Neuromuscular blocking agents are an important component of modern anaesthetic practice to improve surgical conditions by suppression of voluntary or reflex muscle movements. After surgery, reversal agents such as neostigmine or pyridostigmine are commonly administered to accelerate the recovery of neuromuscular function. Unfortunately, these drugs neither provide predictable nor sufficiently fast restoration of neuromuscular function1,2 and may be associated with several side effects, related to the inhibition of cholinesterase activity.3
Sugammadex is a modified γ-cyclodextrin specifically developed for rapid reversal of a rocuronium-induced or vecuronium-induced neuromuscular blockade by forming a stable and inactive complex with these neuromuscular blocking agents.4 Dose-finding studies have shown specific doses of sugammadex that rapidly reverse specific degrees of neuromuscular blockade after rocuronium.5–7
A phase 3 active-controlled, randomised study proved that sugammadex provides significantly faster reversal of a deep (defined as 1–2 post-tetanic counts) rocuronium-induced neuromuscular blockade compared with neostigmine.8 In current clinical practice, however, reversal of neuromuscular blockade ideally takes place after return of the train-of-four (TOF) response to one or two twitches (T1 or T2), which is at a moderate level of blockade. To date, no randomised, active-controlled trial has investigated the recovery from moderate rocuronium-induced neuromuscular blockade, comparing sugammadex with neostigmine. In a placebo-controlled, dose-finding study, sugammadex at doses of 2 mg kg−1 or greater administered at reappearance of T2 following a single dose of rocuronium allowed recovery to a TOF ratio of 0.9 in a median of less than 2 min.5 Similar results were obtained in a dose-finding study in which sugammadex was administered at reappearance of T2 after prolonged rocuronium-induced blockade.9 However, these results need to be verified in a larger cohort of patients.
In this study, we evaluated whether reversal of a rocuronium neuromuscular blockade, using the new agent sugammadex, is faster than reversal, using current standard treatment with neostigmine, from a moderate neuromuscular blockade (recovery of T2 in the TOF response) in patients under sevoflurane anaesthesia.10 This study was undertaken in two parts, with the second part evaluating sugammadex versus neostigmine in the reversal of moderate vecuronium-induced blockade; the two parts of the study were powered separately and the vecuronium data have been published elsewhere.11
Study participants and study design
The trial protocol was approved by the independent ethics committees on human research of each participating trial centre in this phase 3a, European, 13-centre, randomised, parallel-group, comparative, active-controlled, safety-assessor-blinded trial (the AURORA trial). After written informed consent, patients with physical status classed as American Society of Anesthesiologists (ASA) I–III, aged at least 18 years and of any body weight were enrolled. All patients were scheduled for an elective surgical procedure under general anaesthesia. Patients with expected difficult intubation, or those receiving medication known to interact with rocuronium or vecuronium, or having neuromuscular or significant renal disease, a history of malignant hyperthermia, or an allergy or other contraindication to medications used during the study, were excluded. Female patients were excluded if they were pregnant, of childbearing potential and not using a mechanical method of birth control or if they were breast-feeding.
Patients were randomly assigned to receive either rocuronium or vecuronium being administered for tracheal intubation and maintenance of neuromuscular blockade, and to receive either sugammadex (Bridion; MSD, Oss, The Netherlands) or neostigmine–glycopyrrolate mixture for reversal of the neuromuscular blockade. Randomisation codes were entered into a central randomisation system, part of a secured trial website. Enrolled patients were given a number in sequence of their enrolment, receiving a treatment code using the randomisation system. An investigator who was not involved in the safety assessments prepared the drugs.
An intravenous cannula was inserted into a forearm vein and standard anaesthesia monitoring established on arrival in the operating room. Anaesthesia was induced with propofol and maintained with sevoflurane with opioid supplementation according to the clinical need and preference of the anaesthetist. The end-tidal concentration of sevoflurane was adjusted according to clinical need until administration of the reversal agent.
