Comparison of neuromuscular effects, efficacy and safety of rocuronium and atracurium in ambulatory anaesthesia

PURPOSE: To compare the neuromuscular effects, efficacy, and safety of equi-effective doses of rocuronium and atracurium in ambulatory female patients undergoing surgery. METHODS: Forty-one patients undergoing laparoscopic gynaecological surgery were randomized to receive 2 X ED90 rocuronium (0.6 mg.kg-1; n = 20) or atracurium (0.5 mg.kg-1; n = 21) during intravenous propofol/alfentanil anaesthesia with N2O/O2 ventilation. Neuromuscular block was measured with a mechanomyogram eliciting a train-of-four (TOF) response at the wrist. Intubation conditions 60 sec after administration of muscle relaxant and immediate cardiovascular disturbances or adverse events during the hospital stay were noted by blinded observers. RESULTS: Compared with atracurium, rocuronium was associated with a shorter onset time (59.0 +/- 22.2 vs 98.6 +/- 41.4 sec; P < 0.001) and clinical duration of action (33.3 +/- 7.1 vs 44.7 +/- 7.2 min; P < 0.001), but longer spontaneous recovery index (9.6 +/- 2.41 vs 6.9 +/- 1.89 min; P = 0.023) and a similar time to spontaneous recovery to TOF 70%; 53 +/- 6.31 vs 59.2 +/- 7.59 min; P = 0.139). Tracheal intubation was accomplished in < 90 sec in all patients receiving rocuronium but in only 14 of 21 patients receiving atracurium. The incidence of adverse events and the cardiovascular profiles for the two drugs were similar, although one patient receiving atracurium experienced transient flushing of the head and neck. CONCLUSION: Rocuronium has minimal side effects, provides conditions more suitable for rapid tracheal intubation, and is associated with a shorter clinical duration than atracurium. Once begun, the spontaneous recovery profile of rocuronium is slightly slower than that of atracurium.     

Cumulative characteristics of atracurium and vecuronium. A simultaneous clinical and pharmacokinetic study

BACKGROUND: Cumulative effects (increased 25-75% recovery time with increasing dose) are evident with vecuronium but not with atracurium. Pharmacokinetic simulations suggest that vecuronium's cumulation occurs as recovery shifts from distribution to elimination whereas atracurium's recovery always occurs during elimination. The purpose of this study was to examine this pharmacokinetic explanation. METHODS: We assigned 12 volunteers to receive atracurium of vecuronium on three occasions during nitrous oxide-isoflurane anesthesia. Evoked adductor pollicis twitch tension was monitored. On occasion 1, the dose expected to produce 95% block (ED95) was estimated for each subject. On occasions 2 and 3, 1.2 or 3.0 multiples of ED95 were given as a bolus. Plasma was sampled for 128 min to determine muscle relaxant concentrations; pharmacodynamic modeling was used to determine effect-compartment drug concentrations (Ce). For each drug, recovery time, recovery phase half-life (rate of decrease in Ce during recovery), and Ce at 25% and 75% recovery were compared between doses. RESULTS: Atracurium's recovery time increased 2.4 +/- 2.2 min (mean +/- SD) with the larger dose, less than the increase with vecuronium (8.2 +/- 3.8 min). Atracurium's recovery phase half-life was 14.6 +/- 1.7 and 20.1 +/- 2.3 min with the small and large doses (P < 0.05); vecuronium's recovery phase half-life increased similarly from 13.5 +/- 2.3 to 18.5 +/- 5.0 min (P < 0.05). At 75% recovery, vecuronium's Ce decreased from 65 +/- 18 ng/ml with the small dose to 55 +/- 15 ng/ml with the large dose (P < 0.05). Assuming that neuromuscular junction sensitivity was constant, this difference could be explained by considering neuromuscular effects of vecuronium's metabolite, 3-desacetylvecuronium. CONCLUSIONS: Although vecuronium was cumulative (as predicted), atracurium was also slightly cumulative. Inconsistent with our hypothesis, recovery phase half-lives for both drugs increased similarly between doses; therefore, differences in cumulation were not solely explained by pharmacokinetics of the muscle relaxant. It appears that 3-desacetylvecuronium contributes to vecuronium's cumulative effect, even after usual clinical doses.     

