Bevan, Joan C. MD, FRCA; Collins, Linda MB, FFARCSI; Fowler, Carolyn MB, FRCSA; Kahwaji, Raymond MD, FRCPC; Rosen, Harold D. MD, FRCPC; Smith, Michael F. MD, FRCPC; deV Scheepers, Louis MD, FRCPC; Stephenson, Catherine A. MB, FRCA, FRCPC; Bevan, David R. MB, FRCA
There is still controversy concerning the management of intense neuromuscular block (NMB) to ensure safe return of adequate neuromuscular function at the end of surgery. It is uncertain whether antagonists (e.g., neostigmine) should be given in the presence of intense NMB or delayed until appreciable recovery (first twitch [T1] of 25% or two visible twitches in response to train-of-four [TOF] stimulation) has occurred.
Wierda et al.  demonstrated that intense NMB produced by rapacuronium, a new rapid-onset neuromuscular blocking drug was reversed when neostigmine was given only 2 min after the muscle relaxant. When the NMB after the administration of 1.5 mg/kg rapacuronium (approximately 1.5 x the 95% effective dose [ED95]) was reversed with 0.07 mg/kg neostigmine at 2 min, it produced recovery of TOF0.7 in 17.2 +/- 5.4 min .
Several studies have consistently demonstrated the more rapid reversal of vecuronium , rocuronium , and mivacurium  in children than in adults. However, few of these reports made direct comparisons using similar methodology and anesthetic techniques in both children and adults. Two studies of early reversal have been reported in pediatric patients. Meistelman et al.  attempted the reversal of vecuronium with neostigmine at T1 values of 1%, 10%, and 25% and demonstrated more rapid recovery when reversal was attempted at T1 of 25%. Gwinnutt et al.  demonstrated that intense atracurium-induced NMB was antagonized with neostigmine but concluded that there was no clinical advantage in attempting to antagonize intense NMB in children.
In this study, we examined the influence of the timing of neostigmine administration on the duration of rocuronium and vecuronium NMB to determine the feasibility of early reversal of intense NMB. Comparisons were made of reversal in children and adults.
After institutional approval and written, informed consent from patients or parents, we studied 88 pediatric patients (2-12 yr) undergoing dental treatment and 88 women (20-65 yr), ASA physical status I or II, undergoing gynecological surgery. Only those of normal body weight and height (children within the 5th-95th percentile range on normal growth charts and adults with a body mass index of 20-30) scheduled for surgery of at least 1 h duration were included. Pregnant women; patients with a history of hypersensitivity to dairy products, asthma, epilepsy, neuromuscular disease, or drug abuse; and patients who had recently taken medication affecting neuromuscular transmission were excluded.
Routine preoperative care and premedication were at the discretion of the anesthesiologist. Baseline values for blood pressure and heart rate were measured preoperatively. Standard monitoring during anesthesia was used.
Neuromuscular transmission was monitored by electromyography (EMG) using the Relaxograph[registered sign] (Datex, Helsinki, Finland) and following Good Clinical Research Practice guidelines . Surface electrodes were applied over the ulnar nerve on the forearm. Recording electrodes were placed on the hand to record the EMG response of the adductor pollicis, and the arm was secured. A skin thermistor was taped to the hand close to the monitoring site, and the arm was wrapped in a blanket to reduce cooling. Skin temperature was maintained at >32[degree sign]C, and central temperature, measured at the axilla (children) or esophagus (adults), was maintained at >35[degree sign]C. Supramaximal square wave TOF stimulation at 2.0 Hz and 0.2 ms duration was delivered to the ulnar nerve every 10 s, and the evoked EMG response of the adductor pollicis was recorded. Monitoring commenced 2-3 min before administration of the muscle relaxant and continued until the end of anesthesia. Assessments of onset (maximal block and timing) and recovery of block (times to T (1) 10% [T10], 25% [T25], 75% [T75], 90% [T90] and TOF ratio 0.25 [TOF0.25], 0.5 [TOF0.5], 0.7 [TOF0.7], 0.8 [TOF0.8], and 0.9 [TOF0.9]) were made using the final EMG baseline as a reference to calculate neuromuscular recovery . For each recovery variable, the times from administration of neuromuscular relaxant and from administration of neostigmine were calculated. Recovery index was calculated as the time between T25 and T75 recovery.
