Geographic Regional Differences in Rocuronium Bromide Dose-Response Relation and Time Course of Action: An Overlooked Factor in Determining Recommended Dosage

Background: Geographic location is not acknowledged as a stratifying factor that can directly affect drug potency, because drugs are still licensed with the same recommended dose for different geographic regions. The aim of the current study was to compare the potency and duration of action of rocuronium bromide in 54 patients in three countries with different life habits, diet, and ambient conditions, namely white Austrians, white North Americans, and Han Chinese in China.

Methods: Neuromuscular block of six consecutive 50-[mu]g/kg rocuronium incremental doses followed by 300 [mu]g/kg was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, Holland). Dose-response curves were created using log-dose-probit transformation. The authors compared rocuronium bromide ED50, ED90, and ED95 (effective doses required for 50%, 90%, and 95% first twitch depression, respectively) as well as Dur25 and Dur0.8 (times from last incremental dose administration until 25% first twitch and 0.8 train-of-four ratio recovery, respectively) in patients of the three countries.

Results: Rocuronium ED50, ED90, and ED95 were significantly higher in Austrian patients (258 +/- 68, 530 +/- 159, and 598 +/- 189 [mu]g/kg) and Chinese patients (201 +/- 59, 413 +/- 107, and 475 +/- 155 [mu]g/kg) compared with American patients (148 +/- 48, 316 +/- 116, and 362 +/- 149 [mu]g/kg, respectively). Dur25 and Dur0.8 were significantly shorter in Austrian patients (22.3 +/- 5.5 and 36.9 +/- 12.8 min) and Chinese patients (30.4 +/- 7.5 and 45.7 +/- 15.9 min) compared with American patients (36.7 +/- 8.5 and 56.2 +/- 16.7 min, respectively).     

Dose-Response of Rocuronium Bromide in Children Anesthetized with Propofol: A Comparison with Succinylcholine

Background: The aim of this study was to determine the potency of rocuronium during propofol/fentanyl/N2 O anesthesia in children and to compare the time course of action of rocuronium at doses of two and three times the ED95 with that of succinylcholine.

Methods: Rocuronium (120, 160, 200, or 240 micro gram/kg) was administered to 48 children aged 2-10 yr. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor digiti minimi to supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s every 10 s. Potency was determined by log-probit transformation and least-squares linear regression analysis of dose and response. In a second group of 30 children, the onset and recovery profile of rocuronium at doses of two and three times the ED95 was compared with that of succinylcholine (2 mg/kg).

Results: Values for ED50 and ED95 were 210 +/- 24 and 404 +/- 135 micro gram/kg, respectively. The time to 90% neuromuscular block after 1.2 mg/kg rocuronium (three times the ED95), 33 +/- 5 s (mean +/- SD), did not differ significantly from that after succinylcholine, at 30 +/- 7 s; however, both were significantly less than that after 0.8 mg/kg rocuronium, 46 +/- 8 s (P < 0.05). The time to 25% recovery from 1.2 micro gram/kg rocuronium, 41 +/- 13 min, was approximately 50% greater than that after 0.8 mg/kg, at 27 +/- 6 min (P < 0.001), and eight times greater than that after succinylcholine, at 5.2 +/- 1.9 min (P < 0.001).     

The prolonged duration of rocuronium in Chinese patients

We compared the potency and duration of action of rocuronium in Chinese and Caucasian patients during general anesthesia. Thirty-six women (18 Caucasian and 18 Chinese) and 36 children (18 Caucasian and 18 Chinese) were evaluated during the administration of propofol/fentanyl anesthesia. Patients in each age group were randomized into three subgroups to receive single doses of 0.06, 0. 12, or 0.18 mg/kg rocuronium (adults) or 0.12, 0.18, or 0.24 mg/kg rocuronium (children). Neuromuscular blockade was assessed by electromyography of the adductor pollicis after train-of-four (TOF) stimulation of the ulnar nerve. Dose response curves were constructed when maximum neuromuscular depression of the first twitch of the train (T(1)) was obtained. A second bolus dose of rocuronium was then administered to a total dose of 0.6 mg/kg. The times of spontaneous recovery to T(1) 10%, 25%, and 90% of control and to TOF 0.25, 0.50, and 0.70 were recorded. For both adults and children, recovery occurred later in Chinese than in Caucasian patients (P<0.05 for T(1) of 10%, 25%, 75%, and 90% and TOF to 0.7). The 50% effective dose was smaller in Chinese adults (125+/-63 vs. 159+/-66 microg/kg) and Chinese children (171+/-43 vs. 191+/-46 microg/kg) than in Caucasian adults and children, but the difference was not statistically significant. In adults, time to 25% T(1) recovery was 43+/-13 min in Chinese patients and 33+/-10 min in Caucasian patients (P<0.05). The corresponding values were more rapid for children: 30+/-10 and 24+/-6 min (P<0.05). We conclude that the recovery from rocuronium neuromuscular blockade was longer in Chinese compared with Caucasian patients and in adults compared with children.     