The comparative study of LUMIWARD immunoassay system and CAP RAST system for determination of specific IgE antibody against mite in infantile atopic dermatitis

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mg.kg-1 were compared with those of atracurium 0.5 mg.kg-1 during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 micrograms.kg-1 at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mg.kg-1 and atracurium 0.5 mg.kg-1, respectively. After cisatracurium 0.1 mg.kg-1 had been given, the median time to recovery of the train-of-four ratio to 0.8 ('adequate recovery') was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mg.kg-1 and atracurium 0.5 mg.kg-1 were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.     

Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination

We compared the dose-response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide-fentanyl-propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose-response curves were determined by probit analysis. The calculated ED50 values and their 95% confidence intervals were 40.9 (38.1-43.7), 49.8 (47.0-52.6), 187.2 (175.1-199.3), 36.6 (34.7-38.5) and 136.4 (129.2-143.6) micrograms.kg-1 for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED95 values were 57.6 (53.5-61.7), 91.8 (88.1-95.5), 253.1 (238.9-267.3), 52.9 (49.1-56.7) and 288.7 (276.2-301.2) micrograms.kg-1, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.     

Esophageal cyst--a rare cause of backache

BACKGROUND: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. METHODS: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg.kg-1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg.kg-1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg.kg-1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. RESULTS: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). CONCLUSION: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Dose-response relationship of atracurium besylate in the halothane-anaesthetised pig

The dose response relationship for the intermediate-acting non-depolarising muscle relaxant, atracurium besylate in the pig was determined using evoked electromyography. An incremental dose technique was used in seven Large White/Landrace crossbred pigs anaesthetised with nitrous oxide and halothane. ED50 and ED95 were 510 +/- 87 micrograms kg-1 and 1150 +/- 270 micrograms kg-1, respectively. Although these values may represent an overestimate, they provide a reasonable guideline for the use of atracurium by veterinary anaesthetists.     

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

The aim of our randomized controlled study was to compare the neuromuscular characteristics of mivacurium and atracurium by evaluating the intubation conditions, intubation times, onset times and the duration of action of these two muscle relaxants using two different dosing principles. Forty-eight patients were included in this study. All patients were premedicated orally with 0.2 mg/kg diazepam. Anaesthesia was induced with 2.0 mg/kg propofol and 0.02 mg/kg alfentanil and maintained with 6 mg/kg/h propofol and 60% nitrous oxide in oxygen. Neuromuscular monitoring was carried out with supramaximal TOF-stimulation (2 HZ) of the ulnar nerve every 10 seconds and recording of the mechanomyogram (MMG) (Myograph 2000, Biometer) at the adductor pollicis muscle. The patients of group 1 (n = 12) received an intubation dose of 0.15 mg/kg mivacurium (2 x ED95) and the patients of group 2 (n = 12) received a priming dose of 0.015 mg/kg mivacurium (20% of ED95) followed by an intubation dose of only 0.07 mg/kg mivacurium (ED95) two minutes later. The patients of group 3 (n = 12) were intubated with 0.46 mg/kg atracurium (2 x ED95) and the patients of group 4 (n = 12) received a priming dose of 0.046 mg/kg atracurium (20% of ED95) and an intubation dose of 0.23 mg/kg atracurium (ED95) four minutes later. The patients were intubated under normocapnic conditions and following stabilisation of the palmar skin temperature after a 90% neuromuscular block (T1) had occurred. The intubation conditions were measured semiquantitatively using an intubation score.(ABSTRACT TRUNCATED AT 250 WORDS)     

Writing for a medical journal

Cisatracurium (51W89) is one of the ten stereoisomers of atracurium, accounting for about 15% of the racemate. The ED95 of cisatracurium was determined to be about 50 micrograms/kg (cation, molecular weight 929), while the ED95 of atracurium (besylate salt, molecular weight 1245) was 250 micrograms/kg. Thus, on a molar basis in adult patients, cisatracurium is about 3.5 times as potent as the racemic atracurium mixture. We compared atracurium with cisatracurium in healthy adult patients and found an almost identical pharmacodynamic profile. In children, an ED95 of about 40 micrograms/kg was determined, while a 1-min-longer onset of cisatracurium was found in geriatric than in young adult patients. The presence of chronic renal failure did not prolong the duration of action of cisatracurium. The recovery of neuromuscular transmission from a cisatracurium infusion of up to 145 h was investigated in intensive care unit patients. Their time from the end of infusion to a train-of-four ratio > 0.7 (68 +/- 18 min) was on average only some 70% longer than after an infusion of cisatracurium for 2 h in normal surgical patients. In another study, no signs of histamine release nor any clinically relevant cardiovascular effects of cisatracurium were found in doses up to eight times ED95.     

