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Perioperative Medicine  |   September 2017
Reversal of Vecuronium-induced Neuromuscular Blockade with Low-dose Sugammadex at Train-of-four Count of Four: A Randomized Controlled Trial
Author Notes
  • From the Department of Anesthesiology and Intensive Care, University of Debrecen, Debrecen, Hungary (L.A., Z.S.-M., A.G., R.N., A.P., B.F., E.T.); Outcomes Research Consortium, Cleveland, Ohio (B.F.); and Department of Ecology, Danube Research Institute, Centre for Ecological Research, Hungarian Academy of Sciences, Debrecen, Hungary (S.L.).
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication October 7, 2016. Accepted for publication May 11, 2017.
    Submitted for publication October 7, 2016. Accepted for publication May 11, 2017.×
  • Address correspondence to Dr. Fülesdi: Department of Anesthesiology and Intensive Care, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. fulesdi@med.unideb.hu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Clinical Science / Neuromuscular Diseases and Drugs / Neurosurgical Anesthesia
Perioperative Medicine   |   September 2017
Reversal of Vecuronium-induced Neuromuscular Blockade with Low-dose Sugammadex at Train-of-four Count of Four: A Randomized Controlled Trial
Anesthesiology 9 2017, Vol.127, 441-449. doi:10.1097/ALN.0000000000001744
Anesthesiology 9 2017, Vol.127, 441-449. doi:10.1097/ALN.0000000000001744
Abstract

Background: Rocuronium-induced neuromuscular block that spontaneously recovered to a train-of-four count of four can be reversed with sugammadex 0.5 or 1.0 mg/kg. We investigated whether these doses of sugammadex can also reverse vecuronium at a similar level of block.

Methods: Sixty-five patients were randomly assigned, and 64 were analyzed in this controlled, superiority study. Participants received general anesthesia with propofol, sevoflurane, fentanyl, and vecuronium. Measurement of neuromuscular function was performed with acceleromyography (TOF-Watch-SX, Organon Teknika B.V., The Netherlands ). Once the block recovered spontaneously to four twitches in response to train-of-four stimulation, patients were randomly assigned to receive sugammadex 0.5, 1.0, or 2.0 mg/kg; neostigmine 0.05 mg/kg; or placebo. Time from study drug injection to normalized train-of-four ratio 0.9 and the incidence of incomplete reversal within 30 min were the primary outcome variables. Secondary outcome was the incidence of reparalysis (normalized train-of-four ratio less than 0.9).

Results: Sugammadex, in doses of 1.0 and 2.0 mg/kg, reversed a threshold train-of-four count of four to normalized train-of-four ratio of 0.9 or higher in all patients in 4.4 ± 2.3 min (mean ± SD) and 2.6 ± 1.6 min, respectively. Sugammadex 0.5 mg/kg reversed the block in 6.8 ± 4.1 min in 70% of patients (P < 0.0001 vs. 1.0 and 2.0 mg/kg), whereas neostigmine produced reversal in 11.3 ± 9.7 min in 77% of patients (P > 0.05 vs. sugammadex 0.5 mg/kg). The overall frequency of reparalysis was 18.7%, but this incidence varied from group to group.

Conclusions: Sugammadex 1.0 mg/kg, unlike 0.5 mg/kg, properly reversed a threshold train-of-four count of four vecuronium-induced block but did not prevent reparalysis.

What We Already Know about This Topic
  • Rocuronium-induced neuromuscular block can be reversed with sugammadex 0.5 mg/kg and 1.0 mg/kg when four twitches in response to train-of-four stimulation have reappeared

  • The affinity of sugammadex for rocuronium is 3.1 times that for vecuronium

  • Because the neuromuscular blocking potency of vecuronium is six times that of rocuronium, fewer vecuronium molecules are required to produce similar degrees of neuromuscular block

What This Article Tells Us That Is New
  • Sugammadex 0.5 mg/kg did not produce prompt and satisfactory neuromuscular recovery when administered at a threshold train-of-four count of four after vecuronium administration

  • Sugammadex 1.0 mg/kg adequately reversed this level of block, although recovery took twice as long as has been reported after rocuronium

  • Recurrent neuromuscular block occurred after treatment of this level of block with sugammadex doses of 0.5 to 2.0 mg/kg

