Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia.

We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous oxide in oxygen. Neuromuscular block was monitored using train-of-four (TOF) stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered as an initial bolus dose of 0.45 mg kg-1 followed by an infusion adjusted manually to maintain T1 (first response in the TOF) at 10% of control. Mean onset time and time to recovery of T1 to 10% were 72 (SD 19.6) s and 27 (9.6) min, respectively. The infusion rates were stable in 19.8 (6.5) min. The mean requirement for rocuronium for steady state 90% block of T1 was 528 (163.3) micrograms kg-1 h-1. After cessation of surgery the infusion was stopped and patients were allowed to recover spontaneously. The times to attain a T1 of 90% and a TOF ratio of 0.7 were 31 (11.7) min and 36 (7.3) min, respectively. Blood samples were collected for 390 min after cessation of infusion and concentrations of rocuronium and its putative metabolites measured using HPLC. A two-exponential equation was used to describe the pharmacokinetic data. The rate of clearance, mean residence time and volume of distribution at steady state were 3.3 (0.77) ml kg-1 min-1, 67.2 (18.8) min and 212.5 (40.1) ml kg-1, respectively. The distribution (T1/2 alpha) and elimination (T1/2 beta) half-lives were 7.5 (3.33) min and 85.6 (18.4) min, respectively. These values were not significantly different from previously published data for a single bolus dose of rocuronium.

Pharmacokinetics of rocuronium bromide in patients with and without renal failure.

We studied the onset and duration of action and pharmacokinetics of rocuronium bromide during anaesthesia with nitrous oxide, fentanyl and isoflurane after a single bolus dose of rocuronium (0.6 mg kg-1) in nine patients with chronic renal failure requiring regular haemodialysis, and in nine healthy control patients. Blood samples were collected over 390 min and concentrations of rocuronium and its putative metabolites measured using HPLC. Onset time for maximum block and duration of clinical relaxation (DUR25) were 61 (SD 25.0) s and 65 (16.4) s, 55 (26.9) min and 42 (9.3) min, respectively, for patients with and without renal failure. The time for train-of-four ratio to return spontaneously to 0.7 was 99 (41.1) min and 73 (24.2) min, respectively, in the two groups. None of these differences was significant. The pharmacokinetic data were best described by a three-exponential equation. There were significant differences between patients with and without renal failure in the rates of clearance (2.5 (1.1) mL kg-1 min-1 and 3.7 (1.4) mL kg-1 min-1, respectively) and the mean residence times (97.1 (48.7) min and 58.3 (9.6) min) (P < 0.05). The differences in other kinetic parameters were not significant.

Dose-responses for edrophonium during antagonism of vecuronium block in young and older adult patients.

The dose-response relationship for edrophonium during antagonism of vecuronium-induced neuromuscular blockade was studied in two groups of adult patients of mean (SD) age 35 (10.0) years (n = 42) and 77 (5.4) years (n = 42) respectively. Neuromuscular block was monitored by recording the force of contraction of the adductor pollicis muscle following train-of-four stimulation. Six patients in each age group received 0.1, 0.3, 0.5, 0.7, 1.0, or 1.5 mg.kg-1 of edrophonium, or normal saline at 10% recovery of T1 (first response in the train-of-four) after a single dose of vecuronium 0.08 mg.kg-1. The train-of-four ratios were recorded continuously over the next 10 min and the values at 1 min intervals from 5 min onwards were used to construct the dose-response curves. The dose-response curves showed no significant difference between the two age groups except at 10 min. The estimated dose of edrophonium required for attaining a train-of-four ratio of 0.7 at 10 min was 0.9 and 1.3 mg.kg-1 in the younger and older groups, respectively (p < 0.05).

Neuromuscular and haemodynamic effects of mivacurium in elderly and young adult patients.

