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

Abstract

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.

The Use of Neuromuscular Blocking Agents in the ICU

“…Cisatracurium ICU infusion studies (> 24-hr duration) suggest that there is marginal accumulation of the drug. Several studies suggest that the duration of action of cisatracurium is not affected by organ dysfunction (23). Laudanosine, a metabolite of atracurium, has central nervous system stimulating effects.…”

“…Laudanosine, a metabolite of atracurium, has central nervous system stimulating effects. Laudanosine levels have been reported to increase when using long-term atracurium infusions but are typically not high enough to promote seizure activity in humans (13,19,23).…”

Clinical assessment and train-of-four measurements in critically ill patients treated with recommended doses of cisatracurium or atracurium for neuromuscular blockade: a prospective descriptive study

“…This has already been attributed to an up-regulation of acetylcholine receptors, although some authors did not find the same results [13, 22]. The pharmacokinetics of NMBAs in critically ill patients can be affected by many conditions, such as sepsis and/or shock [12]. In addition, it has been shown that ICU patients are less sensitive to neuromuscular blockade than patients in the operating room [14].…”

“…The benefits and limitations of TOF stimulation were primarily determined from studies performed in operative room patients [10, 11], with results that may not be generalizable to ICU patients. In critically ill patients, the duration of neuromuscular blockade is longer, sepsis and/or shock is often present, and pharmacokinetic is difficult to predict [12–14]. Lastly, agreement between subjective and objective means of assessing the degree of neuromuscular blockade has been little studied in ICU [15–17].…”

Pharmacodynamics of cisatracurium in the intensive care unit: an observational study

“…Increasing doses of cisatracurium can shorten the time to obtain a TOF = 0 [12-14]. ICU studies regarding the pharmacokinetics and pharmacodynamics of cisatracurium focused on patients receiving continuous infusions of cisatracurium [1] and mostly described the recovery profiles after continuous administration [21,22]. The doses used in those publications were a bolus of 0.1 mg.kg -1 (2 × ED95) with an average rate of infusion of 2.6 mg.kg -1 .min -1 (0.15 mg.kg -1 .h -1 ) or 3.2 mg.kg -1 .min -1 (0.19 mg.kg -1 .h -1 ) as required to obtain a sufficient degree of neuromuscular blockade for mechanical ventilation [21,22].…”