Dose-response relationship of rocuronium: a comparison of electromyographic vs. acceleromyographic-derived values

BACKGROUND: Acceleromyography (AMG) is being employed with increasing frequency as a research tool. However, there is almost no information available regarding the accuracy of values for drug potency obtained using AMG. This study was an attempt to determine if AMG-derived ED(50/95) values are interchangeable with those measured with a more traditional neuromuscular monitor. METHODS: Thirty adult patients were studied. Anesthesia was induced and maintained with N20, propofol, and supplementation opioid. Tracheal intubation was accomplished without muscle relaxants. Simultaneous ipsilateral AMG and EMG responses to 0.10 Hz stimulation was recorded. Following instrument calibrations, a single dose of rocuronium was administered. The first patient received a bolus of 0.17 mg kg(-1) of rocuronium. Using the Hill equation with a postulated slope of 4.50, the ED(50) was calculated. The second subject received a dose which approximated the calculated ED(50) for patient no. 1. Successive subjects were given a dose based on the running average of the estimated ED(50). RESULTS: The AMG-derived ED50/95 values for rocuronium (0.163 +/- 0.055 and 0.314 +/- 0.105 mg mg(-1)) were virtually identical to those established using EMG (0.159 +/- 0.043 and 0.306 +/- 0.084 mg kg(-1)). While mean peak twitch depression (Delta T1) was the same in both groups for individual subjects Delta T1 differed by +/- 20% (95% confidence interval). DISCUSSION: Acceleromyography-derived twitch heights for individual patients are not necessarily interchangeable with information obtained using electromyography. Nevertheless, acceleromyography appears to be a valid methodology for determining the drug potency when a population rather than an individual subject is being studied.     

Equi-lasting doses of rocuronium, compared to mivacurium, result in improved neuromuscular blockade in patients undergoing gynecological laparoscopy

PURPOSE: To compare equi-lasting doses of a short-acting (mivacurium) to an intermediate-acting (rocuronium) neuromuscular relaxant, with regard to intubating conditions, efficacy, number of maintenance doses, hemodynamic alterations, adverse events and costs, in patients undergoing laparoscopic gynecological surgery. METHODS: Sixty patients were randomly allocated to receive either 0.2 mg*kg(-1) (3 x ED(95)) mivacurium or 0.5 mg*kg(-1) (1.7 x ED(95)) rocuronium, under propofol/fentanyl anesthesia. T1, first twitch of the train-of-four (TOF) and TOF ratio (T4:T1) were used to evaluate neuromuscular block using the Relaxometer(R) mechanomyograph. The trachea was intubated when T1 was maximally suppressed. Neuromuscular block was maintained at 25% T1 with equi-lasting doses of 0.075 mg*kg(-1) mivacurium or 0.15 mg*kg(-1) rocuronium. RESULTS: Mean (min) +/- SD mivacurium onset time (1.9 +/- 0.4) was longer than that of rocuronium (1.3 +/- 0.3). This did not yield a statistical difference in intubating conditions between the two groups. Interval 25-75% T1 recovery and time to 0.8 TOF recovery were prolonged following rocuronium (11.9 +/- 3.9, 52.6 +/- 15.5 respectively) compared to mivacurium (6.7 +/- 2.3, 39.2 +/- 8.1 respectively). More patients, 22/30, required mivacurium maintenance doses compared to 14/30 patients in the rocuronium group. Arterial blood pressure declined and 13/30 patients manifested erythema following mivacurium administration. The acquisition costs of rocuronium (6.93 Euro/patient) were 23% lower compared to mivacurium (8.96 Euro/patient). CONCLUSION: Equi-lasting doses of rocuronium resulted in favourable intubating conditions more rapidly, improved hemodynamic stability, required less frequent administration of maintenance doses and were not associated with erythema, compared to mivacurium.     

