Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans

Abstract

Thermal injury causes resistance to many nondepolarizing muscle relaxants including d-tubocurarine, metocurine, pancuronium, and atracurium. To evaluate the role of pharmacokinetics and pharmacodynamics in this phenomenon, the disposition and effect of atracurium (0.5 mg/kg iv) were studied in thermally injured patients (5 males, 16-43 yr) in comparison with that in nonburned control patients (3 males, 1 female, 24-53 yr) the decline of plasma atracurium concentration with time was biexponential in both groups of patients. There were no significant differences in the mean value of any pharmacokinetic parameter (clearance, V1, V(β), α and β half-lives). The time course of effect was also similar, although the maximum twitch depression was significantly smaller (66.1% vs 100% maximal twitch depression) and time to recover to 50% of maxiaml twitch depression was significantly shorter (14.2 vs 52 min) in thermally injured patients. Patients with thermal injury had an EC50 (plasma concentration of atracurium required for 50% of the maximum possible response) 3.4 times that of control patients. Plasma-free fraction of atracurium in the thermally injured patients was 75% that in controls, and free EC50 (the product of free fraction and EC50) of the thermally injured group was 2.7 times that of controls. The results of this study confirm a pharmacodynamic mechanism for the majority of resistance to atracurium, with a diminished free fraction in plasma also contributing to this effect.