Residual Block after Mivacurium with or without Edrophonium Reversal in Adults and Children

After institutional approval and written, informed consent from the patient or parent, 50 adults (20-60 yr) and 50 children (2-12 yr) were studied. All were ASA physical status 1 or 2 and free of neurologic, respiratory, renal, or hepatic disease and were not receiving drugs that could interfere with normal neuromuscular function. They were scheduled for elective surgical procedures with anticipated durations of at least 1 h.

Premedication was at the discretion of the anesthesiologist, and pediatric patients had local anesthetic cream (EMLA) applied to the dorsum of the hand preoperatively to facilitate intravenous cannulation. Anesthesia was induced with propofol (1.5-3 mg *symbol* kg sup -1 in adults and 5 mg *symbol* kg sup -1 in children), 0.3 mg *symbol* kg sup -1 lidocaine, and 1-2 micro gram *symbol* kg sup -1 fentanyl intravenously. Blood was sampled before administration of mivacurium for estimation of plasma cholinesterase activity and dibucaine number. Tracheal intubation was facilitated with 0.2 mg *symbol* kg sup -1 intravenous mivacurium, and an infusion of mivacurium was commenced as soon as a twitch response of the thumb was elicited by TOF stimulation of the ulnar nerve using a Dualstim III Nerve Stimulator (Lifetech, Houston, TX) or other clinical peripheral nerve stimulator. The initial infusion rates were 10 micro gram *symbol* kg sup -1 *symbol* min sup -1 in adults and 20 micro gram *symbol* kg sup -1 min sup -1 in children. Adjustments to the rate were made at 2-5-min intervals to maintain a level of neuromuscular blockade at which one or two twitch responses to TOF stimulation were visible. Anesthesia was maintained with oxygen and nitrous oxide inhalation and an infusion of propofol (50-300 micro gram *symbol* kg sup -1 *symbol* min sup -1). Incremental doses of fentanyl were given, and the propofol infusion titrated to provide satisfactory levels of anesthesia, which maintained cardiovascular stability without the addition of volatile anesthetic agents.

The mivacurium infusion was stopped at the end of surgery, and spontaneous recovery of neuromuscular blockade was allowed to proceed for 10 min. The patients in both of the age groups were randomized to receive 0.5 mg *symbol* kg sup -1 edrophonium with 0.02 mg *symbol* kg sup -1 atropine or saline for reversal of residual neuromuscular blockade. The reversal agent and placebo were identical in appearance and made up to standard volumes, so that the anesthesiologist who administered the drugs was unaware of the randomization choice. The anesthesiologist in charge of the patient decided on the times for tracheal extubation and transfer of the patient to the recovery room, based solely on clinical criteria, which might include use of a peripheral nerve stimulator. Further doses of edrophonium and atropine could be administered at any time if considered necessary on clinical grounds. On arrival in the recovery room, neuromuscular monitoring was performed using a Puritan Bennett Datex Relaxograph (Helsinki, Finland) to record three consecutive responses of the electromyographic response of the adductor pollicis to TOF supramaximal stimulation of the ulnar nerve at 10-s intervals. The electromyogram was used in the uncalibrated mode to obtain TOF ratios only. The arm free of the intravenous infusion was selected for monitoring, and skin temperature over the adductor pollicis at the recording site was measured and maintained above 32 degrees C by use of warming blankets.

The duration of anesthesia and the total dose of mivacurium administered were noted. Time from the administration of edrophonium or saline to the beginning of electromyogram monitoring in the recovery room was recorded. The three TOF ratios measured were averaged for statistical analysis. Data were expressed as mean+/-SD. In each age group, comparisons were made between the TOF ratios on arrival in the recovery room after edrophonium or saline using Student's t-test and the incidence of postoperative residual blockade, clinical weakness, or TOF ratio less or equal to 0.7 in the adults and children was compared using Fisher's exact text. Values of P < 0.05 were considered to show significant differences.

