Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

Abstract

Objective: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery.

Design and setting: Observational study in a level III referral center.

Patients and methods: Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data.

Results: Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability.

Conclusions: Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.