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Front. Pediatr. | doi: 10.3389/fped.2019.00360

Drug disposition and pharmacotherapy in neonatal ECMO: from fragmented data to integrated knowledge

  • 1Unit of Neonatology and Neonatal Intensive Care, Department Woman-Child-Newborn, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital (IRCCS), Italy
  • 2Department of Clinical and Community Sciences, Faculty of Medicine and Surgery, University of Milan, Italy
  • 3Department of Pediatrics and Adolescence Medicine, First Faculty of Medicine, Charles University, Czechia
  • 4Institute of Pharmacology, First Faculty of Medicine, Charles University, Czechia
  • 5Department of Intensive Care, Sophia Children's Hospital, Netherlands
  • 6Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Netherlands
  • 7Department of Development and Regeneration, KU Leuven, Belgium

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology.
Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. ECMO introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations) and circuits (roller vs centrifugal-based systems; silicone vs hollow-fiber oxygenators; renal replacement therapy).
Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose‐exposure‐response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance.
This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.

Keywords: ECMO - extracorporeal membrane oxygenation, pharmacokinetics - drug interactions, Pharmacodynamics (PD), neonate, Critical Illness, developmental pharmacology

Received: 21 May 2019; Accepted: 16 Aug 2019.

Copyright: © 2019 Raffaeli, Pokorna, Allegaert, Mosca, Cavallaro, Wildschut and Tibboel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Genny Raffaeli, Unit of Neonatology and Neonatal Intensive Care, Department Woman-Child-Newborn, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital (IRCCS), Milan, Italy,