Effect of volatile anesthetics on vecuronium-induced neuromuscular blockade in children

We studied 60 children undergoing elective surgery to evaluate the effect of interactions between vecuronium and isoflurane or halothane on the potency and duration of neuromuscular blockade, as measured by electromyography. Vecuronium was first administered by a logarithm-based cumulative method (14, 22, 35, 56, 89 micrograms/kg) in 10 children anesthetized with thiopental (5 mg/kg), alfentanil (15 micrograms/kg first dose, then 10 micrograms/kg), and N2O/O2 (60:40) until a 95% +/- 2% twitch depression (ED95) was obtained. Thirty children given the same balanced anesthesia were then randomly assigned to three groups (n = 10 in each) to receive a single ED20 (21 micrograms/kg), ED50 (33 micrograms/kg), or ED80 (47 micrograms/kg) intravenous bolus of vecuronium calculated from the mean regression line of twitch responses of the first 10 children. In the second part of the study, 20 children were anesthetized with isoflurane (1.2%) or halothane (0.7%) and compared with the previous 10 children anesthetized with alfentanil-N2O. Potency of vecuronium determined by single-bolus or logarithm-based cumulative techniques was not significantly different. Isoflurane and halothane significantly decreased ED50 (22.3 +/- 1.6 and 25.4 +/- 1.4 micrograms/kg, respectively; mean +/- SE) and ED95 (41.5 +/- 3.3 and 46.7 +/- 3.2 micrograms/kg, respectively) compared with alfentanil-N2O (ED50: 32.8 +/- 0.8 micrograms/kg, ED95: 70.5 +/- 2.6 micrograms/kg). Recovery rate from vecuronium-induced neuromuscular blockade was significantly longer with isoflurane than with alfentanil-N2O or halothane. We conclude that in children single-bolus and logarithm-based cumulative techniques give similar potency estimates for vecuronium. Isoflurane and halothane increase by similar amounts the neuromuscular potency of vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Total intravenous anesthesia with propofol augments the potency of mivacurium

BACKGROUND: Little is known about the potentiating effect of propofol on neuromuscular blocking drugs. However, some animal studies indicate a dose-dependent increase of the potency of neuromuscular blocking drugs by propofol. This study compared mivacurium potency after five minutes and after 20 min of total intravenous anesthesia with propofol (TIVA propofol). METHODS: Twenty-eight patients were randomized into two groups, after approval of the Ethics Committee and written consent. Anesthesia was induced, in all patients, using remifentanil 0.5 microg.kg(-1).min(-1) for two minutes, after which: 3 mg.kg(-1) of propofol was injected; a laryngeal mask airway was inserted; and intermittent, positive pressure ventilation was initiated. Anesthesia was maintained using TIVA propofol (titrated using bispectral index monitoring to 40-45). Neuromuscular monitoring consisted of phonomyography at the adductor pollicis muscle. In Groups 5 min and 20 min, a tetanic stimulation of the ulnar nerve commenced after four minutes and after 19 min of TIVA, respectively, followed by controlled, single twitch stimulation at 1 Hz for one minute. Boli of 60, 30, 30, and 30 microg.kg(-1) mivacurium, respectively, were administered (each drug increment was administered after the effect of the previous dose had caused a stable response), and single twitch stimulation continued at 0.1 Hz. The dose-response curve was determined for both groups; potency was calculated using log-probit analysis. Data were presented as mean (SD) and were compared using two-sided analysis of variance, P < 0.05. RESULTS: Patient characteristics were similar in the two groups. The corresponding ED(50) and ED(95) values were greater, at 76.7 +/- 12.4 microg.kg(-1) and 146.6 +/- 27.6 microg.kg(-1) for Group 5 min, vs 46.7 +/- 12.2 microg.kg(-1) and 101.1 +/- 20.2 microg.kg(-1) for Group 20 min, respectively. CONCLUSIONS: After 20 min of TIVA propofol, the potency of mivacurium is approximately 50% greater than after five minutes of TIVA propofol. For clinical purposes, it is important, therefore, to consider the duration of TIVA propofol before determining the dose of neuromuscular blocking drug.     

