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

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) = θ_CL × (BWi)^3/4 and q0(BWi) = θ_q0 × (BWi)^3/4. The increase in mean arterial pressure (MAP) as a function of norepinephrine concentration was well described using an E_max model. The effects of post‐conceptional age (PCA) and number of organ dysfunctions were significant on basal MAP level (MAP_0i = MAP₀ × PCA/9_i^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.

DOI: 10.1111/bcp.12412

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