Early Reversal of Rapacuronium with Neostigmine 

After institutional approval and written informed consent were obtained, 117 adults (age, 19–64 yr) were enrolled. All were classified as American Society of Anesthesiologists physical status I-III; were free of significant neurologic, renal, or hepatic disease; and were not receiving drugs that could interfere with normal neuromuscular function. In addition, preoperative evaluation indicated that difficult tracheal intubation was not anticipated. They were scheduled for elective surgical procedures expected to last at least 1 h.

Premedication, with midazolam or diazepam, was at the discretion of the anesthesiologist. Routine monitoring was used. Fentanyl (1–5 [micro sign]g/kg) was given intravenously followed 3 min later by induction of anesthesia with propofol (1–3 mg/kg) given intravenously. Anesthesia was maintained with oxygen and nitrous oxide, 60%-70%, inhalation with controlled ventilation, and an infusion of propofol (50–300 [micro sign]g [middle dot](^-1) kg [middle dot] min^-1). Incremental doses of fentanyl were given, and the propofol infusion was titrated to provide anesthesia that maintained cardiovascular stability without the addition of volatile anesthetics. Ventilation was controlled, and the end-tidal carbon dioxide pressure was maintained between 32 and 34 mmHg.

Neuromuscular monitoring was performed using a mechanomyograph (Myograph 2000; Biometer International, Odense, Denmark) or a Grass FT10 force transducer (Grass Instruments, Quincy, MA) to record the mechanomyographic isometric twitch response of the adductor pollicis, with a preload of 200–300 g, to TOF supramaximal stimulation of the ulnar nerve at 10-s intervals. The mechanomyographic apparatus was attached to the patient before anesthesia was induced, and the calibration sequence was completed after the patient lost consciousness, according to criteria for good clinical research practice. [18] Single 1-Hz stimuli were administered for 3 min for stabilization before switching to TOF stimulation. The arm used for neuromuscular monitoring was kept warm (peripheral skin temperature, >or= to 32 [degree sign]C; esophageal temperature, >or= to 35 [degree sign]C).

After the mechanomyographic twitch response was stabilized, the randomized dose of 1.5 or 2.5 mg/kg rapacuronium base was given as a rapid intravenous bolus within 5 s. Tracheal intubation was performed 60 s later. Each patient was randomized to one of five groups to receive no reversal, 0.05 or 0.07 mg/kg neostigmine with 0.01 mg/kg glycopyrrolate at 2 or 5 min after the administration of rapacuronium. Neuromuscular activity was allowed to recover to 90% T¹or a TOF ratio of 0.8 before further muscle relaxant was administered. Times to the following neuromuscular end points were recorded: maximal block; T¹recovery of 25%, 50%, 75%, or 90%; and TOF recovery to 0.7 and 0.8. The recovery index (time from 25% to 75% T¹recovery) was calculated.

After the conclusion of surgery and transfer to the postanesthetic care unit, the patients' conditions were evaluated. Clinically significant postanesthetic events and postoperative complications were recorded.

An adverse experience was defined as an unusual or unexpected symptom that emerged during the study or that increased in frequency or intensity during the study, regardless of whether it was considered to be drug related. A serious adverse experience was defined as an adverse effect that was fatal, life-threatening, permanently disabling, required prolonged hospitalization, or was an overdose. The investigators noted whether they considered the adverse effect to be related to the administration of rapacuronium.

Demographic and other baseline characteristics were summarized by age and dosage groups. Summary statistics, including the mean +/- SD, are presented for pharmacodynamic parameters: maximum T¹; duration of T¹to 25%, 50%, 75% of the control and recovery index; and duration of TOF to 0.7 and 0.8. All tables and graphs were prepared using SAS version 6.09 (SAS Institute, Cary, NC) or StatView 4.5 software (Abacus Concepts Inc., Berkeley, CA). Demographic data and the intensity and duration of neuromuscular block were compared using analysis of variance and the Bonferroni post hoc test. P < 0.05 was considered significant.

One hundred seventeen patients successfully completed the trial, which lasted 9 months. They were recruited from three sites, although recruitment at site 2 was poor and was compensated for by additional recruitment at site 1 (Table 1). Protocol violations with regard to dose or timing of rapacuronium or neostigmine administration occurred in five patients. Two patients were given the wrong dose of rapacuronium, and three others received neostigmine in the wrong dose or at the wrong time. Partial data were available for all patients (at least 109 data points for each variable). Primary analysis was based on the intent-to-treat population of 117 patients.

There were no significant differences among the 10 reversal groups in demographic variables (age, weight, height, American Society of Anesthesiologists status, gender;Table 2). However, substantially more female patients were recruited.