Comparative potency of steroidal neuromuscular blocking drugs and isobolographic analysis of the interaction between rocuronium and other aminosteroids

We have determined the relative potency of rocuronium, pancuronium, pipecuronium and vecuronium, and examined the nature of the interaction of rocuronium with the other three steroidal neuromuscular blocking drugs. We studied the dose-response relationships of each drug and their combination with rocuronium in 200 ASA I or II patients during propofol-fentanyl-nitrous oxide-oxygen anaesthesia. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to single twitch stimulation of the ulnar nerve at 10-s intervals. The dose- response curves were determined by probit analysis. Isobolographic and algebraic (fractional) analyses were used to assess the combined effect of equipotent doses of rocuronium and vecuronium, pipecuronium or pancuronium and to define the type of interaction between these drugs. The isobolograms were constructed by plotting single-drug ED50 points on the dose co-ordinates, and a combined ED50 point in the dose field. The calculated doses producing 50% depression (ED50) of the twitch height for rocuronium, pancuronium, pipecuronium and vecuronium were 144.8 (95% confidence intervals 140.4-149.3), 32.4 (31.7-32.9), 27.1 (26.5-27.6) and 23.7 (22.7-24.8) micrograms kg-1, respectively. Corresponding doses producing 95% depression (ED95) of twitch height were, respectively, 322.1 (307.5-337.3), 58.1 (56.2-60.1), 48.7 (46.9- 50.5) and 39.9 (38.4-41.4) micrograms kg-1. Based on the estimate of ED50, the relative potency was 1:4.5:5.4:6, respectively. The interaction between rocuronium and vecuronium, pipecuronium or pancuronium was found to be additive.      

Lack of interaction between propofol and vecuronium.

We estimated the potency of vecuronium and measured the onset and duration of its action during total intravenous anesthesia with propofol to examine the possibility of any interaction between these two drugs. Propofol infusion was administered according to a three-step dosage scheme, and neuromuscular block was monitored by measuring the force of contraction of the adductor pollicis muscle after single-twitch stimulation of the ulnar nerve at 0.1 Hz. A control group of patients were similarly studied during anesthesia with thiopental, nitrous oxide, oxygen, and fentanyl. The ED50 and ED95 (dose required to produce a 50% and 95% depression of twitch tension, respectively) of vecuronium in patients given total intravenous anesthesia (n = 24) were 24 (22-27, 95% confidence limits) and 41 (37-48, 95% confidence limits) micrograms/kg, respectively, and in the control group (n = 24), 20 (17-24) and 39 (34-37) micrograms/kg, respectively. The onset of action of an 80-micrograms/kg dose (2 x ED95) of vecuronium was 3.6 +/- 1.2 and 4.1 +/- 1.7 min (mean +/- SD), in the propofol (n = 10) and control (n = 10) groups, respectively. The respective times to recovery of the twitch height to 25% of control and the recovery indices (25%-75% recovery of twitch height) in the propofol versus control groups were 28.3 +/- 6.6 and 28.0 +/- 1.7 min and 13.3 +/- 6.8 and 15.4 +/- 11.9 min, respectively. There were no significant differences in any of the measured variables between the propofol and control groups, indicating the lack of any interaction between propofol and vecuronium.     

Evaluation of the endotracheal intubating conditions of rocuronium (ORG 9426) and succinylcholine in outpatient surgery.