The 88 adult patients were randomized by a computer-generated assignment to 11 groups of eight patients. Forty patients received 0.45 mg of rocuronium IV, 40 received 0.075 mg/kg vecuronium IV, and 8 were given 1.5 mg/kg succinylcholine IV 3 min after a defasciculating dose of 0.03 mg/kg rocuronium. Patients receiving rocuronium or vecuronium were further randomized to control groups with no reversal or to receive 0.07 mg/kg neostigmine with 0.1 mg/kg glycopyrrolate 5 min after relaxant or at 1% recovery of maximum block, or T10 or T25. Eighty children were randomized to receive rocuronium or vecuronium with or without neostigmine reversal, as in the adult patients. An additional group of eight children received 1.5 mg/kg succinylcholine. The latter was not included in the randomization for children because succinylcholine is no longer used routinely for elective pediatric procedures by all anesthesiologists
In children, anesthesia was induced with 5 mg/kg propofol, 0.02 mg/kg atropine, 0.3 mg/kg lidocaine, and 2 [micro sign]g/kg fentanyl IV, followed by tracheal intubation without the use of muscle relaxants. Anesthesia was maintained with inhaled N2 O/O2 (2:1) and positive pressure ventilation to maintain normocarbia. A propofol infusion, 200 [micro sign]g [middle dot] kg-1 [middle dot] min-1 initially, was titrated to maintain heart rate and systolic blood pressure within 10% of baseline values. Fentanyl increments, 0.5-2 [micro sign]g/kg, and other drugs, such as midazolam, droperidol, anticholinergic drugs, and opioids, were administered as indicated. In adults, anesthesia was induced with 1.5-3.0 mg/kg propofol, 0.3 mg/kg lidocaine, and 2 [micro sign]g/kg fentanyl. Maintenance of anesthesia was similar to that in children, but the propofol infusion was started at a lower rate of 50-150 [micro sign]g [middle dot] kg-1 [middle dot] min-1. In all other respects, the same study protocol was followed in children and adults.
Efficacy variables (onset time, duration, and recovery indices) and demographic data (age, height, weight) in adults and in children were compared by using one-way analysis of variance for each neuromuscular relaxant and at each reversal group, followed by multiple comparison tests of Bonferroni. Categorical demographic data (gender, ASA physical status) were compared by using Pearson chi squared tests, as well as Fisher's exact test. Comparisons of neuromuscular efficacy variables between children and adults were made by using Student's t-tests (Statview[registered sign] 4.5; Abacus Concepts Inc., Berkeley, CA). A statistical significance level of P < 0.05 was chosen. All data are expressed as mean values +/- SD (range) unless otherwise stated.
All 88 children and 88 adults completed the study. Although the study was terminated in 10 patients before all recovery data had been obtained (for clinical reasons), partial data analysis was available for all patients, so that the primary analysis was based on the intent-to-treat population. Within the child and adult groups, there were no differences across the relaxant/reversal groups in demographic variables (age, weight, height, ASA physical status) (Table 1). All adult patients were female.
Rocuronium and vecuronium produced near maximal NMB in all patients. For each relaxant, maximal block occurred more rapidly in children. Recovery to TOF (0).9 was achieved in most patients (Table 2). Recovery of NMB was more rapid in children than in adults, but there was no difference in the rate of spontaneous recovery of vecuronium and rocuronium in either age group (Table 3 and Table 4).
Neostigmine accelerated recovery of NMB in all patients. In adults and children, with both vecuronium and rocuronium, the time from administration of relaxant to TOF0.7 or TOF0.9 was decreased by approximately 30%-40%. There were no significant differences among the different reversal groups (Table 3 and Table 4, Figure 1A). Times from administration of neostigmine to TOF0.7 or TOF (0).9 decreased as the extent of recovery of NMB when neostigmine was given increased. In all groups, these times were significantly reduced when neostigmine was given at T1 of 25%, compared with administration 5 min after the relaxant (Table 5 and Table 6, Figure 1B). The small (<1 min) negative values of T25 when neostigmine was given at T1 of 25% (Table 5 and Table 6) reflect the differences between the corrected and target reversal group values.
After succinylcholine administration, the onset of maximal block occurred at 1.2 +/- 0.4 min in adults and 0.6 +/- 0.2 min in children (P = not significant) (Table 2). Recovery of NMB to T90 occurred within 9.4 +/- 4.3 and 8.4 +/- 1.1 min in adults and children, respectively (P = not significant). Recovery to T (90) after succinylcholine occurred more rapidly than return to TOF0.7 in any reversal group after either relaxant in adults or in children (Table 3 and Table 4).
In this study, we demonstrated that the times from administration of rocuronium and vecuronium to recovery of NMB were similar whether neostigmine was given early during intense block or later when recovery was well established. Although the time from administration of neostigmine to recovery was shortest when neostigmine was given when T1 was 25%, this may not support deliberately delaying administration of neostigmine.
Similar findings were seen in adults and children. Although spontaneous and assisted recovery occurred more rapidly in children, neostigmine accelerated the time to TOF0.7 by approximately 40% in both age groups. The pharmacodynamic behavior of succinylcholine was similar in adults and in children, but recovery of neuromuscular function after succinylcholine administration was much more rapid than that in any of the rocuronium or vecuronium groups. Recovery from NMB, whether spontaneous or after neostigmine administration, was more rapid in the pediatric group than in the adult group.
These results agree with previous studies showing that recovery from NMB occurs more rapidly in pediatric patients than in adult patients for all nondepolarizing relaxants [3,5]. Both rocuronium and vecuronium are intermediate duration relaxants, which, in equipotent doses, have similar durations of action and recovery patterns . In the present study, the two drugs were compared because, although there are data for vecuronium, early reversal of rocuronium has not been reported. The acceleration of recovery observed in this study was similar to that reported for vecuronium [11,12] and atracurium  in adults and in children [6,7]. When rocuronium blockade in children was reversed at 5 min, recovery to T25 occurred within 7.7 minutes (Table 4), which was similar to the 5.7 minutes found for the same end point after succinylcholine administration (Table 2).
