Reducing hydrophobic drug adsorption in an in-vitro extracorporeal membrane oxygenation model.

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients with heart and lung failure. Patients treated with ECMO receive a range of drugs that are used to treat underlying diseases and critical illnesses. However, the dosing guidelines for these drugs used in ECMO patients are unclear. Mortality rate for patients on ECMO exceeds 40% partly due to inaccurate dosing information, caused in part by the adsorption of drugs in the ECMO circuit and its components. These drugs range in hydrophobicity, electrostatic interactions, and pharmacokinetics. Propofol is commonly administered to ECMO patients and is known to have high adsorption rates to the circuit components due to its hydrophobicity. To reduce adsorption onto the circuit components, we used micellar block copolymers (Poloxamer 188TM and Poloxamer 407TM) and liposomes tethered with poly(ethylene glycol) to encapsulate propofol, provide a hydrophilic shell and prevent its adsorption. Size, polydispersity index (PDI), and zeta potential of the delivery systems were characterized by dynamic light scattering, and encapsulation efficiency was characterized using High Performance Liquid Chromatography (HPLC). All delivery systems used demonstrated colloidal stability at physiological conditions for seven days, cytocompatibility with a human leukemia monocytic cell line, i.e., THP-1 cells, and did not activate the complement pathway in human plasma. We demonstrated a significant reduction in adsorption of propofol in an in-vitro ECMO model upon encapsulation in micelles and liposomes. These results show promise in reducing the adsorption of hydrophobic drugs to the ECMO circuits by encapsulation in nanoscale structures tethered with hydrophilic polymers on the surface.

Direct and continuous dosing of propofol can saturate Ex vivo ECMO circuit to improve propofol recovery.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that provides life-saving complete respiratory and cardiac support in patients with cardiorespiratory failure. The majority of drugs prescribed to patients on ECMO lack a dosing strategy optimized for ECMO patients. Several studies demonstrated that dosing is different in this population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Saturation of ECMO circuit components by drug disposition has been posited but has not been proven. In this study, we have attempted to determine if propofol adsorption is saturable in ex vivo ECMO circuits. METHODS: We injected ex vivo ECMO circuits with propofol, a drug that is highly adsorbed to the ECMO circuit components. Propofol was injected as a bolus dose (50 µg/mL) and a continuous infusion dose (6 mg/h) to investigate the saturation of the ECMO circuit. RESULTS: After the bolus dose, only 27% of propofol was recovered after 30 minutes which is as expected. However, >80% propofol was recovered after the infusion dose which persisted even when the infusion dose was discontinued. CONCLUSION: Our results suggest that if ECMO circuits are dosed directly with propofol, drug adsorption can be eliminated as a cause for altered drug exposure. Field of Research: Artificial Lung/ECMO.

Micellar Encapsulation of Propofol Reduces its Adsorption on Extracorporeal Membrane Oxygenator (ECMO) Circuit.

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass device used on critically ill patients with refractory heart and lung failure. Patients supported with ECMO receive numerous drugs to treat critical illnesses and the underlying diseases. Unfortunately, most drugs prescribed to patients on ECMO lack accurate dosing information. Dosing can be variable in this patient population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Propofol is a widely used anesthetic in ECMO patients and is known to have high adsorption rates in ECMO circuits due to its high hydrophobicity. In an attempt to reduce adsorption, we encapsulated propofol with Poloxamer 407 (Polyethylene-Polypropylene Glycol). Size and polydispersity index (PDI) were characterized using dynamic light scattering. Encapsulation efficiency was analyzed using High performance liquid chromatography. Cytocompatibility of micelles was analyzed against human macrophages and the formulation was finally injected in an ex-vivo ECMO circuit to determine the adsorption of propofol. Size and PDI of micellar propofol were 25.5 ± 0.8 nm and 0.08 ± 0.01, respectively. Encapsulation efficiency of the drug was 96.1 ± 1.3%. Micellar propofol demonstrated colloidal stability at physiological temperature for a period of 7 days, and was cytocompatible with human macrophages. Micellar propofol demonstrated a significant reduction in adsorption of propofol in the ECMO circuit at earlier time points compared to free propofol (Diprivan®). We observed 97 ± 2% recovery of the propofol from the micellar formulation after an infusion. These results demonstrate the potential of micellar propofol to reduce drug adsorption to ECMO circuit.