Neuromuscular monitoring was carried out according to international consensus guidelines12,13, using evoked acceleromyography of the adductor pollicis muscle [TOF-Watch SX and TOF-Watch SX monitoring software (Organon Ireland Ltd., a Division of Merck and Co., Inc., Swords, Co. Dublin, Ireland)]. In brief, the forearm was immobilised and surface skin electrodes were placed over the ulnar nerve proximal to the wrist. Following calibration, the ulnar nerve was stimulated with supramaximal TOF stimulation at 15-s intervals and the evoked contraction of the adductor pollicis muscle was recorded and analysed offline.
Following 3 min of stabilisation of the acceleromyography recording12,13, in this arm of the study, rocuronium 0.6 mg kg−1 was administered and tracheal intubation performed after depression of all twitch responses. During surgery, maintenance doses of 0.1–0.2 mg kg−1 rocuronium were administered according to clinical need. Central body temperature was measured continuously until the end of neuromuscular monitoring and was to be maintained at 35°C or more.
When the clinical situation did not require a neuromuscular blockade any longer, the patient was allowed to recover until reappearance of T2 after the last dose of rocuronium, established using the TOF-Watch SX; at which point, sugammadex 2.0 mg kg−1 or neostigmine 50 μg kg−1 with 10 μg kg−1 glycopyrrolate were administered intravenously. The recommended concentration of sevoflurane was less than 1.5 minimum alveolar concentration at the time of reversal agent administration, without change during the following period of at least 10 min. In all patients, neuromuscular monitoring was continued until the end of the need for anaesthesia or at least until recovery of the TOF ratio to 0.9. Thereafter, anaesthesia was discontinued and the awake patient was extubated. This procedure allowed the anaesthetist to decrease sevoflurane concentrations in patients with a neuromuscular recovery time of longer than 10 min. Any decrease in the TOF ratio below 0.8 during neuromuscular monitoring was recorded as a reoccurrence of neuromuscular blockade. Heart rate (HR) and blood pressure (BP) were recorded before and 2, 5, 10 and 30 min after the administration of the reversal agents. Any patient who had not achieved a TOF ratio of 0.9 remained sedated, intubated and ventilated in the recovery room with the aim of waiting until they had achieved recovery to a TOF ratio of 0.9, which was considered sufficient to allow for safe extubation.
After anaesthesia, the patients' oxygen saturation and respiratory rates were monitored for a minimum of 60 min in the recovery room. Any respiratory signs of reoccurrence of neuromuscular blockade in the postanaesthesia care unit, such as a 20% increase or decrease in the respiratory rate or oxygen saturation below 90%, were recorded. Before transfer to the recovery room, every 15 min on arrival there and before discharge from the recovery room, patients' levels of consciousness (i.e. awake and oriented, arousable with minimal stimulation or responsive only to tactile stimulation) were assessed. A 5-s head-lift test and a test of general muscle weakness were performed in conscious patients who were willing to cooperate with the tests. The rating system for assessing general muscle weakness was based on a scale from 0 to 10, representing 0 for total paralysis, 1 for extreme impairment, 9 for close to no impairment and 10 for normal muscle strength. Scores of 2, 3, 4 and so on denoted increasing muscle strength in approximately 10% increments.8 These postoperative clinical assessments were performed by the blinded safety assessor.
Safety assessments were also performed on the postoperative day, at least 10 h after study drug administration, and 7 days after the surgical procedure. All adverse events, serious adverse events and serious trial procedure-related events, as described by the investigator, were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 9.0; International Federation of Pharmaceutical Manufacturers and Associations, Chantilly, Virginia, USA).
Data management and statistical analysis
All efficacy analyses were performed using the intention-to-treat population, comprising all randomised patients who received sugammadex or neostigmine and had at least one postbaseline efficacy measurement. Safety analyses were performed for the all-patients-treated population, comprising all randomised patients who received sugammadex or neostigmine.
The time from sugammadex or neostigmine administration to recovery of the TOF ratio to 0.9 was the primary endpoint and recovery to ratios of 0.8 and 0.7 were secondary endpoints and were analysed using analysis of variance (ANOVA) adjusted for treatment group and trial site. Because recovery times followed a skewed distribution, the ANOVA was applied to log-transformed recovery times. Consequently, recovery times were summarised using geometric means and corresponding 95% confidence intervals (CIs), as well as medians and ranges.