Return of neuromuscular function after neostigmine is the sum of spontaneous recovery from the relaxant and its acceleration by the reversal drug . Spontaneous recovery is a function of a decrease in the concentration of relaxant at the neuromuscular junction. The in vitro recovery (and onset) from NMB induced by iontophoretic administration is related to the potency of the NMB drug and is likely the consequence of the rate of removal of drug from the receptor by processes such as "buffered diffusion." Consequently, the poorly potent rocuronium has a more rapid onset and recovery than do other nondepolarizing relaxants . In clinical practice, a decrease in receptor concentration may also be affected by the rate of peripheral distribution (rapacuronium) [x] , organ disposition (rocuronium, atracurium), decomposition (atracurium, cisatracurium), and metabolism (mivacurium).
Pharmacokinetically, after the administration of single boluses of most nondepolarizing relaxants, distribution is more important than metabolism or excretion in determining the rate of recovery, except when the latter form a major route of elimination (mivacurium, atracurium, and cisatracurium). Hence, NMB drugs with similar terminal half-lives (e.g., pancuronium and vecuronium) may have different rates of spontaneous recovery because recovery takes place during the distribution phase for vecuronium and during the elimination phase for pancuronium . Administration of the anticholinesterase neostigmine increases the junctional concentration of acetylcholine, the drug unbound to the receptor may increase and diffuse from the junction. The rate of restoration of neuromuscular function after neostigmine administration is affected by the level of block at the time of reversal [18-21], choice and dose of relaxant and reversal drugs , and drug interactions [inhaled anesthetics , and anticonvulsants].
The relevance of the present results for clinical anesthesia is, primarily, that they do not support the established practice of delaying neostigmine administration until neuromuscular activity is well restored. It is important to distinguish between recovery from administration of the relaxant and from the reversal drug. The times from administration of neostigmine to any recovery variable (e.g., TOF0.7) may be shortened when reversal is delayed until T1 has reached 25%. However, the time to TOF0.7 from administration of the relaxant is largely independent of the extent of spontaneous recovery at the time of reversal in both adults and children. Kirkegaard-Nielsen et al.  have shown that, with atracurium NMB, the minimal total recovery time occurred when neostigmine was given early at T1 of 4%.
It is unclear what degree of recovery at the end of anesthesia is acceptable for safety in the postanesthetic care unit. Although it may be possible to detect the detrimental effect of neuromuscular relaxants on the ventilatory response to hypoxia  and on esophageal activity  until TOF0.9, maximal inspiratory and expiratory force is restored at TOF0.7 , and diaphragmatic function has returned by TOF0.25 . This study suggests that restoration of neuromuscular activity may be attempted with neostigmine at the end of surgery as soon as there is no further need for surgical relaxation without waiting for a predetermined level of twitch recovery. The extent of recovery should be assessed by neuromuscular monitoring, and ventilatory support should be provided until adequate recovery is demonstrated.
Several aspects of the present study should be considered before the findings are given more widespread application. First, the single doses of rocuronium and vecuronium were small (approximately 1.5 x ED95). They were chosen to be equipotent with those reported in the early reversal of the new NMB drug rapacuronium , with similar doses of neostigmine, to allow comparison. Previous studies demonstrated slower reversal after large versus small doses of either long-acting pancuronium  or short-acting rapacuronium . Thus, anesthesiologists who are more used to giving larger doses of rocuronium or vecuronium should expect them to be associated with reversal times longer than those reported in the present study. Second, our patients were healthy children or young adults without organ dysfunction who were not taking confounding medication and who were not exposed to volatile anesthetics. The adult patients were all women, reflecting the available healthy, surgical population for study in our institution, although it has been demonstrated that women are more sensitive to NMB drugs than men [30,31]. In women, the onset of block is more rapid and recovery is slower, probably as a consequence of decreased volume of distribution for these hydrophilic compounds . Many of these factors may modify spontaneous recovery and the rates of recovery after reversal and contribute to the findings in our study. Further investigation is required to determine their importance and relevance in other populations.
A study of early reversal of rapacuronium demonstrated that recovery time after reversal was prolonged when the dose of rapacuronium was increased . However, at equipotent doses, the times from administration of relaxant to TOF (0).7 after the administration of 1.5 mg/kg rapacuronium reversed with 0.07 mg/kg neostigmine at five minutes in adults (18.1 +/- 7.3 min) was considerably shorter than that for rocuronium (27.6 +/- 9.2 min) or vecuronium (27.2 +/- 8.2 min) in the present study. None of the available nondepolarizing relaxants, including rapacuronium, can achieve recovery of neuromuscular function as rapid as that of succinylcholine.
In conclusion, these results confirmed that spontaneous recovery from similar levels of rocuronium and vecuronium NMB is indistinguishable, although appreciably faster, in children than in adults. Although neostigmine reversal predictably shortened these recovery times, under the conditions of the study, there was no advantage to delaying its administration to achieve more rapid or effective recovery.
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