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ANESTHETIC PHARMACOLOGY

Reversal of Rocuronium-Induced Neuromuscular Block with the Novel Drug Sugammadex Is Equally Effective Under Maintenance Anesthesia with Propofol or Sevoflurane

Bernard F. Vanacker, MD, PhD^*, Karel M. Vermeyen, MD, PhD, Michel M. R. F. Struys, MD, PhD, Henk Rietbergen, MSc, Eugene Vandermeersch, MD, PhD^*, Vera Saldien, MD, Alain F. Kalmar, MD, and Martine E. Prins, MSc

From the *University Hospitals Leuven, KU Leuven, Belgium; University Hospital Antwerp, Antwerp, Belgium; Ghent University Hospital, Ghent, Belgium; NV Organon, Oss, The Netherlands.

Address correspondence and reprint requests to Bernard F. Vanacker, MD, PhD, Department of Anesthesiology, University Hospitals Leuven, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. Address e-mail to bernard.vanacker{at}uz.kuleuven.ac.be.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
In this study we investigated whether the novel reversal drug, sugammadex, is equally effective at reversing rocuronium-induced neuromuscular block (NMB) in patients under propofol or sevoflurane maintenance anesthesia. After receiving propofol for induction, patients were randomized to propofol (n = 21) or sevoflurane (n = 21). Rocuronium 0.6 mg/kg was administered for tracheal intubation. NMB was monitored using acceleromyography. At reappearance of the second twitch of the train-of-four ratio, sugammadex 2.0 mg/kg was administered by IV bolus. The primary end-point was time from start of sugammadex administration to recovery of train-of-four ratio to 0.9. Mean recovery time was 1.8 min after both propofol and sevoflurane anesthesia. The 95% confidence interval for the difference in recovery time between the 2 groups (–0.5 to +0.4 min) was well within the predefined equivalence interval (–1 to +1 min), indicating that recovery from NMB was unaffected by maintenance anesthesia. Thirteen patients (propofol n = 4; sevoflurane n = 9) experienced adverse events; these were treatment-related in 4 patients (propofol n = 3; sevoflurane n = 1). There were no treatment-related serious adverse events and no discontinuations or deaths. No residual paralysis occurred. The safety profile of sugammadex was somewhat more favorable under propofol than under sevoflurane anesthesia.

	Introduction

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
Once surgery is complete, reversal of the action of neuromuscular blocking drugs (NMBDs) is often performed to accelerate recovery from neuromuscular blockade (1). At present, cholinesterase inhibitors (e.g., neostigmine) are used to reverse the action of NMBDs. These drugs are nonselective and facilitate cholinergic transmission throughout the body. They are only effective when residual neuromuscular function is present, and there is currently no reliable method of reversing profound neuromuscular blockade (2,3).

A novel approach to reversing neuromuscular blockade is sugammadex (Org 25969; NV, Organon International, Oss, The Netherlands), a drug-specific modified -cyclodextrin that is a selective relaxant binding agent (SRBD). Unlike the cholinesterase inhibitors, which increase the activity of the cholinergic system, an SRBD directly prevents the pharmacologic action of the NMBD by decreasing the free concentration of the drug (3). Sugammadex is the first SRBD developed for the reversal of neuromuscular blockade; it acts by rapidly encapsulating steroidal NMBDs such as rocuronium or vecuronium to form a stable complex. The results of several animal studies have shown that sugammadex reverses rocuronium-induced neuromuscular blockade in vitro and in vivo (4–6). In addition, phase I and II trials have shown that sugammadex is effective and safe at reversing rocuronium-induced blockade in healthy volunteers and surgical patients undergoing anesthesia with propofol (7,8).

Propofol and sevoflurane are widely used for the maintenance of anesthesia. In contrast to propofol, sevoflurane enhances the effects of some NMBDs, including rocuronium (9,10). Xue et al. (11) showed that sevoflurane can significantly prolong the duration of action of rocuronium and the time to recovery. These effects are not seen with either propofol or isoflurane (9).