For BP and HR, between-group comparisons were performed using repeated measurement analysis with baseline value as covariate. Rates of patients unable to perform the 5-s head-lift test and of patients showing any grade of general muscle weakness were compared between groups in a post-hoc analysis using the χ2 test. Statistical testing was performed two-sided with a significance level of 0.05. SAS (SAS Institute, Cary, North Carolina, USA) was used for all statistical analysis.
In order to have a power of 95% to detect a difference of at least 5 min between treatment groups, allowing for a SD of up to 1.5 min in the sugammadex group5,14 and up to 9 min in the neostigmine group,15 it was determined that 46 patients needed to be enrolled in each group. Assuming a dropout rate of 5%, it was decided to include 49 patients in each group.
Patients and anaesthesia
A total of 198 patients were enrolled into this study between November 2005 (first patient enrolled) and March 2006 (final assessment of last patient). Of these, one hundred patients were enrolled into the vecuronium arm and are described elsewhere.11 Here, we describe the results for the 98 patients enrolled into the rocuronium arm, 49 in the sugammadex and 49 in the neostigmine groups. One patient in each group did not receive the study drug, the all-patients-treated population being 48 patients in each group. All of these had at least one postbaseline efficacy measurement and, therefore, comprised the intention-to-treat population.
The treatment groups were mostly comparable in terms of their baseline characteristics. The mean (SD) age was 51 (16) years in the sugammadex group and 48 (14) years in the neostigmine group, weight was 73 (14) and 76 (15) kg and height was 170 (9) and 170 (10) cm in the two groups, respectively. Sixty-five percent of patients in the sugammadex group and 50% of patients in the neostigmine group were men, and the majority of patients were ASA physical status I or II (96% in each group), with 4% in each group ASA class III. The relative distribution of surgical procedures in the study [classified according to Nordic Medico-Statistical Committee (NOMESCO) guidelines] was ear, nose and larynx [19 patients (19%)]; teeth, jaws, mouth and pharynx [16 (16%)]; digestive system and spleen [16 (16%), three performed using laparoscopic conditions]; urinary system, male genital organs and retroperitoneal space [13 (13%)]; musculoskeletal system [12 (12%)]; female genital organs [9 (9%), one laparoscopic]; endocrine system [7 (7%)]; eye and adjacent structures [4 (4%)] and mammary gland surgery [2 (2%)]. The distribution of surgery types was generally similar across the two treatment groups.
Many patients received a small range of sevoflurane concentrations over the course of surgery, which was similar before and after administration of sugammadex or neostigmine. The sevoflurane concentration at administration of either sugammadex or neostigmine did not differ significantly between groups (the maximum end-tidal concentration during this period was 3.0% and the minimum was 0.5%, but most patients received concentrations in the 1.0–2.0% range). Over the first 10 min after administration of reversal agent, the sevoflurane concentration was not changed unless a TOF ratio of 0.9 was reached.
Intubating and maintenance doses of rocuronium were similar in the two groups. Fifteen patients in the sugammadex group received at least one rocuronium maintenance dose (median 2, range 1–6) and 19 patients in the neostigmine group received at least one rocuronium maintenance dose (median 3, range 1–9). The median rocuronium maintenance dose was 0.11 mg kg−1 in both groups. Over the course of surgery, the median (range) total amount of rocuronium administered was 46.0 (29.0–94.0) mg in the sugammadex group and 50.0 (31.8–178.0) mg in the neostigmine group.
At reappearance of T2, mean T1/T0 (SD) was 15.9% (4.9%) for patients in the sugammadex group and 16.1% (5.6%) for patients in the neostigmine group. One patient in the sugammadex group had an unstable twitch recording and the times to recovery of the TOF ratio to 0.7, 0.8 and 0.9 were considered unreliable. Three patients in the neostigmine group did not reach a TOF ratio of 0.9 during the monitoring period, although times to a TOF ratio of 0.8 were available. Thus, times to recovery of the TOF ratio to 0.9 were available for 47 (98%) patients in the sugammadex group and 45 (94%) patients in the neostigmine group.
