Determinants of Pharmacokinetic Variability during Extracorporeal Membrane Oxygenation: A roadmap to rational pharmacotherapy in children

Critically-ill infants sometimes require extracorporeal membrane oxygenation (ECMO) to provide adequate oxygenation and perfusion. Pharmacokinetic data are often lacking for this particular population, which leads to dose regimens that are based on personal experience or extrapolation from studies in other patients. This thesis aims to add to the understanding of determinants of drug behavior during ECMO, and to provide dose recommendations for commonly used drugs. Part I addresses practical problems that are encountered in pediatric studies. We give an overview of sampling and assay methods. Ultra-performance liquid chromatography with mass spectrometry (UPLC-MS) drug assays using small volumes of plasma were developed for beta-lactam antibiotics, sildenafil, midazolam, morphine and their main metabolites. In part II, drug adsorption was quantified in in vitro circuits. Oxygenator size has little influence on drug loss, but losses are correlated to the lipophilicity (log P value) of individual drugs. Drug loss is smaller in circuits with a centrifugal pump. Pharmacokinetic studies (part III) with cefotaxime, sildenafil and midazolam show that, in general, ECMO patients have a slower metabolism and excretion than non-ECMO patients, and a higher volume of distribution. This combination would require doses to be increased, and the dose interval lengthened. In contrast, within patients the period between cannulation and decannulation shows an increased clearance compared to pre- and post-ECMO, which suggests drug adsorption by the circuit and membrane oxygenator, CVVH-clearance or improved hepatic and renal perfusion. The poor predictability of these effects leads to the conclusion that individual drugs should be studied in ECMO patients. The methodology we present in this thesis can facilitate these studies.

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