The present study was designed to compare the efficacy of sugammadex in reversing rocuronium-induced block in patients in whom anesthesia was maintained with propofol or with the volatile anesthetic sevoflurane and to further investigate the overall safety profile of sugammadex.

	METHODS

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This was a randomized, multicenter, safety assessor-blinded, phase II, parallel-group, comparative trial conducted at three centers in Belgium. The protocol was approved by an Independent Ethics Committee at each participating center, and the trial was conducted in accordance with the current revision of the Declaration of Helsinki, International Conference on Harmonisation Guidelines, and Good Clinical Practice.

Patients aged 18 yr or older, with ASA physical status I–III, scheduled to undergo surgery in the supine position that was anticipated to last for at least 45 min and required muscle relaxation only for tracheal intubation were eligible for inclusion. All patients gave written informed consent. Patients were excluded from the trial if they had any of the following: expected difficulties with intubation resulting from anatomical malformations; known or suspected neuromuscular disorders and/or significant hepatic or renal dysfunction; history of malignant hyperthermia; known or suspected allergy to muscle relaxants, narcotics, or any other medication used during general anesthesia; or if they were currently receiving medications known to interfere with NMBDs (e.g., anticonvulsants or magnesium [Mg²⁺]); or had previously participated in this trial or another clinical trial. In addition, women of childbearing potential not using an acceptable method of birth control and those who were breastfeeding or pregnant were not eligible for the trial.

Anesthesia was induced with an IV opioid followed by propofol. Patients were then randomized to receive maintenance anesthesia with either propofol (>6.0 mg · kg^–1 · h^–1 by continuous infusion) or sevoflurane (target minimum alveolar concentration 1.5, adjusted for age); in both groups, additional opioid was administered depending on clinical needs. No nitrous oxide was used. Patients were manually ventilated by mask using an oxygen-air mixture until tracheal intubation. Intubation was then performed at maximal neuromuscular block and intermittent positive pressure ventilation was started using low flow. Ventilation was adjusted to maintain normal end-tidal CO₂.

Neuromuscular block was monitored and recorded by acceleromyography (TOF Watch® SX; Organon International, Oss, The Netherlands) using train-of-four (TOF) stimulation. The stimulated arm was positioned on an arm board and kept warm using a warmed blanket. The area where the electrodes were to be placed was cleaned and two electrodes were placed on the ulnar nerve trajectory. The transducer was fixed with its largest flat side against the thumb. After induction of anesthesia, stabilization and calibration were performed. During the stabilization period, a 5-s 50-Hz tetanic stimulation was followed by repetitive TOF stimulation (supramaximal) for at least 2 min. After calibration (100%), the TOF Watch® SX was switched to TOF stimulation every 15 s.

After the stabilization period (at least 5 min), each patient received a single IV bolus dose of rocuronium 0.6 mg/kg for tracheal intubation. When the second twitch (T₂) of the TOF reappeared, a single IV bolus dose of sugammadex 2.0 mg/kg was administered. Anesthesia and neuromuscular monitoring were maintained at least until the ratio between the fourth and first twitches (TOF ratio) had recovered to 0.9 and until the end of surgery (minimum of 30 min after administration of sugammadex).

The occurrence of residual paralysis was also evaluated. Neuromuscular monitoring for the occurrence of residual paralysis was to be continued for at least 30 min after the recovery of the TOF ratio to 0.9, after which the patients could be woken up and tracheally extubated. Oxygen saturation and breath frequency were monitored for at least 60 min after the recovery of the TOF ratio to 0.9.

Adverse events (AEs) were recorded from administration of sugammadex until the postanesthetic visit that took place at least 10 h after administration of sugammadex. Serious AEs (SAEs) were also recorded at follow-up, 7 days after administration of sugammadex. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly or birth defect. Patients were questioned and/or examined to obtain data on AEs. Arterial blood pressure and heart rate were recorded at screening, at stable anesthesia, i.e., just before administration of rocuronium (baseline), at 2, 10, and 30 min after the start of sugammadex administration, and at the postanesthetic visit.