Potency and time course of action of rocuronium during desflurane and isoflurane anaesthesia

We have studied the potency and onset and duration of action of rocuronium in patients anaesthetized with 1 MAC of desflurane or isoflurane (in 66% nitrous oxide). Potency was estimated using the single bolus dose technique. Neuromuscular block was measured by stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. The ED50 and ED95 of rocuronium were estimated as 138 (95% confidence limits 117-162) micrograms kg-1 and 281 (241-328) micrograms kg-1, and 126 (105-151) micrograms kg-1 and 283 (236-339) micrograms kg-1 during desflurane and isoflurane anaesthesia, respectively. The mean times to onset of maximum block after rocuronium 0.6 mg kg-1 were 1.0 (SD 0.10) min and 1.1 (0.15) min, respectively, during anaesthesia with desflurane and isoflurane. The respective times to recovery of T1 (the first response in the train-of-four (TOF) stimulation) to 25% and 90% were 36 (8.3) min and 54 (15.4) min during desflurane anaesthesia and 31 (8.2) min and 45 (12.7) min during isoflurane anaesthesia. The times to recovery of the TOF ratio to 0.7 were 66 (13.4) min and 52 (16.3) min and the 25-75% recovery indices 14 (5.3) min and 10 (3.2) min, respectively, in the desflurane and isoflurane groups. There were no differences in the estimated potency or onset of action of rocuronium during desflurane and isoflurane anaesthesia. However, duration of action tended to be longer curing desflurane anaesthesia although only the differences in times to TOF ratio of 0.7 and the recovery indices were close to being significantly different (P = 0.0503 and 0.0560).     

Pharmacodynamic dose-response and safety study of cisatracurium (51W89) in adult surgical patients during N2O-O2-opioid anesthesia

After administration of doses ranging from 0.025 to 0.25 mg/kg, the neuromuscular blocking effect of cisatracurium was assessed in 119 adult surgical patients receiving N2O-opioid-midazolam-thiopental anesthesia. The calculated 95% effective dose (ED95) for inhibition of adductor pollicis twitch evoked at 0.1 Hz was 0.053 mg/kg. With 0.10 mg/kg injected over 5-10 and 20-30 s, median onset times (range) were 5.8 (3.0-7.7) and 4.8 (1.2-10.2) min, respectively, and median times to 5% and 95% recovery (range) were 27 (19-46) and 48 (25-68) min, respectively. For doses of 0.10, 0.20, and 0.25 mg/kg, median 5%-95% and 25%-75% recovery indexes ranged from 48 to 90 min and 8 to 9 min, respectively. After administration of neostigmine (0.06 mg/kg) at 10%-15% or 16%-30% recovery, the median times to 95% recovery (range) were 6 (2-22) and 4 (2-5) min, respectively. There were no changes in heart rate, blood pressure, or plasma histamine concentrations during the first 5 min after administration of cisatracurium at doses up to 5 x ED95 injected over 5-10 s. No cutaneous flushing or bronchospasm was noted. In summary, cisatracurium is a potent neuromuscular blocking drug with an intermediate duration of action, characterized by excellent cardiovascular stability, with no apparent histamine release.     

Cisatracurium

Cisatracurium is one of ten isomers that form the racemic mix of atracurium (51W89 or 1 R-cis, 1'R-cis atracurium). It is three times more potent than atracurium itself and hemodynamically stable thanks to its scarce release of histamine. Cisatracurium is hydrolyzed mainly by the pathway of Hofmann (77%) and to a lesser degree it is metabolized by organ-dependent modes (mainly by the kidney (16%)). Dose therefore hardly needs to be changed for elderly patients or those with liver, kidney or cardiovascular disease. The calculated ED95 is 0.05 mg.kg-1 (0.04 mg.kg-1 in children), although a dose two to four times greater is used under clinical conditions to shorten tracheal intubation time because of low onset of blockade, particularly in comparison with rocuronium. The period of deep blockade (lack of response to neurostimulation) is prolonged by the higher dose, but recovery is dose-independent and recovery indices are similar. Cisatracurium has proven useful in intensive care because of its hemodynamic stability, which is comparable to that of steroid derivatives but with faster recovery from blockade once administration is discontinued. Its metabolism predominantly through Hofmann's pathway, with less laudanosine formation than is produced by atracurium, is also appreciated. Cisatracurium is described as the nondepolarizing muscle relaxant of choice for medium-to-long-term surgery on hemodynamically unstable patients or those with kidney or liver disease, and for neuromuscular blockade in intensive care.     

