Antifungal Extraction by the Extracorporeal Membrane Oxygenation Circuit

Abstract

Invasive candidiasis is common and often fatal in patients supported with extracorporeal membrane oxygenation (ECMO), and treatment relies on optimal antifungal dosing. The ECMO circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. This ex vivo study determined the extraction of antifungal drugs by the ECMO circuit. Fluconazole and micafungin were studied separately in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction. Each circuit was primed with human blood, and flow was set to 1 L/min. Drug was dosed to achieve therapeutic concentrations. Each antifungal was added to a separate tube of blood to serve as a control. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point: (C _t /C _i )*100, with C _t and C _i the concentrations at time = t and 1 minute, respectively. After 24 hours of recirculation, mean recovery of fluconazole in the ECMO circuit (95-98%) and controls (101%) was high. In contrast, mean recovery of micafungin was dependent on the time and circuit configuration. Recovery at 4 hours was only 46% when a hemofilter was in-line but was much higher when the hemofilter was removed (91%). By 24 hours, however, micafungin recovery was low in all circuit configurations (26-43%), regardless of the presence of a hemofilter, as well as in the controls (57%). In conclusion, these results suggest that micafungin is extracted by the ECMO circuit, which may result in decreased drug exposure in vivo.

Keywords: antifungal extraction; extracorporeal membrane oxygenation; fluconazole; micafungin.

Figure 1.

ECMO circuit configurations.

Figure 2.

Recovery by circuit configuration for each drug. Panel on the left shows recovery over the first 4 hours after dosing, and panel on the right shows recovery for 24 hours. Values are mean; error bars indicate 95% confidence interval.

Figure 3.

Micafungin recovery in Controls under 4 experimental conditions: 1) Standard Controls, 2) Silanized Glass Controls, 3) Dark Standard Controls (i.e., protected from light), and 4) Crystalloid Controls (i.e., Standard Controls primed with crystalloid). Panel on the left shows recovery over the first 4 hours after dosing, and panel on the right shows recovery for 24 hours. Values are mean; error bars indicate 95% confidence interval.

Figure 4.

Micafungin recovery in Complete Circuits and Controls stratified by albumin concentration. Panel on the left shows recovery over the first 4 hours after dosing, and panel on the right shows recovery for 24 hours. Values are mean; error bars indicate 95% confidence interval.