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Background: The linearity of cisatracurium elimination and its concentration-effect relation were determined as part of a traditional rich data study with three dose levels in patients receiving balanced anesthesia., Methods: Forty-eight adults with American Society of Anesthesiologists status I-II were randomized to receive an intravenous bolus dose of 0.075, 0.15, or 0.30 mg/kg cisatracurium. Anesthesia was induced and maintained with nitrous oxide-oxygen, propofol, and fentanyl. The mechanical response of the adductor pollicis muscle was recorded. Arterial blood samples were collected over 8 h. Cisatracurium, laudanosine, and the monoquaternary alcohol concentrations were measured by high-performance liquid chromatography. To assess the relative contribution of the input function, a parametric (assuming elimination from both the central and peripheral compartments) and a nonparametric pharmacokinetic-pharmacodynamic model were both applied to data., Results: Dose proportionality of the body disposition of cisatracurium and its two major metabolites at doses up to 0.30 mg/kg was confirmed. With the parametric approach, the effect compartment concentration at 50% block (EC50) significantly increased with the dose (136 vs. 157 vs. 209 ng/ml), whereas the effect compartment equilibration rate constant decreased (0.0675 vs. 0.0568 vs. 0.0478 min(-1)). A similar dose-dependent effect of the pharmacokinetic-pharmacodynamic relation was observed with the nonparametric approach, but the trend was 50% less pronounced., Conclusion: A dose-related change in pharmacokinetic-pharmacodynamic parameters was identified with both modeling approaches. A pharmacokinetic origin was ruled out, although no definite explanation of the underlying mechanism could be provided. These findings suggest that doses relevant to the anesthetic practice be used for estimation of EC50.

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.

Objectives: To compare recovery times from neuromuscular blockade between two groups of critically ill patients in whom pancuronium was administered by continuous infusion or intermittent bolus injection. To compare the mean pancuronium requirements (milligrams per kilogram per hour) and to assess the incidence of prolonged recovery times (>12 hrs) and residual muscle weakness., Design: Prospective, observational cohort., Setting: Intensive care unit in a university-affiliated hospital., Patients: A total of 30 mechanically ventilated patients who required pharmacologic paralysis. Patients were excluded if they had renal failure (creatinine clearance <30 mL/min), heart rate >130 beats/min, hepatic failure, peripheral nerve disease or myopathy, stroke, spinal cord damage, or myasthenia gravis., Interventions: Patients were assigned to receive pancuronium either by continuous infusion (n = 14) or intermittent bolus (n = 16). Depth of paralysis was titrated to maintain one or two responses to Train-of-Four stimulation with an accelerograph and desired clinical goals. Recovery time was defined as time from discontinuation of muscle relaxant until the amplitude of the fourth twitch, measured every 15-30 min using an accelerograph, was 70% the amplitude of the first twitch (Train-of-Four > or = 0.7)., Measurements and Main Results: These patients included the only three patients with status asthmaticus in our study. The groups were similar with respect to age, sex, weight, Acute Physiology and Chronic Health Evaluation II score, mode of ventilation, creatinine clearance, indications for paralysis, and duration of pancuronium administration. The median time for patients to recover from paralysis was 3.5 hrs (95% confidence interval, 1.82-5.18) in the infusion group vs. 6.3 hrs (95% confidence interval, 3.40-9.19) in the intermittent bolus group (p = .10). Less drug was administered in the intermittent group (mean, 0.02+/-0.01 mg/kg/hr) than by infusion (mean, 0.04+/-0.01 mg/kg/hr; p < .001). Six patients (five in the infusion group and one in the intermittent group) developed persistent severe muscle weakness. In addition, six different patients (three from each group) had prolonged recovery >12 hrs., Conclusions: Our study suggests that recovery time after paralysis with continuous infusion is faster than that after intermittent bolus injection. Although more pancuronium was administered in the continuous-infusion group, recovery time was not prolonged as a consequence. It is uncertain whether pancuronium given by infusion increases the risk of persistent muscle weakness.

