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The Duration of Residual Neuromuscular Block After Administration of Neostigmine or Sugammadex at Two Visible Twitches During Train-of-Four Monitoring

Illman, Hanna L., MD*; Laurila, Päivi, MD, PhD; Antila, Heikki, MD, PhD*; Meretoja, Olli A., MD, PhD; Alahuhta, Seppo, MD, PhD†,§; Olkkola, Klaus T., MD, PhD*

doi: 10.1213/ANE.0b013e3181fdf889
Anesthetic Pharmacology: Research Reports
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BACKGROUND: Adequate recovery from neuromuscular block (NMB) is imperative for the patient to have full control of pharyngeal and respiratory muscles. The train-of-4 (TOF) ratio should return to at least 0.90 to exclude potentially clinically significant postoperative residual block. Fade cannot be detected reliably with a peripheral nerve stimulator (PNS) at a TOF ratio >0.4. The time gap between loss of visual fade by using a PNS until objective TOF ratio has returned to >0.90 can be considered “the potentially unsafe period of recovery.” According to our hypothesis the duration of this period would be significantly shorter with sugammadex than with neostigmine.

METHODS: Fifty patients received volatile anesthetics, opioids, and a rocuronium-induced NMB. TOF-Watch® without a preload was used, but the anesthesiologist relied on visual evaluation of the TOF responses only. At end of operation, patients were randomized to receive either neostigmine 50 μg/kg or sugammadex 2 mg/kg, when 2 twitch responses were detected after the last dose of rocuronium. Timing of tracheal extubation was based on PNS and clinical data. Duration of the potentially unsafe period of recovery after reversal by either neostigmine or sugammadex was analyzed. Mann–Whitney U test and Pearson χ2 test were used for statistical analysis.

RESULTS: The times [mean ± SD (range)] from loss of visual fade to TOF ratio >0.90 were 10.3 ± 5.5 (1.3 to 26.0) minutes and 0.3 ± 0.3 (0.0 to 1.0) minutes in the neostigmine and sugammadex groups, respectively (P < 0.001). The times from reversal by neostigmine or sugammadex to TOF ratio >0.90 were 13.3 ± 5.7 (3.5 to 28.9) and 1.7 ± 0.7 (0.7 to 3.5) minutes, respectively (P < 0.001). The values of TOF ratios at the time of loss of visual fade were 0.34 ± 0.14 (0.00 to 0.56) in patients given neostigmine and 0.86 ± 0.11 (0.64 to 1.04) in patients given sugammadex (P < 0.001).

CONCLUSIONS: There is a significant time gap between visual loss of fade and return of TOF ratio >0.90 after reversal of a rocuronium block by neostigmine. Sugammadex in comparison with neostigmine allows a safer reversal of a moderate NMB when relying on visual evaluation of the TOF response.

Published ahead of print October 26, 2010

From the *Turku University Hospital and University of Turku, Turku, Finland; Oulu University Hospital, Oulu, Finland; Helsinki University Hospital, Helsinki, Finland; and §University of Oulu, Oulu, Finland.

The study was supported by Finnish MSD (Finnish Schering-Plough, Inc.).

Disclosure: Klaus T. Olkkola, Olli A. Meretoja, and Seppo Alahuhta are members of the advisory board of Finnish MSD and have received lecture honoraria from Finnish MSD. Hanna Illman has received lecture honoraria from Finnish MSD and MSD Inc. (Schering-Plough Inc.).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.anesthesia-analgesia.org).

Address correspondence to Hanna Illman, Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital and University of Turku, Kiinamyllynkatu 4–8, P.O. Box 52, FI-20521 Turku, Finland. Address e-mail to hanna.illman@tyks.fi.

Accepted August 31, 2010

Published ahead of print October 26, 2010

A peripheral nerve stimulator (PNS) is the most widely used monitor for assessment of the level of neuromuscular block (NMB) in the clinical environment. The basis for visual or tactile evaluation of the muscle response after a train-of-4 (TOF) stimulation is counting the number of twitches (1, 2, or 3) during moderate block and detection of fade in the twitch response as recovery progresses and all 4 responses are present. In the last years, several studies have shown that the ratio of the 4th response to the 1st response in the TOF sequence (TOF ratio)1,2 should return to at least 0.90 to ensure full control of pharyngeal and respiratory muscles and to maintain a normal hypoxic ventilatory response.3,4 The greatest weakness of visual or tactile evaluation of the muscle response is that a fade cannot be reliably detected whenever the TOF ratio is >0.4, because all 4 muscle contraction responses are seen or sensed equally at and beyond this range of fade.57 The time elapsed between the moment when the clinical anesthesiologist cannot detect a fade by visual or tactile assessment until the TOF ratio has been proven by objective measurement to exceed 0.90 may be called the “potentially unsafe period of recovery” or “no visual or tactile fade paralysis period.” During this period the patient may face a number of risks associated with residual NMB including an increased incidence of critical respiratory events.8,9

