title: Population pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children.
abstract: OBJECTIVE
  The aim of the study was to investigate the pharmacokinetics and pharmacodynamics of norepinephrine in hypotensive critically ill children, including associated variability factors.
  
  
  METHODS
  This was a prospective study in an 18-bed neonatal and paediatric intensive care unit. All children were aged less than 18 years, weighed more than 1500 g and required norepinephrine for systemic arterial hypotension. The pharmacokinetics and haemodynamic effects were described using the non-linear mixed effect modelling software MONOLIX.
  
  
  RESULTS
  Norepinephrine dosing infusions ranging from 0.05 to 2 μg kg(-1)  min(-1) were administered to 38 children whose weight ranged from 2 to 85 kg. A one compartment open model with linear elimination adequately described the norepinephrine concentration-time courses. Bodyweight (BW) was the main covariate influencing norepinephrine clearance (CL) and endogenous norepinephrine production rate (q0) via an allometric relationship: CL(BWi) = θCL × (BWi)(3/4) and q0(BWi) = θq0 × (BWi)(3/4) . The increase in mean arterial pressure (MAP) as a function of norepinephrine concentration was well described using an Emax model. The effects of post-conceptional age (PCA) and number of organ dysfunctions were significant on basal MAP level (MAP0i = MAP0 × PCA/9i (0.166) ) and on the maximal increase in MAP (32 mmHg and 12 mmHg for a number of organ dysfunctions ≤3 and ≥4, respectively).
  
  
  CONCLUSIONS
  The pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children highlight the between-subject variability which is related to the substantial role of age, BW and severity of illness. Taking into account these individual characteristics may help clinicians in determining an appropriate initial a priori dosing regimen.
authors.affiliation: Réanimation pédiatrique, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France; CIC-0109 Cochin-Necker Inserm, Unité de Recherche Clinique, Paris Centre Descartes Necker Cochin, Service de pharmacologie Hôpital Cochin, Assistance Publique- Hôpitaux de Paris et E.A. 3620 Université Paris Descartes, Paris, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Oualha
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tréluyer
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lesage
authors.forename: Laure
authors.initials: L
authors.lastname: de Saint Blanquat
authors.forename: Laurent
authors.initials: L
authors.lastname: Dupic
authors.forename: Philippe
authors.initials: P
authors.lastname: Hubert
authors.forename: Odile
authors.initials: O
authors.lastname: Spreux-Varoquaux
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007022:Hypotension / Q000188:drug therapy* / Q000503:physiopathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011446:Prospective Studies
chemical_list: D009638:Norepinephrine
keywords: children; hypotension; norepinephrine; pharmacokinetic/pharmacodynamic model