Population pharmacokinetics in critically ill neonates and infants undergoing extracorporeal membrane oxygenation: a literature review

Extracorporeal membrane oxygenation (ECMO) increases circulating blood volume, causes capillary leak and temporarily alters kidney function. Consequently, pharmacokinetics (PK) can be affected. When applied to neonates and infants, additional dose adjustments are a major concern, as the volume of distribution (Vd) is already generally greater for water-soluble drugs and the clearance (Cl) of drugs eliminated by glomerular filtration is reduced. A systematic search was performed on MEDLINE (1994–2022) using a combination of the following search terms: “pharmacokinetics”, “extracorporeal membrane oxygenation” and “infant, newborn” using Medical Subject Headings search strategy. Nine out of 18 studies on 11 different drugs (vancomycin, meropenem, fluconazole, gentamicin, midazolam, phenobarbital, theophylline, clonidine, morphine, cefotaxime and cefepime) recommended dose increase/decrease by determining PK parameters. In other studies, it has been suggested to adjust the dose intervals. While the elimination half-life (t(1/2)) and Vd mostly increased for all drugs, the Cl of the drugs has been shown to have variability except for midazolam and morphine. There are a limited number of population PK studies in neonates and infants undergoing ECMO circuits. Despite some divergences, the general pattern suggests an increase in Vd and t(1/2), an increased, stable or decreased Cl, and an increase in variability. Consequently, and if possible, therapeutic drug monitoring and target concentration intervention are strongly recommended to determine appropriate exposure and doses for neonates and infants undergoing ECMO support.