Dexmedetomidine extraction by the extracorporeal membrane oxygenation circuit: results from an in vitro study

Abstract

Background: Dexmedetomidine is a sedative administered to minimize distress and decrease the risk of life threatening complications in children supported with extracorporeal membrane oxygenation. The extracorporeal membrane oxygenation circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. Objective: To determine the extraction of dexmedetomidine by the extracorporeal membrane oxygenation circuit. Materials and methods: Dexmedetomidine was studied 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 according to standard practice for Duke Children’s Hospital, and flow was set to 1 L/min. Dexmedetomidine was dosed to achieve a therapeutic concentration of ~600 pg/mL. Dexmedetomidine was added to a separate tube of blood to serve as a control and evaluate for natural drug degradation. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point. Results: Dexmedetomidine was highly extracted by the oxygenator evidenced by a mean recovery of 62-67% at 4 hours and 23-34% at 24 hours in circuits with an oxygenator in-line. In contrast, mean recovery with the oxygenator removed was 96% at 4 hours and 93% at 24 hours. Dexmedetomidine was stable over time with a mean recovery in the control samples of 102% at 24 hours. Conclusion: These results suggest dexmedetomidine is extracted by the oxygenator in the extracorporeal membrane oxygenation circuit which may result in decreased drug exposure in vivo.

Sequestration of Dexmedetomidine in Ex Vivo Cardiopulmonary Bypass Circuits

“…21 A recent study at a therapeutically relevant concentration (~600 pg/ml), showed lower sequestration of DEX after 4 hours in ECMO circuits. 8 Another important finding of the current study is the increase (12.1 ± 4.25%, p < 0.05) of DEX concentrations post-MUF (in 19 of 23 circuits). Modified ultrafiltration allows hemoconcentration after weaning from bypass and it has been reported to often alter the plasma concentrations of drugs in ECMO circuits.…”

“…[4][5][6]13,15,16 Several studies investigated the sequestration of DEX in ECMO circuits. 7,8,17 A previous study 7 showed that DEX concentration decreased by 59-73% in the first hour and then continued to decline with a loss of 67-93% of the DEX over 24 hours. 11 Another recent study evaluated the sequestration of DEX in an ex vivo infant ECMO circuit utilizing polymethylpentene membrane oxygenator with protein-bounded PVC tubing and showed sequestration of 51% DEX in 24 hours.…”

“…7 However, other recent studies have shown that binding to the membrane oxygenator as the primary cause for sequestration. 8 The influence of the elements of the ECMO circuit on DEX sequestration by the three different brands of tubing (Tygon/Maquet/Terumo) and two different brands of oxygenators (Maquet/Terumo) were recently evaluated in an ex vivo study. 9 After 24 hours, the DEX concentration was significantly reduced in all three types of tubing (<30.1%), the oxygenator heat exchanger from Maquet (41.8%), and the gas exchanger from Terumo (8.6%).…”

“…After target parameters were achieved, CPB flow was increased to 600 ml/ min. To examine the effect of coated versus uncoated circuits on DEX sequestration in ECMO circuits, the following experiments (Table 1) were performed, 1) coated circuits (1-3) with DEX dose of 0.14 µg, 2) coated circuits (4-6) with DEX dose of 0.28 µg, and 3) uncoated circuits (7)(8)(9) with DEX dose of 0.28 µg. A baseline blood gas and study sample was obtained.…”

“…Recent studies show DEX was sequestered by the oxygenator resulting in decreased concentrations in plasma. 8,9 Previous studies have shown that the surface coating of PVC tubing can minimize the sequestration of fentanyl to extracorporeal life support circuits. 10 Other lipophilic drugs such as diazepam have demonstrated adsorption to the PVC tubing affected by both the flow rate and the length of the tubing, and flow rates in the CPB circuit could affect the adsorption of lipophilic agents including DEX.…”