Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction.
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 microg/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 x kg(-1) x min(-1). The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 microg x kg(-1) x min(-1) resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL x kg(-1) x min(-1)), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL x kg(-1) x min(-1)) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 microg x kg(-1) x min(-1) should be considered.
Division of Clinical Pharmacology and Therapeutics, Department of Pediatrics, Abramson Research Center, Philadelphia, Pennsylvania 19104-4318, USA. zuppa@email.chop.edu
Athena F
AF
Zuppa
Susan C
SC
Nicolson
Peter C
PC
Adamson
Gil
G
Wernovsky
John T
JT
Mondick
Nancy
N
Burnham
Timothy M
TM
Hoffman
J William
JW
Gaynor
Lauren A
LA
Davis
William J
WJ
Greeley
Thomas L
TL
Spray
Jeffrey S
JS
Barrett
D002315:Cardiopulmonary Bypass / Q000706:statistics & numerical data*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000097:blood* / Q000188:drug therapy / Q000601:surgery*; D007223:Infant; D007231:Infant, Newborn; D020105:Milrinone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010865:Pilot Projects; D019651:Plastic Surgery Procedures / Q000706:statistics & numerical data; D018709:Statistics, Nonparametric
D020105:Milrinone