Disposition of phenytoin in critically ill trauma patients

Estimates of phenytoin pharmacokinetic variables and protein binding were determined in 10 adult critically ill trauma patients. Each study subject received phenytoin sodium as an intravenous loading dose of 15 mg/kg, followed by an initial intravenous maintenance dose of 6 mg/kg/day. Serial blood samples were obtained throughout the seven-day study period and analyzed for total and unbound serum phenytoin concentrations. The concentration data for each patients were fitted to a one-compartment model with elimination defined by the Michaelis-Menten constant Km and the maximum rate of metabolism (Vmax) and to a one-compartment model with first-order elimination. The Michaelis-Menten model used Bayesian parameter estimation while the linear model used weighted non-linear least-squares regression analysis. Unbound phenytoin fraction ranged from 0.073 to 0.25. Free fraction increased 7% to 108% in 9 of 10 patients (median increase 29%) from day 1 to day 7 of therapy. Variable estimates using the Michaelis-Menten model were as follows: volume of distribution, 0.76 +/- 0.15 L/kg (0.58-1.01 L/kg); Vmax, 568 +/- 197 mg/day (350-937 mg/day); and Km, 4.5 +/- 1.8 mg/L (1.8-6.2 mg/L). These estimates fell within the wide range of values obtained in studies using stable patients or healthy volunteers. The Michaelis-Menten model was significantly less biased and more precise than the linear model. Three of four patients who continued to receive their study maintenance dose had substantially lower measured total serum concentrations of phenytoin than predicted using the study variable estimates.(ABSTRACT TRUNCATED AT 250 WORDS)