Despite apparently adequate clinical reversal of long-acting neuromuscular blocker (NMB), a 44% and 36% incidence of residual block in the recovery room, defined as a train-of-four (TOF) ratio of <0.7, was reported by Viby-Mogensen et al. (1) and Bevan et al. (2), respectively. The frequency (8%–9%) of residual block was noted after the use of the intermediate-acting NMB drug with reversal of neostigmine (2,3). Although perioperative neuromuscular monitoring has been useful in reducing the incidence of residual block (4), many anesthesiologists often do not monitor neuromuscular function when using an intermediate-acting drug because residual curarization after anesthesia is less common after the use of intermediate-acting drugs, such as vecuronium and rocuronium, than after pancuronium (5,6).
Neostigmine had been reported for many years to antagonize the NMB as an anticholinesterase (1–9). Pyridostigmine is widely used in many countries, but there is only limited information available about the incidence of postoperative residual neuromuscular block after the use of vecuronium and rocuronium with reversal by pyridostigmine. In addition, head-lift for 5 s has been used clinically for the assessment of residual block (1–9), but it requires the patient’s active cooperation. Recommendations have suggested that the tongue-depressor test (10) is required to ensure safety in situations where the patient’s active cooperation is not feasible.
The current study was designed to compare the incidence and severity of postoperative residual neuromuscular block in patients entering the recovery room after the use of either vecuronium or rocuronium, which was antagonized with pyridostigmine, and when perioperative neuromuscular function was not monitored. Attempts were made to identify causative factors in patients demonstrating a residual neuromuscular block.
After obtaining Hospital Ethics Committee approval and informed consent, we studied 602 adult patients, ASA physical status I–III, aged 19–64 yr, and scheduled to undergo elective surgical procedures. No patient had any disease or metabolic abnormality known to alter neuromuscular transmission or was receiving any drug known or suspected of interfering with neuromuscular function. Edentulous patients were also excluded from the present study. All patients had similar types of anesthetics. The choice of drugs used for anesthesia and NMB was at the discretion of the anesthesiologist who was unaware that the patient would be assessed in the recovery room. The patients were premedicated with midazolam 0.05 mg/kg IM approximately 1 h before the operation. Anesthesia was induced with thiopental 3–5 mg/kg and fentanyl 2 μg/kg until the patient was asleep and maintained with either 1%–2% enflurane or 1%–1.5% isoflurane and 50% N2O in oxygen. Endotracheal intubation was performed after the administration of either vecuronium 0.1 mg/kg or rocuronium 0.6 mg/kg. If required, relaxation was maintained with a supplementary dose of either vecuronium 2 mg or rocuronium 10 mg, respectively, according to the clinical judgement of the anesthesiologist. After completion of the surgical procedure, a bolus of pyridostigmine was administered in a dose of either 0.143 mg/kg (equivalent to 10 mg/70 kg) or 0.286 mg/kg (equivalent to 20 mg/70 kg) and glycopyrrolate 8 μg/kg, respectively. The timing and dose of administration of pyridostigmine were chosen by the participating anesthesiologist. Adequacy of recovery from neuromuscular block and the decision to extubate the endotracheal tube before arrival in the recovery room were based on clinical criteria only.
Immediately after arrival in the recovery room, an investigator who was unaware of the patient’s group measured the TOF response using an acceleration transducer (TOF Watch®, Organon Teknika, Holland) (11), and the TOF ratio was recorded. The ulnar nerve was stimulated supramaximally (50 mA) by two skin electrodes placed on the forearm, and the transducer was fixed over the distal interphalangeal joint of the thumb. We kept the hand immobilized by fixation on the hard plate for accelerometry. Free movement of the thumb was ensured. Postoperative residual neuromuscular block was defined as a TOF ratio <0.7, as proposed previously (1–3). The groups were compared for frequency and degree of postoperative residual neuromuscular block based on this criterion. After monitoring of the TOF ratio, the body core temperature was measured with a tympanic membrane probe (ThermoScan®, Braun, Germany) in all patients.
Each patient was also asked to perform a head-lift for 5 s. In addition, a standard wooden tongue depressor was placed between each patient’s incisor teeth, and he or she was told not to let the investigator pull it out of his or her mouth. All patients were easily able to retain the device despite rather vigorous attempts to dislodge it (10). If a patient was unable to perform these tests, they were judged to be a failed clinical recovery. The doses of pyridostigmine administered in the groups were retrospectively compared from examination of the anesthetic records.
