Background: Extracorporeal membrane oxygenation (ECMO) can affect the disposition of drugs, notably by sequestering them in a circuit. This review aimed to provide a comprehensive summary of existing ex vivo studies investigating the impact of contemporary ECMO circuits on drug sequestration, and to examine the associations between the physicochemical properties of drugs, the features and settings of ECMO devices, and the extent of drug sequestration. Method: A comprehensive search was conducted to identify ex vivo studies that determined drug concentrations in ECMO circuits. Studies that did not allow for the proper assessment of drug loss by degradation were excluded. Drug characteristics and experimental conditions were recorded. Drug sequestration in the circuit was calculated as the difference between the drug loss measured in the ECMO circuit and the drug loss due to spontaneous degradation measured under control conditions. To identify predictors of drug sequestration, a stepwise multiple linear meta-regression was applied by testing the physicochemical properties of drugs and ECMO device features/settings. Results: A total of 40 studies were identified, of which 21 were included in the analysis, covering 41 drugs. The Maquet membrane oxygenator was the most used brand (73%). About half of the circuits were adult and half were pediatric. Our final regression model retained lipophilicity, and to a lesser extent ionization at a physiological pH, as significant predictors of drug sequestration (R² 0.44, relative standard error 23%). Protein binding had no additional effect. Anti-infectives were the most studied class of drugs (n = 28). Antibiotics were overall not significantly sequestered, while lipophilic drugs such as posaconazole, voriconazole, paracetamol, fentanyl, sufentanil, propofol, thiopental, dexmedetomidine and amiodarone were highly sequestered (≥50%). However, this sequestration occurred mainly within the first few hours of the experiments, possibly reflecting a saturation effect. Conclusions: Lipophilic drugs are significantly sequestered in ex vivo ECMO circuits, although this effect may be limited by early saturation.

Background and Objective Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites’ pharmacokinetics, potentially compromising circulating exposure and efficacy. There are limited data on levosimendan pharmacokinetics in critically ill patients, including those on VA-ECMO, thus emphasising the need for further research in this area. The aim of this study was to characterise the pharmacokinetic profile of levosimendan and its metabolites OR-1855 and OR-1896 in both critically ill adults and neonates/infants on VA-ECMO. Methods We conducted a bicentric, prospective, observational, pharmacokinetic study in critically ill adults and neonates/infants on VA-ECMO receiving levosimendan. Dosage history, sampling and clinical information were gathered. Samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry using a validated highly sensitive method. A population pharmacokinetic model describing levosimendan and its metabolites OR-1855 (inactive) and OR-1896 (active, long-lasting) was developed using non-linear mixed-effects modelling (NONMEM). Model-based simulations were performed to compare exposures produced by various dosing scenarios. Results Twenty-one patients, 15 adults, three neonates and three infants, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1–4 h, then increased to maintenance doses reaching 0.1 (n = 9), 0.15 (n = 3) or 0.2 (n = 3) µg/kg/min for a total infusion time of approximately 24 h. The neonates/infants received a continuous infusion of 0.1 µg/kg/min for 48 h. A two-compartment model best characterised levosimendan pharmacokinetics, with a transit compartment adequately describing the metabolites’ delayed synthesis. The transformation of OR-1855 into OR-1896 was 3.7-fold slower in neonates/infants than in adults. Model-based simulations using a standard 0.1-µg/kg/min regimen for 24 and 48 h in adults and neonates/infants, respectively, achieved lower levosimendan and metabolite concentrations in neonates/infants. Simulations using a 48-h infusion of 0.2 µg/kg/min in neonates/infants predict levosimendan concentrations comparable to those in adults receiving a 0.1-µg/kg/min maintenance dose. However, in this scenario, OR-1896 concentrations would remain considerably lower than in adults. Conclusions Our data indicate that levosimendan and its metabolites exhibit altered the pharmacokinetics in neonates/infants on VA-ECMO. Although some of these changes may be associated with ECMO, definitive conclusions on causality cannot be drawn, as age-dependent specific physiology and critically ill conditions may also contribute. These findings support the consideration of dose optimisation in this population. In adults, levosimendan pharmacokinetics seem unaffected, although metabolite concentrations appear slightly reduced compared with non-critically ill patients with heart failure. Graphical Abstract