The time-course of action and tracheal intubating conditions of rocuronium and succinylcholine under intravenous anesthesia with propofol, alfentanil, and nitrous oxide were studied in 30 patients undergoing outpatient surgery. The neuromuscular effects of both drugs were quantified by recording the indirectly evoked twitch response of the adductor pollicis muscle after ulnar nerve stimulation (0.1 Hz, 0.2 ms supramaximal stimuli). Patients were given either 0.6 mg/kg rocuronium (n = 20) or 1 mg/kg succinylcholine (n = 10) intravenously. Sixty seconds after the administration of the muscle relaxant, the trachea was intubated and the intubating conditions were scored by a "blinded" assessor. Intubating conditions were not different (P = 0.34) between the rocuronium and succinylcholine groups. The onset and duration of neuromuscular blockade were shorter with succinylcholine than with rocuronium. The depression of the twitch response to 5% of control value occurred in 0.8 +/- 0.1 min with 1 mg/kg succinylcholine and 1.2 +/- 0.5 min with 0.6 mg/kg rocuronium (P less than 0.01). The recovery of the twitch response to 25%, 75%, and 90% of its control value was shorter after succinylcholine (P less than 0.001) and occurred at 8.1 +/- 2.6, 10.3 +/- 3.9, 11.3 +/- 4.6 and 25.3 +/- 5.0, 33.1 +/- 5.9, 36.1 +/- 6.3 min after succinylcholine and rocuronium, respectively. Also the time required for spontaneous recovery from 25% to 75% of the control twitch response was significantly shorter (P less than 0.001) after succinylcholine (2.2 +/- 1.4 min) than after rocuronium (7.8 +/- 2.1 min). It is concluded that in spite of the pharmacodynamic differences between succinylcholine and rocuronium, the intubating conditions after administration of both compounds are similar and develop at the same rate.     

Rocuronium potency and recovery characteristics during steady-state desflurane, sevoflurane, isoflurane or propofol anaesthesia

We have studied the potency and recovery characteristics of rocuronium during 1.25 MAC of isoflurane, desflurane, sevoflurane or propofol anaesthesia in 84 patients using electromyography. Potency was determined by a cumulative bolus technique. The mean ED50 of rocuronium was 169 (SD 41), 126 (32), 121 (28) and 136 (25) micrograms kg-1 during propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (ns), and ED90 values were 358 (62), 288 (29), 289 (28) and 250 (28) micrograms kg-1, respectively. The reduction in ED90 was statistically significant for all three inhalation anaesthetics (P < 0.05) compared with propofol. After 120 min, the cumulative infusion rate of rocuronium to obtain twitch depression of 90-95% was 9.0 (1.9), 6.3 (1.6), 6.1 (2.0) and 6.1 (1.1) micrograms kg-1 min-1 during propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (P < 0.01). Recovery index was 22 (13), 27 (10), 28 (13) and 26 (14) min under propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (ns). There were no significant differences between the three potent inhalation anaesthetics in relation to potency, infusion requirements or recovery characteristics of rocuronium.      

Cumulative dose-response curves for atracurium in patients with myasthenia gravis

The potency of atracurium was determined in five patients with moderate to severe generalized myasthenia gravis undergoing thymectomy. Train-of-four stimulation was applied to the ulnar nerve and the force of contraction of the adductor pollicis was measured. Cumulative dose-response curves were obtained during thiopentone-nitrous oxide-fentanyl anaesthesia. The average time to complete the dose-response studies was 12.7 +/- 1.5 minutes. The ED50, ED90 and ED95 of atracurium were (mean +/- SEM) 0.07 +/- 0.01, 0.12 +/- 0.22, and 0.14 +/- 0.04 mg.kg-1, respectively. The time to 25 per cent first twitch recovery was 35 +/- 4 min following maximum blockade. Ten normal patients were studied in the same manner. Their ED50, ED90 and ED95 were 0.13 +/- 0.01, 0.21 +/- 0.02 and 0.24 +/- 0.03 mg.kg-1, respectively. These results demonstrated that, in patients with moderate to severe generalized myasthenia gravis, atracurium was 1.7-1.9 times as potent as in normal individuals.     

