PHARMACOKINETICS AND PHARMACODYNAMICS OF ATRACURIUM IN INFANTS AND CHILDREN

To determine whether maturational changes in body composition and organ function affect distribution and elimination of and sensitivity to atracurium, the authors determined the pharmacokinetics and pharmacodynamics of atracurium in six infants and five children and compared these results with those obtained in five adults. Atracurium, 15.8 ± 1.7 μg · kg-1 · min-1, was infused iv for 6-11 min to subjects anesthetized with nitrous oxide (60%) and halothane (0.9 MAC, age-adjusted) and twitch tension of the adductor pollicis muscle was measured. Plasma samples were obtained for 120 min; concentrations of atracurium were determined using a liquid chromatographic assay. A two-compartment pharmacokinetic model, adapted to account for elimination of atracurium from both central and peripheral compartments, was fit to the plasma concentration data; an effect-compartment model was fit to the twitch tension data. Volume of distribution at steady state (210 ± 118, 129 ± 44, and 100 ± 22 ml/kg for infants, children, and adults, respectively) and total clearance (7.9 ± 2.0, 6.8 ± 1.6, and 5.3 ± 0.9 ml · kg-1 · min-1 for the three groups) decreased with increasing age. Neither elimination half-life (20.0 ± 5.1, 17.2 ± 5.1, and 15.7 ± 2.5 min for the three groups) nor the steady state plasma concentration that resulted in 50% neuromuscular blockade (363 ± 118, 444 ± 121, and 436 ± 122 ng/ml for the three groups) varied with age. The authors conclude that these results are consistent with and explain the previously reported findings that recovery from the neuromuscular effects of atracurium is minimally affected by age. In addition, age-related changes in atracurium's volume of distribution at steady state are similar to those for vecuronium and d-tubocurarine; these changes presumably result from these muscle relaxants distributing into the extracellular fluid space the volume of which decreases during the first year of life.