Pharmacokinetics of phenytoin in children with acute neurotrauma

OBJECTIVETo determine the pharmacokinetics of intravenous phenytoin in critically ill infants and children with acute neurologic injury. DESIGNA prospective, descriptive study. SETTINGA pediatric intensive care unit. PATIENTSSixteen children, 0.5 to 16 yrs of age (mean 7.6), with various types of acute neurologic injuries, receiving intravenous phenytoin therapy. INTERVENTIONSBlood samples were collected to measure total and free phenytoin concentrations in plasma. A 24-hr urine collection was made to determine the concentrations of the major metabolite of phenytoin. MEASUREMENTS AND MAIN RESULTSIn 12 children who survived the acute illness, a lower-than-predicted Michaelis-Menten constant (Km) and higher-than-predicted maximum rate of metabolism (Vmax) were observed. Initial free phenytoin fractions ranged between 0.08 and 0.15. In the eight patients who had additional free fractions measured, six patients demonstrated an increase (9.1% to 34% increase) in free fraction, while two patients demonstrated a decrease (1.8% and 19.8% decrease) in free fraction. The ratio of amount of phenytoin to phenytoin plus 5-(p-hydroxyphenyl)-5-phenyl-hydantoin excreted in the urine in a 24-hr urine collection demonstrated a wide interpatient variability. There was no correlation in the difference between the predicted and calculated Km and Vmax values and Glasgow Coma Score, circulating albumin concentration, or concomitant medications. CONCLUSIONBased on the average Km and Vmax values of the children enrolled in our study, it appears that children with neurologic injury between the ages of 0.5 and 9 yrs may require dosages of at least 8 to 10 mg/kg/day, and children aged 10 to 16 yrs may require 6 to 8 mg/kg/day to attain therapeutic phenytoin concentrations.(Crit Care Med 1995; 23:1418-1424)