We have studied the neuromuscular effects of mivacurium and changes in heart rate and arterial pressure in 40 elderly (aged 70 yr) and 20 young adult (aged 18-40 yr) patients anaesthetized with thiopentone, fentanyl, nitrous oxide in oxygen and halothane. Neuromuscular block was monitored by train-of-four (TOF) stimulation of the ulnar nerve and recording of the force of contraction of the adductor pollicis muscle using a force displacement transducer and a neuromuscular function analyser (Myograph 2000, Biometer Ltd). Twenty elderly and 10 young adults received single doses of mivacurium 0.15 mg kg-1 and spontaneous recovery was recorded. The other 20 elderly and 10 adults received the same dose but an infusion was started at T1 (first response in TOF) of 10% and the block maintained at this level. Haemodynamic effects were studied after administration of mivacurium over 15 or 5 s in elderly (n = 10 each) and over 5 s in adult (n = 10) patients. Onset of maximum block occurred at a mean time of 122 (SD 32) and 125 (49) s in elderly and young adults, respectively. Recovery of T1 to 25% occurred in 22.0 (5.7) and 17.2 (4.4) min, and T1 to 90% in 32.8 (6.9) and 24.4 (5.8) min in elderly and adult subjects, respectively. Recovery of the TOF ratio to 0.7 occurred in 32.8 (7.1) and 26.0 (15.0) min in the elderly and young subjects, respectively (all P < 0.05 between young and elderly).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of rocuronium (Org 9426) by continuous infusion and its reversibility with anticholinesterases.

The use of rocuronium (Org 9426) as a single bolus followed by an infusion was assessed in 50 patients under anaesthesia with nitrous oxide-oxygen and halothane. Neuromuscular block was monitored using train-of-four stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered in an initial bolus dose of 0.45 mg.kg-1 followed by an infusion adjusted manually to maintain the T1, the first response in the train-of-four, at 10% of control. Following cessation of rocuronium infusion the patients were either allowed to recover spontaneously (n = 10) or were given neostigmine 50 micrograms.kg-1 or edrophonium 1 mg.kg-1 at 10 or 25% recovery of the T1 (n = 10 for each group). Adequate antagonism was defined as attaining a sustained train-of-four ratio of 0.7. Rocuronium requirements showed marked variation among individual patients but were relatively constant in individual patients. The mean (SD) time to attain stable infusion rates was 17.4 (10.9) min. The mean (SD) requirement of rocuronium for steady state 90% block of T1 was 572 (190) micrograms.kg-1.h-1 (range 242-1104 micrograms.kg-1.h-1). The mean (SD) time to attain a train-of-four ratio of 0.7 in the group allowed to recover spontaneously was 36.1 (7.3) min. This interval was 7.5 (1.9), 9.3 (7.0), 4.6 (1.9) and 1.9 (0.9) min respectively in the groups receiving neostigmine at T1 of 10%, edrophonium at T1 of 10%, neostigmine at T1 of 25% and edrophonium at T1 of 25%. The antagonism was significantly faster in those reversed at 25% (p < 0.05). Three patients in the group receiving edrophonium at T1 of 10% and one in the group receiving neostigmine at T1 of 25% failed to attain a train-of-four ratio of 0.7. It is concluded that rocuronium can be administered as a continuous infusion for stable neuromuscular block. Neostigmine may be a more reliable antagonist of deep block, whereas edrophonium is advantageous when there is a greater spontaneous recovery.

Recovery of mivacurium block with or without anticholinesterases following administration by continuous infusion.

Thirty patients received a bolus dose of 0.2 mg.kg-1 of mivacurium followed by an infusion during anaesthesia with thiopentone, fentanyl and halothane. Neuromuscular block was monitored using train-of-four stimulation and mechanomyography and the block maintained to keep the first response in the train-of-four (T1) at 10% of control. At the end of surgery the patients were randomly allocated to reversal with neostigmine or edrophonium or to spontaneous recovery. The mean dosage of mivacurium for maintaining the T1 at 10% was 5.7 micrograms.kg-1.min-1. There was a significant (r = -0.81, p < 0.001) negative correlation between time to recovery of T1 to 10% after the bolus dose and infusion rate. The times taken for T1 to reach 25, 75 and 90% of control and for the train-of-four ratio to reach 0.7 were significantly shorter (p < 0.05 to 0.001) with neostigmine and edrophonium compared to the spontaneously recovering group. The average (SD) times for attaining the train-of-four ratio of 0.7 were 7.0 (1.2), 6.8 (1.4) and 13.5 (2.3) min respectively for neostigmine, edrophonium and spontaneously recovering groups. There were no differences between endrophonium and neostigmine in any of the recovery times.

Comparison of the effectiveness of bilateral ilioinguinal nerve block and wound infiltration for postoperative analgesia after caesarean section.

We have studied the effects of bilateral ilioinguinal nerve block and wound infiltration with 0.5% bupivacaine on postoperative pain and analgesic requirements in 62 patients undergoing Caesarean section under general anaesthesia. A control group received no local anaesthetic supplementation. Both ilioinguinal block and wound infiltration reduced significantly the pain scores and analgesic requirements in the immediate postoperative period (P < 0.05). The differences in pain scores and analgesic requirements between the study groups were not statistically significant (P > 0.05).

