title: Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration.
abstract: Clonidine is used for sedation in the paediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during paediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit.
  
  
  
  All children below the age of 18 years who received clonidine during ECMO were eligible. The pharmacokinetic analysis was conducted by nonlinear mixed effect modelling, which enables to establish the separate influences of determinants on drug blood level and to provide individualized dosing.
  
  
  
  Twenty-two patients, median age 1 month (IQR 6.4) and weight at inclusion 4 kg (IQR 3.1) were included of whom 90% in addition to ECMO received pre-emptive continuous venovenous hemofiltration to optimize fluid balance. The clonidine clearance rate was two-fold that measured in patients not on ECMO. Clearance increased steeply with postnatal age: at days 6, 8 and 10, respectively 30%, 50% and 70% of the adult clearance rate was reached. The use of diuretics was associated with a lower clearance. The volume of distribution increased by 55% during ECMO support.
  
  
  
  Our findings suggest that a higher dose of clonidine may be needed during ECMO. The PK parameters on ECMO and the dosing guidelines proposed hold the potential to improve sedation practices on ECMO but need to be repeated with different ECMO systems.
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, P.O. Box 2060, 3000, CB, Rotterdam, The Netherlands.|Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Niina
authors.initials: N
authors.lastname: Kleiber
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Centre, Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
authors.forename: Ron A A
authors.initials: RAA
authors.lastname: Mathôt
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, P.O. Box 2060, 3000, CB, Rotterdam, The Netherlands.|LAP&P Consultants BV, Archimedesweg 3, 1 2333, CM, Leiden, The Netherlands.
authors.forename: Maurice J
authors.initials: MJ
authors.lastname: Ahsman
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, P.O. Box 2060, 3000, CB, Rotterdam, The Netherlands.
authors.forename: Enno D
authors.initials: ED
authors.lastname: Wildschut
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, P.O. Box 2060, 3000, CB, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, P.O. Box 2060, 3000, CB, Rotterdam, The Netherlands.|Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
mesh_terms: D000293:Adolescent; D000375:Aging / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003000:Clonidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D018450:Disease Progression; D015199:Extracorporeal Membrane Oxygenation / Q000379:methods*; D005260:Female; D006440:Hemofiltration / Q000379:methods*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D007231:Infant, Newborn; D007275:Injections, Intravenous; D008297:Male; D015233:Models, Statistical; D011153:Population; D012727:Sex Characteristics
chemical_list: D006993:Hypnotics and Sedatives; D003000:Clonidine
keywords: clonidine; dosing guideline; extracorporeal membrane oxygenation; paediatric intensive care; pharmacokinetics; sedation; α-agonist