Twelve-lead electrocardiograms were taken at stable anesthesia, i.e., before administration of rocuronium (baseline), and at 2 and 30 min after administration of sugammadex. The corrected electrocardiographic QT interval (QTc) was monitored as part of the regular safety monitoring. The QTc is intended to represent the QT interval at a standardized heart rate of 60 bpm. Because of its inverse relationship to heart rate, the QT interval is routinely transformed (normalized) by means of various formulae into a heart rate independent "corrected" value known as the QTc interval. For drugs that prolong the QT/QTc interval, the mean degree of prolongation has been roughly correlated with the observed risk of clinical proarrhythmic events. Prolongation of the QTc interval was reported as a SAE if individual QTc changes were >60 ms relative to baseline or absolute QTc values were >500 ms (12).

Recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg was studied in the "per protocol" (PP) population (i.e., all randomized and treated patients without any major protocol violations) and in the "intent-to-treat" (ITT) population (i.e., all randomized patients who received sugammadex and had at least one efficacy assessment). Safety data were studied in the safety population (i.e., all subjects who received sugammadex).

The primary end-point was the time from the start of administration of sugammadex to recovery of the TOF ratio to 0.9. Secondary end-points were the time from the start of administration of sugammadex to recovery of the TOF ratio to 0.7 and 0.8. The confidence interval (CI) approach was used to demonstrate equivalence in recovery of the TOF ratios to 0.7, 0.8, and 0.9 between the 2 treatment groups. Equivalence was claimed if the 2-sided 95% CI for the difference between the 2 groups was within the interval ranging from –1 min to +1 min. The 95% CI was obtained from a 2-way analysis of variance model, with treatment and study center as factors.

A sample size of 42 patients had 80% power to show equivalence in the time to recovery of the TOF ratio to 0.9 between the two treatment groups (PP population), assuming an sd in the recovery times of 1 min, a 15% dropout rate, and Gaussian distributed data.

In addition to presenting descriptive statistics (mean, sd, and range values per treatment group) a figure was prepared showing, for each of the two treatment groups, the percentage of patients for whom the TOF ratio was not yet recovered to 0.9 as a function of the time from the start of administration of sugammadex.

Baseline data were analyzed using descriptive statistics. Except for QTc interval data, safety data were reported in a descriptive manner. QTc interval data were analyzed using a two-way analysis of variance model and the paired Student's t-test. Two-sided statistical testing was conducted and P values less than or equal to 0.05 were considered statistically significant. No adjustments for multiplicity were done.

	RESULTS

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A total of 42 patients (ASA physical status I–III) were enrolled and randomized; 21 in each treatment group (Table 1). All but one patient were Caucasian. Patients in the propofol group were, on average, older, heavier, and taller than those in the sevoflurane group, and more women were enrolled in the sevoflurane group than in the propofol group. None of these differences were considered to affect the efficacy analysis. All 42 patients who received sugammadex completed the trial and were included in the ITT analysis. One patient in the sevoflurane group had a major protocol violation (sugammadex administered too early, >2 min before reappearance of T₂) and was excluded from the PP analysis.

Mean recovery time from rocuronium administration to reappearance of T₂ was 33.0 min in the propofol group and 51.8 min in the sevoflurane group (P = 0.002) (Table 2).

The mean time from start of administration of sugammadex to recovery of the TOF ratio to 0.9 was 1.8 min in both the propofol and sevoflurane groups (PP population) (Table 3). The estimated difference in the mean time to recovery of the TOF ratio to 0.9 between the two groups was –0.0 min with the corresponding 95% CI ranging from –0.5 to +0.4 min, which was well within the predefined range for equivalent efficacy. Results of the ITT analysis supported those from the PP population with an estimated difference between the propofol and sevoflurane groups of 0.0 min (95% CI: –0.4 to +0.5 min).

