Variability in dobutamine pharmacokinetics in unstable critically ill surgical patients

Abstract

Objective: To delineate the variability in the pharmacokinetics of dobutamine over time in an unstable critically ill adult surgical patient population concurrently receiving therapeutic interventions to optimize oxygen delivery and consumption variables.

Design: Prospective study.

Setting: University hospital adult surgical intensive care unit.

Patients: Sixteen hemodynamically unstable adults (aged 18 to 84 yrs) requiring dobutamine for inotropic support.

Interventions: None.

Measurements and main results: Samples for dobutamine serum concentration determination were collected at selected times during therapy, following at least 30 mins of a constant infusion rate and measured using high-performance liquid chromatography. Clearance and changes in clearance were calculated. A first-order pharmacokinetic model was validated by lack of dependence of dose on clearance and an established graphical method. Mean +/- SD infusion rate of dobutamine was 8.2 +/- 5.7 micrograms/kg/min (range 1.7 to 22.3), which resulted in a mean serum concentration of 214 +/- 183 ng/mL (range 15 to 759). The correlation between infusion rate and steady-state dobutamine concentration was r2 = .67. Variability in steady-state dobutamine concentration at various infusion rates was large. Clearance at initial pharmacokinetic analysis averaged 58.4 +/- 33.3 mL/kg/min (range 19 to 120). The percent change in calculated clearance varies from a 72% decrease to an 88% increase, with the greatest variability in clearance occurring during the first 24 hrs of therapy. There was little correlation between initial dobutamine clearance and weight (r2 = .10), net cumulative fluid balance before initiation of dobutamine (r2 < .01), age (r2 = .20), and estimated creatinine clearance (r2 = .09).

Conclusions: Dobutamine pharmacokinetics in adult critically ill patients is best described by a first-order model. Pathophysiologic factors may have an effect on the pharmacokinetics of dobutamine which appears to change over time. Both inter- and intrapatient variability in infusion rate administered and resultant serum concentrations were wide, suggesting that infusion rate should be guided by clinical end points rather than by predetermined values.