The mean ages were 4.5+/-2.2 and 37.6+/-9.2 yr, and the mean weights were 19.2+/-8.0 and 66.0+/-13.1 kg, of children and adults, respectively. The duration of neuromuscular block was similar in adults and children, 66.0+/-13.1 versus 73.3 +/-30.4 min, but the mivacurium infusion rate required to maintain constant block was greater in children, 0.017+/-0.005 versus 0.006+/-0.003 mg *symbol* kg sup -1 *symbol* min sup -1, and the time interval from reversal to assessment in the PACU was longer in adults, 12.9+/-5.3 versus 8.2+/-3.4 min (P < 0.01). Plasma cholinesterase activity was greater in children than in adults, 8.8 +/-1.6 versus 7.0+/-2.1 kU/l (P < 0.01).

The mean ages and weights and sex distribution were similar in the reversal and saline groups (Table 1). The duration of neuromuscular block was greater in patients who had received edrophonium (P < 0.01), but the infusion rate was similar (Table 2). The times from reversal to PACU assessment and the mean TOF ratios on assessment were similar in the saline-treated and edrophonium-treated patients. However, in the saline group, four had a TOF ratio < 0.7, and two others were so weak on arrival in the PACU (small tidal volume, inability to head-lift, weak hand-grip) that edrophonium was administered to restore ventilation and muscle tone before assessments could be made (Table 2). Thus, six of the saline-treated patients demonstrated residual neuromuscular block in the PACU compared with one patient in the edrophonium group who had a TOF ratio < 0.7 (P < 0.05). In five of these seven patients, recovery to TOF > 0.7 occurred spontaneously within 10 min, but two from the saline group required additional edrophonium before adequate recovery was achieved. The seven adults who demonstrated residual neuromuscular block did not appear to differ from their cohorts with respect to age, duration of infusion, mivacurium requirement, plasma cholinesterase activity, or in the times from reversal to assessment (Table 3).

There were no significant differences in age, weight, sex distribution, duration of infusion, infusion dose, or time from reversal to PACU assessment between the saline- and edrophonium-treated children (Table 1). Although all had TOF > 0.7, the mean TOF ratio was less in the saline than in the edrophonium group (P < 0.01; Table 2).

This study demonstrated that, in adults, after an infusion of mivacurium sufficient to maintain intense neuromuscular block, 6 of 25 patients in whom reversal was not attempted at the end of anesthesia had residual block on arrival in the PACU. Only 1 of 25 patients in whom the block had been reversed with 0.5 mg *symbol* kg sup -1 edrophonium demonstrated residual block. None of the children who had received a neuromuscular block of similar intensity, half of whom had received edrophonium, demonstrated residual neuromuscular block, although the time from reversal of the block in the operating room to assessment in the PACU was less than in adults (P < 0.05), and a greater dose of mivacurium was required to maintain an equivalent degree of neuromuscular block. The incidences of residual block, clinical weakness, and/or TOF < 0.7, in the adult patients (24%) in whom the block was not reversed were similar to rates previously described in adults after reversal of a block produced by long-acting neuromuscular blocking drugs. [15-17]This suggests that failure to reverse mivacurium-induced block may lead to residual neuromuscular block. Avoidance of reversal should be limited to those patients in whom recovery from the block has been confirmed with neuromuscular monitoring.

In children, the risk of residual neuromuscular block is low. Previous studies have demonstrated that spontaneous recovery from neuromuscular block produced by several agents, including mivacurium, [1,6]occurs more rapidly in children than in adults. In addition, Meakin et al. demonstrated, using the same doses of edrophonium or neostigmine to reverse pancuronium-induced block, that more rapid recovery occurred in children than in adults. [20]Similarly, the dose of neostigmine [21]but not of edrophonium [22]required to antagonize d-tubocurarine-induced neuromuscular block was less in infants and children than in adults. In the latter reports, pharmacokinetic studies showed that the volumes of distribution of neostigmine and edrophonium were similar in all age groups, suggesting that the differences were not due to altered pharmacokinetic behavior. Also, in these studies, d-tubocurarine was administered by continuous infusion to maintain a constant level of neuromuscular block, rather than by bolus injection. Nevertheless, the comparisons between children and adults apply.

