Residual neuromuscular block is common after the use of neuromuscular blocking drugs during anesthesia. Although careful reversal [table: see text] techniques usually result in adequate return of neuromuscular recovery, sometimes it is not possible to achieve full recovery of neuromuscular block. Ventilatory support and maintenance of a patent airway are required until recovery can be demonstrated. In those situations, in which some TOF fade is still obvious, the anesthesiologist should consider retaining the endotracheal tube in position; it is not a sign of failure to return a patient whose trachea is still intubated to the postanesthesia care unit. The inadvertent extubation of patients who are partially paralyzed results in increased postoperative morbidity.

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.

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 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.

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.

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=to0.7. 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1. 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=to 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. (Anesth Analg 1998;87:772-8)

S429 Introduction: Sevoflurane, like isoflurane and desflurane [1,2], is expected to decrease mivacurium requirements and prolong recovery. This study compared mivacurium infusion rates and recovery characteristics in adults and children during propofol/narcotic and sevoflurane anesthesia. Methods: After informed consent, 75 adult (20-65 yr) and 75 pediatric (2-12 yr), ASA 1-2, elective surgical patients were randomized to 3 groups to receive anesthesia with propofol/narcotic, 0.5 or 1.0 MAC sevoflurane. Blood was sampled for plasmacholinesterase estimation, and EMG neuromuscular monitoring (Datex Relaxograph: TOF every 10 sec, adductor pollicis) before mivacurium 0.25 mg/kg i.v. bolus. Mivacurium infusion commenced at 10 [micro sign]g/kg/min and was titrated to maintain 90-95% block. Rates were recorded every 5 min. At the end of surgery, the infusion was stopped and spontaneous recovery from mivacurium blockade monitored until TOF 0.7 was achieved. Results: Neither adults nor children showed demographic differences among groups. Plasmacholinesterase concentrations were normal (adults 4-12, children 6-16 KU/L). Mivacurium infusion rates, twice as high in children as in adults, decreased over time, and in proportion to sevoflurane concentration. Recovery was prolonged, but children recovered twice as quickly as adults (Table 1).Table 1Discussion: Sevoflurane halved mivacurium infusion requirements and doubled recovery times. Higher doses were needed in children, but recovery was faster than in adults. Mivacurium rates continued to decrease and, at 45 min, sevoflurane equilibration was incomplete at the neuromuscular junction.

As summarized in Table 1, patients with NM disorders show a wide range of responses to muscle relaxants. Hyperkalemia and contracture after the administration of SDC and either resistance or increased sensitivity to NDNRs are common concerns. Monitoring of the NMJ and titration of NM blockade are recommended.

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.

The effect of early blood sampling on the description of the vecuronium pharmacokinetic-pharmacodynamic relationship was studied following a bolus injection. Sample collection every 10 sec during the first 2 min showed a high concentration peak at 30 to 40 sec, accounting for an important proportion of the total area under the plasma concentration-time curve (AUC). Neglecting it, using only blood samples drawn at 1 and 2 min (limited sampling), led to a significant overestimation of noncompartmentally derived values of mean residence time, clearance, volume of distribution at steady-state and rate of transfer of vecuronium into the effect compartment. Compartmental pharmacokinetics could not be applied to concentration-time curves constructed with early samples, but limited sampling data were fitted to a 2-compartment model. Derived compartmental pharmacokinetic and pharmacokinetic-pharmacodynamic parameters were similar to those obtained noncompartmentally with complete sampling every 10 sec, because back-extrapolation to time zero contributed to the increase in the AUC. However, compartmental analysis does not provide an accurate description of concentration changes following injection.

January 23rd marks the 50th anniversary of the first administration of neuromuscular blocking drugs during anaesthesia.Although preceded by several isolated attempts by surgeons I (Lawen) and anaesthetists 2 (de Caux) Griffith and Johnson 3 began the first systematic administration of curare in Montreal.This marked a change in the direction of anaesthesia, not only in Canada, but throughout the world.Griffith and Johnson's observations were soon confirmed by Cullen 4 in the US and Gray 5 in England.Muscle relaxation could now be provided safely during anaesthesia without the dangers of deep anaesthesia or the inconvenience of high spinal blockade.It is, thus, only appropriate that this anniversary should be marked by the journal's first special supplement dedicated to Griffith's contribution to anaesthesia.Griffith appreciated the wider scope that curare would provide for anaesthetists.Familiar with the problems of controlled ventilation, he became involved in Intensive Care and it was anaesthetists who played such important roles during the polio epidemics of the 1950s.Consequently, it is surprising that the specialty has relinquished its unique position in Critical Care in so many North American institutions.An interest in lung ventilation led naturally to a generation of anaesthetists involved with respiratory physiology and, perhaps, persuaded those with an interest in respiratory physiology to become anaesthetists.In his own university Griffith encouraged the initiation of a Research Department of Anesthesia, at first under the direction of an anaesthetist -Gordon Robson -but for some time an independent department with a particular interest in central neurotransmission.Griffith's contribution to anaesthesia was not restricted to curare.As a leader of the specialty he was president of the CAS for two years, chairman of the board of trustees of the IARS, and the first president of the World Federation of Anaesthesiologists, an honour of which he was particularly proud.As an aside, one suspects that he would be disappointed that so few of the academic community aspire to presidency of the CAS.To his generation, the political and academic activities of the specialty were inseparable.

