The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis.

Abstract

To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg(-1) was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T1:T0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T1:T0, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T1:T0, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T4:T1 to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg(-1) min (-1); P<0.005). The central (V1) and steady state volumes of distribution (V(ss)) did not differ significantly between the groups. The slow redistribution (t1/2,lambda1) and elimination (t1/2,z) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P < 0.005; and 143 (80) vs 92 (40) min, P < 0.05 respectively). The exit rate constant for the effect compartment k(eo) was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min(-1); P < 0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp(ss)(50) and gamma. Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.