A Narrative Review of the Impact of Extracorporeal Membrane Oxygenation on the Pharmacokinetics and Pharmacodynamics of Critical Care Therapies

Abstract

Objective: Extracorporeal membrane oxygenation (ECMO) utilization is increasing on a global scale, and despite technological advances, minimal standardized approaches to pharmacotherapeutic management exist. This objective was to create a comprehensive review for medication dosing in ECMO based on the most current evidence. Data Sources: A literature search of PubMed was performed for all pertinent articles prior to 2022. The following search terms were utilized: ECMO, pharmacokinetics, pharmacodynamics, sedation, analgesia, antiepileptic, anticoagulation, antimicrobial, antifungal, nutrition. Retrospective cohort studies, case-control studies, case series, case reports, and ex vivo investigations were reviewed. Study Selection and Data Extraction: PubMed (1975 through July 2022) was the database used in the literature search. Non-English studies were excluded. Search terms included both drug class categories, specific drug names, ECMO, and pharmacokinetics. Data Synthesis: Medications with high protein binding (>70%) and high lipophilicity (logP > 2) are associated with circuit sequestration and the potential need for dose adjustment. Volume of distribution changes with ECMO may also impact dosing requirements of common critical care medications. Lighter sedation targets and analgosedation may help reduce sedative and analgesia requirements, whereas higher antiepileptic dosing is recommended. Vancomycin is minimally affected by the ECMO circuit and recommendations for dosing in critically ill adults are reasonable. Anticoagulation remains challenging as optimal aPTT goals have not been established. Relevance to Patient Care and Clinical Practice: This review describes the anticipated impacts of ECMO circuitry on sedatives, analgesics, anticoagulation, antiepileptics, antimicrobials, antifungals, and nutrition support and provides recommendations for drug therapy management. Conclusions: Medication pharmacokinetic/pharmacodynamic parameters should be considered when determining the potential impact of the ECMO circuit on attainment of therapeutic effect and target serum drug concentrations, and should guide therapy choices and/or dose adjustments when data are not available.

Maribavir failure in refractory cytomegalovirus infection in a lung transplant patient on extracorporeal membrane oxygenation

“…Protein binding (% bound) both letermovir and maribavir have LogP levels >2 and protein binding >70%, there is high suspicion that these agents would be sequestered by the ECMO circuit. 6 This case demonstrates that prior to maribavir therapy, the patient had stable CMV viral levels for a prolonged period while on ECMO (Figure 1). The introduction of maribavir on day 50 of admission and thus it is failure at day 11 of therapy could be described, in the absence of known resistance, by a lack of obtainment of therapeutic concentrations.…”

“…5 When assessing whether a medication is at an elevated risk of circuit sequestration, both the protein binding of the medication and hydrophobicity (expressed through the use of the LogP values) should be considered. 6 Medications such as analgesics (i.e., fentanyl) or sedatives (i.e., midazolam) that express high levels of protein binding and hydrophobicity have been shown to more likely be sequestered compared to medications that have low protein binding and are hydrophilic. 6,7 Most antiviral agents indicated for the prophylaxis or treatment of CMV have a pharmacokinetic profile that reflects low potential for sequestration.…”

“…6 Medications such as analgesics (i.e., fentanyl) or sedatives (i.e., midazolam) that express high levels of protein binding and hydrophobicity have been shown to more likely be sequestered compared to medications that have low protein binding and are hydrophilic. 6,7 Most antiviral agents indicated for the prophylaxis or treatment of CMV have a pharmacokinetic profile that reflects low potential for sequestration. Table 1 presents the LogP and protein binding of mul-TA B L E 1 Cytomegalovirus (CMV) antiviral agents and their respective sequestration properties.…”

Antimicrobial Pharmacokinetic Considerations in Extracorporeal Membrane Oxygenation

“…Utilizing LogP and protein binding percentages can be a practical starting point while keeping in mind that this strategy will not always be reliable. Nevertheless, a thorough PK understanding can help minimize the incidence of antibiotic dosing variabilities and uncertain treatment responses [ 24 ]. In general, standard dosing regimens are acceptable for antibiotics like most beta-lactams that are hydrophilic with low protein binding.…”

“…The majority of these anti-infectives are thought to follow the general trend that lipophilic medications with higher protein binding undergo a higher degree of drug sequestration in the ECMO circuit (Table 1) [2]. By understanding these mechanisms of PK alterations in ECMO and medication-specific factors that may predispose a drug to sequestration, clinicians may be able to better predict optimal drug selection and appropriate dosing schemes and drug monitoring [24]. As an example, piperacillin-tazobactam is a broad-spectrum combination beta-lactam/ beta-lactamase inhibitor used frequently as an antipseudomonal agent in critically ill patients [25].…”