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 neu romuscular blocking drug to assist mechanical ventilation in an intens ive 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 2x ED(95) of the same drug (cis-atracurium 0.1 mg kg(-1) or atracur ium 0.5 mg kg(-1)). Neuromuscular block was monitored using an acceler ograph and the infusion rate adjusted regularly so that it was possibl e to detect the first response to train-of-four (TOF) stimulation of t he ulnar nerve at the wrist. Blood samples were obtained for estimatio n of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). The re was no apparent haemodynamic or allergic response to either drug. T he 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). Th e 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 an d trans-trans isomers of atracurium. The mean population pharmacokinet ic values for cis-atracurium were: volume of distribution (V) = 21 900 (SEM 416) mt; clearance (Cl) = 549 (79) mi min(-1); half-life (T-1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were : cis-cis, V = 15100 (720) ml, Cl = 449 (42) ml min(-1), T-1/2 = 23.4 (1.2) min; cis-trans, V = 18000 (667) ml, Cl = 1070 (43) ml min(-1), T -1/2 = 11.7 (0.1); trans-trans, V = 13100 (1280) ml, Cl = 1560 (55) ml min(-1), T-1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations wer e lower in the cis-atracurium (peak value 1.3 mu g ml(-1)) than in the atracurium (maximum 4.4 mu g ml(-1)) group.