Abstract
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.
Similar content being viewed by others
References
Somme S, Liu DC. New trends in extracorporeal membrane oxygenation in newborn pulmonary diseases. Artif Organs 2001; 25: 633–7
Extracorporeal Life Support Group. Extracorporeal membrane oxygenation registry report. Ann Arbor (MI): Extracorporeal Life Support Organisation; 2002 Jan
Rais-Bahrami K, Short BL. The current status of neonatal extracorporeal membrane oxygenation. Semin Perinatal 2000; 24: 406–17
Schumacher RE, Baumgart S. Extracorporeal membrane oxygenation 2001: the Odyssey continues. Clin Perinatal 2001; 28: 629–53
Roy BJ, Rycus P, Conrad SA, et al. The changing demographics of neonatal extracorporeal membrane oxygenation patients reported to the Extracorporeal Life Support Organization (ELSO) registry. Pediatrics 2000; 106: 1334–8
Jaggers JJ, Forbess JM, Shah AS, et al. Extracorporeal membrane oxygenation for infant postcardiotomy support: significance of shunt management. Ann Thorac Surg 2000; 69: 1476–83
Hopper AO, Pageau J, Job L, et al. Extracorporeal membrane oxygenation for perioperative support in neonatal and pediatric cardiac transplantation. Artif Organs 1999; 23: 1006–9
Champion MP, Murdoch IA, Sajjanhar T, et al. Extracorporeal membrane oxygenation for refractory shock in fulminant meningococcal sepsis. Lancet 1996; 347: 201–2
Rais-Bahrami K, Short BL. Citrobacter sepsis and severe newborn respiratory failure supported with extracorporeal membrane oxygenation. J Perinatal 2000; 20: 265–6
Southgate WM, DiPiro JT, Robertson AF. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Antimicrob Agents Chemother 1989; 33: 817–9
Cohen P, Collart L, Prober CG, et al. Gentamicin pharmacokinetics in neonates undergoing extracorporeal membrane oxygenation. Pediatr Infect Dis J 1990; 9: 562–6
Dodge WF, Jelliffe RW, Zwischenberger JB, et al. Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation. Ther Drug Monit 1994; 16: 552–9
Bhatt-Mehta V, Johnson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy 1992; 12: 28–32
Buck ML. Assessment of gentamicin dosing intervals in neonates receiving extracorporeal membrane oxygenation [abstract]. Pharmacotherapy 1995; 15: 384
Munzenberger PJ, Massoud N. Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation. ASAIO Trans 1991; 37: 16–8
Szefler SJ, Wynn RJ, Clarke DF, et al. Relationship of gentamicin serum concentrations to gestational age in preterm and term neonates. J Pediatr 1980; 97: 312–5
Moller JC, Gilman JT, Kearns GL, et al. Effect of extracorporeal membrane oxygenation on tobramycin pharmacokinetics in sheep. Crit Care Med 1992; 20: 1454–8
Hoie EB, Swigart SA, Leuschen MP, et al. Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation. Clin Pharm 1990; 9: 711–5
Amaker RD, DiPiro JT, Bhatia J. Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation. Antimicrob Agents Chemother 1996; 40: 1139–42
Buck ML. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy 1998; 18: 1082–6
Wells TG, Fasules JW, Taylor BJ, et al. Pharmacokinetics and pharmacodynamics of bumetanide in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1992; 121: 974–80
Wells TG, Heulitt M, Taylor BJ, et al. Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation. J Clin Pharmacol 1998; 38: 402–7
Mulla H, Nabi F, Nichani S, et al. Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation. Br J Clin Pharmacol 2003; 55: 23–31
Sell LL, Cullen ML, Whittlesey GC, et al. Experience with renal failure during extracorporeal membrane oxygenation: treatment with continuous hemofiltration. J Pediatr Surg 1987; 22: 600–2
Roy BJ, Cornish JD, Clark RH. Venovenous extracorporeal membrane oxygenation affects renal function. Pediatrics 1995; 95: 573–8
Meyer DM, Jessen ME. Results of extracorporeal membrane oxygenation in neonates with sepsis: The Extracorporeal Life Support Organization experience. J Thorac Cardiovasc Surg 1995; 109: 419–25