Neostigmine antagonizes NMB by inhibition of the enzyme acetylcholinesterase, thus increasing the amount of acetylcholine in the neuromuscular junction, but has no effect on the elimination rate of the neuromuscular blocking drug. The onset of action of neostigmine is relatively slow, and because of its ceiling effect, it cannot antagonize deep levels of NMB.6 The novel reversal drug sugammadex is—because of encapsulation of rocuronium, which occurs primarily in the plasma—capable of reversing even a deep or intense NMB, provided the dose is sufficient in comparison with the amount of rocuronium in the body.10 When given at an approximate 90% block of the twitch response (1st twitch is detectable in a TOF sequence), a TOF ratio can be expected to return to 0.90 only after 15 minutes after administration of neostigmine 50 μg/kg and within 3 minutes after sugammadex 2 mg/kg.1113 Thus, there may be a clinically significant potentially unsafe period of recovery between the time when the anesthesiologist assumes normal neuromuscular function to have been regained until this really happens, especially concerning neostigmine. The main purpose of this randomized controlled study was to compare the length of this potentially unsafe period of recovery after reversal of a NMB at the 2nd twitch (T2) with neostigmine and sugammadex, when the clinician relies on visual PNS monitoring only.

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METHODS

This double-blind and randomized multicenter study was conducted at the University Hospitals of Oulu and Turku, Finland. The study protocol was approved by the Ethics Committee of the Hospital District of Southwest Finland and by the Finnish Medicines Agency. The protocol was reported to the European EudraCT clinical trials register and given the code number EudraCT 2009-013537-22.

Fifty patients scheduled for elective surgery requiring general anesthesia were enrolled. The patients were men or women, ages 18 to 70 years and ASA physical status I–IV. To avoid possible bias associated with marked obesity, we included only patients with a body mass index of <32.5. Criteria for exclusion were clinically significant renal, hepatic, or ventilatory dysfunction, increased intracranial pressure, pregnancy, or lactation. Patients with muscular dystrophies, myopathy, or cerebral palsy and patients with a history of intolerance to any of the study drugs were also excluded. Medication known to interfere with neuromuscular transmission and simultaneous participation in other studies were also causes for exclusion. This study was performed in accordance with the good clinical research practice guidelines regarding studies of neuromuscular blocking drugs.14

On the morning of the day of surgery the patients received their normal medication, and routine premedication was administered 1 hour before surgery. General anesthesia was induced by propofol and an opioid, according to the routine of the study center. Depending on estimated duration of anesthesia and other clinical factors, rocuronium 0.6 to 1 mg/kg (actual body weight) was given to facilitate endotracheal intubation. Anesthesia was maintained by a volatile anesthetic (sevoflurane or desflurane) together with opioids. Regional anesthesia, mainly for the management of postoperative pain, was administered whenever indicated. Routine cardiorespiratory monitoring was applied. Specifically, arterial blood pressure (invasive or noninvasive), heart rate, continuous electrocardiogram, minute ventilation, respiration rate, inspiratory and end-tidal O2 and CO2, airway pressure, and pulse oximeter were used. Skin temperature of the hand was measured and kept above 33°C. A forced-air warming blanket was used when necessary. During maintenance of anesthesia, end-tidal PCO2 was kept between 34 to 40 mm Hg (4.5% to 5.3%). Any adverse effects during the study were recorded, together with the time at which the effect was noted, its severity, and duration.

The degree of NMB was measured with 1 monitor but with 2 methods: objective monitoring applying the acceleromyographic technique (TOF-Watch®; Organon, Inc., West Orange, New Jersey) was used in parallel with visual evaluation of the evoked responses. The TOF mode of stimulation (2 Hz; 0.2 ms) was applied at 15-second intervals throughout the procedure. The ulnar nerve was used for nerve stimulation, and the muscle response was measured at the adductor pollicis muscle. Supramaximal stimuli were applied after automatic calibration of the device after an initial tetanic stimulus (CAL 2 mode). No preload was used, but to avoid artifacts caused by movement, we fixed the patient's arm and other 4 fingers throughout the entire duration of the procedure. The anesthesiologist in charge of the patient was blinded to the objective measurements and quantified the degree of NMB only by visual evaluation of the muscle contraction response. The screen of the TOF-Watch device was covered with nontransparent paper. The objective measurements were transferred from TOF-Watch device to personal computer for further evaluation using TOF-Watch SX Monitor 2.2 software. Administration of additional rocuronium and timing of administration of either neostigmine or sugammadex were thus based only on visual evaluation of the TOF responses. Incremental doses of rocuronium 5 to 10 mg were administered whenever 2 twitch responses appeared visually.