Unlabelled: We investigated the influence of the timing of neostigmine administration on recovery from rocuronium or vecuronium neuromuscular blockade. Eighty adults and 80 children were randomized to receive 0.45 mg/kg rocuronium or 0.075 mg/kg vecuronium during propofol/fentanyl/N2O anesthesia. Neuromuscular blockade was monitored by train-of-four (TOF) stimulation and adductor pollicis electromyography. Further randomization was made to control (no neostigmine) or reversal with 0.07 mg/kg neostigmine/0.01 mg/kg glycopyrrolate given 5 min after relaxant, or first twitch (T1) recovery of 1%, 10%, or 25%. Another eight adults and eight children received 1.5 mg/kg succinylcholine. At each age, spontaneous recovery of T1 and TOF was similar after rocuronium and vecuronium administration but was more rapid in children (P < 0.05). Spontaneous recovery to TOF0.7 after rocuronium and vecuronium administration in adults was 45.7 +/- 11.5 min and 52.5 +/- 15.6 min; in children, it was 28.8 +/- 7.8 min and 34.6 +/- 9.0 min. Neostigmine accelerated recovery in all reversal groups (P < 0.05) by approximately 40%, but the times from relaxant administration to TOF0.7 were similar and independent of the timing of neostigmine administration. Recovery to T1 90% after succinylcholine was similar in adults (9.4 +/- 5.0 min) and children (8.4 +/- 1.1 min) and was shorter than recovery to TOF0.7 in any reversal group after rocuronium or vecuronium administration. Recovery from rocuronium and vecuronium blockade after neostigmine administration was more rapid in children than in adults. Return of neuromuscular function after reversal was not influenced by the timing of neostigmine administration. These results suggest that reversal of intense rocuronium or vecuronium neuromuscular blockade need not be delayed until return of appreciable neuromuscular function has been demonstrated., Implications: These results suggest that reversal of intense rocuronium or vecuronium neuromuscular blockade need not be delayed until return of appreciable neuromuscular function has been demonstrated. Although spontaneous and neostigmine-assisted recovery is more rapid in children than in adults, in neither is return of function as rapid as after succinylcholine administration.

Background: Rapacuronium is a rapid-onset, short-acting neuromuscular relaxant. This multiple-center study determined neuromuscular recovery when neostigmine was given 2 or 5 min after rapacuronium., Methods: One hundred seventeen patients were randomized to receive two different doses of rapacuronium and to receive neostigmine in two different doses and at two different times. During propofol anesthesia with nitrous oxide, oxygen, and fentanyl, 1.5 or 2.5 mg/kg rapacuronium was given 1 min before tracheal intubation. Neuromuscular block was measured by train-of-four ulnar nerve stimulation every 12 s: The adductor pollicis force of contraction was recorded mechanomyographically. Two or five minutes after rapacuronium was administered, 0.05 or 0.07 mg/kg neostigmine was administered and recovery was compared with that of control patients who received no neostigmine., Results: Both doses of rapacuronium produced 100% block in all but one patient, who exhibited 97% block. Neostigmine accelerated recovery in all groups. After 1.5 mg/kg rapacuronium, the time to 25% T1 twitch recovery decreased from a mean of 16 min in control patients to mean values of 8-10 min in the treatment groups: The time to train-of-four ratio of 0.7 decreased from 38 min to 17-19 min. After 2.5 mg/kg rapacuronium, the time to 25% T1 was reduced from 23 min to 11-12 min, and the time to train-of-four ratio of 0.7 decreased from 54 min to 26-32 min. Recovery was not different among the the groups that received different doses and timing of neostigmine., Conclusions: Recovery of intense rapacuronium block was accelerated by early neostigmine administration. When given 2 min after rapacuronium, neostigmine was as effective as after 5 min, and 0.05 mg/kg neostigmine was comparable to 0.07 mg/kg neostigmine.

Background: Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics., Methods: Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters., Results: Rapacuronium's weight-normalized plasma clearance was 7.03 x (1 - 0.0507 x (HgB - 13)) ml x kg(-1) x min(-1), where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4+/-1.4 ml x kg(-1) x min(-1), mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration., Conclusions: In this patient population, neither age nor gender influence elimination of rapacuronium. This finding contrasts to an age-related decrease in plasma clearance observed in a study of 10 healthy volunteers and in a pooled analysis of the pharmacokinetic data from 206 adults in multiple clinical studies. Even if ORG9488 has a potency similar to that of rapacuronium, its plasma concentrations after a single bolus dose of rapacuronium are sufficiently small to contribute minimally to neuromuscular blockade.

