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

• Published in: Anesthesia and analgesia Vol. 102; no. 4; pp. 1062 - 1069
• Main Authors: Zuppa, Athena F., Nicolson, Susan C., Adamson, Peter C., Wernovsky, Gil, Mondick, John T., Burnham, Nancy, Hoffman, Timothy M., Gaynor, J William, Davis, Lauren A., Greeley, William J., Spray, Thomas L., Barrett, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD International Anesthesia Research Society 01-04-2006; Lippincott
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Cardiopulmonary Bypass - statistics & numerical data; Humans; Hypoplastic Left Heart Syndrome - blood; Hypoplastic Left Heart Syndrome - drug therapy; Hypoplastic Left Heart Syndrome - surgery; Infant; Infant, Newborn; Medical sciences; Milrinone - pharmacokinetics; Milrinone - therapeutic use; Pilot Projects; Reconstructive Surgical Procedures - statistics & numerical data; Statistics, Nonparametric; Human; Cardiotonic agent; 3',5'-Cyclic-nucleotide phosphodiesterase; Vasodilator agent; Enzyme; Enzyme inhibitor; Cardiovascular disease; Left Heart Hypoplasia; Esterases; Milrinone; Phosphoric diester hydrolases; Congenital disease; Newborn; Heart disease; Hydrolases; Anesthesia; Pharmacokinetics
• ISSN: 0003-2999; 1526-7598
• DOI: 10.1213/01.ane.0000198626.67391.34

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.