For statistical evaluation of the results, the Student’s t-test, χ2 test, and random coefficient linear regression were used. Results were considered statistically significant when P < 0.05.
There was no difference between adequate (TOF ratio >0.7) and inadequate (TOF ratio <0.7) groups concerning ASA physical status, sex, age, weight, and height. Inadequate recovery from neuromuscular block in the recovery room was found in 125 (20.8%) patients (Table 1). There were no differences in TOF ratio between 10 mg and 20 mg of pyridostigmine after the use of either vecuronium or rocuronium. Similarly, no differences were found between the enflurane or isoflurane groups. The recovery of TOF ratio was greater in patients who had received rocuronium than those who had received vecuronium with reversal with pyridostigmine 10 mg or 20 mg (P < 0.01) (Table 2). Figure 1 shows a similar pattern of the recovery of TOF ratio in vecuronium, rocuronium, enflurane, and isoflurane (P < 0.537).
There was a similar incidence of residual block after reversal of pyridostigmine 10 mg (21.5%) and 20 mg (19.9%), respectively (Table 3). The incidence of residual block after vecuronium (24.7%) was more frequent than that after rocuronium (14.7%;P < 0.01). The patients with residual block had received a larger cumulative dose of vecuronium, and a shorter time had elapsed since the last NMB was injected in these patients. However, the time from the injection of pyridostigmine to TOF recording was similar in both groups. Tracheal extubation was performed in 93.4% of patients before arrival in the recovery room. The body core temperature in the patients with residual block was lower compared with that of adequate recovery (P < 0.001).
Head-lift for 5 s and the tongue-depressor test could not be sustained by any patients at a TOF ratio of 0.5. Clinical testing was only possible in cooperative patients. The failed patients in the 5-s head-lift group were a larger proportion than those in the tongue-depressor test group after either vecuronium or rocuronium, respectively (P < 0.001). The TOF ratio of the recovered patients was greater than that of the failed patients in the 5-s head-lift group after either vecuronium or rocuronium, respectively (P < 0.001). There were no differences in the recovery of TOF ratio between the 5-s head-lift test and the tongue-depressor test of patients who were either recovered or failed in the recovery room (Table 4).
Thirty-eight patients below 0.5 of TOF ratio were required further reversal in the recovery room with neostigmine 1.0 mg and atropine 0.5 mg for rapid clinical improvement.
The present study shows that without perioperative neuromuscular monitoring, residual curarization after an intermediate-acting NMB remains a problem, even with reversal using a large dose of pyridostigmine. Also, the five-second head-lift test is a more sensitive clinical index than the tongue-depressor test in the recovery room.
The rate of recovery from nondepolarizing blocking drugs after their reversal with anticholinesterases is dependent upon the spontaneous rate of recovery and its augmentation by reversal drugs (5,6). A TOF ratio of <0.7 in 8%–9% of patients was observed when vecuronium had been used for relaxation and was reversed by neostigmine (2,3). If a TOF ratio <0.8 indicated residual curarization, the frequency of residual block induced by rocuronium was reported to be 16.7% in patients without perioperative neuromuscular monitoring (12). There was a similar result (14.7%) with a TOF ratio of <0.7. In the present study, the frequency of residual block induced by vecuronium and rocuronium was 24.7% and 14.7%, respectively. The more frequent incidence of residual block than previous results in accelerometry might be because of the absence of perioperative neuromuscular monitoring (4), the use of pyridostigmine, which is less potent than neostigmine (13), faulty monitoring technique as hand movement by stimulus pain in awake patients (14), or peripheral cooling. Rocuronium had one sixth of the potency of vecuronium, a more rapid onset, a similar duration of action, and similar pharmacokinetic behavior (15). The incidence of residual block after rocuronium was less than that after vecuronium (12), and we also found similar results. We suspect that less residual block after rocuronium in the recovery room was because of the patients receiving less equivalent drugs based on the one-sixth-potency ratio.
The onset of action of neostigmine was seven to 11 minutes. However, pyridostigmine took as long as 16 minutes to exert its full effect and had one-fifth the potency of neostigmine (13). In the present study, the average time from pyridostigmine administration to TOF recording was 28 minutes. Therefore, we suspect that the difference of potency might be the main reason for a more frequent incidence of postoperative residual neuromuscular block after reversal by pyridostigmine rather than neostigmine. However, pyridostigmine produced fewer complications such as bradycardia, increased salivation, and increased bowel motility than neostigmine (16). The antagonism produced by a large dose (20 mg) of pyridostigmine was similar to that produced by a small dose (10 mg) at 30 minutes after reversal injection (9). We also found similar results of no difference between 10 mg and 20 mg of pyridostigmine. The time of TOF recording was a fairly long interval (13–44 minutes) from pyridostigmine in the current study. If we had tested the TOF stimulation earlier with the strict criteria, we might have confirmed the difference between the doses. The residual block might be caused by too short a time between the last dose of NMB and pyridostigmine (Table 3).
