Comparison of the pharmacodynamics and pharmacokinetics of an infusion of cis-atracurium (51W89) or atracurium in critically ill patients undergoing mechanical ventilation in an intensive therapy unit

We have studied 12 critically ill, sedated patients who required a neuromuscular blocking drug to assist mechanical ventilation in an intensive care unit. Patients were randomized to receive an infusion of cis-atracurium 0.18 mg kg-1 h-1 (group 1, n = 6) or atracurium 0.6 mg kg-1 h-1 (group 2, n = 6) preceded, if necessary, by a bolus dose of 2 x ED95 of the same drug (cis-atracurium 0.1 mg kg-1 or atracurium 0.5 mg kg-1). Neuromuscular block was monitored using an accelerograph and the infusion rate adjusted regularly so that it was possible to detect the first response to train-of-four (TOF) stimulation of the ulnar nerve at the wrist. Blood samples were obtained for estimation of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). There was no apparent haemodynamic or allergic response to either drug. The mean infusion time in group 1 was 37.6 h and in group 2, 27.5 h. On termination of the infusion, the time for the TOF ratio to reach 0.7 was similar in the two groups (group 1 = 60 min; group 2 = 62 min). The mean infusion rate of cis-atracurium was 0.19 mg kg-1 h-1 and of atracurium 0.47 mg kg-1 h-1 (expressed as mg of bis-cation): cis- atracurium was 2.5 times more potent than atracurium. Using the NONMEM program, a single compartment pharmacokinetic model was fitted to the plasma concentrations of cis-atracurium and the cis-cis, cis-trans and trans-trans isomers of atracurium. The mean population pharmacokinetic values for cis-atracurium were: volume of distribution (V) = 21,900 (SEM 416) ml; clearance (Cl) = 549 (79) ml min-1; half-life (T1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were: cis-cis, V = 15,100 (720) ml, Cl = 449 (42) ml min-1, T1/2 = 23.4 (1.2) min; cis-trans, V = 18,000 (667) ml, Cl = 1070 (43) ml min-1, T1/2 = 11.7 (0.1); trans-trans, V = 13,100 (1280) ml, Cl = 1560 (55) ml min-1, T1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations were lower in the cis-atracurium (peak value 1.3 micrograms ml-1) than in the atracurium (maximum 4.4 micrograms ml-1) group.