Interactions between suxamethonium and mivacurium or atracurium

We have compared the dose-response relationships of suxamethonium, mivacurium and atracurium and examined the interactions of suxamethonium with mivacurium or atracurium in humans by isobolographic analysis. We studied 100 adult patients during fentanyl and thiopentone anaesthesia. Neuromuscular function was monitored using a Myograph 2000 (Biometer Co., Odense, Denmark). The dose-response curves were determined by probit analysis. Isobolographic and fractional analyses were used to assess quantitatively the combined effect of equipotent doses of suxamethonium, mivacurium and atracurium and to define the type of interaction between suxamethonium and mivacurium or atracurium. The ED50 values for suxamethonium, mivacurium and atracurium were 198.8 (95% confidence interval 190.7-206.9), 48.6 (45.4-51.8) and 202.1 (197.9-206.2) mg kg-1, respectively. Isobolographic and fractional analyses of the suxamethonium-mivacurium and suxamethonium-atracurium combinations demonstrated antagonistic interactions.     

The effects of age on onset and recovery from atracurium, rocuronium and vecuronium blockade

Elderly patients may show an age-related decline in physiologic functions, which may be responsible for the prolonged duration of some neuromuscular blocking agents. Previous studies have yielded conflicting results as to the effects of these drugs in the elderly. METHODS: After obtaining informed consent and approval of the Ethics Committee, we compared onset and recovery times of single IV doses of atracurium, rocuronium, and vecuronium given to 108 patients divided into three groups according to age (18-50, 51-64, > or = 65 years). Following oxazepam premedication and fentanyl and thiopentone induction, patients were randomly allocated to receive atracurium, rocuronium or vecuronium (0.5, 0.6, or 0.1 mg/kg, respectively) in < or = 0.8 vol.% enflurane (end-tidal)-nitrous oxide anaesthesia. Muscular relaxation was assessed by electromyographic (EMG) recording of the adductor pollicis muscle after supramaximal single-twitch stimulation of the ulnar nerve every 10 s. Onset time and recovery to 25%, 75% and 90% of twitch control values (DUR25, 75, 90) were recorded. Creatinine clearance predicted from serum creatinine (Ccr) was correlated with recovery from neuromuscular block. RESULTS: Onset time was not different among groups or relaxants. The results showed a prolonged duration of action for atracurium (DUR75, DUR90), rocuronium (DUR25, DUR75), and vecuronium (DUR25) in the elderly. A number of patients did not reach DUR75 or DUR90. There was a significant relationship between age and failure to return to control values during recovery from neuromuscular block, especially after atracurium and rocuronium. Ccr showed a negative correlation with age for all relaxants, but a negative significant correlation between Ccr and recovery was found only for rocuronium. CONCLUSIONS: This study suggests that onset time for atracurium, rocuronium and vecuronium is not age-dependent. Recovery was prolonged in the elderly for all three relaxants. This effect appears to be secondary to changes in body composition and function accompanying the aging process. Neither atracurium nor vecuronium depends significantly on the kidney for elimination, but the negative correlation between Ccr and rocuronium suggests an appreciable role for the kidney in the elimination of this relaxant. The long recovery times observed in this study could also be related to enflurane anaesthesia. We suggest that failure of EMG responses to return to baseline values during recovery from neuromuscular block may be related to age, especially for atracurium and rocuronium.     