LIKE rocuronium, vecuronium is an aminosteroid neuromuscular blocking agent with intermediate duration of action.1  Sugammadex is a modified γ-cyclodextrin compound2  that reverses the neuromuscular blockade produced by rocuronium,3  vecuronium,4,5  and pipecuronium6  by encapsulating them, making them unavailable to interact with the nicotinic acetylcholine receptors at the neuromuscular junction. The encapsulation of steroidal relaxants by sugammadex is a one-to-one molecular interaction depending on the affinity of sugammadex for the relaxant,2  on the depth of neuromuscular block at the time of antagonism, and on the dose of sugammadex.7  The affinity of the neuromuscular blocking agent for sugammadex is numerically described by the association constant (Ka). The higher the Ka, the greater the affinity. The Ka is 3.1 times higher for rocuronium than for vecuronium (1.79 × 107 mol/L and 5.72 × 106 mol/L, respectively),8  whereas the dissociation constant (Kd), which is the inverse of the association constant, is 3.1 times higher for vecuronium than for rocuronium (0.17 and 0.055 μM, respectively).8  Several investigators compared the antagonism with sugammadex of moderate (train-of-four [TOF] count of two)4,9  and deep (posttetanic count one to two) vecuronium- and rocuronium-induced neuromuscular block.10–12  Significant dose–response relationships were demonstrated for mean recovery times to TOF ratio 0.9 with sugammadex 0.5, 1.0, 2.0, 4.0, and 8.0 mg/kg showing slower recovery from vecuronium-induced (35.0 vs. 1.7 min) than from rocuronium-induced neuromuscular block (16.0 vs. 1.1 min).9,10  Also, recurrence of acceleromyographic neuromuscular block (TOF ratio less than 0.9) was reported to occur in some patients who received low doses of sugammadex for the reversal of moderate or deep neuromuscular block.9,10,12  However, the comparative literature on this topic is scant. For example, we do not know whether low-dose sugammadex would properly reverse a shallow vecuronium-induced neuromuscular block and whether it would prevent a recurrent block. It has been demonstrated that a threshold TOF count-of-four rocuronium-induced neuromuscular block can be reversed with sugammadex 1.0 mg/kg within 2.1 min, and sugammadex 0.5 mg/kg reversed such neuromuscular block in 4.1 min on average.13  These data, however, may not be valid for vecuronium. Because the neuromuscular potency of vecuronium is six times greater than that of rocuronium (ED95 = 0.05 and 0.30 mg/kg, respectively)1  and their molecular weight is similar (637 and 610 Da, respectively, http://www.scbt.com/datasheet-205880.html; accessed December 15, 2015), fewer vecuronium than rocuronium molecules produce similar degrees of neuromuscular block. To encapsulate 1.0 mg vecuronium 3.4 mg of sugammadex is necessary, and to encapsulate the intubating dose (e.g., 7.0 mg), 2.4 mg sugammadex is sufficient. Theoretically, a sugammadex dose as low as 0.5 mg/kg is enough to encapsulate all vecuronium molecules present in the body at any time after the administration of vecuronium 0.10 mg/kg. Although the affinity of vecuronium for sugammadex is lower than that of rocuronium, we hypothesized that the above-described factors may partially compensate the lower affinity of vecuronium, and thus low doses of sugammadex would adequately reverse a threshold TOF count-of-four vecuronium-induced neuromuscular block.
Materials and Methods
Trial Design and Participants
This single-center, randomized, controlled, five parallel-arm, superiority trial was approved by the local ethics committee at the University of Debrecen (Debrecen, Hungary) and by the National Institute of Pharmaceutics (Budapest, Hungary; OGYI/3194–8/2014). The study is classified under European Clinical Trials Database No. 2013-004666-34.
The investigations and data collections were carried out at the University Hospital of Debrecen (Debrecen, Hungary) between April 2015 and May 2016. The study followed the Consolidated Standards of Reporting Trials 2010 recommendations for randomized controlled trials (http://www.consort-statement.org/consort-2010; accessed June 16, 2017).
Seventy patients undergoing routine elective surgery were assessed for eligibility, and 65 were enrolled in this study (fig. 1). The study staff recruited the participants at the University Hospital of Debrecen. Entrants gave written, informed consent to participate. They were randomly assigned to one of the five study groups to receive sugammadex 0.5, 1.0, or 2.0 mg/kg, neostigmine 0.05 mg/kg and atropine 0.015 mg/kg, or 0.9% saline (placebo; fig. 1). Inclusion criteria were age of 18 to 65 yr, body mass index 18.5 to 25.0 kg/m2, American Society of Anesthesiologists physical status I to III, male/female ratio 1:1, and scheduled for elective surgery with an expected duration of at least 50 min necessitating muscle relaxant administration for intubation of the trachea but not always full relaxation for surgery. Exclusion criteria were suspected difficult airway, bronchial asthma, chronic obstructive pulmonary disease, neuromuscular disease, suspected malignant hyperthermia, significant hepatic or renal dysfunction, glaucoma, allergy to the drugs used in this study, and taking medication known to alter the effect of neuromuscular blocking agents. Patients who participated in another study within 30 days were not included, nor were pregnant or breastfeeding women.
