Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation

Kiran Shekar, Jason A Roberts, Charles I Mcdonald, Stephanie Fisquet, Adrian G Barnett, Daniel V Mullany, Sussan Ghassabian, Steven C Wallis, Yoke L Fung, Maree T Smith, John F Fraser, Kiran Shekar, Jason A Roberts, Charles I Mcdonald, Stephanie Fisquet, Adrian G Barnett, Daniel V Mullany, Sussan Ghassabian, Steven C Wallis, Yoke L Fung, Maree T Smith, John F Fraser

Abstract

Introduction: Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits.

Methods: Four identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays.

Results: Four hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26).

Conclusions: Sequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.

Figures

Figure 1
Figure 1
Percentage of drug remaining in extracorporeal membrane oxygenation circuits and the controls plotted against time. Lipohilic drugs such as fentanyl and midazolam were significantly sequestered in the circuit despite being stable in the controls. Morphine was relatively stable in both controls and the circuits.
Figure 2
Figure 2
Percentage of meropenem and vancomycin remaining in extracorporeal membrane oxygenation circuits and the controls plotted against time. Meropenem was unstable in the controls; however, the extracorporeal membrane oxygenation circuit losses significantly exceeded the levels of degradation seen in the controls at 6 hours. Vancomycin was stable in both controls and the circuits.

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