Onset and duration of action and hemodynamic effects of rocuronium bromide under balanced and volatile anesthesia.

The onset and duration of action, and hemodynamic effects of rocuronium bromide 0.6 or 0.9 mg kg-1 were studied in 4 groups of 10 patients each during anesthesia with nitrous oxide in oxygen and fentanyl or halothane. Neuromuscular block was monitored using mechanomyography and train-of-four (TOF) stimulation. The mean time to onset of complete neuromuscular block was 55 s with the 0.6 mg kg-1 dose during both anesthetic techniques. The times to recovery of T1 (first response in the TOF stimulation) to 25 and 90% of control and to the recovery of the TOF ratio to 0.7 were 36, 45 and 54 min respectively during narcotic anesthesia, and 35, 54 and 58 min during halothane anesthesia. Complete block with the 0.9 mg kg-1 dose occurred in 50, and 52 s respectively in the fentanyl and halothane groups. The recovery of T1 to 25% occurred in 49 and 52 min, to 90% in 66 and 71 min and to TOF ratio of 0.7 in 72 and 79 min respectively during balanced and halothane anesthesia. There were no significant changes in heart rate or mean arterial pressure during the 5 min following administration of either dose of rocuronium during balanced or halothane anesthesia. A separate group of 10 patients received 0.9 mg kg-1 of rocuronium during anesthesia with nitrous oxide, oxygen and isoflurane. Complete block occurred in an average time of 45 s in these patients with 25% recovery of T1 in 53 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular effects and intubating conditions following mivacurium: a comparison with suxamethonium.

Mivacurium chloride has been assessed in respect of intubating conditions and neuromuscular effects. The influence of suxamethonium on the onset and duration of subsequently administered mivacurium was also studied. A dose of 0.15 mg.kg-1 of mivacurium was found to provide unacceptable intubating conditions at 2 min in 9/9 patients and further studies were conducted using 0.2 mg.kg-1. Intubating conditions with this dose were acceptable in 65% and 80% of patients at 2 min and 2.5 min respectively. In comparison, intubating conditions were acceptable in 100% of patients at 1 min following 1 mg.kg-1 of suxamethonium. The onset of block occurred in 96 s and 97 s after 0.15 mg.kg-1 and 0.2 mg.kg-1 respectively, and the durations of block in terms of recovery of the first twitch (T1) to 25% and 90% of control, and to recovery of train-of-four ratio to 0.7, were 16.1 and 17.9; 24.1 and 25.8; and 24.2 and 27.0 min respectively with the two doses. The time for the onset of complete block with suxamethonium 1.0 mg.kg-1 was 50 s and the times to 25% and 90% recovery were 9.8 min and 13.3 min. The differences between suxamethonium and both doses of mivacurium were significant (p < 0.05) but there were no significant differences between the two doses of mivacurium in any of the neuromuscular measurements. Prior administration of suxamethonium had no influence on the effects of mivacurium. Cutaneous flushing was observed in 30 out of 75 patients but this was associated with transient hypotension in only two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical study of interaction between rocuronium and some commonly used antimicrobial agents.

The onset and duration of clinical relaxation and reversibility of rocuronium bromide (ORG 9426) 0.6 mg kg-1 were studied following administration of netilmicin 2 mg kg-1 (n = 10) or cefuroxime 20 mg kg-1 (n = 10) in patients undergoing urological surgery; and cefuroxime 20 mg kg-1 (n = 10) metronidazole 7.5 mg kg-1 (n = 10), metronidazole 7.5 mg kg-1 and cefuroxime 20 mg kg-1 (n = 10), or placebo (n = 10) in patients undergoing abdominal surgery under anaesthesia with thiopentone, nitrous oxide in oxygen, fentanyl and halothane. The antimicrobial agents were administered intravenously 5 min before rocuronium. Neuromuscular function was monitored using mechanomyography and train-of-four (TOF) mode of stimulation. Onset of neuromuscular block occurred in approximately 60 s with all patients achieving complete block. The mean clinical duration (+/- SD) was 50 +/- 10.7 and 44 +/- 6.7 min following netilmicin and cefuroxime respectively in patients undergoing urological surgery; and 49 +/- 13.7, 44 +/- 11.1, 48 +/- 11.1 and 38 +/- 7.3 min in the groups undergoing abdominal surgery receiving cefuroxime, metronidazole, cefuroxime and metronidazole combination and placebo respectively. There were no statistically significant differences between the groups in either the onset or the duration of clinical relaxation. Reversal of neuromuscular block with neostigmine carried out at spontaneous recovery of T1 (first response in the TOF) of 25% or more was easily achieved in all groups in 2-4 min. It is concluded that there is no significant interaction between rocuronium and single doses of the antimicrobial agents used in the present study.

Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (Org 9426) during isoflurane anaesthesia in patients with and without renal failure.

We have studied the onset and duration of action and pharmacokinetics of rocuronium bromide (Org 9426) during anaesthesia with nitrous oxide, fentanyl and isoflurane after a single bolus dose of rocuronium 0.6 mg kg-1 in nine patients with chronic renal failure requiring regular haemodialysis, and in nine healthy control patients. Blood samples were collected over 390 min and concentrations of rocuronium and its putative metabolites measured using HPLC. Onset time for maximum block, duration of clinical relaxation (T1(25)) and recovery index, were 61 (SD 25.0) s and 65 (16.4) s, 55 (26.9) min and 42 (9.3) min and 28 (12.3) min and 19 (8.8) min, respectively, for patients with and without renal failure. The time for TOF ratio to return spontaneously to 0.7 was 99 (41.1) min and 73 (24.2) min, respectively, in the two groups. None of these differences was significant. The pharmacokinetic data were best described by a three-exponential equation. There were significant differences between patients with and without renal failure in the rates of clearance (2.5 (1.1) ml kg-1 min-1 and 3.7 (1.4) ml kg-1 min-1, respectively) and the mean residence times (97.1 (48.7) min and 58.3 (9.6) min) P < 0.05). The differences in other kinetic parameters were not significant. We conclude that the effects of rocuronium may be prolonged in patients with renal disease, because of a decreased clearance of the drug.

Haemodynamic effects of rocuronium during fentanyl anaesthesia: comparison with vecuronium.

Haemodynamic variables were measured following administration of rocuronium 0.6 mg.kg-1 or vecuronium 0.08 mg.kg-1 (approximately equivalent to 2 x ED95 doses) in patients anaesthetized with fentanyl 50 micrograms.kg-1 and scheduled to undergo elective coronary artery bypass grafting. There were increases in stroke volume index (+15%) and cardiac index (+11%), and a decrease in pulmonary capillary wedge pressure (-25%) following administration of rocuronium (P < 0.05). The changes in heart rate (+7%), mean arterial pressure (-5%), systemic vascular resistance (-12%) and other measured or derived indices were insignificant. In comparison the administration of vecuronium was associated with decreases in heart rate (-7%), mean pulmonary artery pressure (-17%), central venous pressure (-15%) and the rate-pressure product (-9%) (P < 0.05). The changes in mean arterial pressure (-7%), cardiac index (-6%) and systemic vascular resistance (-8%) following vecuronium were insignificant. There were no differences in any of the variables between rocuronium and vecuronium. The absolute values of all variables were, however, within acceptable clinical limits. There was no evidence of histamine release in any patient. The present study shows that rocuronium 0.6 mg.kg-1 is associated with changes of only small magnitude in haemodynamic variables.

Myalgia and biochemical changes following suxamethonium after induction of anaesthesia with thiopentone or propofol.

The incidence and severity of muscle pains and changes in creatine kinase were assessed following administration of 1 mg.kg-1 suxamethonium either immediately or 2 min after induction of anaesthesia with propofol or thiopentone in patients undergoing elective dental and ophthalmic surgery. The incidence of muscle pains was 35 and 60% respectively in the groups given suxamethonium immediately and 2 min after propofol, and 35 and 55% when given immediately and 2 min after thiopentone, with no statistically significant differences among the groups. Creatine kinase levels increased in all the groups after operation with the least average increase in the group receiving suxamethonium immediately after propofol and the highest increase in the group receiving suxamethonium 2 min after thiopentone. There was no correlation between the incidence and severity of fasciculations, muscle pains and changes in creatine kinase within or between the groups. It is concluded that neither the induction agent nor the time between the induction agent and suxamethonium administration has any significant influence on the incidence of muscle pains or creatine kinase elevation following suxamethonium.

Potency estimation of mivacurium: comparison of two different modes of nerve stimulation.

