Optimising intravenous salbutamol in children: a phase 2 study

The β2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic–pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model.A prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol.Children were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children’s Acute Transport Service to three London paediatric intensive care units.Patients were eligible if aged 1–15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol.Treatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models.Fifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1–15.2) years, and weight was 13.6 (8–57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained.A two-compartment PK model adequately described the time course of salbutamol–plasma concentrations. An EMAX(maximum drug effect) concentration–effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours.A paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.