Fig. 1.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
Fig. 1.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
×
Interventions and Neuromuscular Monitoring
Patients were given 7.5 mg midazolam orally 60 min before induction of anesthesia. In the operating room, an IV cannula was inserted in a forearm vein, and vital signs monitoring was started. The patients then received prophylactic antibiotic in the form of cefazoline (2 g), cefotaxime (2 g), or metronidazole (500 mg) depending on the type of surgery. Anesthesia was induced with IV propofol (1.5 to 2.0 mg/kg) and fentanyl (2.0 μg/kg) and maintained with inhaled sevoflurane (1.5 to 1.8 vol%) in air–oxygen mixture supplemented with IV fentanyl according to clinical need. Patients’ lungs were manually ventilated with oxygen using a facemask until intubation of the trachea. Oxygen saturation was maintained above 96%, normocapnia was ensured, and esophageal temperature was maintained above 36°C using forced-air warming system (Bair-Hugger, Arizant Healthcare Inc., USA). Neuromuscular monitoring was carried out using TOF-Watch-SX acceleromyograph (Organon Teknika B.V., The Netherlands). The adductor pollicis muscle contractions in response to ulnar nerve stimulation were recorded. The piezoelectric probe of the acceleromyograph was attached to the tip of the thumb. A hand adapter ensured preload of the thumb while making sure that it continued to return to its original position. The forearm and the fingers were immobilized, and surface skin electrodes were placed over the ulnar nerve proximal to the wrist. A TOF mode of stimulation was started and repeated every 15 s for 3 min followed by a 5-s tetanic train of 50 Hz to stabilize the signal. Two minutes later automatic calibration was carried out (calibration-2 to set out supramaximal current intensity and to calibrate the device). TOF stimulation was recommenced delivering supramaximal square wave stimuli of 0.2 ms duration at 2 Hz frequency until the signal was stable. If the signal was not stable, the calibration was repeated. Data were recorded and stored on a computer using TOF-Watch-SX software version 2.2 INT (Organon Ireland Ltd., Ireland). Skin temperature was measured at the forearm near the wrist and maintained above 32°C. Once the neuromuscular recording was stable, vecuronium 0.10 mg/kg (2 times ED95) was injected IV, and the trachea was intubated when the muscle response to TOF stimulation disappeared. If surgical relaxation was necessary, vecuronium 0.015 to 0.02 mg/kg was administered when one to two twitches to TOF stimulation returned. The TOF stimulation was automatically delivered at every 15-s interval.
Reversal of a Threshold TOF Count-of-four Block
When four twitches in response to TOF stimulation reappeared at three consecutive TOF measurements (a threshold TOF count of four), a designated anesthesiologist injected the study drug on the request of the attending anesthesiologist responsible for the patient and for the study, which was blinded to the injected study drug. The evolution of TOF ratio (T4/T1) and T1 amplitude (the first of four twitches to TOF stimulation) was followed online every 15 s and was also recorded for later analysis. Once the displayed TOF ratio reached at least 1.0 (unchanged during 3 min), inhaled sevoflurane was discontinued and the trachea was extubated when the patients emerged from anesthesia. If normalized TOF ratio 0.9 was not reached within 30 min after the study drug injection (time was agreed on a priori to wait for recovery), incomplete reversal was considered, and rescue reversal was given (rescue sugammadex 2.0 mg/kg). During this time period the patient’s trachea remained intubated. Adequate reversal was defined as average time of 5 min or less from the start of the study drug injection to the normalized TOF ratio 0.9.
Postoperative Assessment of Neuromuscular Block
After extubation of the trachea, patients were transferred to the recovery room. During the transport, the nerve stimulator was set on standby mode, the forearm and hand adapter’s positioning was secured, and oxygen was administered by facemask. In the recovery room, vital signs monitoring was continued, and oxygen was delivered via a nasal cannula. A second designated anesthesiologist recommenced the acceleromyography without recalibration of the device (time zero). The measurements were repeated every 20 min for 60 min. At each point in time, three consecutive TOF stimuli were delivered at 15-s intervals, and their average value was considered. Postoperative recurrent neuromuscular block was defined as the reappearance of normalized TOF ratios less than 0.9. Patients were surveyed for muscle weakness, force of coughing, ease of swallowing, and critical respiratory or circulatory events and would be immediately treated had such complications occurred. Supplementary oxygen administration, balloon-mask ventilation, equipment for intubation of the trachea, and rescue sugammadex were available. After discharge from the recovery room, patients were observed by the study team for 24 h to detect late adverse events.
Outcome Measures
Normalized TOF ratios of 0.9 were calculated and assessed as efficacy variables. Normalization was carried out by dividing the recorded values at recovery by baseline values before administration of vecuronium.14 
Primary outcome measures of the study were the time from the start of the injection of the study drug to normalized TOF ratio of 0.9 characterized the effectiveness of reversal and the incidence of no recovery to normalized TOF ratio 0.9 within 30 min characterized the incomplete reversal.
Secondary outcome measure of the study was the incidence of postoperative recurrent neuromuscular block in the recovery room during the first 60 min.
