Population pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children

Br J Clin Pharmacol. 2014 Oct;78(4):886-97. doi: 10.1111/bcp.12412.


Aim: 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).

Conclusion: 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.

Keywords: children; hypotension; norepinephrine; pharmacokinetic/pharmacodynamic model.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Critical Illness
  • Female
  • Hemodynamics / drug effects*
  • Humans
  • Hypotension / drug therapy*
  • Hypotension / physiopathology
  • Infant
  • Infant, Newborn
  • Male
  • Norepinephrine / administration & dosage
  • Norepinephrine / pharmacokinetics*
  • Norepinephrine / pharmacology
  • Prospective Studies


  • Norepinephrine