, and H. Richard Winn

Object. Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury.

Methods. The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years.

The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7–13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8–2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9–4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients.

Conclusions. Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.