Repeated doses of rocuronium bromide administered to cirrhotic and control patients receiving isoflurane. A clinical and pharmacokinetic study.
BACKGROUND
Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients.


METHODS
Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to received an initial dose of rocuronium: 120, 180, 250, or 300 micrograms.kg-1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micrograms.kg-1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects.


RESULTS
ED50 of the initial dose was 144 micrograms.kg-1 in cirrhotic patients and 60 micrograms.kg-1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5 +/- 31.7 ml.kg-1, control 29.8 +/- 17.3 ml.kg-1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0 +/- 20.7 min vs 30.2 +/- 9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264 +/- 92 vs. 151 +/- 59 ml.kg-1); trend toward a lower clearance (189 +/- 60 vs. 296 +/- 169 ml.min-1).


CONCLUSIONS
Rocuronium pharmacodynamics are moderately altered by cirrhosis, possible because of pharmacokinetic alterations. Individual variability in response to rocuronium is great, and dosage should be carefully titrated to that required.
Servin
F S
FS
Département d'Anesthésie et de Réanimation Chirurgicale, Hôpital Bichat, Paris, France.
Lavaut
E
E
Kleef
U
U
Desmonts
J M
JM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000732:Androstanols / Q000493:pharmacokinetics / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D000077123:Rocuronium
D000732:Androstanols; D018685:Anesthetics, Inhalation; D003473:Neuromuscular Nondepolarizing Agents; D007530:Isoflurane; D000077123:Rocuronium