At the end of surgery the anesthetized patients were randomly assigned to 2 groups. The randomization was performed by using computer-generated sealed envelopes to determine which reversal drug the patients were to receive. The envelope contained written instructions to prepare either neostigmine 50 μg/kg + glycopyrrolate 10 μg/kg or sugammadex 2 mg/kg to reverse the NMB. The anesthesiologist remained blinded to the reversal drug given throughout the remaining course of anesthesia. The study nurse or assisting investigator administered the reversal drug to the patient at the point at which the anesthesiologist had detected 2 visual twitch responses (T1 and T2) in 3 consecutive series of TOF stimulation. All participating anesthesiologists were experienced consultants and familiar with the interpretation of the TOF response. The time points when the anesthesiologist detected 1 and 2 twitch responses, 3 and 4 twitch responses after reversal, and the time when he or she was no longer able to detect a fade, were all recorded. Immediately after loss of visual fade, the clinical anesthesiologist discontinued the volatile anesthetic and allowed the patient to emerge from anesthesia. Subsequent timing of tracheal extubation was based on clinical judgment, and this time point was also recorded. Objective recording was continued in all cases until the TOF ratio had returned to 0.90 in 3 consecutive measurements. The patients were visited on the day after surgery unless already discharged from the hospital, in which case a nurse contacted them by telephone. Any adverse events occurring in the postanesthesia care unit or postoperatively were recorded.

The main objective was to determine the time gap between the loss of visual fade to the return of a TOF ratio of 0.90, i.e., the potentially unsafe period of recovery (alternatively the “no visual fade paralysis period”). Secondary end points were the times for return of the TOF ratio to 0.70, 0.80, and 0.90 after reversal, TOF ratio at loss of visual fade and at the time of tracheal extubation. We also recorded the times from loss of visual fade until return of a TOF ratio of 0.70 and 0.80 and the time from tracheal extubation until the return of a TOF ratio of 0.90.

Our neuromuscular data are based on original acceleromyographic recordings that the TOF-Watch documents in digital form. However, because Claudius et al. described the normalization of the raw acceleromyographic data that may improve accuracy,15 we also normalized all data by referring them to the control TOF values obtained during the minute preceding administration of the first rocuronium dose.

Calculation of the sample size was based on the time from the administration of neostigmine or sugammadex to the achievement of TOF ratio of 0.90. On the basis of previous studies,11,12 we calculated that 23 patients would be required in each of the 2 groups to demonstrate a 7-minute difference in the above time at a level of significance of P = 0.05 and power of 90%. We assumed that the SD would be up to 50% of the mean in patients given sugammadex and up to 100% of the mean in patients given neostigmine. Because we wanted to be prepared for dropouts, we decided to recruit 25 patients in each group after they had given their written informed consent.

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Statistical Analysis

All results are given as mean ± SD (range). Mann–Whitney U test and Pearson χ2 test were used for the statistical analysis of the data, as appropriate. P values of 0.05 or less were regarded as significant.

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RESULTS

Enrollment in the study began in November 2009 and ended in January 2010. All enrolled patients completed the study, but 2 patients from the neostigmine group and 1 patient from the sugammadex group were excluded. Reasons for exclusion were technical failure of the TOF-Watch in 2 patients (1 each from the neostigmine and sugammadex groups), and 1 patient (from the neostigmine group) awoke from anesthesia before the TOF ratio of 0.90 was established. Accordingly, 23 patients in the neostigmine group and 24 patients in the sugammadex group were included in the analysis (see Supplement Digital Content 1, Consort Statement Checklist, http://links.lww.com/AA/A198, and Supplement Digital Content 2, Flow Diagram, http://links.lww.com/AA/A199).