We have assessed the potency of mivacurium, a new non-depolarizing neuromuscular blocker, using two different modes of nerve stimulation in patients anaesthetized with thiopentone, fentanyl and nitrous oxide in oxygen. The force of contraction of adductor pollicis was measured after single twitch stimulation at 0.1 Hz or train-of-four stimulation (TOF) at 2 Hz every 10 s. Dose-response curves were constructed using a single-dose method for each mode of stimulation. The ED50 and ED95 were 43 micrograms kg-1 and 83 micrograms kg-1, respectively, for the single twitch responses and 34 micrograms kg-1 and 66 micrograms kg-1, respectively, for the first response of the TOF stimulation. The difference between the ED95 doses was not significant (P = 0.051), but the difference between the ED50 doses was significant (P = 0.03), suggesting greater sensitivity of the neuromuscular junction using TOF stimulation. The results show that the information obtained using single twitch stimulation at 0.1 Hz is not the same as that obtained from the first response of the TOF stimulation.

Neuromuscular effects of rocuronium bromide (Org 9426) during fentanyl and halothane anaesthesia.

The neuromuscular effects of intravenous rocuronium bromide, 0.6 mg.kg-1 or 0.9 mg.kg-1, were studied in four groups of 10 patients during anaesthesia with or without halothane (0.5-0.75% inspired concentration). Neuromuscular block was monitored using mechanomyography and train-of-four stimulation. The mean times to onset of complete neuromuscular block were 58 and 59 s using the 0.6 mg.kg-1 dose in patients anaesthetised with fentanyl and halothane respectively. The times of 34 min and 33 min for 25% recovery of T1 (first response in the train of four), 54 min and 52 min for 90% recovery of T1, 55 min and 60 min for a train of four ratio of 0.7, and 13 and 13 min respectively for the recovery index (25-75% recovery of T1) were not significantly different in these groups. Complete block with the 0.9 mg.kg-1 dose occurred in 47 s and 44 s respectively in the fentanyl and halothane groups. T1 recovered to 25% in 51 min and 58 min, and to 90% in 77 min and 86 min respectively in the two groups. The recovery indices and the times to spontaneous recovery of the train of four ratio to 0.7 were 17 min and 19 min, and 83 min and 93 min respectively. All the parameters were significantly different between the 0.6 mg.kg-1 and 0.9 mg.kg-1 doses. Halothane in the concentrations used did not influence the neuromuscular effects. It is concluded that rocuronium is a rapidly acting non-depolarising muscle relaxant with a duration of action similar to that of vecuronium and may be a useful alternative to suxamethonium for rapid tracheal intubation.

Clinical evaluation of doxacurium chloride.

Doxacurium was administered to 50 adult patients for determination of potency (n = 10), onset and duration of clinical relaxation (n = 40). Cumulative dose-response showed the ED95 to be 33.24 micrograms.kg-1 (95% confidence limits 27.4-39.3). Doxacurium 33 micrograms.kg-1 was then administered to four groups of 10 patients each who had anaesthesia maintained with either fentanyl-droperidol or halothane and nerve stimulation carried out with single-twitch stimulation at 0.1 Hz or train-of-four stimulation at 2 Hz every 12 s. The onset and duration showed wide individual variation. The mean (SD) times to occurrence of maximal block were 8.5 (4.6), 6.1 (1.9), 6.7 (1.8) and 4.7 (1.3) min in the single twitch-fentanyl, train-of-four--fentanyl, single twitch-halothane and train-of-four--halothane groups respectively, although it ranged from 3.4 to 13.1 min in individual patients. The mean (SD) durations of clinical relaxation (recovery of single twitch or first response in train-of-four to 25%) were 65 (22.8), 52 (21.7), 70 (33.4) and 72 (21.0) min respectively with individual values ranging from 31 to 103 min. Although halothane administration increased the duration of clinical relaxation and train-of-four stimulation accelerated the onset of effect, the changes due to these were not significant. There were no adverse effects on heart rate or indirectly measured arterial pressure.

Effect of doxapram on the rate of recovery from atracurium and vecuronium neuromuscular block.

We have studied the effect of doxapram on the rates of spontaneous and neostigmine-induced recovery from neuromuscular block with atracurium and vecuronium, by measurement of the time to recovery of T1 (first twitch in the train-of-four) from 25 to 75% of control (recovery index, RI). After each neuromuscular blocking drug, RI was measured without administering either doxapram or neostigmine (control group), or after administration of doxapram 1 mg kg-1, neostigmine 50 micrograms kg-1 or a combination of doxapram and neostigmine, in groups of 10 patients. RI was significantly longer after vecuronium in the presence of doxapram compared with control (20.1 min vs 14.6 min). There was no significant difference in the RI after atracurium in the presence of doxapram compared with control (12.5 min vs 11.8 min) or when neostigmine was administered with or without doxapram (2.4 min vs 2.4 min, respectively after vecuronium; 3.3 min vs 2.9 min, respectively, after atracurium).