Unlabelled: The purpose of this study was to compare the mivacurium infusion requirements and neuromuscular recovery in adults and children during propofol/opioid and sevoflurane anesthesia. Seventy-five adult and 75 pediatric patients were randomized to receive propofol/opioid 0.5 or 1.0 minimum alveolar anesthetic concentration (MAC) (age-related) sevoflurane anesthesia. Plasma cholinesterase (PChE) activity was measured. Neuromuscular blockade was monitored by train-of-four (TOF) stimulation every 10 s and adductor pollicis electromyography. A bolus of 2 x the 95% effective dose of mivacurium (0.25 mg/kg) was followed by an infusion titrated to maintain 90%-95% blockade. Mivacurium doses were recorded every 5 min. At the end of surgery, the infusion was stopped, and recovery from mivacurium was monitored until TOF > or =0.7. PChE concentrations were within the normal range (adults 4-12 KU/L, children 6-16 KU/L) and correlated with mivacurium dose. Mivacurium infusion rates were higher in children than in adults: at 30 min, the rates in children were 13.1 +/- 6.4, 8.1 +/- 4.7, and 5.2 +/- 2.9 microg x kg(-1) x min(-1) at 0, 0.5, and 1.0 MAC sevoflurane, respectively; the corresponding rates in adults were 5.9 +/- 3.1, 4.3 +/- 1.7, and 2.9 +/- 0.7 microg x kg(-1) x min(-1) (P < 0.01). Sevoflurane decreased mivacurium requirements, maximal decreases at 45 min in children and 10 min in adults, and delayed neuromuscular function recovery. Children recovered twice as quickly as adults, achieving TOF > or =0.7 at 9.8 +/- 2.5, 11.4 +/- 2.8, and 19.6 +/- 6.3 min compared with 19.9 +/- 5.4, 26.4 +/- 8.3, and 32.9 +/- 9.8 min in adults (P < 0.0001). In conclusion, mivacurium requirements were correlated with PChE, were greater in children than in adults, and were reduced by sevoflurane. Neuromuscular recovery occurred more rapidly in children and was delayed by sevoflurane., Implications: The mivacurium infusion requirement to maintain constant 90%-95% neuromuscular block during anesthesia is correlated with plasma cholinesterase activity. It is increased in children and reduced by the inhaled anesthetic sevoflurane. Despite the larger dose administered to children, recovery from block occurred more rapidly in children than in adults and was delayed by sevoflurane.

Purpose: To determine the incidence of residual neuromuscular blockade after cardiac surgery in patients receiving either rocuronium or pancuronium for muscle relaxation., Methods: In a prospective, controlled, double-blind study, 20 patients undergoing coronary artery bypass were randomized to receive either rocuronium (n = 10) or pancuronium (n = 10) during surgery. Anaesthesia was induced with sufentanil, benzodiazepine and propofol or ketamine, and maintained with air/O2/sufentanil/isoflurane. Neuromuscular blockade was induced with 0.1 ml.kg-1 from blinded syringes containing recuronium (6 mg.ml-1) (Group R) or pancuronium (1 mg.ml-1) (Group P). Relaxants were administered according to clinical criteria and reversal agents were not given. After surgery, neuromuscular transmission was assessed by train-of-four stimulation of the ulnar nerve/adductor pollicis EMG (Datex Relaxograph). Mean values from three trains of stimuli were recorded and repeated 30 min later if TOF ratio was < 0.7. Time to extubation was recorded., Results: On arrival in the ICU, nine of 10 patients in group R but only three of 10 patients in group P demonstrated four visible responses (P < 0.05). Mean TOF ratio in group P, 0.03 +/- 0.05, was less than in group R, 0.68 +/- 0.34 (P < 0.001). All patients in group P and 4 of 10 patients in group R had TOF ratio < 0.7 (P = 0.01). Time to extubation in group P (median 18, range 6-48 hr) was not statistically different from that in group R (14, 5-44 hr)., Conclusion: Residual neuromuscular block, TOF ratio < 0.7, is common after cardiac surgery but the incidence is less when pancuronium is replaced by rocuronium.

The purpose of this multicenter, randomized, assessorblind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action < 20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micrograms/kg) and thiopental (3-6 mg/kg) and maintained with N2O/O2 and a propofol infusion (50-300 micrograms.kg-1.min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF > or = 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses > or = 1.5 mg/kg. Mean clinical durations < 20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients.