Resistance to decamethonium neuromuscular block after prior administration of vecuronium

Prior administration of nondepolarizing neuromuscular blocking drugs reduces the potency of subsequently administered succinylcholine. To assess whether this interaction is also observed with the depolarizing drug, decamethonium, the potency of decamethonium alone and decamethonium after vecuronium (10 micrograms/kg) were assessed using a cumulative dose-response technique in two groups of six healthy patients each. Patients were premedicated with meperidine and promethazine and anesthetized with thiopental, isoflurane, and nitrous oxide in oxygen. Twitch tension was monitored using adductor pollicis mechanomyography in response to ulnar nerve stimulation at 0.1 Hz. The mean (SEM) dose of decamethonium producing 80% twitch tension depression (ED80) when administered alone was 37 (4.0) micrograms/kg. After recovery of twitch tension (but persistence of train-of-four fade) from vecuronium, the mean (SEM) ED80 for decamethonium was increased to 89 (4.4) micrograms/kg (P < 0.01). The shift to the right of the dose-response curve for decamethonium was nonparallel. Antagonism is observed when decamethonium is administered after a small dose of vercuronium; this interaction, which is also seen with succinylcholine, is likely to be a feature of depolarizing block. Nonparallel shift of the dose-response curve to decamethonium indicates that this is not likely to be a simple agonist-antagonist effect at a single site.     

Ranitidine reverses gallamine paralysis in rats

The effect of ranitidine on gallamine-induced depression of twitch tension was evaluated in urethane-anaesthetized and mechanically ventilated male Sprague-Dawley rats. Gallamine was administered as an intravenous (IV) bolus and constant rate infusion in 15 rats to maintain 89 +/- 7% (SE) depression of twitch tension induced by electrical stimulation of a sciatic nerve. Ranitidine, IV at either 0.5, 1, 2.5, 5, or 10 mg/kg, was then administered into groups of three rats. Ranitidine produced an immediate dose- and serum concentration-dependent reversal (antagonism) of the twitch tension depression induced with gallamine. The reversal was observed within approximately 30 s and was maintained for 3-26 (12 +/- 2) min. The dose of ranitidine that produced 50% reversal was 2.9 +/- 0.1 mg/kg, and this reversal was associated with a ranitidine serum concentration of 5.2 +/- 0.3 micrograms/mL. Ranitidine administered alone (and without gallamine) did not alter twitch tension at either 2.5 or 20 mg/kg. In addition, ranitidine did not alter either the gallamine neuromuscular blocking concentration in serum or the serum clearance of gallamine. Ranitidine reverses the neuromuscular action of gallamine, and this effect of ranitidine is not due to a pharmacokinetic interaction between ranitidine and gallamine.     

Prolonged mivacurium infusion in young and elderly adults

PURPOSE: This study was designed to evaluate pharmacodynamically and pharmacokinetically if the cis-cis isomer of mivacurium contributed to neuromuscular block during prolonged infusions lasting more than four hours in young adult and elderly (> 60 yr) patients. METHODS: The mechanomyogramic neuromuscular response of the adductor pollicis was recorded in 32 adults 18-59 yr. and 19 elderly (> 60 yr.) patients during N2O:O2:opioid anaesthesia. The mivacurium infusion rate was adjusted to maintain single twitch depression at 95 +/- 4% of control. Blood samples were taken every 30 min to determine the plasma concentration of cis-cis isomer of mivacurium. At the end of the surgical procedure, patients were allowed to recover spontaneously to at least 25% of control twitch response. RESULTS: The mean mivacurium infusion requirement to maintain 97 +/- 1 (mean +/- SD)% depression of the twitch response was 6.0 +/- 0.4 micrograms.kg-1.min-1 in young adults, and 4.3 +/- 0.3 micrograms.kg-1.min-1 in elderly patients (P < 0.001). The infusion requirement in patients with low plasma cholinesterase activity was the lowest 2.4 +/- 1.2 micrograms.kg-1.min-1. Plasma cis-cis isomer concentrations reached peak levels within one-two hours and remained relatively constant throughout the duration of infusion even in patients with low cholinesterase activity. There was no relationship between duration of infusion, plasma concentrations of cis-cis isomer and the early recovery indices of mivacurium (up to 25%). Neuromuscular transmission recovered adequately with or without antagonism in all patients. CONCLUSION: When the mivacurium infusion was titrated to maintain 95 +/- 4% twitch depression, the plasma concentration of the cis-cis isomer did not increase during prolonged infusions (four hours) and neuromuscular transmission recovers satisfactorily.     

