ANALYSIS OF THE VARIABILITY IN THE PHARMACOKINETICS AND PHARMACODYNAMICS OF BUMETANIDE IN CRITICALLY ILL INFANTS

Objectives: Account for the interindividual variability in the pharmac okinetics and pharmacodynamics of bumetanide after intravenous adminis tration of single doses to critically ill infants. Methods: This prosp ective open-label study was carried out in the pediatric intensive car e unit of a university-based children's hospital, Fifty-three volume-o verloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and tho se with lung disease (22 infants), Each patient received a single intr avenous bolus dose of bumetanide, Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variab le to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide Hierarchical multiple regression a nalyses were used to assess the effects of age, disease, and other dru gs on the variability in the effects of bumetanide. Results: Total cle arance, renal clearance, and nonrenal clearance of bumetanide all incr eased with age (p <0.05), but the ratio of renal clearance to total cl earance remained constant at about 0.4. Half-life and mean residence t ime decreased markedly in the first month of Lift (p <0.05). Bumetanid e excretion rate normalized for dose also increased with increasing ag e. Patients with lung disease exhibited a significantly greater cleara nce and shorter half-life (p <0.05) than those with heart disease, whe reas volume of distribution was similar in both groups. The primary de terminant of bumetanide excretion rate was the administered dose (73%) . Dose-response curves for urine flow rate and electrolyte excretion w ere similar between disease groups, The time course of the effect of b umetanide excretion rate on pharmacodynamics responses was similar bet ween disease groups, as was the duration of the diuretic effect. Concl usions: The pharmacokinetics of bumetanide were influenced significant ly by age and disease. Differences in pharmacokinetics between patient s with lung and heart disease were primarily due to differences in tot al clearance, The administered dose of bumetanide and age were positiv e determinants of bumetanide excretion rate and pharmacodynamic respon ses. Pharmacodynamic responses as a function of bumetanide excretion r ate were not significantly different between disease groups.