Sedatives are administered during extracorporeal membrane oxygenation (ECMO) therapy to ensure patient safety, reduce the metabolic rate and correct the oxygen supply-demand balance. However, the concentrations of sedatives can be decreased due to absorption into the circuit. This study examined factors affecting the absorption of a commonly used sedative, midazolam (MDZ). Using multiple ex vivo simulation models, three factors that may influence MDZ levels in the ECMO circuit were examined: polyvinyl chloride (PVC) tubing in the circuit, use of a membrane oxygenator in the circuit, and heparin coating of the circuit. We also assessed changes in drug concentration when MDZ was re-injected in a circuit. The MDZ level decreased to approximately 60% of the initial concentration in simulated circuits within the first 30 minutes. The strongest factor in this phenomenon was contact with the PVC tubing. Membrane oxygenator use tended to increase MDZ loss, whereas heparin circuit coating had no influence on MDZ absorption. Similar results were obtained when a second dose of MDZ was injected to the second-use circuits.