Additional outcome measures were the times from study drug injection to recovery of T1 90% to nonnormalized TOF ratio 1.0 and the number of patients reaching normalized TOF ratio 1.0
Sample Size
Calculation of sample size was carried out assuming that the usual time for recovery is 600 s with an SD of 200 s in patients treated with neostigmine and that sugammadex 0.5 mg/kg decreases the time of recovery to 300 s. Using a type I error rate (α) of 0.05, 10 subjects in the treatment groups would be needed to reach a power of 0.8. Because we assumed that dropouts might occur, we included 13 patients in each group, bringing the total to 65 patients.
Randomization and Blinding
The nature of randomization was 1:1 to obtain equal-sized study groups. The study statistician generated the randomization sequence using a Web-based online program (http://www.randomizer.org; accessed June 16, 2017). The study staff enrolled participants. A designated anesthesiologist possessed the randomization code, which assigned participants to intervention. The designated anesthesiologist prepared the study drug and injected it at the request of the attending anesthesiologist. The size and color of the syringes were similar to each other. Participants, the attending anesthesiologist, and the anesthesiologist who performed the postoperative acceleromyographic measurements were blinded after assignment to interventions.
Statistical Analysis
To analyze the primary outcome of time from the start of injection of the study drug to normalized TOF ratio of 0.9, we used one-way ANOVA. We examined the assumptions of ANOVA using the Shapiro–Wilk W test for the control of normal distribution of variables and the Levene test to check the homogeneity of variances among the study groups. Because the assumptions of normality or homoscedasticity were not met by the data, we applied the Box–Cox transformation for evaluating the primary outcome variable. When variances differed even after transformation, we used the Welch F test for unequal variances. Post hoc testing of differences among group means was based on the Tukey honest significant difference (HSD) test. We also used ANOVA to analyze baseline variables (patient data and perioperative variables) when the assumptions of parametric tests were met by the data. Otherwise, we used the nonparametric Kruskal–Wallis ANOVA to compare groups. For comparing proportions, including the primary outcome measure of the incidence of incomplete reversals and the secondary outcome measure of the incidence of reparalysis, we used the chi-square statistic. When the assumptions of the chi-square statistic were not met, we applied the Cramer V statistic of association. Because there were two components of the primary endpoint, we used α level of 0.025 (or half of the conventional α level of 0.05) to infer significance in analyses of outcome variables. We used α of 0.05 as a significance level in tests of baseline variables. All of the statistical calculations were implemented in PAST 3.0.79 (Øyvind Hammer, Sweden) or in R (version 3.2.2; http://www.r-project.org; accessed August 14, 2015).
Results
Seventy patients were eligible, and 65 agreed to participate in the trial. All of the enrolled patients were assigned to one of the five study groups (fig. 1). One patient in the sugammadex 1.0 mg/kg group was excluded from the study due to technical failure (broken acceleromyographic device), thus the data from 64 cases were analyzed. The trial ended as anticipated, after the 24-h-long observation period after the tracheal extubation of the last patient.
There were no differences in sex, age, body mass index, control TOF ratio, control T1 (%), American Society of Anesthesiologists physical status score, or the duration of surgery among the five study groups (table 1). There were no differences among groups in the dose of vecuronium and in the end-tidal sevoflurane concentrations at antagonism. There were likewise no differences among groups in the time intervals from last vecuronium injection to a threshold TOF count of four blocks (table 2).
Table 1.
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values×
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Table 1.
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values×
×
Table 2.
Comparison of the Study Groups at Antagonism
Comparison of the Study Groups at Antagonism×
Comparison of the Study Groups at Antagonism
Table 2.
Comparison of the Study Groups at Antagonism
Comparison of the Study Groups at Antagonism×
×
Primary Outcome
Reversal with neostigmine took 11.3 min, significantly longer than reversal with sugammadex 1.0 mg/kg (4.4 min) or 2.0 mg/kg (2.6 min; table 3, Tukey HSD test for both comparisons, P < 0.05), whereas the difference between neostigmine and 0.5 mg/kg sugammadex (6.8 min) was not statistically significant (P > 0.05; table 3). However, the variance in time to TOF ratio of 0.9 was significantly larger in the neostigmine group (94.1) than in the 0.5 mg/kg sugammadex group (16.6; F = 5.671; P = 0.023). Within the sugammadex groups, there were significant differences in the times to normalized TOF ratio 0.9 because these times were shorter in the groups receiving sugammadex 1.0 or 2.0 mg/kg (4.4 and 2.6 min, respectively) than in the sugammadex 0.5 mg/kg group (6.8 min; table 3; one-way ANOVA for the three sugammadex groups, F2,31 = 12.450, P = 0.0001, Tukey HSD tests, P < 0.05 for both comparisons). Calculations of the mean differences between pairs of study groups (table 4) confirmed these results and additionally showed a significant difference between the sugammadex 1.0 and 2.0 mg/kg groups (Tukey HSD test, P = 0.047).