Table 1 provides the geometric mean (95% CI) and median (range) times to recovery of the TOF ratio to 0.9, 0.8 and 0.7. The times from administration of the study drug to recovery of the neuromuscular function to TOF ratios of 0.9, 0.8 and 0.7 were significantly faster with sugammadex compared with neostigmine (Table 1). There was no statistically significant treatment by study centre interaction in the primary analysis, which means that the benefit on recovery times for sugammadex versus neostigmine was consistent across study centres. In the sugammadex group, the geometric mean time to recovery of the TOF ratio to 0.9 did not differ in patients who received only the intubating dose of rocuronium (1.5 min, 95% CI 1.3–1.6) compared with those who received one or more additional maintenance doses of rocuronium (1.5 min, 95% CI 1.1–1.9). In the neostigmine group, the geometric mean time to recovery of the TOF ratio to 0.9 was 17.0 min (95% CI 11.6–24.8) in those receiving only the intubating dose of rocuronium and 21.4 min (95% CI 14.4–31.7) in those receiving additional maintenance doses.
Figure 1 shows the percentage of patients who achieved recovery to a TOF ratio of 0.9 over the course of the study. Within 5 min after administering the reversal agent, 98% of sugammadex patients had recovered to a TOF ratio of 0.9 compared with only 11% of neostigmine patients. In comparison, it took 101 min for 98% of patients receiving neostigmine to recover to a TOF ratio of 0.9.
Clinical signs of neuromuscular function did not differ significantly between groups at any time in the postoperative period (Table 2). There was no clinical evidence of residual neuromuscular blockade or reoccurrence of neuromuscular blockade in any patient in either group. Moreover, once recovery had started, no patient demonstrated a decrease in the TOF ratio to less than 0.8.
A total of 41 patients (85%) in the sugammadex group and 43 patients (90%) in the neostigmine group had at least one adverse event. Seven patients (15%) treated with sugammadex and 10 patients (21%) treated with neostigmine experienced one or more adverse events that were considered by the safety assessor to be possibly, probably or definitely related to the study drug. Drug-related adverse events occurring in more than one patient of either group were dry mouth [three patients (6%) in each group], nausea [two patients (4%) in each group], procedural hypertension (two patients in the sugammadex group), vomiting (two patients in the sugammadex group) and albumin present in the urine (two patients in the neostigmine group). There were also isolated reports of diarrhoea, abdominal pain, pharyngolaryngeal pain and tinnitus in the sugammadex group and of involuntary muscle contractions, bradycardia, productive cough, pyrexia, supraventricular extrasystole, visual accommodation disorder, abdominal pain and increased urine β2 microglobulin in the neostigmine group. All drug-related adverse events were mild or moderate in intensity, except for one case of severe abdominal pain in a sugammadex-treated patient and one case of severe bradycardia in a neostigmine-treated patient. Both patients recovered without sequelae. One patient experienced a visual accommodation disorder (as well as dry mouth and involuntary muscle contractions) considered to be potentially related to neostigmine. However, this was not considered to result from residual blockade as the patient had a relatively quick time to recovery of the TOF ratio to 0.9 of 4.7 min and the adverse event occurred on the day after surgery.
Five patients (two treated with sugammadex and three treated with neostigmine) had serious adverse events, but none of these were considered related to study drug. No patient discontinued from the trial because of an adverse event.
Mean arterial pressure at 2 min after dose and HR at 2 and 5 min after dose were significantly higher in the neostigmine group compared with the sugammadex group (all P < 0.0001, Fig. 2).
This study is the first randomised, prospective, controlled study comparing the reversal properties of sugammadex with those of neostigmine, when used to reverse a moderate rocuronium-induced neuromuscular blockade in patients under sevoflurane anaesthesia. We show that 2.0 mg kg−1 sugammadex achieved significantly faster recovery to a TOF ratio of 0.9 compared with 50 μg kg−1 neostigmine, when administered at recovery of T2 in the TOF response. In addition, following reversal with sugammadex, we found lower variability of the recovery times. This resulted in 98% of patients recovering to a TOF ratio of 0.9 within 5 min after sugammadex, a rate of recovery that was not achieved until more than 100 min after neostigmine (Fig. 1).
