Voriconazole Sequestration During Extracorporeal Membrane Oxygenation for Invasive Lung Aspergillosis: A Case Report

Abstract

The increasing use of extracorporeal membrane oxygenation (ECMO) in critical care introduces new challenges with medication dosing. Voriconazole, a commonly used antifungal and the first-choice agent for the treatment of invasive aspergillosis, is a poorly water-soluble and highly protein-bound drug. Significant sequestration in ECMO circuits can be expected; however, no specific dosing recommendations are available. We report on the therapeutic drug monitoring and clinical evolution of a patient treated with voriconazole for invasive pulmonary aspergillosis while receiving ECMO therapy. Voriconazole trough levels were persistently low (<1 µg/mL) after initiation of ECMO despite additional loading doses and dose increases. Voriconazole dose had to be increased to 6.5 mg/kg three times daily to obtain therapeutic trough levels. The inability to achieve therapeutic levels of voriconazole for a prolonged period (a minimum of 9 days) while undergoing ECMO therapy is believed to have been a significant contributing factor in the patient’s fatal outcome. Therapeutic trough levels of voriconazole cannot be guaranteed with standard dosing in patients undergoing ECMO and much higher doses may be necessary. Empirical use of higher doses and/or combination therapy may be reasonable and frequent therapeutic drug monitoring is mandatory.

A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation

“…The ex vivo studies reported voriconazole losses even up to 80% at the end of a 24 h study period [ 11 , 21 , 22 ]. These results were supported by multiple case reports [ 12 , 15 , 18 , 19 , 20 , 23 ]. Undetectable voriconazole concentrations and difficulties to attain therapeutic exposure under ECMO were reported by Ruiz et al and Mathieu et al [ 15 , 18 ].…”

“…These results were supported by multiple case reports [ 12 , 15 , 18 , 19 , 20 , 23 ]. Undetectable voriconazole concentrations and difficulties to attain therapeutic exposure under ECMO were reported by Ruiz et al and Mathieu et al [ 15 , 18 ]. Saturation of the circuit’s binding sites was suggested by Spriet et al who increased the voriconazole dose at the moment of ECMO initiation to successfully avoid subtherapeutic concentrations but after a few days, drug accumulation was observed.…”

“…Literature describing the exposure to voriconazole during ECMO is limited to three ex vivo studies and six case reports [ 11 , 12 , 15 , 18 , 19 , 20 , 21 , 22 , 23 ]. The ex vivo studies demonstrated significant voriconazole losses in ECMO circuits, even up to 80% in some reports [ 11 , 21 , 22 ].…”

“…However, in these studies, patient and disease related factors, such as metabolism, elimination, inflammatory mediators, altered pH and concomitant drugs, were not accounted for [ 21 , 22 ]. Moreover, these studies looked at a limited period of time (24 h) after addition of only one single voriconazole dose [ 11 , 18 , 21 , 22 ]. Low voriconazole exposure and a need for dose augmentation during ECMO were also described in the case reports.…”

“…It has been assumed that voriconazole exposure is impacted by ECMO therapy. However, this insight is only based on three ex vivo studies and six case reports in which it was suggested that voriconazole sequestrates to the extracorporeal circuit, given its relative lipophilicity (log p value of 2.56) [ 11 , 12 , 15 , 18 , 19 , 20 , 21 , 22 , 23 ]. The ex vivo studies reported voriconazole losses even up to 80% at the end of a 24 h study period [ 11 , 21 , 22 ].…”