Both doses of rapacuronium induced 100% neuromuscular block in all except one patient, who exhibited 97% block. Maximum block was achieved at 51.9 +/- 19.2 s after 1.5 mg/kg rapacuronium and at 51.2 +/- 15 s after 2.5 mg/kg. Tracheal intubation was performed at 60 s in each patient. Neostigmine was administered during 100% block in 92 patients. Recovery from neuromuscular block was more rapid after 1.5 than after 2.5 mg/kg rapacuronium in all subgroups (except 0.07 mg/kg neostigmine administered at 5 min in 75% T¹and recovery index, and except for no reversal in recovery index and TOF⁰.8). Neostigmine accelerated recovery in patients compared with controls at each dose and time administration of anticholinesterase. There were no significant differences in any of the indices of recovery among groups that had received neostigmine at each dose of rapacuronium (Table 3, Figure 1).

No serious adverse events, as previously defined, related to rapacuronium were recorded. Probable or possible drug-related effects were reported in 10 patients. In 9 of the 10 patients, the principal presenting feature was bronchospasm. One patient with bronchospasm, which developed on arrival in the postanesthetic care unit, had a transient rash on the forearm into which rapacuronium had been injected 1 h earlier. In this case, bronchospasm and oxygen desaturation, pulse oximetry of 88–90%, were relieved by inhalation of salbutamol. In eight patients, transient bronchospasm (1–6 min) occurred during tracheal intubation but subsided spontaneously without treatment.

Neostigmine, given 2 or 5 min after rapacuronium, accelerated recovery of neuromuscular function. No differences were detected that were caused by the dose (0.05 or 0.07 mg/kg) or timing (2 or 5 min) of neostigmine administration. Recovery was more rapid after 1.5 than after 2.5 mg/kg rapacuronium. If the goal is to achieve TOF⁰.7 within 15 min, this is more likely to be achieved after 1.5 mg/kg than after 2.5 mg/kg rapacuronium. At this dose, tracheal intubation was performed at 1 min, and recovery to TOF (⁰).7 was achieved at 17–19 min when the block was reversed at 2–5 min with neostigmine. At this dose, neostigmine, compared with control, decreased the time to TOF⁰.7 by approximately 50%(i.e., by 20 min;Figure 1). Complete neostigmine-assisted recovery has not been reported within such a short time after administration of any other nondepolarizing neuromuscular-blocking drug.

There are two previous reports of early reversal of rapacuronium. Van den Broek et al. [5] found that after 1.5 mg/kg rapacuronium, spontaneous recovery times to 25% T¹and TOF⁰.7 were decreased from 8.0 +/- 1.9 and 24.1 +/- 6.2 min to 5.7 +/- 0.6 and 11.6 +/- 1.4 min, respectively. However, the dose was based on the bromide salt of the drug, which was equivalent to approximately 1.3 mg/kg in the current study. This may explain the shorter clinical duration and the more modest absolute acceleration obtained by Wierda et al. [6] In addition, isoflurane was included in the anesthetic protocol. In a preliminary report, Mills et al. [19] obtained a TOF⁰.7 of 23.7 +/- 8.5 min after reversal of 1.5 mg/kg rapacuronium with 0.05 mg/kg neostigmine. Recovery occurred more slowly when 1 mg/kg edrophonium was substituted for neostigmine. In addition, no controls were included to allow the extent of acceleration induced by anticholinesterases to be estimated. In the study by Mills et al., the times to TOF⁰.7 were longer than in the current study, even though the clinical durations were similar (9.1 vs. 8.4 min, respectively). The reasons for the differences are uncertain but may have been influenced by differences in responses to neuromuscular relaxants observed in patients in North America and Europe. [20,21] The rates of spontaneous recovery that we observed in the current study were similar to those previously reported. [2]

Previous attempts at early reversal of currently available neuromuscular relaxants have been unsuccessful. Intense neuromuscular block is usually difficult to reverse: The dose of neostigmine required to antagonize 99% block produced by atracurium is twice that needed to reverse a 90% block. [22] Edrophonium is less effective than neostigmine in antagonizing profound pancuronium block. [23] Rupp et al. [12] showed that the time for recovery from profound neuromuscular block produced by pancuronium, atracurium, or vecuronium was prolonged when reversed with neostigmine and, particularly, with edrophonium. Engbaek et al. [15] showed that the total recovery time after an infusion of atracurium was not reduced by early injection of neostigmine, and Magorian et al. [16] concluded that the total time to achieve adequate recovery of neuromuscular function was the same regardless of whether neostigmine was administered 15 min after vecuronium was given or when T¹had recovered to 10% of control levels. Several investigators have tried to determine the optimum reversal regimen for different relaxants. Kirkegaard-Nielson et al. [14] showed that the shortest time from the last dose of atracurium to TOF⁰.7 was achieved when 0.07 mg/kg neostigmine was given when T¹was 4%-8%. After vecuronium, Baurain et al. [13] showed that, 15 min after reversal, the highest TOF and 100-Hz tetanic fade ratios were obtained with 0.04 mg/kg neostigmine given at 25–50% T¹. The same group of researchers found adequate responses to TOF and 100-Hz tetanic stimulation when 0.04 mg/kg neostigmine was given at 25% T¹after rocuronium, vecuronium, and atracurium, but recovery was incomplete after pancuronium. [17] These studies suggested that early reversal of nondepolarizing neuromuscular block with drugs other than rapacuronium is likely to be ineffective, inadequate, or both.