Probability of acceptable intubation conditions with low dose rocuronium during light sevoflurane anaesthesia in children

BACKGROUND: To define the rocuronium doses which would provide 50%, 90%, and 95% probability of 'acceptable' intubation conditions during light sevoflurane anaesthesia, we studied 60 children aged 2-7 years in a prospective, randomised, assessor blinded study. METHODS: After mask ventilation with 1 MAC sevoflurane/N2O for 17+/-1 (x+/-SD) min we administered rocuronium (either 0.15, 0.22, 0.3, 0.5, or 1.0 mg. kg(-1)) or placebo, and quantified the evoked force of the adductor pollicis muscle. Intubation conditions were assessed before and 2 min after injection of the test drug. RESULTS: Intubation conditions were improved significantly with rocuronium and scored 'acceptable' in 70%, 90%, and 100% of the children after injection of rocuronium 0.15, 0.22, and 0.3 mg x kg(-1), respectively. In parallel, twitch tension decreased to 53% (6-100), 26% (11-100), and 11% (0-19) of baseline (median (range)). Recovery of train-of-four ratio to 0.8 was achieved 13 (7-19), 16 (8-28), and 27 (23-44) min after injection of the respective rocuronium doses. Higher rocuronium doses did not further improve intubation conditions but only prolonged time of neuromuscular recovery. Logistic regression analysis revealed that rocuronium 0.11 (CI 0.05-0.16), 0.21 (0.14-0.28), and 0.25 (0.15-0.34) mg x kg(-1) provides a 50%, 90%, and 95% probability of 'acceptable' intubation conditions in children during 1 MAC sevoflurane/N2O anaesthesia, respectively. Furthermore, we calculated that force depression of adductor pollicis muscle to 81% (CI 72-90), 58% (42-74), and 50% (29-71) of baseline is associated with 50%, 90%, and 95% probability of 'acceptable' intubation conditions. CONCLUSIONS: Submaximal depression of muscle force with low dose rocuronium improves intubation conditions in children during light sevoflurane anaesthesia while allowing rapid recovery of neuromuscular function. However, when using low dose rocuronium neuromuscular monitoring may be helpful to detect children with inadequate response to the relaxant so as to avoid an unsuccessful intubation attempt.     

Effect of d-tubocurarine pretreatment on succinylcholine twitch augmentation and neuromuscular blockade

Subparalyzing doses of d-tubocurarine (dTC) given before succinylcholine decrease the duration of neuromuscular blockade. In animal preparations, they also abolish succinylcholine-induced twitch augmentation, defined as a greater-than-maximal contraction in response to a single stimulus. To determine quantitatively the effect of dTC on succinylcholine potency and on twitch augmentation in humans, 60 adult patients, ASA physical status I or II, were assigned randomly to receive either 0.05 mg/kg of dTC or saline 2 min before induction of anesthesia with fentanyl and thiopental. Train-of-four stimulation was applied every 12 s to the ulnar nerve and the force of contraction of the adductor pollicis muscle was measured. One minute after induction of anesthesia, 0.15, 0.20, 0.25, 0.35, or 0.50 mg/kg of succinylcholine was given. The height of the first twitch (T1) reached 121% +/- 6% (mean +/- SEM) of control without dTC, and was virtually abolished by dTC pretreatment (105% +/- 1%, P less than 0.01). Twitch augmentation was more noticeable with lower doses of succinylcholine, and was not observed in the response to the fourth stimulus of the train of four (T4). The potency of succinylcholine was decreased by approximately one-half in the dTC-pretreated groups. The ED50 was 0.27 +/- 0.04 mg/kg without dTC and 0.50 +/- 0.06 mg/kg with dTC (P less than 0.002). The corresponding values for ED90 were 0.51 +/- 0.07 and 1.02 +/- 0.12 mg/kg, respectively (P less than 0.02). The ED95 values were 0.63 +/- 0.09 and 1.28 +/- 0.15 mg/kg, respectively (P less than 0.02). The slopes of the regression lines did not deviate significantly from parallelism.(ABSTRACT TRUNCATED AT 250 WORDS)     

The potency (ED50) and cardiovascular effects of rapacuronium (Org 9487) during narcotic-nitrous oxide-propofol anesthesia in neonates, infants, and children.

We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15-0.61), 0.28 (95% CI 0.11-0.61), and 0.39 (95% CI 0.17-0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 +/-28%, 98 +/- 3%, and 99 +/- 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 +/- 20 s. Maximum percent T1 twitch depression (+/-SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 +/- 34%, 96 +/- 7%, and 100 +/- 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 +/- 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 +/- 23, 83 +/- 11, and 90 +/- 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 +/- 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% +/- 16) is less and time to peak effect (96 +/- 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates. IMPLICATIONS: This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).     