Table 3.
Primary Outcome of the Study
Primary Outcome of the Study×
Primary Outcome of the Study
Table 3.
Primary Outcome of the Study
Primary Outcome of the Study×
×
Table 4.
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups×
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Table 4.
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups×
×
The number of incomplete reversals was 4 in the sugammadex 0.5 mg/kg group, 3 in the neostigmine group, 13 in the placebo group, and 0 in the sugammadex 1.0 and 2.0 mg/kg groups (table 3). The difference in incomplete reversals between the placebo and the four treatment groups combined was significant (Fisher exact P < 0.0001), whereas the difference between the sugammadex 0.5 mg/kg group and the neostigmine group was not significant (Fisher exact P = 0.157). Calculations of odds ratios also confirmed the differences between the placebo and each of the four treatment groups (table 4). All of the patients with incomplete reversal received rescue sugammadex 2.0 mg/kg and recovered to normalized TOF ratio 0.9 thereafter. These patients were not considered for the analysis of reversal times but were included in the assessment of the postoperative recurrent neuromuscular block.
Secondary Outcome
Postoperative recurrent neuromuscular block occurred in 12 patients: 3 were in the sugammadex 0.5 mg/kg group, 4 in the sugammadex 1.0 mg/kg group, 2 in the sugammadex 2.0 mg/kg group, 1 in the neostigmine group, and 2 in the placebo group (table 5). These proportions did not differ significantly among the groups (chi-square = 2.708, degrees of freedom = 4, P = 0.608). Similarly, odds ratios pertaining to the occurrence of reparalysis did not differ in either of the pairwise comparisons of study groups (table 4). The within-patient variation among the three separated TOF measurements was analyzed in each of the 18 reparalyses. The median coefficient of variation was 6.0% (interquartile range of 5.1%), whereas the geometric mean of the percentual coefficient of variation was 5.2. Precision of TOF measurement was deemed satisfactory if the discrepancy between repeated observations was within two times 5.2.14  (Supplemental Digital Content, http://links.lww.com/ALN/B488). Of the 12 patients with postoperative recurrent neuromuscular block, four were asymptomatic (normalized TOF ratios 0.85, 0.87, 0.86, and 0.89). Eight patients with TOF ratios 0.85, 0.86, 0.83, 0.85, 0.86, 0.86, 0.74, and 0.72 complained about muscle weakness, which was associated with weakened coughing in seven, with positive head lift test in four, and with difficulty swallowing in four cases. The duration of recurrent block was 40 min in one subject and 20 min in the others. The lowest TOF ratios were measured at 60 min, one in the sugammadex 2.0 mg/kg group (normalized TOF ratio 0.72) and one in the placebo group (normalized TOF ratio 0.74) after rescue sugammadex 2.0 mg/kg. Both patients complained about muscle weakness; they had weakened coughing, difficulty swallowing, positive head-lift test, and difficulty in eye movement. Discharge of these patients from the recovery room was delayed by 20 to 30 min until they became asymptomatic.
Table 5.
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room×
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Table 5.
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room×
×
Additional Outcome
The number of patients reaching normalized TOF ratio 1.0 was 2, 4, 5, 2, and 0 in the sugammadex 0.5, 1.0, 2.0 mg/kg; neostigmine; and placebo groups, respectively. The times to reach nonnormalized TOF ratio 1.0 did not differ significantly from the times to reach normalized TOF ratio 0.9. There was no difference among the treatment groups in times to achieve T1 90% (table 3).
Harms
No important harms or adverse effects were observed.
