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

Abstract

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.

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

“…MR improves mesenteric perfusion and attenuates myocardial oxydative stress following hypoxia-reoxygenation in piglets (5). Studies in pediatric populations appear to support the clinical usefulness of MR, which is similar to that observed in adults (6)(7)(8)(9)(10)(11).…”

“…In children, weight-normalized MR elimination clearance can be expressed as a linear function of age (9). Information on neonates is scarce, and the application of procedures such as CPB or modified ultrafiltration can affect IND pharmacokinetics (10). With regard to LEVO, only one study has assessed the pharmacokinetics of the drug (given as a 12 μg/kg i.v.…”

Comparison of early and late intravenous infusion of milrinone in pediatric patients undergoing cardiac surgery

“…For neonates undergoing stage I reconstruction of hypoplastic left heart syndrome (HLHS), an initial loading dose of 100 mcg/kg on CPB resulted in plasma concentrations similar to those observed in other therapeutic settings but, the effect of modified ultrafilration (MUF) is to increase plasma milrinone concentrations by approximately 35%. Assuming that renal clearance is minimal during this time, it is possible that MUF provides both hemoconcentration and a second bolus effect, because blood that was returned to the patients from the venous reservoir contained milrinone [16]. A study was done by Duggal B and his colleges to assess the effect of milrinone on myocardial function in pediatric patients with postoperative low cardiac output syndrome.…”

Perioperative manipulation of the circulation in children with congenital heart disease

“…Lower doses were not found to be associated with a significant benefit. More recent investigations have focused on the dosing regimen for high risk neonates in whom the pharmacokinetics might be affected by maturational differences as well as impairment of renal function early after surgery 7 . w12 The recommended starting infusion rate for milrinone in this population following the bolus dose is 0.2 μg/kg/min, increasing to 0.5 μg/kg/min according to clinical effect (mixed venous saturation, acid–base balance, or end organ perfusion) and intrinsic renal function.…”