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

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 beta, alpha and beta 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 maximal 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.