Discussion
Summary of Results
The current study investigated whether sugammadex 0.5 and 1.0 mg/kg adequately reverses a vecuronium-induced neuromuscular block that spontaneously returned to a threshold TOF count of four. Criterion of adequate reversal was achievement of normalized TOF ratio 0.9 in 5 min or less on average. Incomplete reversal was defined as failure to reach normalized TOF ratio 0.9 within 30 min after administration of reversal agent. Also, the incidence of recurrent neuromuscular block (normalized TOF ratios less than 0.9) was studied. Sugammadex 1.0 mg/kg adequately reversed the block in each patient, as did the standard dose (2.0 mg/kg). Of the 13 patients who received sugammadex 0.5 mg/kg, 4 produced incomplete reversal. The mean reversal time for the remaining nine patients was 6.8 min, thus it did not fulfill the criterion of adequate reversal. Neostigmine was not significantly different from sugammadex 0.5 mg/kg, with a mean reversal time of 11.3 min in 10 patients and with incomplete reversal in 3 patients. Recurrent block was detected in 12 patients. These results do not support our hypothesis that a threshold TOF count-of-four vecuronium-induced neuromuscular block can adequately be reversed with limited sugammadex doses similar to a rocuronium-induced block.13 
There are two reasons to use a small-dose of sugammadex for reversal of residual neuromuscular block. The first is an economic one, attempting to decrease the costs required for sugammadex treatment.13  The second is that too much sugammadex on board would limit the options should reintubation of the trachea or repeat surgery be needed shortly after the end of the case.15,16  However, the concept of reversal of residual neuromuscular block with clinically limited dose range of sugammadex generated concern about reparalysis, arguing that sugammadex 1.0 mg/kg or 0.5 mg/kg is insufficient to restore the safety margin of the neuromuscular junction; thus, rebound of the block may happen.17,18  Actually only a few studies have investigated the effect of low-dose sugammadex on the reversal of shallow residual neuromuscular blocks.19  What we know about this topic is that 0.25 mg/kg of sugammadex is able to reverse a rocuronium-induced block at a TOF ratio of 0.5 to 0.9 in an average time of less than 2 min7  and that sugammadex 1.0 or 0.5 mg/kg adequately reversed a threshold TOF count-of-four rocuronium-induced block under sevoflurane anesthesia.13  Also, moderate (T2) rocuronium- and vecuronium-induced neuromuscular blocks were successfully reversed under propofol–remifentanil anesthesia.4 
A multicenter study9  demonstrated a clear dose–response relationship for the reversal of moderate rocuronium- and vecuronium-induced neuromuscular block with sugammadex 0.5, 1.0, 2.0, and 4.0 mg/kg under sevoflurane anesthesia. Recovery times to TOF ratio 0.9 were shorter in the rocuronium versus the vecuronium group, and the difference was the most pronounced at sugammadex 0.5 mg/kg. Recurrence of the block occurred in seven patients due to suboptimal doses of sugammadex but also after the recommended dose of 2.0 mg/kg in one case. Duvaldestin et al.10  investigated the reversal of deep vecuronium- and rocuronium-induced neuromuscular block with increasing doses of sugammadex under sevoflurane maintenance anesthesia. Sugammadex in doses of 4.0 mg/kg or higher provided rapid reversal of deep rocuronium- and vecuronium-induced neuromuscular block. Neuromuscular monitoring showed recurrence of neuromuscular block in five patients, all in the rocuronium group (two received 0.5 mg/kg and three received 1.0 mg/kg sugammadex). Eleveld et al.12  observed the rebound of neuromuscular block after attempting to reverse a deep rocuronium-induced block with sugammadex 0.5 mg/kg. From these studies we know that low-dose sugammadex is unsuitable to reverse moderate or deep rocuronium- or vecuronium-induced neuromuscular block.
What the present study adds to our knowledge is that sugammadex 0.5 mg/kg cannot reverse a threshold TOF count-of-four neuromuscular block to normalized TOF ratio 0.9 in 30% of the patients, and it is not more effective than neostigmine in the remaining 70%. We confirmed that reparalysis can occur even after the reversal of such a neuromuscular block with sugammadex 2.0 mg/kg. Therefore, caution is suggested when using limited clinical doses of sugammadex (2.0 mg/kg or less) for antagonism of vecuronium-induced residual block, and the use of quantitative neuromuscular monitoring is highly recommended.
There may be several explanations for these results. First, the complexation of relaxant sugammadex and its breakdown into constituent molecules depends on the propensity of the two substances to associate and to dissociate.2  Because sugammadex is more selective for rocuronium than for vecuronium (Ka = 1.79 × 107 mol/L and 5.72 × 106 mol/L, respectively),8  the complexation is slower with vecuronium than with rocuronium. Second, because the Kd of vecuronium is 0.17 μM versus 0.055 μM for rocuronium,8  higher relative sugammadex concentrations are required for complex formation with vecuronium compared with rocuronium. This may explain why sugammadex 0.5 mg/kg was limited in reversing the residual effect of vecuronium, in contrast to what was previously found with rocuronium.13  Third, the sugammadex/vecuronium concentration ratio, not the absolute number of vecuronium molecules in the body, appears to be the decisive factor for the reversal of vecuronium block. Therefore, sugammadex 1.0 mg/kg and 2.0 mg/kg were effective, whereas 0.5 mg/kg was not. Furthermore, none of the sugammadex doses administered in this study prevented the recurrence of neuromuscular block. The overall frequency of reparalysis was 18.7%, but this incidence varied from group to group. This was an unexpected outcome, which raises the suspicion of artifacts due to displacement of the arm during the measurement of acceleromyographic TOF responses in patients recovering from anesthesia.20  To prevent this bias, special care was taken by the study anesthesiologists to adequately fasten the arm during TOF stimulation, like in our previous study including 47 awake patients who were monitored for residual neuromuscular blockade during 60 min in the recovery room.6  Because these patients presented neither clinical signs of residual paralysis nor TOF ratio depression, they can be considered as a control group for the current study, thus validating its results. With regard to the mechanism of reparalysis, low doses of sugammadex may be sufficient for complex formation with the relaxant molecules in the central compartment but are insufficient for redistribution from the periphery to the plasma. Furthermore, the dissociation of vecuronium from the complex over time (referring to Kd) also takes place and increases the possibility of rebounding block.12  Although it cannot be excluded with certitude, it is less likely that residual concentrations of sevoflurane enhanced the block in the postoperative period. It is also unlikely that the metabolite of vecuronium caused reparalysis; the doses were too small for this. No severe postoperative reparalysis occurred in the patients, and the majority of recurrent blocks were slight (normalized TOF ratios 0.83 to 0.89), apparently at the limit of the safety margin.