Rocuronium pharmacokinetic-pharmacodynamic relationship under stable propofol or isoflurane anesthesia

PURPOSE: To compare the pharmacokinetics, pharmacodynamics and the concentration-effect relationship of rocuronium in patients under stable propofol or isoflurane anesthesia. METHODS: Ten patients were randomized to receive fentanyl, propofol and nitrous oxide (60%) or fentanyl, thiopental, isoflurane (1.2% end-tidal concentration) and nitrous oxide (60%). To obtain good intubation conditions and maintain adequate muscle relaxation during surgery, patients received two bolus doses of rocuronium: 0.5 mg x kg(-1) (1.7 x ED95) at induction followed one hour later by 0.3 mg x kg(-1) (1 x ED95). Arterial blood samples were obtained over six hours after the second bolus dose. Plasma concentrations of rocuronium were measured using high pressure liquid chromatography. Muscle twitch tension was monitored by mechanomyography for the two doses. Pharmacokinetic and pharmacodynamic parameters were determined. RESULTS: No differences in rocuronium pharmacokinetic parameters were observed between both groups. After the second bolus, clinical duration was 20 +/- 6 min in the propofol group vs 39 +/- 8 min in the isoflurane group (P <0.05). The effect compartment concentration corresponding to 50% block, EC50, was higher under propofol anesthesia: 1008 vs 592 microg x L(-1) (P <0.05). CONCLUSION: Rocuronium body disposition is similar under stable propofol or isoflurane anesthesia. In contrast to isoflurane, propofol does not prolong the neuromuscular block. Therefore, the potentiating effect of isoflurane is of pharmacodynamic origin only, as explained by an increased sensitivity at the neuromuscular junction. In contrast with isoflurane anesthesia where the dose of rocuronium has to be decreased under stable conditions, no dose adjustment is required under propofol anesthesia.     

Rocuronium zur elektiven Narkoseeinleitung Verlauf der neuromuskulären Blockade und Intubationsbedingungen nach 2facher ED95 (0,6 mg/kg) und nach Dosisreduktion (0,4 mg/kg)

BACKGROUND: Rocuronium is a non-depolarising neuromuscular blocking agent structurally related to vecuronium. The compound has a rapid onset and an intermediate duration of action. The rapid onset is of importance in patients at risk for pulmonary aspiration, for elective induction of anaesthesia slower onset properties generally are accepted. In this context, we asked whether the induction dose of rocuronium may be reduced to doses smaller than 2 x ED95 in situations in which slower onset properties may be acceptable. METHODS: The time course of neuromuscular block and intubating conditions of two different doses rocuronium, 2 x ED95 (0.6 mg/kg) and 1.3 x ED95 (0.4 mg/kg), were investigated in 90 patients. We first determined the time course of neuromuscular block using electromyography (EMG), n = 15 for each group. In the second part the intubating conditions 3 min after injection of either rocuronium 0.6 mg/kg or rocuronium 0.4 mg/kg were evaluated, n = 30 for each group. RESULTS: In the present study reduction of the dose of rocuronium led to a slower onset (148 +/- 32 s vs. 220 +/- 30 s; P < 0.05) and a shorter clinical duration (21 min +/- 4 vs. 36 +/- 7 min; P < 0.05). The recovery index was modified by the dose reduction: 11 +/- 3 min after 0.6 mg/kg rocuronium and 9 +/- 2 min after 0.4 mg/kg. After both doses of rocuronium the intubating conditions were good to excellent, no difference between both rocuronium groups were found. CONCLUSION: In the present study dose reduction from 0.6 mg/kg rocuronium to 0.4 mg/kg rocuronium led to a slower onset and reduced clinical duration. However, the intubating conditions, evaluated 3 min after injection of the muscle relaxant were comparable. This offers new possibilities for muscle relaxation for surgical or diagnostic procedures of short duration and may reduce costs.     

Comparative Clinical Pharmacology of Rocuronium, Cisatracurium, and Their Combination

Background: The comparative clinical pharmacology of cisatracurium and rocuronium and their combinations has not been reported. In this study, the authors compared the relative potency and the clinical profile and characterized the interaction of both drugs.

