Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates

Extracorporeal membrane oxygenation (ECMO) is a prolonged form of cardiopulmonary bypass used to support patients with life-threatening respiratory or cardiac failure. In neonates, ECMO is used for a variety of indications, including sepsis and pulmonary diseases such as meconium aspiration syndrome, persistent pulmonary hypertension or congenital diaphragmatic hernia. In recent years, ECMO has been increasingly used after surgery to correct congenital cardiac defects. Despite the need for numerous drugs to maintain the ECMO circuit and treat the patient's underlying illness, relatively little is known of the disposition of drugs in this patient population. To date, the largest number of pharmacokinetic studies have been conducted with gentamicin and vancomycin. Both drugs have been found to have an increased volume of distribution, probably as a result of the addition of a large exogenous blood volume for circuit priming. Elimination half-lives for both drugs are prolonged during ECMO, with several studies demonstrating a return to expected values after decannulation. The reason for this prolonged elimination is probably multifactorial, with a reduction in renal function as the primary determinant. This same pattern of an increased volume of distribution and prolonged elimination has been found for several other drugs, including tobramycin, bumetanide and ranitidine. Other factors that affect drug disposition during ECMO include loss of the drug from adhesion to the circuit components and loss in the circulating blood volume during changes in the equipment. The benzodiazepines and propofol are largely sequestered within the circuit. Serum concentrations of heparin, morphine, fentanyl, furosemide, phenytoin and phenobarbital are also reduced by these mechanisms. The addition of haemofiltration or dialysis in up to a quarter of ECMO patients further complicates the determination of population pharmacokinetic parameters. The literature published to date on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment; however, more research is needed to identify optimal administration strategies for this patient population.