High-Dose Midazolam for Pediatric Refractory Status Epilepticus: A Single-Center Retrospective Study.

OBJECTIVES: We sought to describe the prevalence of midazolam treatment failure in children with refractory status epilepticus (RSE) and define a threshold dose associated with diminishing frequency of seizure cessation. DESIGN: Single center retrospective cohort study. SETTING: Single-center, quaternary-care PICU. PATIENTS: Children younger than 18 years old admitted to the PICU from 2009 to 2018 who had RSE requiring a continuous midazolam infusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified individuals with RSE through a data analytics inquiry. Receiver operating characteristic (ROC) curve analysis and Youden's index were used to assess the midazolam dose threshold associated with the highest sensitivity and specificity in identifying seizure cessation. A logistic regression model was used to determine if there was an association between maximum midazolam dose and seizure cessation. Of the 45 patients who met inclusion criteria for this study, 27 (60%) had seizure cessation with a midazolam infusion, whereas 18 (40%) required an additional pentobarbital infusion for seizure cessation. There was an association between maximum midazolam dose and seizure cessation, with patients more likely to fail treatment when midazolam was administered at higher doses. The maximum midazolam dose displayed high area under the ROC curve value for seizure cessation, and the Youden's J index cut-off point was 525 µg/kg/hr. Treatment above this dose was associated with diminishing frequency of seizure cessation. The median time spent titrating midazolam above 500 µg/kg/hr for those patients who required pentobarbital for seizure cessation was 3.83 hours (interquartile range, 2.28-5.58 hr). CONCLUSIONS: In pediatric patients with RSE requiring high dose midazolam, considerable time is spent titrating doses in a range (above 500 µg/kg/hr) that is associated with diminishing frequency of seizure cessation.

Drug-metabolizing enzyme genotypes and aggressive behavior treatment response in hospitalized pediatric psychiatric patients.

OBJECTIVE: The aim of this study was to examine the association between the CYP2D6 and CYP2C19 genotype-predicted combined phenotypes and short-term measures of psychotropic efficacy and toxicity. METHODS: A rater-blinded, retrospective genotype association design examined a cohort of hospitalized pediatric psychiatric patients genotyped for CYP2D6 and CYP2C19 as part of clinical care. These combined genotypes were used to predict a combined phenotype. The primary efficacy outcome measure was the behavior intervention score (BIS), a function of the number of recorded timeouts/seclusions, therapeutic holds, and physical restraints. Drug tolerability was defined as the total number of recorded adverse drug reactions. RESULTS: Primary analysis was performed on 279 pediatric patients taking CYP2D6- or CYP2C19- dependent psychotropics. Combined phenotype was associated with BIS (p = 0.01) and number of adverse drug reactions (p = 0.03). Combined poor metabolizers treated with psychotropics had the lowest BIS (highest efficacy) and the highest number of adverse drug reactions. Combined ultrarapid metabolizers had the highest BIS (lowest efficacy) and the lowest number of adverse drug reactions. CONCLUSION: Common variants in CYP2D6 and CYP2C19 are associated with the short-term efficacy and tolerability of psychotropic medications in hospitalized pediatric patients.