Methods: Two hundred twenty adults classified as American Society of Anesthesiologists physical status I and anesthetized with propofol-fentanyl-nitrous oxide were studied. In part 1, the neuromuscular-blocking effects of cisatracurium and rocuronium were assessed after administration of bolus doses of 20-50 [micro sign]g/kg and 100-300 [micro sign]g/kg, respectively. In part 2, we compared the time course of 1xED50, 1, 1.5, and 2xED95 doses of both drugs (where ED50 and ED95 are, respectively, the doses producing 50% and 95% depression of the first twitch height [T1]). In part 3, equieffective combinations of both drugs were studied to characterize their interaction.

Results: The calculated ED50 values and their 95% confidence intervals were 111 (107-115) and 215 (207-226) [micro sign]g/kg for rocuronium and cisatracurium, respectively. Compared with equipotent doses of cisatracurium, rocuronium had a faster onset, and a faster spontaneous T1 and train-of-four recovery times that were significant except at maximum recovery with the 2xED95 dose. The interaction between rocuronium and cisatracurium was synergistic, and the time profile of the combination group was different from that of the single-dose groups.     

The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide narcotic anesthesia

The purpose of this study was to evaluate neuromuscular and cardiovascular effects of doxacurium chloride, a new long-acting neuromuscular blocking agent, during a stable state of nitrous oxide and narcotic anesthesia. Ninety-three ASA physical status I or II patients were studied after informed written consent had been obtained. Eighty-one patients (group A) received doxacurium. The 81 patients were divided into nine subgroups according to the dose of doxacurium administered (0.01-0.06 mg.kg-1). Patients in a control group (group B) (n = 12) received pancuronium. To assess neuromuscular responses, a force displacement transducer recorded the twitch response of the adductor pollicis muscle following ulnar nerve stimulation. The ED50 and ED95 for doxacurium were estimated to be 0.013 mg.kg-1 and 0.023 mg.kg-1, respectively. The time to maximum twitch suppression following a dose of 1.0 (ED95) and 1.7 (ED95) was 10.3 +/- 1.3 min and 7.6 +/- 0.8 min, respectively. After an ED95 dose of doxacurium the time to spontaneous recovery to 95% of control twitch height was 73.7 +/- 8.7 min. With larger doses of doxacurium, 0.04 mg.kg-1 (1.7 X ED95) and 0.05 mg.kg-1 (2.2 X ED95), the time to spontaneous recovery to 95% of control twitch height was 125.8 +/- 24.8 and 204.0 +/- 21.2 minutes, respectively. When 25% twitch height recovery or more was present the reversal of doxacurium induced neuromuscular blockade was prompt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-response relationship and infusion requirement of cisatracurium besylate in infants and children during nitrous oxide-narcotic anesthesia

BACKGROUND: To determine the effect of age on the dose-response relation and infusion requirement of cisatracurium besylate in pediatric patients, 32 infants (mean age, 0.7 yr; range, 0.3-1.0 yr) and 32 children (mean age, 4.9 yr; range, 3.1-9.6 yr) were studied during thiopentone-nitrous oxideoxygen-narcotic anesthesia. METHODS: Potency was determined using a single-dose (20, 26, 33, or 40 microg/kg) technique. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor pollicis to supramaximal train-of-four stimulation of the ulnar nerve at 2 Hz. RESULTS: Least-squares linear regression analysis of the log-probit transformation of dose and maximal response yielded median effective dose (ED50) and 95% effective dose (ED95) values for infants (29+/-3 microg/kg and 43+/-9 microg/kg, respectively) that were similar to those for children (29+/-2 microg/kg and 47+/-7 microg/kg, respectively). The mean infusion rate necessary to maintain 90-99% neuromuscular block during the first hour in infants (1.9+/-0.4 microg x kg(-1) x min(-1); range: 1.3-2.5 microg x kg(-1) x min(-1)) was similar to that in children (2.0+/-0.5 microg x kg(-1) x min(-1); range: 1.3-2.9 microg x kg(-1) x min(-1)). CONCLUSION: The authors conclude that cisatracurium is equipotent in infants and children when dose is referenced to body weight during balanced anesthesia.