Neostigmine is currently the most widely used reversal agent in clinical practice. When administered at T1/T0 is equal to 10%, neostigmine in doses of 35–70 μg kg−1 accelerates neuromuscular recovery to TOF values of 0.7 or 0.8 within approximately 10 min.16,17 In the current study, neostigmine was injected at reappearance of T2, a level at which mean T1/T0 was 16%. Geometric mean recovery times to TOF 0.7 and 0.8 were 7.2 and 10.8 min, respectively, confirming the results of a previous neostigmine study for reversal of a rocuronium-induced neuromuscular blockade under sevoflurane anaesthesia.15 The recovery times to TOF 0.9, however, were significantly prolonged (median 18.5 min) and their large variability implied that, in many patients, neuromuscular function was not reversed within an acceptable time. Notably, even 60 min after administration of reversal agent, less than 90% of the patients in the neostigmine group had reached the recommended recovery level for safe extubation (Fig. 1).
Neostigmine does not pharmacologically antagonise muscle relaxants, but works indirectly by virtue of its inhibition of acetylcholinesterase. When the acetylcholine breakdown is completely inhibited and the resulting concentrations of acetylcholine are completely insufficient to remove rocuronium from the receptors, no further effect from a cholinesterase inhibitor can be expected (ceiling effect).18 Clinical data support this idea as increasing the neostigmine dose from 35 to 50 μg kg−1 did not shorten recovery times.17 Therefore, lack of efficacy of 50 μg kg−1 neostigmine in the current study may be a problem of this indirect antagonism rather than an ineffective dose of neostigmine.
Although use of inhalation anaesthetics is not anticipated to have an impact on the efficacy of sugammadex19,20, recovery times with neostigmine may be prolonged. Indeed, sevoflurane anaesthesia must be considered as a reason for the slow and very variable recovery times following neostigmine in the current study.15 In one study,21 the median recovery times after neostigmine reversal at reappearance of T2 were prolonged from 8 min under propofol to 23 min under sevoflurane and their maxima were prolonged from 11 to 57 min. In order to reduce the interference of varying sevoflurane concentrations in the current study, sevoflurane was maintained constant at least until TOF 0.9, but for not longer than 10 min after administration of the reversal drugs. In cases of extremely prolonged recovery, sevoflurane was reduced individually which might have decreased its impact in the most extreme recovery times; as no patient in the sugammadex group had a recovery time outside this 10-min period, sevoflurane wash out would only have an impact on the neostigmine group. Nevertheless, the use of sevoflurane as the maintenance anaesthetic may be considered to decrease the efficacy of neostigmine reversal only. Accordingly, the study design regarding the underlying anaesthesia favours the hypothesis that reversal would be faster with sugammadex than with neostigmine. However, sevoflurane is the most commonly used anaesthetic agent in Europe and it is important to study these reversal agents under clinically relevant conditions.
Sugammadex was given as a 2 mg kg−1 dose in the current study as this appeared to be adequate to restore neuromuscular function in an average time of less than 2 min when administered at reappearance of T2.5,9,14 In the larger population of this comparative study, the median recovery times of less than 2 min met the expectations from the dose-finding studies5,14 and confirmed the results of two studies in which sugammadex 2 mg kg−1 was also given at reappearance of T2 of a rocuronium-induced neuromuscular blockade.19,22 Even more important, the variability of recovery times was clinically irrelevant following reversal with 2 mg kg−1 sugammadex (95% CI <1 min), proving the high predictability of sugammadex, which is not influenced by sevoflurane.19
It would appear that reversal of moderate rocuronium-induced blockade by sugammadex is slightly quicker than reversal of moderate vecuronium-induced blockade [geometric mean (95% CI) times to recovery of the TOF ratio to 0.9 was 1.5 (1.3–1.6) versus 2.7 (2.2–3.3) in the two study arms, respectively].11 As expected, reversal of moderate rocuronium-induced blockade appeared to be faster than reversal of deep (at 1–2 post-tetanic counts) rocuronium-induced blockade (geometric mean time to recovery 2.9 min).8 Nevertheless, these studies show that sugammadex reversal of rocuronium-induced moderate or deep blockade or vecuronium-induced moderate blockade can be achieved within 5 min in the majority of patients.
