Pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.
BACKGROUND
Delayed elimination kinetics of steroidal neuromuscular blocking agents have been observed in patients with cirrhosis. Like other steroidal muscle relaxants, rapacuronium may, in part, be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.


METHODS
Sixteen patients undergoing elective surgery or endoscopy with general anesthesia, eight with cirrhosis and eight with normal liver function, were studied. Anesthesia was induced with fentanyl 2 microg/kg and thiopental 5-7 mg/kg and maintained with 60% nitrous oxide and 0.6-0.8% isoflurane in oxygen and repeated doses of fentanyl 1 microg/kg. Rapacuronium 1.5 mg/kg was administered intravenously before tracheal intubation. Thumb adduction force evoked by supramaximal ulnar nerve stimulation was recorded in 16 patients. Venous blood was sampled at frequent intervals for 8 h. Rapacuronium and its breakdown product Org 9488 were measured in plasma by high-pressure liquid chromatography. Values are reported as median (range).


RESULTS
The central volume of distribution was increased to 131 (104-141) ml/kg in patients with cirrhosis (P < 0.01), compared with 75 (47-146) ml/kg in controls. The total apparent volume of distribution was also increased (P < 0.05) to 331 (284-488) ml/kg in patients with cirrhosis, compared with 221 (124-285) ml/kg in controls. The elimination half-life was 88 (77-102) min in controls and 90 (76-117) min in patients with cirrhosis. Plasma clearance was increased (P < 0.05) to 6.9 (6.1-8.9) ml x min(-1) x kg(-1) in patients with cirrhosis, compared with 5.3 (4.2-8.4) ml x min(-1) x kg(-1) in controls. Rapacuronium neuromuscular blocking effect was similar between the two groups. Onset time was 65 (40-110) s in controls and of 60 (52-240) s in patients with cirrhosis. Time to return to 90% of thumb adduction force control value was of 49 (28-80) min in controls and 47 (28-71) min in patients with cirrhosis.


CONCLUSIONS
The neuromuscular blocking effect of a single bolus dose of rapacuronium in patients with cirrhosis is not different from that of patients with normal hepatic function. No decrease in plasma clearance of rapacuronium was observed in patients with cirrhosis.
Duvaldestin
P
P
Department of Anesthesia and Intensive Care, Henri Mondor Hospital Hospital, Creteil, France. philippe.duvaldestin@ap-hop-paris.fr
Slavov
V
V
Rebufat
Y
Y
D000328:Adult; D000368:Aged; D000768:Anesthesia, General; D002851:Chromatography, High Pressure Liquid; D004558:Electric Stimulation; D005260:Female; D006207:Half-Life; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D003473:Neuromuscular Nondepolarizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014459:Ulnar Nerve / Q000187:drug effects; D014673:Vecuronium Bromide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D003473:Neuromuscular Nondepolarizing Agents; C117887:Org 9488; D014673:Vecuronium Bromide; C082938:rapacuronium