Population Pharmacokinetics of Milrinone in Neonates with Hypoplastic Left Heart Syndrome Undergoing Stage I Reconstruction

In Brief We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 μg/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL · kg−1 · min−1. The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 μg · kg−1 · min−1 resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL · kg−1 · min−1), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL · kg−1 · min−1) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 μg · kg−1 · min−1 should be considered. IMPLICATIONS: This clinical trial describes neonates with hypoplastic left heart syndrome undergoing stage I reconstruction pharmacokinetics of milrinone in this population and characterizes drug disposition during cardiopulmonary bypass, modified ultrafiltration, and in the postoperative period. Future clinical investigation will be required to explore whether the achievable milrinone concentrations are optimal with respect to individual patient outcomes.