Characteristics of the patients and anesthesia are presented in Table 1. The patients were similar, and there were no significant differences in the conduct of anesthesia between the groups. The main results of the study are shown in Table 2 and Figure 1. The potentially unsafe periods of recovery, i.e., the times from loss of visual fade to the return of TOF ratio 0.90, were 10.3 ± 5.5 (1.3 to 26.0) minutes in the neostigmine and 0.3 ± 0.3 (0.0 to 1.0) minutes in the sugammadex groups, respectively (P < 0.001). Times from reversal until return of TOF ratio 0.90 were 13.3 ± 5.7 (3.5 to 28.9) minutes and 1.7 ± 0.7 (0.7 to 3.5) minutes, respectively (P < 0.001). TOF ratios at the time of loss of visual fade were 0.34 ± 0.14 (0.00 to 0.56) and 0.86 ± 0.11 (0.64 to 1.04), and at the time of extubation, 0.82 ± 0.14 (0.44 to 1.00) and 0.99 ± 0.02 (0.93 to 1.04) in the neostigmine and the sugammadex groups, respectively (P < 0.001).

Table 1

Table 1

Table 2

Table 2

Figure 1

Figure 1

Normalized TOF data could be calculated for the return of TOF ratio to 0.70 and 0.80. The control TOF ratio averaged 1.07 ± 0.09 (0.84 to 1.29). Because there is no internal normalization software in the TOF-Watch program, the neuromuscular monitoring was often discontinued before the normalized TOF ratio 0.90 was reached. However, the normalized TOF ratios at the time of loss of visual fade were 0.32 ± 0.15 and 0.80 ± 0.10 and at the time of extubation, 0.77 ± 0.16 and 0.96 ± 0.05 in the neostigmine and the sugammadex groups, respectively (P < 0.001). Times from loss of visual fade until return of TOF ratio to 0.70 and 0.80 were 1.9 and 2.1 minutes longer in the neostigmine group and 0.0 and 0.2 minutes longer in the sugammadex group in comparison with the respective nonnormalized data.

One patient in the neostigmine group suffered from postoperative nausea, but no other adverse events were observed. The incidence of perioperative hypotension requiring medication was similar in both groups (data not shown).

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DISCUSSION

Previous studies on the reversal of rocuronium-induced NMB by neostigmine have shown that neostigmine acts significantly more slowly than does sugammadex.1012,16 Our results fully corroborate these results and, in addition, give clinically important information about the potential risks if a clinician relies solely on visual estimation of NMB by using a PNS. The potentially unsafe period of recovery as defined earlier was reduced from an average time of 10 minutes with neostigmine (with a maximum time of 26 minutes) to <20 seconds with sugammadex (with a maximum time of 1 minute). On the basis of the previous reports, our results may even be expected. However, this study specifically demonstrates in a randomized controlled trial that the use of neostigmine in combination with visual assessment of the muscular response to PNS may increase the risk of postoperative residual paralysis and expose patients to an unnecessary risk of aspiration and hypoxia.3,4,8,17

It is important to bear in mind that our results are valid only at reversal of a moderate rocuronium block. Deeper levels of NMB require a larger dose of sugammadex,10 and speed of reversal is dependent on the level of NMB. Reversal by neostigmine in turn will remain incomplete regardless of the dose administered if reversal is attempted at deeper levels of block,16 because neostigmine will be unable to increase the amount of acetylcholine beyond a ceiling effect and thus cannot return the TOF ratio to the required 0.90 to minimize the risk for symptoms and complications due to postoperative residual paralysis.14 Neostigmine also has a number of well-known adverse effects related to its muscarinic activity—e.g., cardiovascular effects, nausea, and vomiting12—which are likely to become more pronounced if dosage is augmented. It is also important to consider other factors, e.g., residual effects of anesthetics, which may further impair breathing and pharyngeal and laryngeal function in the postoperative period.18 With this in mind, the use of objective neuromuscular monitoring to minimize the incidence of residual paralysis seems even more warranted.

There is a widespread consensus among experts that objective methods of monitoring are far more accurate and reliable than is tactile or visual evaluation of the muscle contraction responses after stimulation by a PNS.7,19 Nevertheless, the use of tactile or visual evaluation instead of objective monitoring, and even relying merely on rather diffuse clinical signs of recovery, is still widespread in the clinical setting.20,21 Among anesthesiologists who regularly use a PNS for assessment of neuromuscular function, it is also commonly believed that no reversal is necessary when fade in the muscular response has disappeared. We compared 2 methods of monitoring TOF response during the recovery phase after reversal of an intermediate level of rocuronium block: visual evaluation of the TOF response and simultaneously measured acceleromyographic TOF ratios. Visual assessment, rather than the more commonly used tactile evaluation, was used with the specific purpose of avoiding any kind of movement of the monitored hand, because this would have rendered the objectively measured results unreliable. Furthermore, visual and tactile evaluations of NMB produce comparable results at low to moderate levels of fade.7,19 Use of the same device, instead of 2 separate ones, for both monitoring methods was likewise done to improve comparability (and thus reliability).

