Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents

Abstract

Pharmacokinetic and pharmacodynamic data on adrenergic agents in children have revealed wide ranges of plasma clearance rates and hemodynamic responses in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, graded i.v. dobutamine infusions of 0.5, 2.5 and 5.0 micrograms/kg/min were sequentially administered to healthy children and adolescents. Plasma dobutamine concentrations and hemodynamic responses, including echocardiographic measures of systolic and diastolic function, were determined at each infusion rate. Pharmacodynamic data were evaluated by both threshold modeling and mean hemodynamic responses to each infusion rate. Mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. These data establish that the previously published wide variability in dobutamine clearance is not due simply to underlying disease states. Dobutamine clearance was linear over the dosage range evaluated. Dobutamine improved systolic function even at plasma concentrations attained with infusion rates as low as 1 to 2 micrograms/kg/min. The improved systolic function was at least partially due to inotropic effects. In addition, dobutamine improved diastolic function and reduced afterload. Chronotropic effects were observed in only two subjects and only at higher plasma concentrations than the other hemodynamic effects. Individualized threshold modeling effectively described the log-linear relationship between plasma dobutamine concentration and hemodynamic response beyond the threshold concentration.