It is not clear why rapacuronium was reversed more quickly than we had anticipated. The more rapid reversal of intermediate-acting than long-acting neuromuscular-blocking drugs is thought to result from the more rapid spontaneous recovery of the intermediate agents and not from greater anticholinesterase-induced acceleration. Rapacuronium is a muscle relaxant with a recovery index that is similar to those of atracurium and vecuronium. Therefore, similar reversal might be anticipated. Rapacuronium is a monoquaternary vecuronium derivative in which lengthening of the 17 [Greek small letter beta]-ester group coincides with lengthening of the alkyl-chain at the 16-N position. These changes lead to decreased potency and increased lipophilicity. [6] Although this is associated with more rapid initial plasma clearance, and probably redistribution, for rapacuronium than for vecuronium or rocuronium, it is not clear if this might also facilitate displacement of rapacuronium from the neuromuscular junction.

There are several differences between the experimental protocol used in this study and clinical anesthesia practice. The patients were healthy young adults, mainly female. Thus, prompt and predictable spontaneous recovery would be expected. The choice of women reflects the available healthy population for study undergoing surgery in our institutions, although research has shown that women are more sensitive to neuromuscular-blocking drugs than men are, and the onset of block is more rapid in women, probably because of the decreased volume of distribution for these hydrophilic compounds. [24] Stabilization of the neuromuscular monitor resulted in some delay between induction of anesthesia and tracheal intubation, when light anesthesia was maintained with propofol infusion. Neuromuscular blockade was assessed using mechanomyographic twitch response, and recovery to TOF⁰.7 was the achievable standard. Avoiding some effects of mild neuromuscular blockade, such as impaired ventilatory response to hypoxia [25] or incoordinate swallowing with the risk of regurgitation and aspiration, [26] may require greater degrees of recovery, to TOF⁰.9. However, adverse clinical effects resulting from persistent postoperative neuromuscular block have only been confirmed after the use of the long-acting relaxant pancuronium in patients in whom TOF was < 0.7 in the postanesthetic care unit. [10]

Adverse events attributed to rapacuronium administration were observed in 10 patients, and eight involved bronchospasm. This is a greater proportion of patients in whom bronchospasm developed compared with previous studies. Kahwaji et al. [2] reported that bronchospasm developed in 2 of 178 patients after rapacuronium. This requires further evaluation because the current study was not designed, primarily, to evaluate the respiratory effects of rapacuronium. Although the investigators suggested that the events were probably or possibly related to rapacuronium, other possible causes include light anesthesia and hyperreactive airways.

Rapacuronium was shown previously to produce intubating conditions similar to those achieved with succinylcholine. [6] In this study, we found that when 1.5 mg/kg rapacuronium is administered and reversed with neostigmine 2–5 min later, recovery to TOF⁰.7 occurs within 20 min of its administration. Thus, it may be used as a nondepolarizing alternative to succinylcholine, which has many side effects and complications. [27] Further studies are needed to determine the optimum dose and timing for rapacuronium and for the reversal drugs, because only one study has been reported using an anticholinesterase other than neostigmine. [19] In addition, the side effect profile of rapacuronium needs careful evaluation to ensure that the incidence of adverse effects is no greater than with other agents. Early investigative studies have shown the possibility of histamine-related phenomena such as bronchospasm and hypotension. [2] In the current study, 10 patients experienced bronchospasm, with one episode lasting more than 6 min.

In conclusion, the intense neuromuscular block produced by an intubating dose of rapacuronium can be reversed with neostigmine (0.05 or 0.07 mg/kg) given 2 or 5 min after the relaxant. Recovery to TOF⁰.7 occurred within 20 min after the reversal with 1.5 mg/kg. Different doses of neostigmine (0.07 or 0.05 mg/kg) or timing (2 or 5 min after rapacuronium) led to similar recovery times.