Purpose: To determine whether detection of residual blockade is improved by using the accelerograph. A secondary objective was to compare acceleromyographic measurements with those obtained by electromyography., Methods: In a prospective, randomized, double-blind investigation, 22 anaesthetized children were studied during recovery from neuromuscular blockade following 0.1 mg.kg-1 vecuronium i.v.. Assessments of depth of block began 10 min after injection and were repeated at one minute intervals using electromyography (Datex, Relaxograph) in one hand, and acceleromyography (Biometer, Tofguard) in the other, to measure response of the adductor pollicis to train-of-four (TOF) stimulation of the ulnar nerve. Monitoring was stopped when no fade was visible and TOF ratio > or = 0.7. The electromyographic (EMG) and acceleromyographic (AMG) data were compared with corresponding observations of the number of twitches and TOF fade in the visible responses of the thumb, made by the attending anaesthetist. The method of Bland and Altman was used to compare differences between AMG and EMG data., Results: During recovery from neuromuscular blockade, fade was no longer visible clinically 38.6 +/- 10.4 min (mean +/- SD) after the administration of vecuronium. This corresponded to TOF ratios of 0.04 +/- 0.23 by AMG and 0.34 +/- 0.21 by EMG. Usually, two twitches were visible before AMG detected the first twitch. The time to TOF ratio > or = 0.7 by AMG and EMG was similar at 49.1 +/- 10.5 and 50.9 +/- 9.0 min, respectively. The bias between AMG and EMG was one minute, with limits of agreement from -10 to nine min., Conclusion: AMG is superior to visual assessment in detecting residual neuromuscular block and provides similar estimates of recovering block as the more cumbersome EMG.

Background: The rapid recovery from mivacurium- induced neuromuscular block has encouraged omission of its reversal. The purpose of this study was to determine, in children and in adults, whether failure to reverse mivacurium neuromuscular block was associated with residual neuromuscular block on arrival in the postanesthesia care unit., Methods: In 50 children, aged 2-12 yr, and 50 adults, aged 20-60 yr, anesthesia was induced and maintained with propofol and fentanyl, and neuromuscular block was achieved by an infusion of mivacurium, to maintain one or two visible responses to train-of-four (TOF) stimulation of the ulnar nerve. At the end of surgery, mivacurium infusion was stopped, and 10 min later, reversal was attempted with saline or 0.5 mg x kg(-1) edrophonium by random allocation. On arrival in the postanesthesia care unit, a blinded observer assessed patients clinically and by stimulation of the ulnar nerve with a Datex electromyogram in the uncalibrated TOF mode., Results: Children arrived in the postanesthesia care unit 8.2 +/- 3-4 min after reversal of neuromuscular block and showed no sign of weakness, either clinically or by TOF stimulation. Although TOF ratio was greater in children who had received edrophonium (1.00 +/- 0.05 vs. 0.93 +/- 0.01, P<0.01), TOF was >0.7 in all children. Adults arrived in the postanesthesia care unit 12.9 +/- 5.3 min after reversal of neuromuscular block(P<0.01 vs. children). Six in the saline group demonstrated weakness (two required immediate reversal of neuromuscular block, and TOF was <0.7 in four others), compared with TOF <0.7 in only one of the edrophonium group (P<0.05)., Conclusions: This study demonstrated that, in adults, failure to reverse mivacurium neuromuscular block was associated with an increased incidence of residual block. Such weakness was not observed in children receiving similar anesthetic and neuromuscular blocking regimens.

Background: Reversal of neuromuscular blockade induced with pancuronium, d-tubocurarine, or doxacurium is achieved using smaller doses of neostigmine in adults than in children. Also, pancuronium- and doxacurium-induced blockade is reversed with smaller doses of edrophonium in children than in adults. The purpose of this study was to compare the spontaneous and neostigmine- and edrophonium-assisted recovery of mivacurium-induced neuromuscular block in adults and children., Methods: Fifty-four adults, aged 40.1 +/- 10.9 yr, and 54 children, aged 4.9 +/- 0.7 yr, physical status ASA 1-2, were studied during propofol/fentanyl/nitrous oxide anesthesia. A Datex relaxograph was used to monitor the electromyographic response of the adductor pollicis to train-of-four stimulation of the ulnar nerve every 10 s. After induction of anesthesia, 0.2 mg x kg(-1) intravenous mivacurium was administered followed by an infusion to maintain 90-95% T1 block. At the end of surgery, one of four doses of neostigmine (5, 10, 20, and 50 micrograms x kg(-1)) or edrophonium (100, 200, 400, and 1,000 micrograms x kg(-1)) or placebo was given, by random allocation, when T1 had recovered to 10%. Values of T1 and train-of-four were measured for 10 min., Results: Spontaneous recovery proceeded more rapidly in children than in adults. At 10 min, T1 had recovered to 97 +/- 2% (SD) in children compared with 69 +/- 11% in adults and train-of-four to 84 +/- 5% versus 30 +/- 13% (P<0.0001). In children, 10 min after reversal, recovery of T1 and train-of-four was not different from control after edrophonium and was enhanced only by the larger doses of neostigmine. In adults, recovery was accelerated by both edrophonium and neostigmine. Five minutes after reversal, recovery was improved by either drug in adults and in children., Conclusions: Spontaneous recovery from mivacurium- induced neuromuscular block is more rapid in children than in adults. Ten minutes after attempted reversal, recovery is accelerated by edrophonium and usually by neostigmine in adults but not in children. Thus, when reversal is required, edrophonium may be preferred to neostigmine.

