Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review

Abstract BACKGROUNDTo identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps and inform future clinical pharmacology studies.METHODSWe systematically searched the following databases from earliest publication until November 2018: MEDLINE, CINAHL and EMBASE, using a controlled vocabulary and keywords related to: “ECMO”, and “pharmacokinetics”, “pharmacology”, “drug disposition”, “dosing” and “pediatrics”. Inclusion criteria were: study population aged <18 years, supported on ECMO for any indications, receiving any medications while on ECMO and reported pharmacokinetics data. Clearance and/or volume of distribution (Vd) values were extracted from the included studies.RESULTS41 studies (total patients=574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were anti-microbials (n=13), and anticonvulsants (n=3). 28 studies (68%) were conducted in children < 1 year of age. 33 studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in Vd attributable to ECMO was demonstrated for 9 (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased Vd was reported for 2 drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine and sildenafil (range: 25-455% increase relative to non-ECMO controls).CONCLUSIONSThere were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes, and those that allow direct comparisons between ECMO and non-ECMO patients, are still lacking. Systematic evaluation of pharmacokinetic alterations of drugs on ECMO that incorporate multi-drug opportunistic trials, physiologically based pharmacokinetic modeling, ex-vivo studies and other methods are necessary for definitive dose recommendations.