The evaluation of the possible effect of positive end expiratory pressure (PEEP) on pharmacokinetics of phenytoin in patients with acute brain injury under mechanical ventilation

Positive ventilation has shown to have an influence on pharmacokinetic and disposition of some drugs. Because phenytoin with a narrow therapautic range, is the most commonly used drug for prophylaxis and treatment of early seizures after acute brain injuries, in the present study the effect of short term PEEP (5-10 cm H ₂O for at least 8 hours) on phenytoin serum concentration and pharmacokinetic parameters such as V _max and clearance in brain injured patients under mechanical ventilation was examined. Ten patients with moderate to severe acute brain injury who were placed on mechanical ventilation with an initial PEEP level of 0-5 cm H ₂O were included in the study. Patients received phenytoin loading dose of 15 mg/kg followed by a maintenance daily dose of 3-7 mg/kg initiated within 12 hours of loading dose. Sampels were taken on two different occasions before and after PEEP elevation. Total phenytoin serum concentrations were determined by HPLC method. A time invarient Michaelis-Menten pharmacokinetic model was used to calculate Vmax and clearance for each patient. Derrived variables were calculated as follows: V _max, 3.5-6.8 and 3.7-8.2 mg/kg/day; Clearance, 0.1-0.7 and 0.1-1.2 l/kg/day (before and after PEEP elevation, respectively). Our data have shown a wide range of variability (2.6-32.5 mg/l) in phenytoin serum concentrations. There were no statistically significant differences in the measured total concentrations (p=0.721) and calculated V _max and clearance (p=0.285) before and after PEEP elevation. Administration of fluid and inotropic agents, limitation in application of higher levels of PEEP and drug interactions, shall be considered as possible explanations for these findings.