Recovery after doxacurium and pancuronium neuromuscular blockade and their acceleration by neostigmine have not been compared in children. Therefore, 60 paediatric surgical patients aged 2-10 yr (ASA 1-2) were studied. They were randomized to receive doxacurium 30 micrograms.kg-1 or pancuronium 70 micrograms.kg-1 iv during propofol, fentanyl, isoflurane and nitrous oxide anaesthesia. Electromyographic (EMG) responses of the adductor pollicis to train-of-four (TOF) stimulation of the ulnar nerve were recorded every ten seconds using a Datex NMT monitor. Six patients in each relaxant group received neostigmine (0, 5, 10, 20 or 40 micrograms.kg-1) with atropine by random allocation when first twitch height (T1) had recovered to 25% of control. Spontaneous recovery after ten minutes was similar following doxacurium (mean +/- SEM values of 45.0 +/- 3.9 vs 49.5 +/- 10.0% for T1 and 25.2 +/- 3.8 vs 14.8 +/- 3.6% for TOF ratios). Dose-responses to neostigmine were calculated from the log dose vs logit of T1 or TOF ratio after ten minutes. Neostigmine-assisted recovery was not different in the two groups, with ED70 and ED90 doses for T1 of 14.3 +/- 1.8 and 25.7 +/- 2.7 micrograms.kg-1 for doxacurium and 12.5 +/- 1.7 and 25.3 +/- 2.3 micrograms.kg-1 for pancuronium. Time to recovery of TOF ratio to 70% after neostigmine 40 micrograms.kg-1 was 2.3 +/- 1.0 and 4.2 +/- 1.7 min (P = NS) following pancuronium and doxacurium, respectively. Adjusted recovery due to neostigmine alone (spontaneous recovery subtracted from the total) required two to three times higher doses of neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular blocking drugs can be divided into those that are: (i) excreted entirely by the kidney; (ii) predominantly by the kidney but also by the liver; (iii) mainly by the liver but also by the kidney or; (iv) removed by other metabolic pathways. Rocuronium is mainly excreted by the liver and pharmacokinetic and pharmacodynamic studies in humans suggest that its duration of action may be prolonged to a greater extent in patients with hepatic disease than in patients with renal disease. The effect is likely to be modest and not a contra-indication to its use.

Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinician have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long-acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non-depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholinesterase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, nondepolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non-polarizing replacement will continue.

The speed of action of several nondepolarizing muscle relaxants (gallamine, rocuronium, D-tubocurarine, atracurium, vecuronium, pancuronium and doxacurium) was tested iontophoretically at the frog cutaneous pectoris neuromuscular junction at various temperatures. If differences in rate of onset and offset are due to different molecular rates of binding (and unbinding), and of resulting conformational changes, they should be strongly temperature dependent. In contrast, if differences are due to differences in buffered diffusion, temperature dependence should be low to moderate. The onset and recovery time constants of inhibition of brief acetylcholine pulses, caused by long pulses of relaxants for all of the muscle relaxants, were inversely related to apparent dissociation constants (KD values), that ranged from 4.56 microM (gallamine) to 0.11 microM (doxacurium). The kinetics showed only modest temperature dependence (Q10 values of 1/time constant of offset were typically < 1.4). Because KD values of all muscle relaxants were even less temperature dependent (Q10 < 1.3), this suggests that the kinetics of inhibition is probably determined by the extent of buffering in the synaptic cleft, and not by binding and unbinding. Diffusion of relaxants from the synaptic cleft is expected to be strongly buffered, because the nerve terminal presents a physical barrier to diffusion, and because of extremely high density of acetylcholine receptors. The density of acetylcholine receptors can be calculated from the time constant of offset and KD values of various relaxants, assuming that buffer diffusion is determining the kinetics of action of muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxacurium (30 micrograms/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxide-isoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (kco) was decreased in the elderly (0.039 versus 0.051 min-1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An age-related reduction in muscle blood flow may be responsible for the decrease in kco. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.

