These findings may have significant implications for both the choice and the dosing of a particular drug prescribed during ECMO. Given the ongoing exteriorization of blood onto the circuit during ECMO, in vivo instability of drugs may also play a significant role in apparent PK during ECMO. By excluding the patient factors, this ex vivo model provides evidence that the adult selleck screening library ECMO circuit is not simply a benign conduit for blood but actively modulates drug PK.The circuit factors were identical for all drugs. In this context, it is difficult to determine which of the drug factors contributed to the significant disparity in the degree of drug sequestration in the circuit and ex vivo stability. Differences in molecular size and lipophilicity and the differences in protein binding may all have contributed to the findings.

This is important as a blanket increase in doses of all antibiotic drugs to avoid under-dosing without identifying the drugs that are most sequestered by the ECMO circuit may potentially result in drug toxicity. Similarly, drug sequestration in the circuit may also explain the increasing sedation requirements seen in patients on ECMO [8,9]. Using sedative and analgesic agents that are highly sequestered in the circuit may necessitate the use of very high doses of these drugs to achieve the desired pharmacological effect and may add to the associated morbidity [6]. This calls for further research in this area to improve drug prescription during ECMO.

Given that meropenem and vancomycin both rely on time-dependent bacterial killing, the data presented here on altered antibiotic concentrations may be clinically relevant and require evaluation in a clinical PK study. Meropenem is degraded and sequestered significantly in the circuit beyond 4 to 6 hours. Hence, a more frequent dosing or use of higher doses may be required to maximize the time above minimum inhibitory concentration of the pathogen [19] as demonstrated in a recent clinical study [20]. Furthermore, administration of meropenem by infusion is questionable given the instability issues at room temperatures [21]. The utility of more stable carbapenem antibiotics such as doripenem may have to be explored in future studies. Clinically, there are no data on meropenem PK in patients receiving ECMO. Neonatal studies have uniformly shown an increase in Vd for vancomycin and a lower CL and consequently a longer vancomycin half-life [22,23].

Similarly, PK studies in neonates have shown increased Vd and decreased CL for morphine, midazolam, and their metabolites during ECMO [24,25]. The extent to which these PK alterations during ECMO are related to Batimastat sequestration of these drugs in the circuit is currently unclear.Studies in the neonatal ECMO circuits have demonstrated significant sequestration of sedative and antibiotic drugs in the circuit.