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

Abstract

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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Haemodynamic response to norepinephrine is variable and unpredictable.• The pharmacokinetics and pharmacodynamics of norepinephrine in adults are well described by a one compartment model with a first order elimination and Emax model, respectively. Clearance is influenced by the severity of illness.• Norepinephrine kinetics and dynamics in children are unknown. WHAT THIS STUDY ADDS• In children, the pharmacokinetics and pharmacodynamics of norepinephrine on between-subject variability are related to age, bodyweight and severity of illness.• The lower the age, the higher the number of organ dysfunctions and the lower the amplitude of the increase in mean arterial pressure.

Cardiovascular Drug Therapy for Human Newborn: Review of Pharmacodynamic Data

“…In a group of children including newborn infants NE has been shown to increase blood pressure on a dose dependent fashion [77]. One prospective cohort study has shown increased blood pressure with NE in newborns with congenital diaphragmatic hernia with no change in microcirculation measured by SDF imaging where peripheral microvascular bed is assessed [23].…”

Treating Hypotension in Preterm Neonates With Vasoactive Medications

“…A pediatric norepinephrine pharmacokinetic and pharmacodynamics study (0.5–3 µg/kg/min) included 11 neonates and indicated that variabilities were related to weight, age, and severity of illness which was related to the production and clearance of norepinephrine ( 59 ). We found two retrospective studies of norepinephrine use in preterm neonates ( n = 48, <32 weeks and n = 30, <34 weeks) ( 60 , 61 ).…”

Clinical Pharmacology Studies in Critically Ill Children

“…There is a significant variability in the PK and PD of exogenously administered epinephrine and norepinephrine. Several studies have investigated the PK/PD of epinephrine [203,204] and norepinephrine [205] in critically ill children. In critically ill children ranging from 0.5 to 16 years of age, epinephrine was reported to have a CL ranging between 15.6–79.2 mL/min/kg and the PK was characterized by a one-compartment model with linear elimination.…”

“…The authors suggested that this may be due to changes in combination of different factors (e.g., plasma concentrations of platelets, electrolytes, calcium, caffeine) that alter the PK of catecholamines in critically ill children [204]. Similarly the CL of norepinephrine was 6.6 L/h/kg and the PK was well-characterized by a one-compartment model with linear elimination [205]. However, there was no difference in the PK of norepinephrine in critically ill children relative to adults [205].…”

“…Similarly the CL of norepinephrine was 6.6 L/h/kg and the PK was well-characterized by a one-compartment model with linear elimination [205]. However, there was no difference in the PK of norepinephrine in critically ill children relative to adults [205]. …”