The impaired recovery may have been caused by the longer durations of surgery, which required prolonged neuromuscular block and prolonged exposure to inhaled drugs, and by profound relaxation from the laparotomy. We suspect that the residual curarization could be caused by an exposure over a longer time to enflurane or isoflurane. However, we were limited when comparing the influence of inhaled anesthetics because all groups received some of these drugs. We could not find significant differences in the recovery pattern of TOF ratio related to the choice of the NMB and inhaled anesthetics. However, an improved tendency of the recovery in the TOF ratio was shown with the use of rocuronium and isoflurane compared with vecuronium and enflurane, respectively (Fig. 1).
Vecuronium is eliminated via the liver by a carrier-mediated active transport process, which is temperature-dependent. Reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium by hypothermia (17). Rocuronium is a structural relative of vecuronium, and its clearance also decreases with hypothermia (18). The present study demonstrated that reduced core temperature might be associated with an increased incidence of impaired recovery related to the reduced metabolism of NMB.
A TOF ratio of 0.7 was chosen as the critical value because studies in awake volunteers have demonstrated impaired ventilatory function at values less than these (19). It has long been suspected that the use of NMB might be responsible for postanesthetic morbidity. In the present study, 38 patients with a ratio less than 0.5 required supplementary reversal in the recovery room. Our choice of this value was based on the fact that head-lift for five seconds could not be sustained by any patients at a TOF ratio of 0.5 (7). However, after 20 mg of pyridostigmine, supplementary reversal might be unreliable to produce any positive effect. It was then thought that residual curarization induced by vecuronium caused pharyngeal dysfunction and increased risk for aspiration at TOF ratio <0.9 (20). A growing consensus now suggests that full recovery implies a TOF ratio of more than 0.9. Thus, residual curarization will be present more frequently than is supposed.
Several authors (1–3,10) found a poor correlation between TOF ratio and ability to sustain a head-lift for five seconds, in contrast to several others (7,8,21) who found that a five-second head-lift seemed to be a better test when residual curarization was clinically evaluated. Engbaek et al. (7) reported that the TOF ratio had to recover to 0.8 before all patients could sustain a head-lift for five seconds, and it could not be sustained for any patient at a TOF ratio of 0.5. Our observations were similar.
Kopman et al. (10) reported that the tongue-depressor test was more sensitive than the five-second head-lift. During emergence from anesthesia, the tongue-depressor test was possible if patients simply open their mouths. It also could be performed by removing a bite block or oral airway when the patient’s jaw could not be opened manually. The tongue-depressor test was performed adequately at a TOF ratio <0.7, and the value at which it was accomplished was >0.85. However, in the present study, the lesser sensitivity of the tongue-depressor test than the five-second head-lift test for detecting block was demonstrated by the fact that the failure rate of the tongue-depressor test was less than that of five-second head-lift test. Despite the similar values of TOF ratio, there was a significant difference of TOF ratio between the failed and recovered groups in the five-second head-lift test, whereas there was no difference in the corresponding values in the tongue-depressor test.
TOF stimulation clearly was not painless in awake volunteers because the median visual analog scale value for TOF at 50 mA was 5.0 (22). In the present study, supramaximal stimulation was only used for the accuracy of the data, and then submaximal stimulation (20 mA) was clinically used to reduce the pain if required. A tactile evaluation cannot satisfactorily assess residual neuromuscular block (23). Therefore, the use of a small monitor that displays TOF values is important. The TOF Watch® is no bigger than a usual nerve stimulator and allows for more immediate assessment of TOF ratio in the recovery room than mechanomyography or electromyography (11).
The present study gave the anesthesiologist a choice of drugs and their doses for premedication, inhaled anesthesia, and NMB. This design has the advantage of making observations relevant to clinical anesthesia. However, it also suffers from disadvantages that can be avoided in a tightly controlled study. Differences between techniques may be difficult to identify.
In conclusion, the results of the present study emphasize the potential of residual neuromuscular block after vecuronium or rocuronium even after reversal with a large dose of pyridostigmine and without perioperative neuromuscular monitoring. Therefore, clinicians should not rely on clinical criteria alone, even when using an intermediate-acting NMB.
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