Pharmacokinetics/Pharmacodynamics

Extracorporeal Membrane Oxygenation – Use of extracorporeal membrane oxygenation (ECMO) in critically

ill patients has increased over the years. Depending on the institution and clinician expertise, ECMO can

play a significant role in the care of critically ill patients with respiratory and/or circulatory failure. With

implementation of this therapy, changes in the PK of medications have been described. The most common

alteration reported is an increase in Vd. Use of ECMO therapy consists of a large volume of blood being

extracted from the patient through catheter tubing (generally polyvinyl chloride), circulated through an

oxygenator and a heat exchanger before the newly oxygenated blood is returned to the patient. Depending

on the type of circuit and/or pump used for ECMO, the volume required to prime the circuit can increase

the Vd of some commonly used medications, especially those with a small Vd. Of importance, data on PK

changes related to ECMO initiation remain limited. Most of the available data are in neonatal and pediatric

patients; however, experience during the COVID-19 pandemic has led to more insight in the adult population.

Prospective studies in adults include evaluations of oseltamivir, vancomycin, and meropenem (AACN

created by ECMO may be less than that found in retrospective studies, at least for the studied medications.

The generally anticipated pharmacokinetic changes created by ECMO are the result of three factors: (1) the

ECMO circuit tubing and membrane oxygenator may bind medications, causing drug sequestration, and the

resulting PK change expected is an increased Vd; (2) circuit priming fluid type, fluid pH, and volume potentially

increase in medication Vd; and (3) as the ECMO circuit ages, medication binding becomes saturated, creating

a scenario in which patient medication requirements may return back to pre-ECMO dosing. Several ex vivo

studies have demonstrated loss of drug in the ECMO circuit, including fentanyl and midazolam. This effect

should prompt clinicians to monitor patients closely for proper analgesia and sedation during ECMO treatment

relate to the critically ill state of the patient and are discussed throughout this chapter. Of note, these concepts

are generalizations, and data for specific drugs may differ. For example, an ex vivo study investigating drug

binding to ECMO circuits found that ciprofloxacin recovery rates were 96%, even though the drug was

study evaluated β-lactam and aminoglycoside PK parameters in patients receiving ECMO. Study results showed

variable achievement of PK objectives, which led the authors to recommend therapeutic drug monitoring

Pain Med 2019;38:493-97). Physiochemical properties of the drug molecule also determine the interaction

with the circuit. Compound characteristics that should be considered include pKa and degree of ionization,

molecular size, plasma protein binding, and lipophilicity. Drug lipophilicity is often reported through the

n-octanol/water partition coefficient, or logP, whereas a high logP indicates a more lipophilic compound at

higher risk of ECMO circuit sequestration. Protein binding and the extent thereof may also influence the

necessitated the use of ECMO and revealed pharmacokinetic changes in several antiviral agents. Changes

in Vd were found for favipiravir and ribavirin. Suspected alterations in cytochrome P450 metabolism were

noted for chloroquine, lopinavir, ritonavir, and favipiravir. The reader is referred to a comprehensive review

by the European Society of Clinical Microbiology, Infectious Diseases (Clin Pharmacokinet 2020;59:1195-

16) for more information about the impact of COVID-19 and ECMO on the pharmacokinetics of antivirals.