J Pediatr Intensive Care
DOI: 10.1055/s-0044-1787262
Original Article

Drug Administration Patterns in Patients on Extracorporeal Membrane Oxygenation

1   Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
,
Jesse G. Norris
1   Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
,
Autumn McKnite
2   Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, United States
,
Mark W. Hall
3   Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, United States
,
Kevin M. Watt
1   Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
4   Division of Clinical Pharmacology, University of Utah, Salt Lake City, Utah, United States
› Author Affiliations
Funding D.J.G. receives support for critical care research from the National Heart, Lung, and Blood Institute (2T32HL105321). A.M. receives support for pediatric pharmacology research from the National Institute of Diabetes and Digestive and Kidney Diseases (1F311DK130542). K.M.W. receives support for pediatric research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD097775).

Abstract

This study aimed to identify drug administration patterns in patients of all ages supported with extracorporeal membrane oxygenation (ECMO) across multiple institutions and determine which of the most commonly administered drugs lack published dosing guidance.

We conducted a retrospective, multicenter database study using the TriNetX data network and the Pediatric Health Information Systems database. All adults and children supported with ECMO were included for analysis. Drug exposure and days of use were described according to age category (Infants [<2 years], Children [≥2 and <18 years], and Adults [≥18 years]). The literature was reviewed for the top 50 most commonly administered drugs in all ages; all pharmacokinetic and ex vivo studies were included.

A total of 17,909 patients were analyzed. The patient population comprised 24% adults (n = 4,253), 18% children (n = 3266), and 58% infants (n = 10,390). The 10 most commonly administered drugs, by days of use, were heparin, furosemide, midazolam, morphine, fentanyl, vancomycin, milrinone, hydrocortisone, epinephrine, and lorazepam. Published literature comprised 86 studies, including 66 pharmacokinetic studies (77%) and 20 ex vivo studies (23%). Of these, 29% (n = 19) were conducted in adults, 14% (n = 9) were conducted in children, and 60% (n = 39) were performed in infants. ECMO-specific dosing guidance for any age was available for only 28% (n = 14) of the top 50 most commonly administered drugs.

Sedatives, antimicrobials, and cardiovascular agents are among the most commonly administered drugs in patients supported with ECMO. This study highlights an urgent need for evidence-based dosing guidance in this patient population.

