Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations

BACKGROUND: In critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner–Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration. AIMS AND OBJECTIVES: Phenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner–Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin. MATERIALS AND METHODS: Blood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit. RESULTS: The median [inter-quartile range (IQR)] for Sheiner–Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63–24.53) and 9.82 (6.02–13.85) μg mL(−1), respectively. Approximately 53 and 5% of patients were found to be subtherapeutic and supratherapeutic for direct-measured total phenytoin concentrations, respectively. In contrast, on applying the Sheiner–Tozer calculation, 23 and 40% had subtherapeutic and supratherapeutic concentrations, respectively, for total phenytoin concentration. The median (IQR) for direct-measured, routine and Sheiner–Tozer equation calculated free phenytoin concentration were 1.92 (1.06–2.76), 0.98 (0.60–1.39), and 1.71 (1.06–2.45) μg mL(−1), respectively. Only 45.7% of patients were in agreement with respect to the therapeutic category when direct-measured free was compared against routine calculation free. CONCLUSION: In patients with low albumin, free phenytoin concentration based on the Sheiner–Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration. HOW TO CITE THIS ARTICLE: Wilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022;26(6):682–687.