The overall recovery of neuromuscular activity after reversal results from spontaneous recovery and its acceleration by anticholinesterases. The more rapid rate of spontaneous recovery and the much greater mivacurium infusion requirement may result, at least in part, from greater plasma cholinesterase (pChe) activity in these children. In adults, it has been shown that the duration of mivacurium-induced neuromuscular blockade is inversely related to pChe [23]and is moderately prolonged in patients who are heterozygous for the usual and the atypical gene for pChe. [24]Recovery is greatly delayed in patients homozygous for the atypical gene. [24,25]Although some authors were unable to demonstrate age-related differences in pChe activity, [26]it is possible to recognize pChe variants using techniques of molecular genetics [27]so that previously unrecognized abnormalities of the enzyme can be identified.

The current study suffers from several of the problems associated with clinical investigations. Mivacurium was used to provide neuromuscular block for clinical indications. Anesthesia with propofol/fentanyl/nitrous oxide was chosen to prevent potentiation of the block and impairment of reversal by inhalational agents, [28]and the intensity of the block was maintained constant by appropriate monitoring and adjustment of the infusion rate. However, although the reversal agent, or saline, was given after some neuromuscular activity had been demonstrated 10 min earlier at the termination of the infusion, the interval from its administration and the subsequent arrival and assessment of neuromuscular activity in the PACU occasionally was delayed in adults. Thus, the assessment was made, as in clinical practice, at different times after reversal. Nevertheless, we believe the findings are applicable to clinical practice. It is interesting that the times from reversal to PACU assessment in the current study were similar to those found in previous investigations of residual neuromuscular block in adults [17]but were less than was previously documented in children. [18]Perhaps, if a longer time had elapsed from stopping the infusion until arrival in the PACU or if a less intense neuromuscular block had been produced, a greater degree of recovery would have been demonstrated in adults. However, in certain circumstances, such as after laparoscopic cholecystectomy, when surgery is terminated quickly, very rapid recovery from neuromuscular block is required.

We have shown that residual neuromuscular block may occur in adults if mivacurium-induced neuromuscular block is not reversed. We suggest that recovery, assessed by neuromuscular monitoring, be confirmed before reversal is omitted. Previous studies have demonstrated the effectiveness of both edrophonium and neostigmine in accelerating recovery from mivacurium in adults [29-31]and in children. [32]However, edrophonium is more effective in antagonizing an intense mivacurium block when neostigmine may impede spontaneous recovery. [33-35]When reversal is necessary, edrophonium is preferable to neostigmine, because the latter inhibits pChe [36]to a greater extent. [37]The inhibition probably is responsible both for the impaired recovery from intense block and for the lower neostigmine:edrophonium potency ratio found in the reversal of mivacurium [31]than of other nondepolarizing relaxants. [38]However, it has been shown that the administration of neostigmine during the course of a mivacurium infusion increased the circulating concentrations of the trans-trans and cis-trans stereoisomers of mivacurium [39]and the authors suggested that this might be responsible for the impaired antagonism of the block. However, similar increases were observed after edrophonium, [40]so that this is an unlikely explanation for any difference between neostigmine and edrophonium. In addition, the relationship between plasma concentrations of mivacurium and neuromuscular block have not been compared in this situation.

In conclusion, this randomized double-blind study has shown that, when mivacurium-induced neuromuscular blockade was allowed to recover spontaneously, residual block was not observed in pediatric patients. However, in adults, residual weakness was identified in 6 of 25 patients in whom edrophonium-reversal was replaced with saline. Consequently, it should not be assumed that the neuromuscular blockade produced by mivacurium does not need to be reversed.