Phenytoin Serum Concentrations in Patients With Left Ventricular Support Devices: A Case Series

Abstract

Purpose: Achieving therapeutic levels of phenytoin is critical to its efficacy and safety. Free serum levels represent pharmacologically active phenytoin due to the high protein binding of the drug. Predicting free serum levels in patients with left ventricular support devices can be challenging, as the pharmacokinetics (PK) can be significantly altered, and equations to correct total levels have not been validated in this population. The aim of this case series was to describe serum phenytoin concentrations in critically ill patients requiring left ventricular support devices. Methods: A retrospective chart review was performed including patients who received phenytoin therapy and had at least 1 set of simultaneously measured free and total serum phenytoin levels during left ventricular support with a mechanical device. Corrected total phenytoin levels were calculated using Sheiner-Tozer equations. Results: Three patients were included in this case series. Patients 1 and 2 required venoarterial extracorporeal membrane oxygenation (ECMO) during phenytoin therapy, and patient 3 had a durable left ventricular assist device (LVAD). Measured phenytoin levels ranged from 4.1 to 11.4 µg/mL, and calculated corrected levels were 6.8 to 18.4. Measured free phenytoin levels ranged from 1.2 to 3.6 µg/mL, which correlated with free fractions of 15.8% to 37.9%. Conclusion: This case series demonstrates a higher percentage of free phenytoin compared to the total serum level than would be predicted and an inability to rely on corrected total phenytoin level to predict whether it is within therapeutic range. Monitoring of free serum phenytoin concentrations should be strongly considered in critically ill patients requiring LVAD or ECMO support.

A Narrative Review of the Impact of Extracorporeal Membrane Oxygenation on the Pharmacokinetics and Pharmacodynamics of Critical Care Therapies

“…21 A single adult case with phenytoin and peripheral VA ECMO is described in the literature. 23 After a 20 mg/kg loading dose, this patient had higher-than-expected free fraction of phenytoin (3.6 µg/mL) based on a total level of 18.3 µg/mL, corrected for albumin levels. Given wide variability in individual phenytoin PK in the critically ill extrapolation is challenging, but measurement of free phenytoin concentrations to guide dosing could be considered.…”

“…Given wide variability in individual phenytoin PK in the critically ill extrapolation is challenging, but measurement of free phenytoin concentrations to guide dosing could be considered. 23 A prospective comparative matched study between 14 infants and neonates receiving ECMO and not receiving ECMO assessed the difference in phenobarbital and phenytoin concentrations. 25 Three patients received only phenytoin, 8 patients received only phenobarbital, and 3 patients received both.…”

“…Given wide variability in individual phenytoin PK in the critically ill extrapolation is challenging, but measurement of free phenytoin concentrations to guide dosing could be considered. 23…”

Phenytoin Pharmacokinetics During Venoarterial Extracorporeal Membrane Oxygenation and Plasma Exchange

“…Further, a 2020 article reported that dose adjustment of fosphenytoin is not necessary with PLEX with the exception of patients undergoing plasma exchange for greater than two days [ 13 ]. Literature in the adult patient population to date regarding ECMO effect on phenytoin pharmacokinetics is scarce, yet one 2019 retrospective chart review examined two patients using phenytoin and requiring ECMO and recommended monitoring free serum phenytoin, given labile total phenytoin concentration [ 14 ].…”