Assessment of midazolam pharmacokinetics in the treatment of status epilepticus. (October 2020)

• Record Type: Journal Article
• Authors: Francoeur, Conall; Welsh, Sarah S.; Ichord, Rebecca; Abend, Nicholas S.; Topjian, Alexis A.; Zuppa, Athena F.
• Is Part Of: Seizure. Volume 81(2020)
• Page Start: 310
• Page End: 314
• Publication Date: 2020-10
• Subjects: Status epilepticus -- Midazolam -- Refractory status epilepticus -- Pharmacokinetic model; Epilepsy -- Periodicals; Epilepsy -- Periodicals; Seizures -- Periodicals; Épilepsie -- Périodiques; Electronic journals; Electronic journals; 616.853
• DOI: 10.1016/j.seizure.2020.09.004
• Languages: English
• ISSNs: 1059-1311

Abstract

Abstract: 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.