Supplementary Material



Publication History

Received: 08 March 2023

Accepted: 23 April 2024

Article published online:
30 May 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Extracorporeal Life Support Organization. ECLS Registry Report International Summary. 2020 . Accessed March 2020 at: https://www.elso.org/Registry/Statistics/InternationalSummary.aspx
  • 2 Watson RS, Crow SS, Hartman ME, Lacroix J, Odetola FO. Epidemiology and outcomes of pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med 2017; 18 (3_suppl, Suppl 1): S4-S16
  • 3 Sherwin J, Heath T, Watt K. Pharmacokinetics and dosing of anti-infective drugs in patients on extracorporeal membrane oxygenation: a review of the current literature. Clin Ther 2016; 38 (09) 1976-1994
  • 4 Bhatt-Meht V, Annich G. Sedative clearance during extracorporeal membrane oxygenation. Perfusion 2005; 20 (06) 309-315
  • 5 Dagan O, Klein J, Bohn D, Koren G. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Crit Care Med 1994; 22 (07) 1099-1101
  • 6 Mehta NM, Halwick DR, Dodson BL, Thompson JE, Arnold JH. Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med 2007; 33 (06) 1018-1024
  • 7 Mulla H, Lawson G, von Anrep C. et al. In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation. Perfusion 2000; 15 (01) 21-26
  • 8 Dagan O, Klein J, Gruenwald C, Bohn D, Barker G, Koren G. Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs. Ther Drug Monit 1993; 15 (04) 263-266
  • 9 Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet 2003; 42 (05) 403-417
  • 10 Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009; 37 (03) 840-851 , quiz 859
  • 11 Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 2001; 92 (2–3): 147-163
  • 12 Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349 (12) 1157-1167
  • 13 Mangoni AA, Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 2004; 57 (01) 6-14
  • 14 Cheng V, Abdul-Aziz MH, Roberts JA, Shekar K. Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis 2018; 10 (Suppl. 05) S629-S641
  • 15 Ha MA, Sieg AC. Evaluation of altered drug pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation. Pharmacotherapy 2017; 37 (02) 221-235
  • 16 Thibault C, Collier H, Naim MY, Heichel J, Schwartz E, Zuppa AF. Patterns of medication exposure in children on extracorporeal membrane oxygenation: a step in prioritizing future pharmacologic studies. Crit Care Explor 2019; 1 (09) e0045
  • 17 Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin Jr DK, Smith PB. Best Pharmaceuticals for Children Act—Pediatric Trials Network. Medication use in the neonatal intensive care unit. Am J Perinatol 2014; 31 (09) 811-821
  • 18 WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index. 2023 . Accessed May 2023 at: https://www.whocc.no/atc_ddd_index/
  • 19 Shekar K, Roberts JA, Mullany DV. et al. Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care 2012; 40 (04) 648-655
  • 20 DeGrado JR, Hohlfelder B, Ritchie BM, Anger KE, Reardon DP, Weinhouse GL. Evaluation of sedatives, analgesics, and neuromuscular blocking agents in adults receiving extracorporeal membrane oxygenation. J Crit Care 2017; 37: 1-6
  • 21 Marhong JD, DeBacker J, Viau-Lapointe J. et al. Sedation and mobilization during venovenous extracorporeal membrane oxygenation for acute respiratory failure: an international survey. Crit Care Med 2017; 45 (11) 1893-1899
  • 22 Patel M, Altshuler D, Lewis TC. et al. Sedation requirements in patients on venovenous or venoarterial extracorporeal membrane oxygenation. Ann Pharmacother 2020; 54 (02) 122-130
  • 23 Vogel AM, Lew DF, Kao LS, Lally KP. Defining risk for infectious complications on extracorporeal life support. J Pediatr Surg 2011; 46 (12) 2260-2264
  • 24 Bizzarro MJ, Conrad SA, Kaufman DA, Rycus P. Extracorporeal Life Support Organization Task Force on Infections, Extracorporeal Membrane Oxygenation. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults. Pediatr Crit Care Med 2011; 12 (03) 277-281
  • 25 Abdul-Aziz MH, Shekar K, Roberts JA. Antimicrobial therapy during ECMO - customised dosing with therapeutic drug monitoring: the way to go?. Anaesth Crit Care Pain Med 2019; 38 (05) 451-453
  • 26 Shekar K, Roberts JA, Mcdonald CI. et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care 2015; 19 (01) 164
  • 27 Wildschut ED, Ahsman MJ, Allegaert K, Mathot RAA, Tibboel D. Determinants of drug absorption in different ECMO circuits. Intensive Care Med 2010; 36 (12) 2109-2116
  • 28 Watt KM, Cohen-Wolkowiez M, Williams DC. et al. Antifungal extraction by the extracorporeal membrane oxygenation circuit. J Extra Corpor Technol 2017; 49 (03) 150-159
  • 29 Lemaitre F, Hasni N, Leprince P. et al. Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood. Crit Care 2015; 19 (01) 40
  • 30 Nasr VG, Meserve J, Pereira LM. et al. Sedative and analgesic drug sequestration after a single bolus injection in an ex vivo extracorporeal membrane oxygenation infant circuit. ASAIO J 2019; 65 (02) 187-191
  • 31 Shekar K, Roberts JA, Mcdonald CI. et al. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care 2012; 16 (05) R194
  • 32 Shekar K, Roberts JA, Smith MT, Fung YL, Fraser JF. The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation. BMC Anesthesiol 2013; 13: 7
  • 33 Watt KM, Cohen-Wolkowiez M, Barrett JS. et al. Physiologically based pharmacokinetic approach to determine dosing on extracorporeal life support: fluconazole in children on ECMO. CPT Pharmacometrics Syst Pharmacol 2018; 7 (10) 629-637
  • 34 Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet 2006; 45 (10) 1013-1034
  • 35 Job KM, Dallmann A, Parry S. et al. Development of a generic physiologically-based pharmacokinetic model for lactation and prediction of maternal and infant exposure to ondansetron via breast milk. Clin Pharmacol Ther 2022; 111 (05) 1111-1120
  • 36 Hornik CP, Wu H, Edginton AN, Watt K, Cohen-Wolkowiez M, Gonzalez D. Development of a pediatric physiologically-based pharmacokinetic model of clindamycin using opportunistic pharmacokinetic data. Clin Pharmacokinet 2017; 56 (11) 1343-1353
  • 37 Rosen DA, Rosen KR. Elimination of drugs and toxins during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11 (03) 337-340
  • 38 Poltak J, Connors C, Wungwattana M, Nicolau D, Mercuro NJ, Liu J. Pharmacokinetics of cefazolin in patients with obesity undergoing surgery requiring cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2022; 36 (8 Pt B): 2942-2947
  • 39 Kim EH, Choi BM, Kang P. et al. Pharmacokinetics of dexmedetomidine in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Paediatr Anaesth 2023; 33 (04) 303-311
  • 40 Silva-Filho CR, Barbosa RAG, Silva Jr CV, Malbouisson LMS, Carmona MJC, Jorge-Santos SRC. Application of a pharmacokinetics-pharmacodynamics approach to the free propofol plasma levels during coronary artery bypass grafting surgery with hypothermic cardiopulmonary bypass. Clinics (São Paulo) 2018; 73 (07) e178
  • 41 Cies JJ, Moore WS, Parker J. et al. Pharmacokinetics of cefazolin delivery via the cardiopulmonary bypass circuit priming solution in infants and children. J Antimicrob Chemother 2019; 74 (05) 1342-1347
  • 42 Hirota K, Wakayama S, Sugihara K. et al. Pharmacokinetics of ketamine during hypothermic cardiopulmonary bypass in cardiac patients. J Anesth 1995; 9 (02) 142-145
  • 43 Grassin-Delyle S, Tremey B, Abe E. et al. Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2013; 111 (06) 916-924
  • 44 Ferreira F, Santos S, Nascimento J, Strabelli T, Carmona M. Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery. Eur J Cardiothorac Surg 2012; 42 (02) 300-305
  • 45 Smeulers NJ, Wierda JMKH, van den Broek L, Gallandat Huet RCG, Hennis PJ. Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium. J Cardiothorac Vasc Anesth 1995; 9 (06) 700-705
  • 46 Kuntz MT, Pereira LM, Matte GS. et al. Sequestration of midazolam, fentanyl, and morphine by an ex vivo cardiopulmonary bypass circuit. ASAIO J 2021; 67 (12) 1342-1348
  • 47 Zeilmaker-Roest GA, van Saet A, van Hoeven MPJ. et al. Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems. Artif Organs 2020; 44 (04) 394-401
  • 48 Millar JE, Fanning JP, McDonald CI, McAuley DF, Fraser JF. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care 2016; 20 (01) 387
  • 49 Parikh AN, Merritt TC, Carvajal HG. et al. A comparison of cardiopulmonary bypass versus extracorporeal membrane oxygenation: Does intraoperative circulatory support strategy affect outcomes in pediatric lung transplantation?. Clin Transplant 2021; 35 (06) e14289