One objective was to evaluate at which TOF ratio a clinician, relying solely on visual evaluation, will detect no fade in the response and thus assume recovery to be adequate. According to our hypothesis, relying on visual evaluation of the TOF responses would lead to significant overestimation of the degree of recovery. This proved to be true especially with neostigmine.

Experienced anesthesiologists could not detect a fade in the TOF response visually at levels beyond an average TOF ratio of 0.34 in the neostigmine group. The corresponding TOF ratio values in the sugammadex group were significantly higher because of its much faster onset of action. In the sugammadex group the lowest TOF ratio value when fade could not be detected was 0.64, whereas in the neostigmine group values <0.10 were observed. Our study clearly shows that adequate recovery from a rocuronium block cannot be ensured by using visual evaluation of NMB, especially when neostigmine is the reversal drug and that objective monitoring is needed to exclude residual paralysis. This finding is in good accordance with previous studies.7,22 The time factor should also be considered, because full recovery obviously will occur eventually in all individuals even without reversal. However, as Debaene et al. have shown in a previous study,23 interindividual variations in the speed of spontaneous recovery are quite large: a significant proportion of patients in their study presented with TOF ratios <0.9 and even <0.7 as long as 2 hours after a single induction bolus of the intermediate-acting neuromuscular blocking drugs rocuronium, vecuronium, and atracurium. Therefore, one cannot rely on time alone when determining whether there is a need for reversal or monitoring of a NMB.

The time elapsing from the moment the clinical anesthesiologist could not see a fade in the TOF responses, and therefore considered full recovery to have taken place, until the return of TOF ratio >0.90 was of particular interest. We refer to this time as the potentially unsafe period of recovery, during which the patient may face numerous risks, such as aspiration and hypoxia.3,4,8 In our study the mean potentially unsafe period of recovery was 10.3 minutes in the neostigmine group and only 0.3 minute in the sugammadex group. However, there was also a significant variation in recovery times between individuals within the neostigmine group, because the longest potentially unsafe period of recovery in this group was 26.0 minutes, whereas in the sugammadex group the longest potentially unsafe period was just 1.0 minute. At extubation, TOF ratios were also significantly lower in the neostigmine group. We used a 50 μg/kg dose of neostigmine in each patient randomized to receive neostigmine.24 Suboptimal doses will lead to even longer potentially unsafe periods. This can also be expected when neostigmine reversal is attempted at a deep level of NMB.

For objective measurements we chose to use acceleromyography, because the TOF-Watch monitor is widely used clinically and therefore familiar to many anesthesiologists. We recalculated our data to normalize all TOF ratio values.15 This procedure made the differences between the groups even greater. TOF ratios at the time of loss of visual fade and at the time of extubation were lower, and the times from loss of visual fade to the return of TOF ratio 0.70 and 0.80 became longer, especially in the neostigmine group. It is easy to extrapolate that the potentially unsafe period of recovery would also have become a few minutes longer in the neostigmine group if monitoring technique had allowed us to calculate this value. Because all studies with sugammadex have used nonnormalized TOF ratio values, we also presented them as our primary results. Furthermore, even Claudius et al. do not recommend normalizing acceleromyographic data.15 It is fair to assume that similar or even more dramatic results would have been observed by using, for instance, electro- or mechanomyography.15

In a study by Kopman et al.,25 a rocuronium NMB was reversed at T2 with neostigmine 50 μg/kg, similar to our study, but electromyography rather than acceleromyography was used. As can be expected, reversal times were somewhat longer when NMB was monitored electromyographically. It is indeed important to consider this tendency of nonnormalized acceleromyographic data to show higher levels of recovery than that with other methods. This further increases the significance of our findings. It has been proposed that the acceleromyographically measured TOF ratio should return to 1.0 rather than 0.9 to ensure adequate neuromuscular recovery.14

The use of 2 different volatile anesthetics and 3 different opioids might be regarded as another weakness of the study. However, because the use of volatile anesthetics and opioids did not differ between the 2 groups, we believe that our conclusions on the neuromuscular recovery are valid.

We conclude that when only visual evaluation of the TOF response is performed, there is a potentially unsafe period of recovery of clinical significance associated with reversal of a moderate rocuronium-induced NMB with neostigmine. Sugammadex is associated with both a statistically and clinically significant shorter period of potentially unsafe recovery.

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