Figure 1 shows the percentage of patients who did not recover to TOF 0.9 as a function of time from the start of administration of sugammadex for the two treatment groups. Complete recovery was achieved in <3 min by 19 of 20 patients receiving sevoflurane for maintenance anesthesia and in 19 of 20 patients receiving propofol (PP population; data for one patient were missing in the propofol group).

View larger version (10K): [in this window] [in a new window]   Figure 1. Percentage of patients who did not recover (train-of-four [TOF] 0.9) as a function of time (min) from the start of administration of sugammadex (2.0 mg/kg) [per protocol population].

The mean times from start of administration of sugammadex to recovery of the TOF ratios to 0.8 and 0.7 were 1.5 and 1.3 min, respectively, in both the propofol and sevoflurane groups (PP population) (Table 3). Estimated between-group differences in the mean times to recovery of the TOF ratios to 0.8 and 0.7 were –0.0 min (95% CI: –0.3 to +0.3 min) and –0.0 min (95% CI: –0.3 to +0.2 min), respectively, again showing equivalent recovery in both treatment groups. Results from the ITT analysis were similar and also showed equivalent efficacy.

Two examples of TOF Watch® traces obtained under propofol and sevoflurane maintenance anesthesia are presented in Figure 2.

View larger version (23K): [in this window] [in a new window]   Figure 2. Two examples of recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg followed by sugammadex 2.0 mg/kg at reappearance of the second twitch (T2) under (A) propofol and (B) sevoflurane maintenance anesthesia.

No residual paralysis was observed in any of the patients. Two patients were not monitored for at least 30 min after recovery of the TOF ratio to 0.9. One patient in the sevoflurane group was monitored for only 11 min, during which time no residual paralysis was observed. Data on the second patient, in the propofol group, were not available as a result of technical difficulties with the TOF Watch® SX. No residual paralysis was evident in either patient.

Thirteen patients experienced at least 1 AE, 9 in the sevoflurane group, and 4 in the propofol group. All AEs were of mild to moderate intensity, except in one patient in the sevoflurane group who reported severe nausea.

In the sevoflurane group one patient developed hypotension that was considered drug-related, i.e., possibly, probably, or definitely related to sugammadex. In the propofol group, one patient developed drug-related AEs (bradycardia, nausea, and vomiting), and two patients each developed one drug-related AE (hiccups and hypotension).

SAEs due to QTc prolongation were observed in eight patients in the sevoflurane group. These were mild and were considered unlikely to be related to sugammadex. Two of these patients had additional SAEs that were not considered to be treatment related. One patient experienced postoperative pain that started 4 days after sugammadex administration and continued for 3 days. The patient recovered from the event, which was judged to be related to surgery. The second patient had urinary retention 8 days after sugammadex administration, which was not considered related to sugammadex. The event was of moderate intensity and lasted for 4 days, after which time the patient recovered.

Results for the QTc interval are based on the Fridericia correction (13). Prolongation of the QTc interval seen in the sevoflurane group was already evident 2 min after administration of sugammadex (P < 0.01 versus baseline) (Table 4). The QTc interval continued to increase and was significantly longer at 30 min compared with baseline (P < 0.001) or compared with the value at 2 min (P = 0.006). Results from the propofol group echoed these findings to a lesser degree. In the propofol group, the difference at 30 min compared with 2 min was not statistically significant (P = 0.078), suggesting that QTc prolongation was already apparent before administration of sugammadex. The difference in QTc prolongation between the 2 treatment groups approached significance at 2 min (P = 0.053) and was highly significant at 30 min (P < 0.01).