It is the specific mechanism of action of sugammadex, which allows the study of faster reversal, at deeper levels of blockade,8,23 and to higher levels of recovery. In contrast, previous studies15–17,24 investigating reversal of neuromuscular blockade mostly included later reversal (e.g. TOF = 0.25), evaluated the effect at lower levels of neuromuscular recovery (TOF >0.7 or TOF >0.8) and advocated a time between administration and complete recovery of less than 10 min as acceptable. On the basis of these less advanced endpoints, in this study, the average recovery times following neostigmine and sugammadex did not differ as much; they were 13 times longer for the TOF 0.9 endpoint but only 9 and 6.5 times longer for the TOF 0.8 and TOF 0.7 endpoints, respectively. The clinical and procedural implications of the options supplied by sugammadex have not been investigated, so far. Nevertheless, approximately 29% of neostigmine patients did not reach even a TOF ratio of 0.7 within 10 min and the last patient did not even reach a TOF ratio of 0.7 until 41 min after administration.
Acceleromyography may at times be associated with less stable twitch responses than other quantitative techniques, such as mechanomyography, even with thoroughly fixed fingers and forearm as carefully done in the current trial. Despite these limitations, acceleromyography is considered an acceptable device for research purposes.13 It has been suggested that acceleromyography may overestimate recovery of neuromuscular function25 and that to exclude residual paralysis a TOF ratio of 1.0 should be achieved.26 In this study, we considered a TOF ratio of at least 0.9 to be sufficient to allow safe extubation of the patient. However, all patients were carefully monitored in the recovery room and there were no signs of residual paralysis in any patient.
As neostigmine is associated with an increased risk for muscarinergic side effects, parasympatholytic anticholinergic drugs such as atropine or glycopyrrolate are added, as was done in this study. Although the use of glycopyrrolate is advantageous,27 the increase in HR and arterial pressure observed in other studies28 are confirmed in the current study with this combination due to faster onset of glycopyrrolate compared with neostigmine.28,29 In the current study, no specific side effects have been observed following sugammadex; however, the study was not powered to decide on the incidence of side effects, and only adds to the database of information available.
Recovery of neuromuscular function after rocuronium to a TOF ratio of 0.9 is on average about 13 times faster with 2 mg kg−1 sugammadex compared with 50 μg kg−1 neostigmine. Even more important, 98% of the patients were sufficiently recovered within 5 min following sugammadex but it was 100 min following neostigmine before 98% of patients were sufficiently recovered. The safety profile did not differ between sugammadex-treated and neostigmine-treated patients.
This work was supported by MSD, Oss, The Netherlands.
The authors thank all investigators involved in this study, including Professor Dr Karin S. Khünl-Brady, MD, PhD (Klinik für Anaesthesiologie und Intensivmedizin, Leopold-Franzens Universität, Innsbruck, Austria); Professor Dr Michel M.R.F. Struys, MD, PhD (Department of Anesthesia, Universitair Ziekenhuis Gent, Gent, Belguim); Professor Dr Bernard F. Vanacker, MD, PhD (Department of Anesthesia, Universitair Ziekenhuis Gasthuisberg: Leuven, Belgium); Professor Dr José A. Álvarez-Gómez, MD (Departamento en anesthesia e Reanimacion, Hospital Universitario Santa María Del Rosell, Cartagena, Spain); Professor Dr José I. Lora-Tamayo, MD (Hospital Universitario Puerta de Hierro, Madrid, Spain); Professor Dr Magnus Wattwil, MD, PhD (Department of Anesthesiology and Intensive Care, Universitetssjukhuset Örebro, Örebro, Sweden); Professor Ravi M. Mahajan, MD, FRCA (Department of Anesthesiology and Intensive Care, Queen's Medical Centre, Nottingham, UK).
Henk Rietbergen, MSc (Principal Statistician, MSD, Oss, The Netherlands) conducted the statistical analysis of the study data. Valerie Moss, PhD (Principal Medical Writer, Prime Medica Ltd., Knutsford, Cheshire, UK) provided editorial assistance during the preparation of this paper funded by Merck, Kenilworth, New Jersey, USA. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions and interpretation of the data, were the responsibility of the authors.
M.B. and J.S. have received honoraria and travel grants from MSD within the past 3 years. L.I.E. is a scientific adviser to MSD and Abbott Scandinavia AB; his institution has received an institutional grant from MSD. M.E.P. is an employee of MSD. J.M. and G.D.R. have no conflicts of interest.
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