Dose-response relationships for edrophonium and neostigmine antagonism of rocuronium bromide (ORG 9426)-induced neuromuscular blockade

BACKGROUND: Rocuronium bromide (ORG 9426) is a new nondepolarizing muscle relaxant with a rapid onset but an intermediate duration of action. The dose-response relationships for neostigmine and edrophonium were studied during antagonism of neuromuscular block induced by rocuronium bromide. METHODS: Sixty-four ASA physical status 1 or 2 adults were given 0.6 mg/kg rocuronium bromide during thiopental-fentanyl-nitrous oxide-isoflurane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg/kg) or neostigmine (0.005, 0.01, 0.02, or 0.05 mg/kg) was administered by random allocation. Neuromuscular function in another eight subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery in patients who were not given antagonists. RESULTS: The dose-response curves for neostigmine- and edrophonium-assisted antagonism of rocuronium bromide neuromuscular blockade for the single twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% and 80% recovery (ED50 and ED80, respectively) of the first twitch after 10 min were 0.017 (0.001) and 0.033 (0.001) mg/kg (mean (standard error of estimate for the mean)), respectively. Corresponding ED50 and ED80 values for edrophonium were 0.161 (0.001) and 0.690 (0.001) mg/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.5 (0.56) and 21 (0.67) for first twitch ED50 and ED80 height, respectively. The calculated doses producing ED50 of the TOF ratio at 10 min were 0.017 (0.001) and 0.469 (0.001) mg/kg for neostigmine and edrophonium, respectively. These values corresponded to a potency ratio of 27.5 (1.66). CONCLUSIONS: Under the conditions described in this study, if reversal was attempted at 10% first twitch recovery, edrophonium was less capable than neostigmine of reversing fade (potency ratio of 19.2 and 27.5 at 5 and 10 min, respectively) than first twitch (potency ratio of 6.7 and 9.5 at 5 and 10 min, respectively) during antagonism of rocuronium bromide-induced blockade. Edrophonium was found to be less effective than neostigmine at reversing rocuronium bromide-induced TOF fade.     

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 microg/kg and 100-300 microg/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 26.2 (25.8-26.5) microg/kg [corrected] 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. CONCLUSIONS: Cisatracurium is four to five times more potent than rocuronium. Rocuronium had a faster onset of action, a shorter clinical duration, and a faster spontaneous recovery rate compared with equipotent doses of cisatracurium.     

The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists

Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.     

An open-label study of the safety and tolerability of converting stable liver transplant recipients to neoral

STUDY OBJECTIVES: (1) To compare the dose-response relations of rocuronium and vecuronium in healthy adult patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental; and (2) to evaluate the time-course of action of two drugs following equipotent doses. DESIGN: Prospective, randomized, clinical comparison. SETTING: Operating room, Plastic Surgery Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College. PATIENTS: 60 ASA physical status I patients, aged 17-51 years, scheduled for elective plastic surgery. INTERVENTIONS: All patients were randomly assigned to either the rocuronium or vecuronium group. General anesthesia was induced with thiopental 4 to 6 mg/kg and fentanyl 2 to 4 micrograms/kg intravenously (i.v.), and maintained with 60% nitrous oxide (N2O) in oxygen. Further increments of thiopental or fentanyl were given as required. The dose-response relations of rocuronium and vecuronium were determined by the cumulative dose-response technique. MEASUREMENTS AND MAIN RESULTS: Neuromuscular function was assessed mechanomyographically with train-of-four (TOF) stimulation at the wrist every 12 seconds. The percentage depression of first twitch (T1) was used as the study parameter. The cumulative dose-response curve of vecuronium was shifted to the left in a parallel fashion compared with that of rocuronium. As assessed by linear regression, the potency ratio of vecuronium: rocuronium was 1:7.2. There were significant differences in the ED50, ED90, and ED95 between the two drugs. After i.v. administration of equipotent doses of both drugs (2 x ED90), the duration of peak effect, clinical duration, recovery index, and total duration were not significantly different between the two drugs. CONCLUSIONS: Compared with vecuronium, rocuronium is a low-potency, nondepolarizing relaxant, and its neuromuscular blocking potency is approximately 15% that of vecuronium in adult patients anesthetized with N2O and fentanyl. Following equipotent doses, the time-course of recovery for rocuronium is similar to that of vecuronium.