This study compared the potency and time course of action of rocuronium (ORG 9426) in elderly and young patients during nitrous oxide-opioid anaesthesia. One hundred ASA physical status I-II patients (60, aged 65-80 yr, and 40, aged 20-45 yr) were studied by measuring the force of contraction of the adductor pollicis in response to train-of-four stimulation of the ulnar nerve. After induction of anaesthesia with thiopentone and maintenance with N2O/O2 and fentanyl, rocuronium 120, 160, 200, or 240 micrograms.kg-1 was administered to determine dose-response curves. When maximum block had been obtained, further rocuronium to a total of 300 micrograms.kg-1 was given. Additional doses of 100 micrograms.kg-1 were administered when the first twitch height (T1) had recovered to 25% control. At the end of surgery neuromuscular blockade was allowed, whenever possible, to recover spontaneously until T1 was 90% of control before administration of neostigmine. There was no difference in the potency of rocuronium in the elderly and the younger patients. The ED50 was 196 +/- 8 (SEE for the mean) in elderly, vs 215 +/- 17 micrograms.kg-1 in young patients (NS). When individual cumulative dose-response curves were constructed, the ED50 was 203 +/- 7 (SEM) and 201 +/- 10 micrograms.kg-1 in the elderly and the young respectively (NS). However, the onset of maximum neuromuscular block was slower in the elderly 3.7 +/- 1.1 (SD) vs 3.1 +/- 0.9 min, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The speed of action of nondepolarizing muscle relaxants is inversely related to potency. The hypothesis that this effect occurs at the end plate was tested in a frog (Rana pipiens) cutaneous pectoris muscle preparation. Brief acetylcholine pulses (10-100 ms) were applied iontophoretically from a central barrel of a triple-barrelled microelectrode located near an end plate. Long pulses (10-200 s) of muscle relaxant (gallamine, rocuronium, d-tubocurarine, atracurium, vecuronium, pancuronium, and doxacurium) were applied from one of two other barrels. The responses were a voltage change at the end plate, measured with an intracellular electrode. To evaluate potency, intracellular voltage changes following iontophoretic acetylcholine pulses were measured after application of various concentrations of muscle relaxants. The following were the equilibrium dissociation constants, which represent concentration of relaxant for 50% inhibition of response (mean plus or minus standard deviation): gallamine, 4.56 +/- 0.44 microM (n = 5); rocuronium, 0.71 +/- 0.09 microM (n = 6); d-tubocurarine, 0.59 +/- 0.07 microM (n = 4); atracurium, 0.31 +/- 0.03 microM (n = 4); vecuronium, 0.23 +/- 0.02 microM (n = 5); pancuronium, 0.18 +/- 0.03 microM (n = 3); doxacurium, 0.11 +/- 0.03 microM (n = 5). Both onset and offset of effect of muscle relaxant proceeded with an exponential time course.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response relationships for doxacurium and neostigmine were established in 24 young (18-40 yr) and 24 elderly (70-85 yr) patients, ASA physical status I or II, anesthetized with thiopental, fentanyl, nitrous oxide, and isoflurane. Mechanomyographic response of the adductor pollicis muscle to the train-of-four stimulation of the ulnar nerve was recorded. Doxacurium (5, 10, 15, or 20 micrograms/kg IV) was administered by random allocation. After maximal blockade, and additional dose, for a total of 30 micrograms/kg, was administered. When first twitch height recovered to 25%, incremental doses of 5 micrograms/kg were administered for maintenance of relaxation. Neostigmine (5, 10, 20, or 40 micrograms/kg) was injected at 25% first twitch recovery, and neuromuscular monitoring was continued for 10 min. The doses of doxacurium (+/- SEM) required to produce a 50%, 90%, and 95% depression of twitch tension in the young patients were, respectively, 13.3 +/- 1.6, 23.6 +/- 2.8, and 28.6 +/- 3.4 micrograms/kg, not statistically different from corresponding values in the elderly, 11.8 +/- 1.3, 21.2 +/- 2.3, and 25.9 +/- 2.9 micrograms/kg, respectively. Time to 25% recovery after 30 micrograms/kg was 80.2 +/- 12.2 min in the young versus 133.0 +/- 17.1 min in the elderly (P less than 0.05). Neostigmine-assisted recovery was not significantly different in both groups. The estimated doses of neostigmine to obtain 70% train-of-four recovery after 10 min were 53.6 +/- 7.5 micrograms/kg in the young and 41.6 +/- 5.8 micrograms/kg in the elderly (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)