Clinical signs of reparalysis were observed in 8 patients without other adverse event. Nevertheless, recurrent neuromuscular block may be associated with postoperative complications such as hypoxia, weakness, pulmonary aspiration of gastric content, and respiratory failure. The prevention of these complications may improve patient safety and decrease mortality rates.21 
Limitation of This Study
This study was based on acceleromyographic measurements of neuromuscular transmission, which is known to overestimate the recovery. However, we used preload and normalization to improve its accuracy.14  Had we considered nonnormalized TOF ratios for postoperative recurrent neuromuscular block, five recurrent blocks would have been detected. We did not measure the plasma concentrations of sugammadex, vecuronium, or 3-desacetylvecuronium, and spirometry was not carried out for the diagnosis of possible respiratory depression. Although the explanation of the result was based on published data, presumptions about the mechanism of reversal and postoperative recurrent neuromuscular block could not be avoided. Due to ethical reasons and tight operating schedules, a 30-min cutoff point in time was a priori included, resulting in reduction of the sample size in three treatment groups. Although the placebo control was excluded from the comparison of the reversal times, it allowed for distinguishing the effect of sugammadex 0.5 mg/kg and neostigmine from spontaneous recovery. Of note, the administration of rescue treatment to placebo patients confirmed the occurrence of postoperative recurrent neuromuscular block after sugammadex 2.0 mg/kg. This issue is clinically relevant and, therefore, additional studies are highly desirable to confirm these results.
In conclusion, this study demonstrated that sugammadex 0.5 mg/kg is insufficient to reliably guarantee prompt and satisfactory neuromuscular recovery after vecuronium administration at a threshold TOF count of four. Increasing the dose to 1.0 mg/kg adequately reversed this level of block, although recovery took twice as long as has been reported after rocuronium. In addition, recurrent neuromuscular block occurred in each treatment group. Sugammadex 0.5 mg/kg should not be used for the reversal of vecuronium-induced neuromuscular block, and the use of quantitative neuromuscular monitoring is highly recommended.
Research Support
Supported by the Hungarian Brain Research Program grant 510 No. KTIA 13 NAP A II/5 and funded by the University of Debrecen Department of Anesthesiology and Intensive Care (Debrecen, Hungary).
Competing Interests
The authors declare no competing interests.
Reproducible Science
Full protocol available at: http://aitt.med.unideb.hu. Raw data available at: http://aitt.med.unideb.hu.
References
Lee, C . Structure, conformation, and action of neuromuscular blocking drugs. Br J Anaesth 2001; 87:755–69 [Article] [PubMed]
Bom, A, Bradley, M, Cameron, K, Clark, JK, Van Egmond, J, Feilden, H, MacLean, EJ, Muir, AW, Palin, R, Rees, DC, Zhang, MQ . A novel concept of reversing neuromuscular block: Chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl 2002; 41:266–70 [Article] [PubMed]
Gijsenbergh, F, Ramael, S, Houwing, N, van Iersel, T . First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005; 103:695–703 [Article] [PubMed]
Suy, K, Morias, K, Cammu, G, Hans, P, van Duijnhoven, WG, Heeringa, M, Demeyer, I . Effective reversal of moderate rocuronium- or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant binding agent. Anesthesiology 2007; 106:283–8 [Article] [PubMed]
Khuenl-Brady, SK, Wattwil, M, Vanacker, FB, Lora-Tamayo, LJ, Rietbergen, H, Álvarez-Gomez, AJ . Sugammadex provides faster reversal of vecuronium induced neuromuscular blockade compared with neostigmine: A multicenter, randomized, controlled trial. Anesth Analg 2010; 110:64–73 [Article] [PubMed]
Tassonyi, E, Pongrácz, A, Nemes, R, Asztalos, L, Lengyel, S, Fülesdi, B . Reversal of pipecuronium-induced moderate neuromuscular block with sugammadex in the presence of a sevoflurane anesthetic: A randomized trial. Anesth Analg 2015; 121:373–80 [Article] [PubMed]
Schaller, SJ, Fink, H, Ulm, K, Blobner, M . Sugammadex and neostigmine dose-finding study for reversal of shallow residual neuromuscular block. Anesthesiology 2010; 113:1054–60 [Article] [PubMed]
Zwiers, A, van den Heuvel, M, Smeets, J, Rutherford, S . Assessment of the potential for displacement interactions with sugammadex: A pharmacokinetic-pharmacodynamic modelling approach. Clin Drug Investig 2011; 31:101–11 [Article] [PubMed]
