Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium

Objective: To study the influence of hypothermic cardiopulmonary bypass (CPB) on the pharmacodynamics and pharmacokinetics of rocuronium.Design: Prospective, descriptive study.Setting: Operating room at a university hospital.Participants: Ten ASA class III end IV patients, ranging in age from 35 to 75 years, scheduled for elective coronary artery bypass grafting.Interventions: Neuromuscular transmission was monitored mechanomyographically. The time course of action of maintenance doses and plasma concentration-response relationships were determined before, during, and after OPE. The plasma concentration decay and renal elimination were studied simultaneously. Plasma and urine concentration of rocuronium ware determined by high-performance liquid chromatography.Measurements and Main Results: Hypothermic CPB prolonged the duration of action of coincided with a lower plasma concentration at a twitch response of 5% of control. The duration of action of maintenance doses returned to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37 degrees C. The plasma concentration-response relationship did not return to precooling control value, probably owing to persisting peripheral hypothermia. Both the renal elimination of rocuronium and the plasma concentration decay after the last maintenance dose under normothermic conditions resembled values obtained in patients not undergoing hypothermic CPB.Conclusions: Hypothermic CPB prolongs the duration of action of maintenance doses and alters the plasma concentration-response relationship of rocuronium. These changes may be the result of, on the one hand, an increased sensitivity of the neuromuscular transmission and/or decreased muscle contractility and, on the other hand, the result of a reduced plasma clearance during hypothermia. (C) 1995 by W.B. Saunders Company</p

PRELIMINARY INVESTIGATIONS OF THE CLINICAL-PHARMACOLOGY OF 3 SHORT-ACTING NONDEPOLARIZING NEUROMUSCULAR BLOCKING-AGENTS, ORG 9453, ORG 9489 AND ORG 9487

Three muscle relaxants, Org 9453, Org 9489 and Org 9487, short-acting in animals, were investigated to establish their profiles in humans. Potency, time course of action, and pharmacokinetic behaviour were studied in 90 healthy patients during fentanyl/halothane/N2O anaesthesia. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations (three patients per compound) were measured by HPLC, and these data were analyzed by iterative linear least square regression analysis. The ED(90) valuesfor Org 9453, Org 9489 and Org 9487 were 1.4, 0.45 and 1.15 mg kg(-1) respectively. The onset times of Org 9453 (1.5 mg.kg(-1), 1.1 X ED(90)), Org 9489 (0.9 mg.kg(-1) 2 X ED(90)) and Org 9487 (1.5 mg.kg(-1), 1.3 X ED(90)) were 1.2, 1.6 and 1.5 min, and the durations until 25% twitch recovery were 8.6, 22.0 and 8.9 min, respectively. Clearances of these doses were 6.9, 5.8, and 11.1 ml.kg(-1).min(-1), and mean residence times 26, 79, and 41 min, respectively. Mean renal excretion (parent compound and metabolites) within 24 hr amounted to 5, 11.3 and 12.2% respectively. No side effects other than a moderate short-lasting decrease of blood pressure and a concomittant increase in heart rate were noted. It is concluded that Org 9453 and Org 9487 are short-acting muscle relaxants in humans

Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent

We have evaluated in 10 anaesthetized patients the time course of action, infusion requirements, reversibility and pharmacokinetics of Org 9487. Org 9487 was administered as a bolus dose of 1.5 mg kg(-1), followed by an infusion to maintain a block of 75-85 % for 60 min. After recovery from the bolus dose, a mean dose of Org 9487 3.4 (SD 1.0) mg kg(-1) h(-1) was administered to maintain a mean neuromuscular block of 83 (3) %. During the final 15 min of infusion, the infusion requirements were 2.5 (1.1) mg kg(-1) h(-1). In the five patients who were allowed to recover spontaneously, a TOF ratio of 0.7 was reached 37.9 (12.4) min after stopping the infusion of Org 9487. In the five patients who received neostigmine, a TOF ratio of 0.7 was reached after 14.5 (6.1) min. Plasma clearance was 8.5 (30 %) ml kg(-1) min(-1). Volume of distribution at steady state was 293 (55 %) ml kg(-1). Terminal half life and mean residence time were 71.7 (34 %) and 33.4 (31 %) min, respectively. The concentration of the 3-OH metabolite remained relatively low. Urinary excretion of Org 9487 and its metabolites was 22 % in 24 h. In conclusion, a 1-h infusion of the short-acting drug Org 9487 changed its time course characteristics gradually from that of a short acting neuromuscular blocking agent to that of a neuromuscular blocker with an intermediate duration of action

Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium

Objective: To study the influence of hypothermic cardiopulmonary bypass (CPB) on the pharmacodynamics and pharmacokinetics of rocuronium. Design: Prospective, descriptive study. Setting: Operating room at a university hospital. Participants: Ten ASA class III end IV patients, ranging in age from 35 to 75 years, scheduled for elective coronary artery bypass grafting. Interventions: Neuromuscular transmission was monitored mechanomyographically. The time course of action of maintenance doses and plasma concentration-response relationships were determined before, during, and after OPE. The plasma concentration decay and renal elimination were studied simultaneously. Plasma and urine concentration of rocuronium ware determined by high-performance liquid chromatography. Measurements and Main Results: Hypothermic CPB prolonged the duration of action of coincided with a lower plasma concentration at a twitch response of 5% of control. The duration of action of maintenance doses returned to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37 degrees C. The plasma concentration-response relationship did not return to precooling control value, probably owing to persisting peripheral hypothermia. Both the renal elimination of rocuronium and the plasma concentration decay after the last maintenance dose under normothermic conditions resembled values obtained in patients not undergoing hypothermic CPB. Conclusions: Hypothermic CPB prolongs the duration of action of maintenance doses and alters the plasma concentration-response relationship of rocuronium. These changes may be the result of, on the one hand, an increased sensitivity of the neuromuscular transmission and/or decreased muscle contractility and, on the other hand, the result of a reduced plasma clearance during hypothermia. (C) 1995 by W.B. Saunders Compan

CLINICAL-PHARMACOLOGY OF ROCURONIUM (ORG-9426) - STUDY OF THE TIME-COURSE OF ACTION, DOSE REQUIREMENT, REVERSIBILITY, AND PHARMACOKINETICS

Study Objective: To evaluate the time course of action, dose requirement, reversibility, and pharmacokinetics of rocuronium (Org 9426) under 3 anesthetic techniques (nitrous oxide-fentanyl supplemented with propofol halothane, or isoflurane). Design: Prospective, randomized study. Setting: Operating suite at a university hospital. Patients: 36 ASA physical status I-III patients aged 18 to 65 years who were scheduled for elective surgery. Interventions: The time course of action of an intubation, close of rocuronium 600 mu g/kg was investigated in 36 patients. In 18 of these patients, the maintenance dose requirement of rocuronium and reversibility by neostigmine were evaluated. In the remaining 18 patients, the pharmacokinetics of rocuronium rocuronium after the intubating dose were studied. Neuromuscular transmission was monitored by mechanomyography. Venous blood samples and urine were analyzed by high-performance liquid chromatography. Measurements and Main Results: With the exception of a longer clinical duration of rocuronium-induced neuromuscular block in the isoflurane group compared with the propofol group (p = 0.03), time course of action variables were similar in the 3 groups. In patients receiving maintenance doses of rocuronium, the dose requirement until reversal was 636 +/- 191 mu/g/kg/hr, 496 +/- 107 mu g/kg/hr, and 384 +/- 127 mu g/kg/hr for the propofol halothane, and isoflurane groups, respectively (p = 0.02 for the isoflurane group vs. the propofol group). With respect to the reversal of a rocuronium-induced neuromuscular block, there were no differences in the percentage recovery or rate of recovery among the 3 groups. Pharmacokinetic analysis showed no significant differences for rocuronium during the 3 anesthetic techniques. Conclusion: Isoflurane potentiates the rocuronium-induced neuromuscular block resulting in a longer clinical duration and lower maintenance dose requirement. This difference is not explained by differences in pharmacokinetics but is probably due to increased sensitivity of the neuromuscular junction to rocuronium during isoflurane anesthesia