• Mehdi Oualha, Jean-Marc Tréluyer, Fabrice Lesage, Laure de Saint Blanquat, Laurent Dupic, Philippe Hubert, Odile Spreux-Varoquaux, and Saïk Urien.
• 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.
• Br J Clin Pharmacol. 2014 Oct 1;78(4):886-97.

AimThe aim of the study was to investigate the pharmacokinetics and pharmacodynamics of norepinephrine in hypotensive critically ill children, including associated variability factors.MethodsThis 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.ResultsNorepinephrine 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).ConclusionThe 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.© 2014 The British Pharmacological Society.

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