After anesthesia employing nondepolarizing muscle relaxants, 30%-40% of adult patients demonstrate residual paralysis with a train-of-four ratio less than 70%, but it is not known if the same is true for children. This study was designed to investigate neuromuscular transmission in 91 ASA physical status I or II day-care children (aged 0-10 yr) after halothane anesthesia in which pancuronium (n = 34), atracurium (n = 32), or vecuronium (n = 25) was administered. Peripheral nerve stimulation was used clinically to assess neuromuscular blockade during surgery. In the recovery room, the evoked response of the adductor pollicis muscle was measured by train-of-four stimulation of the ulnar nerve. This measurement was made (mean +/- SEM) at 18.0 +/- 1.5, 15.0 +/- 1.3, and 15.0 +/- 1.7 min after pharmacologic antagonism with 0.02 mg/kg atropine and 0.06 mg/kg neostigmine in the pancuronium, atracurium, and vecuronium groups, respectively. There were no differences in the ages of the patients in the three groups at 4.3 +/- 0.4, 4.0 +/- 0.4, and 5.0 +/- 0.5 yr, with 17 children less than 2 yr. Recovery from neuromuscular blockade in all three groups was almost complete. The train-of-four ratio (height of fourth twitch compared with the first) was similar in patients who had received pancuronium (96.7% +/- 0.9%), atracurium (95.5% +/- 0.9%), or vecuronium (96.3% +/- 1.3%). Therefore, postoperative muscle weakness or respiratory impairment is unlikely in pediatric day-care surgical patients more than 2 yr old when these anesthetic techniques are used.

This study was designed to determine the time required for potentiation of atracurium neuromuscular blockade after the introduction of enflurane. Ten ASA physical status I and II adults anesthetized with thiopental, nitrous oxide, and alfentanil were given 0.4 mg/kg atracurium besylate. The force of contraction of the adductor pollicis muscle in response to train-of-four stimulation of the ulnar nerve was recorded. When the first twitch (T1) of the train-of-four recovered to 10% of control, an atracurium infusion was started and adjusted to keep the level of blockade constant. After 15 min of stable blockade, 1.6%-1.7% end-tidal enflurane was started and maintained for up to 2 h. Venous blood samples were drawn and plasma atracurium concentrations were measured 15 min before and 0, 5, 10, 15, 30, 45, 60, 90, and 120 min after the introduction of enflurane. Atracurium plasma concentrations were 730 +/- 127 (SEM) ng/mL at time 0. During the first 30 min, no significant decrease in plasma levels occurred; but at 45 min, concentrations were only 67% +/- 8% of their initial value (P less than 0.01) and 48% +/- 2% at 120 min (P less than 0.01). This suggests that the interaction between enflurane and atracurium is time-dependent. Clinically, the interaction between atracurium and enflurane is negligible during procedures of less than 45 min.

Edrophonium administered in divided doses has been reported to accelerate antagonism of neuromuscular blockade, i.e., a "priming" effect. Since measured onset times can be affected by the type of stimulation used, this effect was studied using both train-of-four (TOF) and single twitch (ST) stimulation. During thiopentone-nitrous oxide-enflurane anaesthesia 20 adults were given atracurium 0.5 mg.kg-1. Both ulnar nerves were stimulated with TOF every 12 sec until one per cent recovery of first twitch (T1). At this time, ST stimulation was applied to one arm, selected at random. When the mean value of T1 and ST reached ten per cent of control, edrophonium, 1 mg.kg-1, preceded by atropine was given either as a single dose, or in two doses consisting of 0.2 mg.kg-1 followed by 0.8 mg.kg-1 three minutes later. No statistically significant differences were observed between T1 and ST for the next ten minutes, whether edrophonium had been given in single or divided doses. Giving edrophonium in divided doses did not improve recovery significantly, measured with either T1, ST or train-of-four ratio (T4/T1). Five minutes after the first administration of edrophonium, T1 was (mean +/- SEM) 86 +/- 3 and 86 +/- 2 per cent control in the single and divided dose groups respectively. Corresponding values for ST were 89 +/- 1 and 89 +/- 2 per cent (NS), and for TOF, 49 +/- 3 and 57 +/- 3 per cent (NS), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)