Assessment of midazolam pharmacokinetics in the treatment of status epilepticus.

OBJECTIVES

Refractory status epilepticus (RSE) is often treated with midazolam boluses and continuous infusions, but there is considerable variability in dosing and efficacy. We aimed to evaluate the performance of a clinical midazolam dose escalation pathway for the treatment of pediatric RSE that was designed based on a novel midazolam pharmacokinetic model.

DESIGN

Prospective pharmacokinetic study of midazolam bolus and escalation of continuous midazolam infusion.

SETTING

Pediatric Intensive Care Unit in quaternary-care academic hospital.

SUBJECTS: Children between two months to seventeen years of age who received clinically-indicated midazolam infusion for treatment of RSE.

INTERVENTION: Blood sampled at regular intervals during treatment. Main study outcome measure was the accuracy of a pharmacokinetic model to predict serum midazolam concentrations.

MEASUREMENTS AND MAIN

RESULTS

We analysed data from six subjects. Three subjects had serum midazolam concentrations close to those predicted by our initial model (accuracy 88.9-170.2 %) which incorporates body weight, hepatic function, and renal function. For the other three subjects, all of whom were receiving pre-existing chronic benzodiazepine therapy prior to the RSE episode, the model grossly overestimated serum concentrations (predictive error 420.3-722.5 %). Once the model was corrected for the impact of pre-existing chronic benzodiazepine use on clearance, predicted concentrations more closely reflected those measured in subjects.

CONCLUSION

We evaluated a clinical midazolam RSE treatment pathway but discovered that the model on which the pathway was based was not accurate for all patients. We therefore developed a novel pharmacokinetic midazolam model in children with RSE treated with continuous midazolam infusion. This model incorporates body weight, hepatic and renal function, and importantly, a correction factor for pre-existing chronic benzodiazepine use. Once validated, this model may guide dosing and drive the development of more effective treatment pathways for continuous midazolam in RSE.