Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery.

BACKGROUND AND OBJECTIVE: Milrinone is used for the prevention of low cardiac output syndrome in pediatric patients after cardiac surgery. Milrinone is mainly eliminated by the kidneys; however, there is limited information on milrinone pharmacokinetics in infants who have acute kidney injury (AKI). The aim of this study was to develop a milrinone population pharmacokinetic model in neonates and infants with or without AKI. The developed milrinone pharmacokinetic model was utilized for a Monte Carlo simulation analysis to identify age-appropriate dosing regimens in neonates and infants. METHODS: Population pharmacokinetic analysis was performed with a total of 1088 serum milrinone concentrations obtained from 92 infants as part of a prospective clinical study in neonates and infants following cardiac surgery (ClinicalTrials.gov identifier NCT01966237). AKI stages were determined based on the Kidney Injury Improving Global Outcomes (KDIGO) Clinical Practice Guideline within the first three postoperative days. RESULTS: A two-compartment model was found to adequately describe the pharmacokinetic data. Allometrically scaled body weight, AKI stages, and maturation function were identified as significant predictors of milrinone clearance. The proposed dosing regimens for milrinone continuous infusions were determined based on a target concentration attainment of simulated steady-state concentration and covered three age groups across 0-12 months of age for each AKI stage. CONCLUSION: This study provides a milrinone population pharmacokinetic model in neonates and infants and captures the developmental changes in clearance. Age-appropriate dosing regimens were determined based on the simulation analysis with the developed pharmacokinetic model. The findings will facilitate model-informed precision dosing of milrinone in infants with or without AKI.

Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome.

OBJECTIVES: To delineate the prevalence of cardiac findings in hypermobile and classic Ehlers-Danlos syndrome and provide longitudinal analysis of aortic root growth. STUDY DESIGN: A retrospective chart review was conducted, and data were analyzed for cross-sectional prevalence of aortic dilation and valvular anomalies. The clinical implications of aortic root growth were determined by assessment of progression of aortic root measurements over time and clinical symptoms. RESULTS: Patients whose first echocardiogram was obtained in late childhood or adulthood were less likely to have aortic dilation (P < .002) than those whose first echocardiogram was obtained in early childhood. Longitudinally, seven individuals had dilated aortas before age 14, and only one individual continued to show dilation after age 14 (P = .0143). No patient with a normal aortic root in childhood had development of dilation in adulthood. Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate. CONCLUSIONS: Although aortic root size and MVP are increased in patients with these types of Ehlers-Danlos syndrome, they tend to be of little clinical consequence. Echocardiography may still be warranted as part of cardiovascular assessment, but decreased frequency of screening is recommended especially in symptom-free adults.