Pühringer, FK, Gordon, M, Demeyer, I, Sparr, HJ, Ingimarsson, J, Klarin, B, van Duijnhoven, W, Heeringa, M . Sugammadex rapidly reverses moderate rocuronium- or vecuronium-induced neuromuscular block during sevoflurane anaesthesia: A dose-response relationship. Br J Anaesth 2010; 105:610–9 [Article] [PubMed]
Duvaldestin, P, Kuizenga, K, Saldien, V, Claudius, C, Servin, F, Klein, J, Debaene, B, Heeringa, M . A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia. Anesth Analg 2010; 110:74–82 [Article] [PubMed]
Jones, RK, Caldwell, JE, Brull, SJ, Soto, RG . Reversal of profound rocuronium-induced blockade with sugammadex: A randomized comparison with neostigmine. Anesthesiology 2008; 109:816–24 [Article] [PubMed]
Eleveld, DJ, Kuizenga, K, Proost, JH, Wierda, JM . A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Anesth Analg 2007; 104:582–4 [Article] [PubMed]
Pongrácz, A, Szatmári, S, Nemes, R, Fülesdi, B, Tassonyi, E . Reversal of neuromuscular blockade with sugammadex at the reappearance of four twitches to train-of-four stimulation. Anesthesiology 2013; 119:36–42 [Article] [PubMed]
Claudius, C, Skovgaard, LT, Viby-Mogensen, J . Is the performance of acceleromyography improved with preload and normalization? A comparison with mechanomyography. Anesthesiology 2009; 110:1261–70 [Article] [PubMed]
Donati, F . Sugammadex: An opportunity for more thinking or more cookbook medicine? Can J Anaesth 2007; 54:689–95 [Article] [PubMed]
Cammu, G, de Kam, PJ, De Graeve, K, van den Heuvel, M, Suy, K, Morias, K, Foubert, L, Grobara, P, Peeters, P . Repeat dosing of rocuronium 1.2 mg kg-1 after reversal of neuromuscular block by sugammadex 4.0 mg kg-1 in anaesthetized healthy volunteers: A modelling-based pilot study. Br J Anaesth 2010; 105:487–92 [Article] [PubMed]
Carron, M . Sugammadex after the reappearance of four twitches during train-of-four stimulation: Monitoring and dose considerations. Anesthesiology 2014; 120:508 [Article] [PubMed]
Naguib, M . Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007; 104:575–81 [Article] [PubMed]
Keating, MG . Sugammadex: A review of neuromuscular blockade reversal. Drugs 2016; 76: 1041–52 [Article] [PubMed]
Baillard, C, Bourdiau, S, Le Toumelin, P, Ait Kaci, F, Riou, B, Cupa, M, Samama, CM . Assessing residual neuromuscular blockade using acceleromyography can be deceptive in postoperative awake patients. Anesth Analg 2004; 98:854–7 [PubMed]
Arbous, MS, Meursing, AE, van Kleef, JW, de Lange, JJ, Spoormans, HH, Touw, P, Werner, FM, Grobbee, DE. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005; 102:257–68; quiz 491–2 [Article] [PubMed]
Fig. 1.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
Fig. 1.
Study flowchart. The administration of sugammadex, neostigmine, and placebo was randomized and double blinded. The administration of vecuronium was open. nTOF 0.9 = normalized train-of-four ratio 0.9. Light gray quadrangles show comparison for recovery times; dark gray quadrangles show those excluded from comparison of recovery times; rescue sugammadex = 2 mg/kg. Intraop = intraoperative; Postop = postoperative.
×
Table 1.
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values×
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Table 1.
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values
Comparison of Baseline Characteristics, Duration of Surgery, and Control Acceleromyographic Values×
×
Table 2.
Comparison of the Study Groups at Antagonism
Comparison of the Study Groups at Antagonism×
Comparison of the Study Groups at Antagonism
Table 2.
Comparison of the Study Groups at Antagonism
Comparison of the Study Groups at Antagonism×
×
Table 3.
Primary Outcome of the Study
Primary Outcome of the Study×
Primary Outcome of the Study
Table 3.
Primary Outcome of the Study
Primary Outcome of the Study×
×
Table 4.
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups×
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Table 4.
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups
Estimates of the Mean Differences (and Their 95% CIs) in the Time from Injection of the Study Drug to Normalized TOF Ratio of 0.9 between Pairs of Study Groups and Odds Ratios for the Number of Failed Reversals at 30 min and the Number of Patients with PORNB between Pairs of Study Groups×
×
Table 5.
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room×
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Table 5.
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room
Secondary Outcome of the Study: Incidence of Postoperative Reparalysis during the First 60 min in the Recovery Room×
×