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OBJECTIVE: Literature in pediatric patients suggests dosing sirolimus 1.6 mg/m2/day divided twice daily for lymphatic disorders with limited evidence available for dosing in neonates and infants. The objective of this research was to determine the sirolimus dose required to achieve therapeutic trough concentrations in infants with lymphatic disorders at Children's Hospital of Philadelphia. METHODS: This retrospective review included patients <1 year of age at Children's Hospital of Philadelphia who were initiated on sirolimus for lymphatic disorder. Patients were included if they received at least 5 days of consecutive sirolimus therapy prior to trough concentration monitoring. Measures of central tendency and variability were used for statistical analysis. RESULTS: A total of 16 patients met criteria for inclusion. The median initial sirolimus dose was 1 mg/m2/day (IQR, 0.5-1.6 mg/m2/day). Fourteen patients (87.5%) achieved therapeutic trough concentrations on a median sirolimus dose of 0.5 mg/m2/day. Dosing frequency to achieve therapeutic trough concentrations included 1 patient (6.25%) on twice daily dosing, 12 patients (75%) on once daily dosing, and 1 patient (6.25%) requiring every 48-hour dosing. The median time to first therapeutic trough was 15.5 days (IQR, 5.5-18.5 days), and patients required a median of 1 dose adjustment. CONCLUSIONS: A median sirolimus dose to achieve therapeutic sirolimus trough concentrations in infants with lymphatic disorders was 0.5 mg/m2/day with a median of 1 dose adjustment. Sirolimus was well tolerated in the study population.
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To identify medications administered to pediatric patients on extracorporeal membrane oxygenation and to review the available pharmacokinetics and pharmacodynamics literature for the most commonly administered medications. DESIGN: Retrospective single-center study. SETTING: ICUs at Children's Hospital of Philadelphia. PATIENTS: Pediatric patients supported by extracorporeal membrane oxygenation between October 1, 2014, and September 30, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Drug exposure was described according to age group (< 1 mo, 1 mo to < 2 yr, 2 to < 12 yr, and > 12 yr) and ICU (cardiac, neonatal, pediatric). The association of drug exposure with patient's characteristics was examined using one-way analysis of variance for categorical variables and linear regression for continuous variables. All pharmacokinetics and pharmacodynamics literature for the 50 most commonly administered medications on extracorporeal membrane oxygenation was reviewed, with inclusion of studies that reported dosing regimens in conjunction with pharmacokinetics or pharmacodynamics data. A total of 179 different medications were administered to 254 children. Cumulative drug exposure increased with the duration of extracorporeal membrane oxygenation from a median (interquartile) of 10 drugs (6-14) at 1 week to 31 drugs (21-45) at 5 weeks following cannulation. There were significant differences in total drug exposure between age groups and ICUs. With exclusion of in vitro studies, published literature was available to support the use of 40% (20/50) of the most commonly administered medications. Dosing guidance was available for 20% (10/50) of medications and was primarily based on simulations and retrospective studies focusing on neonates and infants. CONCLUSIONS: This study highlights specific needs for future pharmacokinetics and pharmacodynamics studies. Dosing guidelines are essential to optimize the care of critically ill children supported by extracorporeal membrane oxygenation.
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OBJECTIVES: To evaluate if institutionally established calculations for transitioning continuous IV midazolam to enteral benzodiazepines maintain Withdrawal Assessment Tool-Version 1 scores equal to or less than preconversion values. DESIGN: Retrospective cohort study evaluating the effectiveness and safety of benzodiazepine conversion calculations embedded within an institution-specific clinical pathway for sedation and weaning of mechanically ventilated pediatric patients. SETTING: A 55-bed, mixed-medical, noncardiac surgical PICU in a tertiary care children's hospital. PATIENTS: All patients age 6 months to 18 years who received continuous midazolam for 5 days or longer while mechanically ventilated for 5-21 days and were then converted to either enteral diazepam or lorazepam following extubation (or return to baseline ventilator settings in tracheostomy-dependent patients) between January 1, 2015, and June 30, 2016. INTERVENTIONS: Benzodiazepine conversion calculations were applied according to institutional clinical pathway guidance. MEASUREMENTS AND MAIN RESULTS: Withdrawal Assessment Tool-Version 1 scores were compared pre and post benzodiazepine conversion. Patient demographics, benzodiazepine dose escalations, as needed benzodiazepine requirements, and severe adverse events within 48 hours of conversion were assessed. Seventy-one patient encounters were analyzed (median age, 2.5 yr; interquartile range, 1.2-5.3). The median Withdrawal Assessment Tool-Version 1 scores pre conversion and post conversion were not significantly different (1 [interquartile range, 0.75-2] and 1 [interquartile range, 0.25-2], respectively, p = 0.1). As needed benzodiazepine doses were administered in 38% of encounters post conversion, but escalation of a scheduled enteral benzodiazepine regimen was only required in 2.8% of encounters. Post conversion, one patient (1.4%) had increased seizure activity, and four patients (5.6%) required fluid boluses secondary to tachycardia or dehydration, but not hypotension. CONCLUSIONS: These findings suggest that standardized benzodiazepine conversions successfully achieved consistent Withdrawal Assessment Tool-Version 1 scores compared with preconversion values. Severe adverse events associated with oversedation and/or withdrawal were minimal and confounded by underlying disease states.