Overall, arterial blood pressure and heart rate values were within the agreed safety ranges. An abnormal value was observed at 2, 10, or 30 min post-dose for systolic blood pressure and/or diastolic blood pressure in 7 subjects. None of these were considered to be an AE. For one patient, a decrease in heart rate from 62 bpm at baseline to 44 and 45 bpm was reported at 2 and 10 min post-dose, respectively. This was not considered clinically relevant, and the heart rate returned to 53 bpm at the 30-min post-dose assessment.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
This study demonstrates that sugammadex, 2.0 mg/kg, is equally effective at reversing rocuronium-induced block, regardless of whether the maintenance anesthetic regimen is propofol or sevoflurane. The mean times to recovery of the TOF ratio to 0.9 observed in this trial were comparable to those observed in other trials: 1.3 minutes (8) and 1.7 minutes (14). The time to reversal of the TOF ratio to 0.9 was longer in one patient in the sevoflurane group but was within the clinically acceptable limits of reversal times.

Unlike propofol, sevoflurane enhances the neuromuscular blocking action of rocuronium (9–11). This was confirmed in our trial, in which the mean time from the start of administration of rocuronium to the reappearance of T₂ was almost 19 minutes longer under sevoflurane anesthesia compared with propofol anesthesia. However, the results show that anesthesia with sevoflurane does not reduce the efficacy of sugammadex in reversing rocuronium-induced blockade. This is consistent with the direct mechanism of action of sugammadex, which encapsulates steroidal NMBDs, thus producing block reversal (5). In a study by Kim et al. (15) on the reversibility of rocuronium-induced block by neostigmine under propofol and sevoflurane anesthesia, the results showed that the recovery time of the TOF ratio to 0.7, 0.8, and 0.9 was significantly longer under sevoflurane anesthesia than under propofol anesthesia (P < 0.0001).

In this trial, sugammadex reversed neuromuscular block within 3 min of administration in the majority of patients in both treatment groups. This represents a substantial improvement versus conventional cholinesterase inhibitors, which take much longer. Kim et al. (15) reported a median recovery time of the TOF ratio to 0.9, after neostigmine administration, of 7.5 (range, 3.4–11.2) minutes under propofol anesthesia and 22.6 (range, 8.3–57.4) minutes under sevoflurane anesthesia. Suzuki et al. (16) reported a mean (sd) recovery time of the TOF ratio to 0.9, after edrophonium administration, of 24.7 (14.3) minutes under propofol anesthesia.

Sugammadex was well tolerated with minimal side effects with both propofol and sevoflurane. Few AEs were reported that were considered related to sugammadex. All AEs except one were of mild-to-moderate intensity. The most common AEs were nausea and QTc prolongation. Eight patients in the sevoflurane group experienced QTc prolongation that met the criteria for a SAE. None of these patients had values placing them at risk of arrhythmia, and the events were considered unlikely to be related to sugammadex. Although this study was not designed to evaluate the effect of sugammadex on QTc prolongation, the most likely cause was the anesthetics themselves. Sevoflurane prolongs the QTc interval (17,18) and although it is generally accepted that propofol can reduce an already elongated QTc interval (19,20), it has also been shown to prolong it (20,21).

A previous phase II study has shown that sugammadex is effective and safe at reversing rocuronium-induced block in surgical patients anesthetized with propofol (8). The present trial confirms these results and demonstrates that sugammadex, 2 mg/kg, administered at reappearance of T₂ is safe and equally effective in rapidly reversing rocuronium-induced blockade in surgical patients under propofol or sevoflurane maintenance anesthesia, but with a later appearance of T₂ in the sevoflurane group. It is anticipated that larger studies planned for the future, evaluating the efficacy and safety of sugammadex in different patient populations and at different times of reversal, will more fully elucidate the role of sugammadex in the reversal of neuromuscular blockade.

	ACKNOWLEDGMENTS

 
Editorial assistance was provided by Julie Adkins at Prime Medica during the preparation of this paper, supported by NV Organon. Responsibility for opinions, conclusions, and interpretation of data lies with the authors.

	Footnotes

 
Accepted for publication May 23, 2006.

Supported, in part, by NV Organon, Oss, The Netherlands.

	REFERENCES

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999