Phenytoin protein binding in pediatric patients with acute traumatic injury

Abstract

Phenytoin (DPH) is commonly used to treat seizures associated with acute head injury. Consequent to decreases in DPH protein binding in such patients, the DPH free fraction (DPHff) may increase and thereby produce symptoms compatible with DPH toxicity despite the presence of total serum concentrations within the usually accepted therapeutic range. We examined the effect of acute traumatic injury on DPH protein binding in 13 hospitalized pediatric patients. In addition to total and free DPH serum concentrations, biochemical variables including blood pH, total and direct bilirubin, serum urea nitrogen, creatinine, albumin, gamma glutamyltransferase (GGT), and free fatty acid concentration were measured serially over 10 days. The DPHff was compared between selected time intervals in hospitalized patients and data obtained in a control population of 27 epileptic outpatients who were maintained on DPH. Additionally, a multiple regression model was used to examine for covariance between the DPHff and the respective biochemical variables in the hospitalized patients. In the study patients, the DPHff progressively increased, attaining a maximum value (8.5 .+-. 0.7%) on the fifth hospital day which was significantly greater (6.4 .+-. 0.7%, p < .05) than that on day 1 and also in the control group (6.1 .+-. 0.3%; p < .01). Blood pH, serum albumin, free fatty acids, creatinine and bilirubin concentrations did not change, but GGT did increase significantly over the 10-day sampling period. A significant (r = .51, p < .0001) linear relationship was found between the DPHff and the serum albumin concentration. Additionally, the multiple regression analysis revealed a predictive relationship between DPHff and both serum albumin and GGT concentration (y = -2.5 [albumin]-0.1 [GGT] +13.3; r = .8; p < .01) on hospital day 3 in the study group. Our data demonstrate that significant elevations in DPHff occur in critically ill pediatric patients. This binding alteration may confound the interpretation of total DPH serum concentrations and, possibly, may alter the disposition of the drug. Accordingly, it is necessary to quantitate both free and total serum DPH concentrations to individualize DPH therapy in pediatric patients with acute traumatic injury.