Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury

Abstract

Objective: Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.

Design: Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.

Setting: ICU at the Children's Hospital of Pittsburgh.

Patients: Nineteen children with severe traumatic brain injury.

Interventions: None.

Measurements and main results: A sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32-33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period.

Conclusions: Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.

Figure 1. Schematic representation of the selected pharmacokinetic model

Two compartments represent the amount of free phenytoin (unbound) and of bound drug in plasma. V₁ is the volume of distribution, θ_prop is the proportionality constant between the bound and unbound drug amounts, k_m is the Michaelis-Menten elimination rate constant (mg/L), V_max is the maximum velocity of metabolism (mg/h), V_max0 is the time-invariant maximum velocity of metabolism at baseline (mg/h), V_maxi is the time-dependent velocity defined by the rate constant k_ind (h⁻¹) and t is time (h). The total amount of phenytoin in plasma is the sum of unbound and bound phenytoin.

Figure 2. Patient temperatures, free phenytoin concentrations, and dosing

Protocol timing is organized into three shaded periods based on time from injury: hypothermia (or normothermia) from 10 – 58 h; rewarming (if in the hypothermia group) from 58 – 106 h; and post-treatment from 106 – 168 h. A. Hourly patient rectal temperatures demonstrate the success of the study protocol in achieving goal temperatures. Shaded regions are the 95% confidence intervals. B. There was a trend towards elevated free phenytoin concentrations in the hypothermia group in the rewarming and post-treatment periods (temp effect: p=0.051; study period effect: p=0.023; interaction: p=0.633). Dotted lines indicate the therapeutic range of 1– 2 mg/L. Box and whiskers graphs depict the mean, 95% confidence intervals, and range of each group. C. The cumulative dose of fosphenytoin administered to each patient was not different between the groups (temp effect: p=0.853; study period effect: p=0.249; interaction: p=0.660).

Figure 3. Impact of covariates on the estimated pharmacokinetic parameters

Circles(red) and squares(blue) are patients in the normothermic and hypothermic groups, respectively. A/B. Estimates of volume distribution (V₁) and time-invariant maximum velocity of metabolism at baseline (V_max0) for each patient is positively-correlated with weight. C/D. Estimated time-dependent velocity of metabolism (V_maxi) on the log scale is reduced with lower temperatures for the normothermic and hypothermic patients versus temperature.

Figure 4. The magnitude and timing of the effects of temperature on free phenytoin concentrations

Simulations of 1000 children receiving either therapeutic hypothermia or controlled normothermia. Solid lines/lightest(red) shading represents the normothermic group while dashed lines/darkest(blue) shading represents the hypothermic group. The simulated fosphenytoin dosing schedule was 20 mg/kg IV loading dose followed by 6 mg/kg/day divided every 12 h. The cooling protocol involved hypothermia induction over 6 h to 33 °C, hold at 33 °C for 48 h, and then slow rewarming (1 °C per 24 h) to 37 °C (depicted in Figure E3, Supplemental Digital Content). Controlled normothermia patients were fixed at 37 °C. All individuals were simulated with a weight of 40 kg. A. Unbound phenytoin concentrations are elevated in patients receiving hypothermia versus normothermia as shown by the population predicted median (lines) and 90% confidence interval (shading) over time. B. Percentage of simulated children with free phenytoin concentrations above the 2 mg/L toxicity threshold in each group versus time.