Hoie EB, Hall MC, Schaaf LJ. Effects of injection site and flow rate on the distribution of injected solutions in an extracorporeal membrane oxygenation circuit. Am J Hosp Pharm 1993; 50: 1902–6
Dagan O, Klein J, Gruenwald C, et al. Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs. Ther Drug Monit 1993; 15: 263–6
Mulla H, Lawson G, von Anrep C, et al. In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation. Perfusion 2000; 15: 21–6
Muntean W. Coagulation and anticoagulation in extracorporeal membrane oxygenation. Artif Organs 1999; 23: 979–83
Graves DF, Chemin JM, Kurusz M, et al. Anticoagulation practices during neonatal extracorporeal membrane oxygenation: survey results. Perfusion 1996; 11: 461–6
Green TP, Isham-Schopf B, Irmiter RJ, et al. Inactivation of heparin during extracorporeal circulation in infants. Clin Pharmacol Ther 1990; 48: 148–54
Kawada T, Kitagawa H, Hoson M, et al. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin North Am 2000; 14: 445–57
Caron E, Maguire DP. Current management of pain, sedation, and narcotic physical dependency of the infant on ECMO. J Perinat Neonatal Nurs 1990; 4: 63–74
Arnold JH, Truog RD, Orav EJ, et al. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology 1990; 73: 1136–40
Arnold JH, Truog RD, Scavone JM, et al. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991; 119: 639–43
Burda G, Trittenwein G. Issues of pharmacology in pediatric cardiac extracorporeal membrane oxygenation with special reference to analgesia and sedation. Artif Organs 1999; 23: 1015–9
Franck LS, Vilardi J, Durand D, et al. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care 1998; 7: 364–9
Geiduschek JM, Lynn AM, Bratton SL, et al. Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation. Crit Care Med 1997; 25: 360–4
Dagan O, Klein J, Bohn D, et al. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Crit Care Med 1994; 22: 1099–101
Koren G, Crean P, Klein J, et al. Sequestration of fentanyl by the cardiopulmonary bypass. Eur J Clin Pharmacol 1984; 27: 51–6
Hynynen M. Binding of fentanyl and alfentanil to the extracorporeal circuit. Acta Anaesthesiol Scand 1987; 31: 706–10
Leuschen MP, Willett LD, Hoie EB, et al. Plasma fentanyl levels in infants undergoing extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 1993; 105: 885–91
Scala JL, Jew RK, Poon CY, et al. In vitro analysis of furosemide disposition during neonatal extracorporeal membrane oxygenation (ECMO) [abstract]. Pediatr Res 1996; 39: 78A
Marx CM, Litmanovitz I, Ksenich R, et al. Investigation of increased phenobarbital dose requirements for newborn infants on ECMO: in vitro adsorption to ECMO circuit [abstract]. Pharmacotherapy 1991; 11: 270
Elliott ESR, Buck ML. Phenobarbital dosing and pharmacokinetics in a neonate receiving extracorporeal membrane oxygenation. Ann Pharmacother 1999; 33: 419–22
Kroh UF, Holl T, Fueussner KD. Pharmacokinetics and dosage adjustment of antibiotics during continuous extracorporeal lung assistance and hemofiltration. Artif Organs 1992; 16: 457–60
Aebi C, Headrick CL, McCracken GH, et al. Intravenous ribavirin therapy in a neonate with disseminated adenovirus infection undergoing extracorporeal membrane oxygenation: pharmacokinetics and clearance by hemofiltration. J Pediatr 1997; 130: 612–5
Lindsay CA, Bawdon R, Quigley R. Clearance of ticarcillinclavulanic acid by continuous venovenous hemofiltration in three critically ill children, two with and one without concomitant extracorporeal membrane oxygenation. Pharmacotherapy 1996; 16: 458–62
Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Buck, M.L. Pharmacokinetic Changes During Extracorporeal Membrane Oxygenation. Clin Pharmacokinet 42, 403–417 (2003). https://doi.org/10.2165/00003088-200342050-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200342050-00001